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1 Introduction Anti N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a synaptic autoimmune disorder that was first characterized in 2007 [1]. Since then, the definition evolved to include a wide spectrum of ages and presentations, and it is now considered to be one of the most common causes of encephalitis in children [2]. In children, the most commonly reported clinical manifestations include abnormal behavior, movement disorders, and seizures [2]. Although around 40% of all reported cases with anti-NMDA receptor encephalitis are children [2], however, the number of studies that report infants and toddlers (below 36 months of age) with anti-NMDA encephalitis are rare; not exceeding 20 cases [[3], [4], [5], [6], [7], [8], [9], [10]]. Furthermore, reports on anti-NMDA encephalitis in children from the Middle East are extremely rare [[11], [12], [13]]. Under reporting may be related to the misrecognition of symptoms, as well as the unavailability of diagnostic testing in many countries. We report a 22-month-old Jordanian female toddler with anti-NMDA encephalitis who initially presented with behavioral changes and some autistic features. 2 Case report The patient was a healthy girl. At 21 months, she developed sudden behavioral changes manifesting as bouts of irritability, aggression, inconsolable crying, and self-mutilatory behavior (self-biting). She developed a fever a few days later which was attributed to a urinary tract infection and was followed by vomiting and diarrhea resulting from Rota virus gastroenteritis.

loped sudden behavioral changes manifesting as bouts of irritability, aggression, inconsolable crying, and self-mutilatory behavior (self-biting). She developed a fever a few days later which was attributed to a urinary tract infection and was followed by vomiting and diarrhea resulting from Rota virus gastroenteritis. Her condition worsened over the course of two weeks and the fever persisted. She no longer made eye contact nor spoke and developed insomnia which was managed with clonazepam. In addition, she developed a progressive regression in gross and fine motor skills and an inability to swallow. She also had focal seizures which were controlled with valproic acid. Conducted investigations included a CSF analysis which was normal (WBC 2 cells/mm;one neutrophil and one lymphocyte, protein 15 mg/dl, glucose 69 mg/dl, RBC zero cells/mm, PCR viral work up for enteroviruses, herpes simplex, varicella and mumps viruses were negative, gram stain and bacterial culture were negative), multiple brain images (brain MRI, MRA and MRV), a nerve conduction study, metabolic work up, copper and ceruloplasmin levels, rheumatoid factor, and antinuclear antibody testing; all were normal. Sleep electroencephalogram revealed occasional spikes in the left parietal region. She had elevated creatine phosphokinase (524 U/L; normal range: < 190 U/L).

MRA and MRV), a nerve conduction study, metabolic work up, copper and ceruloplasmin levels, rheumatoid factor, and antinuclear antibody testing; all were normal. Sleep electroencephalogram revealed occasional spikes in the left parietal region. She had elevated creatine phosphokinase (524 U/L; normal range: < 190 U/L). She was transferred to our hospital two weeks following the onset of her symptoms. Her general examination was normal apart from a persistent fever. Her neurological examination revealed poor eye contact, choreoathetotic movements in the right upper limb, oro-buccal dyskinesia, hypotonia with preserved deep tendon reflexes in addition to reduced power (2/5 on the MRC Scale) in her right upper limb. We suspected NMDAR encephalitis, blood and CSF samples were sent to a lab outside of Jordan. Results were received one month later and revealed positive blood and CSF titers (1:320 and 1:160 respectively). Initially, we treated her empirically with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone. This resulted in an improvement in some of her symptoms as the fever and insomnia disappeared; her behavioral and developmental skills however did not improve. Follow-up during the next six months necessitated monthly IVIg. Several relapses occurred during treatment, manifesting as a reemergence of her irritability, insomnia and poor eye contact. She received plasma exchange during her second and third relapses, in addition to rituximab. A dramatic improvement in her social skills and irritability appeared within hours following plasma exchange.

relapses occurred during treatment, manifesting as a reemergence of her irritability, insomnia and poor eye contact. She received plasma exchange during her second and third relapses, in addition to rituximab. A dramatic improvement in her social skills and irritability appeared within hours following plasma exchange. Follow-up at six months after her initial presentation showed continuous improvement. Apart from mild speech delay, her neurological exam and developmental milestones are normal. 3 Discussion We present the clinical picture of a 22-month-old toddler with NMDAR encephalitis. Previous studies on toddlers with NMDAR encephalitis have shown that the earliest presentation in this age group is behavioral changes, manifesting commonly as temper tantrums, agitation and inconsolable crying [3,4,8,14]. Nevertheless, distinguishing NMDAR encephalitis in infants and toddlers on initial presentation may be quite challenging as initial symptoms could be non-specific. Although the initial symptoms in our patient were behavioral changes, the presence of a fever and gastroenteritis posed an initial diagnostic challenge. Children with NMDAR encephalitis commonly experience prodromal symptoms such as fever and vomiting [10]. Furthermore, persistent fever could be part of the autonomic instability of encephalitis [4,10].

ur patient were behavioral changes, the presence of a fever and gastroenteritis posed an initial diagnostic challenge. Children with NMDAR encephalitis commonly experience prodromal symptoms such as fever and vomiting [10]. Furthermore, persistent fever could be part of the autonomic instability of encephalitis [4,10]. The spectrum of symptoms usually progresses to include seizures, speech and sleep disturbances [15]. In addition to these, our patient also experienced symptoms that are rarely reported in the literature, including autistic-like features such as the loss of eye contact [9], self-mutilatory behavior (self biting) [3,16,17] and dysphagia [3,18]. The choreo-athetoid movements and oro facial dyskinesia noted in our patient are the most commonly reported motor manifestation in toddlers [19]. Investigations are usually necessary to exclude other pathologies that may mimic NMDAR encephalitis, notably other types of encephalitis; in addition to neuro-metabolic disorders, which are reported to be significant causes of childhood developmental disorders and epilepsy in Jordan [20,21]. In our patient, the results of investigations also posed a diagnostic challenge. The CPK was high on initial presentation. High CPK is related to rhabdomyolysis; a rarely reported complication of NMDAR encephalitis as a consequence of the excessive muscle contraction associated with the agitation [22].

Investigations are usually necessary to exclude other pathologies that may mimic NMDAR encephalitis, notably other types of encephalitis; in addition to neuro-metabolic disorders, which are reported to be significant causes of childhood developmental disorders and epilepsy in Jordan [20,21]. In our patient, the results of investigations also posed a diagnostic challenge. The CPK was high on initial presentation. High CPK is related to rhabdomyolysis; a rarely reported complication of NMDAR encephalitis as a consequence of the excessive muscle contraction associated with the agitation [22]. Furthermore, the results of CSF analysis and brain MRI were normal in our patient. Normal CSF and normal neuro-imaging are present in more than half of infants and toddlers with NMDAR encephalitis [4,10,8], posing another challenge for initial diagnosis, especially in countries where diagnostic titers are not available. The diagnosis of anti-NMDAR encephalitis is confirmed upon the detection of anti-NMDAR autoantibodies in serum and cerebrospinal fluid (CSF) [23].

of infants and toddlers with NMDAR encephalitis [4,10,8], posing another challenge for initial diagnosis, especially in countries where diagnostic titers are not available. The diagnosis of anti-NMDAR encephalitis is confirmed upon the detection of anti-NMDAR autoantibodies in serum and cerebrospinal fluid (CSF) [23]. Our patient responded only partially to IVIG and methylprednisolone and she relapsed monthly, which necessitated the use of plasma exchange and Rituximab. Currently, no guidelines exist for the treatment of NMDAR encephalitis in children. Commonly used first line immune-therapies include high-dose corticosteroids, IVIG and plasmapheresis. Second-line therapies include rituximab and cyclophosphamide [14,24]. Within only hours of the plasma exchange there was a marked improvement in our patient's behaviour and social interaction. Plasma exchange was reported to be used in a small proportion of pediatric cases, however, full recovery or partial improvement immediately after plasma exchange was reported in 63.5% of pediatric patients [25]. Our patient improved gradually. Earlier treatment of anti-NMDAR encephalitis is associated with better outcomes [26]. Children have been reported to recover faster than adults [27], usually within six months [27]. Toddlers have a good prognosis, with full recovery in 67% of patients and no reports of mortality [3].

Our patient responded only partially to IVIG and methylprednisolone and she relapsed monthly, which necessitated the use of plasma exchange and Rituximab. Currently, no guidelines exist for the treatment of NMDAR encephalitis in children. Commonly used first line immune-therapies include high-dose corticosteroids, IVIG and plasmapheresis. Second-line therapies include rituximab and cyclophosphamide [14,24]. Within only hours of the plasma exchange there was a marked improvement in our patient's behaviour and social interaction. Plasma exchange was reported to be used in a small proportion of pediatric cases, however, full recovery or partial improvement immediately after plasma exchange was reported in 63.5% of pediatric patients [25]. Our patient improved gradually. Earlier treatment of anti-NMDAR encephalitis is associated with better outcomes [26]. Children have been reported to recover faster than adults [27], usually within six months [27]. Toddlers have a good prognosis, with full recovery in 67% of patients and no reports of mortality [3]. In conclusion, we believe that NMDAR encephalitis is probably underreported in infants and toddlers. This case, initially presenting with behavioral changes and autistic features, highlights the diagnostic challenges presenting in this age group. Conflicts of interest All authors declare no conflict of interest. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction It is clearly evident that physical activity plays an important role in improving health. Being physically active is negatively associated with the risk of mortality, heart diseases, cancers, diabetes, high blood pressure, obesity, osteoporosis and mental health disorders [1,2]. Studies show that there are numerous factors affecting the decision of people to participate in physical activity (i.e. demographic, lifestyle and health factors) [[3], [4], [5]]. Interestingly, there are evidences suggesting that individuals who are physically active in adolescent years are more likely to engage in physically active behaviour in their adulthood than their peers who are physically inactive in adolescent years [6]. In Malaysia, a recent report of the Ministry of Health showed that the prevalence of being physically active among adolescents is very low (14.1%) [7]. As a consequence of this phenomenon, the number of obese adolescents has increased tremendously [7], which may lead to various diseases in adulthood. Therefore, physical inactivity among adolescents has become a serious public health issue and has been given attention by researchers and policy makers. If policy makers have a better understanding of factors affecting level of physical activity among adolescents, a more effective intervention measure directed towards promoting physically active lifestyle among adolescents can be introduced.

ic health issue and has been given attention by researchers and policy makers. If policy makers have a better understanding of factors affecting level of physical activity among adolescents, a more effective intervention measure directed towards promoting physically active lifestyle among adolescents can be introduced. Numerous studies related to participation in physical activity among adolescents in Malaysia were conducted [[8], [9], [10]]. However, only few used a nationwide data with a large sample size. Study by Baharudin et al. [11] is by far the most comprehensive study. The authors used a nationwide data and found that demographic factors, such as age and gender are associated with participation in physical activity. Other non-demographic factors such as school session, breakfast intake and body weight were also found to be significant in influencing physical activity. However, there are other potential determining factors of physical activity which are not examined by Baharudin et al. [11] but are worthy of consideration. These include dietary behaviour, cigarette smoking, alcohol drinking, sex behaviour and participation in physical education (PE) class. The present study anticipates that physical activity is associated with these factors because they reflect health awareness. Since physical activity is a health investment, health awareness may be closely related to it. It is also noteworthy that study by Baharudin et al. [11] only examined whether adolescents were physically inactive or not, and did not analyse time that adolescent spent in physical activity. As a result, factors affecting decisions related to time spent in physical activity remain unidentified.

losely related to it. It is also noteworthy that study by Baharudin et al. [11] only examined whether adolescents were physically inactive or not, and did not analyse time that adolescent spent in physical activity. As a result, factors affecting decisions related to time spent in physical activity remain unidentified. Given the gaps in the literature related to physical activity among adolescents, a more comprehensive study is needed. The present study makes an effort to investigate factors associated with physical activity among adolescents in Malaysia, and attempts to contribute to existing literature in several ways. Firstly, various demographic and lifestyle factors are taken into account in the analysis, which include dietary behaviour, cigarette smoking, alcohol drinking, sex behaviour and PE class. Secondly, different from previous studies, the present study uses a count data regression to examine time spent in physical activity (i.e. amount of physical activity). Thirdly, the statistical analysis is performed based on a nationwide data that consists of a large sample. Taken together, findings of the present study can assist policy makers in identifying which group of adolescents tends to spend more or less time in physical activity. Hence, the prevalence of physical inactivity among adolescents can be reduced.

is performed based on a nationwide data that consists of a large sample. Taken together, findings of the present study can assist policy makers in identifying which group of adolescents tends to spend more or less time in physical activity. Hence, the prevalence of physical inactivity among adolescents can be reduced. 2 Methods 2.1 Sample The present study was based on a secondary analysis of a cross-sectional dataset. Data was extracted from the Malaysia Global School-based Student Health Survey (GSHS) 2012 [7]. The survey used a two-stage cluster sampling in order to ensure that the sample could represent secondary school students in Malaysia. In the first-stage sampling, secondary schools were selected based on the probability proportional to the size of school. Of all the secondary schools in Malaysia, 234 were selected to take part in the survey. In the second-stage sampling, systematic random sampling was applied to select classrooms from each school. All the students in the selected classrooms were surveyed.

cted based on the probability proportional to the size of school. Of all the secondary schools in Malaysia, 234 were selected to take part in the survey. In the second-stage sampling, systematic random sampling was applied to select classrooms from each school. All the students in the selected classrooms were surveyed. A total of 25507 questionnaires were distributed. The response rate was 88.7%. The survey was carried out from 23 February to 26 April 2012. The data was made available to the public in 2014 after the 2-year window. While the survey was not the latest dataset, it had a large sample size and was representative. Ethical approval was obtained from the Ministry of Health Research and Ethics Committee and Ministry of Education Ethics Committee (Project code: NMRR-11-974-10401). Parental consent forms were obtained before the survey. Adolescents who were not given consent by their parents were not canvassed. 2.2 Questionnaire Self-administered bilingual questionnaires (English and Malay) were used. They were designed according to the standard questionnaire used by the GSHS. All the information was self-reported. The demographic data used in the present study consisted of age, gender and education level. Age was formatted as a discrete variable (11–18 years) to allow for a linear relationship. Education level was assessed based on the grades of adolescents. It was divided into six categories: Remove, Form 1, Form 2, Form 3, Form 4 and Form 5. Remove until Form 3 were lower secondary, while Form 4 and Form 5 were upper secondary.

rmatted as a discrete variable (11–18 years) to allow for a linear relationship. Education level was assessed based on the grades of adolescents. It was divided into six categories: Remove, Form 1, Form 2, Form 3, Form 4 and Form 5. Remove until Form 3 were lower secondary, while Form 4 and Form 5 were upper secondary. The lifestyle factors comprised information on physical activity, fruits and vegetables (FV) consumption, carbonated soft drink consumption, cigarette smoking, alcohol drinking, sex behaviour, participation in PE class and obesity. The definition of physical activity was explained prior to asking questions about physical activity. Adolescents were asked: ‘During the past 7 days, on how many days were you physically active for a total of at least 60 min?’ They answered with: ‘0 day’, ‘1 day’, ‘2 days’, ‘3 days’, ‘4 days’, ‘5 days’, ‘6 days’ or ‘7 days’. In terms of dietary behaviours, the survey asked adolescents about their FV consumption behaviour: ‘During the past 30 days, how many time per day did you usually eat vegetables and fruits?’ The possible answers were: ‘not at all’, ‘1 time’, ‘2 times’, ‘3 times’, ‘4 times’ and ‘5 or more times’. Carbonated soft drinks consumption behaviour was also assessed. Adolescents were asked: ‘During the past 30 days, how many times per day did you usually drink carbonated soft drinks?’ They responded with: ‘not at all’, ‘1 time’, ‘2 times’, ‘3 times’, ‘4 times’ or ‘5 or more times’.

es’, ‘4 times’ and ‘5 or more times’. Carbonated soft drinks consumption behaviour was also assessed. Adolescents were asked: ‘During the past 30 days, how many times per day did you usually drink carbonated soft drinks?’ They responded with: ‘not at all’, ‘1 time’, ‘2 times’, ‘3 times’, ‘4 times’ or ‘5 or more times’. The smoking behaviour was measured based on the following question: ‘During the past 30 days, on how many days did you smoke cigarettes?’ with plausible responses: ‘did not smoke’, ‘1–2 days’, ‘3–5 days’, ‘6–9 days’, ‘10–19 days’, ‘20–29 days’ and ‘30 days’. Adolescents were categorised as non-smokers if they chose ‘did not smoke’. Otherwise, they were coded as smokers. Alcohol drinking behaviour was assessed on the basis of the following question: ‘During the past 30 days, on the days you drank alcohol, how many drinks did you usually drink per day?’ The choices were: ‘did not drink’, ‘1 drink’, ‘2 drinks’, ‘3 drinks’, ‘4 drinks’ and ‘5 or more drinks’. Non-alcohol drinkers referred to those who chose ‘did not drink’.

ssed on the basis of the following question: ‘During the past 30 days, on the days you drank alcohol, how many drinks did you usually drink per day?’ The choices were: ‘did not drink’, ‘1 drink’, ‘2 drinks’, ‘3 drinks’, ‘4 drinks’ and ‘5 or more drinks’. Non-alcohol drinkers referred to those who chose ‘did not drink’. Adolescents were also asked to self-report their sexual behaviour. The question was designed as: ‘Have you ever had sexual intercourse?’. Adolescents were considered to have sexual intercourse if they answered ‘yes’ and were considered to have no sexual intercourse if they answered ‘no’. In addition, adolescents were requested to self-report their height and weight. These heights and weights were used to calculate body mass index (BMI) and determine whether adolescents were obese. Although self-reported information on height and weight may have reporting error, it was appropriate for research [12].

o’. In addition, adolescents were requested to self-report their height and weight. These heights and weights were used to calculate body mass index (BMI) and determine whether adolescents were obese. Although self-reported information on height and weight may have reporting error, it was appropriate for research [12]. 2.3 Statistical analysis The dependent variable used in the present study was time spent in physical activity (i.e. the days of being physically active for at least 60 min). The maximum value of the dependent variable was 7 days and the minimum value was 0 day. The independent variables consisted of demographic (age, gender, education) and lifestyle variables (FV consumption, carbonated soft drink consumption, cigarette smoking, alcohol drinking, sex behaviour, participation in PE class, obesity). All the independent variables were categorical variables, except age. Since the dependent variable was discrete with count data, the present study used a binomial regression (i.e. a count data regression) to examine the factors associated with time spent in physical activity, assuming that overdispersion exists. A simple statistical test for overdispersion was conducted in order to confirm that there was overdispersion. Binomial regression and the test for overdispersion were described in great detail elsewhere [13]. Significant level was based on P < .05. Adolescents with missing information were removed from the sample. As a result, only 25399 respondents were used for analyses.

ted in order to confirm that there was overdispersion. Binomial regression and the test for overdispersion were described in great detail elsewhere [13]. Significant level was based on P < .05. Adolescents with missing information were removed from the sample. As a result, only 25399 respondents were used for analyses. 3 Results Demographic and lifestyle characteristics of total sample and adolescents participating in physical activity are presented in Table 1. The mean age of all respondents and physical activity participants is approximately 15 years. However, the standard deviation age of total sample is slightly greater than that of participants. The gender distributions of total sample and participants are almost equal. Of all respondents, the majority are Form 3 class students (22.01%), followed by Form 2 (20.94%), Form 1, (20.72%) Form 5 (17.97%), Form 4 (17.75%) and Remove (0.60%). Physical activity participants have somewhat similar education characteristics.Table 1 Demographic and lifestyle characteristics of total sample and adolescents participating in physical activity.

class students (22.01%), followed by Form 2 (20.94%), Form 1, (20.72%) Form 5 (17.97%), Form 4 (17.75%) and Remove (0.60%). Physical activity participants have somewhat similar education characteristics.Table 1 Demographic and lifestyle characteristics of total sample and adolescents participating in physical activity. Table 1Variables Definitions Total sample (n = 25399) frequency (%) Participating (n = 20697) frequency (%) Demography Age Age (years) [mean (standard deviation)] 14.91 (1.43) 14.92 (0.01) Gender Male Gender is male 12690 (49.96) 10391 (50.21) Female Gender is female 12709 (50.04) 10306 (49.79) Education Remove Remove class student 153 (0.60) 106 (0.51) Form 1 Form 1 class student 5262 (20.72) 4145 (20.03) Form 2 Form 2 class student 5319 (20.94) 4318 (20.86) Form 3 Form 3 class student 5591 (22.01) 4634 (22.39) Form 4 Form 4 class student 4509 (17.75) 3699 (17.87) Form 5 Form 5 class student 4565 (17.97) 3795 (18.34) Lifestyle FV 0 Do not consume 2670 (10.51) 1953 (9.44) 1 1 time per day 2963 (11.67) 2306 (11.14) 2 2 times per day 4298 (16.92) 3399 (16.42) 3 3 times per day 4533 (17.84) 3784 (18.28) 4 4 times per day 3714 (14.62) 3168 (15.31) 5 ≥5 times per day 7221 (28.43) 6087 (29.41) Soft drink 0 Do not consume 18242 (71.82) 15050 (72.72) 1 1 time per day 3751 (14.77) 3006 (14.52) 2 2 times per day 1833 (7.22) 1458 (7.04) 3 3 times per day 788 (3.10) 617 (2.98) 4 4 times per day 288 (1.13) 214 (1.03) 5 ≥5 times per day 497 (1.96) 352 (1.70) Cigarette 0 Do not smoke 22710 (89.41) 18551 (89.63) 1-2 1 to 2 days 962 (3.79) 764 (3.69) 3-5 3 to 5 days 426 (1.68) 333 (1.61) 6-9 6 to 9 days 262 (1.03) 203 (0.98) 10-19 10 to 19 days 237 (0.93) 196 (0.95) 20-29 20 to 29 days 176 (0.69) 138 (0.67) 30 30 days 626 (2.46) 512 (2.47) Alcohol 0 Do not drink 24124 (94.98) 19772 (95.53) 1 1 serving 674 (2.65) 488 (2.36) 2 2 servings 277 (1.09) 203 (0.98) 3 3 servings 122 (0.48) 89 (0.43) 4 4 servings 47 (0.19) 38 (0.18) 5 ≥5 servings 155 (0.61) 107 (0.52) Sex Yes Yes 1872 (7.37) 1338 (6.46) No No 23527 (92.63) 19359 (93.54) PE 0 0 day 2884 (11.35) 1793 (8.66) 1 1 day 10788 (42.47) 8941 (43.20) 2 2 days 5031 (19.81) 4207 (20.33) 3 3 days 851 (3.35) 709 (3.43) 4 4 days 567 (2.23) 487 (2.35) 5 ≥5 days 5278 (20.78) 4560 (22.03) Obese Yes Obese 2448 (9.64) 2029 (9.80) No Not obese 22951 (90.36) 18668 (90.20) Note: Age is a discrete variable. Hence, mean and standard deviation are reported. FV refers to fruits and vegetables. PE refers to physical education.

51 (3.35) 709 (3.43) 4 4 days 567 (2.23) 487 (2.35) 5 ≥5 days 5278 (20.78) 4560 (22.03) Obese Yes Obese 2448 (9.64) 2029 (9.80) No Not obese 22951 (90.36) 18668 (90.20) Note: Age is a discrete variable. Hence, mean and standard deviation are reported. FV refers to fruits and vegetables. PE refers to physical education. Source: GSHS 2012 More than a quarter of all respondents (28.43%) and participants (29.41%) consume 5 times or more of FV per day. Only a small amount of all respondents (10.51%) and participants (9.44%) do not consume FV. A large proportion of total respondents (71.82%) and participants (72.72%) do not consume soft drink. Only less than 2% of each group consume 4 times or more of soft drink per day. In terms of cigarette smoking, almost 90% of total respondents and participants do not smoke, and only less than 4% smoke 1–2 days in the past 30 days. Likewise, a very large proportion of all respondents (94.98%) and participants (95.53%) do not drink alcohol, and only less than 3% drink 1 serving on the days they drank alcohol in the past 30 days. Considering the sexual behaviour, only 7.37% of total sample and 6.46% of participants engage in sexual intercourse. Of all respondents, the majority (42.47%) attend 1 day of PE class per week, followed by 5 days (20.78%), 2 days (19.81%), 0 day (11.35%), 3 days (3.35%) and 4 days (2.23%). Somewhat similar characteristics are observed among physical activity participants. In terms of bodyweight, only the minority of total respondents (9.64%) and participants (9.80%) are obese.

tend 1 day of PE class per week, followed by 5 days (20.78%), 2 days (19.81%), 0 day (11.35%), 3 days (3.35%) and 4 days (2.23%). Somewhat similar characteristics are observed among physical activity participants. In terms of bodyweight, only the minority of total respondents (9.64%) and participants (9.80%) are obese. Demographic and lifestyle factors associated with physical activity are described in Table 2. It appears that the data has overdispersion given that the estimate of α is highly significant. Therefore, a negative binomial regression is appropriate for the current analysis. In terms of the overall significance of the regression, the likelihood ratio (LR) statistics is significant, thereby concluding that all the independent variables are jointly significant in explaining physical activity.Table 2 Demographic and lifestyle factors associated with physical activity.

or the current analysis. In terms of the overall significance of the regression, the likelihood ratio (LR) statistics is significant, thereby concluding that all the independent variables are jointly significant in explaining physical activity.Table 2 Demographic and lifestyle factors associated with physical activity. Table 2Variables Estimates SE IRR 95% CI P Constant 2.040 0.273 7.687 4.498, 13.137 <.001 Demography Age −0.086 0.016 0.917 0.889, 0.946 <.001 Gender Male 0.315 0.012 1.370 1.339, 1.402 <.001 Female – – 1.000 – – Education Remove −0.263 0.092 0.769 0.642, 0.920 .004 Form 1 −0.432 0.065 0.649 0.571, 0.738 <.001 Form 2 −0.325 0.051 0.723 0.655, 0.798 <.001 Form 3 −0.218 0.036 0.804 0.749, 0.864 <.001 Form 4 −0.105 0.024 0.900 0.858, 0.944 <.001 Form 5 – – 1.000 – – Lifestyle FV 0 – – 1.000 – – 1 0.035 0.025 1.036 0.987, 1.087 .124 2 0.085 0.023 1.088 1.041, 1.138 <.001 3 0.176 0.022 1.192 1.141, 1.245 <.001 4 0.244 0.023 1.277 1.220, 1.336 <.001 5 0.301 0.021 1.351 1.297, 1.407 <.001 Soft drink 0 – – 1.000 – – 1 −0.104 0.016 0.902 0.873, 0.931 <.001 2 −0.105 0.022 0.901 0.862, 0.941 <.001 3 −0.128 0.033 0.880 0.825, 0.939 <.001 4 −0.179 0.055 0.836 0.752, 0.931 <.001 5 −0.215 0.042 0.806 0.743, 0.876 <.001 Cigarette 0 −0.106 0.036 0.900 0.839, 0.965 .003 1–2 −0.180 0.045 0.835 0.765, 0.912 <.001 3–5 −0.174 0.055 0.840 0.754, 0.935 .002 6–9 −0.187 0.065 0.829 0.731, 0.941 .004 10–19 −0.011 0.065 0.989 0.871, 1.123 .865 20–29 −0.088 0.074 0.916 0.793, 1.058 .234 30 – – 1.000 – – Alcohol 0 – – 1.000 – – 1 −0.202 0.037 0.817 0.760, 0.878 <.001 2 −0.176 0.056 0.839 0.751, 0.936 .003 3 −0.134 0.084 0.874 0.742, 1.030 .145 4 0.089 0.128 1.093 0.851, 1.404 .502 5 −0.046 0.073 0.955 0.828, 1.103 .467 Sex Yes −0.112 0.022 0.894 0.856, 0.934 <.001 No – – 1.000 – – PE 0 – – 1.000 – – 1 0.247 0.020 1.281 1.232, 1.331 <.001 2 0.297 0.022 1.346 1.289, 1.404 <.001 3 0.299 0.035 1.349 1.259, 1.445 <.001 4 0.354 0.041 1.424 1.314, 1.543 <.001 5 0.434 0.021 1.543 1.480, 1.609 <.001 Obese Yes −0.092 0.019 0.912 0.879, 0.947 <.001 No – – 1.000 – α 0.412 – – – <.001 LR 1727.100 – – – <.001 Observations 25399 Note: IRR refers to incidence rate ratio. CI refers to confidence interval. LR refers to likelihood ratio. α is used to determine whether the data is over dispersed. FV refers to fruits and vegetables. PE refers to physical education.

7 <.001 No – – 1.000 – α 0.412 – – – <.001 LR 1727.100 – – – <.001 Observations 25399 Note: IRR refers to incidence rate ratio. CI refers to confidence interval. LR refers to likelihood ratio. α is used to determine whether the data is over dispersed. FV refers to fruits and vegetables. PE refers to physical education. Source: GSHS 2012 Because the coefficients estimated from the negative binomial regression do not have direct interpretations, incidence rate ratio (IRR) is calculated for each independent variable. Age is negatively associated with time spent in physical activity (IRR = 0.917). In other words, older adolescents are less likely to spend more time exercising than their younger counterparts. Males are more likely to spend more time in physical activity than females (IRR = 1.370). Setting Form 5 students as the reference group, Remove until Form 4 students are less likely to spend more time in physical activity (IRR = 0.796–0.900).

e less likely to spend more time exercising than their younger counterparts. Males are more likely to spend more time in physical activity than females (IRR = 1.370). Setting Form 5 students as the reference group, Remove until Form 4 students are less likely to spend more time in physical activity (IRR = 0.796–0.900). Controlling for other variables, FV consumption is positively associated with time spent in physical activity (IRR = 1.036–1.351). In particular, the likelihood of allocating more time for physical activity increases with frequency of FV consumption. However, frequency of soft drink consumption reduces with the probability of spending more time in physical activity, holding other factors fixed (IRR = 0.806–0.902). Compared to adolescents who smoke 30 days, those who do not smoke (IRR = 0.900), smoke 1–2 days (IRR = 0.835), smoke 3–5 days (IRR = 0.840) and smoke 6–9 days (IRR = 0.829) have a lower likelihood of spending more time in physical activity. Adolescents who consume one to two servings of alcohol on the days they drank alcohol are more likely to spend less time in physical activity than their non-drinking counterparts (IRR = 0.817–0.839). Having sexual intercourse seems to reduce the likelihood of spending more time in physical activity (IRR = 0.894). Frequency of attending physical education class is positively associated with the probability of allocating more time for physical activity (IRR = 1.281–1.543). If other factors are held constant, adolescents who are obese are more likely to spend less time exercising (IRR = 0.912).

in physical activity (IRR = 0.894). Frequency of attending physical education class is positively associated with the probability of allocating more time for physical activity (IRR = 1.281–1.543). If other factors are held constant, adolescents who are obese are more likely to spend less time exercising (IRR = 0.912). 4 Discussion The present study uses a nationwide data and a binomial regression to examine the effects of demographic and lifestyle factors on physical activity with a focus on adolescents. Findings of the present study offer a new insight into factors associated with time spent in physical activity. The factors include age, gender, education, FV consumption, carbonated soft drink consumption, cigarette smoking, alcohol drinking, sexual behaviour, PE class and obesity. It is noteworthy that adoption of healthy lifestyle, such as consuming more FV and less carbonated soft drink, and avoidance of smoking and drinking can increase time allocated for physical activity. Incorporating more PE classes in school may also improve the likelihood of being physical active among adolescents because results of the present study provide a strong evidence that attending PE class promotes physical activity.

, and avoidance of smoking and drinking can increase time allocated for physical activity. Incorporating more PE classes in school may also improve the likelihood of being physical active among adolescents because results of the present study provide a strong evidence that attending PE class promotes physical activity. The findings related to age in the present study are consistent with those evidenced in previous studies [11,[14], [15], [16]]. Zimmermann-Sloutskis et al. [14] conducted a nationwide survey in Switzerland and found that physical inactivity is more prevalent among older adolescents than younger adolescents. Similar finding was evidenced by Rezende et al. [15], who used the National Adolescent School-based Health Survey in Brazil. In Malaysia, Baharudin et al. [11] also found that age is positively associated with the likelihood of adopting a physically inactive lifestyle. Although the negative relationship between age and physical activity was clearly evidenced, its contributing factor was not explained in previous studies. The present study postulates that lack of time is a likely reason explaining physical inactivity among older adolescents. Older adolescents often take more household responsibilities than their younger counterparts, and consequently have less time for physical activity. Since analysis of the present study is not based on a primary data, this suggested reason needs to be validated by a future study. Nevertheless, an important implication of the present study's findings is that an intervention measure directed towards promoting physically active lifestyle among late adolescents may yield promising outcomes. A policy that possesses direct impacts on late adolescents should be implemented.

alidated by a future study. Nevertheless, an important implication of the present study's findings is that an intervention measure directed towards promoting physically active lifestyle among late adolescents may yield promising outcomes. A policy that possesses direct impacts on late adolescents should be implemented. As pointed out in previous studies, gender is significantly associated with physical activity [11,[17], [18], [19], [20], [21], [22]]. Using a sample of two school districts, Sallis et al. [17] found that vigorous physical activity is more frequent among male students than female students. Vilhjalmsson and Thorlindsson [22] used a nationwide data of Iceland and observed that male adolescents are more likely to participate in physical activity than their female counterparts. In more recent studies, Al-Hazzaa et al. [19] and Baharudin et al. [11] also evidenced that male students are more physically active than female students. Findings of the present study suggest likewise. Several reasons may explain these outcomes. The first reason is attributed to cultural factor. Female adolescents are usually encouraged to spend more time in study and household activities instead of physical activities [11]. Moreover, the sport opportunities for females are also limited [19]. Another reason is that physical activity promotes masculinity [22]. Therefore, female adolescents may tend to avoid it in order to maintain their girlie characteristics. An important implication of these findings is that policy makers need to pay special attention to female students if the objective of reducing the prevalence of physical inactivity among adolescents is to be met. A policy that can alter female adolescents' perspective about physical activity is worthy of consideration.

An important implication of these findings is that policy makers need to pay special attention to female students if the objective of reducing the prevalence of physical inactivity among adolescents is to be met. A policy that can alter female adolescents' perspective about physical activity is worthy of consideration. Education is independently associated with physical activity. Higher grade adolescents tend to spend more time in physical activity than their lower grade peers. This is consistent with the findings of previous studies [15,23]. Cheah et al. [23] made use of data from the Malaysian Adolescent Health Risk Behaviour study and found that in general, adolescents with self-perceived excellent or good academic performance allocate more time for physical activity than their counterparts with self-perceived poor or very poor academic performance. Also, they found that having well-educated parents is associated with a high frequency of physical activity. Similarly, Rezende et al. [15] identified that level of education is positively associated with the likelihood of being physically active. These findings may be attributed to the fact that higher educated adolescents are more aware of the benefits of physical activity than lower educated adolescents because they have better interpreting skills and health knowledge [23]. In addition, higher educated adolescents have higher self-efficacy than lower adolescents [24]. It is believed that people who are confident in their capabilities to participate in physical activity have a higher tendency to adopt a physically active lifestyle than people who lack confidence [25]. Based on these findings, one can suggest that adolescents who are in low grades should be the main focus of policy makers. A strategy directed towards improving the health knowledge of low grade adolescents can be considered.

a higher tendency to adopt a physically active lifestyle than people who lack confidence [25]. Based on these findings, one can suggest that adolescents who are in low grades should be the main focus of policy makers. A strategy directed towards improving the health knowledge of low grade adolescents can be considered. In the present study, FV consumption, soft drink consumption, cigarette smoking, alcohol drinking and sexual behaviour are used to identify how lifestyle factors affect adolescents' physical activity levels. The findings are consistent with the hypothesis that unhealthy lifestyle is associated with low levels of physical activity. In particular, adolescents who do not consume FV, consume soft drink, drink alcohol and engage in sexual behaviour are unlikely to spend time in physical activity. Somewhat similar findings were shared by previous studies [6,19]. Al-Hazzaa et al. [19] found that level of physical activity is positively associated with breakfast and fruit intake. Findings evidenced by Romaguera et al. [6] suggested that physically active female students tend to consume more fruits and vegetables than their physically inactive counterparts. The explanation for these findings is simple. Adolescents who are aware of their health often adopt a healthy lifestyle. Since physical activity can improve health, adolescents who have healthy lifestyle behaviours are likely to spend more time in it [6,19]. Surprisingly, however, the present study finds that frequency of smoking is positively associated with time spent in physical activity, which contradicts findings of Romaguera et al [6]. The authors found that smokers have a lower likelihood of being physically active than non-smokers. A plausible explanation for this unexpected finding is that adolescents may engage in smoking and physical activity in order to reduce stress. Hence, to some extent, smoking is a complement to physical activity. This explanation, however, has to be verified by an in-depth qualitative study that focuses particularly on the relationship between smoking and physical activity. In terms of policy implication, government may want to shift its focus to adolescents who adopt an unhealthy lifestyle. A programme that can directly improve health awareness among unhealthy adolescents may generate a worthwhile contribution to the reduction in physical inactivity.

etween smoking and physical activity. In terms of policy implication, government may want to shift its focus to adolescents who adopt an unhealthy lifestyle. A programme that can directly improve health awareness among unhealthy adolescents may generate a worthwhile contribution to the reduction in physical inactivity. The present study finds a positive relationship between the frequency of attending PE classes and time spent in physical activity. Using a nationwide data of the United States, Gordon-Larsen et al. [26] also found that attending PE classes is positively associated with participation in physical activity. They argued that PE classes provide adolescents with opportunities to participate in physical activity. These findings were also shared by Cheah et al. [23], who claimed that health awareness is the contributing factor. Adolescents who attend PE classes are more aware of the benefits of physical activity than their counterparts who do not attend PE classes, and consequently are more likely to participate in physical activity. Taken together, it can be concluded that PE class plays an important role in promoting physically active lifestyle among adolescents. Therefore, a policy aimed at increasing physical activity levels among adolescents should focus on introducing more PE classes to primary and secondary schools.

ate in physical activity. Taken together, it can be concluded that PE class plays an important role in promoting physically active lifestyle among adolescents. Therefore, a policy aimed at increasing physical activity levels among adolescents should focus on introducing more PE classes to primary and secondary schools. Another interesting finding evidenced in the present study is the negative effect of obesity on physical activity levels. The reason is that obese individuals are usually present oriented and less aware of their health. In other words, they are willing to sacrifice their future health for the current pleasures of engaging in unhealthy eating behaviour [27]. Since physical activity is unpleasant and only generates health benefits in the future, obese individuals are unlikely to allocate time for it. The relationship between BMI and physical activity was also examined in previous studies [6,11]. However, their findings are in contrast to that of the present study. Romaguera et al. [6] found that physically active individuals tend to have a higher BMI than physically inactive individuals. Although Baharudin et al.’s [11] scope was also Malaysia, they observed that individuals who are overweight or obese are more likely to be physically active than their peers with normal weight. Policy makers may want to take note of this.

ctive individuals tend to have a higher BMI than physically inactive individuals. Although Baharudin et al.’s [11] scope was also Malaysia, they observed that individuals who are overweight or obese are more likely to be physically active than their peers with normal weight. Policy makers may want to take note of this. One of the advantages of the present study is the representative data which consists of a large sample size. Additionally, a rigorous statistical method is applied to analyse time spent in physical activity. Nonetheless, the present study has several limitations. Firstly, the present study cannot examine the causality between physical activity and demographic, and lifestyle factors because the data is obtained from a cross-sectional study. Secondly, the information is self-reported by the respondents. Hence, the data may be biased. Thirdly, work related physical activity and travel related physical activity are not taken into account. As a result, time spent in physical activity among adolescents may be biased downward. Despite these limitations, the present study has substantial contributions to literature and policy development. Ethical statement Ethical approval was obtained from the Ministry of Health Research and Ethics Committee and Ministry of Education Ethics Committee (Project code: NMRR-11-974-10401). Parental consent forms were obtained before the survey. Adolescents who were not given consent by their parents were not canvassed.

One of the advantages of the present study is the representative data which consists of a large sample size. Additionally, a rigorous statistical method is applied to analyse time spent in physical activity. Nonetheless, the present study has several limitations. Firstly, the present study cannot examine the causality between physical activity and demographic, and lifestyle factors because the data is obtained from a cross-sectional study. Secondly, the information is self-reported by the respondents. Hence, the data may be biased. Thirdly, work related physical activity and travel related physical activity are not taken into account. As a result, time spent in physical activity among adolescents may be biased downward. Despite these limitations, the present study has substantial contributions to literature and policy development. Ethical statement Ethical approval was obtained from the Ministry of Health Research and Ethics Committee and Ministry of Education Ethics Committee (Project code: NMRR-11-974-10401). Parental consent forms were obtained before the survey. Adolescents who were not given consent by their parents were not canvassed. Acknowledgement The authors would like to thank the Director General of Health, Malaysia for sharing data from the Malaysia Global School-based Student Health Survey 2012. Research support from Universiti Utara Malaysia (Research Generation University Grant) (KOD SO 13892) is gratefully acknowledged. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Vitamin D plays a major role in calcium homeostasis and bone mineralization. Vitamin D is a cholesterol derived pro-hormone which is available in two forms: ergocalciferol (D2) produced in plants and cholecalciferol (D3) produced in animal by the action of ultraviolet B radiation on 7-dehydrocholesterol in animal skin. Vitamin D undergoes sequential hydroxylation steps by cytochrome P-450 enzyme system to produce its active form. First hydroxylation takes place in liver due to 25 hydroxylase enzyme activity producing 25-hydroxy vitamin D [25(OH)D]; this is the most abundant circulating form of vitamin D. Active metabolite of vitamin D is produced by rate limiting step of 1α-hydroxylase enzyme in renal tubules producing 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1-α-hydroxylase activity is tightly regulated by parathyroid hormone, calcium, phosphorus and 1, 25-dihydroxyvitamin D [1,2]. Hypocalcemic rickets is mainly due to either nutritional deficiency or genetic disorders of vitamin D. Nutritional rickets is caused by poor intake of calcium and vitamin D or lack of exposure to sun causing vitamin D deficiency. Genetic disorders of vitamin D dependent rickets include vitamin D dependent rickets type 1A (VDDR1A; MIM 264700) and vitamin D dependent rickets type 1B (VDDR1B; MIM 600081). The other genetic disorders cause resistance to vitamin D and include vitamin D dependent rickets type 2A (VDDR2A; MIM 277440) and vitamin D dependent rickets type 2B (VDDR2B; MIM 6007850).

ets include vitamin D dependent rickets type 1A (VDDR1A; MIM 264700) and vitamin D dependent rickets type 1B (VDDR1B; MIM 600081). The other genetic disorders cause resistance to vitamin D and include vitamin D dependent rickets type 2A (VDDR2A; MIM 277440) and vitamin D dependent rickets type 2B (VDDR2B; MIM 6007850). Vitamin D dependent rickets type 1A (VDDR1A; MIM 264700) occurs due to mutation in CYP27B1 gene that codes for 1 α hydroxylase enzyme. The deficiency of 1α-hydroxylase enzyme results in inability to produce active vitamin D 1, 25-dihydroxyvitamin D [1,25(OH)2D]. Active vitamin D [1,25(OH)2D] binds to a nuclear receptor having ligand binding and DNA binding domains to produce target proteins [3]. Vitamin D dependent rickets type 1 A is a rare autosomal recessive disorder having a variable presentation at an early age (2–5 months) with hypocalcemic seizures or a late presentation (9–22 months) with signs of rickets, delayed/regressing motor milestones, recurrent infections, failure to thrive and hypotonia. Biochemical profile and radiological findings are similar to nutritional and vitamin D deficiency rickets including hypocalcaemia, hypophosphatemia, elevated alkaline phosphatase and parathyroid hormone, widening of epiphyses and bowing of long bones [4]. We present a case of a two-year-old boy presented with acute respiratory failure, severe hypotonia, hypocalcaemia and hypophosphatemia secondary to D dependent rickets type 1A.

Vitamin D dependent rickets type 1 A is a rare autosomal recessive disorder having a variable presentation at an early age (2–5 months) with hypocalcemic seizures or a late presentation (9–22 months) with signs of rickets, delayed/regressing motor milestones, recurrent infections, failure to thrive and hypotonia. Biochemical profile and radiological findings are similar to nutritional and vitamin D deficiency rickets including hypocalcaemia, hypophosphatemia, elevated alkaline phosphatase and parathyroid hormone, widening of epiphyses and bowing of long bones [4]. We present a case of a two-year-old boy presented with acute respiratory failure, severe hypotonia, hypocalcaemia and hypophosphatemia secondary to D dependent rickets type 1A. 2 Case history A two-year-old boy was previously healthy until the age of one year. He was born full term with spontaneous vaginal delivery to consanguineous parents; birth weight was 2 kg (−2.5SD). Neonatal course was uneventful with exclusive breast feeding until the age of 6 months. He started rolling side to side and sitting with support at the age of 7 months. He was able to pull himself to standing at 12 months. He never walked on his own. Parents noted at the age of one that he was not progressing in motor development and not gaining weight. He developed clinical signs of rickets with widening epiphysis and bowing of long bones. He was diagnosed with nutritional rickets by his pediatrician and commenced on vitamin D3 supplements. He was fed with powdered milk (Nido) and regular solid food. He continued to regress in his milestones and lost the ability to sit or roll. He suffered several respiratory tract infections despite regular bronchodilator and steroid inhalers since the age of 1. He required two hospital admissions for respiratory symptoms. There is no available record of his bone profile from previous hospital admissions.

n his milestones and lost the ability to sit or roll. He suffered several respiratory tract infections despite regular bronchodilator and steroid inhalers since the age of 1. He required two hospital admissions for respiratory symptoms. There is no available record of his bone profile from previous hospital admissions. He presented to the emergency room with severe respiratory distress requiring high oxygen via face mask. He was apathetic looking although did not have any obvious dysmorphic features. Physical examination revealed malnourished child with weight of 6.8 kg (−6 SD) and length of 70 cm (−4.75SD). There were obvious signs of rickets including palpable widening of wrist and ankle joints, prominent forehead, soft skull bone, rachitic rosary and narrow bell-shaped chest (Fig. 1A). He had normal scalp hairs and eyebrows. He had generalized muscle wasting with severe hypotonia. He was unable to sit or roll side by side. His speech and cognitive function was appropriate for his age.Fig. 1 A: Narrow bell shaped chest with rachitic rosary. B: Bilateral atelactasis and parenchymal haziness. Fig. 1 2.1 Investigations He was admitted to pediatric intensive care unit and ventilated for 2 days for hypoxia and hypercapnia. Chest x-ray showed bilateral atelectasis and diffuse parenchymal haziness (Fig. 1B). He was weaned to CPAP and nasal oxygen to room air over 5 days.

He presented to the emergency room with severe respiratory distress requiring high oxygen via face mask. He was apathetic looking although did not have any obvious dysmorphic features. Physical examination revealed malnourished child with weight of 6.8 kg (−6 SD) and length of 70 cm (−4.75SD). There were obvious signs of rickets including palpable widening of wrist and ankle joints, prominent forehead, soft skull bone, rachitic rosary and narrow bell-shaped chest (Fig. 1A). He had normal scalp hairs and eyebrows. He had generalized muscle wasting with severe hypotonia. He was unable to sit or roll side by side. His speech and cognitive function was appropriate for his age.Fig. 1 A: Narrow bell shaped chest with rachitic rosary. B: Bilateral atelactasis and parenchymal haziness. Fig. 1 2.1 Investigations He was admitted to pediatric intensive care unit and ventilated for 2 days for hypoxia and hypercapnia. Chest x-ray showed bilateral atelectasis and diffuse parenchymal haziness (Fig. 1B). He was weaned to CPAP and nasal oxygen to room air over 5 days. He was investigated for rickets and hypotonia. Biochemical testing showed calcium 1.98 mmol/L (2.10–2.55), phosphate 0.33 mmol/L (1.00–2.00), alkaline phosphatase 538 U/L (0–281), parathyroid hormone 821 ng/L (10.0–65.0), 25 OH vitamin D 66 ng/ml (20–50), 1,25 OH vitamin D 39 pg/ml (24–86) and normal renal function, ammonia and lactic acid. Urine chemistry showed high renal calcium and phosphate excretion; calcium creatinine ratio 4.17 mmol/mmol, urinary phosphate 20.9 mmol/L with renal tubular absorption of 74%. X-ray of lower and upper limbs revealed severe osteopenia, cupping and fraying of long bones metaphysis and bilateral fibular mid-shaft fracture (Fig. 2A).Fig. 2 A: Bilateral fibular fracture. B: After 3 months of treatment.

inine ratio 4.17 mmol/mmol, urinary phosphate 20.9 mmol/L with renal tubular absorption of 74%. X-ray of lower and upper limbs revealed severe osteopenia, cupping and fraying of long bones metaphysis and bilateral fibular mid-shaft fracture (Fig. 2A).Fig. 2 A: Bilateral fibular fracture. B: After 3 months of treatment. Fig. 2 The differential diagnosis after the initial work up was vitamin D dependent rickets type 1 (VDDR1A), vitamin D dependent rickets type 2A and X-linked hypophosphatemic rickets. He did not have alopecia, which is present in the majority of cases with vitamin D dependent rickets type 2A [5]. Hypophosphatemic rickets is not usually associated with hypocalcemia and raised parathyroid hormone. 1,25 OH vitamin D level is although with in normal reference range but with the severity of hypocalcemia and raised parathyroid hormone level it is considered as inappropriately low.

min D dependent rickets type 2A [5]. Hypophosphatemic rickets is not usually associated with hypocalcemia and raised parathyroid hormone. 1,25 OH vitamin D level is although with in normal reference range but with the severity of hypocalcemia and raised parathyroid hormone level it is considered as inappropriately low. 2.2 Management The treatment was started with high suspicion of vitamin D dependent rickets type 1A. He was commenced on alfacalcidiol, oral calcium and phosphate. He responded very quickly to oral therapy and calcium normalized in two days. We also placed a port-a-cath for intravenous calcium infusion. High dose calcium infusion protocol for vitamin D dependent rickets type 2A [6] is followed due to severe clinical and radiological picture to achieve rapid improvement. Serum calcium was closely monitored and kept in lower normal range. Two weeks after calcium infusion urinary calcium creatinine ratio was 0.92 mmol/mmol. Calcium infusion continued for one month; at the end of therapy there was no nephrocalcinosis on renal ultrasound. Laboratory testing showed calcium 2.27 mmol/L (2.10–2.55), phosphate 1.13 mmol/L (1.00–2.00), alkaline phosphatase 1532 U/L (0–281) and parathyroid hormone 65.4 ng/L (10.0–65.0). There was complete resolution of respiratory symptoms and marked improvement in muscle tone as he started rolling and sitting. He was discharged home on oral alfacalcidiol and calcium.

/L (2.10–2.55), phosphate 1.13 mmol/L (1.00–2.00), alkaline phosphatase 1532 U/L (0–281) and parathyroid hormone 65.4 ng/L (10.0–65.0). There was complete resolution of respiratory symptoms and marked improvement in muscle tone as he started rolling and sitting. He was discharged home on oral alfacalcidiol and calcium. 2.3 Follow up At three months follow up, he was maintaining bone profile and parathyroid hormone in normal range and improved alkaline phosphatase. X-ray of lower limb showed improvement in the signs of rickets and healing of fibular fracture. He started walking without support and did not have any respiratory symptoms. 2.4 Genetic testing Vitamin D dependent rickets has mutation in CYP27B1 gene coding for 1α hydroxylase protein. Our patient DNA analysis showed homozygous mutation p.Arg429Pro (R429P) at exon c.1286 G > C. This mutation is previously reported and shown absence of detectable in vitro activity of 1α hydroxylase protein [7].

2.4 Genetic testing Vitamin D dependent rickets has mutation in CYP27B1 gene coding for 1α hydroxylase protein. Our patient DNA analysis showed homozygous mutation p.Arg429Pro (R429P) at exon c.1286 G > C. This mutation is previously reported and shown absence of detectable in vitro activity of 1α hydroxylase protein [7]. 3 Discussion Vitamin D dependent rickets type 1 is a rare autosomal recessive disorder which is more prevalent in societies with high number of inter-family and consanguineous marriages. We reported the case of a two-year-old boy that has history of typical rickets presenting at the age of 1 year but did not respond to Vitamin D3 supplements. He deteriorated over 1 year with severe hypotonia and recurrent respiratory symptoms requiring hospital admissions. The diagnosis is delayed because there is high prevalence of vitamin D deficiency in Saudi population therefore clinicians have low clinical suspicion to consider other differential diagnosis of rickets. Genetic testing revealed homozygous mutation in CYP27B1 gene. He responded very quick to oral alfacalcidiol and calcium therapy. Motor milestones and hypotonia improved within 3 months of treatment.

in Saudi population therefore clinicians have low clinical suspicion to consider other differential diagnosis of rickets. Genetic testing revealed homozygous mutation in CYP27B1 gene. He responded very quick to oral alfacalcidiol and calcium therapy. Motor milestones and hypotonia improved within 3 months of treatment. Vitamin D deficiency is a major global health issue. A systemic review of 103 studies from different global regions has shown highest prevalence of Vitamin D deficiency in Middle East among all age groups and particularly in adolescent girls and women. Adolescent female in Saudi Arabia has 81% prevalence of Vitamin D deficiency [8]. Children presenting with rickets in this region are rationally diagnosed as nutritional rickets and commenced on vitamin D3; as compliance with the treatment is culturally not always adequate slow improvement would not immediately raise the suspicion of wrong diagnosis. Vitamin D level measurement is readily available but 1,25OH D measurement is available in few specialized centers.

agnosed as nutritional rickets and commenced on vitamin D3; as compliance with the treatment is culturally not always adequate slow improvement would not immediately raise the suspicion of wrong diagnosis. Vitamin D level measurement is readily available but 1,25OH D measurement is available in few specialized centers. Saudi Arabia has a high tradition of inter-family marriages particularly between first cousins. This tradition is part of Arab societies and their majority religion Islam permits inter-family marriages. This trend facilitates the families to keep their cultural and religious norms intact. First cousin and close relation marriages comprise 25–42% of marriages in Saudi society. International consanguinity workshop (2011) reports a consensus on association of congenital malformation and autosomal recessive diseases causing increased postnatal mortality in consanguineous marriages [9].

ligious norms intact. First cousin and close relation marriages comprise 25–42% of marriages in Saudi society. International consanguinity workshop (2011) reports a consensus on association of congenital malformation and autosomal recessive diseases causing increased postnatal mortality in consanguineous marriages [9]. Our case has a striking finding of severe hypotonia associated with regressing milestones and respiratory symptoms due to proximal muscle weakness. Yun Yan et al. also reported a similar case of VDDR1 in infant with severe hypotonia [10]. Etiology of this severe hypotonia is contributed by direct effect of vitamin D on muscle fibers length and also due to hypophosphatemia causing decrease muscle strength. Muscle fibers of striated muscles are studied in vitamin d receptor null mice (VDR −/−) and compared with wild type; fibers are significantly smaller in VDR null mice [11]. Hypophosphatemia secondary to vitamin D deficiency and hyperparathyroidism plays major role in hypotonia as vitamin deficient mice do no show hypotonia as long serum phosphate and calcium level is maintained with in normal range [12].

and compared with wild type; fibers are significantly smaller in VDR null mice [11]. Hypophosphatemia secondary to vitamin D deficiency and hyperparathyroidism plays major role in hypotonia as vitamin deficient mice do no show hypotonia as long serum phosphate and calcium level is maintained with in normal range [12]. CYP27B1 gene (MIM #609506) encodes for 1 αhydroxylase enzyme. The human gene was first mapped at chromosome 12q14 by linkage analysis in 1990 and later on cloned in 1997 [13,14]. This gene contains 9 exons spanning 5 kb and eight introns. More than 50 mutations are reported to date including missense or nonsense mutations, deletions, splicing and duplications. Phenotype of VDDR1A can be modified by endogenous and exogenous factors other than gene mutation. Residual enzyme activity may cause only milder phenotype. Alzahrani et al. reported a large family with six siblings having a gene mutation but variable clinical and biochemical profile; three of them are clinically asymptomatic but biochemical profile is suggestive of disease while the other three has mild rickets and growth retardation [15]. 4 Learning points • Clinician should have a low threshold to consider rare genetic disorders in the differential diagnosis in societies with high rate of inter-family and consanguineous marriages. • Vitamin D deficiency is a global phenomenon particularly in Middle East and is the most common cause of rickets; but children not responding to Vitamin D supplements should be considered for rare hereditary causes of rickets.

4 Learning points • Clinician should have a low threshold to consider rare genetic disorders in the differential diagnosis in societies with high rate of inter-family and consanguineous marriages. • Vitamin D deficiency is a global phenomenon particularly in Middle East and is the most common cause of rickets; but children not responding to Vitamin D supplements should be considered for rare hereditary causes of rickets. • Severe hypotonia and motor milestones regression is associated with rickets. Rickets should be considered in differential diagnosis of hypotonia along with neurological and metabolic conditions. • Active vitamin D metabolites (alfacalcidiol and calcitriol) therapy deserves regular screening for nephrocalcinosis and intraocular calcification. Conflict of interest We declare that we have no conflict of interest and we have not received any financial support for this case report. Ethical statement We have an informed consent from parents to publish this case without disclosing any personal identification. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Comfrey, generally described as Symphytum officinale senso latu, has a long history of use in the treatment of injuries. The botanical taxonomical description is rather wide and includes a broad variety of hybrids with similar phytochemical constituents but with distinct differences with regard to potentially toxic pyrrolizidine alkaloids. A medicinal comfrey variety was specifically selected and cultivated for exclusive use in the topical preparation examined in this study. The exact botanical description of this comfrey variety is Symphytum × uplandicum Nyman ‘Harras’ [[1], [2], [3]] – a specific taxon within the general group of S. officinale, which is devoid of detectable pyrrolizidine alkaloids in the aerial parts. It has been used as a consistent and reproducible starting material in the manufacture of the study medication for several decades. The topical preparation containing an extract from the freshly harvested flowering plant parts of S. x uplandicum has proven its usefulness in the treatment of blunt traumas such as sprains, contusions, and strains [[4], [5], [6], [7], [8], [9]] and also against muscle pain [[10], [11], [12]]. In the past years, an acceleration of wound healing was demonstrated as an additional benefit [13,14], based on earlier observations [4,15].

as proven its usefulness in the treatment of blunt traumas such as sprains, contusions, and strains [[4], [5], [6], [7], [8], [9]] and also against muscle pain [[10], [11], [12]]. In the past years, an acceleration of wound healing was demonstrated as an additional benefit [13,14], based on earlier observations [4,15]. The benefits of the comfrey cream in pediatric use were examined in observational studies including 361 children with blunt traumas [16,17] and in a clinical double-blind trial with 108 children treated for fresh abrasions [14]. The currently available data support an excellent tolerability and efficacy of the comfrey cream formulation used in these trials, including the application in children and adolescents. For the age group of children between 4 and 12 years, the documented exposure in interventional and noninterventional clinical trials accumulates to approximately 520 patients treated for blunt traumas and abrasions [13,14,16]. The number of children treated to date would statistically translate into the conclusion of any given adverse effect being unlikely to be observed in approximately 1.5 out of 100 children with intact skin and, due to the smaller documented case numbers, in approximately 2 out of 100 cases with broken skin. The aim of this study was securing an upper limit of the theoretical incidence rate of approximately one case of any given adverse reaction in 100 patients in those with injured and uninjured skin. Statistically, this requires the treatment of approximately 300 patients, which defined the number of children to be included in this study.

udy was securing an upper limit of the theoretical incidence rate of approximately one case of any given adverse reaction in 100 patients in those with injured and uninjured skin. Statistically, this requires the treatment of approximately 300 patients, which defined the number of children to be included in this study. 2 Material and methods 2.1 Ethical issues In planning the study, the principles of the Declaration of Helsinki/Somerset West and the International Conference on Harmonization (ICH)–Good Clinical Practice recommendations (Center for Medicine and Public Health [CMPH]/ICH/135[95]) were adhered to. As this study was an open, uncontrolled observational trial, vote from an ethics committee did not have to be obtained. Relevant governmental authorities were notified about the study. In all cases, the parents or legal guardians of the children signed a written informed consent form. 2.2 Study design The study was designed as an open, noninterventional prospective trial with an observation of the application of the topical medication for 7 days and, if medically justified, a follow-up for a maximum of 14 days. Three ambulatory study centers specialized on orthopedic diseases in Prague and one general physician with specific expertise in skin disorders in Brno (Czech Republic) were involved in recruiting patients and assessing case data.

medication for 7 days and, if medically justified, a follow-up for a maximum of 14 days. Three ambulatory study centers specialized on orthopedic diseases in Prague and one general physician with specific expertise in skin disorders in Brno (Czech Republic) were involved in recruiting patients and assessing case data. The design of the study specifically considered the German recommendations on the conduct of observational studies published by the German regulatory authorities on 7 July 2010 [18], already circulated before the official publication and therefore applied for this study. In addition, the European recommendations on postapproval safety studies written down in “Volume 9A of the Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use” (Final version of 2008) and the 2008 Guidelines for Good Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology [19] were used for the definition of the study parameters. The study was performed in two parts between January 2010 and May 2011 by recruiting and treating children with blunt traumas and/or sports injuries. The first substudy involved children suffering from blunt traumas with intact skin, whereas for the second substudy, children suffering from blunt traumas with concomitant superficial wounds or abrasions were recruited.

ary 2010 and May 2011 by recruiting and treating children with blunt traumas and/or sports injuries. The first substudy involved children suffering from blunt traumas with intact skin, whereas for the second substudy, children suffering from blunt traumas with concomitant superficial wounds or abrasions were recruited. 2.3 Study duration and visits The duration of the study was up to 14 days. Safety of application and therapeutic effects were assessed after 1 week and, if the patient came back for a second consultation, again after 2 weeks.

ary 2010 and May 2011 by recruiting and treating children with blunt traumas and/or sports injuries. The first substudy involved children suffering from blunt traumas with intact skin, whereas for the second substudy, children suffering from blunt traumas with concomitant superficial wounds or abrasions were recruited. 2.3 Study duration and visits The duration of the study was up to 14 days. Safety of application and therapeutic effects were assessed after 1 week and, if the patient came back for a second consultation, again after 2 weeks. 2.4 Study preparation and dosing The testing of the study medication was carried out with a comfrey herb cream preparation authorized as a medicinal product in Germany, the Czech Republic, and other countries for the treatment of blunt traumas such as contusions and sprains (Traumaplant®, Harras Pharma Curarina, München, Germany). The study was conducted in the Czech Republic, where, as in most countries where the study preparation is authorized as a medicinal product, the application on nonintact skin (e.g., on abrasions and superficial wounds) is part of the authorized indication. Per 10 g of cream, the study preparation contains 1 g of a preparation of freshly harvested aerial parts of medicinal comfrey from controlled cultivation (S. x uplandicum Nyman) consisting of a blend of 0.4 g of pressed plant juice (drug-to-extract ratio of 3–8:1) and 0.6 g of an extract from the press residue with 30% ethanol v/v (drug-to-extract ratio 3–10:1). The combined herbal active substance is characterized by a ratio of fresh plant to extract of 2–3:1, which corresponds to an average quantity of 25 g of fresh comfrey herb in 100 g of cream preparation, with a defined and reproducible composition and quality. Potentially toxic pyrrolizidine alkaloids were not present in either the active substance concentrate or the cream preparation (detection limit <0.01 μg/g). Further constituents (excipients) are macrogol-20-glycerol monostearate, glycerol mono/di (palmitate and stearate), octyldodecanol, isopropyl myristate, propylene glycol, dimeticone 100, rosemary oil, all-rac-α-tocopherol acetate, citric acid, purified water, sorbic acid, and hydroxyethyl salicylate.

limit <0.01 μg/g). Further constituents (excipients) are macrogol-20-glycerol monostearate, glycerol mono/di (palmitate and stearate), octyldodecanol, isopropyl myristate, propylene glycol, dimeticone 100, rosemary oil, all-rac-α-tocopherol acetate, citric acid, purified water, sorbic acid, and hydroxyethyl salicylate. The official recommendation for application is “several times daily,” which was not more closely defined by the investigators. The typical frequency of application is 2–4 times daily. The individual dose cannot be predefined, as it depends on the size of the injury. Frequency of administration was recorded from patient/caretaker indications at each visit, as was the area of the lesion. The latter parameter was, however, not statistically examined. 2.5 Assessment parameters Local tolerability of the cream was assessed by the physician using a four-step verbal rating scale (0 = normal, 1 = slight reaction, 2 = moderately strong reaction, 3 = severe reaction), specifically judging visible occurrences of scratching and inflammation, and asking the patient or their caretaker at each visit for the following symptoms: burning sensation, scaling of skin, reddening, itching, urticaria, and folliculitis. Other symptoms could be freely defined and assessed in the same manner. Eventually observed adverse reactions were to be described as precisely as possible. Patients/caretakers were instructed to report adverse events at any time.

oms: burning sensation, scaling of skin, reddening, itching, urticaria, and folliculitis. Other symptoms could be freely defined and assessed in the same manner. Eventually observed adverse reactions were to be described as precisely as possible. Patients/caretakers were instructed to report adverse events at any time. Effectiveness of treatment was assessed at each visit by the physician and the patients or their caretakers for comparison with previous experience and observations in double-blind trials using a five-step verbal rating scale (1 = very good effect, 2 = good effect, 3 = moderate effect, 4 = minor effect, and 5 = no effect). In the case of children with intact skin, the assessment of effects was focused on the healing process of the blunt traumas, i.e., the overall impression of pain reduction, reduction in swelling, and improvement in joint mobility. The assessment in the case of children with broken skin also included the impression of the healing process of the wound. 2.6 Inclusion and exclusion criteria Children in the age range of 4–12 years suffering from blunt traumas or sports accidents were included, with a separate assessment of children with intact skin and children with concomitant superficial wounds or abrasions. Eligible patients were enrolled only after the physicians had decided to recommend treatment with the study preparation.

ge of 4–12 years suffering from blunt traumas or sports accidents were included, with a separate assessment of children with intact skin and children with concomitant superficial wounds or abrasions. Eligible patients were enrolled only after the physicians had decided to recommend treatment with the study preparation. Patients showing skin disorders in the treatment area (e.g., burning, scaling, reddening, itching, urticaria, folliculitis, and superinfection) or having an allergy to comfrey or one of the excipients of the cream (sorbic acid, rosemary oil, isopropyl myristate, propylene glycol, and salicylates) were not included. Concomitant treatment with other preparations in the treatment area was not permitted. 2.7 Case number calculation The number of patients to be included was calculated to possess a power of 95% to detect adverse events with an incidence rate of ≥1%. This condition requires the treatment of 300 patients per subgroup: if any given adverse event is not detected in this sample, its incidence is below one in 100 treated patients. 2.8 Statistical analysis Data obtained in this observational study were evaluated descriptively. Statistical tests were not applied. Missing values were not replaced. SPSS was used for the calculation of 95% confidence intervals for the incidence of adverse events.

2.7 Case number calculation The number of patients to be included was calculated to possess a power of 95% to detect adverse events with an incidence rate of ≥1%. This condition requires the treatment of 300 patients per subgroup: if any given adverse event is not detected in this sample, its incidence is below one in 100 treated patients. 2.8 Statistical analysis Data obtained in this observational study were evaluated descriptively. Statistical tests were not applied. Missing values were not replaced. SPSS was used for the calculation of 95% confidence intervals for the incidence of adverse events. 3 Results 3.1 Study populations A total of 712 children were recruited: 386 children with intact skin and 326 children with broken skin (ITT-populations for the subgroup analyses). The flowchart of patient group allocation is presented in Fig. 1. There were three protocol deviations in the subgroup of children with intact skin, as three of the recruited children were aged 3 years and therefore younger than the age defined in the protocol (4–12 years). The per-protocol population (PP population) of the subgroup with intact skin therefore consisted of 383 patients. Similarly, there were three children younger than 4 years (3 years) and one child older than 12 years (15 years) in the substudy with children with broken skin. In addition, there was one drop-out because of an intolerability reaction with the first application (see Safety results). The PP population of the substudy with children with broken skin was therefore n = 321.Fig. 1 Flowchart of patient allocation to treatment groups.

esearch impossible. The two cases represented an outbreak for us. Hence, NICU and laboratory teams were alerted to initiate a more in-depth investigation if another case appeared, but fortunately, this did not occur. We did not perform a culture of milk, parenteral nutrition, or any other kind of parenteral medication. 4 Conclusion Neonatal infection from C. magnoliae is a rare condition. We had two cases in a short period of time, both with a fatal evolution. To date, the sensitivity of these microorganisms to antifungal agents existent on the market is unknown. Further pharmacological and clinical research is necessary to elucidate the best treatment in these cases. Conflict of interest The corresponding author on behalf of all the authors declares that there is no conflict of interest. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

s) in the substudy with children with broken skin. In addition, there was one drop-out because of an intolerability reaction with the first application (see Safety results). The PP population of the substudy with children with broken skin was therefore n = 321.Fig. 1 Flowchart of patient allocation to treatment groups. Fig. 1 The results were in both substudies practically identical for the ITT and the PP population. The presentation of results is therefore made with the ITT populations (n = 386 and n = 326). In the subgroup of children with intact skin, 198 of 386 (51%) came back for this additional visit after 2 weeks, whereas almost all of the patients with broken skin (n = 324, 99%) returned for a second consultation after 2 weeks. 3.2 Demographic data Twenty-six percent of the children with intact skin and 41% of the children with broken skin were female (n = 99 and 135). The median time between occurrence of the trauma and the first application of the study medication was 12 h for children with intact skin and 6 h for children with broken skin. The mean age was 8.6 (2.6) and 7.6 (2.6) years, respectively. The age distribution is displayed in Fig. 2.Fig. 2 Distribution of patient age in the two study groups. Fig. 2 The major indications for the application of the study medication in patients with intact skin were in 90.4% of cases contusions, distortions, muscle pain, strains, and joint pain. The major indications for the application of the study medication in patients with broken skin were superficial wounds and abrasions with and without blunt traumas.

the application of the study medication in patients with intact skin were in 90.4% of cases contusions, distortions, muscle pain, strains, and joint pain. The major indications for the application of the study medication in patients with broken skin were superficial wounds and abrasions with and without blunt traumas. 3.3 Frequency of application The majority of patients had applied the cream two to three times daily (Fig. 3). The patients returning for the second visit had mostly reduced the frequency of application. The theoretical maximum number of exposures (number of applications per day times number of patients with this exposure times 7 days) amounted to 10,507 exposures for patients with intact skin and 11,459 exposures for patients with injured skin.Fig. 3 Frequency of application of the study preparation. Fig. 3 3.4 Safety results None of the patients with intact skin showed a local reaction or any other adverse event. One of the patients with broken skin developed severe local burning and reddening at the application site within 15 min after the first application of the study medication. The patient terminated study participation. There were otherwise no systemic or other adverse reactions. The 95% confidence intervals for the incidence of local intolerability reactions and of adverse events in general after application of the study medication to intact skin were calculated as 0.0–0.77%, thus indicating that the true incidence of adverse reactions is below 0.8% with 95% certainty.

3.4 Safety results None of the patients with intact skin showed a local reaction or any other adverse event. One of the patients with broken skin developed severe local burning and reddening at the application site within 15 min after the first application of the study medication. The patient terminated study participation. There were otherwise no systemic or other adverse reactions. The 95% confidence intervals for the incidence of local intolerability reactions and of adverse events in general after application of the study medication to intact skin were calculated as 0.0–0.77%, thus indicating that the true incidence of adverse reactions is below 0.8% with 95% certainty. Similarly, the 95% confidence interval for the incidence of local intolerability reactions after application to broken skin, specifically for burning and reddening, was calculated for both the ITT and the PP group as 0.31% (95% CI 0.01–1.7%). The theoretical 95% confidence intervals for the incidence of systemic adverse events and local intolerability reactions (which were not observed, i.e., scaling of skin, itching, urticaria, and folliculitis) with the application of the study medication to nonintact skin was calculated as 0.00–0.92%, again with no difference between the ITT and PP groups.

vals for the incidence of systemic adverse events and local intolerability reactions (which were not observed, i.e., scaling of skin, itching, urticaria, and folliculitis) with the application of the study medication to nonintact skin was calculated as 0.00–0.92%, again with no difference between the ITT and PP groups. Combining the patient populations of the two substudies accumulates to 712 children exposed to the study medication. The overall point estimate and 95% CI for the overall incidence of local intolerability reactions were calculated as 0.14% (0.00–0.78%). The 95% CI interval for the overall incidence of systemic adverse events was calculated as 0.00–0.42%. 3.5 Effectiveness results The global assessment of treatment effectiveness by the physicians and the patients or their caretakers is given in Table 1. Both physicians and caretakers came to highly comparable assessment. In both cases, there was still improvement during the second week (Fig. 4, Fig. 5).Table 1 Assessment of effectiveness by physicians and patients/caretakers.

ent effectiveness by the physicians and the patients or their caretakers is given in Table 1. Both physicians and caretakers came to highly comparable assessment. In both cases, there was still improvement during the second week (Fig. 4, Fig. 5).Table 1 Assessment of effectiveness by physicians and patients/caretakers. Table 1Physicians Intact skin Injured skin Week 1 n = 386 (%) Week 2 n = 198 (%) Week 1 n = 325 (%) Week 2 n = 325 (%) Very good 173 (44.8) 151 (76.6) 146 (44.9) 196 (60.5) Good 173 (44.8) 35 (17.7) 118 (36.3) 99 (30.6) Moderate 35 (9.1) 10 (5.1) 36 (11.1) 25 (7.7) Minor 5 (1.3) 2 (1.0) 25 (7.7) 4 (1.2) No effect 0 (0) 0 (0) 0 (0) 0 (0) Patients/caretakers Intact skin Injured skin Week 1 n = 386 (%) Week 2 n = 198 (%) Week 1 n = 324 (%) Week 2 n = 324 (%) Very good 206 (53.4) 198 (75.3) 166 (51.1) 230 (71.0) Good 155 (40.2) 38 (19.2) 104 (32.0) 86 (26.5) Moderate 20 (5.2) 5 (2.5) 54 (16.6) 7 (2.2) Minor 5 (1.3) 6 (3.0) 1 (0.3) 1 (0.3) No effect 0 (0) 0 (0) 0 (0) 0 (0) Fig. 4 Global assessment of effectiveness of treatment in children with intact skin by the physician. Fig. 4Fig. 5 Global assessment of effectiveness of treatment in children with broken skin by the physician. Fig. 5

Table 1Physicians Intact skin Injured skin Week 1 n = 386 (%) Week 2 n = 198 (%) Week 1 n = 325 (%) Week 2 n = 325 (%) Very good 173 (44.8) 151 (76.6) 146 (44.9) 196 (60.5) Good 173 (44.8) 35 (17.7) 118 (36.3) 99 (30.6) Moderate 35 (9.1) 10 (5.1) 36 (11.1) 25 (7.7) Minor 5 (1.3) 2 (1.0) 25 (7.7) 4 (1.2) No effect 0 (0) 0 (0) 0 (0) 0 (0) Patients/caretakers Intact skin Injured skin Week 1 n = 386 (%) Week 2 n = 198 (%) Week 1 n = 324 (%) Week 2 n = 324 (%) Very good 206 (53.4) 198 (75.3) 166 (51.1) 230 (71.0) Good 155 (40.2) 38 (19.2) 104 (32.0) 86 (26.5) Moderate 20 (5.2) 5 (2.5) 54 (16.6) 7 (2.2) Minor 5 (1.3) 6 (3.0) 1 (0.3) 1 (0.3) No effect 0 (0) 0 (0) 0 (0) 0 (0) Fig. 4 Global assessment of effectiveness of treatment in children with intact skin by the physician. Fig. 4Fig. 5 Global assessment of effectiveness of treatment in children with broken skin by the physician. Fig. 5 4 Discussion and conclusions The study presented herein was not a controlled clinical trial and hence not intended to present a formal proof of efficacy. The focus of this study was on safety, with the aim to produce an impression of hazards and their statistical importance under real-life conditions. These real-life conditions also included the recording of adverse events during the next visit (although patients and their caretakers were encouraged to call in with any observation of adverse events) and thus potentially several days after the occurrence of the event. Particularly, very mild events not re-occurring with continued application might therefore not be remembered. This procedure was still deemed sufficient for addressing safety because (a) it reflects clinical realities applicable to all kinds of medication and (b) it was assumed that a true adverse event such as a skin reaction would aggravate with continued application and would therefore be noted and reported. There would even be visible signs upon examination by the physician.

sing safety because (a) it reflects clinical realities applicable to all kinds of medication and (b) it was assumed that a true adverse event such as a skin reaction would aggravate with continued application and would therefore be noted and reported. There would even be visible signs upon examination by the physician. The open study design also implies that the frequency of identified adverse events cannot be compared with a placebo group. This potential weakness of the study is, however, irrelevant in this case, as there was no adverse event in the group of children with intact skin and only one event of irritation in the group with broken skin. This adverse event was assumed to be causally related to the study medication, but technically, it cannot be attributed to comfrey as the active ingredient, as it also has been caused by one of the cream excipients. Patients applied the study preparation 1–5 times daily for up to 2 weeks, which accumulates to a theoretical maximum exposure to 22,148 applications in the study period, 11,459 of which occurred on the injured skin. The calculations are made for orientation only, as they assume that the frequency of application indicated by an individual patient after the first and the second week of treatment would not change for the entire week. The calculated exposures are therefore probably very high, but still they provide a background for comparing the single observed adverse event with exposure estimates.

t the frequency of application indicated by an individual patient after the first and the second week of treatment would not change for the entire week. The calculated exposures are therefore probably very high, but still they provide a background for comparing the single observed adverse event with exposure estimates. The practical applicability of the same preparation as used in the two observational studies presented herein was already demonstrated in children in observational studies with blunt traumas [16] and in randomized clinical double-blind trials [13,14]. The number of children exposed to the study preparation described in the literature adds up to 529 patients. The safety and effectiveness/efficacy profile reported in these previously published studies was fully confirmed herein. The results are also in accordance with those reported in recent studies performed in adults [[8], [9], [10], [11], [12], [13]]. The available data show that experience with efficacy and safety in adults is apparently transferable to the situation in pediatric patients.

sly published studies was fully confirmed herein. The results are also in accordance with those reported in recent studies performed in adults [[8], [9], [10], [11], [12], [13]]. The available data show that experience with efficacy and safety in adults is apparently transferable to the situation in pediatric patients. Comfrey herb extract cream is a popular medication for the treatment of blunt traumas, both in adults and in children. Traditional uses of comfrey also include the treatment of injuries with broken skin; however, such uses are usually discommended because comfrey may contain toxic pyrrolizidine alkaloids [20]. In the case of the study medication, this specific problem was avoided by the selection and cultivation of a comfrey variety devoid of measurable quantities of pyrrolizidine alkaloids in the aerial plant parts [1,3], a variety exclusively used for the manufacture of the study preparation. Because of the selection of this specific comfrey variety, safety concerns with regard to pyrrolizidine alkaloids do not apply and the corresponding medicinal preparation can be used in medical conditions in adults and children where the skin is injured. This may be considered as an advantage in comparison to other local treatments of blunt traumas, e.g., diclofenac is typically contraindicated on broken skin.

rolizidine alkaloids do not apply and the corresponding medicinal preparation can be used in medical conditions in adults and children where the skin is injured. This may be considered as an advantage in comparison to other local treatments of blunt traumas, e.g., diclofenac is typically contraindicated on broken skin. The spontaneous reporting systems for adverse drug reactions never showed signals for any untoward reaction. The data presented in this study indicate that this lack of signals from spontaneous reporting is clearly not due to underreporting. The results reported herein increase the number of children exposed to the study medication to 1,241, which allows concluding on the statistical absence of any adverse event in far less than one child in 100 treated patients. The global assessment of effects corresponds to the findings in previous controlled studies with regard to the clinical improvement of symptoms of blunt traumas and wound healing. It therefore underlines the transferability of the observations to daily routine practice. 5 Summary declaration of interest statement The study was sponsored by Harras Pharma Curarina Arzneimittel GmbH (München, Germany). The sponsor contributed to the definition of the general study parameters in the study plan and provided the medication but was otherwise not involved in the execution, evaluation, and publication of the clinical trial. These tasks were carried out under the responsibility of the principal investigator. Ethical statement The following details on the ethical conduct of the study are also part of the manuscript:

5 Summary declaration of interest statement The study was sponsored by Harras Pharma Curarina Arzneimittel GmbH (München, Germany). The sponsor contributed to the definition of the general study parameters in the study plan and provided the medication but was otherwise not involved in the execution, evaluation, and publication of the clinical trial. These tasks were carried out under the responsibility of the principal investigator. Ethical statement The following details on the ethical conduct of the study are also part of the manuscript: In planning the study, the principles of the Declaration of Helsinki/Somerset West and the International Conference on Harmonization (ICH)–Good Clinical Practice recommendations (Center for Medicine and Public Health [CMPH]/ICH/135[95]) were adhered to. As this study was an open, uncontrolled observational trial, vote from an ethics committee did not have to be obtained. Relevant governmental authorities were notified about the study. In all cases, the parents or legal guardians of the children signed a written informed consent form.

MPH]/ICH/135[95]) were adhered to. As this study was an open, uncontrolled observational trial, vote from an ethics committee did not have to be obtained. Relevant governmental authorities were notified about the study. In all cases, the parents or legal guardians of the children signed a written informed consent form. The design of the study specifically considered the German recommendations on the conduct of observational studies published by the German regulatory authorities on 7 July 2010 [18], already circulated before the official publication and therefore applied for this study. In addition, the European recommendations on postapproval safety studies written down in “Volume 9A of the Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use” (Final version of 2008) and the 2008 Guidelines for Good Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology [19] were used for the definition of the study parameters. Declaration of interests We wish to draw the attention of the Editor to the following facts that may be considered as potential conflicts of interest and to significant financial contributions to this work.

The design of the study specifically considered the German recommendations on the conduct of observational studies published by the German regulatory authorities on 7 July 2010 [18], already circulated before the official publication and therefore applied for this study. In addition, the European recommendations on postapproval safety studies written down in “Volume 9A of the Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use” (Final version of 2008) and the 2008 Guidelines for Good Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology [19] were used for the definition of the study parameters. Declaration of interests We wish to draw the attention of the Editor to the following facts that may be considered as potential conflicts of interest and to significant financial contributions to this work. This study did not receive any specific grant from funding agencies in the public or not-for-profit sectors. It was sponsored by Harras Pharma Curarina Arzneimittel GmbH (München, Germany). The sponsor contributed to the definition of the general study parameters in the study plan and provided the medication but was otherwise not involved in the execution, evaluation, and publication of the clinical trial. These tasks were carried out under the responsibility of the principal investigator.

chen, Germany). The sponsor contributed to the definition of the general study parameters in the study plan and provided the medication but was otherwise not involved in the execution, evaluation, and publication of the clinical trial. These tasks were carried out under the responsibility of the principal investigator. Acknowledgements A.K. was the principal investigator of the study. M.B., S.H. and O.H. were treating physicians. M.H. was responsible for statistical evaluations. O.B. created the study plan and the study report. This study did not receive any specific grant from funding agencies in the public or not-for-profit sectors. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Inflammation of the pancreas (pancreatitis) occurs as a result of the spillage and autodigestion of the pancreatic parenchyma by the digestive enzymes. Acute pancreatitis (AP) is characterized by the presence of inflammatory cells and results in reversible structural and functional changes over a short duration. In contrast, chronic pancreatitis causes irreversible changes that ultimately result in fibrosis and loss of exocrine and/or endocrine function [1]. According to the International Study Group of Pediatric Pancreatitis: in Search for a Cure (INSPPIRE), two of three criteria must be fulfilled to diagnose AP in the pediatric population; namely, abdominal pain, serum amylase or lipase levels that are three times the upper normal limit and radiological findings diagnostic of AP [2,3]. AP is a rare disorder among individuals aged younger than 20 years, the number of pediatric AP cases recorded worldwide has increased dramatically over the past few years [4]. A 10-year American study estimated that the incidence of primary AP among children had increased from 6350 cases to 9561 cases between 2000 and 2009, representing a 51% increase [5]. A retrospective chart review conducted in the United States of America (USA) found that the incidence of first pediatric AP admission increased from 2.3 per 100,000 children in 1993 to 13.2 per 100,000 children in 2004 [6]. The authors concluded that the observed rise might reflect increased testing for AP among the pediatric population.

rt review conducted in the United States of America (USA) found that the incidence of first pediatric AP admission increased from 2.3 per 100,000 children in 1993 to 13.2 per 100,000 children in 2004 [6]. The authors concluded that the observed rise might reflect increased testing for AP among the pediatric population. To date, no national or regional studies have been conducted in Saudi Arabia to assess pediatric AP. Therefore, the aim of the current study was to describe the etiology, clinical characteristics of this disease among Saudi children and increase clinical awareness pediatric AP. 2 Methods A 20-year retrospective chart review study was conducted at King Abdullah Specialized Children Hospital and King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia. Institutional Review Board (IRB) was obtained from the King Abdullah International Medical Research Center (KAIMRC), National Guard Health Affairs, Riyadh, Saudi Arabia, with a reference number of RC16/110/R. Medical records were reviewed to identify all pediatric patients (age ≤19 years) who were diagnosed with primary AP between 1994 and 2015. Patients with missing data were excluded from the analysis. We defined age groups as the following; pre-schooler (0–5 years), schooler (6–11 years) and adolescent (12–19 years). Demographic, clinical and outcome data were evaluated to establish shared features among patients with primary AP in our population. Imaging techniques, including kidney–ureter–bladder (KUB) plain film, ultrasonography (US) and computed tomography (CT), were also evaluated.

Medical records were reviewed to identify all pediatric patients (age ≤19 years) who were diagnosed with primary AP between 1994 and 2015. Patients with missing data were excluded from the analysis. We defined age groups as the following; pre-schooler (0–5 years), schooler (6–11 years) and adolescent (12–19 years). Demographic, clinical and outcome data were evaluated to establish shared features among patients with primary AP in our population. Imaging techniques, including kidney–ureter–bladder (KUB) plain film, ultrasonography (US) and computed tomography (CT), were also evaluated. 3 Statistical analysis Statistical analysis was performed using JMP version 12 (SAS Institute, Cary, NC, USA). Continuous and categorical variables are given as the mean ± standard deviation (SD) and as the number and percentage, respectively. The Student's t-test was used to assess the differences in means. Differences in categorical variables were analyzed with the chi-squared test. Analysis of variance (ANOVA) was used to assess continuous variables. A test with P value of less than .05 was statistically significant. 4 Results A total of 50 patients (n = 26; 52% males vs. n = 24; 48% females) were included. The mean age at diagnosis was 11.6 years. Patients were diagnosed with primary AP during the present study at a rate of two to three cases per year. (Baseline demographics are presented in Table 1).Table 1 Baseline demographics.

4 Results A total of 50 patients (n = 26; 52% males vs. n = 24; 48% females) were included. The mean age at diagnosis was 11.6 years. Patients were diagnosed with primary AP during the present study at a rate of two to three cases per year. (Baseline demographics are presented in Table 1).Table 1 Baseline demographics. Table 1 Male Female Total Mean of Age, yr 11.8 11.4 11.6 Male/Female 26 (52) 24 (48) 50 (100) Nationality, n (%) Saudi 26 (52) 24 (48) 50 (100) Non-Saudi 0 0 0 Clinical Presentation, n (%) 1. Abdominal Pain 24 (92.3) 23 (95.8) 47 (94) 2. Vomiting 20 (76.9) 18 (75) 38 (76) 3. Nausea 5 (20.8) 5 (21.7) 10 (20) 4. Anorexia 2 (8.3) 3 (13) 5 (9.2) 5. Fever 4 (16.6) 0 4 (8) Blood Pressure, mean 115/66 113/68 114/68 Heart Rate, mean 106.3 106.3 106 Respiratory Rate, mean 26.8 21.3 24 O2 Saturation, mean 97.6 97.9 98 Temperature (C°), mean 36.9 36.9 37 Length of Admission, days 11.2 9.7 10.5 Recurrences, n (%) 6 (23) 3 (12.5) 9 (18) Idiopathic AP was the most frequent etiology (n = 21; 42%), followed by gallstones (n = 11; 22%) (Summary of etiologies is shown in Table 2). 2 (4%) had drug-induced AP, where one was taking isoniazid while the other had ingested a large amount of pain killers and antibiotics (erythromycin, amoxicillin and ibuprofen). 2 patients had choledochal cysts complicated by AP (n = 2; 4%). Congenital and non-congenital pancreaticobiliary diseases, as a complete entity, accounted for 34% (n = 17).Table 2 Summary of etiologies.

hile the other had ingested a large amount of pain killers and antibiotics (erythromycin, amoxicillin and ibuprofen). 2 patients had choledochal cysts complicated by AP (n = 2; 4%). Congenital and non-congenital pancreaticobiliary diseases, as a complete entity, accounted for 34% (n = 17).Table 2 Summary of etiologies. Table 2Etiology, n (%) Male Female 0-5 yr 6-12 yr 12-19 yr Total Idiopathic 10 (47.6) 11 (52.3) 2 (9.5) 6 (28.5) 13 (61.9) 21 (42) Gallstone 6 (54.5) 5 (45.5) 0 2 (18.1) 9 (81.9) 11 (22) Pancreatic Divisum 1 (33.3) 2 (66.6) 1 (33.3) 0 2 (66.6) 3 (6) DKAa 1 (50) 1 (50) 0 1 (50) 1 (50) 2 (4) Drug-Induced 1 (50) 1 (50) 0 1 (50) 1 (50) 2 (4) Familial Hyperlipidaemia 1 (50) 1 (50) 1 (50) 1 (50) 0 2 (4) Post ERCPb 2 (100) 0 0 0 2 (100) 2 (4) Choledochal Cyst 1 (50) 1 (50) 1 (50) 1 (50) 0 2 (4) Familial Hypertriglyceridemia 1 (100) 0 0 1 (100) 0 1 (2) Herbs 0 1 (100) 0 0 1 (100) 1 (2) CBDc sludge 0 1 (100) 0 0 1 (100) 1 (2) Trauma 1 (100) 0 1 (100) 0 0 1 (2) Viral Infection 1 (100) 0 0 0 1 (100) 1 (2) a DKA; Diabetic Ketoacidosis. b ERCP; Endoscopic Retrograde Cholangiopancreatography. c CBD; Common Bile Duct. The co-morbid conditions of patients with gallstone induce AP were: morbid obesity, i.e. BMI>40 (n = 2; 18%), chronic recurrent cholecystitis (n = 1; 9%), Haemophilia A (n = 1; 9%), Sickle Cell Anaemia (n = 1; 9%), Chronic Kidney Disease complicated by Disseminated Intravascular Coagulation (n = 1; 9%), Epilepsy Syndrome manged by Levetiracetam (n = 1; 9%). The rest of the patient with gasllstones (n = 4; 36%) were medically free.

nic recurrent cholecystitis (n = 1; 9%), Haemophilia A (n = 1; 9%), Sickle Cell Anaemia (n = 1; 9%), Chronic Kidney Disease complicated by Disseminated Intravascular Coagulation (n = 1; 9%), Epilepsy Syndrome manged by Levetiracetam (n = 1; 9%). The rest of the patient with gasllstones (n = 4; 36%) were medically free. Most of the patients (n = 47; 94%) had abdominal pain, with vomiting (n = 28; 76%) and nausea (n = 10; 20%). Amylase levels were high in 96% (n = 48) of the patients and normal in 2% (n = 1). The mean amylase level was 1168 U/L, the median was 861 U/L and the standard deviation was 1009 U/L. Lipase were less tested (n = 5; 10%). Lipase mean level was 538 U/L. All patients underwent KUB had non-significant findings (n = 21; 42%). 37% of US were non-yielding (n = 14). Enlarged and bulky pancreas was commonly detected (n = 11; 46%). CT was the superior imaging modality as it showed pancreatic changes suggestive of AP 84% (n = 16). 6 patients (12) had endoscopic retrograde cholangiopancreatography (ERCP). One patient (16.6%) underwent ERCP for removal of common bile duct (CBD) stone, while another was diagnosed with choledochal cyst involving the CBD. (See Radiographic Findings of Pediatric Acute Pancreatitis in Table 3).Table 3 Main radiographic findings of pediatric acute pancreatitis.a

holangiopancreatography (ERCP). One patient (16.6%) underwent ERCP for removal of common bile duct (CBD) stone, while another was diagnosed with choledochal cyst involving the CBD. (See Radiographic Findings of Pediatric Acute Pancreatitis in Table 3).Table 3 Main radiographic findings of pediatric acute pancreatitis.a Table 3Radiological findings, n (%) USb (# Pt = 38) CTc (# Pt = 19) Normal 14 (22.5) 3 (8.1) Enlarged, bulky pancreas 11 (17.7) 8 (21.6) Acute peripancreatic fluid collections 1 (1.6) 9 (24.3) Gallstone 9 (14.5) – Peritoneal fluid 6 (9.6) 3 (8.1) Dilated CBDd 4 (6.4) – Dilated intrahepatic duct 3 (4.8) – Dilated gallbladder 3 (4.8) – Necrotic pancreatitis – 2 (5.4) pseudocyst 1 (1.6) 2 (5.4) Dilated pancreatic duct – 2 (5.4) Choledochal cyst – 1 (2.7) Budd-Chiari Syndrome 1 (1.6) – Choledocholithiasis 1 (1.6) – a 2 patients had ERCP and 1 patient had MRCP. b US; Ultrasound. c CT; Computed Topography. d CBD; Common Bile Duct. The mean length of stay (LOS) was 10.5 days (2–62), median 6. The pre-schooler group had a mean LOS of 12 days, whereas the schooler and adolescent groups had a mean LOS of 15 and 8.1 days, respectively. Patients who were admitted to the pediatric Intensive Care Unit (PICU) had a mean LOS in the unit of 2.7 (1–7), median 2. The pre-schooler group had a mean LOS of 5.5 days, and the schooler and adolescent groups had a mean LOS of 2.75 and 2 days, respectively. Patients who presented with abdominal pain and fever had significantly longer PICU stay (P = .0007, P = .0211, respectively).

ICU) had a mean LOS in the unit of 2.7 (1–7), median 2. The pre-schooler group had a mean LOS of 5.5 days, and the schooler and adolescent groups had a mean LOS of 2.75 and 2 days, respectively. Patients who presented with abdominal pain and fever had significantly longer PICU stay (P = .0007, P = .0211, respectively). 18% (n = 9) experienced recurrence of AP. 8% (n = 4) had complications; 2 (33.3%) acute respiratory distress syndrome, 1 (16.6%) septic shock, 1 (16.6%) hypocalcemia, 1 (16.6%) pseudocyst and 1 (16.6%) pancreatic necrosis. No patients died due to AP. 5 Discussion The present study aimed to define a baseline for pediatric AP in Riyadh, Saudi Arabia, by describing the etiological factors, clinical presentation, relevant laboratory tests and imaging findings among all cases of primary disease identified at our institute. Pediatric AP was diagnosed at a rate of approximately two to three cases per year in the present study. The etiology of AP among children is variable. A US-based study published in 1999 found that 25% of pediatric AP cases are of unknown etiology, with 13%–33% of cases attributed to blunt trauma, making it the most common cause of pancreatitis among both adults and children [7]. However, a study published in 2013 claimed that pediatric AP due to trauma is less common than previously believed [8]. A long list of causes includes biliary tract disease, systemic diseases, autoimmune disorders, anatomic anomalies, drugs and genetic and hereditary diseases [8].

is among both adults and children [7]. However, a study published in 2013 claimed that pediatric AP due to trauma is less common than previously believed [8]. A long list of causes includes biliary tract disease, systemic diseases, autoimmune disorders, anatomic anomalies, drugs and genetic and hereditary diseases [8]. Geographic, racial, demographic and nutritional variations have recognizable effects on the course and etiology of pediatric AP [9]. One study found that congenital dilatation of the common bile duct was the most frequent cause of pediatric AP among Japanese, Chinese and other Asian children, whereas trauma was more common among Western children [10]. Most cases of AP identified in our present study were either idiopathic or had occurred because of gallstones. Unlike western findings, trauma (n = 1; 2%) was not the most commonly encountered etiology [7]. Suzuki et al. stated that biliary diseases, including gallstones, was much more common in eastern Asian Population [10]. Even though it is not the number one cause in our analysis, gallstones were associated with 22% of pediatric AP. However, our analysis showed that idiopathic AP and pancreaticobiliary disorders accounted for 42% and 34%, respectively. Though idiopathic causes were more common, pancreaticobiliary diseases contributed to a huge bulk of the AP cases. In terms of racial differences, Majbar et al. reported that United Kingdom children of Pakistani origin have a seven-fold increased risk of developing AP compared to white children [11]. This could have not been assessed by us, as all patients were Arabs/Saudis.

iary diseases contributed to a huge bulk of the AP cases. In terms of racial differences, Majbar et al. reported that United Kingdom children of Pakistani origin have a seven-fold increased risk of developing AP compared to white children [11]. This could have not been assessed by us, as all patients were Arabs/Saudis. The diagnosis of idiopathic AP is not quite reassuring, as some genetic and/or congenital anomalies could be the reason. Physicians should reasonably exhaust resources to exclude all possible causes of AP before labelling it as idiopathic. Our review does not show any genetic causes, despite the fact some patients had multiple recurrences. Childhood AP trend is increasing. This should alert healthcare providers, i.e pediatricians, to fully work-up patients before making such diagnosis. However, Ballinger et al. stated that 1 in 31 patients with first attack of idiopathic AP suffers from another one in median of 36 moths [12]. This suggests that looking for other underlying cause of AP after only the 1st attack is not cost-effective, as most of them will not have another. This is quite similar to our study where 9 out 50 had subsequent attacks. In conclusion, there is no clear guidelines to when to work up a patient for other underlying causes and when not. This study demonstrated this lack of clear pathway to assist in patients' diagnosis.

ective, as most of them will not have another. This is quite similar to our study where 9 out 50 had subsequent attacks. In conclusion, there is no clear guidelines to when to work up a patient for other underlying causes and when not. This study demonstrated this lack of clear pathway to assist in patients' diagnosis. Furthermore, we believe that it is highly unlikely that some of the common causes mentioned in the literature were missed, i.e. trauma, due to the fact that the study was conducted in a tertiary trauma center, where AP post motor vehicle accident or handle-bar injury was unlikely to be missed. In addition, some other form of trauma, such as child abuse, is hard to diagnose especially in our culture. On the other hand, one 5.5-year-old male presented with AP as result isoniazid (INH) ingestion. INH is relatively safe tuberculosis chemoprophylaxis and INH-induced AP is uncommon, however, there have been case reports of INH-induced AP around the world in both children and adults [[13], [14], [15]]. INH-induced hepatitis (21/100,000) is well recognized since the early 1970s, however, INH-induced AP is less common and not well described in the literature [15]. Badalov and colleagues had built a classification drug-induced AP [16]. Their system had 4 classes, in which isoniazid had been classified into Class I. They defined Class I as “include medications in which at least 1 case report described a recurrence of acute pancreatitis with a rechallenge with the drug”. To our knowledge, this is the first time INH-induced AP has been reported in Saudi Arabia.

stem had 4 classes, in which isoniazid had been classified into Class I. They defined Class I as “include medications in which at least 1 case report described a recurrence of acute pancreatitis with a rechallenge with the drug”. To our knowledge, this is the first time INH-induced AP has been reported in Saudi Arabia. Another case of drug-induced acute pancreatitis (DIAP) was shown in our analysis. A 17-year-old female who had ingested multiple medication, including erythromycin, amoxicillin and ibuprofen. These medications have been reported in the global literature as an etiology of AP [[17], [18], [19]]. There is an obvious shortage in the local literature of DIAP, where clinicians and researchers of our nation should aid in filling this gap.

sted multiple medication, including erythromycin, amoxicillin and ibuprofen. These medications have been reported in the global literature as an etiology of AP [[17], [18], [19]]. There is an obvious shortage in the local literature of DIAP, where clinicians and researchers of our nation should aid in filling this gap. The association between choledochal cysts and acute pancreatitis is well-established [20,21]. Acute pancreatitis tends to reoccur in the presence of any type of choledochal cysts. Saluja and colleagues had reported 6 cases of chronic pancreatitis in the presence of choledochal cysts. Interestingly, pancreatitis occurrence, weather acute or chronic, with choledochal cysts are less likely to be reported in the Middle East, North Africa, North America and/or Europe. Most of the reports of this pheromone has been described in eastern and central Asia, such as China, Japan and India [[20], [21], [22], [23]]. In Saudi Arabia, Crankson et al. reported a case of choledochal cyst in 10-month-old boy, however, the patient was surgically manged without developing pancreatitis [24]. Another case report form Saudi Arabia has been described by Al Saleem et al., however, pancreatitis occurrence was not described [25]. To our knowledge, this is the first time where choledochal cysts and acute pancreatitis have reported in Saudi Arabia.

atient was surgically manged without developing pancreatitis [24]. Another case report form Saudi Arabia has been described by Al Saleem et al., however, pancreatitis occurrence was not described [25]. To our knowledge, this is the first time where choledochal cysts and acute pancreatitis have reported in Saudi Arabia. Most patients included in the current analysis complained of abdominal pain at presentation, with or without vomiting/nausea. One of the INSPIRE criteria for AP diagnosis was almost always fulfilled by our patients, where abdominal pain was, by far, the most common symptom (n = 47; 96%). Pediatric AP has a better prognosis than AP diagnosed among adults [26]. Compared to pediatric patients without AP, US children with AP have longer LOS (median 4 days vs. 2 days), higher financial costs ($22,663 vs. $11,364) and a higher mortality rate (7.6 per 100,000 individuals vs. 2.7 per 100,000 individuals) [5]. Pediatric AP has decreased LOS, increased costs and decreased mortality rates. Our study shows AP LOS had a mean of 10.5 days and median of 6 days. A US-based study found that both AP patients with pseudocysts and those who were malnourished had longer LOS than other patients [27]. Furthermore, African American children had a greater need for pediatric intensive care unit (PICU) admission than white children (18% vs. 7%, respectively white) [27]. In the current series, there were statistically significant differences in patients who presented with abdominal pain and fever and length of PICU admission (P = .0007, P = .0211, respectively).

a greater need for pediatric intensive care unit (PICU) admission than white children (18% vs. 7%, respectively white) [27]. In the current series, there were statistically significant differences in patients who presented with abdominal pain and fever and length of PICU admission (P = .0007, P = .0211, respectively). No clear guideline or protocol is currently available for working-up a patient with suspicion of pediatric AP, nor when to admit. Ultrasonography detected abnormal findings in approximately 50% of the patients included in the present study, with an enlarged pancreas the most frequent finding. US findings were confirmed using CT. KUB was of no use in diagnosing children with AP. Summary of pediatric AP characteristics from different studies is shown in Table 4.Table 4 Pediatric acute pancreatitis characteristics from different studies [11,[28], [29], [30], [31], [32], [33], [34], [35], [36], [37]].

finding. US findings were confirmed using CT. KUB was of no use in diagnosing children with AP. Summary of pediatric AP characteristics from different studies is shown in Table 4.Table 4 Pediatric acute pancreatitis characteristics from different studies [11,[28], [29], [30], [31], [32], [33], [34], [35], [36], [37]]. Table 4Study Country Year # Cases #1 Etiology #1 Presentation Berny et al. [32] Switzerland 1996 21 Systemic (38%) Abdominal Pain (83%) Suzuki et al. [29] Japan 2008 135 Pancreaticobiliary Anomalies (54.5%) – Park et al. [33] USA 2009 271 Biliary (32.6%) Abdominal Pain (88%) Nydegger et al. [30] Australia 2007 279 Trauma (36.3%) – DeBanto et al. [28] USA 2002 301 Idiopathic (34%) – Werlin et al. [31] USA 2002 180 Systemic & Trauma (14% per each) Abdominal Pain (68%) Yeung et al. [34] Taiwan 1996 43 Trauma (37%) Abdominal Pain (95%) Lautz et al. [35] USA 2011 211 Idiopathic (31.3%) – Poddar et al. [36] India 2017 320 Idiopathic (52.5%) – Majbar et al. [11] UK 2016 94 Idiopathic (37%) – Minen et al. [37] Italy 2012 34 Medications (28%) –

& Trauma (14% per each) Abdominal Pain (68%) Yeung et al. [34] Taiwan 1996 43 Trauma (37%) Abdominal Pain (95%) Lautz et al. [35] USA 2011 211 Idiopathic (31.3%) – Poddar et al. [36] India 2017 320 Idiopathic (52.5%) – Majbar et al. [11] UK 2016 94 Idiopathic (37%) – Minen et al. [37] Italy 2012 34 Medications (28%) – The limitation is that it is a retrospective study in a one center, hence the small number of cases. We recommend multicenter study to fully assess the characteristics of AP in children. Another limitation is the lack of proper documentation in patients' charts, especially the older ones. This is most apparent in this study where viral cause of AP was not documented in the file. The main strength of the present study was it is the first report from our nation to shed the light on pediatric AP. Also, our paper report one of the rarest causes of AP, i.e., INH-induced AP and choledochal cysts, both locally and globally. 6 Conclusion Although still relatively uncommon in Saudi Arabia, approximately 2–3 cases of pediatric AP were diagnosed annually at our institution. Idiopathic AP and pancreaticobiliary disorders accounted for 42% and 34%, respectively. Isoniazid-induced AP and choledochal cysts are rare causes, even though, they were reported in the study. Conflicts of interest None. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction It is estimated that about 1% of newly born babies require resuscitation [1] and it was reported that approximately 16,000 American children (8–20 per 100,000 children each year) suffer a cardiac arrest each year [2]. A vital goal of training programs for pediatric residents is the acquisition of knowledge and skills to provide vital organ resuscitation and physiological stabilization to acutely ill or injured children. Residency training programs provide an environment for learning and the acquisition of practical experience in resuscitation. At present, four courses are offered nationally in Saudi Arabia to train health care providers in neonatal and pediatric resuscitation: pediatric basic life support (BLS), pediatric advanced life support (PALS), neonatal resuscitation program (NRP), and pediatric fundamental critical care support (PFCCS). These life support courses provide a platform for training healthcare providers, including residents, in how to identify critically ill patients and resuscitate them in a timely manner. However, certification in these life support courses does not necessarily reflect the readiness of a resident to conduct a cardiopulmonary resuscitation (CPR) code [3]. Assuming the role of a team leader is critical in resuscitation but this role is not standardized by an appropriate set of guidelines [4].

mely manner. However, certification in these life support courses does not necessarily reflect the readiness of a resident to conduct a cardiopulmonary resuscitation (CPR) code [3]. Assuming the role of a team leader is critical in resuscitation but this role is not standardized by an appropriate set of guidelines [4]. Leadership skills are important and they should be addressed during the pediatric residency training program [5]. Leadership is one of the seven roles in the CanMEDS physician competency framework [6,7]. The CanMEDS framework was adopted by the Saudi Commission for Health Specialties, including Saudi Pediatric Board training [8,9]. Effective leadership is important for managing critically ill patients and during resuscitation efforts [1,2,10,11]. Teams that function with an effective team leader adhere to protocols better, commit fewer medical errors, and perform the necessary medical procedures in time without delays, which might have favorable impacts on patient outcomes [12]. The current Saudi Pediatric Residency Training Program curriculum does not include specific educational courses in leadership skills despite their importance [9]. Therefore, this study aimed to identify the perceived level of confidence among participants in running a real pediatric CPR code as a team leader and as a team member, as well as identifying the different factors that might influence the self-confidence of residents when assuming the role of a team leader during a real pediatric CPR.

study aimed to identify the perceived level of confidence among participants in running a real pediatric CPR code as a team leader and as a team member, as well as identifying the different factors that might influence the self-confidence of residents when assuming the role of a team leader during a real pediatric CPR. 2 Materials and methods A cross-sectional questionnaire-based survey was conducted in February 2017. The target population comprised of Saudi Pediatric Residency program trainees in Saudi Arabia. The survey was distributed during the 5th Saudi Pediatric Association Conference. Attendees at this scientific conference were invited to complete the survey. The survey was also circulated by email via the Saudi Commission for Health Specialties e-mailing group for pediatric residents in order to improve the recruitment process and reach the entire target population, some of whom might not have been in the conference venue. An online, web-based, survey tool (www.surveymonkey.com) was used to collect the responses for analysis. Two reminders were sent within four weeks to those who did not respond initially. The questionnaire was drafted by the authors based on a review of previous studies regarding leadership skills in pediatric residents during CPR. The final version was prepared at a multidisciplinary team focus group meeting. Experts from our pediatric department reviewed the questionnaire. It was then piloted in our department and tested to ensure its clarity before sending it to the targeted group.

regarding leadership skills in pediatric residents during CPR. The final version was prepared at a multidisciplinary team focus group meeting. Experts from our pediatric department reviewed the questionnaire. It was then piloted in our department and tested to ensure its clarity before sending it to the targeted group. After receiving institutional review board approval, the survey was piloted within the authors' institution. Some questions that were not clear to the pilot participants were removed from the survey. The study aimed to investigate the perceived level of confidence among participants in running a real pediatric CPR code as a team leader and as a team member. The questionnaire was divided into the following three sections: The first section asked the responding resident to enroll in the study and provide their demographic details, including their level of training, training center, gender, and age. The second part asked questions about the life support courses that they attended previously and the date of the last PALS course attended. Furthermore, they were asked about the obstacles that prevented them from attending these courses.

The first section asked the responding resident to enroll in the study and provide their demographic details, including their level of training, training center, gender, and age. The second part asked questions about the life support courses that they attended previously and the date of the last PALS course attended. Furthermore, they were asked about the obstacles that prevented them from attending these courses. The last section asked whether the participants had any real pediatric CPR experiences during their residency, before rating their confidence level in acting as a pediatric CPR team leader or member during these recent codes. Ratings were given on a Likert-like scale ranging from 1 to 10, where 1 denoted “not confident” and 10 indicated “very confident.” Next, they completed questions regarding their understanding of the characteristics of an effective CPR team leader based on binary dichotomous multiple response characteristics, which allowed them to select more than one option. This study received prior ethical approval by the Institutional Review Board (IRB) of King Saud University (IRB #15/0520).

The last section asked whether the participants had any real pediatric CPR experiences during their residency, before rating their confidence level in acting as a pediatric CPR team leader or member during these recent codes. Ratings were given on a Likert-like scale ranging from 1 to 10, where 1 denoted “not confident” and 10 indicated “very confident.” Next, they completed questions regarding their understanding of the characteristics of an effective CPR team leader based on binary dichotomous multiple response characteristics, which allowed them to select more than one option. This study received prior ethical approval by the Institutional Review Board (IRB) of King Saud University (IRB #15/0520). 3 Statistical analysis Data were represented as means and standard deviations (SDs) for continuous variables, and frequencies and percentages for categorical and binary dichotomous variables. Multiple response dichotomy analysis was applied to the multiple response questions. The parametric t-test and one-way analysis of variance were used to compare demographics and PALS certification levels in order to determine statistically significant differences in the mean perceived self-rated confidence in leading a pediatric CPR while at work, where post-hoc test adjustments were employed as needed. Multivariate linear regression was employed to assess the combined and individual effects of the characteristics of residents (age, sex, PALS certification time, time since most recent real CPR attended, and the usual roles in real CPR events) on their self-reported confidence in leading a real pediatric CPR. SPSS IBM Version 21 was used for all analyses and the alpha significance level was set to 0.05.

cts of the characteristics of residents (age, sex, PALS certification time, time since most recent real CPR attended, and the usual roles in real CPR events) on their self-reported confidence in leading a real pediatric CPR. SPSS IBM Version 21 was used for all analyses and the alpha significance level was set to 0.05. 4 Results The survey was disseminated to 1052 residents, where it was received by 640; only 231 responded (response rate = 36%). Table 1 shows the demographic characteristics of the respondents. All of the respondents (231 [100%]) were BLS certified, 190 (82.3%) were NRP certified, 42 (18.2%) were PFCCS certified, and 49 (21.3%) were certified in other life support courses, such as advanced trauma life support, advanced cardiac life support, or pediatric advanced emergency assessment, recognition, and stabilization.Table 1 Characteristics of respondents.

certified, 190 (82.3%) were NRP certified, 42 (18.2%) were PFCCS certified, and 49 (21.3%) were certified in other life support courses, such as advanced trauma life support, advanced cardiac life support, or pediatric advanced emergency assessment, recognition, and stabilization.Table 1 Characteristics of respondents. Table 1Residents Characteristics (Number = 231) Characteristics Number and percentage Sex: Female 122 (52.8%) Male 109 (47.2%) Age: 21–30 years 200 (86.5) 31–40 years 29 (12.6) 41–50 years 2 (0.9) Training Level: R1 57 (24.7) R2 46 (19.9) R3 52 (22.5) R4 45 (19.5) Board eligible 22 (9.5) Fellow 9 (3.9) Latest PALS course attended: One month ago or less 15 (6.5) One month to one year ago 100 (43.3) Around two years ago 71 (30.7) Three years or more ago 16 (6.9) Never attended a PALS course 29 (12.6) Latest real CPR code attended: One month ago or less 63 (27.3) One month to one year ago 126 (54.5) Around Two years ago 13 (5.6) Three years or more ago 2 (0.9) Never attended a real pediatric CPR 27 (11.7) Role assumed in attended CPR code events: Team leader 24 (11.4) Team member 131 (62.1) Either team leader or team member 56 (26.5) Life support courses attended other than PALS: BLS 231 (100) NRP 190 (82.3) PFCCS 42 (18.2) Others 49 (21.2) R = residency training year; PALS = pediatric advanced life support; CPR = cardiopulmonary resuscitation; BLS = basic life support; NRP = neonatal resuscitation program; PFCCS = pediatric fundamental critical care support.

t courses attended other than PALS: BLS 231 (100) NRP 190 (82.3) PFCCS 42 (18.2) Others 49 (21.2) R = residency training year; PALS = pediatric advanced life support; CPR = cardiopulmonary resuscitation; BLS = basic life support; NRP = neonatal resuscitation program; PFCCS = pediatric fundamental critical care support. Among the respondents, 202 (87.45%) were PALS certified. Fifteen residents (6.5%) were PALS certified within or less than one month prior to the survey, 100 (43.3%) were PALS certified within one month to one year prior to the survey, 71 (30.7%) were PALS certified within 1–2 years prior to the survey, 16 (6.9%) were PALS certified more than 3 years prior to the survey, and 29 (12.6%) residents had not yet received their PALS certification at the time of survey. Furthermore, 63 residents (27.3%) had attended a real pediatric CPR code within one month before the survey, 126 (54.5%) reported that their most recent real pediatric CPR experience was month to one year before the survey, 13 (5.6%) reported attending a real pediatric CPR code 1–2 years prior to the survey, and only two (0.9%) residents reported attending a real pediatric CPR code more than 3 years prior to the survey. Interestingly, 27 (11.7%) of the residents reported no real pediatric CPR code experience.

o one year before the survey, 13 (5.6%) reported attending a real pediatric CPR code 1–2 years prior to the survey, and only two (0.9%) residents reported attending a real pediatric CPR code more than 3 years prior to the survey. Interestingly, 27 (11.7%) of the residents reported no real pediatric CPR code experience. Our analysis showed that 24 residents (10.4%) reported their roles within a real pediatric CPR code as team leaders, 131 residents (56.7%) indicated that their roles were as CPR team members, and 56 residents (27.2%) had assumed mixed roles in the CPR team (alternating between team leaders and team members). Table 2 shows the perceived obstacles that prevented the respondents from attending life support training courses. Lack of time to attend life support courses was the most frequently reported obstacle (182 [78.7%]), and the least frequently reported obstacle (15 (6.5%)) was the belief that it is only necessary to attend a course once. The other obstacles are shown in the table. The self-reported confidence in being a CPR team member was reported significantly more frequently than that in being a team leader (mean ± SD = 7.8 (2.1) versus 6.3 (2.4); P < .001). Moreover, the self-reported confidence in being a CPR team leader was reported significantly more frequently by male respondents than females (mean ± SD = 6.7 (2.4) versus 5.9 (2.4); P < .013).Table 2 Perceived obstacles to attending life support training courses reported by the respondents.

ersus 6.3 (2.4); P < .001). Moreover, the self-reported confidence in being a CPR team leader was reported significantly more frequently by male respondents than females (mean ± SD = 6.7 (2.4) versus 5.9 (2.4); P < .013).Table 2 Perceived obstacles to attending life support training courses reported by the respondents. Table 2Total number = 231 Obstacles Number and percentage (%) Lack of time 182 (78.8) Financial cost of the courses 90 (38.9) Courses are not available within the hospital 48 (20.8) These courses are intended for training critical care professionals only 25 (6.3) (10.8) I have taken the course once and there is no need to renew 15 (6.5) Other obstacles 37 (16.02)

d percentage (%) Lack of time 182 (78.8) Financial cost of the courses 90 (38.9) Courses are not available within the hospital 48 (20.8) These courses are intended for training critical care professionals only 25 (6.3) (10.8) I have taken the course once and there is no need to renew 15 (6.5) Other obstacles 37 (16.02) Fig. 1A shows that there was a significant positive correlation between the mean self-reported confidence in being a pediatric CPR team leader and the number of training years from residency training year 1 to fellow (P < .001). The junior trainees (R1 and R2) had a mean confidence level of 5.3 out of 10 and the senior trainees had a mean confidence level of 7.1 (P < .001). There were significant negative correlations between the mean self-reported confidence in being a pediatric CPR team leader and the time since the latest PALS course (Fig. 1B) and real pediatric CPR code attendance (Fig. 1C) (P < .05 and P < .001, respectively).Fig. 1 A. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR code events. B. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR code events. C. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR codes. Fig. 1

Fig. 1A shows that there was a significant positive correlation between the mean self-reported confidence in being a pediatric CPR team leader and the number of training years from residency training year 1 to fellow (P < .001). The junior trainees (R1 and R2) had a mean confidence level of 5.3 out of 10 and the senior trainees had a mean confidence level of 7.1 (P < .001). There were significant negative correlations between the mean self-reported confidence in being a pediatric CPR team leader and the time since the latest PALS course (Fig. 1B) and real pediatric CPR code attendance (Fig. 1C) (P < .05 and P < .001, respectively).Fig. 1 A. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR code events. B. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR code events. C. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR codes. Fig. 1 We also found that residents who frequently assumed a team leadership role during a real pediatric CPR code reported significantly higher perceived self-confidence compared with those who assumed a team member role, or alternated between team leader and team member roles (P < .05).

Fig. 1A shows that there was a significant positive correlation between the mean self-reported confidence in being a pediatric CPR team leader and the number of training years from residency training year 1 to fellow (P < .001). The junior trainees (R1 and R2) had a mean confidence level of 5.3 out of 10 and the senior trainees had a mean confidence level of 7.1 (P < .001). There were significant negative correlations between the mean self-reported confidence in being a pediatric CPR team leader and the time since the latest PALS course (Fig. 1B) and real pediatric CPR code attendance (Fig. 1C) (P < .05 and P < .001, respectively).Fig. 1 A. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR code events. B. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR code events. C. Correlations between self-reported confidence in being a CPR team leader and the level of training, life support course attendance, and attending CPR codes. Fig. 1 We also found that residents who frequently assumed a team leadership role during a real pediatric CPR code reported significantly higher perceived self-confidence compared with those who assumed a team member role, or alternated between team leader and team member roles (P < .05). 5 Discussion Life support courses are an integral part of general medical education, but particularly critical care education. Simulation-based courses are increasingly utilized in clinical practice training and education to improve knowledge and skills, and thus safety and outcomes for patients [13]. Moreover, if CPR is provided in an appropriate and timely manner, the likelihood of the victim surviving can be doubled or tripled [14].

cation. Simulation-based courses are increasingly utilized in clinical practice training and education to improve knowledge and skills, and thus safety and outcomes for patients [13]. Moreover, if CPR is provided in an appropriate and timely manner, the likelihood of the victim surviving can be doubled or tripled [14]. Intra-hospital pediatric cardiopulmonary arrests (CPAs) are infrequent events [3,6,[15], [16], [17], [18]] and they have potentially good outcomes if the patients are successfully resuscitated [19,20]. Given the rarity of these actual events, the skills required for the successful resuscitation of acutely ill or injured children must be taught to pediatric residents through a structured curriculum, which is designed to provide them with the required knowledge and skills to manage these events. The leadership skills of the medical team leaders who provide CPR are an important part of the effective management of patients [21]. In this study, we aimed to identify the possible factors that might affect the self-confidence of physicians from pediatric residency training programs as leaders in pediatric CPR code event.

The leadership skills of the medical team leaders who provide CPR are an important part of the effective management of patients [21]. In this study, we aimed to identify the possible factors that might affect the self-confidence of physicians from pediatric residency training programs as leaders in pediatric CPR code event. We found that residents who attended a real pediatric CPR code or PALS course before the survey had significantly higher self-reported confidence in acting as team leaders during pediatric CPR code events. Our results are comparable to those obtained in another study, which showed that attending a PALS course significantly increased the short-term knowledge of pediatric resuscitation among all professional groups who attended the course [22]. Another study reported a significant decline in the knowledge and skills acquired from life support training courses over time [23]. Assessing the impact of NRP certification or neonatal resuscitation course attendance on the perceived self-confidence of respondents in serving as a pediatric CPR code team leader was beyond the scope of this study. Furthermore, inadequate knowledge and skills retention following CPR training courses among nursing and medical staff has been documented over the past 20 years [24]. These variations in the loss of knowledge might be attributed to a lack of practice or infrequent application.

We found that residents who attended a real pediatric CPR code or PALS course before the survey had significantly higher self-reported confidence in acting as team leaders during pediatric CPR code events. Our results are comparable to those obtained in another study, which showed that attending a PALS course significantly increased the short-term knowledge of pediatric resuscitation among all professional groups who attended the course [22]. Another study reported a significant decline in the knowledge and skills acquired from life support training courses over time [23]. Assessing the impact of NRP certification or neonatal resuscitation course attendance on the perceived self-confidence of respondents in serving as a pediatric CPR code team leader was beyond the scope of this study. Furthermore, inadequate knowledge and skills retention following CPR training courses among nursing and medical staff has been documented over the past 20 years [24]. These variations in the loss of knowledge might be attributed to a lack of practice or infrequent application. We found that the self-reported confidence in serving as a pediatric CPR code team leader was positively correlated with the number of training years, which might be explained by the acquisition of greater knowledge, more clinical practice and exposure, and the possibility of being involved in more real CPA situations. A previous study showed that out-of-hospital emergency physicians retained more advanced life support knowledge and skills compared with non-emergency course participants [25]. Almost 20% of our respondents had not yet renewed their PALS certificates or never attended PALS training. These findings might be attributed to the pre-enrollment requirements and continuation of residency training program within this country, and it may be necessary to improve the quality of the training program, and thus the knowledge and skills of physicians in order to ensure patient safety and obtain better outcomes in cardiac arrest situations. Moreover, incorporating life support education and training into the training program curriculum might ensure that up to date knowledge and skills are provided to trainees during their residency training.

and skills of physicians in order to ensure patient safety and obtain better outcomes in cardiac arrest situations. Moreover, incorporating life support education and training into the training program curriculum might ensure that up to date knowledge and skills are provided to trainees during their residency training. The self-reported confidence in being a pediatric CPR code team leader determined in the current study among those who were recently involved in a real code might reflect the importance of clinical practice for enhancing confidence, and experience in managing these situations might play an important role in improving outcomes. The rarity of in-hospital pediatric CPR events can potentially be addressed by running regular pediatric CPR mock codes, and actively involving residents in these codes and assigning them as team leaders in order to evaluate their performance, thereby providing them with the necessary knowledge, skills, and guidance to act appropriately as a team member or leader. It has been reported that implementing mock codes increased the survival rate to almost 50% [26]. Similarly, other innovative methods are being devised to ensure that residents are well prepared for resuscitation events [3].

the necessary knowledge, skills, and guidance to act appropriately as a team member or leader. It has been reported that implementing mock codes increased the survival rate to almost 50% [26]. Similarly, other innovative methods are being devised to ensure that residents are well prepared for resuscitation events [3]. Several factors were identified that might have determined why a limited number of residents reported self-confidence in being a CPR code team leader. These factors include the infrequent pediatric CPR codes that residents encounter in real practice and the lack of structured material for life support courses in the current training curriculum, especially BLS, PALS, PFCCS, and NRP. These barriers can be overcome by incorporating life support courses in the training curriculum, providing education in leadership skills, and regularly conducting pediatric CPR mock codes in order to ensure that knowledge is retained and updated among trainees at different levels. Other barriers mentioned by the participants included a lack of time, financial costs, and the perception that these courses are more beneficial for critical care physicians. These barriers might be addressed by institutional or national regulations to support trainees with free registration and participation in courses, as well as increasing awareness of the importance and impact of completing these courses for the outcomes of CPR code events.

more beneficial for critical care physicians. These barriers might be addressed by institutional or national regulations to support trainees with free registration and participation in courses, as well as increasing awareness of the importance and impact of completing these courses for the outcomes of CPR code events. Finally, leadership workshops would be very helpful for improving and developing leadership skills among residents [27]. It is necessary to invest more in the competency of trainees because this would improve the performance of teams and provide better outcomes for patients. We recommend that attending life support courses such as PALS, NRP, and PFCSS should be a mandatory requirement for the promotion of residents, and these courses should be incorporated in the training curriculum. Residents should be licensed after receiving these certificates because this would increase their level of self-confidence as team leaders during pediatric CPR. 6 Conclusion The self-reported confidence as a team leader during pediatric CPR was higher in residents who had been certified in life support courses, those who were exposed to real pediatric CPR during their training, and those who had assumed the role of a team leader during CPR. We suggest incorporating life support courses and simulation-based mock code programs with an emphasis on leadership in the pediatric residency training program curriculum.

upport courses, those who were exposed to real pediatric CPR during their training, and those who had assumed the role of a team leader during CPR. We suggest incorporating life support courses and simulation-based mock code programs with an emphasis on leadership in the pediatric residency training program curriculum. 7 Strengths and limitations One of the strengths of our study is that it involved trainees from different centers throughout Saudi Arabia who had different levels of training, and this is the first study to investigate this issue in Saudi Arabia. However, this study had some limitations. One of the main limitations of our study is that we only reported the self-confidence of pediatric CPR team leaders but without actually testing its impact on CPR outcomes. However, we consider that perceived self-confidence is an important factor that influences the performance of any skill. Funding This project was supported by the College of Medicine Research Centre, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank the Deanship of Scientific Research for funding and supporting this research through Research Project No R 17-02-45. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

estricted diet such as physical status, neuropsychological conditions and even social. In addition, the measurement of psychosocial development was excluded from the variance in the current study, as it could not be applied on patients because of unavailability of additional funding that was required for the parameter. 4.4 Is the long term dietary restriction affecting the quality of life? The paradox of dietary managing amino acid metabolic disorders from our experience, that long term diet restriction is affecting the family as it becomes a way of living. This could easily keep the patient and his family in isolation. This will significantly reduce the quality of life as it been reported especially in adulthood period [43]. Moreover, 84 (85.7%) of the participants expressed that they had better dietary adherence post introducing the medical foods. However, almost half of the enrolled subjects (53%) reported positive improvement in the social life post introducing the medical foods. Therefore, steps towards improving the dietary adherence are counted as factors to improve the quality of life [44].

1 Introduction Disorders of protein and amino acid metabolism: Phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), Tyrosinemia (TYR), Homocystinuria (HCU) and Organic Acidemias (OA) are a class of inherited metabolic conditions that occur when certain amino acids either cannot be broken down or produced by the body, resulting in toxic accumulation of some substances and/or the deficiency of others. While Urea Cycle Disorder (UCD) defined as a genetic disorder caused by urea cycle enzymes deficiencies that result in waste nitrogen accumulating as ammonia and glutamine which are neurotoxin. These disorders are managed by life-long diet restriction. The aims of nutrition therapy in these disorders are: (a) reducing the production of toxic substances by restricting the offended nutrient in the patient's diet, (b) providing adequate calories, protein, vitamins and minerals which are necessary for optimal growth and development. To achieve this, amino acid metabolism disorders diet consists of:(a) synthetic amino-acid based formula,(b) calculated and measured amount of natural protein source, (c) carbohydrates and/or fat polymers are added to diet to build up calories and prevent catabolism, (d) specific calculated amino acid supplement as needed, (e) specially designed low protein foods/products. An individual approach combining all of the above will help in achieving expected outcomes. Specially designed low protein foods are products (i.e. low-protein pasta, rice, flour and bread) formulated to have ≤1 g protein per serving which are expected to provide 50–75% of estimated daily energy needs in patients with amino acid metabolism disorders [1]. For this reason patients are likely to need a large quantity and variety of products on an ongoing basis. They are substantially more expensive than regular food [2,3], and not readily available to purchase.

expected to provide 50–75% of estimated daily energy needs in patients with amino acid metabolism disorders [1]. For this reason patients are likely to need a large quantity and variety of products on an ongoing basis. They are substantially more expensive than regular food [2,3], and not readily available to purchase. For patients with inherited metabolic disorder (IMD) the capacity to adhere to dietary restriction and overall management depends on both the patients and their caregivers [4]. Not adhering to the dietary restriction usually starts at school age (5–6 year old), leading to very poor compliance as children grow older (10–15 year old) [3,[5], [6], [7], [8]]. Reasons may be due to lack of dietary variation, cost and unavailability of specially designed low protein products/medical foods [9]. Additionally, feeding difficulties were common in children with IMD as reported in the literature [10,11]. It is also a dynamic process, with many patients varying in their levels of acceptance and willingness to adapt to such a strict diet or be selective in the adherence [4,12]. In addition to diet restriction, patients and caregivers usually complain about the frequent laboratory tests. It is also common that adult patients would improve their compliance just before lab test to ensure better results [3,8]. Furthermore, some of the amino acid metabolism disorders pose no risks of acute crisis e.g. PKU, HCU and TYR. While other disorders such as UCD, MSUD and OA could lead to frequent hospital admissions due to metabolic crisis secondary to poor dietary adherence [13]. Frequent admissions subsequently will negatively affect dietary adherence. As stated in the WHO report of adherence to long term therapies, compliance defined as (the extent to which a person's behavior – taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider) [12,14,15]. Therefore, no clear measurement of compliance has been defined [4]. The degree of dietary control required in these cases remains a controversial topic. However, from our practice, it is impossible to state that dietary liberalization is completely safe, equally it is futile to continue a strict dietary approach if our patients are refusing such a regimen.

pliance has been defined [4]. The degree of dietary control required in these cases remains a controversial topic. However, from our practice, it is impossible to state that dietary liberalization is completely safe, equally it is futile to continue a strict dietary approach if our patients are refusing such a regimen. Worldwide, a lot of research is done in regards to diet in the treatment of PKU which is the most common amino acid metabolism disorder in USA and UK. Most of these state a significant beneficial effect of phenylalanine restricted diet on intellectual achievement, neurologic status and behavioral improvement [8,[16], [17], [18], [19]]. However it could have a negative effect on physical growth [20,21] and an enhanced quality of life for both the patients and their caregivers in early and even late diagnosed patients [22]. Moreover, health related quality of life was reported to be compromised in IMD patients, which leads to increased demands of emotional and psychosocial support [23]. Most of the studies involved PKU patients with few papers published on other protein and amino acids metabolism disorders.

n late diagnosed patients [22]. Moreover, health related quality of life was reported to be compromised in IMD patients, which leads to increased demands of emotional and psychosocial support [23]. Most of the studies involved PKU patients with few papers published on other protein and amino acids metabolism disorders. Growth parameter for these patients is usually compromised due to dietary restriction [24,25]. Lack of international publications related to growth and development of such patients impedes the comparison process. Vitamins and minerals deficiencies were reported in those groups of patients which can rapidly impair growth [7,26]. That could be due to the insufficient adherence to the synthetic amino-acid based formula provided or as consequences of the multiple dietary modifications that may place the patients at risk of macro and micronutrient deficiency [27,28]. Zinc, selenium, vitamin B12 and other deficiencies were reported long time ago mainly in PKU patients and other IMD [17,20,[29], [30], [31], [32], [33], [34], [35], [36]]. Saudi Arabia is one of the pioneers in treating patients affected with IMD around the world due to the high prevalence of these diseases (almost 4 times higher incidence than in USA) as per the Saudi national lab newborn screening program database [37,38]. This is related to our society's high rate of consanguinity and inter-caste marriages.

the pioneers in treating patients affected with IMD around the world due to the high prevalence of these diseases (almost 4 times higher incidence than in USA) as per the Saudi national lab newborn screening program database [37,38]. This is related to our society's high rate of consanguinity and inter-caste marriages. Dietary management is crucial for these patients through well trained metabolic dietitians which are unfortunately scarce in the rural areas of Saudi Arabia. Thus, such cases are referred to KFSH&RC-Riyadh from all over the Middle East, adding to the importance of this study.

the pioneers in treating patients affected with IMD around the world due to the high prevalence of these diseases (almost 4 times higher incidence than in USA) as per the Saudi national lab newborn screening program database [37,38]. This is related to our society's high rate of consanguinity and inter-caste marriages. Dietary management is crucial for these patients through well trained metabolic dietitians which are unfortunately scarce in the rural areas of Saudi Arabia. Thus, such cases are referred to KFSH&RC-Riyadh from all over the Middle East, adding to the importance of this study. 2 Method 2.1 Study design This is a non-randomized, retrospective/prospective study. Data before medical foods usage was retrospectively collected while post usage was prospectively gathered. Data were collected over around 2.6 year period, using (COMPLE) Microsoft access which was designed by the metabolic nutrition clinic at KFSH&RC-Riyadh. A written questionnaire was developed for this study. It was written in Arabic and also available in English, translated from Arabic to English by a professional translator. Questionnaire was validated through 3 well-educated mothers with affected patient/s, 4 clinical dietitians and 2 medical genetic physicians. It was developed covering socio-demographic data and technical challenges, and addressing the following topics: (a) compliance to dietary management and biochemical work-up from the view of patients and caregivers, (b) difficulties in choosing the appropriate food while following the restricted diet, (c) social life and academic performance, and (d) palatability and preparation of medical foods.

addressing the following topics: (a) compliance to dietary management and biochemical work-up from the view of patients and caregivers, (b) difficulties in choosing the appropriate food while following the restricted diet, (c) social life and academic performance, and (d) palatability and preparation of medical foods. The study was conducted in accordance with the ethical principles contained in the Declaration of Helsinki (2000), the ICH Harmonized Tripartite Good Clinical Practice Guidelines, the policies and guidelines of the Research Advisory Council of KFSH&RC, and the laws of Saudi Arabia. A verbal informed consent was taken from the patients caregivers. 2.2 Participants Inclusion criteria included (a) patients 2 years old and above, (b) affected with one of the selected amino acid metabolism disorders, (c) following up in the metabolic nutrition clinics at KFSH&RC-Riyadh, SA. Exclusion criteria comprised of (a) patients below 2 years old, (b) inability to obtain verbal consent, (c) total incompliance to the synthetic amino-acid based formula or restricted protein diet, and (d) patients with mild form of the disease (known mutation biochemically and phonetically) as per charted diagnosis. However, patients below 2 years old were included at the beginning of this study, and due to limitation of using medical foods during the weaning months, they were excluded.

restricted protein diet, and (d) patients with mild form of the disease (known mutation biochemically and phonetically) as per charted diagnosis. However, patients below 2 years old were included at the beginning of this study, and due to limitation of using medical foods during the weaning months, they were excluded. In a median period of 1 year and 7 months, we approached 182 patients who met the inclusion criteria, all of which were affected with one of the selected amino acid metabolism disorders: PKU, TYR I & II, MSUD and HCU (Table 1). Biochemical data and growth parameters were taken as part of their routine metabolic-nutrition clinic visit. In addition, they were provided with a questionnaire with the patients and their caregivers prior to initiating the medical foods and after approximately 6 months. Post enrollment, 84 patients were withdrawn (Table 2) and the majority of them 69% (n = 58) were due to total incompliance or very poor compliance to synthetic mino-acid based formula and/or restricted protein diet or medical foods intake.Table 1 Characteristic of subjects completed the study.

r approximately 6 months. Post enrollment, 84 patients were withdrawn (Table 2) and the majority of them 69% (n = 58) were due to total incompliance or very poor compliance to synthetic mino-acid based formula and/or restricted protein diet or medical foods intake.Table 1 Characteristic of subjects completed the study. Table 1 All n = 98 Pre low protein products usage Post low protein products usage P value Gender, n (%) Male 44 (44.9) Female 54 (55.1) Age at start low protein products, years, Median (range) 8.7 (2.1–31) Usage length of low protein products, years, Median (range) 1.8 (0.7–2.6) Weight kg, Mean (STD) 34.2 (20.9) 38.3 (22) <.0001 Height cm, Mean (STD) 127.1 (25.7) 133.3 (22.4) <.0001 BMI kg/m2, Mean (STD) 19.1 (5.3) 19.7 (6.0) .0066 Diagnosis, n (%) PKU 44 (44.9) TYR 17 (17.35) MSUD 30 (30.61) HCU 7 (7.14) Table 2 List of causes for the excluded subjects from the selected amino acid metabolism disorders (PKU, TYR, HCU & MSUD) n = 84. Table 2Cause for exclusion Number of subjects Total incompliance, very poor compliance to medical formula or restricted protein diet/products 58 Below 2 years old 8 Poor oral intake or tube feeding (NGT/GT) dependent 7 Deceased 2 Did liver transplant 1 Inactive file 7 Stable patients/with mild form of the disease 1

Table 1 All n = 98 Pre low protein products usage Post low protein products usage P value Gender, n (%) Male 44 (44.9) Female 54 (55.1) Age at start low protein products, years, Median (range) 8.7 (2.1–31) Usage length of low protein products, years, Median (range) 1.8 (0.7–2.6) Weight kg, Mean (STD) 34.2 (20.9) 38.3 (22) <.0001 Height cm, Mean (STD) 127.1 (25.7) 133.3 (22.4) <.0001 BMI kg/m2, Mean (STD) 19.1 (5.3) 19.7 (6.0) .0066 Diagnosis, n (%) PKU 44 (44.9) TYR 17 (17.35) MSUD 30 (30.61) HCU 7 (7.14) Table 2 List of causes for the excluded subjects from the selected amino acid metabolism disorders (PKU, TYR, HCU & MSUD) n = 84. Table 2Cause for exclusion Number of subjects Total incompliance, very poor compliance to medical formula or restricted protein diet/products 58 Below 2 years old 8 Poor oral intake or tube feeding (NGT/GT) dependent 7 Deceased 2 Did liver transplant 1 Inactive file 7 Stable patients/with mild form of the disease 1 2.3 Anthropometric/demographic data Demographic data were obtained from patient's medical and metabolic dietetic records, including gender, age at start of medical foods, length of usage, weight & height pre and post usage (Table 1). Body mass index was calculated for the given data pre and post medical foods usage, using the equation BMI = weight (kg) ÷ height (m2). Furthermore, BMI was compared with healthy peers and with general population standards using LMS growth excel add-in in order to obtain the international cut-offs that classify BMI in children age 2–18 years old depending on the child's age and gender and it was expressed as percentage (Fig. 1A and B) [39]. Growth parameters were plotted against National Center for Health Statistics reference data growth charts for all ≤ 18 year old patients and translated into Z-score correspond to the exact percentiles using LMS growth excel add-in Fig. 2 & Fig. 3(A and B,C&D) [40]. However, 13 patients classified as per WHO adult cut-offs due to their age, they were above 18 year old [41]. Total of (n = 37) boys and (n = 48) girls patients were analyzed at the baseline (pre medical foods usage) and at the end of the study (post medical foods usage) (Table 3).Fig. 1 A and B. Percentage of children whose BMI for age Z-score is below or equal −2 (thinness) between −1 and +1 (normal), and above or equal 2 (obesity) 1C. Percentage of obesity=(2), overweight=(1), nor,al-(0) and thinness grade 1=(-1), 2=(-2) & 3=(-3) for children age 2–18 years based on the BMI international cut-offs.

1 A and B. Percentage of children whose BMI for age Z-score is below or equal −2 (thinness) between −1 and +1 (normal), and above or equal 2 (obesity) 1C. Percentage of obesity=(2), overweight=(1), nor,al-(0) and thinness grade 1=(-1), 2=(-2) & 3=(-3) for children age 2–18 years based on the BMI international cut-offs. Fig. 1Fig. 2 A–D Z-scores for height and weight for female patients, age 2–18 years, pre and post medical foods usage. Fig. 2Fig. 3 A–D. Z-scores for height and weight for male patients, age 2–18 years, pre and post medical foods usage. Fig. 3Table 3 NCHS z-scores for height and weight at the start and the end of the study for the analyzed boy's and girl's data. Table 3 Weight for age Height for age Baseline (pre low protein usage) End of study (post low protein usage) Baseline (pre low protein usage) End of study (post low protein usage) z-scores for Boys (n = 37), Mean (SD) 0.003 (1.84) 0.66 (2.236) −0.675 (1.618) 0.393 (2.076) P < .0001 P < .0001 z-scores for Girls (n = 48), Mean (SD) −0.873 (1.956) 0.257 (1.904) −1.317 (1.775) 0.315 (2.069) P < .0001 P < .0001

low protein usage) Baseline (pre low protein usage) End of study (post low protein usage) z-scores for Boys (n = 37), Mean (SD) 0.003 (1.84) 0.66 (2.236) −0.675 (1.618) 0.393 (2.076) P < .0001 P < .0001 z-scores for Girls (n = 48), Mean (SD) −0.873 (1.956) 0.257 (1.904) −1.317 (1.775) 0.315 (2.069) P < .0001 P < .0001 2.4 Procedure The first enrollment visit at the metabolic nutrition clinic at KFSHRC, Riyadh included: (a) thorough explanation of the importance of medical foods usage, value and effects, (b) completion of the pre-study questionnaire (consisting of multiple choices) by caregivers with the assistance of the metabolic dietitian present at that time, (c) comprehensive disease specific labs drawn as per the clinic routine follow up policy that included the following: Iron, Ferritin, CBC, Zinc, Selenium, Vitamin B12, Pre-albumin, Quantitative Amino Acid, TMS, Homocysteine level and others as needed(vitamin D levels were checked but not considered in the current study), (d) provision of low protein recipes booklet (developed by the metabolic dietitians at KFSR&RC-Riyadh) which contains amino acid analysis of each recipe, (e) free of charge issuance of the medical foods items (low protein flour, macaroni, spaghetti, rice, egg replacer, cake mix with two flavors, crackers and wafer, plus one item specifically for infant which is baby cereal,. (f) ensuring verbalized understanding of the given instructions, and follow up appointment after 3–6 months in the metabolic nutrition clinic as needed. Maximum of 4 clinic visits summary were collected and compared. In the period between the first and second clinic visits, adjustments of the synthetic amino-acid based formula were done as necessary according to the lab results or depending on clinical judgment. Additionally, medical genetic physician/s was contacted for a medication prescription to correct any nutritional deficiencies. Abnormal labs were repeated 3 months post the intervention or as required. Median results of TMS samples were ensured to be considered when the patient is stable (not sick) under similar circumstances, usually instructed to be drawn 3–4 h post feed, no fasting is recommended. The post-study questionnaire was completed almost at the third or the fourth clinic visit.

ntervention or as required. Median results of TMS samples were ensured to be considered when the patient is stable (not sick) under similar circumstances, usually instructed to be drawn 3–4 h post feed, no fasting is recommended. The post-study questionnaire was completed almost at the third or the fourth clinic visit. 2.5 Statistical analysis All the statistical analysis of data was done using the software package SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Descriptive statistics for the continuous variables were reported as mean ± standard deviation or (range) and categorical variables are summarized as frequencies and percentages. All the continuous variables as appropriate for comparisons between subgroups of pre and post medical foods usage were compared by Student's paired t-test. The level of statistical significance is set at P < .05. 3 Results 3.1 Subjects Ninety eight patients (44 male and 54 female; median age 8.7 years [range from 2.1 to 31 years]) completed the study (Table 1). Their amino acid metabolism disorders were PKU (n = 44), TYR (n = 17), MSUD (n = 30) and HCU (n = 7) (Table 1). Dietary restrictions consisted mainly of synthetic amino-acid based formula, protein modified metabolic diet and medical foods which was issued to each patient at the first enrollment visit. The usage length period ranged from (0.7 year up to 2.6 years) with a median of 1.7 year. As per family responses, 29 (29.6%) patients had good tolerance to the taste of the medical foods, while 63 (64.3%) fairly tolerated one to two items, and 6 (6.1%) disliked them.

sued to each patient at the first enrollment visit. The usage length period ranged from (0.7 year up to 2.6 years) with a median of 1.7 year. As per family responses, 29 (29.6%) patients had good tolerance to the taste of the medical foods, while 63 (64.3%) fairly tolerated one to two items, and 6 (6.1%) disliked them. 3.2 Biochemical status At the study period, there were significant improvement in Iron, Hemoglobin, zinc, Vitamin B12, TMS Phenylalanine and TMS Leucine &Isoleucine from the baseline pre using the medical foods to post usage checkup (Table 4). In PKU patients; the TMS Phenylalanine level post usage significantly decreased (P value < .0001). This was also the case in MSUD patients with significant decrease in Leucine &Isoleucine levels (P value = .0008) but not in Valine levels (P value = .1148) as 11 (36.7%) of them received Valine supplements while enrolled in the study. Additionally, all other biochemical markers had no significant differences as shown in the given table. However, there was a decrease in the percentage of selenium and pre-albumin below the reference range from the baseline to the end of the study (Fig. 4).Table 4 Percentage of subjects with blood measurements less than and above the plasma reference ranges and a comparison of blood marker levels at the start and the end of the study.

was a decrease in the percentage of selenium and pre-albumin below the reference range from the baseline to the end of the study (Fig. 4).Table 4 Percentage of subjects with blood measurements less than and above the plasma reference ranges and a comparison of blood marker levels at the start and the end of the study. Table 4Blood Marker (reference range) Baseline % blood levels (number) < reference range End of study % blood levels (number) < reference range Baseline (pre low protein usage) mean (range) End of study (post low protein usage) mean (range) P value comparing mean blood levels Iron, umol/L (6–7) 11.46 (11) 4.08 (2) 13.6 (3.5–38.1) 18.9 (5.7–170) .0493 Hemoglobin, g/L (110–150) 5.15 (5) 4.29 (3) 129.2 (84–165) 132 (100–164) .0006 Zinc, umol/L (10.6–19) 37.76 (37) 23.68 (18) 11.2 (7.6–19.6) 11.9 (6.5–29.8) .0065 Selenium, umol/L (0.89–1.52) 3.61 (3) 2.38 (1) 1.3 (0.7–1.9) 1.3 (0.7–1.7) .0744 Pre-albumin, mg/L (200–400) 48.98 (48) 48.95 (35) 212.2 (37–441) 208 (121–369) .1229 Vitamin B12, Pmol/L (145–637) 4.76 (4) 6.52 (3) 751.3 (77–1476) 792.3 (57–1476) .0349 Baseline % blood levels (number) > reference range End of study % blood levels (number) > reference range TMS- Phenylalanine, uM (10–180) 93.18 (41) 4.55 (2) 873.2 (11–2719) 487.5 (91–1134) <.0001 TMS- Leucine (+Isoleucine), uM (<245) 86.67 (26) 86.67 (26) 655.6 (67–1499) 472.5 (68–987) .0008 TMS- Valine, uM (10–290) 13.33 (4) 0 193.3 (32–415) 166.6 (67–281) .1148 TMS- Tyrosine, uM (16–200) 94.12 (16) 100 (17) 686.3 (107–1463) 606.1 (294–947) .2874 Amino acid-Methionine, umol/L (0–50) 80 (4) 100 (7) 248.6(35–616) 259.9 (51–511) .4920 Homocystinuria, umol/L (5–15) 100 (7) 100 (7) 149 (61–206) 135 (49–204) .6442 Fig. 4 Comparison of amino acids measure * levels at the start and the end of the study.

16–200) 94.12 (16) 100 (17) 686.3 (107–1463) 606.1 (294–947) .2874 Amino acid-Methionine, umol/L (0–50) 80 (4) 100 (7) 248.6(35–616) 259.9 (51–511) .4920 Homocystinuria, umol/L (5–15) 100 (7) 100 (7) 149 (61–206) 135 (49–204) .6442 Fig. 4 Comparison of amino acids measure * levels at the start and the end of the study. *TMS was used for (Tyrosine, Valine, Leucine & Isoleucine and Phenylalanine) Methionine was measured using quantitative amino acid measure, plus homocysteine level. Fig. 4

16–200) 94.12 (16) 100 (17) 686.3 (107–1463) 606.1 (294–947) .2874 Amino acid-Methionine, umol/L (0–50) 80 (4) 100 (7) 248.6(35–616) 259.9 (51–511) .4920 Homocystinuria, umol/L (5–15) 100 (7) 100 (7) 149 (61–206) 135 (49–204) .6442 Fig. 4 Comparison of amino acids measure * levels at the start and the end of the study. *TMS was used for (Tyrosine, Valine, Leucine & Isoleucine and Phenylalanine) Methionine was measured using quantitative amino acid measure, plus homocysteine level. Fig. 4 3.3 Anthropometry and growth velocity There were significant changes in weight and height between the baseline and the end of the study for all the enrolled subjects (Table 1). Additionally, the reported Z-scores for the analyzed (n = 48) girls and (n-37) boys, aged ≥ 2 years old to ≤ 18 years old were significantly different for weight and height pre and post the usage of medical foods (Table 3). Fig. 1 (A,B&C), Fig. 2 (A,B,C&D) and Fig. 3 (A,B,C&D) shows the growth indicators for all patients (male and female) pre and post the medical foods usage expressed as Z-scores according to the WHO definition. Sixteen percent of the male children were stunted and it was decreased to 13% at the end of the study. While in female children 31% were stunted and it was decreased to 12%. Additionally, 22% of the male children were underweight and it was decreased to 14% at the end of the study. While 29% of the female children were underweight and it was decreased to 14%. In the BMI reported for age (Fig. 1A&B), the percentage of obesity and over wt based on the international cut-offs to classify BMI in children age 2–18 years were increased by (7%) at the end of the study period. Moreover, with further analysis, 14 patients (16.5%) who reported to be obese or overweight at the end of the study period, were overweight or normal respectively previous the medical foods usage. Additionally, 12 patients (14%) continued to be overweight or obese through the study period. However, 10 patients (11.8%) who had normal BMI and became underweight at the end of the study period.

bese or overweight at the end of the study period, were overweight or normal respectively previous the medical foods usage. Additionally, 12 patients (14%) continued to be overweight or obese through the study period. However, 10 patients (11.8%) who had normal BMI and became underweight at the end of the study period. 3.4 Questionnaire All the 98 subjects filled the provided questionnaire; first section was pre initiating the medical foods and second section post usage. In the view of patients' and caregivers' opinion; 31 patients (31.6%) had an excellent compliance to the restricted diet regimen, 58 (59.2%) had good compliance and 9 (9.2%) were poorly compliant. In addition, 74 of the patients (75.5%) tolerated most of the medical foods items daily. Additionally, 71 (72.5%) were routinely doing the biochemical work-up. Interestingly, 91 (92.9%) of the caregivers reported difficulties in choosing the appropriate food pre introducing the medical foods . However, 84 (85.7%) reported positively that the products availability facilitated the adherence to the restricted diet. Additionally, 75 of the families (76.5%) reported that the social life of the affected member/s was influenced by the unavailability of the medical foods. While 52 (53%) noticed improvement in the social events after providing the products. Furthermore, 33 of the caregivers (33.7%) reported good academic performance among their affected children. And it continued to be 34 (34.7%) post the medical foods usage. Moreover, 43 of the families (43.9%) never tried any form of the medical foods pre-initiating the current study. In addition, in regards to the taste; post the medical foods usage 47 (47.9%) reported products tasted good, 42 (42.9%) reported acceptable taste, and 9 (9.2%) taste was unacceptable to them. Lastly, in regards to the preparation of medical foods; 30 (30.6%) found it easy, 51 (52%) found it moderate, and 17 (17.4%) found it difficult to prepare the products.

st the medical foods usage 47 (47.9%) reported products tasted good, 42 (42.9%) reported acceptable taste, and 9 (9.2%) taste was unacceptable to them. Lastly, in regards to the preparation of medical foods; 30 (30.6%) found it easy, 51 (52%) found it moderate, and 17 (17.4%) found it difficult to prepare the products. 4 Discussion 4.1 Was it easy to introduce these products? One of the factors associated with difficulty introducing the medical foods was the wide range age group. Although high percentage 75.5% of patients were obliged to consume the medical foods on daily basis, In some cases it was introduced as late as school age (median age was 8.7 years) at which incompliance to the dietary restriction is common. We theorize that tolerance of these foods would have been better if it was introduced as early as possible. Additionally, compliance of adult patients was more difficult to the restricted protein modified metabolic diet pre medical foods; what more when they had specially designed foods that could keep their meal away from the other family members. Supplies, transport, storage, preparation, time consuming, effort spent were taking long process that will not be repeated if the patient had poor tolerance to them [3].

fied metabolic diet pre medical foods; what more when they had specially designed foods that could keep their meal away from the other family members. Supplies, transport, storage, preparation, time consuming, effort spent were taking long process that will not be repeated if the patient had poor tolerance to them [3]. 4.2 Why children below two year were excluded? These children are most likely to be unstable to wean or developmentally delayed. Furthermore, caregivers usually have anxiety regarding the quantity and quality of weaning food that should be used [5,42]. However, synthetic amino-acid based formula was found to almost provide 80–90% of their estimated daily needs, which consequently minimize the benefits of utilizing the medical foods at this stage [26]. In addition, most of the provided medical foods in the current study were not suitable as weaning food. There was only one product that would seldom be available. Additionally, the substantial expensive value of the products was not applied as it was free of charge issued to each enrolled patient. However, as the awareness of these products are scarce, hospital administration and logistics had to argue the cost and take exception to consider the value to benefit ratio.

4.2 Why children below two year were excluded? These children are most likely to be unstable to wean or developmentally delayed. Furthermore, caregivers usually have anxiety regarding the quantity and quality of weaning food that should be used [5,42]. However, synthetic amino-acid based formula was found to almost provide 80–90% of their estimated daily needs, which consequently minimize the benefits of utilizing the medical foods at this stage [26]. In addition, most of the provided medical foods in the current study were not suitable as weaning food. There was only one product that would seldom be available. Additionally, the substantial expensive value of the products was not applied as it was free of charge issued to each enrolled patient. However, as the awareness of these products are scarce, hospital administration and logistics had to argue the cost and take exception to consider the value to benefit ratio. 4.3 Why selected disorders? Upon initiating of this research, methylmalonicacidemia (MMA), Propionic academia (PA) and UCD patients were given an opportunity to be part of this project aiming for equalization among all the protein and amino acid metabolism disorders. However, the selected amino acid metabolism disorders (PKU, TYR, HCU& MSUD) have a direct biochemical parameters that can be measured to check compliance and effectiveness of the medical foods, but on the other hand the other disorders (MMA, PA and UCD) don't have such parameters. Consequently, we believe that modification was done to provide validated proper results in the selected amino acid metabolism disorders. Additionally, the other included diagnoses were reflecting the high rate of incidence in our region. Adherence was more problematic with these chronic disorders which are more stable in regard to crisis and hospital admission (PKU, TYR & HCU). However, MSUD patients might be prone to crisis. This make the selected amino acid metabolism disorders a priority to control. However, most of the inherited metabolic disorders have several barriers to adherence to the restricted diet such as physical status, neuropsychological conditions and even social. In addition, the measurement of psychosocial development was excluded from the variance in the current study, as it could not be applied on patients because of unavailability of additional funding that was required for the parameter.

y had better dietary adherence post introducing the medical foods. However, almost half of the enrolled subjects (53%) reported positive improvement in the social life post introducing the medical foods. Therefore, steps towards improving the dietary adherence are counted as factors to improve the quality of life [44]. 4.5 Did we reach metabolic control? Metabolic controls were achieved in PKU and MSUD patients in regard to their biochemical measures post using the medical foods. However, Valine deficiency was more apparent which was expected due to lower Valine content of medical foods compared to regular food, which increased the consumption of Valine supplementation. Additionally, some patients reached normal stable levels with weekly doses, as in MSUD patients, to promote anabolism of Leucine, when Leucine blood concentration is high; additional supplementation of Valine and Isoleucine was often required. On the other hand, most of the TYR and HCU patients were towards adulthood when the medical foods introduced. And that made the compliance and adherence more challenging. Furthermore, the sample size of TYR and HCU patients who reached the end of the study period was small compared to the PKU and MSUD patients. This could be a reason for not reflecting the significant differences.

s adulthood when the medical foods introduced. And that made the compliance and adherence more challenging. Furthermore, the sample size of TYR and HCU patients who reached the end of the study period was small compared to the PKU and MSUD patients. This could be a reason for not reflecting the significant differences. Regarding the other biochemical markers, it was reported frequently that amino acid metabolic disorder patients could show a specific nutrient deficiencies due to the diet restriction and poor tolerance of the synthetic amino-acid based formula [7]. However, monitoring these markers during the follow up clinic visits could significantly improve them. As noted in our study, micronutrients/and or vitamins oral supplementations were received to correct the reported deficiencies in zinc, Iron, Hgb, vitamin B12 but rarely selenium were used. Patients with borderline low levels of these markers were encouraged to consume the total prescribed volume of the synthetic amino-acid based formula and that was in charge of correcting them. 4.6 Any effect on growth parameters was noted? The statistically significant differences in weight and height for male and female data, pre and post the medical foods could be referred to the rapid developmental years of age. During the period of the data collection; most of the enrolled subjects grew well and had significant improvement even if they are below the ideal developmental status compared to their healthy peers.

ght for male and female data, pre and post the medical foods could be referred to the rapid developmental years of age. During the period of the data collection; most of the enrolled subjects grew well and had significant improvement even if they are below the ideal developmental status compared to their healthy peers. One other point worth to mention at this stage, is the percentage of obesity and overweight that increased post using the medical foods. This could be related to multiple reasons: as the patient had higher energy intake from the products that is freely allowed among their dietary restrictions. In addition, the decreased intake of fruits and vegetables in comparison to the starchy based food intake resulted in increased risk of developing obesity. And a conflict of evidence had been reported for PKU patients especially in regards to trend toward developing overweight and obesity [24,26,35,[45], [46], [47]]. 4.7 Limitations There are several limitations to the current study: nutrient analysis was not done by the investigators, and the intake of the synthetic amino-acid based formula was not considered as a variable. Outcome was not analyzed based on stratification (type of IMD). Other potential limitations of the study could be: a) illiterateness and un-cooperative care givers, b) inaccurate information, c) missed metabolic nutrition clinic appointments and irregular lab tests, d) picky eaters, e) possibility of disease crisis. These factors affected quality of data collected. Finally, worldwide use of quality of life measuring tools were not utilized in this paper.

n-cooperative care givers, b) inaccurate information, c) missed metabolic nutrition clinic appointments and irregular lab tests, d) picky eaters, e) possibility of disease crisis. These factors affected quality of data collected. Finally, worldwide use of quality of life measuring tools were not utilized in this paper. 4.8 Future research Research is needed to evaluate the factors that affect the IMD patients' growth and development in an international study comparison. Further long term studies are needed to assess the vitamin and mineral status in those amino acid metabolic disorders patients. In addition, finding more practical ways to measure the compliance in long term dietary restriction needs to be investigated in order to gain acceptable dietary adherence and reach that level of concordance which is crucial for an optimal outcome. 4.9 Conclusion The specially designed low protein products/medical foods availability was successful in improving selected amino acid metabolic disorder biochemical outcomes; especially in patients affected with PKU and MSUD. Additionally, growth parameters were improved, as the products contributed to the increased energy intake among the participants. Furthermore, this study highlighted the importance of vitamins and minerals supplementation as needed with individualized periodic adjustment to maintain adequate nutrition and physical development. However, due to compliance issues and impracticality of the diet, the results were not significant in all enrolled patients.

thermore, this study highlighted the importance of vitamins and minerals supplementation as needed with individualized periodic adjustment to maintain adequate nutrition and physical development. However, due to compliance issues and impracticality of the diet, the results were not significant in all enrolled patients. Conflicts of interest The authors declare that they have no conflict of interest. No funding is declared. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Idiopathic Nephrotic Syndrome (INS) is one of the most common glomerular disorder of childhood worldwide. The reported incidence is about 1.5 per 100,000 children per year [1]. It represents 90% of cases between 1 and 10 years of age with a male: female ratio of 2:1 [2]. Majority of patients show minimal change disease (MCD) on histopathology (almost 80%) [2]. 90% of MCD respond to daily corticosteroid therapy within 4 weeks [3]. Among these steroid responsive cases, 40–50% will have either frequent relapses or will be steroid dependent [3]. These multiple relapses predispose these children to complications of INS like infections, thrombotic episodes and acute renal insufficiency. Furthermore, these relapses require repeated courses of steroids which lead to several adverse effects of steroids such as Cushingoid appearance, obesity, striae, hypertension, hyperglycemia, cataracts, metabolic bone disease, osteoporosis, stunted growth, infections and psychological disturbances. Henceforth, these patients may require certain second line drugs like Alkylating agents, calcineurin inhibitors, antiCD-20 monoclonal antibodies like Rituximab. These immunosuppressive drugs can result in serious side-effects like gonadal toxicity, cancer, bonemarrow suppression, nephrotoxicity and serious infections.

These multiple relapses predispose these children to complications of INS like infections, thrombotic episodes and acute renal insufficiency. Furthermore, these relapses require repeated courses of steroids which lead to several adverse effects of steroids such as Cushingoid appearance, obesity, striae, hypertension, hyperglycemia, cataracts, metabolic bone disease, osteoporosis, stunted growth, infections and psychological disturbances. Henceforth, these patients may require certain second line drugs like Alkylating agents, calcineurin inhibitors, antiCD-20 monoclonal antibodies like Rituximab. These immunosuppressive drugs can result in serious side-effects like gonadal toxicity, cancer, bonemarrow suppression, nephrotoxicity and serious infections. The standard therapy developed by the International Study of Kidney Disease in Children (ISKDC) and later modified by the Arbetsgemein Schaft for Pediatrische Nephrologie (APN) consisted of 4 weeks daily and 4 weeks of alternate day prednisolone (total 8 weeks). However, this protocol was associated with a high relapse rate (65%) and approximately 40% of these children developed frequent relapses [3]. Surveys in both North America and the United Kingdom found considerable diversity in the approach of pediatric nephrologists to the initial therapy of children with INS. Another APN trial, showed that a 12-weeks course of prednisolone significantly reduced the relapse rate from 61% to 36% [4].

The standard therapy developed by the International Study of Kidney Disease in Children (ISKDC) and later modified by the Arbetsgemein Schaft for Pediatrische Nephrologie (APN) consisted of 4 weeks daily and 4 weeks of alternate day prednisolone (total 8 weeks). However, this protocol was associated with a high relapse rate (65%) and approximately 40% of these children developed frequent relapses [3]. Surveys in both North America and the United Kingdom found considerable diversity in the approach of pediatric nephrologists to the initial therapy of children with INS. Another APN trial, showed that a 12-weeks course of prednisolone significantly reduced the relapse rate from 61% to 36% [4]. In a meta-analysis [5], 6 RCTs compared a 2-months protocol of prednisolone to a 3-months or more protocol in the initial episode of INS. The relative risk of relapse was significantly reduced by the longer duration at 1–2 years (RR 0.70, 95% CI 0.58–0.84). Furthermore, in 4 trials, it was shown that the risk of relapse reduced significantly with 6 months of prednisolone therapy as compared to a 3-month protocol (RR 0.5, 95% of CI 0.45–0.71). Subsequently, several studies were done on prolonging the prednisolone therapy from 3 months upto 6 or 7 months [[5], [6], [7], [8], [9], [10], [11]]. It was shown that prolonging the duration upto 6 or 7 months showed better results in reducing the relapse rate, risk of relapse and the incidence of frequent relapses.

In a meta-analysis [5], 6 RCTs compared a 2-months protocol of prednisolone to a 3-months or more protocol in the initial episode of INS. The relative risk of relapse was significantly reduced by the longer duration at 1–2 years (RR 0.70, 95% CI 0.58–0.84). Furthermore, in 4 trials, it was shown that the risk of relapse reduced significantly with 6 months of prednisolone therapy as compared to a 3-month protocol (RR 0.5, 95% of CI 0.45–0.71). Subsequently, several studies were done on prolonging the prednisolone therapy from 3 months upto 6 or 7 months [[5], [6], [7], [8], [9], [10], [11]]. It was shown that prolonging the duration upto 6 or 7 months showed better results in reducing the relapse rate, risk of relapse and the incidence of frequent relapses. The long protocols were classified as 3 months or 6,7 months protocols. Several studies have reported significantly better efficacy and safety of the prolonged 6,7 months protocol [[5], [6], [7], [8], [9], [10], [11]]. We undertook this RCT in order to statistically compare the efficacy and safety of a 3 months versus a long prednisolone (7 months) protocol for the initial episode of INS at a large Saudi center.

The long protocols were classified as 3 months or 6,7 months protocols. Several studies have reported significantly better efficacy and safety of the prolonged 6,7 months protocol [[5], [6], [7], [8], [9], [10], [11]]. We undertook this RCT in order to statistically compare the efficacy and safety of a 3 months versus a long prednisolone (7 months) protocol for the initial episode of INS at a large Saudi center. 2 Subjects and methods 2.1 Subjects and randomization This was a randomized trial comparing the efficacy and safety of a 3 months versus a 7 months prednisolone protocol for the first attack of childhood INS. Children who presented with the first episode of INS between January 1, 2011 to December 31, 2014 were assessed for study enrollment at the Pediatric Nephrology Unit of the King Saud Medical City (KSMC) Riyadh, Saudi Arabia. The follow-up period was 2 years from the point where therapy was stopped. The hospital ethical committee approved the study and the parents gave an informed consent. The patients were randomized into two groups (group A and group B) based on simple randomization using sealed envelopes. Consort guidelines for RCTs were followed. 2.1.1 Randomization method: concealment The clinicians participating in the study were randomly given sealed envelopes containing treatment allotments. When a patient agreed for the treatment, the envelope was opened and the allotted treatment given [12].

2 Subjects and methods 2.1 Subjects and randomization This was a randomized trial comparing the efficacy and safety of a 3 months versus a 7 months prednisolone protocol for the first attack of childhood INS. Children who presented with the first episode of INS between January 1, 2011 to December 31, 2014 were assessed for study enrollment at the Pediatric Nephrology Unit of the King Saud Medical City (KSMC) Riyadh, Saudi Arabia. The follow-up period was 2 years from the point where therapy was stopped. The hospital ethical committee approved the study and the parents gave an informed consent. The patients were randomized into two groups (group A and group B) based on simple randomization using sealed envelopes. Consort guidelines for RCTs were followed. 2.1.1 Randomization method: concealment The clinicians participating in the study were randomly given sealed envelopes containing treatment allotments. When a patient agreed for the treatment, the envelope was opened and the allotted treatment given [12]. 2.2 Treatments (a)Children in group A (3 months protocol) were administered prednisolone in a single once daily dose of 60 mg/m2 for 1 ½ months taken soon after breakfast, then 40 mg/m2 on alternate days for another 1 ½ months then tapered as follows: 20 mg/m2/EOD x 1 week then 10 mg/m2/EOD for another week then stopped [13]. (b)Children in group B (7 months protocol) were treated as follows: 60 mg/m2/OD for 1 month then 40 mg/m2/EOD for 2 months then 30 mg/m2/EOD for 2 months then 20 mg/m2/EOD for 2 months then stopped [8].

2.2 Treatments (a)Children in group A (3 months protocol) were administered prednisolone in a single once daily dose of 60 mg/m2 for 1 ½ months taken soon after breakfast, then 40 mg/m2 on alternate days for another 1 ½ months then tapered as follows: 20 mg/m2/EOD x 1 week then 10 mg/m2/EOD for another week then stopped [13]. (b)Children in group B (7 months protocol) were treated as follows: 60 mg/m2/OD for 1 month then 40 mg/m2/EOD for 2 months then 30 mg/m2/EOD for 2 months then 20 mg/m2/EOD for 2 months then stopped [8]. (c)Relapses were treated as follows: Prednisolone 60 mg/m2 daily once till urine protein is negative for 5 days, then 40 mg/m2 on alternate days for 1 month then stop. In case of frequent relapsers and steroid dependent cases, relapses were treated as follows; prednisolone 60 mg/m2/OD till urine protein was negative for 5 days then 40 mg/m2/EOD x 1 month then 30 mg/m2/EOD for 1 month then 20 mg/m2/EOD x another 1 month and then stop [13]. 2.3 Patients and their parents We informed the parents about the side effects of corticosteroids. Patients were advised to take low salt, high protein and low-fat diet during the relapse but otherwise high biological value protein diet. Subjects were followed regularly for up to 2 years after completion of the initial prednisolone regimen.

r parents We informed the parents about the side effects of corticosteroids. Patients were advised to take low salt, high protein and low-fat diet during the relapse but otherwise high biological value protein diet. Subjects were followed regularly for up to 2 years after completion of the initial prednisolone regimen. 2.4 Outcome measures The primary study end point was the time to initial relapse. The secondary end point/outcome measures were: rate of relapse, relative risk of relapse, incidence of frequently relapsing steroid sensitive nephrotic syndrome, incidence of steroid dependent nephrotic syndrome, incidence of use of second line drugs, rate of adverse events, rate of serious adverse events and the incidence of psychological changes. Monitoring of prednisolone related adverse effects was done by doing the following: clinical data including BP, cushingoid features, acne, striae, hirsutism, psychological changes, poor vision, backache. Investigations included half yearly eye checkup for cataracts, bone mineral density at the end of each year and psychological evaluation at the end of each year, calcium, phosphate, alkaline phosphate and vitamin D level, X-ray spine, AP lateral in case of suspected fractures or osteoporosis, fasting and if necessary, random and postprandial blood glucose, checkup of vaccination card and screening for infections. All side effects were assessed by the same observer. Upper GIT Endoscopy was done when gastritis was suspected.

amin D level, X-ray spine, AP lateral in case of suspected fractures or osteoporosis, fasting and if necessary, random and postprandial blood glucose, checkup of vaccination card and screening for infections. All side effects were assessed by the same observer. Upper GIT Endoscopy was done when gastritis was suspected. Metabolic bone disease was assessed by serum Ca, PO4, ALP, X-Ray bone and bone mineral density. DSM criteria were applied for psychological changes. Those patients who had no relapse at all were said to be cured. 2.5 Definitions The definitions of relapse, remission, frequent relapse, steroid dependent resistant were as per the ISKDC (Table 1) [2].Table 1 The international study of kidney disease in children (definitions).

Metabolic bone disease was assessed by serum Ca, PO4, ALP, X-Ray bone and bone mineral density. DSM criteria were applied for psychological changes. Those patients who had no relapse at all were said to be cured. 2.5 Definitions The definitions of relapse, remission, frequent relapse, steroid dependent resistant were as per the ISKDC (Table 1) [2].Table 1 The international study of kidney disease in children (definitions). Table 1Nephrotic syndrome: proteinuria>40  mg/h/m2 or >50 mg/kg/day or protein/creatinine ratio >0.2 g/mmol (>2 g/g) and hypoalbuminemia <25 g/l with or without edema Remission: proteinuria <4 mg/h/m2 or 0-trace on Albustix for 3 consecutive days Steroid responsive: complete remission achieved with steroid therapy Steroid resistant: failure to achieve remission following 4 week’ prednisolone 60 mg/m2 followed by 3 methylprednisolone pulses Relapse: proteinuria>>40  mg/h/m2 or >50 mg/kg/day or Albustix +++ for 3 consecutive days after having been in remission Frequent relapse: 2 or more relapses within 6 months of initial response or 4 or more relapses within a period of 1 year Steroid dependence: 2 consecutive relapses during corticosteroid therapy or within 14 days after cessation of therapy Early nonresponder: steroid resistance during the first episode Late nonresponder: steroid resistance in a patience who had previously responded to corticosteroid therapy 2.6 Inclusion criteria • Children with the initial episode of INS (secondary causes excluded). • Age range: 1–12 years. • No prior therapy with steroids or immunosuppressive therapy. • Informed consent.

Table 1Nephrotic syndrome: proteinuria>40  mg/h/m2 or >50 mg/kg/day or protein/creatinine ratio >0.2 g/mmol (>2 g/g) and hypoalbuminemia <25 g/l with or without edema Remission: proteinuria <4 mg/h/m2 or 0-trace on Albustix for 3 consecutive days Steroid responsive: complete remission achieved with steroid therapy Steroid resistant: failure to achieve remission following 4 week’ prednisolone 60 mg/m2 followed by 3 methylprednisolone pulses Relapse: proteinuria>>40  mg/h/m2 or >50 mg/kg/day or Albustix +++ for 3 consecutive days after having been in remission Frequent relapse: 2 or more relapses within 6 months of initial response or 4 or more relapses within a period of 1 year Steroid dependence: 2 consecutive relapses during corticosteroid therapy or within 14 days after cessation of therapy Early nonresponder: steroid resistance during the first episode Late nonresponder: steroid resistance in a patience who had previously responded to corticosteroid therapy 2.6 Inclusion criteria • Children with the initial episode of INS (secondary causes excluded). • Age range: 1–12 years. • No prior therapy with steroids or immunosuppressive therapy. • Informed consent. 2.7 Exclusion criteria • Congenital nephrotic syndrome. • Infantile nephrotic syndrome. • Children with a prior history of poor compliance with medical therapy. • Children with known allergy to prednisolone. • Children below 1 year and above 12 years. • Children with persistent hypertension or gross hematuria. • Children with family history of known genetic causes of nephrotic syndrome.

2.7 Exclusion criteria • Congenital nephrotic syndrome. • Infantile nephrotic syndrome. • Children with a prior history of poor compliance with medical therapy. • Children with known allergy to prednisolone. • Children below 1 year and above 12 years. • Children with persistent hypertension or gross hematuria. • Children with family history of known genetic causes of nephrotic syndrome. 2.8 Statistical analysis The following statistical tests were performed:• Student's t-test was used for comparison of means. • Chi-square test was used for comparison of percentages. • Relative risk calculation was done using MedCalc • P value < .05 was taken as a significant result. • Statistical power for the study was 80% (Value: 0.8416) • Calculation of sample size [14]. • Intention to treat analysis was applied. • Help of an experienced statistician was taken when necessary • SPSS version 16.0 (SPSS Chicago, USA) was used when necessary. 3 Results 124 patients were assigned for eligibility for the study. Four patients were excluded: 2 for not meeting inclusion criteria and 2 declined to participate. The 2 patients who did not meet exclusion criteria were steroid resistant. Sixty patients were allotted to both group A and group B, but only 58 from each group completed the study. Two patients from each group were lost to follow-up (Table 2). No significant difference was observed in the baseline characteristics of the two groups (Table 3).Table 2 Consort 2010 flow diagram. Table 2Table 3 The baseline characteristics of the patients in the 2 study groups at the beginning of the study.

3 Results 124 patients were assigned for eligibility for the study. Four patients were excluded: 2 for not meeting inclusion criteria and 2 declined to participate. The 2 patients who did not meet exclusion criteria were steroid resistant. Sixty patients were allotted to both group A and group B, but only 58 from each group completed the study. Two patients from each group were lost to follow-up (Table 2). No significant difference was observed in the baseline characteristics of the two groups (Table 3).Table 2 Consort 2010 flow diagram. Table 2Table 3 The baseline characteristics of the patients in the 2 study groups at the beginning of the study. Table 3Parameters Group A Group B P value Mean age (SD) (years) 5(2) 5.2(1.8) .5659 (NS) Mean weight (SD) (kg) 15.1(3) 15.6(2.5) .3233 (NS) Mean Height (SD) (cms) 105(2) 105(2) 1.0000 (NS) Sex (M: F) Ratio 1.9: 1 2:1 - Mean BP (SD)mmofHg 100/70(5/3) mmofHg 101/68 (4.6/2.9) mmofHg .5367 (NS) .3552 (NS) Mean Hb g/dl + Platelet count (SD) Hb = 13(2) PLT = 300(58) 12.8(1.5) 310(6) .5367 (NS) .3552 (NS) Mean Serum (SD) Creatinine μmol/L 24(4.1) 25(4) .1789 (NS) Mean Serum protein (SD) mmol/L 30(3) 29(4) .1240 (NS) Mean Serum Albumin (SD) mmol/L 12(2) 11.8(2) .5849 (NS) Mean Serum cholesterol (SD) mmol/L 12(2.2) 11.8(2.3) .6273 (NS) Mean LDL cholesterol (SD) mmol/L 3.6(1.0) 3.5(0.8) .5464 (NS) Mean Serum Triglyceride (SD) mmol/L 2.0(0.5) 2.2(0.7) 1.000 (NS) Fasting Blood glucose mmol/L (SD) 4.1(0.8) 4.0(0.6) .04401 (NS) Urine Protein/Creatinine Ratio (mg of protein/mmol of creatinine) (SD) 1000(150) 1005(146) .8535 (NS)

2(2.2) 11.8(2.3) .6273 (NS) Mean LDL cholesterol (SD) mmol/L 3.6(1.0) 3.5(0.8) .5464 (NS) Mean Serum Triglyceride (SD) mmol/L 2.0(0.5) 2.2(0.7) 1.000 (NS) Fasting Blood glucose mmol/L (SD) 4.1(0.8) 4.0(0.6) .04401 (NS) Urine Protein/Creatinine Ratio (mg of protein/mmol of creatinine) (SD) 1000(150) 1005(146) .8535 (NS) The group B protocol was found to be significantly better than group A protocol in both efficacy (Table 4) and safety (Table 5). The relative risk of relapse was significantly less in group B (RR 0.839,95% CI 0.6566 to 0.9843 significance P = .0346).Table 4 Comparing the efficacy of the two prednisolone regimens. Table 4Relapses Group A Group B P value Duration of Follow-up 2 years 2 years – Mean Time of First Relapse (SD) 6months (2) 10months(3)  < .0001 (significant) Mean Relapse rate (1st yr) (SD) (Relapses/year) 1.5(1) 1.0(0.8) .0031 (significant) Mean Relapse rate (2nd yr) (SD) (Relapses/year) 1.8(0.9) 1.2(0.7) .0002 (significant) Cumulative Steroid dose (1st yr) mg/m2/month 620(150) 550(107) .0039 (significant) Cumulative Steroid dose (2nd yr) mg/m2/month 580(140) 510(106) .0026 (significant) Percentage Frequent Relapsers 50 28 .0139 (significant) Percentage steroid dependent case 20 6  < .0232 (significant) Percentage Cured 15 31 .00381 (significant) Infrequent relapsers percentage 15 35 .0118 (significant) Percentage using second line drugs 40 20 .00173 (significant) Table 5 Comparing steroid side effects (Follow up 2 years).

elapsers 50 28 .0139 (significant) Percentage steroid dependent case 20 6  < .0232 (significant) Percentage Cured 15 31 .00381 (significant) Infrequent relapsers percentage 15 35 .0118 (significant) Percentage using second line drugs 40 20 .00173 (significant) Table 5 Comparing steroid side effects (Follow up 2 years). Table 5S.no Side effects of steroids Group A Group B P value 1 Cushingoid 25(47%) 15(15%) .0002 2 Gastritis 21(35%) 10(17%) .0252 3 Hirsutism acne 12(20%) 3(5%) .0134 4 Hypertension 12(20%) 4(6.7%) .0329 5 Infections 12(20%) 4(6.7%) .0329 6 Stunted growth 14(23.33%) 5(8.3%) .0250 7 Metabolic bone disease 10(16.6%) 2(3.33%) .0157 8 Hyperglycemia 0 0 - 9 Psychological disturbances 4(6.66%) 0 .0429 10 Striae 5(8.33%) 0 .0230 11 Posteriorsubcapsular cataracts 0 0 - The mean relapse rate was significantly better in group B as compared to group A (P = .031) in the first year as well in the second year (P < .00002). The percentage of frequent relapsers (FRNS) was significantly less (P = .0139) in group B. Second line drugs were used both in the first year and second year of followup. The metabolic bone disease observed was osteomalacia. No serious psychological changes were seen. The two most commonly observed psychological changes were euphoria and hyperactivity.

The percentage of frequent relapsers (FRNS) was significantly less (P = .0139) in group B. Second line drugs were used both in the first year and second year of followup. The metabolic bone disease observed was osteomalacia. No serious psychological changes were seen. The two most commonly observed psychological changes were euphoria and hyperactivity. 4 Discussion Our study comprised of 2 groups: Group A and Group B. Group A received the 3 months prednisolone protocol and Group B received the 7 months protocol. All the patients had new onset childhood idiopathic nephrotic syndrome. There were no significant differences in the baseline characteristics of the two groups. Group B regimen was found to be significantly better as regards to the relapse rate, time of first relapse, relative risk of relapse, cumulative steroid dose, percentage of frequent relapsers and steroid dependent cases. Furthermore, the adverse effects of corticosteroids were significantly better in group B regimen than group A. Thus, our study showed that the 7 months prednisolone regimen was significantly better than the 3 months in both efficacy and safety. A meta-analysis of 5 RCTs was done comparing an 8 weeks prednisolone protocol to a 12 weeks protocol [6]. The risk of relapse at 2 years was significantly reduced (RR 0.73;95% CI 0.6 to 0.89). There was no increase in side effects. They concluded that the initial prednisolone regimen should be of 12 weeks duration. They also observed that increasing the prednisolone duration to 7 months was associated with an excellent outcome.

isk of relapse at 2 years was significantly reduced (RR 0.73;95% CI 0.6 to 0.89). There was no increase in side effects. They concluded that the initial prednisolone regimen should be of 12 weeks duration. They also observed that increasing the prednisolone duration to 7 months was associated with an excellent outcome. In a 2015 update [7], the addition of three well-designed studies has changed the conclusion of the previous Cochrane database. It was found that high risk of bias studies overestimated the effect of longer course therapy compared with recent low risk bias studies. These low risk bias studies showed no significant difference in the risk of FRNS between prednisolone for 2–3 months and longer durations prednisolone indicating no benefit in prolonging the duration beyond 2–3 months. In a study by O.P Mishra et al. [8] significantly better results were seen in the 5 months prednisolone protocol as compared to a 3 months protocol. The mean relapse rate was significantly lower (0.63 vs 1.54 P = .011), the mean cumulative dose of prednisolone was significantly less (P = .033), the total relapses up to 1 year were significantly less (21.6% vs 70.2% P = .001), the percentage of patients with no relapse at 1 year were (76% vs 29%) and the cumulative risk of relapse was significantly lower (0.05 vs 1.31). The side effects were similar in both groups.

ednisolone was significantly less (P = .033), the total relapses up to 1 year were significantly less (21.6% vs 70.2% P = .001), the percentage of patients with no relapse at 1 year were (76% vs 29%) and the cumulative risk of relapse was significantly lower (0.05 vs 1.31). The side effects were similar in both groups. There was another study by Hiroka M et al. [9], This study comprised of 2 groups: 3 months versus a 6 months prednisolone regimen. In children less than 4 years of age, the 6 months protocol showed less steroid toxicities, had significant persistent remission (P = .01) and there were less children with frequent relapses (P = .05). In children older than 4 years, no significant difference was found in the persistent remission in the 2 groups. Yet another study by ALT Ma et al. [10] compared the standard 8 weeks ISKDC protocol to the 6 months prednisolone protocol. It was a retrospective study. The results were significantly better in the long prednisolone protocol: higher sustained remission (P = .0046), lower relapse rate (33% versus 75% P = .026) and less side effects (no growth retardation or hypertension seen). In a randomized study by Ksiazek, J et al. [11], patients were divided into 3 groups: 2 months, 3 months and 6 months prednisolone regimens. Best results were seen with the 6 months protocol. Percentage of relapse free patients at 2 m, 3 m and 6 months were: 36.4%, 32.4% and 65.3%. Percentage of relapses free at 2 years were 27.3%, 20.6% and 50%. The number of relapses per patient per year at 2 m,3 m and 6 months were as follows: 0.79, 0.77 and 0.49.

imens. Best results were seen with the 6 months protocol. Percentage of relapse free patients at 2 m, 3 m and 6 months were: 36.4%, 32.4% and 65.3%. Percentage of relapses free at 2 years were 27.3%, 20.6% and 50%. The number of relapses per patient per year at 2 m,3 m and 6 months were as follows: 0.79, 0.77 and 0.49. However, contrary results were obtained in a multicenter randomized trial from Netherlands [15]. The patients were randomized into 2 broad groups: a 3 months prednisolone and a 6 months prednisolone. The cumulative dose of steroids was similar in both groups. The results were as follows: 3 m versus 6 months protocol: relapse rate (77%,80%), frequent relapses (45%,50%), the use of maintenance prednisolone and other second line drugs used (50%,59%). Their conclusion was that prolongation of the prednisolone regimen alone to 6 months without increasing the cumulative dose of steroids did not show any additional benefit. We observed that except for a few studies, most of the previous studies showed significantly better efficacy and safety with the long course prednisolone regimen for the first episode of INS in children. Their findings were similar to our observations.

However, contrary results were obtained in a multicenter randomized trial from Netherlands [15]. The patients were randomized into 2 broad groups: a 3 months prednisolone and a 6 months prednisolone. The cumulative dose of steroids was similar in both groups. The results were as follows: 3 m versus 6 months protocol: relapse rate (77%,80%), frequent relapses (45%,50%), the use of maintenance prednisolone and other second line drugs used (50%,59%). Their conclusion was that prolongation of the prednisolone regimen alone to 6 months without increasing the cumulative dose of steroids did not show any additional benefit. We observed that except for a few studies, most of the previous studies showed significantly better efficacy and safety with the long course prednisolone regimen for the first episode of INS in children. Their findings were similar to our observations. 5 Conclusion Thereby, we conclude that the prolonged prednisolone protocol of 7 months duration is significantly better than standard prednisolone regimen of 3 months duration in both efficacy and safety. We recommend, however, that more multicenter trials should be conducted worldwide in order to finalize the best and optimum prednisolone regimen for the first episode of new onset idiopathic nephrotic syndrome. Conflict of interest There was no conflict of interest in this randomized trial. Ethical statement The hospital ethical committee was approached and the RCT has been approved by them.

5 Conclusion Thereby, we conclude that the prolonged prednisolone protocol of 7 months duration is significantly better than standard prednisolone regimen of 3 months duration in both efficacy and safety. We recommend, however, that more multicenter trials should be conducted worldwide in order to finalize the best and optimum prednisolone regimen for the first episode of new onset idiopathic nephrotic syndrome. Conflict of interest There was no conflict of interest in this randomized trial. Ethical statement The hospital ethical committee was approached and the RCT has been approved by them. Acknowledgement First, I thank all our staff for their help in completing this important study. I also thank all the patients and parents for their cooperation. I also want to thank the Hospital Research & Ethical committee for their help in getting the study approved by the KSMC ethical committee. My special thanks to Mr. Shahroze (MSc) and Miss Husna for their secretarial help. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction The incidence of fungal infections in neonates has increased during recent decades. Prematurity, low birth weight, use of antibiotic treatments, and prolonged stays in neonatal care units favor the occurrence of sepsis due to fungal species [1]. For many years, the main causative agent of invasive candidiasis was Candida albicans; however, recent studies have shown a change in profile of invasive candidiasis. Rare species of emergent pathogens are appearing at a frequency of 1.2–3.2%. These species include Candida ernobii, Candida pelliculosa, Candida lipolytica, and Candida norvegensis [[2], [3], [4], [5]]. Two cases have been reported in the literature on infections caused by Candida magnoliae: one tenosynovitis case in an immunocompetent child in the United States and the other case in a terminal oncology patient in Italy [6,7]. In the present study, we describe two low birth weight neonates with primary bloodstream infections caused by C. magnoliae.

the literature on infections caused by Candida magnoliae: one tenosynovitis case in an immunocompetent child in the United States and the other case in a terminal oncology patient in Italy [6,7]. In the present study, we describe two low birth weight neonates with primary bloodstream infections caused by C. magnoliae. 2 Case reports The first case of C. magnoliae infection occurred in a male neonate born on September 18, 2017, at 27 weeks of gestation in a maternity hospital. The birth was a cesarean delivery because the mother presented a serious gestational hypertension disease. The newborn had depression at birth with an Apgar score of 6/9 and weighing 0.985 g. In the birth room, the patient evolved bradycardia and was ventilated and placed in continuous positive airway pressure (CPAP). Subsequently, the child was admitted to the neonatal intensive care unit (NICU) with hypothermia (33 °C). In the unit, an umbilical catheter was introduced and the total parenteral nutrition (TPN) installed. After culture collection, ampicillin and gentamicin were prescribed. At 48 h, respiration worsened, and hence, mechanical ventilation was initiated. Additionally, a reduction in platelets and an increase in C-reactive protein (CRP) were observed. The child remained stable, and culture results from the first day of life after 48 h were negative. On day 3, the umbilical catheter was removed and a peripherally inserted central catheter (PICC) was introduced. On September 24, the child continued to present tachycardia, hyperthermia (38 °C), apnea, desaturation, bleeding through the orotracheal tube, and thrombocytopenia; new culture samples were collected, and the antibiotic treatment was changed to oxacillin and amikacin. On the same day, the child received a red blood cell transfusion (10 ml), and there was an increase in the ventilatory parameters. Two days later, the condition remained serious and the pulmonary auscultation presented diffuse rhonchus and an irregular respiratory pattern. In the following days, the patient remained in a serious condition, with abdominal distention, hyperthermia, hypoactivity, thrombocytopenia, and an increase in CRP level. There was infiltration of the PICC, which was changed. On October 1, because of the worsening of the condition, a new culture collection was performed, and there was a change in antibiotics, with cefepime and vancomycin being administered.

ion, hyperthermia, hypoactivity, thrombocytopenia, and an increase in CRP level. There was infiltration of the PICC, which was changed. On October 1, because of the worsening of the condition, a new culture collection was performed, and there was a change in antibiotics, with cefepime and vancomycin being administered. On October 2, pulmonary hemorrhage and pneumothorax were observed; a chest drain was introduced and the culture collected on September 24 was received, which was positive for C. magnoliae. Given the culture result, amphotericin B was administered. In the following days, the patient remained in a serious condition, with hypoactivity; discolored, high volume of secretion through the tube; hyperthermia continuing for some days (reaching an axillary temperature of 40 °C); and secretion through the drain. Cultures were collected during this period, and antibiotics were changed from cefepime to meropenem. On day 21, the culture collected on day 13 was positive for Serratia marcescens, which was the microorganism responsible for the outbreak that the NICU was experiencing at that moment. Therefore, according to an antibiogram, the antibiotics were changed to ciprofloxacin and tigecycline. A peripheral puncture was made, and concentrated red blood cells (15 ml) were introduced; the baby was then placed in contact precaution and transferred to another bed. From then on, the patient presented worsening clinical and laboratory signs, with death being the final outcome on October 19 and 31 days of life.

ine. A peripheral puncture was made, and concentrated red blood cells (15 ml) were introduced; the baby was then placed in contact precaution and transferred to another bed. From then on, the patient presented worsening clinical and laboratory signs, with death being the final outcome on October 19 and 31 days of life. The second case of C. magnoliae occurred in a female neonate born on August 28, 2017, at 37 weeks of gestation. The birth was a cesarean delivery because the neonate presented gastroschisis. The patient was born with an Apgar score of 7/9, weighing 1.625 g, and presenting cyanosis in the extremities, and the silo was placed soon after. After being admitted to the NICU, culture collection was realized and a peripheral puncture was made through which the analgesic and antibiotic ampicillin and gentamicin were administered. The following day, the closure of the abdominal wall was surgically performed, and tests were conducted; the results showed an increased CRP level and a normal blood count. However, the abdomen was distended and painful to touch and the orogastric tube presented bilious residue. The PICC was inserted on the same day. The patient continued to present a distended abdomen with time, which was painful to the touch, with bilious residue and the CRP remained altered, however, diminished. On day 6, the culture result was positive for oxacillin-resistant Staphylococcus epidermidis, and the antibiotic was changed to vancomycin (treatment for 15 days). Subsequent cultures were performed, all presenting negative results. Because of the persistence of symptoms, the absence of positive culture results, and the continuity of an altered CRP level, cefepime was administered (treatment for 11 days) on day 10. As the newborn showed improvement, an abdominal ultrasound was performed on day 14, which showed the presence of distended handles with liquid content in their interior. Given this result, it was decided to perform a new surgical intervention on September 16. During the surgical intervention, the release of the flanges and an appendectomy were carried out. On the day following surgery, the patient presented a large volume of bilious residue and thrombocytopenia. On September 21, the newborn initiated episodes of regurgitation, hypoactivity, and tachycardia and presented a distended and painful abdomen.

ion, the release of the flanges and an appendectomy were carried out. On the day following surgery, the patient presented a large volume of bilious residue and thrombocytopenia. On September 21, the newborn initiated episodes of regurgitation, hypoactivity, and tachycardia and presented a distended and painful abdomen. The patient remained in this state for two more days until new examinations were performed; the results continued to show thrombocytopenia and an elevated CRP level. A new culture was collected after obtaining negative results, and the antibiotic treatment was changed to meropenem and vancomycin. During the following days, the patient presented worsening clinical and laboratory signs, with death as the final outcome on October 1. On the patient's final day, cultures were collected, and results proved positive, postmortem, for C. magnoliae.

s, and the antibiotic treatment was changed to meropenem and vancomycin. During the following days, the patient presented worsening clinical and laboratory signs, with death as the final outcome on October 1. On the patient's final day, cultures were collected, and results proved positive, postmortem, for C. magnoliae. 3 Discussion A prospective study found 89 cases of candidemia in neonatology. The average age was 16 days at the start of the infection (1–28 days). The main species isolated were C. albicans (44%), Candida parapsilosis (27%), Candida tropicalis (15%), and Candida guilliermondii (5%) [8]. Epidemiological studies have shown that non-C. albicans species have emerged as important agents causing fungemia [9]. The incidence of candidemia is 3% in neonates with weight between 751 and 1000 g and 1% in neonates with weight between 1001 and 1500 g [10]. In October 2007, a clinically related Candida species appeared in the blood culture of a 42-year-old Chinese patient with stomach cancer [7]. The species observed, C. magnoliae, is commonly used in the food industry because of its high capacity to produce erythritol and mannitol, which are used as functional substitutes for sugar in various foods [11,12]. This microorganism has the ability to quickly consume fructose and grow in various pH levels (2.5–8.0) [13,14].

cies observed, C. magnoliae, is commonly used in the food industry because of its high capacity to produce erythritol and mannitol, which are used as functional substitutes for sugar in various foods [11,12]. This microorganism has the ability to quickly consume fructose and grow in various pH levels (2.5–8.0) [13,14]. C. magnoliae infections are rare. In literature, to date, two cases of C. magnolia infection have been described. Low birth weight, preterm neonates present high morbidity and mortality rates because of the immaturity of their lungs, the immune system, and other factors [15]. In our maternity unit, we use the MALDI-TOF MS method for microbiological identification. In these two cases, we did not have the opportunity to confirm the results by another microbiological identification method. The treatment for one of the cases was done with amphotericin B deoxycholate; however, there was a fatal evolution similar to that of the other case. The antibiogram showed sensitivity to echinocandins. Amphotericin was not tested because of the lack of a kit at the local laboratory. The result for the second case was received postmortem; therefore, antifungal treatment was not administered. There are few cases for us to be able to arrive at a conclusion, but there remains a doubt regarding the lethality that this yeast possesses in neonates. Both neonates had worsening clinical and laboratory conditions, and this led us to use a broad-spectrum antibiotic.

refore, antifungal treatment was not administered. There are few cases for us to be able to arrive at a conclusion, but there remains a doubt regarding the lethality that this yeast possesses in neonates. Both neonates had worsening clinical and laboratory conditions, and this led us to use a broad-spectrum antibiotic. The first step before infection is colonization, and the time between two culture collections was 7 days, which suggests a possible common source of contamination. The children were fed with natural milk, which discarded the possibility of contamination through milk bank. In the case of contaminated parenteral nutrition, this would have presented more cases, given that the majority of neonates from the sector are premature with low birth weight and also susceptible to developing infection through the same agent. Another possibility may be the ingestion of industrialized products by family members or health professionals who transmitted the colonizing yeasts to the neonates. This hypothesis, however, remains difficult to prove, given that when receiving the microbiological result, 120 hours after the start of the infection, the colonization had already passed, thus making causal/root research impossible. The two cases represented an outbreak for us. Hence, NICU and laboratory teams were alerted to initiate a more in-depth investigation if another case appeared, but fortunately, this did not occur. We did not perform a culture of milk, parenteral nutrition, or any other kind of parenteral medication.

1 Introduction The importance of exclusive breast milk is unquestionable for any neonate. Exclusively breastfed preterm neonates have better short-term (reduced rates of necrotizing enterocolitis) and long-term outcomes and obtain maximum immunological benefits [[1], [2], [3]]. The human milk feeding through neonatal intensive care unit (NICU) has been adopted into clinical best practices. Although the rates of “any” human milk use in NICU have improved during the last decade, efforts to help mothers in expressing and maintaining mother's own milk (MOM) through discharge remains a concern [4]. In our neonatal unit, we found many challenges faced by mothers in the initiation and maintenance of breastfeeding. From the retrospective analysis of our own data, we identified that there was a delay in first milk expression (sometimes no milk up to the first 24–48 h) and reduced frequency of expression, which was limited to 2–3 times a day, thus resulting in most neonates relying predominantly on formula feeds until the end of 1 week. With this background, we designed a quality improvement (QI) initiative to increase exclusive breastfeeding rates in admitted preterm neonates. The purpose of the present study is to evaluate the proportion of preterm neonates receiving MOM by day 7 of life after such an initiative.

rmula feeds until the end of 1 week. With this background, we designed a quality improvement (QI) initiative to increase exclusive breastfeeding rates in admitted preterm neonates. The purpose of the present study is to evaluate the proportion of preterm neonates receiving MOM by day 7 of life after such an initiative. 2 Materials and methods This work was carried out in accordance with tenets of the Declaration of Helsinki for experiments involving humans. The institutional ethics committee approved the study protocol, and an informed consent was obtained from the mother of the neonates. The QI initiative was conducted at a level 3 NICU from May 10, 2018, to August 10, 2018. Inborn preterm neonates <34 weeks with a minimum hospital stay of 7 days were included in the study (Fig. 1). Neonates of critically ill mothers who were admitted in maternal intensive care unit and neonates having major congenital malformations and requiring surgical intervention (hence nonestablishment of breastfeeding) were excluded from the study.Fig. 1 A flowchart depicting the number of neonates evaluated, included, and excluded in the present study. Fig. 1

2 Materials and methods This work was carried out in accordance with tenets of the Declaration of Helsinki for experiments involving humans. The institutional ethics committee approved the study protocol, and an informed consent was obtained from the mother of the neonates. The QI initiative was conducted at a level 3 NICU from May 10, 2018, to August 10, 2018. Inborn preterm neonates <34 weeks with a minimum hospital stay of 7 days were included in the study (Fig. 1). Neonates of critically ill mothers who were admitted in maternal intensive care unit and neonates having major congenital malformations and requiring surgical intervention (hence nonestablishment of breastfeeding) were excluded from the study.Fig. 1 A flowchart depicting the number of neonates evaluated, included, and excluded in the present study. Fig. 1 Baseline data of the first provision of expressed breast milk (EBM) to the babies, daily amount of EBM given from days 1–7, and the exact amount and type of milk (EBM or formula) were collected. After baseline data collection and detailed introspection, a “breastfeeding support group” was formed comprising a neonatologist in charge, an NICU Resident, a nurse in charge, three staff nurses (one in each work shift), and a lactation counselor. The team collaboratively evaluated the reasons for poor establishment of breast milk in preterm mothers by fish bone analysis. The team found the lack of maternal understanding on the importance of breast milk for preterm babies and the lack of maternal sensitization to initiate early breastfeeding and sustain exclusive breastfeeding as the major reasons, and they formulated various steps for improving the same.

mothers by fish bone analysis. The team found the lack of maternal understanding on the importance of breast milk for preterm babies and the lack of maternal sensitization to initiate early breastfeeding and sustain exclusive breastfeeding as the major reasons, and they formulated various steps for improving the same. A leaflet depicting the importance of breastfeeding in preterm neonates and a video explaining the methods of milk expression both manually and with the help of breast pumps were designed. Mothers were given structured antenatal and postnatal counseling regarding expressing breast milk and its importance. The team also counseled other family members and the husband to help them provide better support to the mother once she initiates breastfeeding. Postnatal visits within half an hour of delivery, then every 3–4 h for the first three days, and subsequently daily visits were conducted to provide information and encourage mothers for milk expression. The breastfeeding support group conducted meetings with on-duty nursing staff and resident doctors involved in clinical care on a daily basis to ensure all mothers and preterm neonates were involved in the quality intervention. A continuous feedback loop was maintained.

mation and encourage mothers for milk expression. The breastfeeding support group conducted meetings with on-duty nursing staff and resident doctors involved in clinical care on a daily basis to ensure all mothers and preterm neonates were involved in the quality intervention. A continuous feedback loop was maintained. The changes were analyzed as part of a Plan-Do-Study-Act cycle (Fig. 2). During the retrospective analysis (observation phase), we observed 180 inborn babies admitted <34 weeks in our NICU per year, and we reviewed 30 case sheets from the medical records of inborn preterm neonates <34 weeks during the last three months (February to April 2018) just before the intervention phase. During the intervention phase, a total of 30 babies were recruited for a period of 3 months. Proportions of mothers expressing breast milk within 6 h of birth, within 24 h of birth, and subsequently on day 3 and 7 were assessed. The amount of EBM on days 1, 3, and 7 and the proportion of neonates fed on MOM on day 7 of life were evaluated. Data of time to reach full enteral feeds, time to regain birth weight, rate of necrotizing enterocolitis (NEC), rate of sepsis, duration of hospital stay, and proportion of babies on exclusive MOM during discharge were also collected.Fig. 2 A flowchart depicting the Plan-Do-Study-Act cycle followed in the present study. Fig. 2

The changes were analyzed as part of a Plan-Do-Study-Act cycle (Fig. 2). During the retrospective analysis (observation phase), we observed 180 inborn babies admitted <34 weeks in our NICU per year, and we reviewed 30 case sheets from the medical records of inborn preterm neonates <34 weeks during the last three months (February to April 2018) just before the intervention phase. During the intervention phase, a total of 30 babies were recruited for a period of 3 months. Proportions of mothers expressing breast milk within 6 h of birth, within 24 h of birth, and subsequently on day 3 and 7 were assessed. The amount of EBM on days 1, 3, and 7 and the proportion of neonates fed on MOM on day 7 of life were evaluated. Data of time to reach full enteral feeds, time to regain birth weight, rate of necrotizing enterocolitis (NEC), rate of sepsis, duration of hospital stay, and proportion of babies on exclusive MOM during discharge were also collected.Fig. 2 A flowchart depicting the Plan-Do-Study-Act cycle followed in the present study. Fig. 2 Statistical analysis was performed using STATA version 11.1 (Stata Corp., College Station, Texas, US). Continuous data were checked for the normality of the distribution by the Shapiro–Wilk test. Because all the data were not distributed normally, they were described by median and interquartile range (IQR). Categorical data were described in proportions. Comparisons between the study and control groups were performed using the chi-square test or Fisher-exact test for categorical data and the Mann–Whitney test for continuous data. A p-value of <.05 was considered statistically significant.

an and interquartile range (IQR). Categorical data were described in proportions. Comparisons between the study and control groups were performed using the chi-square test or Fisher-exact test for categorical data and the Mann–Whitney test for continuous data. A p-value of <.05 was considered statistically significant. 3 Results Table 1 summarizes the demographics and the amount of EBM expressed in both the study groups. Age and gender were comparable between the two groups. The proportion of neonates receiving EBM on day 1 in the study group was significantly higher than that in the control group. Although the proportion of neonates on exclusive MOM on day 7 did not show significant difference between the two groups, the amount of EBM on days 1, 3, and 7 in the study group was significantly higher than that in the control group.Table 1 Demographics and amount of EBM in study and control group. Table 1Characteristic Study group with quality improvement initiative (n = 30) Control group with no initiative (n = 30) p-value Age (weeks), median (IQR) 30 (27–32) 31 (28–32) .47 Male:female 15:15 12:18 .60 Neonates receiving EBM on Day 1 24 (80%) 6/25* (24%) <.0001 Amount of EBM in ml (Day 1), median (IQR) 1 (1–4) 0 (0–0) <.0001 Amount of EBM in ml (Day 3), median (IQR) 15 (10–40) 6 (0–18) .005 Amount of EBM in ml (Day 7), median (IQR) 115 (60–170) 60 (40–120) .01 Exclusive MOM on Day 7 22 (73.3%) 14 (46.7%) .07 (*Five neonates were kept nil by mouth on day 1, hence excluded from analysis). EBM-Expressed breast milk, MOM-Mother's own milk.

Table 1Characteristic Study group with quality improvement initiative (n = 30) Control group with no initiative (n = 30) p-value Age (weeks), median (IQR) 30 (27–32) 31 (28–32) .47 Male:female 15:15 12:18 .60 Neonates receiving EBM on Day 1 24 (80%) 6/25* (24%) <.0001 Amount of EBM in ml (Day 1), median (IQR) 1 (1–4) 0 (0–0) <.0001 Amount of EBM in ml (Day 3), median (IQR) 15 (10–40) 6 (0–18) .005 Amount of EBM in ml (Day 7), median (IQR) 115 (60–170) 60 (40–120) .01 Exclusive MOM on Day 7 22 (73.3%) 14 (46.7%) .07 (*Five neonates were kept nil by mouth on day 1, hence excluded from analysis). EBM-Expressed breast milk, MOM-Mother's own milk. In the study group, the first milk expression (≤6 h) was observed in 25 subjects (83.3%), and all mothers expressed milk within 24 h. Although all mothers received postnatal counseling, only 18 of them (60%) received antenatal counseling in the study group. Table 2 compares the characteristics between the mothers who received antenatal counseling and those who did not. There appeared to be no effect of antenatal counseling on the expression or quantity of EBM in the study group. Median age of the first EBM in the control group was 2.5 days, whereas, it was lower in the study group (1.16 days).Table 2 Comparison of maternal characteristics in both the groups on basis of antenatal counseling.

ppeared to be no effect of antenatal counseling on the expression or quantity of EBM in the study group. Median age of the first EBM in the control group was 2.5 days, whereas, it was lower in the study group (1.16 days).Table 2 Comparison of maternal characteristics in both the groups on basis of antenatal counseling. Table 2Characteristic Antenatal counseling in the study group (n = 18) No antenatal counseling in the study group (n = 12) p-value Age (weeks), median (IQR) 29.5 (27–31) 31 (30–32) .06 Male:female 6:12 9:3 .06 First milk expression (≤6 h) 15 (83.3%) 10 (83.3%) 1.00 Amount of EBM in ml (Day 1), median (IQR) 1 (0–2.5) 1.5 (1–4) .33 Amount of EBM in ml (Day 3), median (IQR) 15 (12–20) 17.5 (8–66) .50 Amount of EBM in ml (Day 7), median (IQR) 115 (40–130) 132.5 (60–205) .62 Exclusive MOM on Day 7 14 (77.8%) 8 (66.7%) .68 Table 3 compares the secondary outcome measures between the study and control groups. All the measures such as time to reach full enteral feeds, time to regain birth weight, rate of NEC, rate of sepsis, duration of stay, and proportion of babies on exclusive MOM during discharge did not show significant difference between the two groups.Table 3 Secondary outcomes.

s between the study and control groups. All the measures such as time to reach full enteral feeds, time to regain birth weight, rate of NEC, rate of sepsis, duration of stay, and proportion of babies on exclusive MOM during discharge did not show significant difference between the two groups.Table 3 Secondary outcomes. Table 3Characteristic Study group with quality improvement initiative (n = 30) Control group with no initiative (n = 30) p-value Time to reach full enteral feeds (days), median (IQR) 8 (6–11) 9 (6–11) .55 Time to regain birth weight (days), median (IQR) 11 (7–15) 15 (8–17) .34 Necrotizing enterocolitis 1 (3.3%) 3 (10%) .61 Sepsis 4 (13.3%) 5 (16.7%) 1.00 Duration of hospital stay (days), median (IQR) 26 (17–56) 35 (17–60) .42 Exclusive MOM on discharge 18 (64.3%) 14 (48.3%) .34* (*Two babies in the study group and one in the control group died during the hospital stay and were excluded from analysis).

g enterocolitis 1 (3.3%) 3 (10%) .61 Sepsis 4 (13.3%) 5 (16.7%) 1.00 Duration of hospital stay (days), median (IQR) 26 (17–56) 35 (17–60) .42 Exclusive MOM on discharge 18 (64.3%) 14 (48.3%) .34* (*Two babies in the study group and one in the control group died during the hospital stay and were excluded from analysis). 4 Discussion With our simple QI initiative for a short period of three months, we could demonstrate that the formation of a dedicated breastfeeding support group, structured counseling, and presentation of informative leaflets and videos helped in increasing the early and frequent milk expression in mothers and hence increasing the exclusive breastfeeding rates in preterm babies in a busy unit. This QI initiative was based on previously published QI projects on early milk expression in preterm mothers, how special care bundles and structured approach affects MOM use, and benefits of exclusive MOM in preterm and very-low-birth-weight babies [[5], [6], [7], [8], [9], [10], [11]].

preterm babies in a busy unit. This QI initiative was based on previously published QI projects on early milk expression in preterm mothers, how special care bundles and structured approach affects MOM use, and benefits of exclusive MOM in preterm and very-low-birth-weight babies [[5], [6], [7], [8], [9], [10], [11]]. We studied the problems in our unit and planned interventions accordingly. We realized during the observation phase that parents of sick preterm neonates are completely unfamiliar with the NICU environment and hence rely on the healthcare professionals for every kind of support and guidance either before or after the delivery. Evidence suggests that both health care professionals and peer support for mothers contribute to the success of breastfeeding in babies [12,13]. Literature also proposes a positive effect of education and lactation support on maternal decision to provide exclusive MOM for very-low-birth-weight infants and switch over from formula to MOM [[14], [15], [16], [17]]. Although the babies in the intervention group achieved full enteral feeds slightly earlier than those in the control group, the results were not statistically significant and comparable to the study results of Healy et al. [9]. Similar to the results in previous studies [9,18], birth weight was regained earlier in the intervention group, babies also had lesser duration of hospital stay, and there appeared to be a decreased trend in neonatal morbidities such as NEC and sepsis in comparison to the control cohort, although the results were not statistically significant.

previous studies [9,18], birth weight was regained earlier in the intervention group, babies also had lesser duration of hospital stay, and there appeared to be a decreased trend in neonatal morbidities such as NEC and sepsis in comparison to the control cohort, although the results were not statistically significant. In our study, antenatal counseling did not make an impact on the expression or quantity of milk on day 1, 3, and 7. The reason could be the smaller sample size, which is a limitation in the study. Every neonate's mother in the intervention group received postnatal counseling with the help of informative leaflets, videos, and regular visits of the breastfeeding support group providing reassurance and encouragement to all the mothers, which significantly improved the amount of MOM. Our study protocol did not affect the duration of the hospital stay of the mother. Mothers were discharged and followed up with obstetricians as per their postpartum protocol. We provided support to the mothers during the neonatal counseling sessions of their hospital visits and through telephonic conversations as performed in other studies [19].

ffect the duration of the hospital stay of the mother. Mothers were discharged and followed up with obstetricians as per their postpartum protocol. We provided support to the mothers during the neonatal counseling sessions of their hospital visits and through telephonic conversations as performed in other studies [19]. In the future, we plan to continue the quality initiative on a larger scale. Although this study is a very effective initiative for our NICU, the sample size is small. Although support group made every effort that interventions are appropriately placed, it must be acknowledged that these are motivational and behavioral interventions that are user dependent and may not reflect the best practices. Another limitation is that many previous studies enrolled only one of the babies in multiple births, whereas we included all the babies for better clinical correlation, as multiple births formed a considerable proportion of very preterm births. Moreover, we have compared our outcome variables of the intervention group with those of the retrospective cohort, as we cannot have prospective controls of not supporting breastfeeding (randomized controlled trial). 5 Conclusions The team's approach and proper channeling of available resources through a simple quality initiative has resulted in significant improvement in milk expression from mothers who delivered prematurely. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

5 Conclusions The team's approach and proper channeling of available resources through a simple quality initiative has resulted in significant improvement in milk expression from mothers who delivered prematurely. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical statement This work was carried out in accordance with tenets of the Declaration of Helsinki for experiments involving humans. The Institutional Ethics Committee approved the study protocol, and an informed consent was obtained from the mother of the neonates. Declarations of interest None. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Herpes simplex virus 1 (HSV-1) encephalitis (HSE) in children is a serious but manageable condition, where its outcome is mainly dependent on early diagnosis and immediate initiation of treatment. Despite advances in diagnostic methods and antiviral medications, it remains a high-risk condition with significant morbidity and mortality [1]. Recurrent herpes encephalitis in children is an uncommon illness and reports were found in the literature for both adult and pediatric age groups [2]. Although it is rare, the management of such condition is challenging in the sense of treatment dose and duration where the recent Infectious Diseases Society of America guideline has demonstrated that relapses were not documented in increased dose and prolonged period of treatment with acyclovir up to 20 mg/kg every 8 h for 21 days (IDSA guideline). Even though this treatment modality has been used, still there are reported cases of relapses long time up to 5 years after initial treatment had stopped provided negative PCR on follow-up in one of the reported cases [3]. Other treatment modalities were also used and are discussed in the treatment section. For the recurrence of HSE Table 1 [[4], [5], [6], [7], [8], [9]] demonstrate some reports of HSE recurrence among pediatric population with proven presence of HSV using PCR in both episodes of encephalitis to role out other causes, e.g., post-herpetic autoimmune encephalitis provided the fact that most reports in the literature labeled as recurrence of herpetic encephalitis positive PCR in both or at least one of the episodes. Giving these facts, many researches were conducted to provide explanations on the pathogenesis behind the recurrence of HSV encephalitis in immunocompetent hosts. In this study, many aspects of recurrent HSE are explained, and approach is provided so that an optimal management plan can be recommended for children with recurrent HSE.Table 1 Relapsing HSE case reports and their management with proven recurrence in all episodes of HSE by positive PCR for HSV [[4], [5], [6], [7], [8], [9]].

study, many aspects of recurrent HSE are explained, and approach is provided so that an optimal management plan can be recommended for children with recurrent HSE.Table 1 Relapsing HSE case reports and their management with proven recurrence in all episodes of HSE by positive PCR for HSV [[4], [5], [6], [7], [8], [9]]. Table 1Age Gender Type of HSV antiviral/s used Treatment duration Outcome Author and reported time 17 months Not reported Not reported Acyclovir 38 days Death Carpentier et al., 1995 [4] 8 months Not reported Not reported Acyclovir 15 days Severe impairment 4 months Male Not reported Acyclovir Not specifically reported Severe sequalae Kimura et al., 1992 [5] 5 years Female Not reported Acyclovir Moderate sequalae 3 months Male Not reported Acyclovir Not specifically reported Severe sequalae Ito et al., 2000 [6] 5 years Female Not reported Acyclovir Moderate sequalae 8 months Female HSV-2 Acyclovir 3 weeks Language and mental function delay Mandyla et al., 2001 [7] 11 months Male Not reported Acyclovir 3 weeks Mild developmental delay 7 months Girl HSV-1 Acyclovir 6 weeks Clinical improvement Bonkowsky et al., 2006 [8] 10 years Girl HSV-1 Acyclovir 8 weeks Clinical improvement Mario Arturo Alonso-Vanegas et al., 2016 [9]

Language and mental function delay Mandyla et al., 2001 [7] 11 months Male Not reported Acyclovir 3 weeks Mild developmental delay 7 months Girl HSV-1 Acyclovir 6 weeks Clinical improvement Bonkowsky et al., 2006 [8] 10 years Girl HSV-1 Acyclovir 8 weeks Clinical improvement Mario Arturo Alonso-Vanegas et al., 2016 [9] 2 Epidemiology Herpes simplex encephalitis (HSE) annual incidence is 1 in every 250–500 thousand in the developed countries which makes it the most common virus to cause encephalitis. Encephalitis caused by HSV-1 accounts for most of the cases, and it typically affects older children [10]. There is a peak of incidence in early childhood, which does not reflect the age at primary infection [11]. In the United States, the incidence of viral encephalitis, in general, is 20,000 per year and roughly up to 20% of them are caused by HSV-1, and one in every three patients is a child. It used to be known that HSV-2 is an etiological agent in genital herpes and neonatal cases of herpes encephalitis, but recent studies indicate that both HSV-1 and HSV-2 are capable of causing oral and genital herpes where in regard to herpetic encephalitis HSV-1 is the major cause, but still there are some reports link HSV-2 to cause encephalitis in up to 10% of cases mainly in immunocompromised hosts and neonates [10,12,13]. A large study included 4871 hospital admissions of all age groups in the United States admitted under the diagnosis of herpetic encephalitis revealed that mortality rate among neonates and adults were higher than older children [14]. Recurrence of HSE is uncommon, but relapse rate up to 5% was reported. (IDSA).

12,13]. A large study included 4871 hospital admissions of all age groups in the United States admitted under the diagnosis of herpetic encephalitis revealed that mortality rate among neonates and adults were higher than older children [14]. Recurrence of HSE is uncommon, but relapse rate up to 5% was reported. (IDSA). 3 Virology and pathogenesis Herpes simplex virus (HSV) also known as human herpesvirus (HHV) is a double-stranded DNA enveloped virus member of the Herpesviridae family generally categorized into two types HSV-1 and HSV-2. Other members of the family include varicella zoster virus (HHV-3), Epstein–Barr virus (HHV-4), cytomegalovirus (HHV-5), HHV-6, HHV-7, and HHV-8. Both HSV type 1 and 2 viruses are capable of invading human central nervous system and can replicate in the neuronal cells a phenomenon known as neurovirulence [15]. For infection to occur an exposed site of damaged skin (e.g. abrasion) or mucosal surface must come in contact with the virus, then replication of the virus is initiated at the site of primary infection followed by retrograde transport of viral parts toward neural ganglion (dorsal root ganglia) [16]. The pathogenesis of HSV is mainly dependent upon host immune response toward the infection and the mechanism in which HSV invade the brain is still not very well explained, but the established latency of HSV in the trigeminal ganglia where colonized ganglia after a stimulus leads to viral reactivation and appearing as mucocutaneous vesicles and ulcers might give a good explanation to HSE predilection to the frontotemporal lobes by retrograde transport into the CNS through trigeminal or olfactory cranial nerves [17]. HSE of the forebrain is caused by viral migration through the olfactory bulb, whereas HSE of the brainstem is caused by migration via the trigeminal nerve [18].

ve a good explanation to HSE predilection to the frontotemporal lobes by retrograde transport into the CNS through trigeminal or olfactory cranial nerves [17]. HSE of the forebrain is caused by viral migration through the olfactory bulb, whereas HSE of the brainstem is caused by migration via the trigeminal nerve [18]. 4 Genetic predisposition Most primary immunodeficiencies compromise host immunity to be susceptible for most infections, and some may predispose to certain pathogens due to defect in specific immune pathway involved in particular pathogens (e.g. IL-12/IFN gamma deficiency vulnerability to mycobacterial and salmonella infections) [19]. These immunodeficiencies can come in familial and sporadic forms which makes their screening and diagnosis challenging. Herpetic encephalitis in children is involved in some of these primary immunodeficiencies, and mainly due to defects antiviral respond by cellular interferon, but these defects usually predispose to broad infectious susceptibility and other clinical (or immunological) manifestations [20,21]. Lately many reports found in the literature indicating recurrent HSE in the absence of an underlying immunodeficiency and it usually attributed to latent viral reactivation. Recent studies were published indicating single or multiple gene mutations that linked to increased host susceptibility to HSE and its recurrence in some of the cases without compromising immunity to other pathogens (examples found in Table 2 [[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]]). Toll-like receptor 3 (TLR3) pathway defect account for almost 5% of all HSE cases [22]. Most gene mutations found in HSE cases are leading to a defect in interferon-mediated immunity mainly IFN-α/β and λ [23,34]. These genetic etiologies disrupt cell-autonomous immunity in neurons and oligodendrocytes [35]. An observational study was published in 2010 by Abel et al. involved total of 85 children with HSE concluded a high rate of consanguinity (14%) and some were compatible with Mendelian genetic origin of HSV-1 to cause HSE [11]. HSE of the brainstem was recently shown in a multiplex kindred to be caused by mutations in DBR1, which is the RNA lariat debranching enzyme [18]. Interestingly, other viral infections of the brainstem can also be caused by DBR1 mutations.

d some were compatible with Mendelian genetic origin of HSV-1 to cause HSE [11]. HSE of the brainstem was recently shown in a multiplex kindred to be caused by mutations in DBR1, which is the RNA lariat debranching enzyme [18]. Interestingly, other viral infections of the brainstem can also be caused by DBR1 mutations. The genetic etiologies of HSE of the forebrain are mainly due to TLR3-IFN-α/β and their receptor in STAT1 pathways which their mutation would lead to HSE susceptibility of the frontal and temporal lobes of the forebrain.Table 2 Genetic mutations leading to increase susceptibility to herpes simplex encephalitis HSE [[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]]. Table 2Gene Mode of inheritance Other pathogens Report/s IKBKG (NEMO) XL Mycobacteria and other pyogenic infections. Audry et al., 2011 [23] Puel 2006 et al. [24] Filipe-Santos et al., 2006 [25] Niehues et al., 2004 [26] TLR3 AD and AR Zhang et al., 2007 [27] Hye Kyung Lim et al., 2014 [22] TRAF3 AD Pérez de Diego et al., 2010 [28] TBK1 AD Herman et al., 2012 [29] IRF3 AD Andersen et al., 2015 [30] STAT1 AR Other viruses and mycobacterial infections. Dupuis et al., 2003 [31] Chapgier et al., 2006 [32] TRIF AR and AD Sancho-Shimizu et al., 2011 [33] UNC93B1 AR Casrouge et al., 2006 [21]

m et al., 2014 [22] TRAF3 AD Pérez de Diego et al., 2010 [28] TBK1 AD Herman et al., 2012 [29] IRF3 AD Andersen et al., 2015 [30] STAT1 AR Other viruses and mycobacterial infections. Dupuis et al., 2003 [31] Chapgier et al., 2006 [32] TRIF AR and AD Sancho-Shimizu et al., 2011 [33] UNC93B1 AR Casrouge et al., 2006 [21] 5 Clinical presentation In the review of reports found to meet our criteria, the common clinical presentations were abnormal movements/seizure, fever, and altered level of consciousness. Duration of recurrence in majority of the cases varies from 2 weeks up to 1 year and longer durations have been reported. The recurrence has been reported in 50% of pediatric cases with HSE proven by positive PCR for HSV in both episodes while the patients were on Acyclovir. Neurological surgery and treatment with corticotropin for infantile spasms have been reported in patients with recurrent HSE. HSE is strictly limited to the central nervous system. The virus does not disseminate to other tissues or even the bloodstream. Patients with HSE almost never suffer from herpes labialis, not only during HSE but also prior to and after HSE. This reflects the occurrence of HSE during primary infection and its mechanism involving an impairment of CNS-intrinsic immunity. Moreover, the lack of herpes labialis might result from the high proportion of T cells specific for HSV1 in these patients (quote Shen-Ying Zhang's recent paper in Journal of Pediatric Infectious Diseases with the Seattle group) [18].

rimary infection and its mechanism involving an impairment of CNS-intrinsic immunity. Moreover, the lack of herpes labialis might result from the high proportion of T cells specific for HSV1 in these patients (quote Shen-Ying Zhang's recent paper in Journal of Pediatric Infectious Diseases with the Seattle group) [18]. 6 Diagnosis Lumbar puncture (LP) is crucial for the diagnosis of HSE and should be done for all patients with suspension for HSE provide no contraindication such as an elevated intracranial pressure. Elevated protein and pleocytosis with predominance of lymphocyte are the commonest finding in HSE. CSF glucose is usually normal although CSF with low glucose In HSE has been reported. CSF RBCs are usually normal if not traumatic LP unless the patient has advance HSE (necrosis) or hemorrhagic encephalitis which will increase RBCs in CSF. Normal CSF values has been reported in HSE 5–10%. If HSE highly suspected and the initial CSF result is negative, it is advisable to repeat LP [13,36,37]. The gold standard test for diagnosis of HSE is HSV DNA PCR which is highly sensitive and specific (reach up to 96% in both). HSV DNA PCR can yield negative result if the CSF sample tested early in the disease course and it can persist positive for 7–10 days despite acyclovir therapy. HSV antibody in CSF is not helpful for early diagnosis, but it helps in retrospective HSE identification. HSV viral culture in CSF is rarely positive [[38], [39], [40]]. The neuroimaging of choice for HSE diagnosis is MRI brain which is more sensitive and specific than CT scan. Edema, hemorrhage, and necrosis in the inferomedial temporal lobe is the common imagining abnormality. The brain involvement could be unilateral or bilateral. EEG finding is abnormal in the majority of patient. Periodic lateralization epileptiform discharge is characteristic for HSE. Worsening bilateral abnormality with slow wave activity and recurrent periodic complexes are seen in recurrent HSE [3,41,42].

abnormality. The brain involvement could be unilateral or bilateral. EEG finding is abnormal in the majority of patient. Periodic lateralization epileptiform discharge is characteristic for HSE. Worsening bilateral abnormality with slow wave activity and recurrent periodic complexes are seen in recurrent HSE [3,41,42]. 7 Treatment High index of suspicion, early diagnosis and prompt start of antiviral pending diagnosis confirmation is crucial. Intravenous Acyclovir is the mainstay of treatment in addition to supportive management and good hydration. The current recommended dose is 45 mg/kg per day in 3 divided doses in children and 60 mg/kg per day in 3 divided doses for neonate. Acyclovir resistant to HSV which mostly due to mutation of the viral thymidine-kinase gene is rare in immunocompetent patient. Foscarnet is an alternative antiviral for the treatment of acyclovir-resistant HSV. There is controversy about adjuvant corticosteroids therapy for HSE, and it is not routinely recommended, it may be indicated in HSE complicated by vasogenic brain edema. The role of suppressive oral antiviral is not clear and need further study in patients with recurrent HSE. However, there is reported relapsed cases while they are receiving oral acyclovir prophylaxis. [2,7,43,44]. In the future, it is tempting to speculate that additional recombinant IFN-alpha might help some children, especially those whose genetic lesion disrupts the production of endogenous IFNs in the CNS. Clinical trials are warranted to test this hypothesis.

while they are receiving oral acyclovir prophylaxis. [2,7,43,44]. In the future, it is tempting to speculate that additional recombinant IFN-alpha might help some children, especially those whose genetic lesion disrupts the production of endogenous IFNs in the CNS. Clinical trials are warranted to test this hypothesis. 8 Conclusion HSV Encephalitis is a life-threatening condition and associated with high rates of morbidity and mortality. HSV is a well-known virus to establish human latency, and some case reports has linked its reactivation to encephalitis recurrence. Recurrent HSE has been associated with certain gene mutations such as IKBKG (NEMO) and STAT1. As early diagnosis is challenging, rapid empirical initiation of Acyclovir as soon as possible will play a major role in preventing devastating complications. To date, there is no strong recommendation to use oral suppressive antivirals to prevent HSE recurrence. Screening for known mutations that might predispose to HSV recurrence could help in early diagnosis and initiation of treatment of recurrent herpetic encephalitis and for future family counseling. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction In the United States, obesity rates for children have doubled during the past 30 years, with approximately 17% (12.7 million individuals aged 2–19 years) reported as obese (BMI ≥ 95th percentile) [1]. Moreover, evidence suggests that obesity rates vary by age of the cohort, such that during 2011–2012, the obesity rate was 8.9% for children aged 2–5 years old, 17.5% for those aged 6–11 years old, and 20.5% for individuals aged 12–19 years old [1]. The general epidemiological increase in obesity is also associated with a significant increase in medical expenditures, increasing from $78.5 billion in 1998 to $147 billion in 2008 (9% of all medical costs) [2,3]. By 2010, net costs increased to $190.2 billion, or 21% of all medical costs, with $14 billion attributed to childhood obesity alone [[3], [4], [5]]. Although obesity may be noted across all socioeconomic status (SES) strata, not all children appear to be equally at risk for becoming obese [6]. Children and adolescents who live in poverty-stricken areas with a high area deprivation index (ADI) and/or who are ethnic minorities have an increased risk for developing obesity and other comorbidities [[7], [8], [9]]. Lack of physical activity, unsafe neighborhoods, food deserts, and underfunded school districts without consistent exercise and health education programs are some of the many potential factors that may increase the risk for developing and maintaining obesity [6].

eloping obesity and other comorbidities [[7], [8], [9]]. Lack of physical activity, unsafe neighborhoods, food deserts, and underfunded school districts without consistent exercise and health education programs are some of the many potential factors that may increase the risk for developing and maintaining obesity [6]. Despite these alarming trends, historically, obesity has remained among the least addressed comorbidities in all populations, including among children who attend family medicine clinics, despite the fact that family physicians are well positioned to intervene in pediatric obesity [6,[10], [11], [12]]. There has been a call to recognize this potential need at a national level to facilitate appropriate screening and intervention [13,14]. Specifically, family physicians and other health care providers are assigned with identifying risk factors, selecting prevention measures, accurately diagnosing obesity and its severity, and initiating timely treatment plans [6]. Considering that health behaviors learned at a young age have the potential to be carried throughout life, early detection and intervention may nurture the development of lifelong healthy behaviors [15]. Many studies have noted that pediatricians are increasingly underdiagnosing and failing to manage weight-related problems in obese children [16,17]. To improve quality of care in obese children, in 2009, the National Committee for Quality Assurance released the Healthcare Effectiveness Data and Information Set (HEDIS), which contains nationally standardized performance measures. In 2010, the United States Preventive Services Task Force lowered the age for recommended screening for obesity from 6 years to 2 years [18]. Despite this, most family medicine physicians—and primary care physicians in general—report that they do not consistently track children's weight or weight-related problems with time [19]. Population health measurements, including assessments of patterns of comorbidities, are an important first step. Therefore, collecting and analyzing data regarding childhood obesity in family medicine practice could encourage “next steps” in identifying ways to address the extent of the issue in a patient-centered manner [6].

ion health measurements, including assessments of patterns of comorbidities, are an important first step. Therefore, collecting and analyzing data regarding childhood obesity in family medicine practice could encourage “next steps” in identifying ways to address the extent of the issue in a patient-centered manner [6]. This study represents one step toward fulfilling a call in the literature for family physicians to take a larger role in recognition and interventional phases of obesity management in pediatric populations [14,[20], [21], [22]]. To our knowledge, this is the first study employing an exploratory, electronic health record-driven, and population health-based approach to examine differences among obese and nonobese children visiting an academic family medicine practice. This study has three aims: (1) to explore the prevalent patterns in comorbidities among obese and nonobese children, (2) to evaluate patterns of in-network health care utilization among obese and nonobese children, and (3) to assess whether there are potential differences in quality of care among obese and nonobese children using measures from the Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA) 2017 Core Data Set [23].

luate patterns of in-network health care utilization among obese and nonobese children, and (3) to assess whether there are potential differences in quality of care among obese and nonobese children using measures from the Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA) 2017 Core Data Set [23]. 2 Methodology This study was approved by the Thomas Jefferson University (TJU) Institutional Review Board. The children in this study were identified according to their visit to Jefferson's primary academic family medicine practice in downtown Philadelphia, PA, within the study period. Data were obtained from the institution's electronic medical record (EMR). We first reviewed the demographics of all children aged 2–17 years (in 2015) who were patients at the institution's core academic family medicine practice (n = 1982). BMI is automatically calculated in the EMR using the patient's height and weight. BMI scores were then compared using the Centers for Disease Control and Prevention's BMI Percentile Calculator for Child and Teen [24] to determine BMI percentile categories for each patient. Of the 1982 children, 219 of them were obese (BMI of the 95th percentile and higher) in 2015. We then created a comparison group of nonobese children within the same practice using a random sample matched to the obese sample by age categories of 2–5, 6–11, and 12–17 years old (n = 219). Upon subsequent chart review, six children initially placed in the obese category during EMR data extraction were found to not be obese during the study period. Subsequently, these six children were excluded from the study, thus leaving a total of 213 obese and 219 nonobese children (obese, n = 213; nonobese, n = 219).

Upon subsequent chart review, six children initially placed in the obese category during EMR data extraction were found to not be obese during the study period. Subsequently, these six children were excluded from the study, thus leaving a total of 213 obese and 219 nonobese children (obese, n = 213; nonobese, n = 219). ICD-10 diagnosis codes, medications, outpatient primary care and specialty care visits, and in-network emergency department visits and hospital admissions were linked from the EMRs of the hospital system. Chart reviews were conducted for children identified as obese, as well as the matched nonobese children, to confirm the patient's BMI demographic information (age, race, sex, and zip code). Each patient's ADI was calculated. The ADI is a measure of socioeconomic deprivation based on 17 Census measures depending on an individual's nine-digit zip code. The ADI is designed to have a national mean of 100 and a standard deviation of 10, with a higher score indicating greater deprivation [25]. The ADI has been used in prior studies tracking socioeconomic inequalities and their relationship with pediatric health outcomes [26]. The number of ambulatory visits in the study period was abstracted, as well as completion of lead screening and an annual wellness visit during that time.

ting greater deprivation [25]. The ADI has been used in prior studies tracking socioeconomic inequalities and their relationship with pediatric health outcomes [26]. The number of ambulatory visits in the study period was abstracted, as well as completion of lead screening and an annual wellness visit during that time. Data were analyzed using IBM SPSS Statistics 23. To examine differences among the obese and nonobese cohorts, a descriptive analysis including frequencies and percentages for all categorical variables was conducted. An independent-samples t-test was conducted to determine a mean difference in utilization patterns between obese and nonobese patients (aim 2). Chi-square analyses were performed to understand the prevalent patterns in comorbidities among obese and nonobese children (aim 1) and to determine differences in lead screening and annual wellness visit completion among the obese and nonobese children (aim 3).

tion patterns between obese and nonobese patients (aim 2). Chi-square analyses were performed to understand the prevalent patterns in comorbidities among obese and nonobese children (aim 1) and to determine differences in lead screening and annual wellness visit completion among the obese and nonobese children (aim 3). 3 Results The mean age of all pediatric patients in the practice was 9.89 years (m = 9.89; SD = 4.79) with approximately 50% female and 50% male children. Individuals from the three most common racial/ethnic categories were identified as African American/Black (n = 1361; 79.6%), Caucasian (n = 181; 10.6%), and Asian (n = 69; 4%). Among the entire pediatric patient panel, the three most common single medical conditions were asthma (n = 404; 23.6%), obesity (n = 215; 12.6%), and hearing loss (n = 83; 4.9%). A more detailed list of demographics and comorbidities is given in Table 1.Table 1 Demographics of all Pediatric patients at Primary care practice in 2015. Table 1Characteristics Category N = 1710 n (%) Age 2–5 420 (25%) 6–11 591 (35%) 12–17 699 (40%) Sex Female 859 (50%) Male 851 (49.8%) Race African American or Black 1361 (79.6%) Caucasian 181 (10.6%) Asian 69 (4%) Not Reported 74 (4.3%) Native Hawaiian or Other 21 (1.2%) American Indian or Alaskan 2 (.1%) Declined 2 (.1%) Top 10 Comorbidities Asthma 404 (23.6%) Obesity 215 (12.6%) Hearing Loss 83 (4.9%) Hypertension 26 (1.5%) Anxiety 25 (1.5%) Depression 24 (1.4%) Fatigue 20 (1.2%) Weight loss 19 (1.1%) Unspecified Fall 15 (.9%) Gait Instability 12 (.7%)

ive Hawaiian or Other 21 (1.2%) American Indian or Alaskan 2 (.1%) Declined 2 (.1%) Top 10 Comorbidities Asthma 404 (23.6%) Obesity 215 (12.6%) Hearing Loss 83 (4.9%) Hypertension 26 (1.5%) Anxiety 25 (1.5%) Depression 24 (1.4%) Fatigue 20 (1.2%) Weight loss 19 (1.1%) Unspecified Fall 15 (.9%) Gait Instability 12 (.7%) As noted previously, among the 432 (n = 432) pediatric patients examined further, 208 (49%) were obese and 213 (51%) were nonobese. The mean age of obese patients was 12.17 (m = 12.17; SD = 4.05), and the mean age of nonobese patients was 12 (m = 12.34; SD = 3.95). Both obese and nonobese children in the practice had ADIs more than one standard deviation above the mean, thus indicating above-average levels of SES deprivation. Table 2 describes the demographics of the obese and nonobese patient panel used in this study. There were no statistically significant differences between obesity and age, race, and ADIs. Sex and obesity trended toward statistical significance.Table 2 Demographics of obese and nonobese pediatric patients at primary care practice in 2015. Table 2Characteristics Category Obese Nonobese (n = 208) (n = 213) n (%) n (%) Age 2–5 22 (10.5%) 18 (8.5%) 6–11 55 (26.5%) 59 (27.7%) 12–17 131 (62.9%) 136 (64%) Sex* Male 94 (45.2%) 116 (54.5%) Female 114 (54.8%) 97 (45.5%) Race African American or Black 175 (84.1%) 161 (75.6%) White 17 (8.2%) 27 (12.7%) Asian 4 (1.9%) 6 (2.8%) Not Reported 11 (5.3%) 12 (5.6%) Native Hawaiian or Other Pacific Islander 1 (0.5%) 7 (3.3%)

5%) 6–11 55 (26.5%) 59 (27.7%) 12–17 131 (62.9%) 136 (64%) Sex* Male 94 (45.2%) 116 (54.5%) Female 114 (54.8%) 97 (45.5%) Race African American or Black 175 (84.1%) 161 (75.6%) White 17 (8.2%) 27 (12.7%) Asian 4 (1.9%) 6 (2.8%) Not Reported 11 (5.3%) 12 (5.6%) Native Hawaiian or Other Pacific Islander 1 (0.5%) 7 (3.3%) Characteristic Obese Nonobese (n = 208) (n = 213) m (SD) m (SD) Area Deprivation Index 114.72 (8.25) 113.66 (12.53) *P = .057. Chi-squared tests were performed to examine the relationship between obesity status and three characteristics: (1) Most Common Comorbidities, (2) Food or Medication Allergies, and (3) Medications. A significant difference was found in the following four categories in the characteristics Most Common Comorbidities: (1) No Comorbidity on File, (2) Hypertension, (3) Sleep Apnea, and (4) Environmental Allergy as shown in Table 3.Table 3 Comorbidities, food or medication allergies, and medication frequencies and percentages for obese and nonobese children, 2015.

lowing four categories in the characteristics Most Common Comorbidities: (1) No Comorbidity on File, (2) Hypertension, (3) Sleep Apnea, and (4) Environmental Allergy as shown in Table 3.Table 3 Comorbidities, food or medication allergies, and medication frequencies and percentages for obese and nonobese children, 2015. Table 3Characteristics Category Obese (n = 208) Nonobese (n = 213) χ [2] n (%) n (%) Most Common Comorbidities Allergic Rhinitis 70 (33%) 62 (28.6%) .26 Asthma 58 (27.8%) 57 (26.7%) .79 Dermatitis/Eczema 57 (27.4%) 52 (24.4%) .48 Acne 34 (16.3%) 32 (15%) .68 No Comorbidity on File 18 (8.6%) 37 (17.3%) .008b Hearing Loss 13 (6.2%) 12 (5.6) .78 Hypertension 12 (5.7%) 2 (.93%) .006b Iron Deficiency 12 (5.7%) 9 (4.2%) .46 Sleep Apnea 6 (2.8%) 1 (0.46%) .05a Lower Back Pain 6 (2.8%) 2 (0.93%) .14 Depression 5 (2.4%) 5 (2.3%) .97 Acid Reflux 5 (2.4%) 7 (3.2%) .58 Environmental Allergy 1 (0.4%) 13 (6.1%) .001b Food or Medication Allergies Dye/Other 8 (3.8%) 3 (1.4%) .11 Shellfish 3 (1.4%) 1 (.46%) .30 Peanuts 3 (1.4%) 2 (.93%) .63 Medications Contraceptives 9 (4.3%) 10 (4.6%) .85 Sinus/Environmental Allergy 19 (9.1%) 15 (7%) .43 Asthma/Respiratory 21 (10%) 22 (10.3%) .93 Dermatologic 15 (7.2%) 11 (5.1%) .38 Analgesic 7 (3.3%) 2 (.93%) .08 ADD/ADHD 2 (.96%) 6 (2.8%) .16 Psychiatric/Neurologic 3 (1.4%) 4 (1.8%) .72 Genital/Urine 2 (.96%) 1 (.46%) .54 Infection 1 (.4%) 1 (.46%) .98 Diabetes 3 (1.4%) 0 .07 a ≤.05 b <.01

Table 3Characteristics Category Obese (n = 208) Nonobese (n = 213) χ [2] n (%) n (%) Most Common Comorbidities Allergic Rhinitis 70 (33%) 62 (28.6%) .26 Asthma 58 (27.8%) 57 (26.7%) .79 Dermatitis/Eczema 57 (27.4%) 52 (24.4%) .48 Acne 34 (16.3%) 32 (15%) .68 No Comorbidity on File 18 (8.6%) 37 (17.3%) .008b Hearing Loss 13 (6.2%) 12 (5.6) .78 Hypertension 12 (5.7%) 2 (.93%) .006b Iron Deficiency 12 (5.7%) 9 (4.2%) .46 Sleep Apnea 6 (2.8%) 1 (0.46%) .05a Lower Back Pain 6 (2.8%) 2 (0.93%) .14 Depression 5 (2.4%) 5 (2.3%) .97 Acid Reflux 5 (2.4%) 7 (3.2%) .58 Environmental Allergy 1 (0.4%) 13 (6.1%) .001b Food or Medication Allergies Dye/Other 8 (3.8%) 3 (1.4%) .11 Shellfish 3 (1.4%) 1 (.46%) .30 Peanuts 3 (1.4%) 2 (.93%) .63 Medications Contraceptives 9 (4.3%) 10 (4.6%) .85 Sinus/Environmental Allergy 19 (9.1%) 15 (7%) .43 Asthma/Respiratory 21 (10%) 22 (10.3%) .93 Dermatologic 15 (7.2%) 11 (5.1%) .38 Analgesic 7 (3.3%) 2 (.93%) .08 ADD/ADHD 2 (.96%) 6 (2.8%) .16 Psychiatric/Neurologic 3 (1.4%) 4 (1.8%) .72 Genital/Urine 2 (.96%) 1 (.46%) .54 Infection 1 (.4%) 1 (.46%) .98 Diabetes 3 (1.4%) 0 .07 a ≤.05 b <.01 There were no statistically significant differences between obese and nonobese patients regarding their utilization patterns for scheduled visits, their utilization patterns for same-day visits, or in their in-network emergency department visits as shown in Table 4.Table 4 Utilization of Obese and Nonobese Pediatric Patients in our Primary Care Practice in 2015.

erences between obese and nonobese patients regarding their utilization patterns for scheduled visits, their utilization patterns for same-day visits, or in their in-network emergency department visits as shown in Table 4.Table 4 Utilization of Obese and Nonobese Pediatric Patients in our Primary Care Practice in 2015. Table 4Characteristics Category Obese (n = 208) Nonobese (n = 213) t-test m (SD) m (SD) Utilization Routine Care 1.47 (1.24) 1.36 (.959) .30 Same-day Visit 0.51 (.736) 0.39 (.669) .09 Emergency Room 0.06 (.272) 0.02 (.152) .06 There were no significant differences in the wellness check visits between obese (n = 68) and nonobese (n = 65) pediatric patients, χ [2](420) = 0.231, P = .63, or between obese (n = 17) and nonobese (n = 9) lead screening quality measures, χ [2](420) = 2.830, P = .09. 4 Discussion We applied a conceptually population health-based method of analysis among pediatric patients in a large urban, academic family medicine practice. We first aggregated outpatient, emergency department, and inpatient data, with administrative SES data, to produce a nonclaims-based dataset for analysis. We then used cluster analysis to identify general trends in individual disease and comorbid disease among pediatric patients, noting high rates of conditions such as asthma and obesity. Next, we focused on differences in demographics, comorbidities, utilization, and quality of care among the obese pediatric patients and an age-matched random comparison cohort of nonobese children from within the same practice.

isease among pediatric patients, noting high rates of conditions such as asthma and obesity. Next, we focused on differences in demographics, comorbidities, utilization, and quality of care among the obese pediatric patients and an age-matched random comparison cohort of nonobese children from within the same practice. We found that both obese and nonobese pediatric patients in the practice had a high ADI, which indicates a high level of SES deprivation at the nine-digit zip code level. While this reflects the particular community served by the clinic system in this study, it is also consistent with the findings reported in prior literature showing an association between low SES and obesity [6]. Many EMRs have limited information on patients’ SES; however, if zip code information is available, associated ADIs are publically available and can serve as a useful proxy for SES, which can be benchmarked against local, regional, and national averages [25]. Arpilleda and Paul (2012) stated that children who were overweight or obese had a higher risk for comorbidities such as asthma, sleep apnea, hypertension, type II diabetes, and depression [27]. The findings reported in the study was consistent with our findings, shown in Table 4, where sleep apnea had a higher prevalence in obese patients than in nonobese patients in the current study. Additionally, the absence of comorbidities was more common in nonobese children than in obese children.

and depression [27]. The findings reported in the study was consistent with our findings, shown in Table 4, where sleep apnea had a higher prevalence in obese patients than in nonobese patients in the current study. Additionally, the absence of comorbidities was more common in nonobese children than in obese children. Interestingly, more nonobese patients were reported as having environmental allergies than obese children, a finding with mixed support in the literature to date. NHANES III data from 1988 to 1994 showed no association between BMI and a heightened immune response to common allergies [28]. A study of Portuguese children by Silva et al. (2007) showed a small association between childhood BMI and atopic syndrome [29].

hildren, a finding with mixed support in the literature to date. NHANES III data from 1988 to 1994 showed no association between BMI and a heightened immune response to common allergies [28]. A study of Portuguese children by Silva et al. (2007) showed a small association between childhood BMI and atopic syndrome [29]. Multiple conditions that did not reach to the level of statistical significance were present, but these conditions were suggestive. These conditions are important to report because each condition has a potential biological connection with obesity and has been found to be associated with obesity in the literature to date. Our analysis detected an interesting relationship between obesity and lower back pain (P = .14), thus showing that more children who were obese were also diagnosed with lower back pain. Lower back pain has been shown in the literature to be associated with obesity. De Sa Pinto et al. (2006) conducted a cross-sectional study to determine the osteoarticular alterations in obese children and found that 55% (P = .001) of participants had at least one negative bone and joint biomechanical change in the lower lumbar spine due to obesity compared to nonobese children [30].

with obesity. De Sa Pinto et al. (2006) conducted a cross-sectional study to determine the osteoarticular alterations in obese children and found that 55% (P = .001) of participants had at least one negative bone and joint biomechanical change in the lower lumbar spine due to obesity compared to nonobese children [30]. As shown in Table 3, we also found a nonsignificant but suggestive result that our obese pediatric population used the emergency room more often than nonobese children, which is consistent with the findings reported in literature. A study by Trasande and Chatterjee (2009) showed that obese children used the emergency room 11% more than normal-weight children [31]. Arpilleda and Paul (2012) also stated that multiple comorbidities in obese children could increase the amount of emergency room visits each year when compared to nonobese children [26]. We also found a positive correlation between analgesic medications and obesity, which is suggestive while not statistically significant (P = .08) in light of similar findings in the literature. Miller et al. (2010) conducted a study assessing the relationship between inpatient obese children and antimicrobial and analgesic dosing errors at a children's hospital. Miller suggested that obese children (age: 5–12 years) were at a greater risk for analgesic dosing error than nonobese children [32].

the literature. Miller et al. (2010) conducted a study assessing the relationship between inpatient obese children and antimicrobial and analgesic dosing errors at a children's hospital. Miller suggested that obese children (age: 5–12 years) were at a greater risk for analgesic dosing error than nonobese children [32]. Our last interesting relationship was between obese children and diabetes medication (P = .07), thus indicating that more obese children were prescribed diabetes medication, potentially for “pre-diabetes.” Childhood obesity and type II diabetes rates have increased significantly in recent years, especially in youth populations, and although the relationship was not statistically significant in our study sample, these findings suggest that it is important for primary care providers and clinics to remain vigilant about the risk of childhood-onset diabetes [33]. We are encouraged by our finding that obese and nonobese children were equally likely to meet the CHIPRA quality measures of having a wellness visit and blood lead screening, particularly given that adult patients with obesity typically have poorer overall quality of care [29]. This is likely due to population health monitoring by our practice's clinical quality team, which has included efforts to increase lead screening rates and annual wellness visit rates for all pediatric patients.

ing, particularly given that adult patients with obesity typically have poorer overall quality of care [29]. This is likely due to population health monitoring by our practice's clinical quality team, which has included efforts to increase lead screening rates and annual wellness visit rates for all pediatric patients. While the observations and patterns described in this study find support in the literature, they do also represent patient demographics specific to the study site. The methodology presented is nonetheless applicable to many if not most institutions and clinical settings, particularly given the increased uptake of EMRs with reporting capabilities. Our approach thereby may allow other institutions to reveal patterns among their own clinical panels, identify children with obesity and related comorbidities, and, in turn, empower clinical providers to initiate appropriate screening and intervention. Our study represents findings from one large, academic, urban family medicine practice with a unique sample and may not be generalizable to other settings. Additionally, our sample was small and may not have been sufficiently powered to detect significant differences in comorbidities between obese and nonobese children. We also used in-network care data and did not use claims data, which would have permitted the inclusion of data on subjects’ healthcare utilization at nearby centers. Finally, underdocumentation of obesity, a noted challenge in primary care [34,35], may have resulted in some patients being misclassified as nonobese.

a research requirement encourages pediatric residents to become more involved in research and scholarly activities [13,14,16]. However, there have been mixed opinions as to whether a research requirement can help residents in light of concerns that they do not have enough time to acquire pediatric clinical skills [6]. Medical school administrators in various training programs have attempted to develop residents' research skills in pediatrics and other disciplines, such as medicine and surgery [5,[12], [13], [14],17,18]. However, challenges have been met in successfully conducting research during residency training. In the current study, the five cited obstacles to research, in decreasing importance, were a lack of dedicated time, lack of supervision, lack of research infrastructure, lack of interest from staff, and lack of interest from residents. Similar findings were reported by Alhaider et al. [8], who found that a lack of protected time was cited as the main barrier to research training among pediatric residents in seven medical schools in Saudi Arabia. Other factors that were perceived as obstacles included a lack of research skills and knowledge, lack of mentoring, lack of research topics, and lack of ideas for research questions [8].

n. We also used in-network care data and did not use claims data, which would have permitted the inclusion of data on subjects’ healthcare utilization at nearby centers. Finally, underdocumentation of obesity, a noted challenge in primary care [34,35], may have resulted in some patients being misclassified as nonobese. Family medicine practices and primary care institutions may consider applying population health-based methods to identify patterns in diseases and comorbidities among their patient panels, particularly among at-risk cohorts such as obese pediatric patients. 5 Conclusion This exploratory study examined the pediatric population of a large academic urban family medicine practice and found that the obese pediatric population had a higher prevalence of hypertension and sleep apnea and a higher total number of comorbidities, whereas nonobese children had a higher prevalence of environmental allergies. There were no statistically significant differences in single-year in-network health care utilization and selected quality measures. More research is needed to clarify potential patterns of comorbidities among at-risk pediatric patients in family medicine practices to develop targeted interventions. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest The authors declare no conflict of interest. Ethical statement The study was approved by the Institutional Review Board of Thomas Jefferson University.

5 Conclusion This exploratory study examined the pediatric population of a large academic urban family medicine practice and found that the obese pediatric population had a higher prevalence of hypertension and sleep apnea and a higher total number of comorbidities, whereas nonobese children had a higher prevalence of environmental allergies. There were no statistically significant differences in single-year in-network health care utilization and selected quality measures. More research is needed to clarify potential patterns of comorbidities among at-risk pediatric patients in family medicine practices to develop targeted interventions. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest The authors declare no conflict of interest. Ethical statement The study was approved by the Institutional Review Board of Thomas Jefferson University. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Background Child undernutrition is one of the global public health concerns, as it results in irreversible damage to the physical and mental health of children. Undernutrition further impacts adult health and human capital. It accounts for morbidity and premature mortality in developing countries [1]. Undernutrition is known to severely impact children in the first two years of life marked as the critical period [2]. Globally, over a hundred million children are undernourished [3]. India is home to highest proportion of undernourished children in the world [4]. One third of children under the age of five years in the country are stunted, another one third are underweight and about 21% are wasted. A major concern in child undernutrition in the Indian subcontinent is that despite a considerable decline in the prevalence of stunting, the magnitude of wasting has significantly increased across the states [5]. In particular, data on prevalence of undernutrition are scarce among children under two years of age. According to National Family Health Survey 3, the prevalence of stunting was 45% and wasting 23% among children under three years of age [6]. The prevalence of stunting and underweight rapidly increases between 20 and 23 months peaking at 20 months indicating poor infant and young child feeding practices [7]. National Nutrition Monitoring Bureau (NNMB) 2006 identifies undernutrition between 0 and 6 months as 26% that increased to 39% in 12–23 months [8]. It is therefore evident that children in this critical age group manifest growth faltering. Undernutrition if uncorrected during these years may have lasting impact on the development of children.

oring Bureau (NNMB) 2006 identifies undernutrition between 0 and 6 months as 26% that increased to 39% in 12–23 months [8]. It is therefore evident that children in this critical age group manifest growth faltering. Undernutrition if uncorrected during these years may have lasting impact on the development of children. Conventional indicators used for assessment of undernutrition are stunting, wasting and underweight. These indices reflect distinct metabolic changes and are used in determining appropriate nutritional interventions [9]. Developmental economist Peter Svedberg indicated that the conventional indices used for measuring undernutrition overlap and are insufficient for measuring the overall prevalence of undernutrition among children. He suggested that if children with stunting, wasting and underweight are all considered being in a state of anthropometric failure, an aggregate indicator is needed that incorporates all categories of undernourished children. This aggregate indicator, known as the Composite Index of Anthropometric Failure (CIAF) comprises of six categories under which children experiencing one or more forms of anthropometric failure are grouped [10]. This assessment method has been used by several workers to study undernutrition [[9], [10], [11], [12], [13]], and concluded that CIAF identifies a greater percentage as undernourished compared to traditional indices. However, this method too does not address wasting masked by edema or fat [14].

protected time was cited as the main barrier to research training among pediatric residents in seven medical schools in Saudi Arabia. Other factors that were perceived as obstacles included a lack of research skills and knowledge, lack of mentoring, lack of research topics, and lack of ideas for research questions [8]. In Western countries, surveys assessing residents' perceived barriers during residency found that a lack of time, lack of financial support, undefined curricular requirements, and lack of research training during the early years of medical training were cited as perceived obstacles [6,19,20]. It was recently reported [20] that pediatric chief residents believed a lack of time to be the most significant barrier to research, even among those who had more than 8 weeks of protected time. The lack of mentoring has also been cited as one of the major factors precluding participation of residents in research during their training [6,12,14,15,21], which is consistent with our findings.

ilure are grouped [10]. This assessment method has been used by several workers to study undernutrition [[9], [10], [11], [12], [13]], and concluded that CIAF identifies a greater percentage as undernourished compared to traditional indices. However, this method too does not address wasting masked by edema or fat [14]. To further assess the type of undernutrition that is widespread and its severity, Mandal and Bose [15] proposed three other indices viz, Stunting Index (SI), Wasting Index (WI) and Underweight Index (UI), to emphasize the significance of each manifest relative to CIAF. These indices are calculated using the conventional measures of stunting, wasting and underweight along with CIAF. Most prevalence studies assessing undernutrition in India have used Z scores to classify the various forms and severity. Limited studies have used CIAF that assess both the magnitude and severity identifying a combination of two or three manifests coexisting in children. In a developing country setting where the prevalence of undernutrition is high, there is a need to determine the true burden and severity of undernutrition using composite index. This work aimed to assess the prevalence and severity of undernutrition using CIAF and conventional anthropometric indices among children 12–23 months of age. It also evaluated SI, WI and UI to recognize the significance of each manifest of undernutrition relative to CIAF.

Most prevalence studies assessing undernutrition in India have used Z scores to classify the various forms and severity. Limited studies have used CIAF that assess both the magnitude and severity identifying a combination of two or three manifests coexisting in children. In a developing country setting where the prevalence of undernutrition is high, there is a need to determine the true burden and severity of undernutrition using composite index. This work aimed to assess the prevalence and severity of undernutrition using CIAF and conventional anthropometric indices among children 12–23 months of age. It also evaluated SI, WI and UI to recognize the significance of each manifest of undernutrition relative to CIAF. 2 Methodology A cross-sectional study was conducted in government pre-school centers among children aged 12–23 months in Pune district, Maharashtra, India. Considering 36% prevalence of underweight children in Maharashtra, (NFHS-4, 2016) [13] with 5% precision and 95% confidence interval, the sample size estimated was 360 children. Ethics clearance was obtained from Savitribai Phule Pune University's institutional ethics committee. Permission from the authorities was taken to work in various anganwadis under Public Health Centres (PHC). Informed consent from parents was obtained before the commencement of the study. Fig. 1 explains the multistage random sampling technique. Participants both boys and girls were recruited using multistage random sampling technique. Pune district comprises of 13 talukas of which 10 correspond to non-tribal areas. A sample of 328 children representing 10 talukas and 30 anganwadis (government run preschool centers) were recruited. From the remaining three tribal talukas, 32 children representing five anganwadi centers were recruited to achieve the estimated sample size. In all, the study covered seven villages in Pune district. Kuppuswamy scale was used to categorize the socioeconomic status [16]. Infantometer was used to measure length and digital weighing scalewas used to record weight. Z scores for Weight for height (WHZ) height for age (HAZ) and weight for age (WAZ) were calculated as per WHO international growth standards using Anthro Software [17]. The anthropometric measures were further categorized as per CIAF [10,11] provided in Table 1. According to this classification children who have normal HAZ,WAZ, WHZ scores were included under category A. Secondly, children with any one manifest of undernutrition i.e., either stunting or wasting or underweight were categorized under B,C and D respectively. Further, children with any two manifests combined such as wasting and underweight; or stunting and wasting were categorized in divisions E and F respectively. All three manifestations of undernutrition i.e., stunting, wasting and underweight are indicated as G.

underweight were categorized under B,C and D respectively. Further, children with any two manifests combined such as wasting and underweight; or stunting and wasting were categorized in divisions E and F respectively. All three manifestations of undernutrition i.e., stunting, wasting and underweight are indicated as G. Further, to identify the rates of prevalence of stunting, underweight and wasting relative to the overall prevalence, three more indicators Stunting Index (SI), Wasting Index (WI) and Underweight Index (UI) were calculated using the formulas: Wasting Index = Wasting/CIAF; Stunting Index = Stunting/CIAF; and Underweight Index = Underweight/CIAF.Fig. 1 Multistage random sampling of children from Pune district, Maharashtra including tribal and non tribal talukas. Fig. 1Table 1 Classification of anthropometric failure as per CIAF and distribution of participants as per CIAF categories. Table 1Categories of undernutrition [8] Wasting Stunting Underweight N = 360 N % A No failure No No No 89 24.7 B Underweight No No Yes 0 0 C Wasting Yes No No 39 10.8 D Stunting No Yes No 111 30.8 E Stunting and underweight No Yes Yes 57 15.8 F Wasting and underweight Yes No Yes 26 7.2 G Wasting, stunting and underweight Yes Yes Yes 38 10.6

ndernutrition [8] Wasting Stunting Underweight N = 360 N % A No failure No No No 89 24.7 B Underweight No No Yes 0 0 C Wasting Yes No No 39 10.8 D Stunting No Yes No 111 30.8 E Stunting and underweight No Yes Yes 57 15.8 F Wasting and underweight Yes No Yes 26 7.2 G Wasting, stunting and underweight Yes Yes Yes 38 10.6 3 Results The sample consisted of 55% (n = 200) boys and 44% (n = 160) girls. Majority of the children belonged to the lower socio economic status as per Kuppuswamy scale. Distribution of participants as per the categories of undernutrition in CIAF is provided in Table 1. Nearly one fourth (25%) of the children studied were free from any form of undernutrition. Underweight as a single manifest was not observed among any of the children. Wasting was observed among 11%, while stunting was observed among 31% of the children. Combinations of two manifests of undernutrition i. e, stunting and underweight, as well as wasting and underweight were observed among 16% and 7% respectively. A combination of three manifests of undernutrition was observed among 11% of the children.

ved among 11%, while stunting was observed among 31% of the children. Combinations of two manifests of undernutrition i. e, stunting and underweight, as well as wasting and underweight were observed among 16% and 7% respectively. A combination of three manifests of undernutrition was observed among 11% of the children. Table 2 presents the sexwise distribution of rates of wasting, stunting and underweight and their respective indices among the children. It also provides the sexwise prevalence of anthropmetric failure using CIAF. According to the WHO Z score classification total prevalence of wasting was 29%. Of this nearly 58% boys were wasted, compared to 42% girls. Total prevalence of stunting was 58% of whom 59% boys and 41% girls were stunted. Similar observation of high prevalence of underweight was observed among boys (63%) as compared to girls (37%). As per CIAF too, greater percent boys suffered anthropometric failure (57%) as compared to girls (43%). According to CIAF, 75% children suffered from anthropometric failure. Undernutrition relative to CIAF revealed higher stunting index (76) followed by underweight index (47) and wasting index (38).Table 2 Sexwise distribution of rates of stunting, wasting, underweight, and CIAF among children 12–23 months.

girls (43%). According to CIAF, 75% children suffered from anthropometric failure. Undernutrition relative to CIAF revealed higher stunting index (76) followed by underweight index (47) and wasting index (38).Table 2 Sexwise distribution of rates of stunting, wasting, underweight, and CIAF among children 12–23 months. Table 2Categories of malnutrition Boys N = 200 Girls N = 160 Total N = 360 Wasting 60 (58%) 43(42%) 103 (29%) Stunting 123 (59%) 84(41%) 207 (58%) Underweight 76 (63%) 45(37%) 121 (34%) CIAF 154 (57%) 117(43%) 271 (75%) Wasting index (WI) 60/154 = 0.389 43.5/117 = 0.371 103/271 = 38 Stunting Index (SI) 123/154 = 0.798 84/117 = 0.717 207/271 = 76.38 Underweight index (UI) 76/154 = 0. 0.493 45/117 = 0.384 121/271 = 46.64 WI= Wasting/CIAF; SI= Stunting/CIAF; UI= Underweight/CIAF.

(63%) 45(37%) 121 (34%) CIAF 154 (57%) 117(43%) 271 (75%) Wasting index (WI) 60/154 = 0.389 43.5/117 = 0.371 103/271 = 38 Stunting Index (SI) 123/154 = 0.798 84/117 = 0.717 207/271 = 76.38 Underweight index (UI) 76/154 = 0. 0.493 45/117 = 0.384 121/271 = 46.64 WI= Wasting/CIAF; SI= Stunting/CIAF; UI= Underweight/CIAF. 4 Discussion While comparing WHO standards and CIAF to assess undernutrition, this work also indirectly addresses the limitation of a single measure for assessing undernutrition. In contrast to the conventional indices, relative approach used in this study identified the overall magnitude of undernutrition. To the best of our knowledge ours is the first study to assess anthropometric failure using CIAF among children in the critical age group of 12–24 months in India. In this study, we estimated the magnitude of undernutrition using CIAF as 75% which is higher than Z score observations. This high prevalence was not unexpected, as earlier work using composite index have also provided similar results [[11], [12], [13]]. CIAF among preschool children shows prevalence ranging from 26% in Kashmir [18], to 73% in West Bengal [15]. Recent evidence shows > 50% prevalence of anthropometric failure raising public health concern [[19], [20], [21]]. High prevalence of anthropmetric failure indicates simultaneous coexistance of acute and chronic forms of undernutrition in this critical group. The characteristic outcome in this group is growth faltering that has been attributed to the extent and severity of ponderal growth faltering [22]. The outcome of different levels of severity would manifest either as mortality or developmental delay. Non-fatal outcomes due to undernutrition among children are a serious public health concern globally. The Lancet maternal and child health series has quantified deaths as well as disability adjusted life years (DALY) as a consequence of undernutrition emphasing the need for immediate interventions [1,23].

mental delay. Non-fatal outcomes due to undernutrition among children are a serious public health concern globally. The Lancet maternal and child health series has quantified deaths as well as disability adjusted life years (DALY) as a consequence of undernutrition emphasing the need for immediate interventions [1,23]. As observed in other Indian studies [13,15], in our work too stunting emerges as the commonly prevalent type of undernutrition. This calls for strengthening long term interventions to address the intergenerational perpetuation of undernutrition. Between boys and girls in our study, boys showed higher prevalence of stunting, wasting and underweight. Gender differences in nutritional status have been reported in earlier studies as well [[24], [25], [26]]. Culturally if women are given emphasis for their agricultural productivity there is a likelihood for increased attention to female children. There seems to be no biological explanation for male children being more undernourished. Morbidity both symptomatic and asymptomatic has been reported among male children under five years which perhaps could explain the high prevalence of undernutrition among them [27].

ihood for increased attention to female children. There seems to be no biological explanation for male children being more undernourished. Morbidity both symptomatic and asymptomatic has been reported among male children under five years which perhaps could explain the high prevalence of undernutrition among them [27]. Screening for undernutrition is an integral part of the programme of the Ministry of Women and Child Development (MWCD), Government of India [28]. National reports provide data for children under five years [5]. Carefully selected indicators provide right measures of undernutrition. Age appropriate screening and assessment methods are vital to estimate intervention needs. The screening techniques in existing programmes use WAZ to screen underweight, and Mid Upper Arm Circumference (MUAC) to identify extreme wasting. Although targeted interventions for wasting [Severe Acute Malnutrition (SAM) and Modern Acute Malnutrition (MAM)] has been operational in the State, there is a significant increase in wasting. The increased prevalence of wasting in the subcontinent has been attributed to poor maternal health, specifically low prepregnancy BMI, intrauterine growth restriction, acute and severe infections and food insecurity [29]. As the existing interventions follow a curative approach, the likelihood of lack continuum of care as a risk, from the programmatic view cannot be ignored. This could probably be a consequence of screening using single measure for targeted interventions, excluding significant proportions who demonstrate multiple manifests. This is apparent from the NFHS 4 [5] results where there is a decline in one manifest but increase in another. Composite indices for screening and assessment, entwined with continuum of care are likely to address the increase in prevalence of single manifest when another declines. Also, as the manifest of undernutrition varies with age it is important to assess the importance of composite index in different age groups to identify vulnerability and plan age appropriate interventions. Measures to identify common risk factors for any manifest would facilitate in addressing undernutrition relatively.

lso, as the manifest of undernutrition varies with age it is important to assess the importance of composite index in different age groups to identify vulnerability and plan age appropriate interventions. Measures to identify common risk factors for any manifest would facilitate in addressing undernutrition relatively. 5 Conclusion In India, interventions based on current screening appear to harbour a huge burden of undernourished children in the vulnerable group suggesting the need for a composite index for screening, assessment and intervention. Ethical statement The study was approved by the institutional ethics committee of Savitribai Phule Pune University. Informed consent was obtained from parents before commencement of the study. Conflicts of interest The authors declare no conflict of interest. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Pediatric health research is necessary to improve children's health and well-being, as well as that of their families. In pediatric medicine, significant scientific and clinical advancements are made when pediatric residents can hone their research skills. Furthermore, by facilitating scholarly thinking, a larger proportion of graduates will pursue physician-scientist careers, and future pediatricians will have acquired the research skills required to become research mentors [1,2].

nd clinical advancements are made when pediatric residents can hone their research skills. Furthermore, by facilitating scholarly thinking, a larger proportion of graduates will pursue physician-scientist careers, and future pediatricians will have acquired the research skills required to become research mentors [1,2]. To develop residents' competencies in research, the professional associations and academic institutions responsible for medical training have acknowledged that scholarly activity is a crucial element of residency training. The Royal College of Physicians and Surgeons of Canada stipulates that physicians should strive to master their skills in research and implement a planned strategy to learning to improve in each CanMEDS role [3]. They should also be able to discern pertinent evidence, using specified criteria to evaluate the data, disseminate medical knowledge, and apply their findings in clinical practice and scholarly activities—which constitute one of the seven key competencies that residents must achieve during residency [3]. Other professional bodies, such as the Accreditation Council for Graduate Medical Education, acknowledge that research is an essential component of residency training programs. The Accreditation Council for Graduate Medical Education also supports the idea that residents should be encouraged to participate in scholarly activities and acquire knowledge of the fundamental principles of research, including the conception and conducting of research, the evaluation of data, the involvement of patients, and the application of research findings to patient care [4].

rts the idea that residents should be encouraged to participate in scholarly activities and acquire knowledge of the fundamental principles of research, including the conception and conducting of research, the evaluation of data, the involvement of patients, and the application of research findings to patient care [4]. Nevertheless, many pediatric leaders have voiced concerns that pediatric residency programs do not sufficiently expose residents to research training, and consequently, pediatric graduates and pediatricians do not have the skills to appraise and implement scientific findings to solve practical problems in the clinical setting [1,5,6]. This deficiency is especially true in Saudi Arabia, where research activity and training are not fully incorporated into the curricula of residency programs [7]. Furthermore, a cross-sectional survey conducted in 2013 of residents enrolled in pediatric training programs in Saudi Arabia showed that although trainees were interested in participating in research, few trainees had the opportunity to do so [8]. The current study investigates pediatric residents' involvement in research and their attitudes toward potential barriers to conducting research. 2 Methods 2.1 Participants This cross-sectional survey was conducted in February 2017 and targeted residents enrolled in the Saudi Pediatric Residency Program. A total of 1052 residents were enrolled in the program, and the size of the calculated representative sample was 282 participants (95% confidence interval and 5% marginal error).

icipants This cross-sectional survey was conducted in February 2017 and targeted residents enrolled in the Saudi Pediatric Residency Program. A total of 1052 residents were enrolled in the program, and the size of the calculated representative sample was 282 participants (95% confidence interval and 5% marginal error). 2.2 Ethical consideration Permission to conduct this survey was obtained from the Institutional Review Board of King Saud University. Participation in the survey was voluntary and potential participants were assured of the confidentiality of their responses. 2.3 Questionnaire distribution The questionnaire was designed with SurveyMonkey (https://www.surveymonkey.com), and the survey link was provided in the invitation email that was sent to potential participants using the Saudi Commission for Health Specialties' emailing groups. Reminders were sent twice within a 4-week period to nonrespondents to ensure maximum participation in the survey. 2.4 Survey instrument After review of the published literature, a structured questionnaire was developed to determine residents' perceptions of their competencies and training needs based on the CanMEDS competency framework. A multidisciplinary team reviewed the questionnaire and produced the final version after a pilot test had been conducted to detect flaws in the questionnaire in terms of content and format. Questions were edited out of the questionnaire when they were marked as unclear.

needs based on the CanMEDS competency framework. A multidisciplinary team reviewed the questionnaire and produced the final version after a pilot test had been conducted to detect flaws in the questionnaire in terms of content and format. Questions were edited out of the questionnaire when they were marked as unclear. The questionnaire was designed to assess residents' involvement in different domains of scholarly activity and their perception of barriers to research. All items used a five-point Likert-type scale, with response options varying depending on the question. Residents were asked to rate their involvement in different domains of scholarly activity on a scale from 1 to 5, with 1 meaning no involvement at all, and 5 meaning extremely involved. Similarly, they were asked to rate their perception of obstacles to research training on a scale from 1 to 5, with 1 meaning not an obstacle at all, and 5 meaning always an obstacle. 2.5 Statistical analysis IBM SPSS Statistics for Windows version 23 (IBM, Armonk, NY, United States) was used to analyze the data. Descriptive statistics were computed for all study variables. Continuous variables are expressed as means and standard deviations (SDs), whereas categorical and binary variables are expressed as numbers and percentages.

PSS Statistics for Windows version 23 (IBM, Armonk, NY, United States) was used to analyze the data. Descriptive statistics were computed for all study variables. Continuous variables are expressed as means and standard deviations (SDs), whereas categorical and binary variables are expressed as numbers and percentages. The internal consistency of the questionnaire was analyzed with use of Cronbach's α coefficient. A summative analysis and the recode features in IBM SPSS Statistics were then used to compute the mean and SD for each of the indicators that formed the main perceptive concepts of the study. The relative importance index (RII) was used to analyze the relative contribution of each indicator to its main theme. This statistic is a reliable way of identifying the top and bottom key relevant perceptions in terms of weighted contribution. The method described by Holt [9] was used to compute the RII. 3 Results The total number of pediatric residents who agreed to complete the survey (n = 314) represents approximately 111% of the calculated representative sample. Women formed more than half of the sample (n = 168; 53.5%). Most of the residents were younger than 30 years (82.2%), and approximately 25.5% were in their fourth year of residency training. Residents hailed from all regions of Saudi Arabia, but those from the central province were the most heavily represented (48.7%) (Table 1).Table 1 Sociodemographic characteristics of the respondents.

e residents were younger than 30 years (82.2%), and approximately 25.5% were in their fourth year of residency training. Residents hailed from all regions of Saudi Arabia, but those from the central province were the most heavily represented (48.7%) (Table 1).Table 1 Sociodemographic characteristics of the respondents. Table 1Variable Number Percentage Age 25–30 years 258 82.2 >30 years 56 17.8 Sex Male 146 46.5 Female 168 53.5 Residency level R1 72 22.9 R2 46 14.6 R3 70 22.3 R4 80 25.5 Graduated R5 46 14.6 Region Eastern 46 14.6 Western 106 33.8 Northern and southern 9 2.9 Central 153 48.7 Table 2 shows the means, SDs, and RIIs for respondents' responses and how they ranked their perception of research involvement and obstacles to research training. In general, residents rated their involvement in all aspects of research as low. Specifically, the top-ranked item was residents' participation in data collection for research (mean [SD] rating, 2.74 [1.3]; RII, 54.2%), followed by residents' participation in a structured literature review of a topic (mean [SD] rating, 2.6 [1.3]; RII, 52.1%) and residents' involvement in preparing research proposals for submission to an institutional review board (mean [SD] rating, 2.55 [1.3]; RII, 50.97). The lowest-rated items were residents' involvement in manuscript writing (mean [SD] rating, 2.3 [1.24]; RII, 46.1%) and residents' participation in statistical analysis (mean [SD] rating, 1.23 [1.21]; RII, 44.5%).Table 2 Residents' perceived level of involvement in scholarly activities during their training.

I, 50.97). The lowest-rated items were residents' involvement in manuscript writing (mean [SD] rating, 2.3 [1.24]; RII, 46.1%) and residents' participation in statistical analysis (mean [SD] rating, 1.23 [1.21]; RII, 44.5%).Table 2 Residents' perceived level of involvement in scholarly activities during their training. Table 2Indicator Mean (SD) RII (%) Rank Research involvement level Literature review 2.6 (1.3) 52.08 2 Research proposal and IRB application drafting 2.55 (1.3) 50.97 3 Data collection for research 2.74 (1.3) 54.74 1 Biostatistical analysis 1.23 (1.21) 44.53 5 Manuscript writing 2.3 (1.24) 46.08 4 Research obstacles Lack of dedicated time 3.44 (1.3) 68.83 1 Lack of supervision 3.27 (1.29) 65.32 2 Lack of interest from residents 2.85 (1.2) 56.96 5 Lack of interest from staff 3.12 (1.28) 62.36 4 Lack of research infrastructure (e.g., no research assistants or data analysts) 3.14 (1.41) 62.74 3 RII, relative importance index; SD, standard deviation. The residents ranked the lack of dedicated time as the most significant barrier to their participation in scholarly activities (mean [SD] rating, 3.44 [1.3]; RII, 68.83%). Conversely, they ranked the lack of interest as the lowest barrier to research participation (mean [SD] rating, 2.85 [1.2]; RII, 56.96%).

Table 2Indicator Mean (SD) RII (%) Rank Research involvement level Literature review 2.6 (1.3) 52.08 2 Research proposal and IRB application drafting 2.55 (1.3) 50.97 3 Data collection for research 2.74 (1.3) 54.74 1 Biostatistical analysis 1.23 (1.21) 44.53 5 Manuscript writing 2.3 (1.24) 46.08 4 Research obstacles Lack of dedicated time 3.44 (1.3) 68.83 1 Lack of supervision 3.27 (1.29) 65.32 2 Lack of interest from residents 2.85 (1.2) 56.96 5 Lack of interest from staff 3.12 (1.28) 62.36 4 Lack of research infrastructure (e.g., no research assistants or data analysts) 3.14 (1.41) 62.74 3 RII, relative importance index; SD, standard deviation. The residents ranked the lack of dedicated time as the most significant barrier to their participation in scholarly activities (mean [SD] rating, 3.44 [1.3]; RII, 68.83%). Conversely, they ranked the lack of interest as the lowest barrier to research participation (mean [SD] rating, 2.85 [1.2]; RII, 56.96%). 4 Discussion An assessment for improvement is necessary to gain insight into how well residents participate in programs and use the knowledge acquired during their training. Curriculum developers and scientific committee members can then use the findings of such an assessment to improve the pedagogical approaches to learning [10,11]. However, since the Saudi Commission for Health Specialties implemented a dedicated scholarly research program (involving 8 weeks of research rotation) in the pediatric residency program in 2014 [8], no study has been formally conducted to assess the efficacy of a scholarly concentration program in promoting research involvement among pediatric residents. The research program was divided into two parts, each lasting 4 weeks. The first part included a basic module on the fundamental principles of clinical research and was offered during the second year of training, and the second part—an advanced module that focused mainly on statistical analysis and methods of research communication—was offered in the third year of residency training.

eks. The first part included a basic module on the fundamental principles of clinical research and was offered during the second year of training, and the second part—an advanced module that focused mainly on statistical analysis and methods of research communication—was offered in the third year of residency training. Currently available data are limited to residents' productivity in research, as well as their perceptions of factors precluding them from participating in research. The present research expands on previous research regarding pediatric residents' perceptions of barriers to research training in Saudi Arabia [8]. Furthermore, it attempts to identify the level of involvement of pediatric residents in different research domains.

f factors precluding them from participating in research. The present research expands on previous research regarding pediatric residents' perceptions of barriers to research training in Saudi Arabia [8]. Furthermore, it attempts to identify the level of involvement of pediatric residents in different research domains. These analyses show that residents rate their involvement in all aspects of research as low, with the top-ranked items being their involvement in collecting data for research and preparing a structured literature review of a topic. Manuscript writing and participation in statistical analysis were the lowest-rated items. While several studies have addressed pediatric residents' involvement in research [6,[12], [13], [14]], much of the published literature originates from North America. The existing literature suggests that although resident research training is an integral part of most residency training programs [14], scholarly activity involvement is suboptimal among pediatric residents [6]. Research involvement among pediatric residents has been reported to range between 14% and 26% in studies conducted in the United States [1,15]. Previous studies mainly support the theory that a research requirement encourages pediatric residents to become more involved in research and scholarly activities [13,14,16]. However, there have been mixed opinions as to whether a research requirement can help residents in light of concerns that they do not have enough time to acquire pediatric clinical skills [6].

lack of time to be the most significant barrier to research, even among those who had more than 8 weeks of protected time. The lack of mentoring has also been cited as one of the major factors precluding participation of residents in research during their training [6,12,14,15,21], which is consistent with our findings. Before the introduction of a dedicated scholarly research program in the pediatric residency program in 2014, research training was not incorporated in any practical sense into the curricula of Saudi residency programs [7]. Although a needs assessment was conducted in 2015 to support the development of a research curriculum for Saudi pediatric residency, there is a general lack of evidence for the best strategy to adopt to encourage the culture of a residency training program in our context. As training centers consider strategies to tackle these obstacles, the focus should be placed on the need to cultivate and recruit faculty members who can mentor and instruct residents and fellows in several aspects of research. Other obstacles, such as a lack of infrastructure, can be circumvented by the creation of a collective research activity among the training centers and investment in infrastructure, especially staffing, to encourage the involvement of residents in research. Additionally, training centers should have a core curriculum and allocate protected time.

lack of infrastructure, can be circumvented by the creation of a collective research activity among the training centers and investment in infrastructure, especially staffing, to encourage the involvement of residents in research. Additionally, training centers should have a core curriculum and allocate protected time. This study has several limitations, including those inherent to cross-sectional studies. We cannot exclude the possibility that some conditions may have caused a response bias, including interest in the survey topic. Furthermore, our study design makes it hard to determine where respondents rate with respect to response bias. 5 Conclusion Overall, pediatric residents rated their involvement in all aspects of research as low, especially in manuscript writing and statistical analysis. This underscores the need to focus more on manuscript preparation and statistical analysis of data obtained from a basic laboratory and/or clinical research setting. Furthermore, we identified some barriers to research participation, including a lack of dedicated time, lack of mentorship, lack of research infrastructure, lack of interest from staff, and lack of interest from residents. These findings suggest the need to provide support for the development of a mentoring program as well as to develop a robust and longitudinal research curriculum for the pediatric residency program to encourage the involvement of trainees in research.

e, lack of interest from staff, and lack of interest from residents. These findings suggest the need to provide support for the development of a mentoring program as well as to develop a robust and longitudinal research curriculum for the pediatric residency program to encourage the involvement of trainees in research. Additionally, pediatric residents need more dedicated research time, a mentorship program, and a better research infrastructure to increase their involvement in several aspects of research. Acknowledgments The author thanks the residents who participated in this survey and the staff of the Academic Department at the Saudi Commission for Health Specialties for facilitating the delivery of the survey to pediatric residents across Saudi Arabia. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Background and Objectives Provision of antiretroviral therapy (ART) for prevention of mother-to-child transmission of HIV (PMTCT) has reduced risk of perinatal transmission to 2–5%, vs. 30–40% without PMTCT [1]. The efficiency of PMTCT has limits, however, as inevitably some children are still infected with HIV, requiring care and support. Indeed, 150,000 children worldwide became infected with HIV in 2015, including 19,000 in Asia and the Pacific, and 190,000 youth now live with HIV in that region [2]. In 2015, 41% of HIV-infected children under age 15 in the region received ART—over a 50% increase compared to 2010 [2], [3]. In China, substantial progress has been made in PMTCT among mother-infant child pairs registered in care, but there are still concerning gaps in access, as in 2013, the overall HIV perinatal transmission rate was 17.4% when including transmissions outside the PMTCT care continuum [4]. Pediatric ART is widely available in the country, and it is estimated that 59% of all HIV-infected children accessed ART in 2015, compared to 52% in 2013 [5]. There is also a rising concern in China about new infections among youth; in 2015, 14.7% of all new infections in the country were among young people aged 15 to 24 [6].

ic ART is widely available in the country, and it is estimated that 59% of all HIV-infected children accessed ART in 2015, compared to 52% in 2013 [5]. There is also a rising concern in China about new infections among youth; in 2015, 14.7% of all new infections in the country were among young people aged 15 to 24 [6]. With increasing access to ART, HIV-infected youth are living well through adolescence and into adulthood [7]. While a relatively small group, youth face unique challenges in receiving care and support, particularly adolescents. Adolescents living with HIV (ALHIV) must navigate the transition from childhood to adulthood while managing a highly stigmatized condition. Given both ethical considerations surrounding an individual's ‘right to know’ and public health concerns about HIV transmission [8], [9], it is critical that ALHIV know their HIV status. Although international guidelines such as those published by the World Health Organization recommend disclosure of HIV to school-aged children [10], [11], disclosure is inherently difficult. Consequently, in many contexts, complete disclosure is often delayed through adolescence [12].

that ALHIV know their HIV status. Although international guidelines such as those published by the World Health Organization recommend disclosure of HIV to school-aged children [10], [11], disclosure is inherently difficult. Consequently, in many contexts, complete disclosure is often delayed through adolescence [12]. Caregivers may be reluctant to disclose to adolescents for numerous reasons, including concerns about negative emotional impacts on children [12], [13], [14], [15], [16]; fear of resentment [16], [17]; feelings of guilt in transmitting the virus [12], [16], [18], [19]; and discomfort in discussing HIV transmission [20]. For HIV-positive parents, informing an older child of his/her status may entail disclosure of their own HIV infection [21]. Parents may fear that the adolescent will be unable to maintain secrecy [13], [14], [15], [17], [19], risking stigma and isolation for the entire family [13], [14], [15], [19], [22]. Moreover, some parents may avoid discussion of HIV with their adolescent child because of their own denial, struggles coping with HIV, and negative experiences with disclosure and stigma [11], [13], [18], [22]. Finally, many caregivers report feeling that they lack the skills necessary to disclose, especially answering questions in an accurate, age-appropriate manner [13], [14], [16], [18], [23].

because of their own denial, struggles coping with HIV, and negative experiences with disclosure and stigma [11], [13], [18], [22]. Finally, many caregivers report feeling that they lack the skills necessary to disclose, especially answering questions in an accurate, age-appropriate manner [13], [14], [16], [18], [23]. In China, where culture emphasizes family honor (“face”), disclosure may be particularly daunting for families and health care providers [15], [24], [25]. Although several studies in China have focused on parental disclosure of their own HIV status to their children [21], [25], [26], there is no published evidence regarding disclosure of HIV-infected children's HIV status to the children themselves. Given the increasing numbers of ALHIV in China, and indications from providers that ALHIV face numerous challenges including poor ART adherence, we conducted a study in Nanning, China that included piloting use of adherence monitoring devices among ALHIV [27]. Using qualitative methods, we also explored issues related to medication adherence, understanding of HIV, and disclosure of HIV status to ALHIV with clinicians, parents of ALHIV, and the ALHIV themselves. To help fill the gap in understanding of HIV disclosure issues with ALHIV, here we provide findings from our investigation of practices for disclosure to ALHIV among Chinese caregivers and clinicians, and the disclosure experiences of the adolescents themselves.

h clinicians, parents of ALHIV, and the ALHIV themselves. To help fill the gap in understanding of HIV disclosure issues with ALHIV, here we provide findings from our investigation of practices for disclosure to ALHIV among Chinese caregivers and clinicians, and the disclosure experiences of the adolescents themselves. 2 Methods and materials 2.1 Design and Setting The study was conducted in 2014 at the Guangxi Center for Disease Control and Prevention ART (CDC-ART) clinic in Nanning, China, where at the time of the study, 370 children aged 15 years and younger were in HIV care and treatment. All adolescent patients had contracted HIV perinatally, were on three-drug NNRTI-based regimens taken twice daily, and obtained their medications monthly. We planned four focus group discussions (FGDs) with adolescents in two age groups (10–12 years; 13 years and older) and one with HIV clinicians; and forty in-depth interviews (IDIs) with twenty adolescent/caregiver dyads.

were on three-drug NNRTI-based regimens taken twice daily, and obtained their medications monthly. We planned four focus group discussions (FGDs) with adolescents in two age groups (10–12 years; 13 years and older) and one with HIV clinicians; and forty in-depth interviews (IDIs) with twenty adolescent/caregiver dyads. 2.2 Procedures With assistance from clinicians, we purposively sampled ALHIV aged 10 years and older who were receiving care at the study clinic for both IDIs and FGDs. All patients aged 10 years and older were eligible to participate, along with their caregivers. Knowledge of HIV status was not a prerequisite for participation. Adolescents participated in an IDI, a FGD, or both. All clinic personnel involved in patient care were eligible to participate in the clinician FGD. IDIs and FGDs were conducted in Mandarin Chinese by two trained interviewers in a private room at the CDC-ART clinic using semi-structured interview guides. Sessions were audio-recorded; one interviewer took notes. Respondents were given a small stipend to cover transport.

eligible to participate in the clinician FGD. IDIs and FGDs were conducted in Mandarin Chinese by two trained interviewers in a private room at the CDC-ART clinic using semi-structured interview guides. Sessions were audio-recorded; one interviewer took notes. Respondents were given a small stipend to cover transport. Adolescent IDIs explored youths' understanding of their medication, how they had learned about their condition, and their challenges taking medications. FGDs with adolescents focused on respondents' understanding of their condition and medication-taking, including challenges and strategies. As not all adolescents knew their HIV status, interviewers did not refer explicitly to HIV unless participants themselves spoke openly about it, indicating awareness of their status. IDIs with caregivers explored disclosure to the participant's child and future plans for disclosure, in addition to challenges related to adherence. The FGD with clinicians focused on perceptions of challenges faced by ALHIV and caregivers related to medication-taking, adherence, stigma, and disclosure, in addition to clinicians' role in supporting adherence and disclosure.

ant's child and future plans for disclosure, in addition to challenges related to adherence. The FGD with clinicians focused on perceptions of challenges faced by ALHIV and caregivers related to medication-taking, adherence, stigma, and disclosure, in addition to clinicians' role in supporting adherence and disclosure. 2.3 Data analysis Recordings were transcribed, supplemented by written notes, and translated into English by a bilingual translator. We coded and analyzed the English-language transcripts using NVivo™ software. Following a grounded theory approach, we summarized major themes related to disclosure, and explored all reports of disclosure experiences and challenges. While our analysis highlighted important themes based on how often they were raised by participants, we considered the full spectrum of experiences, including divergent accounts. 2.4 Ethical considerations Institutional Review Boards at Boston University Medical Center; the National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention in Beijing; and the Guangxi Provincial Center for Disease Control in Nanning approved the study. Caregivers provided written informed consent prior to enrollment for their own and their child's participation, adolescents provided written assent, and clinicians provided written consent.

or Disease Control and Prevention in Beijing; and the Guangxi Provincial Center for Disease Control in Nanning approved the study. Caregivers provided written informed consent prior to enrollment for their own and their child's participation, adolescents provided written assent, and clinicians provided written consent. 3 Results We conducted five FGDs (four with adolescents, one with clinicians) and thirty-eight IDIs with 19 adolescent/caregiver dyads. A total of 61 individuals participated. Five ALHIV participated in both an IDI and a FGD. Demographic features of adolescent and caregiver participants are summarized in Table 1, Table 2. The mean age of adolescent participants was 12.0 years (SD 1.9 years); the majority (21/35) were male. Most caregivers (11/19) were mothers of ALHIV and had primary school education. Participants in the older FGDs all knew their status; the proportion of participants in younger FGDs that knew their status is uncertain. Participants in the clinician FGD were all female and included four nurses, one physician, one counselor, and the clinic's administrative director.Table 1 Characteristics of adolescent respondents (N = 35). Table 1Characteristics In-depth interviews (IDIs) only (N = 14) Focus group discussions (FGDs) only (4 FGDs; n = 16) Both IDIs and FGDs (n = 5) N (%) or Mean (SD) N (%) or Mean (SD) N (%) or Mean (SD) Gender (female) 3 (21.4) 9 (56.2) 2 (40.0) Age (years) 12.1 (1.6) 11.6 (2.1) 13.0 (1.6) Table 2 Characteristics of caregiver respondents (N = 19).

epth interviews (IDIs) only (N = 14) Focus group discussions (FGDs) only (4 FGDs; n = 16) Both IDIs and FGDs (n = 5) N (%) or Mean (SD) N (%) or Mean (SD) N (%) or Mean (SD) Gender (female) 3 (21.4) 9 (56.2) 2 (40.0) Age (years) 12.1 (1.6) 11.6 (2.1) 13.0 (1.6) Table 2 Characteristics of caregiver respondents (N = 19). Table 2Characteristic N (%) or Mean (SD) Gender (female) 10 (52.6) Age (years) 42.1 (11.7) Relationship to child Mother 11 (57.9) Father 5 (26.3) Grandparent 3 (15.8) Education level Primary 11 (57.9) Middle school 5 (26.3) Secondary school or higher 3 (15.8) Analysis of IDIs and FGDs revealed several clear themes, encompassing: disclosure as a process, fear of stigma, concern about children's reactions on the part of caregivers and clinicians, and caregivers' feelings of inadequate preparedness and skills to carry out full disclosure. Additional issues encompassed debate about who is the most appropriate party to lead disclosure to a child and recognition of disclosure and the importance of understanding one's status to promote successful treatment and good adherence. We present the main themes below, with supplementary statements organized by theme in Table 3.Table 3 Supplementary statements by theme.

most appropriate party to lead disclosure to a child and recognition of disclosure and the importance of understanding one's status to promote successful treatment and good adherence. We present the main themes below, with supplementary statements organized by theme in Table 3.Table 3 Supplementary statements by theme. Table 3Caregivers' impressions of disclosure as a process He is still young now. I have the feeling that he may not be able to understand this, and that's why we haven't told him yet. (IDI, mother of 10 year-old boy) I should tell her slowly and little by little. After all, she is growing up and she will learn a lot of things on her own. (IDI, mother of 12 year-old girl) We have told her this. When she grew up, and began to understand a little. She knows that she has this disease. We told her how she got infected, and she understood. However, she is a kid after all, and cannot understand this disease very well. That's probably why she doesn't take her medication seriously enough. I plan to tell her clearly when she gets a little older. (IDI, mother of 14 year-old girl) I have told her about her condition. But she doesn't really understand about the harm of this disease. I'll probably tell her when she is 14 or 15. She will have better understanding then. (IDI, mother of 11 y-o girl) Some older kids asked me why they were on medication, because they did not know about their condition. They wonder why they were taking so many drugs every day and when they could stop. (FGD, clinician) She won't be able to understand now even if I told her. All she knows is to take her medicine. She doesn't understand this condition at all. (IDI, mother of 11 year-old girl) … he is too young now. He wouldn't understand even if we tell him. (IDI, mother of 10 year-old boy) We don't let her read those materials displayed in the clinic. We are afraid that she might know. Let her learn about it gradually when she grows up. (IDI, grandmother of 10 year-old girl) He is 14 now. We plan to wait and discuss with him when he is 18 or 19. At that time, we would talk to him about having a girlfriend. We will probably tell him to be careful and not to infect his girlfriend. (IDI, mother of 14 year-old boy) He should be able to understand slowly. I ask the counselors here and she told me to discuss this with him little by little. (IDI, mother of 14 year-old boy) He does, a little. We have told him some vaguely since two or three years ago, but he is probably not 100 per cent clear.

friend. (IDI, mother of 14 year-old boy) He should be able to understand slowly. I ask the counselors here and she told me to discuss this with him little by little. (IDI, mother of 14 year-old boy) He does, a little. We have told him some vaguely since two or three years ago, but he is probably not 100 per cent clear. (IDI, mother of 14 year-old boy) Full disclosure to young child: one example He knows everything. We have already explained to him when he was little … We just said that this disease was serious. (IDI, father of 14 year-old boy)

friend. (IDI, mother of 14 year-old boy) He should be able to understand slowly. I ask the counselors here and she told me to discuss this with him little by little. (IDI, mother of 14 year-old boy) He does, a little. We have told him some vaguely since two or three years ago, but he is probably not 100 per cent clear. (IDI, mother of 14 year-old boy) Full disclosure to young child: one example He knows everything. We have already explained to him when he was little … We just said that this disease was serious. (IDI, father of 14 year-old boy) Adolescents' accounts of learning HIV status themselves I read the label on my pill bottles and the instructions. (IDI, boy, age 13) I learned about it when I went to the hospital, in recent years. I read [the results] myself, and I learned more about it later, slowly. (FGD, girl, age 17) Eavesdropping. On my parents. (FGD, 13 year-old boy) [I learned when I was] about 6 or 7 years old. [My parents] dared not to tell me at the beginning, but I found out myself later. I didn't learn from here. I learned it from promos on TV. I asked my mum what that disease was, and my mum told me that's what we have. At that time, I didn't know exactly what it was, I learned about it later slowly. (FGD, boy, age 15) We haven't talked about this officially, but he loves internet, so he has probably looked them up on the Internet. There are labels on the pill bottle, he should know. He never asked me, but I didn't talk to him about this either … I think he knew two years ago. Once when we argued, he asked ‘do you really think I don't know why I have to take medicine every day?’ I stopped yelling at him then. (IDI, father of 13 year-old boy) When I was 6 or 7 … all my classmates were talking, and they wouldn't play with me. (FGD, 13 year-old girl)

this either … I think he knew two years ago. Once when we argued, he asked ‘do you really think I don't know why I have to take medicine every day?’ I stopped yelling at him then. (IDI, father of 13 year-old boy) When I was 6 or 7 … all my classmates were talking, and they wouldn't play with me. (FGD, 13 year-old girl) Fear of stigma by caregivers and children My mum told me not to tell anyone that I was on medication. They won't play with me anymore if I tell them. (IDI, girl, age 10) I also told him to avoid being seen when he takes his dose (IDI, mother of 13 year-old boy) He is still too young to keep a secret, so we cannot tell him. If he knows now and tells other people, I don't know what other people will think of him, nor how other people will treat us. (IDI, mother of 12 year-old boy) I told her not to tell her classmates. (IDI, grandmother of 10 year-old girl) He doesn't know about it yet. I plan to tell him when he is older, probably when he is about 16. He won't understand even if I tell him now. If I do tell, I'll worry that he tells other people. (IDI, mother of 12 year-old boy) Some children in the facilities are orphans, and they were told clearly about their conditions … They are worried that they might be discriminated against … when they have to go to school. (FGD, clinician) Some parents also worry that their children may tell other people about their conditions. Once, one child overheard his parents' conversation and learned about his condition. When he went to see a doctor for his cold, he told the doctor really loudly that he was HIV-positive when the doctor asked what was wrong. His mum was shocked and … worried that the child hadn't had any idea about the discrimination against this disease. (FGD, clinician) The school he use to go to won't take him because his teachers know about his condition. (IDI, father of 14 year-old boy) Some children living on campus are worried that their classmates may see them take drugs. (FGD, clinician) It's most difficult at school. Those people would ask me why I took those pills when I was taking my medicine. I told them that I had a cold. After one semester, no one talked to me. Then I had a cold [more recently] and went to see the doctor for my rhinitis, I would then lie to them that they were for my rhinitis. I then had this idea together with my teacher, and communicated with my teacher. It got better. (IDI, 13 year-old boy)

d them that I had a cold. After one semester, no one talked to me. Then I had a cold [more recently] and went to see the doctor for my rhinitis, I would then lie to them that they were for my rhinitis. I then had this idea together with my teacher, and communicated with my teacher. It got better. (IDI, 13 year-old boy) Caregivers' worries about children's reactions to disclosure He blamed me. He blamed me for infecting him. His dad was gone then, he probably heard of it from his grandma. He heard that his dad contracted and infected his mum, and then mum infected him. Once when we came here to see the doctor, he also said that he blamed me for giving him the disease. Later I explained to him, and he understood. Please ask whether he still blames me for it. (IDI, mother of 13 year-old boy) I am just worried that she cannot accept it. She has to be on medication for life. (IDI, mother of 13 year-old girl) No, he did not ask. I'm worried that he might have some thoughts or attitudes towards his parents when he knows. I'll tell him when the time is right. (IDI, father of 12 year-old boy) Just don't tell her everything at one time. I'm afraid that she can't handle it. (IDI, mother of 10 year-old girl) Not yet. I think he is still too young. I'm afraid that he would carry it as a psychological burden. (IDI, father of 13 year-old boy)

I'll tell him when the time is right. (IDI, father of 12 year-old boy) Just don't tell her everything at one time. I'm afraid that she can't handle it. (IDI, mother of 10 year-old girl) Not yet. I think he is still too young. I'm afraid that he would carry it as a psychological burden. (IDI, father of 13 year-old boy) Caregivers' sense of lack of preparedness No [we have never talked with her about her condition]. We don't know how to begin. We don't dare to tell her either. (IDI, mother of 10 year-old girl) I can tell him when he is 15 or older. I don't know where to start, and I'm both worried and scared. (IDI, mother of 12 year-old boy) I have the feeling that the biggest problem we have now is we don't know how to tell her. (IDI, mother of 10 year-old girl) I'm not entirely sure [whether he knows his status), but we have never talked about this, and I'm not ready either. I don't plan to tell him now, and I thought about telling him in two or three years. (IDI, mother of 13 year-old boy) I'm not well educated myself, so I'm not able to explain to him clearly. (IDI, mother of 14 year-old boy) To be honest, I, for myself, also wish that this disease can be cured one day. With this wish in my mind, I don't know how to talk to him about this. (IDI, father of 13 year-old boy) At this age, he could easily get into something bad without proper education. That's why I'm so concerned about how to tell him. (IDI, mother of 13 year-old boy)

elf, also wish that this disease can be cured one day. With this wish in my mind, I don't know how to talk to him about this. (IDI, father of 13 year-old boy) At this age, he could easily get into something bad without proper education. That's why I'm so concerned about how to tell him. (IDI, mother of 13 year-old boy) Ownership of disclosure: dialogue between caregivers and clinicians I haven't told him about his condition … the doctor has told him some. I don't know how to tell him. You [clinicians] can say however much you want to. It's better if you tell him. (IDI, grandfather of 10 year-old boy) I think it's better if you can tell her. You're professionals, and she may listen to you more. (IDI, mother of 14 year-old girl) I think you will be more suitable, because he may not pay attention to what I say to him. He may ignore it or never take it seriously. He may listen to you more. (IDI, mother of 11 year-old boy) There are not many people at home. His grandma is too old, and I'm the only one left, but I can't really explain it clearly. It would be best if you can help me with this. It would be rather easy for him to understand if the counselor could tell him a little every time when we are here. (IDI, mother of 14 year-old boy) I haven't decided which way I'm going to use to tell them, but I think it would be better if they learn about it from their parents. It might be easier to take it if they are told by someone close to them. (IDI, mother of 11 year-old girl) I think it would be better to let us tell him. He is quite good with us. (IDI, mother of 10 year-old boy) It must be me. Who else could tell him that? (IDI, mother of 12 year-old boy) I think it is the obligation of both parents and medical workers to tell the children. (FGD, clinician) Some parents believe that they should tell their children when they are older, and some children were told by their counselors. Most of them before were told by counselors. (FGD, clinician) We haven't developed any standard on exactly when is a good time to tell and how. This is also part of what we would like to explore in the future. It is rather difficult as, domestically, relevant people also don't have any good experience about when and how to tell. (FGD, clinician)

ld by counselors. (FGD, clinician) We haven't developed any standard on exactly when is a good time to tell and how. This is also part of what we would like to explore in the future. It is rather difficult as, domestically, relevant people also don't have any good experience about when and how to tell. (FGD, clinician) 3.1 The process of disclosure Among the IDI dyads, only 6/19 caregivers reported having disclosed to their child (5/9 caregivers of ALHIV aged 13 years and older; 1/10 caregivers of ALHIV aged 10–12 years). From matched adolescents' statements, we estimated that 9/19 children actually knew their HIV status (6/9 older ALHIV; 3/10 younger ALHIV). Most caregivers who had not disclosed said they planned to do so when their child was 14 years or older. Many caregivers (13/19) referred to disclosure as a process, requiring attention to a child's developmental stage and maturity (Table 3). Typical descriptions included:I should tell her slowly and little by little. After all, she is growing up and she will learn a lot of things on her own. (IDI, mother of 12 year-old girl) She won't be able to understand now even if I told her. All she knows is to take her medicine. She doesn't understand this condition at all. (IDI, mother of 11 year-old girl)

Many caregivers (13/19) referred to disclosure as a process, requiring attention to a child's developmental stage and maturity (Table 3). Typical descriptions included:I should tell her slowly and little by little. After all, she is growing up and she will learn a lot of things on her own. (IDI, mother of 12 year-old girl) She won't be able to understand now even if I told her. All she knows is to take her medicine. She doesn't understand this condition at all. (IDI, mother of 11 year-old girl) Both caregivers and clinicians stated that they began disclosure by telling children that they had a less-stigmatized condition, such as eye problems or chronic respiratory issues. Clinicians often described HIV to younger children as “bugs in the belly”; ART medications were frequently called vitamins or calcium tablets by both clinicians and caregivers. Adolescents' responses confirmed this stage of the process; one gave this typical explanation:Yes, my eyes will get worse if I don't take my medicine. My other eye will be affected and I won't be able to see. (IDI, 10 year-old girl) In one case, an adolescent's status was withheld from the child's caregivers, her grandparents:I told them that she was ill, but not exactly what she had. I told them to watch her take her medicine … I'm not going to tell her now. She is living with her grandpa now and she tells him everything. (IDI, mother of 12 year-old girl)

se, an adolescent's status was withheld from the child's caregivers, her grandparents:I told them that she was ill, but not exactly what she had. I told them to watch her take her medicine … I'm not going to tell her now. She is living with her grandpa now and she tells him everything. (IDI, mother of 12 year-old girl) Sometimes children wanted more information about their condition. One clinician described a parent whose daughter frequently asked why she had to take so many calcium tablets: “Now this has become her [the mother's] biggest concern, and she doesn't know how to answer it.” (FGD, clinician). A 13 year-old boy described being thwarted by caregivers and clinicians: “I asked them what disease I had, but they wouldn't tell me.” Instead, numerous children described learning their status independently in a variety of ways (Table 3), including from medication labels and eavesdropping on parents. Only one caregiver reported full disclosure at a young age:He knows everything. We have already explained [it] to him when he was little … We just said that this disease was serious. (IDI, father of 14 year-old boy)

Sometimes children wanted more information about their condition. One clinician described a parent whose daughter frequently asked why she had to take so many calcium tablets: “Now this has become her [the mother's] biggest concern, and she doesn't know how to answer it.” (FGD, clinician). A 13 year-old boy described being thwarted by caregivers and clinicians: “I asked them what disease I had, but they wouldn't tell me.” Instead, numerous children described learning their status independently in a variety of ways (Table 3), including from medication labels and eavesdropping on parents. Only one caregiver reported full disclosure at a young age:He knows everything. We have already explained [it] to him when he was little … We just said that this disease was serious. (IDI, father of 14 year-old boy) 3.2 Challenges to disclosure: stigma, anxiety about children’s reaction, and lack of preparedness 3.2.1 Stigma Caregivers' fear of stigma, both for their child and for the family, represented a main challenge to disclosure. These were typical statements (also see Table 3):For the time being, we don't plan to [disclose]. He is still too young to keep a secret, so we cannot tell him. If he knows now and tells other people, I don't know what other people will think of him, nor how other people will treat us. (IDI, mother of 12 year-old boy) No [we have never told her about her condition]. We don't know how to begin. We don't dare to tell her either. (IDI, mother of 10 year-old girl)

3.2 Challenges to disclosure: stigma, anxiety about children’s reaction, and lack of preparedness 3.2.1 Stigma Caregivers' fear of stigma, both for their child and for the family, represented a main challenge to disclosure. These were typical statements (also see Table 3):For the time being, we don't plan to [disclose]. He is still too young to keep a secret, so we cannot tell him. If he knows now and tells other people, I don't know what other people will think of him, nor how other people will treat us. (IDI, mother of 12 year-old boy) No [we have never told her about her condition]. We don't know how to begin. We don't dare to tell her either. (IDI, mother of 10 year-old girl) School and peer relationships presented particular challenges stemming from fear of stigma. Caregivers worried about interactions with teachers and classmates; ALHIV reported problems when peers learned about their status. Here are illustrative accounts (additional statements in Table 3):My mum told me not to tell anyone that I was on medication. They won't play with me anymore if I tell them. (IDI, 10 year-old girl) It's most difficult at school. Those people would ask me why I took those pills … After one semester, no one talked to me. (IDI, 13 year-old boy) Some children in the orphan facilities … were told clearly about their conditions … They are worried that they might be discriminated against when they have to go to school (FGD, clinician) The school he use to go to won't take him because his teachers know about his condition. (IDI, father of 14 year-old boy)

It's most difficult at school. Those people would ask me why I took those pills … After one semester, no one talked to me. (IDI, 13 year-old boy) Some children in the orphan facilities … were told clearly about their conditions … They are worried that they might be discriminated against when they have to go to school (FGD, clinician) The school he use to go to won't take him because his teachers know about his condition. (IDI, father of 14 year-old boy) One clinician described the challenges of the school environment:Besides home, school is the children's main environment. It is also very important to conduct HIV campaign and education for normal healthy children … It would have great impact on children if teachers at school didn't discriminate against HIV patients. It is certain that children will be affected if teachers at school treat those [HIV+] children differently. If teachers don't have discrimination, then children won't be treated unfairly even if they are infected. However, this is a social issue, and it is complex. (FGD, clinician) Several caregivers went to great lengths to protect their child from potential stigmatization, which seemed related to their own status. For example:I was rather sensitive when I just learned about my condition, and I distanced myself from both my own family and my in-law's family. That's why I have always stayed in Guangdong with my child during Spring Festival, rather than going home. I have the feeling that their attitudes towards the child have changed. (IDI, mother of 13 year-old boy)

en I just learned about my condition, and I distanced myself from both my own family and my in-law's family. That's why I have always stayed in Guangdong with my child during Spring Festival, rather than going home. I have the feeling that their attitudes towards the child have changed. (IDI, mother of 13 year-old boy) Conversely, one family reported disclosing to an adolescent in order to prevent stigma and its consequences:He [knows} his status. He knew when he came here for treatment. We have told him, so he won't tell other people. We have also given him examples from the brochures. …. For example, when the people in the village learned about a kid's infection, they isolated him in a cave on the mountain. His grandma tried to send food to him, but the villagers prohibited her from doing this, so the child died in the cave. (IDI, mother of 13 year-old boy) 3.2.2 Children's reactions Caregivers also worried about their children's anticipated and actual reactions when they learned of their status. These fell into two categories: fear of blaming the parents for infection, and concern about the child's ability to handle information emotionally. The following passages describe fear of blame and actual experience of resentment by two caregivers:… he did not ask [about how he was infected]. I'm worried that he might have some thoughts or attitudes towards his parents when he knows. I'll tell him when the time is right. (IDI, father of 12 year-old boy)

otionally. The following passages describe fear of blame and actual experience of resentment by two caregivers:… he did not ask [about how he was infected]. I'm worried that he might have some thoughts or attitudes towards his parents when he knows. I'll tell him when the time is right. (IDI, father of 12 year-old boy) He blamed me for infecting him. His dad was gone then, [and] he probably heard of it from his grandma. He heard that his dad contracted HIV and infected his mum, and then mum infected him. Once, when we came here to see the doctor, he also said that he blamed me for giving him the disease. Later I explained it to him, and he understood … (IDI, mother of 13 year-old boy) Here, two caregivers share their worries about the psychosocial impact of disclosure on their children:Not yet. I think he is still too young. I'm afraid that he would carry it as a psychological burden. (IDI, father of 10 year-old boy) Just don't tell her everything at one time. I'm afraid that she can't handle it (IDI, mother of 10 year-old girl) One parent reported anger on the part of his child during a disclosure conversation:I was going to talk to him over this vacation. I tried twice to slowly lead to this topic, but he stopped me and said that I was really mean. (IDI, father of 13 year-old boy) Additional statements regarding adolescents' reactions (actual and anticipated) to learning their HIV status appear in Table 3.

One parent reported anger on the part of his child during a disclosure conversation:I was going to talk to him over this vacation. I tried twice to slowly lead to this topic, but he stopped me and said that I was really mean. (IDI, father of 13 year-old boy) Additional statements regarding adolescents' reactions (actual and anticipated) to learning their HIV status appear in Table 3. 3.2.3 Lack of preparedness The final major barrier to disclosure described by caregivers involved feeling emotionally unprepared and lacking the necessary knowledge and skills:I don't know where to start, and I'm both worried and scared. (IDI, mother of 12 year-old boy) … the biggest problem we have now is we don't know how to tell her. (IDI, mother of 10 year-old girl) I'm not entirely sure [whether he knows his status), but we have never talked about this, and I'm not ready either. (IDI, mother of 13 year-old boy) I'm not well educated myself, so I'm not able to explain to him clearly. (IDI, mother of 14 year-old boy)

… the biggest problem we have now is we don't know how to tell her. (IDI, mother of 10 year-old girl) I'm not entirely sure [whether he knows his status), but we have never talked about this, and I'm not ready either. (IDI, mother of 13 year-old boy) I'm not well educated myself, so I'm not able to explain to him clearly. (IDI, mother of 14 year-old boy) 3.3 Ownership of disclosure process There was some debate among caregivers about who should lead the disclosure process. Several caregivers requested assistance with disclosure from clinicians. Typical statements included: “I think it's better if you can tell her. You're professionals, and she may listen to you more.” (IDI, mother of 14 year-old girl). Conversely, several caregivers insisted that caregivers are best suited to disclose. As one mother stated,I haven't decided which way I'm going to use to tell them, but I think it would be better if they learn about it from their parents. It might be easier to take it if they are told by someone close to them. (IDI, mother of 11 year-old girl)

ivers insisted that caregivers are best suited to disclose. As one mother stated,I haven't decided which way I'm going to use to tell them, but I think it would be better if they learn about it from their parents. It might be easier to take it if they are told by someone close to them. (IDI, mother of 11 year-old girl) Finally, although clinicians expressed frustration at not knowing how best to advise caregivers, one expressed the opinion that caregivers and clinicians have an obligation to tell children.Based on my experience, telling the child why he is on medication and the importance of adherence is very important. If you just keep on holding back the truth, you can keep them from knowing for one day, or two days, but eventually, they will know. If the child knows that their parents have kept the truth from them for so long, they may also become resentful. I think it is the obligation of parents and medical workers to tell the children. (FGD, clinician) 3.4 Importance of disclosure to good adherence Several older adolescents expressed the view that knowing one's disease status was important to good ART adherence. For example:I would secretly throw away my medicine when I was in Grade 5 or 6 because I didn't want to take it, but I won't throw them away now. I stopped since I got to middle school and learned that I have HIV. (FGD, boy, age 14) My mum told me that I had AIDS, so if I don't take my medicine on time, the virus will spread all over my body. That's why I must take my medicine. (IDI, girl, age 10)

3.4 Importance of disclosure to good adherence Several older adolescents expressed the view that knowing one's disease status was important to good ART adherence. For example:I would secretly throw away my medicine when I was in Grade 5 or 6 because I didn't want to take it, but I won't throw them away now. I stopped since I got to middle school and learned that I have HIV. (FGD, boy, age 14) My mum told me that I had AIDS, so if I don't take my medicine on time, the virus will spread all over my body. That's why I must take my medicine. (IDI, girl, age 10) Others appeared motivated to take their medication due to knowledge of their status. In response to queries about what is helpful for adherence, older ALHIV participants in a FGD responded with statements such as “Correct understanding of HIV/AIDS” (FGD, boy, age 14) and “Understanding of the consequences of not taking the medicine” (FGD, boy age 15).

their medication due to knowledge of their status. In response to queries about what is helpful for adherence, older ALHIV participants in a FGD responded with statements such as “Correct understanding of HIV/AIDS” (FGD, boy, age 14) and “Understanding of the consequences of not taking the medicine” (FGD, boy age 15). 4 Discussion To our knowledge, this is the first study examining issues surrounding disclosure to HIV-infected children in China. Several notable themes emerged among these HIV-positive adolescent patients and their caregivers. With respect to WHO guidelines, disclosure of HIV status to children occurred late. Concerns about a child's maturity and ability to understand his/her condition, stigma and discrimination toward the child and family, in addition to caregivers' feelings of unpreparedness and worries about the child's reaction (blame and burden), were associated with a reluctance to disclose. However, children expressed a desire to understand their disease status, and some who knew their status considered disclosure important for medication adherence. A compelling aspect of our study was the use of caregiver-child dyads for the IDIs, which allowed us to see vivid cases in which the caregiver was concerned about what the child might know, when in fact, the child already was aware of his or her status. This dyad approach has been used to a limited extent in a very few previous studies of HIV disclosure in sub-Saharan Africa [28], [29], but never in an Asian setting, and without our interviewers' emphasis on trying to elicit and understand the child's understanding of disease.

d already was aware of his or her status. This dyad approach has been used to a limited extent in a very few previous studies of HIV disclosure in sub-Saharan Africa [28], [29], but never in an Asian setting, and without our interviewers' emphasis on trying to elicit and understand the child's understanding of disease. Late disclosure is common in the literature. Caregivers in sub-Saharan Africa, Thailand, and elsewhere frequently report avoiding disclosure of infected children's status, using deception and secrecy to avoid informing youth of their diagnosis [13], [18], [30]. Concerns of inadequate caregiver knowledge or skills are also seen throughout the literature [11], [13], [14], [17], as is fear of children's inability to maintain secrecy of HIV status [14], [16], [19]. In addition to school-related concerns shared in our study, several caregivers reported withholding the child's status from family for fear of differential treatment of the child. Similar social dynamics to those identified in our study have been found in studies of disclosure of parental HIV status to children in China, including fears of stigma, psychological burden for the child, and negative social consequences for family [21], [25], [26], [31].

r fear of differential treatment of the child. Similar social dynamics to those identified in our study have been found in studies of disclosure of parental HIV status to children in China, including fears of stigma, psychological burden for the child, and negative social consequences for family [21], [25], [26], [31]. Despite the challenges, timely disclosure of children's status may have benefits for children and caregivers. Youth who know their HIV status can play a greater role in their medical care [32], seek social support [23], [32], and benefit from more open communication with caregivers [17], [33], [34]. In several studies, children who knew their status demonstrated improved medication adherence [16], [35], more autonomous self-care [23], [33], and reduced psychological distress [33], [36], [37]. In addition to benefits for children, some caregivers report reduced anxiety and depression following disclosure [17], [36], [38], in addition to greater trust of the caregiver, strengthened of relationships with their child via more open communication, and less perceived need for deception [17], [33], [34]. Although no children or caregivers in our sample explicitly mentioned distrust, clinicians observed that withholding HIV status from some children appeared to result in these patients' resentment towards their caregivers, and other studies have suggested that inadvertent disclosure can create mistrust of caregivers, especially among older children who may feel “lied to” [23], [39].

ioned distrust, clinicians observed that withholding HIV status from some children appeared to result in these patients' resentment towards their caregivers, and other studies have suggested that inadvertent disclosure can create mistrust of caregivers, especially among older children who may feel “lied to” [23], [39]. Quite distinct from settings where caregivers conceptualize disclosure to HIV-infected children as a discrete event centered on the naming of HIV [18], in this Chinese context, the “process” of disclosure described by caregivers resembled the preferred approach described in behavioral literature [13], [14], [18], [33], [40], which portrays disclosure as a dialogue beginning months to years culminating in the naming of HIV [33] that evolves alongside the child's cognitive development over time [26]. In determining each conversation's timing and content, caregivers and providers assess the child's age, maturity, medication adherence, and likelihood of soon learning his/her diagnosis elsewhere, as well as caregivers' fears and family factors, that will inform the disclosure experience [13], [32]. This model provides multiple opportunities for the child to ask questions and express concerns; caregivers and providers can reiterate educational concepts and stress importance of medication adherence [33], [39], while reinforcing support. Such an approach is believed to benefit both the child's acceptance of the disease and his/her psychological adjustment [41].

the child to ask questions and express concerns; caregivers and providers can reiterate educational concepts and stress importance of medication adherence [33], [39], while reinforcing support. Such an approach is believed to benefit both the child's acceptance of the disease and his/her psychological adjustment [41]. Gradual disclosure should be distinguished from deception, however. Our study found that caregivers and clinicians sometimes use alternative or narrow explanations for acute illnesses to explain the need for daily medications. Similar patterns are seen in other studies, including selective disclosure and provision of misleading information [15], [16], [42]. In the short term, such strategies may be useful to caregivers, but long-term deception may mislead and harm children, rather than enhance understanding of their illness. It may be that caregivers require substantial help learning how to disclose a child's HIV status and more interventions, such as one focused on the decision-making process surrounding disclosure piloted recently in China among HIV-positive parents considering disclosing their own status to their children [43]. Our qualitative findings also suggest that children seem to be discovering their status at earlier ages on their own, contrary to what clinicians and caregivers believe—a tendency which is unlikely to change.

ed recently in China among HIV-positive parents considering disclosing their own status to their children [43]. Our qualitative findings also suggest that children seem to be discovering their status at earlier ages on their own, contrary to what clinicians and caregivers believe—a tendency which is unlikely to change. In China, the honor of the family (“face”) is often prioritized over an individual's right to know their HIV diagnosis [44]. Traditionally it has been commonplace for providers to disclose an HIV diagnosis to an adult patient's family prior to the individual [44]. Providers tend to use subjective judgment, considering the family's best interests and illness severity when deciding whether to inform a patient of his/her HIV status [44]. In one study, Chinese providers felt that hiding an HIV diagnosis from an adult patient was protective of his/her physical and psychological health [45]. Furthermore, in Chinese culture, death, sex and other emotional topics are often taboo [25], [46]. and HIV is still a highly stigmatized and emotional subject [47]. In the context of youth with HIV, these cultural dimensions may explain why health professionals in China have historically disclosed status to children unilaterally; having a provider tell the child first is an indirect, more traditional approach for families. In this evolving context (caregivers' increasing role in disclosure but commonly cited feelings of unpreparedness), healthcare providers, who tend to be highly respected and trusted in China [44], will likely continue to play a critical role in facilitating disclosure to HIV-infected youth, although they, too, need adequate training to improve their counseling skills so that they can better support both caregivers and children in the disclosure process.

who tend to be highly respected and trusted in China [44], will likely continue to play a critical role in facilitating disclosure to HIV-infected youth, although they, too, need adequate training to improve their counseling skills so that they can better support both caregivers and children in the disclosure process. 5 Limitations There are several limitations to this study. First, the clinician FGD was dominated to some extent by one clinician, and it is possible that some participants' views were expressed inadequately. Second, the CDC-ART clinic is a specialized facility that cares for HIV patients in Guangxi province, and participants may not be representative of adolescent ART patients in China. Finally, because participants were purposively selected by clinicians, cooperative patients with supportive caregivers may have been disproportionately represented. 6 Conclusions Disclosure of HIV status occurred late in this group of adolescents living with HIV in China. Fear of stigma, toward not only the caregiver and child but also the broader family, was an important factor underlying delayed disclosure. Caregivers, clinicians, and adolescents identified school and peer interactions as a particularly concerning environment for discrimination, and an important target for interventions aimed to reduce HIV stigma. Clinicians voiced the need to better educate teachers, as teachers' modeled behaviors influenced the behavior of children.

linicians, and adolescents identified school and peer interactions as a particularly concerning environment for discrimination, and an important target for interventions aimed to reduce HIV stigma. Clinicians voiced the need to better educate teachers, as teachers' modeled behaviors influenced the behavior of children. As the population of HIV-infected pediatric patients in China surviving beyond adolescence to adulthood grows, culturally appropriate guidelines for clinician-supported disclosure should be adapted and developed, focusing on ways of supporting caregivers in the disclosure process. The potential to use peer support strategies for both caregivers and adolescents in this process might also be explored. Because individual patients are viewed within the context of the family, and the reputation (‘face’) of families is so critical in China, efforts to de-stigmatize HIV in China more broadly, and in schools in particular, will help with the process of HIV disclosure to adolescents. Conflict of interest The authors declare that they have no conflicts of interest. Funding The study was made possible by a grant from Boston University School of Public Health. Acknowledgments We thank the adolescent patients, their caregivers, and clinicians who participated in the study, as well as the staff of the Guangxi CDC STI/AIDS clinic in Nanning. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Cough is the most common presenting symptom to primary care settings in many countries [1]. Persistent cough is one of the most common reasons for a child to be referred to a pediatrician or respiratory physician. On average, normal children cough 11 times per day when they are well, and this increases in frequency and severity during winter, when upper respiratory tract infections (URTI) are frequent [2]. Cough can impact a child's activity level and ability to sleep well, play or attend school and is often a source of parental anxiety. Cough in children is different from that in adults in terms of duration, presentation, etiology and management (see Table 1 for possible etiologies based on child age). This paper presents the clinical statement of the Saudi Pediatric Pulmonology Association (SPPA) in relation to the management of cough in children.Table 1 Common etiologies of chronic cough based on child age. Young children (<5 years) Older children (>5 years) Infections Asthma Gastroesophageal reflux Infection Congenital malformation Post-nasal drip Asthma Protracted bacterial bronchitis Protracted bacterial bronchitis Passive smoking Passive smoking & environmental pollution Bronchiectasis Foreign body inhalation Psychogenic cough

ldren (<5 years) Older children (>5 years) Infections Asthma Gastroesophageal reflux Infection Congenital malformation Post-nasal drip Asthma Protracted bacterial bronchitis Protracted bacterial bronchitis Passive smoking Passive smoking & environmental pollution Bronchiectasis Foreign body inhalation Psychogenic cough 2 Pathophysiology Cough is one of the most important protective reflexes, and it contributes significantly to the innate immunity of the respiratory system by enhancing mucociliary clearance [3]. Cough is under both voluntary and involuntary control. Cough receptors are terminations of vagal afferent nerves located in the larynx, pharynx and tracheobronchial tree. Extrapulmonary sites, such as the external ear, can trigger cough due to stimulation of the auricular branch of the vagus nerve [4]. These receptors send signals back to the cough center in the medulla oblongata, which then triggers the sequence of events that constitutes a cough. Cough mechanics includes three sequential phases: inspiratory, compressive and expiratory [5]. Factors that influence cough efficiency include adequate airway caliber (airway narrowing decreases efficiency, e.g., malacia), mucus properties and respiratory muscle strength [6]. Given that cough is a protective reflex, it is crucial not to suppress it without identifying and treating its underlying cause.

tory [5]. Factors that influence cough efficiency include adequate airway caliber (airway narrowing decreases efficiency, e.g., malacia), mucus properties and respiratory muscle strength [6]. Given that cough is a protective reflex, it is crucial not to suppress it without identifying and treating its underlying cause. The sensitivity of the cough receptors are modulated by disease state. Up-regulation of cough receptors has been demonstrated after viral URTI, asthma, gastroesophageal reflux disease (GERD), and treatment with angiotensin-converting enzyme inhibitors. This causes cough to be triggered through relatively non-specific provocation [7]. Cough undergoes considerable developmental phases; it can be elicited in 10% of 27-week gestational age preterm infants and up to 90% of full-term infants [8]. 3 Defining cough in children Cough can be defined based on duration of presentation, suggested etiology, and sound quality. The following terms have been used in various publications.

The sensitivity of the cough receptors are modulated by disease state. Up-regulation of cough receptors has been demonstrated after viral URTI, asthma, gastroesophageal reflux disease (GERD), and treatment with angiotensin-converting enzyme inhibitors. This causes cough to be triggered through relatively non-specific provocation [7]. Cough undergoes considerable developmental phases; it can be elicited in 10% of 27-week gestational age preterm infants and up to 90% of full-term infants [8]. 3 Defining cough in children Cough can be defined based on duration of presentation, suggested etiology, and sound quality. The following terms have been used in various publications. 3.1 Duration of cough Cough classification based on the duration of presentation in children relies on the available data of coughs related to URTI in children [9]. Between 35% and 40% of school age children continue to cough 10 days after the onset of a common cold, and 10% of preschool children continue to cough 25 days after a respiratory tract infection [10]. Most cases of acute cough in children are associated with viral upper respiratory tract infections and do not require specific diagnostic evaluation. There are no studies that have clearly defined when cough should be labeled as chronic or persistent [11]. The definition of chronic cough in children varies and ranges from 3 to 12 weeks based on some published guidelines [11], [12]. The general basis for the definition of chronic cough is based on the fact that the most common etiology for acute/sub-acute cough in children is viral/post-viral URTI; 10% of children with a viral URTI continue to cough for 25 days [10]. It is important to use definitions of cough duration in the context of individual patient presentations, as some serious etiologies of cough require early attention and intervention. We suggest the following definitions:• Acute: cough lasting less than 4 weeks.

dren with a viral URTI continue to cough for 25 days [10]. It is important to use definitions of cough duration in the context of individual patient presentations, as some serious etiologies of cough require early attention and intervention. We suggest the following definitions:• Acute: cough lasting less than 4 weeks. • Chronic: cough lasting more than 4 weeks. 3.2 Etiology of cough • Normal or expected cough: the occasional daily cough, as described above, or a mild cough that has an obvious cause (e.g., after URTI) and does not require further intervention. • Specific cough: cough associated with other symptoms and signs suggestive of an underlying problem (see Table 2 for the indicators of specific cough).Table 2 Indicators of the presence of specific cough. • Coughing initiates suddenly with a choking episode • Coughing is progressive • Shortness of breath – chronic or exertional • Failure to thrive • Hypoxemia • Constitutional symptoms • Clubbing • Hemoptysis • Chest wall abnormality • Noisy breathing and/or abnormal lung auscultation • Coughing with a background history of recurrent pneumonia • Cough initiates in neonatal period • Swallowing difficulties • Craniofacial abnormality • Neuromuscular disorder • Wet cough lasting more than 3–4 weeks • Non-specific cough: dry cough in the absence of an identifiable respiratory disease of known etiology. The majority of cases are due to non-serious etiology (e.g., post-viral cough and/or increased cough receptor sensitivity) and may spontaneously resolve.

• Craniofacial abnormality • Neuromuscular disorder • Wet cough lasting more than 3–4 weeks • Non-specific cough: dry cough in the absence of an identifiable respiratory disease of known etiology. The majority of cases are due to non-serious etiology (e.g., post-viral cough and/or increased cough receptor sensitivity) and may spontaneously resolve. 3.3 Quality of cough Cough can be classified based on its quality. The quality of a cough is related to either the sound pattern or its dry or wet nature (see Table 3).• Classically recognized cough sounds: Data on sensitivity and specificity of each classic type of cough are limited. Parents usually are able to describe the pattern of the cough sound or even to provide recordings of their child's cough. Physician's direct observation of cough sound during clinic assessment should always be used to validate the information obtained from the medical history. The pattern of cough sound can help indicate its underlying etiology.

describe the pattern of the cough sound or even to provide recordings of their child's cough. Physician's direct observation of cough sound during clinic assessment should always be used to validate the information obtained from the medical history. The pattern of cough sound can help indicate its underlying etiology. • Wet vs. Dry Cough: The distinction between dry and wet cough can be valid in directing the differential diagnosis of the cough. Clinicians should be aware that dry cough can be converted to wet cough when airway secretions increase. Even when airway secretions are present, young children rarely expectorate sputum, so wet cough, rather than productive cough, is the preferred term. Wet cough indicates an underlying cause of mucous hypersecretion or impaired mucociliary clearance, whereas a dry cough indicates an underlying cause of airway irritation or inflammation or a non-airway cause [13]. Wet cough warrants detailed investigation whenever it becomes chronic or associated with other manifestations (e.g., failure to thrive or clubbing). Table 3 Example of cough classification based on the quality of cough sounds. Cough characteristic Possible etiology Dry, staccato Chlamydophila Wet Protracted bacterial bronchitis, cystic fibrosis, bronchiectasis, pneumonia, primary ciliary dyskinesia Barking/brassy Croup, tracheomalacia Barking/honking Habit/psychogenic Paroxysmal/spasmodic/whoop Pertussis or pertussis-like syndrome

Table 3 Example of cough classification based on the quality of cough sounds. Cough characteristic Possible etiology Dry, staccato Chlamydophila Wet Protracted bacterial bronchitis, cystic fibrosis, bronchiectasis, pneumonia, primary ciliary dyskinesia Barking/brassy Croup, tracheomalacia Barking/honking Habit/psychogenic Paroxysmal/spasmodic/whoop Pertussis or pertussis-like syndrome 4 Assessment of cough in children 4.1 Clinical history & physical examination Detailed history and physical examination represent the cornerstones of the evaluation of a child complaining of cough. The history should focus on identifying the duration, quality, triggers, progress and diurnal/seasonal variation of the cough, associated symptoms, neonatal history, family history, environmental exposures, in particular second hand smoking (or other irritants e.g., wood smoke exposure), medications and allergy history. Physical examination should be directed at determining the general well-being of the child and should include the measurement of vital signs and growth parameters, a detailed respiratory system (including ENT) examination, determination of nutritional status and examination for certain physical signs (e.g., noisy breathing and clubbing). Efforts should be directed to directly observe cough quality during the clinical assessment and to obtain respiratory samples, if indicated.

rs, a detailed respiratory system (including ENT) examination, determination of nutritional status and examination for certain physical signs (e.g., noisy breathing and clubbing). Efforts should be directed to directly observe cough quality during the clinical assessment and to obtain respiratory samples, if indicated. 4.2 Investigations • Acute cough: The majority of acute cough attacks in children are related to viral/post-viral URTI and do not require further investigation. A chest radiograph should be considered when signs indicate lower respiratory tract involvement, progressive nature, hemoptysis or features of an undiagnosed chronic respiratory disorder. If an inhaled foreign body is suspected as the cause of an acute cough, then urgent bronchoscopy should be considered [12].

igation. A chest radiograph should be considered when signs indicate lower respiratory tract involvement, progressive nature, hemoptysis or features of an undiagnosed chronic respiratory disorder. If an inhaled foreign body is suspected as the cause of an acute cough, then urgent bronchoscopy should be considered [12]. • Chronic cough: Investigations should include chest radiograph and lung function test, at appropriate ages, and a test of bronchodilator responsiveness should be considered, if applicable. The extended investigation should be individualized based on the clinical presentation of each patient (feeding/swallowing assessment for aspiration, immune work-up for immunodeficiency, sweat chloride test for cystic fibrosis, CT scan for bronchiectasis, bronchoscopy for inhaled foreign bodies and/or to obtain bronchoalveolar lavage). For wet cough, an attempt should be made to obtain a sample of sputum. Allergy testing (skin prick or RAST specific testing) may be helpful in determining if a child is atopic [12]. A therapeutic trial of asthma medication can be used as a diagnostic tool for chronic cough in young children, when there is a lack of other objective indicators of asthma. This trial should be monitored and time-bound (6–8 weeks), and medications should be stopped after the trial period if no benefits are observed. However, in otherwise healthy children with an isolated dry cough and no specific disease indicators, empirical trials of anti-asthma, anti-allergic rhinitis and anti-gastroesophageal reflux therapy are unlikely to be beneficial and are generally not recommended [12].

after the trial period if no benefits are observed. However, in otherwise healthy children with an isolated dry cough and no specific disease indicators, empirical trials of anti-asthma, anti-allergic rhinitis and anti-gastroesophageal reflux therapy are unlikely to be beneficial and are generally not recommended [12]. 5 Management of cough in children 5.1 General concepts • The goal should always be to identify an underlying cause of cough in children. • In the majority of children presenting with cough, the etiology is related to URTI and requires only supportive measures (e.g., antipyretics, good hydration, and saline washes). • Over-the-counter antitussives, antihistamines and decongestants are as effective as placebo for acute cough and have the potential to cause adverse effects; thus, they should be avoided in children less than 2 years of age. Intranasal steroids can be effective in children with allergic rhinitis presenting with cough during pollen season. • Bronchodilators are not effective and should be avoided in non-asthmatic children presenting with acute cough. • Antibiotics are generally not effective and should be avoided in children presenting with acute cough caused by viral URTI. When pertussis infection is diagnosed, macrolide antibiotics should be prescribed early (1–2 weeks of illness). • Specific causes of acute cough (e.g., asthma, bronchiolitis, croup, and community-acquired pneumonia) should be managed based on the evidence-based guidelines specific for such entities.

• Antibiotics are generally not effective and should be avoided in children presenting with acute cough caused by viral URTI. When pertussis infection is diagnosed, macrolide antibiotics should be prescribed early (1–2 weeks of illness). • Specific causes of acute cough (e.g., asthma, bronchiolitis, croup, and community-acquired pneumonia) should be managed based on the evidence-based guidelines specific for such entities. • Honey products are a natural and safe therapeutic option with a slight effect that can be considered for acute cough following URTI in children greater than 2 years of age [14], [15]. • Parental and community education is indicted to increase the awareness of the natural course and supportive measures for acute cough caused by URTI in young children. 5.2 Management of chronic cough • Efforts should be directed to identify the exact underlying cause of chronic cough in children so that a specific management plan can be initiated. • The application of a standardized algorithm in the management of children with chronic cough improves clinical outcomes (earlier cough resolution and improved parental quality of life) [16]. See Fig. 1 for a suggested clinical algorithm for the management of chronic cough in children.Figure 1 Clinical algorithm for the evaluation and management of chronic cough in children. • Evidence-based recommendations should always be applied in the management of specific causes of chronic cough in children (e.g., asthma, cystic fibrosis, primary ciliary dyskinesia, immunodeficiency, and tuberculosis).

• The application of a standardized algorithm in the management of children with chronic cough improves clinical outcomes (earlier cough resolution and improved parental quality of life) [16]. See Fig. 1 for a suggested clinical algorithm for the management of chronic cough in children.Figure 1 Clinical algorithm for the evaluation and management of chronic cough in children. • Evidence-based recommendations should always be applied in the management of specific causes of chronic cough in children (e.g., asthma, cystic fibrosis, primary ciliary dyskinesia, immunodeficiency, and tuberculosis). • Foreign body inhalation should always be considered in children with chronic cough. This is important, even if a chocking episode was not witnessed, especially if the cough onset was clearly abrupt. • Protracted (i.e., persistent) bacterial bronchitis has been recently defined as a common cause of chronic cough in children and is defined as a chronic wet cough with positive bronchoalveolar lavage (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) that resolves with antibiotic therapy [17]. Other possible diagnoses (e.g., asthma) should be excluded. For these children, a trial of prolonged antibiotics (typically amoxicillin and clavulanate for 2–4 weeks) is recommended. Such children should be followed at the end of the therapeutic trial for assessment of response and consideration of an alternative diagnosis.

possible diagnoses (e.g., asthma) should be excluded. For these children, a trial of prolonged antibiotics (typically amoxicillin and clavulanate for 2–4 weeks) is recommended. Such children should be followed at the end of the therapeutic trial for assessment of response and consideration of an alternative diagnosis. • In otherwise healthy children with non-specific chronic cough, the approach of “watchful observation” with follow-up assessment (in 6–8 weeks) is acceptable. Parental assurance is indicated. This is based on the fact that the majority of non-specific chronic cough cases in otherwise healthy children are self-limiting. It is not recommended to apply empirical therapy of specific chronic cough conditions (e.g., asthma, allergic rhinitis and gastroesophageal reflux). • A diagnostic trial of anti-asthma therapy (namely inhaled corticosteroids) can be considered for bothersome chronic cough cases, especially in situations where objective assessment (e.g., pulmonary function testing) is lacking. It is important to ensure proper use of the therapy (i.e., dosage, device and compliance) and to have a well-defined period for the trial (6–8 weeks) before assessing the patient's response. • In obviously atopic children with features of allergic rhinitis, the use of inhaled nasal corticosteroids, anti-histamines and allergen avoidance are recommended. • Children with features suggestive of habit (psychogenic) cough can benefit from psychotherapy, such as suggestion and/or behavioral therapy. Organic causes should be excluded in those children.

• In obviously atopic children with features of allergic rhinitis, the use of inhaled nasal corticosteroids, anti-histamines and allergen avoidance are recommended. • Children with features suggestive of habit (psychogenic) cough can benefit from psychotherapy, such as suggestion and/or behavioral therapy. Organic causes should be excluded in those children. 5.3 When to consider referral for sub-specialist advice? General practitioners should consider referring a child to a pediatric pulmonologist for further evaluation in the following situations:• Chronic wet cough unresponsive to antimicrobial therapy. • Specific-cough indicating an underlying disease (e.g., cystic fibrosis or primary ciliary dyskinesia). • Uncertain diagnosis of chronic non-specific cough. • Partially resolved, prolonged (>3 months) or recurrent protracted bronchitis (>2 times/year). • Suspicion of foreign body inhalation. • Suspicion of congenital/developmental defect. • Chronic cough associated with persistent hypoxemia. 6 Conclusions Despite the high prevalence of cough in children, the subject has not been thoroughly investigated. Children with cough should be managed according to child-specific guidelines, which are different from adult guidelines. Treatment of cough in children should be based on the cough's underlying etiology. Conflict of Interest The authors have no conflicts of interest to disclose. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

indicated that their parents never attended any of the school activities or attended only some of the activities (40%) in which they were involved. These data reflect low parental involvement in school-related activities, demonstrating the need for school officials to plan activities that promote parental involvement. In the Saudi culture, less emphasis has been placed on extra-curricular activities in general, which makes it more difficult for parents to become involved with their children's school. The annual parent-teacher meeting is the main opportunity for a parent to visit the schools. Only conscientious parents schedule additional visits. Furthermore, it is not a social expectation nor is it painted into the “ideal family picture” in which parents should attend their children's school activities, which is a typical behaviour of Western cultures. This could be due to the inherent lack of activities in the school systems or the parents' pre-occupation with other activities that often have a priority over becoming involved with their children's school events. Social roles in Saudi culture are strictly defined, such that the father is the sole bread-winner and the mother is the housekeeper.

herent lack of activities in the school systems or the parents' pre-occupation with other activities that often have a priority over becoming involved with their children's school events. Social roles in Saudi culture are strictly defined, such that the father is the sole bread-winner and the mother is the housekeeper. The striking evidence that school-student connectedness reduces the odds of school risk behaviours is the highlight of our findings. Our findings highlight the components of school connectedness and identifies specific actions that schools can take to increase connectedness with adolescents. The items that we included in this scale refer to the attachment and bonding between teachers, school and students as well as the care displayed to the students in the school environment. The feeling that there is someone at the school to help with problems is critical in establishing a positive school environment. Students are more likely to engage in healthy behaviours and to succeed academically when they feel connected to their school. The National Longitudinal Study found that family, school, and individual factors, such as school connectedness, parent-family connectedness, and high parental expectations for academic achievement, were protective against a range of adverse behaviours [32], [33]. School connectedness was found to be the strongest protective factor for both boys and girls against substance use, school absenteeism, early sexual initiation, violence, and risk of unintentional injury (e.g., drinking and driving, not wearing seat belts) [32]. Furthermore, school connectedness was second in importance, after family connectedness, as a protective factor against emotional distress, disordered eating, and suicidal ideation and attempts [32], [33], [34]. A strong relationship between school connectedness and educational outcomes, including school attendance and better grades, was also noted in the research [35]. Better school performance (higher grades) is a protective factor against carrying a weapon, smoke cigarettes, or consuming alcohol [36], [37], [38].

1 Introduction Dilated cardiomyopathy (DCM) refers to a large group of heterogeneous myocardial disorders that are characterized by ventricular dilation and depressed myocardial contractility in the absence of abnormal loading conditions, such as hypertension or valvular disease [1]. The Pediatric Cardiomyopathy Registry in North America reported the annual incidence of DCM to be 0.57 per 100,000 children per year [2]. Almost half of these patients die or undergo a heart transplant within 2 years of diagnosis [2], [3]. In addition, two-thirds of patients with DCM are thought to have DCM that is idiopathic in origin. Such a high frequency of idiopathic DCM may lead the practitioner to pay less attention during the search for an etiology of a newly diagnosed case, thereby committing the patient to a poor prognosis with high mortality. However, finding and appropriately treating the primary cause of DCM may result in the total restoration of cardiac function and reversal of its sequela. One of the routine and important tests in investigating DCM is an electrocardiogram (ECG). Unlike blood tests that produce quantitative results, the ECG result is based on physician interpretation that requires prior knowledge and experience. Failure to recognize the cardiac etiology of DCMs that manifest on an ECG can result in a delayed or missed diagnosis with potentially morbid or even fatal outcomes.

). Unlike blood tests that produce quantitative results, the ECG result is based on physician interpretation that requires prior knowledge and experience. Failure to recognize the cardiac etiology of DCMs that manifest on an ECG can result in a delayed or missed diagnosis with potentially morbid or even fatal outcomes. We report two patients who, on initial assessment, were misdiagnosed as idiopathic DCM or DCM following presumed myocarditis. Twelve months later, after careful interpretation of their ECGs, these patients were appropriately diagnosed and treated. Both underwent corrective intervention. One had complete recovery of cardiac function with reverse remodeling; the other patient is still undergoing follow-up treatment and is expected to improve. 2 Case 1 The first patient is a 2-year-old boy born at 36 weeks of gestation with a birth weight of 2.6 kg. As a one year old, he was admitted for two weeks with a history of tachypnea and poor weight gain. His weight at the time was 5.7 kg, and he had a height of 62 cm and a head circumference of 44 cm (all below the 5th percentile).

st patient is a 2-year-old boy born at 36 weeks of gestation with a birth weight of 2.6 kg. As a one year old, he was admitted for two weeks with a history of tachypnea and poor weight gain. His weight at the time was 5.7 kg, and he had a height of 62 cm and a head circumference of 44 cm (all below the 5th percentile). As part of the initial work-up, a chest X-ray and ECG were performed. The chest X-ray showed cardiomegaly, while the ECG showed sinus tachycardia, with a deep Q wave in leads I and aVL and left ventricular hypertrophy with a strain pattern in leads V5 and V6 (Fig. 1). These findings were not reported at the time.Figure 1 ECG of case 1. There is sinus tachycardia with deep Q wave in leads I and aVL strongly suggesting ALCAPA. There is also LVH with ST segment depression and T wave inversion most evident in V5 and V6. The patient was referred for cardiac evaluation, and the diagnosis of idiopathic DCM was made after the echocardiogram showed a dilated left ventricle with an ejection fraction (EF) of 35% and mild mitral regurgitation. No comment was made about the origin of the left coronary artery.

As part of the initial work-up, a chest X-ray and ECG were performed. The chest X-ray showed cardiomegaly, while the ECG showed sinus tachycardia, with a deep Q wave in leads I and aVL and left ventricular hypertrophy with a strain pattern in leads V5 and V6 (Fig. 1). These findings were not reported at the time.Figure 1 ECG of case 1. There is sinus tachycardia with deep Q wave in leads I and aVL strongly suggesting ALCAPA. There is also LVH with ST segment depression and T wave inversion most evident in V5 and V6. The patient was referred for cardiac evaluation, and the diagnosis of idiopathic DCM was made after the echocardiogram showed a dilated left ventricle with an ejection fraction (EF) of 35% and mild mitral regurgitation. No comment was made about the origin of the left coronary artery. The patient was started on anti-failure medication (furosemide, captopril and digoxin) and was discharged home. One year later, the patient was seen by a different cardiologist who spotted the ECG abnormalities and referred the patient to our center with a suspected anomalous left coronary artery from the pulmonary artery (ALCAPA). The clinical evaluation at our center was not different from the referring site; however, echocardiography showed the right coronary artery (RCA) to be dilated with multiple collaterals, while the left coronary artery (LCA) origin was not clearly observed. With color Doppler, the flow in the LCA was retrograde, which is highly suspicious for ALCAPA. To confirm the diagnosis, cardiac catheterization was performed. A selective angiogram showed a dilated RCA with multiple collaterals filling the LCA that originated from the pulmonary artery instead of the aorta (Fig. 2). The patient was taken for surgery, and the LCA was found to originate high on the MPA at the takeoff of the right pulmonary artery (Fig. 3). Such a high LCA takeoff is unusual for cases of ALCAPA, which explains the difficulty in visualizing its origin on echocardiography. The LCA was implanted to the aorta, and after a smooth post-operative course, the patient was discharged home on anti-failure medications four days after surgery. One month after surgery, he continues to be on medical therapy for his heart failure with the hope that cardiac function will improve with time.Figure 2 Selective right coronary artery angiogram showing dilated right coronary system with multiple collaterals to the left coronary artery which fills retrograde. There is spill of the contrast into the pulmonary artery (arrow) further confirming ALCAPA.

re with the hope that cardiac function will improve with time.Figure 2 Selective right coronary artery angiogram showing dilated right coronary system with multiple collaterals to the left coronary artery which fills retrograde. There is spill of the contrast into the pulmonary artery (arrow) further confirming ALCAPA. Figure 3 During surgery, the main pulmonary artery (MPA) is opened and a probe is placed in the LCA which arises close to the takeoff of the right pulmonary artery. The aorta (Ao) is posterior and to the right of the pulmonary artery. 3 Case 2 A 3-year-old boy presented for the first time to a local hospital with a one month history of shortness of breath, lethargy, and weight loss. These symptoms were preceded by an upper respiratory tract infection. His chest X-ray showed cardiomegaly, and echocardiography showed a dilated LV with depressed systolic function and an EF of 20%. The initial evaluation did not include an ECG. He was treated as having viral myocarditis and was started on anti-failure medications (furosemide, captopril and digoxin). With no improvement in his condition, he was referred to our center for further management as a case of DCM. At our initial evaluation, his weight was 14.2 kg and his heart rate was regular at 160 beats per minute. The mother reported that the heart rate had been rapid for the last nine months. The clinical examination was otherwise unremarkable apart from a pansystolic murmur at the apex.

He was treated as having viral myocarditis and was started on anti-failure medications (furosemide, captopril and digoxin). With no improvement in his condition, he was referred to our center for further management as a case of DCM. At our initial evaluation, his weight was 14.2 kg and his heart rate was regular at 160 beats per minute. The mother reported that the heart rate had been rapid for the last nine months. The clinical examination was otherwise unremarkable apart from a pansystolic murmur at the apex. A chest X-ray showed marked cardiomegaly, while the ECG showed narrow complex tachycardia at a rate of 160 beats per minute and an abnormal P-wave shape consistent with ectopic atrial tachycardia (EAT) or a permanent form of junctional reciprocating tachycardia (PJRT); both are a common cause of tachycardia-induced DCM (Fig. 4). The echocardiogram showed a severely dilated left atrium (SD + 8) and left ventricle (SD + 18) with severely depressed left ventricular systolic function (EF 10%). Based on the initial evaluation, a preliminary diagnosis of EAT was made and was confirmed by a 24-h ambulatory ECG recording that demonstrated the incessant nature of the rhythm. Amiodarone was introduced to the patient's medical regime to restore a sinus rhythm. Based on the behavior of the tachycardia and the good response to therapy, the tachycardia is likely to be EAT; however, PJRT remains a possibility that can only be excluded by an electrophysiology study. Nevertheless, the medical treatment and approach to radiofrequency ablation are the same in both situations. One month after the initiation of treatment with amiodarone, all symptoms disappeared and the EF increased to 30%. Within nine months, the cardiac function was normalized to an EF of 62% and the cardiomegaly was no longer evident on chest X-ray (Fig. 5).Figure 4 Case 2, ECG showing Narrow QRS long RP tachycardia at a rate of 160/minute with abnormal deep “P” wave in the inferior leads (circled) suggesting a non-sinus i.e. ectopic atrial tachycardia or permanent form of junctional reciprocating tachycardia.

the cardiomegaly was no longer evident on chest X-ray (Fig. 5).Figure 4 Case 2, ECG showing Narrow QRS long RP tachycardia at a rate of 160/minute with abnormal deep “P” wave in the inferior leads (circled) suggesting a non-sinus i.e. ectopic atrial tachycardia or permanent form of junctional reciprocating tachycardia. Figure 5 Case 2. Chest X-ray at presentation (a) showing marked cardiomegaly and (b) nice months of restoration of sinus rhythm showing reverse cardiac remodeling and normalization of cardiac size. 4 Discussion The outcome of symptomatic heart failure with DCM has not changed significantly over the last few decades [2], [3], [4]. Data from the pediatric DCM registry showed that about half of the children with DCM and symptomatic heart failure will die or require a cardiac transplant within two years of diagnosis. Controlling the symptoms of heart failure can be challenging in these patients; however, identifying the etiology causing the cardiomyopathy in the first place is the initial challenge. Multiple disorders can affect the heart [5], ranging from primary genetic abnormalities involving the myocardium, infectious pathogens causing myocarditis, storage diseases and exposure to toxins. However, in most pediatric cardiomyopathy studies, an etiology is found in only about one third of the cases, while the remainders are labeled as idiopathic.

heart [5], ranging from primary genetic abnormalities involving the myocardium, infectious pathogens causing myocarditis, storage diseases and exposure to toxins. However, in most pediatric cardiomyopathy studies, an etiology is found in only about one third of the cases, while the remainders are labeled as idiopathic. The search for a cardiomyopathy cause may be incomplete or misinterpreted if the clinician is inexperienced or careless. In one case, our patient had an ECG that was misinterpreted, while in the other case, an ECG was not performed at all. Both patients were assumed to have idiopathic DCM based on the initial incomplete evaluation. Although statistics indicate that the majority of DCM cases are idiopathic, it is unwise to assume this diagnosis unless a complete work-up is performed and other etiologies are ruled out.

ase, an ECG was not performed at all. Both patients were assumed to have idiopathic DCM based on the initial incomplete evaluation. Although statistics indicate that the majority of DCM cases are idiopathic, it is unwise to assume this diagnosis unless a complete work-up is performed and other etiologies are ruled out. In our first case, the diagnosis was evident on the initial ECG obtained at the time of presentation, and in both cases, the cause was treatable and the DCM was potentially reversible. Case 1 had an abnormal ECG that was suggestive of ischemia in addition to changes resulting from the disease process. The presence of Q waves in leads I and aVL should raise suspicion for ALCAPA in any child or infant presenting with cardiomyopathy [6]. Additionally, the ECG showed features of left ventricular strain with an ST-segment depression and T-wave inversion in the lateral leads. These findings should prompt the clinician to exclude coronary anomalies as a cause of the DCM. Systematic coronary artery evaluation by echocardiography using both 2D and color Doppler will identify the majority of these cases [7]. However, echocardiography can be misleading in some cases as a result of the “drop-out” at the coronary origin and the close proximity of the left coronary artery, which runs beside the aorta and redirects itself to the pulmonary artery [8]. In addition, color Doppler may not show the abnormal flow into the main pulmonary artery clearly if the pulmonary artery pressure is significantly elevated. In such cases, a more definitive study, such as a coronary angiogram or CT angiography, is indicated. In our patient, the echocardiogram was highly suggestive of ALCAPA, and to confirm the diagnosis, we elected to proceed with coronary angiography.

ery clearly if the pulmonary artery pressure is significantly elevated. In such cases, a more definitive study, such as a coronary angiogram or CT angiography, is indicated. In our patient, the echocardiogram was highly suggestive of ALCAPA, and to confirm the diagnosis, we elected to proceed with coronary angiography. Typically, patients with ALCAPA present with heart failure in early infancy once the pulmonary pressure and resistance drops [6]. This results in the under-perfusion of the left ventricular myocardium, and eventually, the flow is reversed, flowing from the left coronary artery into the pulmonary artery. This in turn leads to myocardial ischemia, then infarction, dilated cardiomyopathy and eventually congestive heart failure. Initially, myocardial ischemia is transient, and if caught early enough, the damage is reversible with surgical correction. This outlines the importance of early recognition of ALCAPA as a cause of DCM in children.

to myocardial ischemia, then infarction, dilated cardiomyopathy and eventually congestive heart failure. Initially, myocardial ischemia is transient, and if caught early enough, the damage is reversible with surgical correction. This outlines the importance of early recognition of ALCAPA as a cause of DCM in children. Case 2 presented with an ECG, also indicating an etiology for DCM. The persistent narrow QRS tachycardia with long R–P interval and abnormal P-wave axis raised suspicion of tachycardia-induced cardiomyopathy. After successful treatment of the tachycardia, most patients enjoy a favorable outcome with the recovery of ventricular function and reverse ventricular remodeling [9]. However, failure to recognize the tachycardia for an extended period of time could result in permanent myocardial damage or even sudden death. In a multicenter study that included eighty-one patients with tachycardia-induced DCM from 17 centers, Moore et al reported LV function recovery in 92% of the patients following control of the arrhythmia [9]. In that cohort, there was one mortality and two patients underwent heart transplant after controlling the arrhythmia. In a multivariate analysis, younger age and a faster tachycardia rate were associated with a higher chance for function recovery.

recovery in 92% of the patients following control of the arrhythmia [9]. In that cohort, there was one mortality and two patients underwent heart transplant after controlling the arrhythmia. In a multivariate analysis, younger age and a faster tachycardia rate were associated with a higher chance for function recovery. Our patient had tachycardia-induced DCM. With the restoration of a sinus rhythm after initiating amiodarone, the DCM resolved and reverse ventricular modeling led to normalized values. The plan is to consider ablation of the tachycardia mechanism once the patient is in an appropriate size to perform this procedure safely. In both cases, the computer interpretations of the ECGs were not accurate in identifying the abnormalities. Despite the improvement in algorithms and programs that read ECGs, computer interpretation demonstrates frequent errors in the interpretation of rhythm disturbances [10], [11]. Pediatricians' interpretation of ECGs also has a high rate of inaccuracy. A wide United Kingdom online study that included 764 pediatricians demonstrated an accuracy rate of 64% only when interpreting 10 common clinical conditions with recognizable ECGs [12]. This alarming rate underscores the importance of teaching the skill of ECG interpretation in pediatric training programs and continuous medical education. Our cases suggest that having these skills will enable the ability to save lives and/or prevent morbidities.

common clinical conditions with recognizable ECGs [12]. This alarming rate underscores the importance of teaching the skill of ECG interpretation in pediatric training programs and continuous medical education. Our cases suggest that having these skills will enable the ability to save lives and/or prevent morbidities. 5 Conclusion It cannot be overstated that early recognition of a primary treatable cause of DCM along with relatively simple interventions could save patients' lives. Practicing pediatricians, as well as cardiologists, must be thorough and diligent in searching for a primary cause of DCM. The findings on an ECG, in particular, can be missed because they are dependent on the clinician's own expertise in interpreting the recording. In both cases that are reported here, the automated computer reading did not identify the diagnosis nor suggest the etiology, which emphasizes the importance of interpreting the ECG correctly. A second opinion is advised if the ECG findings are not clear. Conflict of Interest The authors declare that they have no financial or other relationship that constitute a conflict of interest. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction The research focus on the Saudi adolescent population has been on diet, exercise, physical inactivity [1] and related health conditions, including nutritional deficiencies [2]. However, recent studies on the mental health of adolescents, such as depression, anxiety and stress, have begun to emerge [3]. Other health-compromising behaviors, such as smoking, have also been frequently studied among youths [4], [5], [6], which is a major public health concern in Saudi Arabia. Smoking rates among youths range between 30% and 37% [7], [8], [9]. Although school children are recurrent subjects for the study of nutrition, obesity, and smoking, risk behaviours associated with school achievement and factors that might affect those behaviors have not been addressed in the Kingdom. School-based data provide a great opportunity to address other risk behaviors, such as school absenteeism and engaging in violence on school property, which have scarcely been addressed. School climate has also been linked to multiple student behavioral, academic, health, and social-emotional outcomes [10].

he Kingdom. School-based data provide a great opportunity to address other risk behaviors, such as school absenteeism and engaging in violence on school property, which have scarcely been addressed. School climate has also been linked to multiple student behavioral, academic, health, and social-emotional outcomes [10]. The current study aimed to examine school behaviors, including school absenteeism and engaging in physical violence at school as well as their association with student connectedness with the school and their parents. Habitual absenteeism from school can be a serious health concern for mental health professionals, physicians, and educators. The prevalence of unexcused absences from school may be a major childhood behavioral disorder and a key risk factor for violence, injury, substance use, psychiatric disorders, and economic deprivation [11]. To the best of our knowledge, contextual risk factors, such as school violence and victimization, school environment and connectedness, parental involvement, and family variables, have not been examined in the Saudi culture.

ctor for violence, injury, substance use, psychiatric disorders, and economic deprivation [11]. To the best of our knowledge, contextual risk factors, such as school violence and victimization, school environment and connectedness, parental involvement, and family variables, have not been examined in the Saudi culture. School connectedness refers to the belief held by students that adults and peers in the school care about their education as well as about themselves as individuals, which is an important protective factor. Research has shown that youths who feel connected to their school are less likely to engage in many risk behaviors, including early sexual initiation, alcohol, tobacco, and other drug use, and violence and gang involvement. Students who feel connected to their school are also more likely to have better academic achievement, including higher grades and test scores, have better school attendance, and stay in school longer [12], [13]. Efforts to improve child and adolescent health have typically addressed specific health risk behaviours, such as tobacco use or violence. However, a growing body of research suggests that enhancing protective factors help children to avoid multiple behaviors that place them at risk for adverse health and educational outcomes [14]. In addition, a positive school environment has proven to deter children from engaging in school violence, particularly in preventing the initiation and reducing the severity of school violence [15]. However, little is known regarding the relative importance of various characteristics of the school environment or their differential effects on skipping school and engaging in school violence in Arab school youths. These important factors have never been systematically studied in the Kingdom of Saudi Arabia.

nce [15]. However, little is known regarding the relative importance of various characteristics of the school environment or their differential effects on skipping school and engaging in school violence in Arab school youths. These important factors have never been systematically studied in the Kingdom of Saudi Arabia. Parental monitoring is “a set of correlated parenting behaviours involving attention to and tracking of the child's whereabouts, activities, and adaptations” [16]. Research on parenting practices has revealed parental monitoring to be relevant to the development of childhood antisocial behavior and substance use [17], [18]. Parental monitoring is also associated with the positive dimensions of the children's adjustment in middle childhood, including self-esteem [19], academic achievement [20], and high school completion [21]. A number of risk factors have been identified, including familial environment, however, few studies have examined the effect of parental monitoring on risk behaviors associated with school, in particular, among Saudi adolescents. Given this background, the main purpose of this study was to investigate select school behaviors, including school absenteeism and engaging in physical violence, and discipline for misconduct at school and their association with the school environment, adolescent school and home connectedness. We hypothesized that a positive school environment and connectedness with the school and home have negative associations with school-related risk behavior.

engaging in physical violence, and discipline for misconduct at school and their association with the school environment, adolescent school and home connectedness. We hypothesized that a positive school environment and connectedness with the school and home have negative associations with school-related risk behavior. 2 Materials and methods The study participants were randomly drawn from high schools in Riyadh, the capital and largest city in Saudi Arabia. Schools were selected on the basis of their geographical location and type of institution. Riyadh was divided into three geographical areas for sampling purposes (North, South, Middle). In each geographical area, the two largest public schools, one private school, and one international school were selected. Approximately 60 classes with a free period were selected at random, which had 25–40 students per classroom on average. All of the students in the selected classrooms were eligible to participate in this study.

aphical area, the two largest public schools, one private school, and one international school were selected. Approximately 60 classes with a free period were selected at random, which had 25–40 students per classroom on average. All of the students in the selected classrooms were eligible to participate in this study. Prior to the administration of this the survey, a committee visited each school to explain the purpose of the study to the students, and an informational letter and consent form were sent home to the parents. Students were informed that participation in the study was completely voluntary. Four research teams consisting of health professionals (e.g., nurses, health coordinators) collected data from November 2010 to February 2012. Ethical approval for the study was obtained from the King Fahad Medical City Institutional Review Board, and permission was obtained from the Ministry of Education in Riyadh to administer the survey in the schools.

lth professionals (e.g., nurses, health coordinators) collected data from November 2010 to February 2012. Ethical approval for the study was obtained from the King Fahad Medical City Institutional Review Board, and permission was obtained from the Ministry of Education in Riyadh to administer the survey in the schools. 2.1 Survey development and validity A comprehensive adolescent health survey was developed for Saudi youth on the basis of an extensive literature review of adolescent health and questions adopted from the Youth Risk Behaviour Survey used in the United States. This national survey has been validated over the past several years in the United States. Using these standard questions, our survey has high face validity and credibility. Questions on family and school connectedness were developed by consulting experts in adolescent health to achieve face validity. Furthermore, we also performed exploratory factor analysis and used principal component analysis (PCA) to examine factor loadings for scale construction. The validity of the scales was confirmed by computing Cronbach's Alpha for each scale. The survey inquired about the adolescents' behaviors and attitudes and included questions on smoking behavior, perceptions of school and family, student attachment to school and family, use of technology, school activities, and activities outside of school. The survey items were translated to Arabic and then back translated to English by bi-lingual professionals. The survey was administered in the language that the student preferred.

tions of school and family, student attachment to school and family, use of technology, school activities, and activities outside of school. The survey items were translated to Arabic and then back translated to English by bi-lingual professionals. The survey was administered in the language that the student preferred. 2.2 Measures Outcomes (dependent variables): We considered the following three school-related risk behaviors as outcomes for this study.a) School absenteeism was assessed by asking “During the last month, how many times have you skipped or “cut” classes or school days?” with response categories of none, 1–3, 4–6, or more than 6 h. b) Engaged in school fights on school property: “In the past and/or the current academic year, how often have you been involved in a physical fight on school property?” with response categories of none, 1 or 2 times, 3–5 times, or 6 or more times. c) Disciplined for misconduct, i.e., engaging in school fights, thefts or damaging school property: “In the past and/or the current academic year, how often have you been disciplined at school for fighting, theft, or damaging property?” with response categories of none, 1 or 2 times, 3–5 times, or 6 or more times. 2.3 Independent variables Demographic information of the schools and students included: Type of school: Government, Private, or International, Grade: 8th thru 12th grades, Gender: Male or Female, and Ethnic group: Saudi, Arab, Neither Saudi nor Arab.

c) Disciplined for misconduct, i.e., engaging in school fights, thefts or damaging school property: “In the past and/or the current academic year, how often have you been disciplined at school for fighting, theft, or damaging property?” with response categories of none, 1 or 2 times, 3–5 times, or 6 or more times. 2.3 Independent variables Demographic information of the schools and students included: Type of school: Government, Private, or International, Grade: 8th thru 12th grades, Gender: Male or Female, and Ethnic group: Saudi, Arab, Neither Saudi nor Arab. Scales: The following scales were constructed for this study. Factor analysis was performed using school-related items and parent-related items separately to reduce the number of variables and to detect the structure of the relationships between variables. We used principal component analysis with the varimax rotation option and retained only factors with eigen values greater than 1. On the basis of the factor analysis, the following scales were computed and used. All of the items used in the following scales construction were measured on a 4-point-Likert scale (ranging from strongly agree (1) to strongly disagree (4)) and were reverse encoded appropriately and summed. Higher scores indicated the desired direction.a) School environment assessed whether there were opportunities to engage in after school activities (sports, music, etc.) and was grouped into two categories: yes = strongly/agree and no = disagree/strongly disagree.

(4)) and were reverse encoded appropriately and summed. Higher scores indicated the desired direction.a) School environment assessed whether there were opportunities to engage in after school activities (sports, music, etc.) and was grouped into two categories: yes = strongly/agree and no = disagree/strongly disagree. b) School policies scale included two items (alpha = .56) (“There are clear rules about what students can and cannot do” and “The school principal and teachers consistently enforce school rules”, students caught smoking will be punished”) with a mean = 7.9, SD = 2.6). c) School-student connectedness scale included 7 items (alpha = .82) – (“my teachers care about me,” “teachers are available to talk with a student one-on-one,” “When I am doing a good job, my teachers notice and let me know about it,” “Students in my school treat each other with respect,” “I feel safe at school,” “I care about my school,” and “There is at least one adult at school who I could go to for help with a problem.”), mean = 17.87, SD = 5.5). d) School-parent communication scale includes 3 items (alpha .60) – “If I skipped school at least one of my parents/guardians would be notified,” “If I got in trouble at school for breaking a rule, at least one of my parents/guardians would support the school's disciplinary action,” and “My school lets a parent/guardian know if I've done something wrong.” (mean = 8.2, SD = 2.64).

60) – “If I skipped school at least one of my parents/guardians would be notified,” “If I got in trouble at school for breaking a rule, at least one of my parents/guardians would support the school's disciplinary action,” and “My school lets a parent/guardian know if I've done something wrong.” (mean = 8.2, SD = 2.64). e) The parent monitoring scale includes 8 items, (alpha = .77, mean = 14.6, SD = 5.3) with response categories: never, sometimes, often, and always (Items: A parent knows where I am and who I am with, particularly in the evening and on weekends., A parent/guardian generally determines if I have done something wrong, and then punishes me, When I am doing a good job, someone in my home lets me know about it, “Someone in my home helps me with my school work,” “At least one of my parents goes to school activities that I am involved in,” “I can talk about the things that bother me or I don't understand with someone in my house,” and “My family influence what I do.”).

doing a good job, someone in my home lets me know about it, “Someone in my home helps me with my school work,” “At least one of my parents goes to school activities that I am involved in,” “I can talk about the things that bother me or I don't understand with someone in my house,” and “My family influence what I do.”). 2.4 Data analysis Univariate descriptive statistics were examined, and the variables were regrouped as suggested by the distribution. Descriptive statistics were calculated and expressed as the mean and standard deviation or as a percentage. To test for bivariate associations between the three school risk behaviours and predictors, cross tabulations with the χ2 option were performed for categorical variables with a significance level set at P < .05. To test the group mean differences for scale scores, T-tests were performed with a significance level set at P < .05. For multivariable analysis, logistic regression models were run separately for each of the three risk behaviors, absenteeism (at least 1 h vs. never), engaged in school fights (at least once vs. never), and disciplined for misconduct (at least once and never), which were classified into dichotomous variables on the basis of the distribution. The relative odds and 95% confidence intervals were estimated. All analyses were performed using SPSS Statistics (Version 22.0) software (IBM Corp., Armonk, NY, USA).

vs. never), and disciplined for misconduct (at least once and never), which were classified into dichotomous variables on the basis of the distribution. The relative odds and 95% confidence intervals were estimated. All analyses were performed using SPSS Statistics (Version 22.0) software (IBM Corp., Armonk, NY, USA). 3 Results A total of 1668 students (7th through 12th grade) from governmental (41%), private (32%), and international schools (27%) in Riyadh were surveyed. Male and female (51%) students were equally represented in the survey, and nearly all of the students were of the Islamic faith (98.4%). Nearly two-thirds of the participants were Saudi (61%), 30% were Arab, and approximately 9% were of other cultures. 3.1 School risk behaviours and relationship with predictors Nearly 54% of students skipped school or cut classes for at least 1 h, and out of those students who had skipped school, 37% of the students skipped school for 1–3 h and 20% of the students skipped school for 3 or more hours during the last month prior to the survey. Thirty-eight percent of the surveyed students reported engaging in fights on school property at least once during the past or current academic year. Discipline for engaging in school fights, thefts or damaging school property at least once was reported in 37% of students.

ours during the last month prior to the survey. Thirty-eight percent of the surveyed students reported engaging in fights on school property at least once during the past or current academic year. Discipline for engaging in school fights, thefts or damaging school property at least once was reported in 37% of students. Table 1 represents bivariate associations between the outcomes and predictor variables considered in the analysis. Absenteeism was significantly associated with all of the demographic variables, and students who skipped school had significantly lower mean scores on school policies, school-student connectedness, and parental monitoring. As shown in Table 1, absenteeism demonstrated a positive association, which was reflected by higher proportions with an increase in grade. School absenteeism was also significantly higher in male Saudi students.Table 1 Association between school risk behavior, demographics, and school and family connectedness (N = 1668).

shown in Table 1, absenteeism demonstrated a positive association, which was reflected by higher proportions with an increase in grade. School absenteeism was also significantly higher in male Saudi students.Table 1 Association between school risk behavior, demographics, and school and family connectedness (N = 1668). Absenteeism (%) Involved in school fight (%) Disciplined for school misconduct (%) Yes No Χ2 (df) sig Yes No Χ2 (df) sig Yes No Χ2 (df) sig Type of school 26.0 (2)*** 16.5 (2)*** 7.1 (2)* Govt (n = 662) 56 44 32 68 34 66 Private (n = 520) 61 39 42 58 41 59 International (n = 445) 44 56 42 58 38 62 Grade 17.6(4)** 18.2(4)*** 14.2(4)** 7/8 (n = 286) 48 52 30 70 29 71 9 (n = 271) 49 51 41 59 37 63 10 (n = 333) 55 45 46 54 44 56 11 (n = 402) 57 43 36 64 36 64 12 (n = 320) 63 37 36 64 38 62 Gender 24.2(1)*** 97.2(1)*** 30.7(1)*** Male (n = 799) 61 39 49 51 44 56 Female (n = 822) 48 52 25 75 30 70 Ethnic group 42.9(2)*** 3.8(2) 9.0(2)** Saudi (n = 1014) 61 39 36 64 38 62 Arab (n = 490) 47 53 42 58 39 61 Neither (n = 144) 35 65 37 63 25 75 Opportunities for extracurricular activities at school 17.7(1)*** 0.56(1) 1.1(1) Yes(n = 982) 59 41 38 62 38 62 No (n = 479) 47 53 36 64 35 65 Scales (T-test) Absenteeism (%) Involved in school fights (%) Disciplined for school misconduct (%) Mean difference t-Value sig Mean difference t-Value sig Mean difference t-Value sig School policies −0.384 −2.9** −0.481 −3.54*** −0.214 −1.56 School-parent communication −0.255 −1.9 −0.197 −1.41 −0.143 −1.03 School-student connectedness −0.703 −2.5** −1.77 −6.06*** −0.942 −3.27*** Parental monitoring −1.765 −6.42*** −0.438 −1.55 −0.524 −1.91* Percentages rounded to the closest integer. P-value sig * ≤.05 ** ≤.01 *** ≤.001.

−2.9** −0.481 −3.54*** −0.214 −1.56 School-parent communication −0.255 −1.9 −0.197 −1.41 −0.143 −1.03 School-student connectedness −0.703 −2.5** −1.77 −6.06*** −0.942 −3.27*** Parental monitoring −1.765 −6.42*** −0.438 −1.55 −0.524 −1.91* Percentages rounded to the closest integer. P-value sig * ≤.05 ** ≤.01 *** ≤.001. Nearly two-thirds (67%) of the students surveyed reported that there were abundant opportunities for involvement in after school activities, including sports, music, and so on. However, bivariate analyses indicated that this factor was only associated with absenteeism. Engagement in school fights was significantly associated with all of the demographic variables, except with the ethnic group. Students who reported engaging in school fights had significantly lower mean scores on school policies and school-student connectedness. Discipline for school misconduct was also significantly associated with all of the demographic variables. Students who were disciplined at school had significantly lower scores on school-student connectedness and parental monitoring. In general, a higher proportion of male students engaged in physical fights and was disciplined for school misconduct. The main interesting observation from the bivariate analyses differed from absenteeism and engaging in school fights, and discipline for misconduct decreased with an increase in grade.

ntal monitoring. In general, a higher proportion of male students engaged in physical fights and was disciplined for school misconduct. The main interesting observation from the bivariate analyses differed from absenteeism and engaging in school fights, and discipline for misconduct decreased with an increase in grade. Table 2 shows the results obtained from the logistic regression models. Male students showed a clear increase in the odds for all three school risk behaviours. Importantly, male students also demonstrated three times greater odds to engage in school fights and nearly twice the odds for disciplinary action at school compared to female students. Native Saudi students also demonstrated higher odds for absenteeism and receiving disciplinary actions at school. School-student connectedness demonstrated reduced odds for all three risk behaviours. In addition, parental monitoring also reduced the odds for absenteeism and school policies in reducing student involvement in school fights.Table 2 Results from logistic regression – odds ratios and 95% confidence intervals (CI) predicting school risk behaviours.

demonstrated reduced odds for all three risk behaviours. In addition, parental monitoring also reduced the odds for absenteeism and school policies in reducing student involvement in school fights.Table 2 Results from logistic regression – odds ratios and 95% confidence intervals (CI) predicting school risk behaviours. Absenteeism (n = 1283) Involved in school fight (n = 1395) Disciplined for school misconduct (n = 1374) OR 95% CI OR 95% CI OR 95% CI School type (ref: International) Govt 0.73 0.49, 1.1 1.24 0.896, 1.7 1.32 0.97, 1.8 Private 0.96 0.64, 1.4 1.67** 1.15, 2.4 1.45 0.99, 2.1 Grade (ref:7–8th grade) 9 1.2 0.83, 1.84 1.36 0.91, 2.1 1.27 0.86,1.9 10 0.95 0.62, 1.45 1.1 0.704, 1.7 1.29 0.85, 1.95 11 1.3 0.86, 1.9 1 0.79 0.532, 1.2 0.99 0.67, 1.5 12 1.73** 1.15, 2.6 0.72 0.474, 1.1 1.01 0.68, 1.5 Gender (ref: female) Male 1.3* 1.01, 1.66 3.3*** 2.53, 4.25 1.77*** 1.38, 2.26 Ethnic group (ref: other) Saudi 2.41*** 1.48, 3.9 – – 2.07** 1.25, 3.4 Arab 1.41 0.88, 2.6 – – 2.2*** 1.35, 3.6 Extracurricular opportunities – – – – School policies 0.98 0.93, 1.03 0.95* 0.900, .99 0.99 0.945, 1.04 School-parent communication 0.98 0.94, 1.04 1.02 0.97, 1.08 0.99 0.946 , 1.04 School-student connectedness 0.96** 0.94, 0.98 0.95*** 0.93, .98 0.97* 0.95, 0.997 Parental monitoring 0.96** 0.93, 0.98 0.98 0.953, 1.01 0.98 0.95, 1.01 P-value sig * ≤.05 ** ≤.01 *** ≤.001.

0.98 0.93, 1.03 0.95* 0.900, .99 0.99 0.945, 1.04 School-parent communication 0.98 0.94, 1.04 1.02 0.97, 1.08 0.99 0.946 , 1.04 School-student connectedness 0.96** 0.94, 0.98 0.95*** 0.93, .98 0.97* 0.95, 0.997 Parental monitoring 0.96** 0.93, 0.98 0.98 0.953, 1.01 0.98 0.95, 1.01 P-value sig * ≤.05 ** ≤.01 *** ≤.001. 4 Discussion Mental health professionals and educators are encouraged to fully understand the dynamics of the parameters that result in school risk behaviours to develop better, consensual policies and intervention programs. In this study, we examined the relationship between school risk behaviours in adolescents and connectedness and bonding between adolescents and their school and parents. School-student connectedness reduced the odds of school absenteeism, engagement in school fights, and discipline for misconduct. Our study provides strong evidence in support of school-student connectedness in the reduction of school risk behaviours. Furthermore, parental monitoring also reduced the odds of absenteeism, and school policies reduced student involvement in school fights. Parent monitoring of their children's behaviour is considered to be an essential parenting skill. Numerous studies have shown that well-monitored youths are less involved in delinquency and other norm-breaking behaviours. Parental monitoring and school policies are also important for reducing absenteeism and engaging in school fights, respectively. Parental involvement in their child's education has been consistently found to be positively associated with the child's academic performance [22], [23]. In particular, positive outcomes are achieved when the parents remain cognizant of their child's activities, monitor their child's behaviour, and raise their children in a structured environment [16], [24]. Cross-sectional, longitudinal, and interventional studies have demonstrated that monitored youths are less likely to engage in substance use and delinquent behaviour or to spend time with deviant peers [24], [25], [26], [27], [28], [29]. Research evidence indicates a direct link between parental monitoring and positive youth outcomes [27], and parental monitoring can deter deviant peer influences on youth substance use or anti-social behaviour [29], [30]. A recent meta-analysis by Jeynes indicated that the association between father involvement and the educational outcomes of youth overall is significant [31].

monitoring and positive youth outcomes [27], and parental monitoring can deter deviant peer influences on youth substance use or anti-social behaviour [29], [30]. A recent meta-analysis by Jeynes indicated that the association between father involvement and the educational outcomes of youth overall is significant [31]. When we examined parental involvement in school-related activities separately, one-third of the students surveyed reported that their parents never helped them with their homework (38%) or only helped sometimes (36%). One-third of students (35%) indicated that their parents never attended any of the school activities or attended only some of the activities (40%) in which they were involved. These data reflect low parental involvement in school-related activities, demonstrating the need for school officials to plan activities that promote parental involvement.

33], [34]. A strong relationship between school connectedness and educational outcomes, including school attendance and better grades, was also noted in the research [35]. Better school performance (higher grades) is a protective factor against carrying a weapon, smoke cigarettes, or consuming alcohol [36], [37], [38]. Our study found school policies to be associated with a reduction in student involvement in school fights. Schools in Riyadh may also focus on creating a positive environment by offering after school activities and organized events for students to participate in. The psychosocial climate at school is affected by school policies related to discipline, opportunities for meaningful student participation, and the teachers' classroom management practices. Research indicates that in schools with a harsh and punitive discipline climate, there is lower student connectedness [34], [35], [36], [37], [38], [39]. However, a positive school environment must also include caring and supportive interpersonal relationships, opportunities to participate in school activities and decision-making, and shared positive norms, goals, and values [40]. Schools that have higher rates of participation in extracurricular activities during or after school tend to have higher levels of school connectedness [34]. Connectedness is enhanced by a healthy and safe school environment and a supportive psychosocial climate. School staff who are dedicated to the education of their students build school communities that enable students to develop emotionally, socially, and mentally as well as academically. Committed school staff can also engage students in learning, foster mutual respect and caring, and meet the personal learning needs of each student.

who are dedicated to the education of their students build school communities that enable students to develop emotionally, socially, and mentally as well as academically. Committed school staff can also engage students in learning, foster mutual respect and caring, and meet the personal learning needs of each student. 4.1 Study strengths and limitations As with any survey research, our study also suffers from classic limitations. The study involved self-reporting, and therefore, many of the risk behaviours measured might have been under reported, resulting in lower prevalence estimates. Furthermore, students with literacy challenges may not have understood or answered reliably. The other challenges included missing data due to nonresponses or the selection of the “don't know” option, which was set as missing, resulting in at least 15% missing responses for any given variable. The study was conducted only in the city of Riyadh, thus, these results may not be representative of adolescents in the entire Kingdom, particularly, rural provinces. This result would limit the generalisability of our study results for other youths living in rural and urban areas in the Kingdom. Nevertheless, the study strengths included a large sample that was randomly selected to represent students across age groups and that schools were selected based on the type and geographical location in Riyadh, the largest city in the Kingdom, with a population of nearly five million people.

urban areas in the Kingdom. Nevertheless, the study strengths included a large sample that was randomly selected to represent students across age groups and that schools were selected based on the type and geographical location in Riyadh, the largest city in the Kingdom, with a population of nearly five million people. 5 Conclusion Families, schools, and communities need to work together to create an environment that facilitates the healthy development of children and adolescents. Effective parenting practices play a critical role in preventing and reducing youth problem behaviours. Our study and other relevant research showed that students who feel connected to school are more likely to have positive health and education outcomes. Evidence-based health promotion programs and strategies that enhance connectedness can also help schools to have the greatest impact on the health and education outcomes of their students. Because school connectedness is a particularly promising protective factor, strategies to increase connectedness must be developed by the Saudi Ministry of Education and implemented in schools across the Kingdom. For example, the CDC has proposed a framework consisting of six key strategies to improve student connectedness that can be easily adopted in any school setting [37]. Engaging students, parents, school staff, and community members in teams to develop school policies, plan school-wide activities, and create trusting and caring relationships that promote open communication among administrators, teachers, staff, students, families, and communities are some of the key strategies.

[37]. Engaging students, parents, school staff, and community members in teams to develop school policies, plan school-wide activities, and create trusting and caring relationships that promote open communication among administrators, teachers, staff, students, families, and communities are some of the key strategies. 5.1 Implications for school health This study has implications for the development of strategies to enhance the best practices in a school setting to promote student positive behaviour and school achievement. Schools and parents should be encouraged to work as a team and to recognize the importance of school connectedness in improving the students' health and education outcomes. It is also important to evaluate efforts to increase school connectedness to learn which actions will have the greatest effect. Relationships with parents are a key factor in the development of youths. Youths who feel close to their caregivers tend to value their opinions more highly and are more likely to seek guidance for difficult situations [41]. For the most part, it is not customary for schools in Saudi Arabia to involve parents, in part because most existing parental interventions require a significant time commitment by parents. There is also a great need for risk-reduction intervention programs that are implemented by schools. Human subjects approval statement Ethical approval for the study was obtained from King Fahad Medical City Institutional Review Board along with the permission from the Ministry of Education in Riyadh to administer the survey in schools.

5.1 Implications for school health This study has implications for the development of strategies to enhance the best practices in a school setting to promote student positive behaviour and school achievement. Schools and parents should be encouraged to work as a team and to recognize the importance of school connectedness in improving the students' health and education outcomes. It is also important to evaluate efforts to increase school connectedness to learn which actions will have the greatest effect. Relationships with parents are a key factor in the development of youths. Youths who feel close to their caregivers tend to value their opinions more highly and are more likely to seek guidance for difficult situations [41]. For the most part, it is not customary for schools in Saudi Arabia to involve parents, in part because most existing parental interventions require a significant time commitment by parents. There is also a great need for risk-reduction intervention programs that are implemented by schools. Human subjects approval statement Ethical approval for the study was obtained from King Fahad Medical City Institutional Review Board along with the permission from the Ministry of Education in Riyadh to administer the survey in schools. Conflict of interest None. Acknowledgements The authors would like to extend their acknowledgement to all of the school principals and teachers who facilitated the administration of the survey and extended needed support. We greatly appreciate the teams who contributed their effort in collecting the data, specifically, Basma and Othman.

Conflict of interest None. Acknowledgements The authors would like to extend their acknowledgement to all of the school principals and teachers who facilitated the administration of the survey and extended needed support. We greatly appreciate the teams who contributed their effort in collecting the data, specifically, Basma and Othman. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Medication related errors at admissions and the discharge of patients at health institutions are common and preventable [1], [2], [3]. One of the best measures to prevent these errors is the use of an accurate medication reconciliation process that integrates the effort of different health care providers [4], [5]. Medication reconciliation improves patient safety and reduces the risk of medication error by ensuring that health care providers and patients have an up-to-date list of the medications that a patient is taking [6]. The Joint Commission has defined medication reconciliation as “the process of comparing a patient's medication orders to all of the medications that the patient has been taking.” Medication errors may include omissions, duplications, dosing errors, or harmful drug interactions. This process should be performed at every transition of care in which new medications are ordered or existing orders are rewritten [7]. King Faisal Specialist Hospital and Research Centre (KFSH&RC) is a tertiary care center located in Riyadh, the capital city of Kingdom of Saudi Arabia. It is a 894-bed medical institution that has been accredited by the Joint Commission International Accredited (JCIA) academic medical facility. KFSH&RC receives referrals from across the nation in multiple disciplines. It is well known in the fields of Oncology, Organ Transplantation, Cardiovascular Diseases, Neurosciences and Genetic Diseases. Furthermore, KFSH&RC has well established training programs in multiple medical and allied health specialties [8].

King Faisal Specialist Hospital and Research Centre (KFSH&RC) is a tertiary care center located in Riyadh, the capital city of Kingdom of Saudi Arabia. It is a 894-bed medical institution that has been accredited by the Joint Commission International Accredited (JCIA) academic medical facility. KFSH&RC receives referrals from across the nation in multiple disciplines. It is well known in the fields of Oncology, Organ Transplantation, Cardiovascular Diseases, Neurosciences and Genetic Diseases. Furthermore, KFSH&RC has well established training programs in multiple medical and allied health specialties [8]. One of the major departments at KFSH&RC is the Department of Pediatrics. There are more than ten sections with more than 44 physicians all delivering state of the art medical care as well as providing a friendly educational environment to trainees. Annually, the Pediatric department admits approximately 3000 inpatient cases and about the same number of outpatient cases. From primary prevention to advanced tertiary care, the Department of Pediatrics provides up-to-date and state-of-the-art child health care [8]. The historical background of King Faisal Specialist Hospital in regard to medication reconciliations can be summarized as follows:• 20 January 2010 – Medication Reconciliation functionality was available in the Cerner Millennium Integrated Clinical Information System (ICIS), an electronic patient records system used at KFSH&RC. • Between 2010 and 2014, the ICIS Medication Reconciliation functionality proved to be non-user friendly and was not used due to this fact.

From primary prevention to advanced tertiary care, the Department of Pediatrics provides up-to-date and state-of-the-art child health care [8]. The historical background of King Faisal Specialist Hospital in regard to medication reconciliations can be summarized as follows:• 20 January 2010 – Medication Reconciliation functionality was available in the Cerner Millennium Integrated Clinical Information System (ICIS), an electronic patient records system used at KFSH&RC. • Between 2010 and 2014, the ICIS Medication Reconciliation functionality proved to be non-user friendly and was not used due to this fact. • In 04 September 2014, HITA improved this system and launched the Enhanced Medication Reconciliation, a much needed user-friendly version. 2 Objective To improve the compliance of the medication reconciliation process at the time of admission to the Department of Pediatrics.

• Between 2010 and 2014, the ICIS Medication Reconciliation functionality proved to be non-user friendly and was not used due to this fact. • In 04 September 2014, HITA improved this system and launched the Enhanced Medication Reconciliation, a much needed user-friendly version. 2 Objective To improve the compliance of the medication reconciliation process at the time of admission to the Department of Pediatrics. 3 Materials and methods We reviewed the medication reconciliation process at the Department of Pediatrics at KFSH&RC. Physician compliance for admission medication reconciliation documentation in ICIS ranged from (0–15%) between the first quarter of 2012 and the first quarter 2015, according to official audits completed by the Quality Management Department at KFSH&RC. The audit process starts by selecting a random representative sample from the total number of quarterly admitted patients. The target is to audit six charts per consultant, as applicable. The length of stay for the selected random sample of patients should be from 3 to 10 days (Table 1).Table 1 Department of Pediatrics – medication reconciliation report. Clinical documentation report 2012 Q1 Q2 Q3 Q4 Total number of charts reviewed 12 51 36 34 Admission Medication Reconciliation documented 0% 12% 15% 13% Reconciliation on transfer documented (by the receiving physician) na 50% na 0% Clinical documentation report 2013 Q1 Q2 Q3 Q4 Total number of charts reviewed 58 43 45 54 Admission Medication Reconciliation documented 6% 0% 0% 0% Reconciliation on transfer documented (by the receiving physician) 100% na na na

Clinical documentation report 2012 Q1 Q2 Q3 Q4 Total number of charts reviewed 12 51 36 34 Admission Medication Reconciliation documented 0% 12% 15% 13% Reconciliation on transfer documented (by the receiving physician) na 50% na 0% Clinical documentation report 2013 Q1 Q2 Q3 Q4 Total number of charts reviewed 58 43 45 54 Admission Medication Reconciliation documented 6% 0% 0% 0% Reconciliation on transfer documented (by the receiving physician) 100% na na na Clinical documentation report 2014 Q1 Q2 Q3 Q4 Total number of charts reviewed 43 52 34 40 Admission Medication Reconciliation documented 0% 0% 0% 5% Reconciliation on transfer documented (by the receiving physician) na na na na Clinical documentation report 2015 Q1 Q2 Q3 Q4 Total number of charts reviewed 36 Admission Medication Reconciliation documented 0% Reconciliation on transfer documented (by the receiving physician) na Compliance Rate: ≤75% = Severe deficiency; 76%–89% = areas for improvement; ≥90% = Compliant. The “Improving Medication Reconciliation” working group was established by the Department of Pediatrics Quality Team to examine potential factors affecting non-compliance during the medication reconciliation process and to find solutions for improvement. The rationale of specifying only one department was twofold; by focusing on areas under our direct and daily control we could better understand the challenges faced by physician end-users. The group was set to meet weekly to discuss and evaluate the implementation process. It consisted of the following:○ Quality Director of the Department of Pediatrics

The “Improving Medication Reconciliation” working group was established by the Department of Pediatrics Quality Team to examine potential factors affecting non-compliance during the medication reconciliation process and to find solutions for improvement. The rationale of specifying only one department was twofold; by focusing on areas under our direct and daily control we could better understand the challenges faced by physician end-users. The group was set to meet weekly to discuss and evaluate the implementation process. It consisted of the following:○ Quality Director of the Department of Pediatrics ○ Residency Training Program Director ○ Pediatric Consultant Staff representative ○ Healthcare Information Technology Affairs (HITA) representative ○ Quality Assurance Department representative ○ Head nurses of the Pediatric Wards ○ Pediatric resident representative ○ A biostatistician Most of the recent efforts at our institution to revamp the medication reconciliation process have failed (Table 1). Thus, the working group designed and implemented an innovative approach to improve medication reconciliation. This approach is twofold:1. We formed a working group with multiple members from different support areas in the hospital; these focused efforts were planned to potentially give us more control over the process at the departmental level. This focused working group can be used as a model to lead the way and motivate other departments at KFSH&RC.

1. We formed a working group with multiple members from different support areas in the hospital; these focused efforts were planned to potentially give us more control over the process at the departmental level. This focused working group can be used as a model to lead the way and motivate other departments at KFSH&RC. 2. We designed and implemented an evidenced-based systematic method of improvement. The following steps were used to improve the process of medication reconciliation at our department; the effectiveness of some of these steps have yet to be evaluated [9]:2.1. We clearly defined the steps of the reconciliation process to the concerned parties during the focused educational sessions; in addition, a general introductory lecture was given to all staff before the focused sessions started. 2.2. We clearly identified responsibilities for the process across the three disciplines generally involved: medical, pharmacy, and nursing. 2.3. We defined an explicit time frame for the completion of the educational and close monitoring processes, which was 2 months starting June 1, 2015. 2.4. We designed and provided educational sessions for the residents involved in the process. 2.5. We carefully designed and implemented a monitoring process including close observation by three assigned consultants. We also trained a super-user and requested periodic audit reports by the HITA specifically made for this project. 2.6. We obtained the support of Department of Pediatrics physicians and nurses.

2.4. We designed and provided educational sessions for the residents involved in the process. 2.5. We carefully designed and implemented a monitoring process including close observation by three assigned consultants. We also trained a super-user and requested periodic audit reports by the HITA specifically made for this project. 2.6. We obtained the support of Department of Pediatrics physicians and nurses. 2.7. Finally, we obtained executive leadership support for our initiative. We were able to encourage the main players to actively participate in the design and implementation of our initiative. Participating in this initiative was very challenging because providers were already burdened by clinical work. However, we were successful at obtaining full Department of Pediatrics executive leadership support for this program. Our first step was to design and implement an education campaign through lectures and focused hands-on training for a group of no more than 5–6 residents. One super-user (a resident who was assigned to be the departmental reference to receive and handle any clarification from the end users in the department) was identified and trained intensively to assist the medical staff at all occasions. A main part of the project was to closely monitor compliance with the process. A HITA representative with a nursing background was asked to provide reports on compliance every two weeks that were specifically tailored for and used by this project. These audit reports were based on a random electronically based screening process for all pediatric inpatients at different time periods.

the process. A HITA representative with a nursing background was asked to provide reports on compliance every two weeks that were specifically tailored for and used by this project. These audit reports were based on a random electronically based screening process for all pediatric inpatients at different time periods. Three consultants were asked to review these reports once received by the group and to nudge the residents/staff who relinquished their duties to try to improve their efforts. Once nurses in the general Pediatrics Wards completed the nursing part of the medication reconciliation process, they reminded and encouraged physicians to complete the reconciliation process, thereby supporting the medical part of the medication reconciliation process. 4 Inclusion criteria All patients admitted to the Department of Pediatrics during the study period, i.e., June–July 2015, were eligible for this study. 5 Exclusion criteria • Pediatric patients who were not cared for by the Pediatric Department • In-patient transfers to the Department of Pediatrics This project was reviewed and approved by a member of the Department of Quality Management at KFSH&RC.

4 Inclusion criteria All patients admitted to the Department of Pediatrics during the study period, i.e., June–July 2015, were eligible for this study. 5 Exclusion criteria • Pediatric patients who were not cared for by the Pediatric Department • In-patient transfers to the Department of Pediatrics This project was reviewed and approved by a member of the Department of Quality Management at KFSH&RC. 6 Results From 16 June to 12 July 2015, a major improvement in compliance with the medication reconciliation process had been noticed for the admitted patients in Pediatrics departments (Fig. 1). One member of the research group belongs to HITA and had no direct contact with the patients and had no influence on the residents performing the medication reconciliation; this member conducted four audits through ICIS. From 0 to 15% of physician compliance for admission medication reconciliation from first quarter of 2012 up to first quarter of 2015 (Table 1), we managed to improve this figure to 96%. As demonstrated in Table 2, there was a gradual marked improvement in the number of patients with completed medication reconciliation upon admission. For example, on the B1 floor, which is the major area of admission for Pediatrics, 57.6% of the total number of patients had medication reconciliation performed for them in the first report from the 16th of June. In the July 12th report, this percentage improved to 92.4%. A similar improvement occurred in other pediatric areas, including the B3-1 (from 88.8% in the first report to 90% in the second), the NICU 1 (from 83.4% to 100%) and the NICU 2 (from 90% to 100%). For more details, please refer to Table 2. These findings indicate that most of the patients admitted to the Pediatrics floors had their admission medication reconciliation properly performed, and the trend increased gradually over time. This improvement places the Department of Pediatrics first among all hospital medical departments.Figure 1 Admission medication reconciliation compliance improvement over the project time.

he Pediatrics floors had their admission medication reconciliation properly performed, and the trend increased gradually over time. This improvement places the Department of Pediatrics first among all hospital medical departments.Figure 1 Admission medication reconciliation compliance improvement over the project time. Table 2 Audit results from different areas within the Department of Pediatrics by the audit date. Areas June 16 June 24 July 2 July 12 Total N Completed N (%) Total N Completed N (%) Total N Completed N (%) Total N Completed N (%) B1 26 15 (57.6) 27 22 (81.4) 22 20 (90) 13 12 (92.4) B3-1 9 8 (88.8) 10 8 (80) 7 6 (86) 10 9 (90) B3-2 1 1 (100) 1 1 (100) 7 3 (44) 2 2 (100) NICU 1 18 15 (83.4) 13 10 (77) 14 14 (100) 14 14 (100) NICU 2 10 9 (90) 10 8 (80) 11 9 (82)8 8 8 (100) Total 64 49 (77) 61 49 (80) 61 52 (87) 47 45 (96)

) Total N Completed N (%) B1 26 15 (57.6) 27 22 (81.4) 22 20 (90) 13 12 (92.4) B3-1 9 8 (88.8) 10 8 (80) 7 6 (86) 10 9 (90) B3-2 1 1 (100) 1 1 (100) 7 3 (44) 2 2 (100) NICU 1 18 15 (83.4) 13 10 (77) 14 14 (100) 14 14 (100) NICU 2 10 9 (90) 10 8 (80) 11 9 (82)8 8 8 (100) Total 64 49 (77) 61 49 (80) 61 52 (87) 47 45 (96) Despite our eminent success, we faced many challenges. For example, the distribution of patients in the B1 area, where other services admit their pediatric patients under their care, created conflict for the team and required extra work to exclude these patients from consideration. Another challenge was conducting the study in the B3-2 area, where pediatric patients represent a very small percentage, which required extra work from the team to identify and follow pediatric patients. The discrepancy among the types of patients between the wards may also have played a role in the discrepancy among the compliance rate for admission medication reconciliation. Finally, pediatric patients were admitted to other non-pediatric areas, and the study team had to extend extra efforts to track them.

patients. The discrepancy among the types of patients between the wards may also have played a role in the discrepancy among the compliance rate for admission medication reconciliation. Finally, pediatric patients were admitted to other non-pediatric areas, and the study team had to extend extra efforts to track them. 7 Discussion Improving the quality of patient care is the core aim of all healthcare institutions. One way to improve the quality of patient care is to have clearly written policies and procedures that regulate the working process; one of the hospital policies at KFSH&RC pertains to the need to complete medication reconciliations for all patients. Unfortunately, physician compliance to the medication reconciliation process was very poor despite multiple attempts to make this process more user-friendly. Our aim at the Department of Pediatrics was to initiate the focused efforts of a core team of leader physicians with the support of other non-medical departments, such as HITA. In doing so, we expected to have more control over and the ability to monitor the medication reconciliation process. Once we succeeded in this attempt, we then expanded it to the whole hospital. Over two months of extensive, evidence-based efforts, including education and monitoring, we were able to significantly improve compliance during the medication reconciliation process at admission.

nitor the medication reconciliation process. Once we succeeded in this attempt, we then expanded it to the whole hospital. Over two months of extensive, evidence-based efforts, including education and monitoring, we were able to significantly improve compliance during the medication reconciliation process at admission. Due to our limited resources available for auditing, only medication reconciliation at the time of admission was audited by HITA. Further results will follow, including compliance at the time of transfer and discharge. As soon as the official hospital audit is released, we believe that this improvement will have a snowball effect that starts from one department and builds upon itself, becoming larger and capable of encompassing the whole hospital. Our success at this stage occurred due to many factors, including the clear commitment of the core team for improvement, the cooperation of our residents across the Department, the learning abilities and commitment of our staff as well as the full understanding of our research team of the need of medication reconciliation to improve the care of our patients. This significant improvement in the overall compliance rate at admission can be explained by the initial very poor scores, which were mainly due to a lack of awareness by the majority of our staff regarding the importance of medication reconciliations rather than ignorance and technical difficulties, and once awareness was increased by education and close monitoring, stakeholder compliance improved.

plained by the initial very poor scores, which were mainly due to a lack of awareness by the majority of our staff regarding the importance of medication reconciliations rather than ignorance and technical difficulties, and once awareness was increased by education and close monitoring, stakeholder compliance improved. 8 Conclusion The use of an evidenced-based initiative to improve medication reconciliation at admission, which relied on structuring intensive educational and monitoring programs, achieved a significant improvement in compliance. We predict that this initial local success will continue and will have a snowball effect that begins at our department and builds upon itself, becoming larger and eventually resulting in a hospital-wide improvement in compliance. Conflict of interest The presentation of the information that the authors are involved with promotes quality and improvement in health care and will not promote any specific business interest. The authors have declared that no conflict of interest exists. Ethical approval Approved for publication by the office of research affairs, in KFSH&RC with Publication Number: 2150209. Acknowledgement We thank the Health Information and Technology Affairs (HITA), Nursing Affairs, and all members under the Department of Pediatrics at KFSH&RC for their support with this project. We also thank Medical and Clinical Affairs and the Hospital Quality Management team for auditing and reporting. Data of the hospital have been used after permission was received from the hospital administration and quality department.

rs under the Department of Pediatrics at KFSH&RC for their support with this project. We also thank Medical and Clinical Affairs and the Hospital Quality Management team for auditing and reporting. Data of the hospital have been used after permission was received from the hospital administration and quality department. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Henoch–Schönlein Purpura (HSP), a non-granulomatous, immunoglobulin A-mediated small vessels vasculitis. It is the most common vasculitis in pediatric age group with an incidence of 20 per 100,000 in children less than 17 years of age with a peak incidence of 70 per 100,000 in children between the ages of 4 and 6 years [1], [2], [3], [4], [5]. It presents with a tetrad of palpable purpura, arthritis or arthralgia, abdominal pain, and renal disease. Gastrointestinal (GI) manifestations may vary from solely colicky abdominal pain in about one-half of patients to GI bleeding in approximately 20–30 percent of patients [2], [3]. However, rarely GI complications including acute pancreatitis and bowel perforation may occur [1]. A previous study by Prenzel have reported an association between severe HSP and factor XIII deficiency [5]. In this study, we report 3 cases of HSP with severe GI manifestations in the form of melena, hematemesis, acute pancreatitis, and erosive gastritis. All were unresponsive to corticosteroids. Low levels of factor XIII were found in all patients. Fortunately, they showed dramatic response to Cryoprecipitate transfusion.

1 Introduction Henoch–Schönlein Purpura (HSP), a non-granulomatous, immunoglobulin A-mediated small vessels vasculitis. It is the most common vasculitis in pediatric age group with an incidence of 20 per 100,000 in children less than 17 years of age with a peak incidence of 70 per 100,000 in children between the ages of 4 and 6 years [1], [2], [3], [4], [5]. It presents with a tetrad of palpable purpura, arthritis or arthralgia, abdominal pain, and renal disease. Gastrointestinal (GI) manifestations may vary from solely colicky abdominal pain in about one-half of patients to GI bleeding in approximately 20–30 percent of patients [2], [3]. However, rarely GI complications including acute pancreatitis and bowel perforation may occur [1]. A previous study by Prenzel have reported an association between severe HSP and factor XIII deficiency [5]. In this study, we report 3 cases of HSP with severe GI manifestations in the form of melena, hematemesis, acute pancreatitis, and erosive gastritis. All were unresponsive to corticosteroids. Low levels of factor XIII were found in all patients. Fortunately, they showed dramatic response to Cryoprecipitate transfusion. 2 Case 1 An 11-year-old girl, previously healthy, admitted with history of skin rash, abdominal pain, and vomiting for 12 days. The skin rash started at the lower extremities then progressed gradually to the buttocks area, upper extremities and face. The abdominal pain was periumbilical, colicky in nature, severe, and associated with vomiting. The vomiting had been associated with streaks of blood. She was admitted initially to a local hospital where she was treated conservatively, but she had worsening symptoms with significant abdominal distension and severe pain. She was referred to our hospital for further workup and management.

associated with vomiting. The vomiting had been associated with streaks of blood. She was admitted initially to a local hospital where she was treated conservatively, but she had worsening symptoms with significant abdominal distension and severe pain. She was referred to our hospital for further workup and management. Physical examination upon arrival revealed ill-looking girl, in pain, conscious, oriented, and well hydrated. Her vitals were stable. She had purpuric rash over the face in a malar distribution (Fig. 1), upper and lower extremities with ulcerated lesions over both elbows and malleoli (Figure 2, Figure 3, Figure 4). She had a distended abdomen with generalized tenderness, more in the epigastric and umbilical regions. Other examinations were unremarkable.Figure 1 Purpuric rash in a malar distribution. Figure 2 Purpuric rash over upper and lower extremities. Figure 3 Purpuric rash over upper and lower extremities. Figure 4 Purpuric rash over upper and lower extremities.

Physical examination upon arrival revealed ill-looking girl, in pain, conscious, oriented, and well hydrated. Her vitals were stable. She had purpuric rash over the face in a malar distribution (Fig. 1), upper and lower extremities with ulcerated lesions over both elbows and malleoli (Figure 2, Figure 3, Figure 4). She had a distended abdomen with generalized tenderness, more in the epigastric and umbilical regions. Other examinations were unremarkable.Figure 1 Purpuric rash in a malar distribution. Figure 2 Purpuric rash over upper and lower extremities. Figure 3 Purpuric rash over upper and lower extremities. Figure 4 Purpuric rash over upper and lower extremities. Laboratory data revealed: high white blood cell count at 22 × 109/L (normal 5–15) with predominant neutrophils (79%), low hemoglobin 10.4 mg/dl (normal 11–14), high platelet count 358 × 109/L (normal 140–350), normal erythrocyte sedimentation rate (ESR) at 2 mm/hr, high C-reactive protein (CRP) at 39.8 mg/L (normal > 3), normal renal functions and electrolytes, high amylase at 275 U/L (normal range 3–110), high lipase at 584 IU/L (normal range 0–60), and normal complements levels. Antinuclear antibodies, anti-SSB, anti-SSA, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), occult blood in stool and urinalysis were negative.

lytes, high amylase at 275 U/L (normal range 3–110), high lipase at 584 IU/L (normal range 0–60), and normal complements levels. Antinuclear antibodies, anti-SSB, anti-SSA, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), occult blood in stool and urinalysis were negative. Abdominal radiograph showed evidence of paralytic ileus with multiple air-fluid levels suggestive of intestinal obstruction. Abdominal ultrasound reported moderate, free intraperitoneal fluid with inability to visualize the pancreas due to marked bowel gas shadowing. Abdominal computerized tomography (CT) showed diffuse swollen edematous pancreas, which confirmed the diagnosis of pancreatitis.

uid levels suggestive of intestinal obstruction. Abdominal ultrasound reported moderate, free intraperitoneal fluid with inability to visualize the pancreas due to marked bowel gas shadowing. Abdominal computerized tomography (CT) showed diffuse swollen edematous pancreas, which confirmed the diagnosis of pancreatitis. She was started on daily intravenous (IV) methylprednisolone pulse (30 mg/kg/dose) for 3 days without significant improvement. She was kept NPO (null per oral), on nasogastric tube (NGT) suctioning and analgesia. Skin biopsy showed leukocytoclastic vasculitis with IgA deposition confirming the diagnosis of HSP (Fig. 5). A week later, she developed melena; hence, upper endoscopy was performed and showed evidence of severe erosive gastritis with normal esophagus and duodenum. Therefore, NGT suctioning was continued and IV omeprazole and total parental nutrition (TPN) were started. IV methylprednisolone and IV immunoglobulin (IVIG) were administered, but it was without any significant improvement. Assay of Factor XIII showed low level at 0.3 IU/ml (normal range 0.7–1.2 IU/ml). Subsequently, Cryoprecipitate transfusion (60 ml equivalent to 3 units) was given 2 weeks after admission (on day 11 after methylprednisolone and IVIG treatment), and the patient had dramatic improvement; her abdominal pain subsided and the rash lessened. The transfusion was well tolerated with adverse occurrences. Her oral intake improved and TPN was stopped. She became asymptomatic and was discharged in a stable condition.Figure 5 Leukocytoclastic vasculitis with IgA deposition.

d the patient had dramatic improvement; her abdominal pain subsided and the rash lessened. The transfusion was well tolerated with adverse occurrences. Her oral intake improved and TPN was stopped. She became asymptomatic and was discharged in a stable condition.Figure 5 Leukocytoclastic vasculitis with IgA deposition. 3 Case II A 3-year-old previously healthy girl presented one month prior to her admission with purpuric rash which started on her feet then progressed proximally to involve lower limbs, upper limbs, trunk, buttocks, and face. Simultaneously, she complained from mild abdominal pain, so she was diagnosed as HSP. Two days later, she had severe abdominal pain followed by vomiting, hematemesis, and melena. Methylprednisolone pulse (30 mg/kg/day) was given for 3 days followed by oral prednisolone 1 mg/kg/day for 8 days with partial improvement. She was then referred to our hospital for further management.

she was diagnosed as HSP. Two days later, she had severe abdominal pain followed by vomiting, hematemesis, and melena. Methylprednisolone pulse (30 mg/kg/day) was given for 3 days followed by oral prednisolone 1 mg/kg/day for 8 days with partial improvement. She was then referred to our hospital for further management. Upon arrival to our hospital, she had recurrent abdominal pain, vomiting, and rash reappeared on face, ears, trunk, lower, and upper extremities. However, there was no more hematemesis or melena. Investigations revealed normal complete blood counts, ESR, CRP, renal, and hepatic profiles. Urinalysis was negative for blood or protein. Abdominal radiograph showed fecal loading up to the cecum. Ultrasound abdomen was normal. Skin biopsy was consistent with leukocytoclastic vasculitis, and immunofluorescence was positive for fibrinogen in blood vessels, but it was negative for complements C3, C1q, immunoglobulin G, A, and M. Factor XIII assay showed low level at 0.39 IU/ml so Cryoprecipitate transfusion (40 ml equivalent to 2 units) was given (on day 16 after methylprednisolone treatment) with marked improvement of abdominal pain, vomiting, and rash. There were no complications encountered during or after transfusion.

globulin G, A, and M. Factor XIII assay showed low level at 0.39 IU/ml so Cryoprecipitate transfusion (40 ml equivalent to 2 units) was given (on day 16 after methylprednisolone treatment) with marked improvement of abdominal pain, vomiting, and rash. There were no complications encountered during or after transfusion. 4 Case III A previously healthy 4-year-old boy presented 3 weeks prior to admission with periumbilical abdominal pain. It was intermittent, colicky, severe enough to interfere with daily activities, and associated with vomiting. On the same day, he developed purpuric skin rash on lower limbs and buttocks. He was admitted twice due to recurrent abdominal pain and treated conservatively in the local hospital. In the third admission, he received steroid 15 mg/kg/day intravenously followed by maintenance on 1 mg/kg/day in divided doses with no significant response. Subsequently, he was referred to our hospital for further management.

itted twice due to recurrent abdominal pain and treated conservatively in the local hospital. In the third admission, he received steroid 15 mg/kg/day intravenously followed by maintenance on 1 mg/kg/day in divided doses with no significant response. Subsequently, he was referred to our hospital for further management. Examinations showed a well-looking boy, normotensive, has scattered purpuric rash mainly over both elbows with fewer lesions on upper and lower extremities. His initial abdominal examination was reassuring, but he continued to have bouts of colicky severe abdominal pain associated with vomiting. His workup showed leukocytosis at 16.75 × 109/L with 82% neutrophils but normal hemoglobin, platelets, and inflammatory markers. Coagulation profile, lipase level, renal function, and hepatic profile were within normal ranges. Stool was positive for occult blood on more than one occasion. Abdominal X-ray showed moderate fecal loading, and abdominal ultrasonography showed normal viscera apart from fatty liver with no organomegaly and stool distended large bowel compatible with constipation. On the 4th day of admission, he developed a severe attack of abdominal pain associated with recurrent vomiting, hematemesis, and melena. An urgent ultrasound ruled out the presence of intestinal intussusception, and it only showed distended large bowel. Repeated CBC showed leukocytosis up to 26.75 × 109/L with 67% neutrophils, elevated CRP at 15.7 mg/L and normal ESR at 3 mm/Hr. Methylprednisolone pulse (10 mg/kg/day) was given for 2 days after the GI bleeding with no major effect. Factor XIII level was low at 0.58 IU/ml. Cryoprecipitate transfusion (60 ml equivalent to 3 units) was given 4 days after methylprednisolone pulses which shortly resulted in a significant improvement. However, the patient required a repeat transfusion of 3 extra units after which his symptoms completely resolved with no transfusion complications.

0.58 IU/ml. Cryoprecipitate transfusion (60 ml equivalent to 3 units) was given 4 days after methylprednisolone pulses which shortly resulted in a significant improvement. However, the patient required a repeat transfusion of 3 extra units after which his symptoms completely resolved with no transfusion complications. 5 Discussion HSP is the most common childhood vasculitis which has usually self-limited course with excellent prognosis. Purpura occurs in all cases, joint pains and arthritis in 80%, and abdominal pain in 62%. Some include gastrointestinal hemorrhage as a fourth criterion; this occurs in 33% of cases, sometimes, but not necessarily always, due to intussusception [6]. Severe clinical manifestations, including gastrointestinal, can be seen either at presentation or during the disease course. Intestinal bleeding and obstruction or intussusceptions can complicate the disease course [6]. Acute Pancreatitis was reported in a 3-year-old girl who presented with abdominal pain then developed characteristic rash of HSP at the fifth day of clinical onset [7]. A correlation between reduced plasma factor XIII activity, and the severity of multiple organ disorders, especially abdominal symptoms, has been shown in pediatric HSP in previous case studies [8].

d girl who presented with abdominal pain then developed characteristic rash of HSP at the fifth day of clinical onset [7]. A correlation between reduced plasma factor XIII activity, and the severity of multiple organ disorders, especially abdominal symptoms, has been shown in pediatric HSP in previous case studies [8]. In our series, we report 3 children with typical HSP but severe GI manifestations including severe abdominal pain, hematemesis, melena in all patients, in addition to pancreatitis, and erosive gastritis in the first patient. High dose steroid pulses or oral prednisone as well as IVIG in the first patient did not help in alleviating the symptoms. All the three patients had low levels of factor XIII during their presentation then dramatic improvement within few hours following Cryoprecipitate transfusion which contain factor XIII. Factor XIII (FXIII) is the last enzyme in the clotting cascade. Its main function is to convert the loose fibrin polymer into a firm, highly organized, cross-linked structure with increased tensile strength, firmly anchored to the site of the wound and possessing an in-built resistance to fibrinolysis. In factor XIII deficiency, standard clotting tests are normal, as the clotting end point is not affected by the absence of factor XIII [9]. All our patients had normal basic coagulation profile including PT, PTT, and INR despite significant hemorrhagic gastrointestinal symptoms.

an in-built resistance to fibrinolysis. In factor XIII deficiency, standard clotting tests are normal, as the clotting end point is not affected by the absence of factor XIII [9]. All our patients had normal basic coagulation profile including PT, PTT, and INR despite significant hemorrhagic gastrointestinal symptoms. Acquired factor XIII deficiency, when the level drops to 20–70% [10], remains a doubtful entity. Low plasma levels of factor XIII activity have been reported in some conditions like inflammatory bowel disease, systemic lupus erythematosus, and rheumatoid arthritis which are characterized by the presence of autoantibodies [11], [12], [13]. Whether the low factor XIII levels contribute to hemorrhagic complications in these diseases remains to be proven. Factor XIII deficiency might result into life-threatening bleeding. Massive intracerebral hemorrhage [14] and compartment syndrome of the forearm due to hemorrhage [15] were reported in two children with HSP and severe deficiency of factor XIII. Treatment of patients bleeding from the small bowel in HSP and from the large bowel in ulcerative colitis with factor XIII concentrate has been reported to be effective in controlling the bleeding [16]. The benefits of such therapy remain unconfirmed and factor XIII therapy in these circumstances cannot be recommended until more scientific evidence emerges in support of such an approach, and the possible mechanisms of factor XIII action in these situations elucidated.

to be effective in controlling the bleeding [16]. The benefits of such therapy remain unconfirmed and factor XIII therapy in these circumstances cannot be recommended until more scientific evidence emerges in support of such an approach, and the possible mechanisms of factor XIII action in these situations elucidated. In our reported cases, the first patient has the lowest level of factor XIII (0.3 IU/ml) and the most severe purpuric rash and gastrointestinal manifestations in form of acute pancreatitis and erosive gastritis, in addition to severe abdominal pain, hematemesis, and melena which were seen in the two other patients. All our patients showed remarkable improvement of their gastrointestinal symptoms shortly after the transfusion of Cryoprecipitate. The amount transfused was one unit per 10 kg of body weight as per the blood products transfusion guidelines of our blood bank. Cryoprecipitate contains fibrinogen, factor VIII, von Willbrand factor, factor XIII, and fibonectin. Factor XIII substitution therapy using a fibrinogen preparation containing abundant factor XIII with an antiplasmin agent resulted in improvement of severe gastrointestinal hemorrhage in 13 out of 17 HSP affected children [17]. As well, other studies showed that administration of factor XIII in a group of moderate HSP showed remarkable improvement of joint symptoms and renal dysfunction in addition to gastrointestinal symptoms [18]. It is worth mentioning that all our patients had no significant renal or articular involvement despite the severe GI symptoms and widespread purpura.

inistration of factor XIII in a group of moderate HSP showed remarkable improvement of joint symptoms and renal dysfunction in addition to gastrointestinal symptoms [18]. It is worth mentioning that all our patients had no significant renal or articular involvement despite the severe GI symptoms and widespread purpura. Prenzel et al supported the hypothesis that factor XIII activity correlates well with the severity of abdominal symptoms. There was no improvement after treatment with prednisone and symptoms resolved after factor XIII concentrate administration. Matayoshi et al showed that there was no correlation between factor XIII activities and the distribution of purpura, which in turn, was not correlated with the severity of organ disorders in adult patients [19]. Few studies have reported a correlation between the severity of HSP and factor XIII deficiency. Hogendorf et al showed improvement of factor XIII and symptoms resolution in 2 affected children without any intervention [20]. A case series of 3 children with HSP and isolated gastrointestinal symptoms described a reduction in factor XIII activity prior to the development of skin rash without the need for substitution treatment [21]. There is no literature differentiating the pathophysiological effects of cryoprecipitate, and it remains unclear if cryoprecipitate modify the inflammatory or thrombotic processes in such disease or similar vasculitic or inflammatory diseases.

Prenzel et al supported the hypothesis that factor XIII activity correlates well with the severity of abdominal symptoms. There was no improvement after treatment with prednisone and symptoms resolved after factor XIII concentrate administration. Matayoshi et al showed that there was no correlation between factor XIII activities and the distribution of purpura, which in turn, was not correlated with the severity of organ disorders in adult patients [19]. Few studies have reported a correlation between the severity of HSP and factor XIII deficiency. Hogendorf et al showed improvement of factor XIII and symptoms resolution in 2 affected children without any intervention [20]. A case series of 3 children with HSP and isolated gastrointestinal symptoms described a reduction in factor XIII activity prior to the development of skin rash without the need for substitution treatment [21]. There is no literature differentiating the pathophysiological effects of cryoprecipitate, and it remains unclear if cryoprecipitate modify the inflammatory or thrombotic processes in such disease or similar vasculitic or inflammatory diseases. Our study main limitation is the small number of patients, and the retrospective study type. Standardization of such therapy regarding treatment regimen and dosage needs to be tested in larger prospective studies.

There is no literature differentiating the pathophysiological effects of cryoprecipitate, and it remains unclear if cryoprecipitate modify the inflammatory or thrombotic processes in such disease or similar vasculitic or inflammatory diseases. Our study main limitation is the small number of patients, and the retrospective study type. Standardization of such therapy regarding treatment regimen and dosage needs to be tested in larger prospective studies. In conclusion, Severe HSP manifestations particularly those related to GI symptoms like life-threatening GI bleeding might be associated with an acquired factor XIII deficiency. Factor XIII assay should be routinely measured in any patient with severe HSP since the replacement treatment of such temporarily deficient factor is curative. Cryoprecipitate should be an excellent alternative if factor XIII concentrate is not available. Conflict of interest The authors declare that they have no conflict of interest related to this study. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Current research indicates childhood obesity is increasing at an alarming rate in the United States. The increased incidence and prevalence, coupled with significant morbidity and financial burden, clearly suggest the need for implementation of effective pediatric obesity identification and prevention strategies. The National Health and Nutrition Examination Survey (NHANES), 1999–2004, with a sample size of 12,384 American children 2–19 years of age, found that almost 16% of children were obese. NHANES data showed obesity in children correlated with high morbidity that continued into adulthood including increased cardiovascular risks of elevated cholesterol and abnormally high blood pressure [1]. Obesity predisposes children to poorer pulmonary function, asthma, orthopedic problems, sleep apnea, polycystic ovary disease, and poor psychosocial health related to obesity-associated bullying and discrimination [2].

luding increased cardiovascular risks of elevated cholesterol and abnormally high blood pressure [1]. Obesity predisposes children to poorer pulmonary function, asthma, orthopedic problems, sleep apnea, polycystic ovary disease, and poor psychosocial health related to obesity-associated bullying and discrimination [2]. The National Association of Pediatric Nurse Practitioners developed Healthy Eating and Activity Together (HEAT), evidence-based clinical guidelines that provide concise, culturally appropriate information on the identification and prevention of childhood obesity in primary care settings [3]. The major objectives of the guidelines are to increase healthcare provider effectiveness in identifying children at risk for obesity and encourage optimal eating and activity practices in families. Noteworthy characteristics of the HEAT approach include a focus on prevention and cultural appropriateness. Emphasis is placed on identifying strengths within the family and fostering strong relationships between parents, children, and healthcare professionals. Motivational interviewing is the cornerstone of HEAT guidelines and provides an evidence-based approach for encouraging patients and their families to make healthy lifestyle behavioral modifications [3].

engths within the family and fostering strong relationships between parents, children, and healthcare professionals. Motivational interviewing is the cornerstone of HEAT guidelines and provides an evidence-based approach for encouraging patients and their families to make healthy lifestyle behavioral modifications [3]. Motivational interviewing (MI) is directive, patient-centered counseling that is designed to be nonjudgmental, empathetic, and encouraging. The technique elicits intrinsic motivation for behavior change and is effective in individuals who are initially resistant to change [4]. The basic premise of the technique is to facilitate an awareness of discrepancies between the patient's current lifestyle and future goals [5]. For example, if a patient wants to play soccer in the fall, but it has no plans for physical activity in the summer, MI techniques would encourage the patient to identify the discrepancies between his future goals and current lifestyle and make appropriate behavioral modifications. The positive effect of MI techniques on childhood obesity is consistent with the literature. Evidence illustrates an improvement in healthy lifestyle decisions when MI is introduced and maintained in a clinical setting to promote behavioral modification [6]. 2 The local problem Kentucky has one of the highest childhood obesity prevalence rankings which places a significant burden on healthcare systems [7]. Unfortunately, there is limited time in the context of routine pediatric primary care visits for healthcare providers to focus on childhood obesity.

Motivational interviewing (MI) is directive, patient-centered counseling that is designed to be nonjudgmental, empathetic, and encouraging. The technique elicits intrinsic motivation for behavior change and is effective in individuals who are initially resistant to change [4]. The basic premise of the technique is to facilitate an awareness of discrepancies between the patient's current lifestyle and future goals [5]. For example, if a patient wants to play soccer in the fall, but it has no plans for physical activity in the summer, MI techniques would encourage the patient to identify the discrepancies between his future goals and current lifestyle and make appropriate behavioral modifications. The positive effect of MI techniques on childhood obesity is consistent with the literature. Evidence illustrates an improvement in healthy lifestyle decisions when MI is introduced and maintained in a clinical setting to promote behavioral modification [6]. 2 The local problem Kentucky has one of the highest childhood obesity prevalence rankings which places a significant burden on healthcare systems [7]. Unfortunately, there is limited time in the context of routine pediatric primary care visits for healthcare providers to focus on childhood obesity. Research suggests that socioeconomically disadvantaged children, particularly those of Hispanic and African American ethnicity, are at increased risk for childhood obesity [2]. Demographic characteristics of patients in a local pediatric practice in Kentucky reflected a high proportion from this underserved, high-risk patient population. The Kentucky Cabinet for Health and Family Services reported 16%–23% of children in the local community were significantly obese, with a BMI greater than the 95th percentile [8]. These findings ultimately solidified the need to implement effective pediatric obesity identification and prevention strategies including the use of MI to facilitate lifestyle behavior modifications. Project aims included enhancing the consistency of childhood obesity identification and prevention within the clinic population as evidenced by identification of obesity risk factors and increased family focused education through the use of a tracking tool based on current evidence. The purpose was to determine if the use of a tracking tool, based on current evidence based guidelines emphasizing MI would significantly increase childhood obesity identification and documentation of education strategies implemented by healthcare professionals in a primary care setting.

tool based on current evidence. The purpose was to determine if the use of a tracking tool, based on current evidence based guidelines emphasizing MI would significantly increase childhood obesity identification and documentation of education strategies implemented by healthcare professionals in a primary care setting. 3 Patients and methods 3.1 Scope of the project The practice project involved quality improvement of childhood obesity identification and education within the practice and did not include research interventions that affected participants' well-being. IRB approval was obtained through the Duke University Institutional Review Board. 3.2 Setting The practice setting was a pediatric primary care office serving rural and semi-rural communities. Practice staff included a physician, nurse practitioner and physician assistant as well as medical assistants and front office staff. The patients ranged in age from four years to young adulthood. The population represented a large underserved minority group; 42% of the patients received Medicaid benefits and 33% of those patients identified were Hispanic.

urse practitioner and physician assistant as well as medical assistants and front office staff. The patients ranged in age from four years to young adulthood. The population represented a large underserved minority group; 42% of the patients received Medicaid benefits and 33% of those patients identified were Hispanic. 3.3 Planning the intervention Stakeholders and change agents were identified within the practice. The barrier for adopters was having little prior knowledge of effective obesity prevention strategies. As a result, multiple educational sessions occurred at the outset of the project to familiarize the staff with clinical guidelines. Training strategies include education on MI techniques such as open-ended questions, reflective listening, and assessing patient's interest and confidence levels [4]. Implementation was broken down into smaller steps: measurement, education, documentation and referrals. The Plan Do Study Act model guided practice changes and outcome measures [9]. Providers had frequent contact with one another making increased communication feasible. The practice change was not mandated, but it was implemented using the principles of change theory.1. Communication: Communication with practice staff occurred on numerous occasions. Staff acknowledged growing childhood obesity rates within the practice and verbally committed to making changes to address the problem. Education on HEAT guidelines and MI strategies was provided through informal and formal communication.

Communication: Communication with practice staff occurred on numerous occasions. Staff acknowledged growing childhood obesity rates within the practice and verbally committed to making changes to address the problem. Education on HEAT guidelines and MI strategies was provided through informal and formal communication. 2. Taskforce Development: Following communication with staff, a taskforce of providers and nurses was created to develop a user-friendly “Get Healthy! Tracking Tool” (Fig. 1). The tool was used during annual physical examinations and became a part of the patient chart. This data form was used to document important quality indicators including anthropometric measurements, nutritional and physical activity history, motivational interviewing, referral to appropriate community resources, and follow-up.Figure 1 Excerpt from tracking tool. 3. Implementation: At each physical examination visit, staff nurses collected patient anthropometric data and nutritional and physical activity history. The nurses included the Tracking Tool in the patient's chart and practice providers committed to using the tracking form during physical examinations. The tool served as a reference guide to education and motivational interviewing strategies as well as community resources.

and nutritional and physical activity history. The nurses included the Tracking Tool in the patient's chart and practice providers committed to using the tracking form during physical examinations. The tool served as a reference guide to education and motivational interviewing strategies as well as community resources. Using MI techniques, appropriate evidence based strategies that encouraged behavioral modification important for obesity prevention were negotiated with the patient and family. For example, during an office visit, a provider had the opportunity to encourage the patient and family to choose an issue regarding the child's diet or physical activity that they would like to change thereby facilitating behavioral modification. Documentation of this agenda-setting technique provides an opportunity to explore the patient's work towards the goal at subsequent office visits [10]. Referral education included appropriate knowledge of applicable community resources such as pedometer programs, physical activity opportunities at local community parks, sporting events, and school programs. In addition, information on local gardens and farmers markets was provided to encourage healthy eating habits.

. Referral education included appropriate knowledge of applicable community resources such as pedometer programs, physical activity opportunities at local community parks, sporting events, and school programs. In addition, information on local gardens and farmers markets was provided to encourage healthy eating habits. A clinic staff member reviewed all well-child patient encounters between October 2010 and January 2011 and collected study indicators on those with a diagnosis of overweight or obesity, or where there was mention in the chart of any intervention related to weight reduction and diet. These data were compared with data from the tracking tool found in the medical records of all patients who had a well-child visit after its implementation in October 2011–January 2012. Patient identifiers were removed from the tracking tools and saved in a secure file until the end of the project. Fidelity of data collection, implementation, and follow-up were evaluated through the use of quality indicators including the presence of weight, height, and body mass index calculation within the chart, documentation of appropriate history and assessment, documentation of familial obesity prevention education/MI, and evidence of community referral and follow-up as needed. Data were cleaned and organized in Excel where variables were recoded into binomial data. The data were exported to SPSS. Fisher's Exact Test was used to compare pre and post data indicators with significance set at (P < .05).

obesity prevention education/MI, and evidence of community referral and follow-up as needed. Data were cleaned and organized in Excel where variables were recoded into binomial data. The data were exported to SPSS. Fisher's Exact Test was used to compare pre and post data indicators with significance set at (P < .05). 4 Results Implementing evidence-based guidelines resulted in increased identification of children at risk for childhood obesity and enhanced familial obesity prevention education. Data on fidelity illustrated a significant increase in provider documentation of childhood obesity identification and prevention topics discussed during preventative care examinations. Fig. 2 illustrates the improvement in the consistency of obesity identification and prevention education using motivational interviewing in the primary care setting.Figure 2 Pre-implementation and post-implementation. A significant increase (P < .0001) occurred in provider documentation of favorite foods and drinks, school lunch preference, fast food consumption, snacking in front of the television, amount of screen time (Fig. 3), amount of physical activity, sports participation, and neighborhood safety.Figure 3 Documentation of Screen Time >2 h.

ncrease (P < .0001) occurred in provider documentation of favorite foods and drinks, school lunch preference, fast food consumption, snacking in front of the television, amount of screen time (Fig. 3), amount of physical activity, sports participation, and neighborhood safety.Figure 3 Documentation of Screen Time >2 h. A positive provider change in healthy lifestyle community referrals also occurred. Examples of community resources discussed during visits included local farmers markets, neighborhood playgrounds, local parks, and public sports teams (Table 1). Discussion of resources enabled providers to align healthy lifestyle goals explored during preventative examinations with opportunities in the patient's local community and encouraged healthy living options for the entire family. Pre-implementation data illustrated community referrals were rarely documented (n = 1/38) while post-implementation data showed a positive increase in community referral documentation (n = 47/64).Table 1 Community resources. Community resources: Local farmers market Local parks Local sports teams Local farm stores Public swimming pool Yoga & Dance Classes Community “Healthy Lifestyle” Events Pedometer program Neighborhood Playgrounds

A positive provider change in healthy lifestyle community referrals also occurred. Examples of community resources discussed during visits included local farmers markets, neighborhood playgrounds, local parks, and public sports teams (Table 1). Discussion of resources enabled providers to align healthy lifestyle goals explored during preventative examinations with opportunities in the patient's local community and encouraged healthy living options for the entire family. Pre-implementation data illustrated community referrals were rarely documented (n = 1/38) while post-implementation data showed a positive increase in community referral documentation (n = 47/64).Table 1 Community resources. Community resources: Local farmers market Local parks Local sports teams Local farm stores Public swimming pool Yoga & Dance Classes Community “Healthy Lifestyle” Events Pedometer program Neighborhood Playgrounds 5 Discussion In the world of primary care, it is sometimes difficult to incorporate lengthy evidence-based guidelines into practice. Through an innovation model, the practice incorporated the HEAT guidelines by developing a user-friendly tracking tool that had significant staff buy-in, increasing fidelity of use. The tool served as a reminder of childhood obesity during preventative examinations and created a seamless way to follow the progression of individual patients. Prior research clearly suggests the value of lifestyle behavioral modification used as a childhood obesity prevention and intervention strategy [11] and supports implementation of childhood obesity identification and familial education within in pediatric primary care.

to follow the progression of individual patients. Prior research clearly suggests the value of lifestyle behavioral modification used as a childhood obesity prevention and intervention strategy [11] and supports implementation of childhood obesity identification and familial education within in pediatric primary care. This translation of evidence into practice empowered staff to become change agents while enhancing the care provided to pediatric patients. Using the tracking tool significantly improved practice documentation of obesity identification and therapeutic interventions for pediatric patients resulting in increased awareness of obesity prevention and provision of opportunities to effectively monitor at-risk children. The tracking form served as a successful evidenced based tool for pediatric primary care providers in the practice to empower patients and families to make healthy lifestyle choices through motivational interviewing techniques. 6 Implications The incorporation of MI on the tracking tool provides an evidence-based approach for encouraging patients and their families to make healthy lifestyle decisions. Although the tool has not been used long enough to indicate a change in patient behavior or clinical outcomes, an increase in provider awareness and education is the beginning step for creating healthier lifestyles and decreasing risk factors in a vulnerable population. Research is needed to evaluate the effects of the evidence based-guidelines on positive behavior change and obesity rates in patients and families.

al outcomes, an increase in provider awareness and education is the beginning step for creating healthier lifestyles and decreasing risk factors in a vulnerable population. Research is needed to evaluate the effects of the evidence based-guidelines on positive behavior change and obesity rates in patients and families. 7 Sustainability Sustainability is important to maintain the clinical gains of increased documentation rather than reverting to old practices. This innovation will require continued revision and improvement in an effort to decrease the likelihood that the innovation becomes an antiquated practice. Through this continual feedback and revision, the innovation will ultimately serve as a catalyst for future changes in childhood obesity identification and prevention education in the primary care practice. Conflict of interest None. Ethical clearance The practice project involved quality improvement of childhood obesity identification and education within the practice and did not include research interventions that affected participants’ well-being. IRB approval was obtained through the Duke University Institutional Review Board. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Gynaecomastia of adolescence is a common pubertal occurrence and is often associated with persistent physical discomfort and psychological distress in males. Many treatment options have been proposed, ranging from watchful waiting (no treatment), modification of hormonal axes using medication and surgical intervention. The following case discussion provides an overview of the condition and describes the successful effect from using a six-month course of tamoxifen, a Selective Oestrogen Receptor Modulator (SERM), to treat pubertal gynaecomastia in a typical teenage male. 2 Case report A 14-year-old boy presented with unilateral left-sided gynaecomastia present for the past twelve months (Fig. 1). There was associated breast pain (mastodynia) of 5/10 severity, which was worse when wearing tight-fitting shirts. He was a keen swimmer and due to feeling self-conscious and being teased by peers in the locker room had not been attending sports sessions. He had been referred for suction lipectomy (liposuction) and was presented for pediatrician review for possible medical therapy to avoid surgery.Figure 1 Prominent unilateral pubertal gynaecomastia at baseline. Left breast measures 3 cm [2].

ing teased by peers in the locker room had not been attending sports sessions. He had been referred for suction lipectomy (liposuction) and was presented for pediatrician review for possible medical therapy to avoid surgery.Figure 1 Prominent unilateral pubertal gynaecomastia at baseline. Left breast measures 3 cm [2]. The lesion measured 3 cm in diameter with marked prominence (Fig. 2). A tender ‘disk’ of firm tissue was palpable beneath the areolar region. The boy was not overweight (body mass index (BMI) of 20.2, 60th centile) and was in Tanner Stage 3 puberty (right testicular volume 10 mL, left 15 mL) with normal secondary sexual characteristics for his age. He denied taking any regular medication or having used any illicit substances, such as cannabis. There was a positive family history of pubertal gynaecomastia in his two older brothers, with one having had liposuction performed. Blood tests showed a high normal testosterone level (27 nmol/L), raised sex-hormone binding globulin (SHBG) 93 nmol/L (normal range 15–50 nmol/L) and slightly raised dehydroepiandrosterone sulphate (DHEAS) at 5 μmol/L (normal range 0.1–4.2 μmol/L). Other indices were normal; including a free androgen index (FAI) of 29%; oestradiol: <50 pmol/L; prolactin: 305 mIU/L; quantitative beta-human chorionic gonadotropin (β-hCG): <5 IU/L; follicle stimulating hormone (FSH): 1.7 IU/L; luteinising hormone (LH): 2.0 IU/L; and a full blood count, electrolytes and karyotype (46 XY), excluding Klinefelter Syndrome.Figure 2 Side view of prominent left unilateral pubertal gynaecomastia at baseline.

uantitative beta-human chorionic gonadotropin (β-hCG): <5 IU/L; follicle stimulating hormone (FSH): 1.7 IU/L; luteinising hormone (LH): 2.0 IU/L; and a full blood count, electrolytes and karyotype (46 XY), excluding Klinefelter Syndrome.Figure 2 Side view of prominent left unilateral pubertal gynaecomastia at baseline. 3 Discussion Pubertal gynaecomastia is a benign physiological process arising from a transient imbalance between the greater stimulatory effects of oestrogens and lesser inhibitory effects of androgens on breast tissue during puberty. It is usually bilateral and affects up to 70% of adolescent males [1], with a peak incidence at approximately 14 years of age [2]. Oestrogen levels may become elevated from increased peripheral aromatase activity (often occurring in the adipose tissue of obese males and delaying puberty). This increases the SHBG levels, which bind free (active) testosterone, reducing its antitrophic action on breast tissue. Glandular proliferation, ductal hyperplasia and periductal inflammation occur as a result. This rapid growth often occurs over the first six months of Tanner Stage 3 puberty, when pubertal gynaecomastia is most symptomatic (enlargement, pain and tenderness). While pubertal gynaecomastia is a cosmetic condition and the natural history is spontaneous regression in 90% of cases within three years [3], it is frequently psychologically distressing and causes embarrassment until it does so, with some adolescents electing to undergo potentially disfiguring surgery [4].

nderness). While pubertal gynaecomastia is a cosmetic condition and the natural history is spontaneous regression in 90% of cases within three years [3], it is frequently psychologically distressing and causes embarrassment until it does so, with some adolescents electing to undergo potentially disfiguring surgery [4]. Gynaecomastia is clinically defined by the presence of a rubbery-to-firm disk-like mass that is often mobile, located directly inferior to the areolar region and extending concentrically from the nipple. It is distinct from pseudogynaecomastia (or lipomastia), which is an adipose tissue deposition without glandular proliferation, where no firm mass is palpable. Histological examination of mastectomy samples taken from males under 21 years of age for adolescent gynaecomastia show the incidence of breast cancer being extremely low [5]. The malignant lesion invariably involves the unilateral breast; is often hard, fixed and, eccentric; and may be associated with spontaneous bloody nipple discharge, axillary lymphadenopathy or overlying skin discolouration, dimpling or tethering (peau d'orange). A family history of gynaecomastia is reported in approximately 60% of cases [2]. The contributing factors for gynaecomastia need to be considered. These include hypogonadism, medication (notably antipsychotics, including the newer atypical agents, such as risperidone, as well as other drugs, for instance, spironolactone), alcohol, marijuana or anabolic steroid use. In such cases, the precipitating cause should be attended to first.

comastia need to be considered. These include hypogonadism, medication (notably antipsychotics, including the newer atypical agents, such as risperidone, as well as other drugs, for instance, spironolactone), alcohol, marijuana or anabolic steroid use. In such cases, the precipitating cause should be attended to first. Three management options are available: (i) reassurance (i.e., no treatment), (ii) surgery and (iii) medication. The first is the safest option, although does not ameliorate symptoms and is best for small, pain-free cases of recent onset (<6 months). Surgery is usually a combination of direct excision of the glandular tissue and liposuction. Performing surgery is recommended after adult testicular size (Tanner Stage 5 puberty) is attained, as there may be regrowth of the breast tissue if performed earlier. Surgery may also involve complications, such as scarring, skin retraction and hyperaesthesia. Thus, it should be reserved for persistent cases, large and pendulous breasts unresponsive to medical therapy, removing redundant tissue or if significant fibrosis is present [6].

wth of the breast tissue if performed earlier. Surgery may also involve complications, such as scarring, skin retraction and hyperaesthesia. Thus, it should be reserved for persistent cases, large and pendulous breasts unresponsive to medical therapy, removing redundant tissue or if significant fibrosis is present [6]. Medications aim to increase the effective androgen/oestrogen imbalance and fall into three classes: (i) selective oestrogen receptor modulators, SERMs (tamoxifen and raloxifene); (ii) aromatase inhibitors (anastrozole); and (iii) androgens (for hypogonadism). Aromatase inhibitors block the biosynthesis of oestrogen and have inferior results compared to SERMs in clinical studies of the treatment of pubertal gynaecomastia. SERMs block the growth-stimulating effects of oestrogen on breast tissue, although they are oestrogenic elsewhere in the body (bone and adipose tissues).

. Aromatase inhibitors block the biosynthesis of oestrogen and have inferior results compared to SERMs in clinical studies of the treatment of pubertal gynaecomastia. SERMs block the growth-stimulating effects of oestrogen on breast tissue, although they are oestrogenic elsewhere in the body (bone and adipose tissues). There have been no randomised controlled trials (RCTs) of SERMs for the treatment of pubertal gynaecomastia, and the medications are not registered for this indication in Australia. While RCTs exist for the use of tamoxifen in anti-androgen-induced gynaecomastia in adults treated for prostatic cancer [7], it may be difficult to extrapolate the clinical effect between these patient populations, although the theoretical role of tamoxifen is sound. A recent systematic review of tamoxifen therapy for the management of pubertal gynaecomastia [8] found it to be a safe and effective medical option. Doses of 10–40 mg of tamoxifen per day were used in adolescent males under the age of twenty for 1–12 months, with the resolution of mastodynia and ≥80% reduction in swelling noted. The response was dependent on the length of therapy, and recurrence of gynaecomastia occurred in up to 14% of cases after therapy cessation. SERMs appear to be most effective within the first 6 months of gynaecomastia when the breast tissue growth is most abundant and before fibrosis occurs.

eduction in swelling noted. The response was dependent on the length of therapy, and recurrence of gynaecomastia occurred in up to 14% of cases after therapy cessation. SERMs appear to be most effective within the first 6 months of gynaecomastia when the breast tissue growth is most abundant and before fibrosis occurs. One observational study [2] has shown that tamoxifen administered at a dose of 20 mg per day (as a single or divided dose) for three months was a safe option in treating pubertal gynaecomastia. Significant regression occurred in approximately 90% of teenage boys, involving a mean reduction in the breast nodule diameter of 2.1 cm (almost half of the baseline diameter). Individuals with a smaller breast diameter at baseline had a better outcome. Mastodynia was also reduced. The same study found similar and slightly superior results with a different SERM, raloxifene. However, as there is even less experience and available data regarding the use of raloxifene for the treatment of pubertal gynaecomastia than with tamoxifen; its current use in clinical practice is limited.

a was also reduced. The same study found similar and slightly superior results with a different SERM, raloxifene. However, as there is even less experience and available data regarding the use of raloxifene for the treatment of pubertal gynaecomastia than with tamoxifen; its current use in clinical practice is limited. Importantly, no clinically significant side-effects, changes in the gonadotrophin levels or height during treatment have been reported. Tamoxifen was well-tolerated in the doses and duration used to treat pubertal gynaecomastia in males [9]. While adverse events are rare, tamoxifen use should be avoided in individuals with known risk factors for venous thromboembolism and in the very sedentary, as the potential for deep vein thrombosis (DVT) exists. Any mood changes and leg cramps should be investigated. Occasional nausea and headaches may be expected. Breast tissue was found to regress spontaneously in up to half of cases in trial control groups, so tamoxifen should be used judiciously. Recurrence of gynaecomastia may occur in up to 25% cases after tamoxifen is ceased, so a further course for six months may be indicated, as well as for non-responders [2]. However, fewer individuals treated with tamoxifen went on to have breast surgery, so its role in surgery prevention is pivotal.

be used judiciously. Recurrence of gynaecomastia may occur in up to 25% cases after tamoxifen is ceased, so a further course for six months may be indicated, as well as for non-responders [2]. However, fewer individuals treated with tamoxifen went on to have breast surgery, so its role in surgery prevention is pivotal. The boy in the case study was treated with tamoxifen, 20 mg per day, for six months. Within the first few weeks, the patient's mastodynia completely resolved and he noticed that his left gynaecomastia began to reduce in size. After three months, his body image satisfaction improved and he resumed participation in sports involving being bare-chested and changing in front of his peers. After six months, the residual left breast was 2 cm in diameter (33% reduction from baseline), flatter, without any palpable underlying firm tissue and was symmetrical in size to the other breast (Fig. 3). The boy did not report any adverse effects while being treated with tamoxifen, consistent with the published reports. Auxological parameters, including anthropometry, growth velocity, progress pubertal staging, bone age X-ray and repeat hormonal studies, were found to be similar to the baseline values at the conclusion of treatment (the testosterone level was 23.7 nmol/L; the SHBG was 75 nmol/L, which was still elevated though less than previously and could possibly indicate treatment resistance and/or gynaecomastia recurrence on tamoxifen cessation; the DHEAS was 5.6 μmol/L; the FAI was 31.6%; the FSH was 1.1 IU/L; the LH was 1.9 IU/L; and the oestradiol value was 70 pmol/L). This confirmed that tamoxifen therapy did not adversely affect the hypogonadal pituitary axis in this patient.Figure 3 After 6 months of tamoxifen treatment. The left breast now measures 2 cm [2] (33% reduction).

l/L; the FAI was 31.6%; the FSH was 1.1 IU/L; the LH was 1.9 IU/L; and the oestradiol value was 70 pmol/L). This confirmed that tamoxifen therapy did not adversely affect the hypogonadal pituitary axis in this patient.Figure 3 After 6 months of tamoxifen treatment. The left breast now measures 2 cm [2] (33% reduction). This case study demonstrates tamoxifen to be a safe, well-tolerated and effective treatment option for male pubertal gynaecomastia. It resolved mastodynia and quickly reduced psychological distress by acting on the cause of male pubertal gynaecomastia (blocking the action of oestrogen-induced breast tissue proliferation). Tamoxifen treatment was more effective than previous months of watchful waiting (no management). It was also a less invasive treatment approach and reduced the need for planned cosmetic surgery. An even greater effect of tamoxifen therapy may have been observed if the patient had received medical treatment earlier. Tamoxifen may be effective for the treatment of pubertal gynaecomastia, and it seems to be safe according to the many similar case reports. However, we need evidence from randomised controlled trials (RCTs) to confirm these findings. Until such results are known, tamoxifen should be used on a judicial basis in carefully selected adolescent males with pubertal gynaecomastia causing significant symptoms (both physical and psychological), who are fully informed of the risks and potential benefits (from available studies) and who are considering surgical reduction procedures.

nown, tamoxifen should be used on a judicial basis in carefully selected adolescent males with pubertal gynaecomastia causing significant symptoms (both physical and psychological), who are fully informed of the risks and potential benefits (from available studies) and who are considering surgical reduction procedures. Conflict of interest None.Key learning points • Pubertal gynaecomastia affects up to 70% of male adolescents, peaking at 14 years of age • Medication, drugs (e.g., cannabis), hypogonadism and obesity are causative differential diagnoses • Tamoxifen, a selective oestrogen receptor modulator (SERM), appears to be a safe and effective alternative treatment option in adolescent males with significant symptoms considering surgery • Randomised controlled trials (RCTs) are needed for definitive therapeutic recommendations • Surgery/liposuction should be reserved for persistent cases present at the end of puberty Appendix Multiple choice questions 1. Which individual is at the greatest risk of developing pubertal gynaecomastia? a. An overweight 7-year-old boy whose father has prostate cancer b. A 12-year-old boy with growing pains from a recent growth spurt who is medicated with olanzapine c. A 17-year-old male who smokes 1 g of cannabis daily d. A 13-year-old boy with XYY Syndrome and significant facial acne e. A 16-year-old boy on androgen replacement therapy that shaves and has one alcoholic drink monthly at parties Answer: (b)

b. A 12-year-old boy with growing pains from a recent growth spurt who is medicated with olanzapine c. A 17-year-old male who smokes 1 g of cannabis daily d. A 13-year-old boy with XYY Syndrome and significant facial acne e. A 16-year-old boy on androgen replacement therapy that shaves and has one alcoholic drink monthly at parties Answer: (b) (a) An overweight child may exhibit pseudogynaecomastia (or lipomastia) as an adolescent. Gynaecomastia occurs in 10–20% of men treated with LHRH agonists for prostate cancer, although this factor would not affect the son. (b) Increased growth velocity in boys usually occurs at the onset of Tanner Stage 3 when pubertal gynaecomastia also occurs. Antipsychotic medication, including the newer second-generation atypical agents, block dopamine and induce hyperprolactinaemia, causing gynaecomastia and/or galactorrhoea, with risperidone being the most frequently implicated medication. (c) Pubertal gynaecomastia is uncommon in males over 17 years of age. Cannabis use has less effect on gynaecomastia once puberty is completed, although it may still have a deleterious effect on testosterone levels and spermatogenesis. (d) Boys with XYY Syndrome rarely have hypogonadism and display gynaecomastia. This is more commonly seen in Klinefelter syndrome (XXY). Significant facial acne indicates virilisation and makes hypogonadism less likely.

(c) Pubertal gynaecomastia is uncommon in males over 17 years of age. Cannabis use has less effect on gynaecomastia once puberty is completed, although it may still have a deleterious effect on testosterone levels and spermatogenesis. (d) Boys with XYY Syndrome rarely have hypogonadism and display gynaecomastia. This is more commonly seen in Klinefelter syndrome (XXY). Significant facial acne indicates virilisation and makes hypogonadism less likely. (e) A virilised adolescent male in mid-to-late puberty on appropriate androgen replacement is unlikely to have hypogonadism, as well as pubertal gynaecomastia, based on age. Chronic alcohol use may reduce testosterone levels and induce gynaecomastia, although this would not occur with mild, infrequent use. 2. Which one of the following statements best describes a typical clinical presentation of pubertal gynaecomastia on palpation? (a) A unilateral painful hard mass with axillary lymphadenopathy (b) Bilateral mobile and tender disc-like mounds of tissue just beneath the nipple–areolar complex (c) A mass associated with nipple discharge (d) Multiple fixed peripheral masses with overlying skin discolouration (e) A dimpled appearance to the breast similar to an orange peel Answer: (b)

(a) A unilateral painful hard mass with axillary lymphadenopathy (b) Bilateral mobile and tender disc-like mounds of tissue just beneath the nipple–areolar complex (c) A mass associated with nipple discharge (d) Multiple fixed peripheral masses with overlying skin discolouration (e) A dimpled appearance to the breast similar to an orange peel Answer: (b) Pubertal gynaecomastia is often bilateral with the proliferated breast tissue palpable, as described in answer (b). Any lesion which is fixed, hard, peripherally located and/or associated with lymphadenopathy (a), discharge (c), skin discolouration (d) or tethering (peau d'orange in answer (e)) should raise the suspicion of breast cancer (invariably unilateral), and the patient should be referred for mammography. 3. Which one of the following statements best describes treatment for pubertal gynaecomastia? (a) Liposuction should be performed as early as possible (b) Tamoxifen is effective, but produces serious adverse effects (c) Anastrozole is a superior medical therapy compared to tamoxifen (d) Tamoxifen may reduce the incidence of patients undergoing gynaecomastia surgery (e) Pharmacotherapy is most effective when instituted after 12 months of watchful waiting Answer: (d)

(a) Liposuction should be performed as early as possible (b) Tamoxifen is effective, but produces serious adverse effects (c) Anastrozole is a superior medical therapy compared to tamoxifen (d) Tamoxifen may reduce the incidence of patients undergoing gynaecomastia surgery (e) Pharmacotherapy is most effective when instituted after 12 months of watchful waiting Answer: (d) (a) Suction lipectomy (liposuction) should be performed when puberty has been completed (Tanner Stage 5) as there is a risk of gynaecomastia recurrence and complication. As 90% of pubertal gynaecomastia will resolve within three years, surgery should be reserved for persistent cases, large and pendulous breasts unresponsive to medical therapy, for removing redundant tissue or if a high degree of fibrosis is present. (b) In multiple studies using low doses and short treatment courses for pubertal gynaecomastia, tamoxifen has been well-tolerated without significant side effects. Headache and nausea may be reported. A potential risk of deep vein thrombosis (DVT) would preclude its use in sedentary individuals or those at an increased risk of venous thrombosis. This has not been reported in the generally fit and active adolescents it has been used in to date, who are at very low cardiovascular risk. Any mood changes and leg cramps should be investigated, as with adults taking tamoxifen. (c) Aromatase inhibitors block the biosynthesis of oestrogen from testosterone and have been shown to be inferior to Selective Oestrogen Receptor Modulators (SERMs), such as tamoxifen, in clinical trials to treat gynaecomastia.

(b) In multiple studies using low doses and short treatment courses for pubertal gynaecomastia, tamoxifen has been well-tolerated without significant side effects. Headache and nausea may be reported. A potential risk of deep vein thrombosis (DVT) would preclude its use in sedentary individuals or those at an increased risk of venous thrombosis. This has not been reported in the generally fit and active adolescents it has been used in to date, who are at very low cardiovascular risk. Any mood changes and leg cramps should be investigated, as with adults taking tamoxifen. (c) Aromatase inhibitors block the biosynthesis of oestrogen from testosterone and have been shown to be inferior to Selective Oestrogen Receptor Modulators (SERMs), such as tamoxifen, in clinical trials to treat gynaecomastia. (d) By reducing breast size and pain over the long term in 75% cases, patients treated with tamoxifen have less need to undergo surgery for pubertal gynaecomastia. (e) Watchful waiting is best for small, pain-free cases of pubertal gynaecomastia of recent onset (<6 months). Breast tissue growth is most abundant within the first six months, and most symptoms occur during this time. Medical therapy has the greatest effect when initiated on large, painful lesions before six months have elapsed. After 12 months, there is a higher chance of breast tissue fibrosis and less response to medical therapy. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Foreign body ingestion is a common case encountered in pediatric. Most of these cases result in no harm, a few cases have significant complications and rare cases remain unnoticed for some time. Our case represents one of the unusual missed cases and was even labeled as congenital esophageal stenosis, an uncommon disease, after radiological and endoscopic studies. 2 Case presentation A 2-year-old girl was referred to our center for further management of suspected congenital esophageal stenosis. Upon presentation, the patient was unable to tolerate a solid or pureed diet. She was vomiting and was having feed refusal in the last 6 months. She also had poor weight gain. No specific history of a preceding or predisposing event was given by the family. The barium swallow study and esophagoscopy from the referring hospital indicated a severely stenotic area at the mid-esophagus. A repeat barium swallow at our hospital showed a 1 cm long and 2–3 mm in diameter upper thoracic esophageal stenosis with proximal dilatation (Fig. 1). Esophagoscopy with dilatation, using a Savary-Gilliard dilator up to size 13, was performed. A month later, a second session of dilatation up to size 15 was performed. Following the second dilatation session, the patient's status improved and she became asymptomatic. She was able to tolerate both liquid and solid food.Figure 1 Barium swallow showing the esophageal stenosis in the mid-esophagus.

was performed. A month later, a second session of dilatation up to size 15 was performed. Following the second dilatation session, the patient's status improved and she became asymptomatic. She was able to tolerate both liquid and solid food.Figure 1 Barium swallow showing the esophageal stenosis in the mid-esophagus. During the second esophageal dilatation, a hardening on the esophageal wall was noticed, so a chest CT was arranged to evaluate for the presence of a cartilaginous ring. However, the CT showed a focal inflammatory process in the upper thoracic esophagus surrounding an impacted esophageal wall tongue-like foreign body, most likely an aluminum can cover (Figure 2, Figure 3, Figure 4).Figure 2 CT scan sagittal view showing the metallic foreign body as a curved hyperdensity posterior to the trachea (arrow). Figure 3 Axial CT scan with IV contrast showing the foreign body as a linear hyperdensity (narrow arrow) with a low attenuation posterior to it representing a posterior wall esophageal abscess (wide arrow). Figure 4 3D reconstruction showing the tongue like metallic foreign body (arrow) anterior to the inserted nasogastric tube

Figure 3 Axial CT scan with IV contrast showing the foreign body as a linear hyperdensity (narrow arrow) with a low attenuation posterior to it representing a posterior wall esophageal abscess (wide arrow). Figure 4 3D reconstruction showing the tongue like metallic foreign body (arrow) anterior to the inserted nasogastric tube The patient was admitted urgently. Repeat esophagoscopy showed a bulge in the esophageal wall with a slit-like area. However, the esophageal mucosa was grossly normal. No foreign body was identified. An exploratory thoracoscopy was performed. It revealed a cystic dilatation on the wall of the esophagus, which was accidentally incised and drained pus. The foreign body was identified and retrieved from the muscular layer of the esophagus (Figure 5, Figure 6, Figure 7). The site of the esophageal break was repaired with primary sutures. Irrigation with normal saline was performed, and a chest tube was left in place. A specimen from the cystic wall was sent to the pathology lab and revealed submucosal fibrosis and unremarkable squamous epithelium. A culture was not performed.Figure 5 Thoracoscopy showing a yellowish esophageal cystic lesion, representing the abscess (arrow). Figure 6 Pus draining from the abscess (arrow). Figure 7 An aluminum can cover is retrieved from the esophageal muscular layers. The child was kept nil per mouth for five days, during which peripheral total parenteral nutrition was started.

The patient was admitted urgently. Repeat esophagoscopy showed a bulge in the esophageal wall with a slit-like area. However, the esophageal mucosa was grossly normal. No foreign body was identified. An exploratory thoracoscopy was performed. It revealed a cystic dilatation on the wall of the esophagus, which was accidentally incised and drained pus. The foreign body was identified and retrieved from the muscular layer of the esophagus (Figure 5, Figure 6, Figure 7). The site of the esophageal break was repaired with primary sutures. Irrigation with normal saline was performed, and a chest tube was left in place. A specimen from the cystic wall was sent to the pathology lab and revealed submucosal fibrosis and unremarkable squamous epithelium. A culture was not performed.Figure 5 Thoracoscopy showing a yellowish esophageal cystic lesion, representing the abscess (arrow). Figure 6 Pus draining from the abscess (arrow). Figure 7 An aluminum can cover is retrieved from the esophageal muscular layers. The child was kept nil per mouth for five days, during which peripheral total parenteral nutrition was started. Subsequently, a follow-up barium swallow was performed and showed interval improvement of the mid-esophagus narrowing with no leak (Fig. 8). The child was started on a liquid diet, which progressed to a normal-for-age diet, which she tolerated well with no complications. The chest tube was removed. She was discharged on postoperative day 6.Figure 8 Barium swallow after removal of the foreign body showing significant improvement in the stenosis.

ak (Fig. 8). The child was started on a liquid diet, which progressed to a normal-for-age diet, which she tolerated well with no complications. The chest tube was removed. She was discharged on postoperative day 6.Figure 8 Barium swallow after removal of the foreign body showing significant improvement in the stenosis. Retrospectively, a history of an episode of choking and vomiting along with the inability to tolerate oral liquids at the age of 13 months was identified. Initial investigation and management at that time revealed a whole bean, which was coughed up by the patient and assumed to be the causative agent. Following this incident, the patient tolerated only a liquid diet. Her mother overlooked this incident and did not recall it in subsequent clinic visits. Two months after discharge, she presented to the clinic for regular follow-up. There were no complaints. She was tolerating all types of food and had gained 1 kg from the time of admission. 3 Discussion Infants are at a greater risk of ingesting foreign bodies due to their orolingual curiosity. It is most common between the ages of 6 months and 3 years [1], [2]. A positive history of ingestion is not always present [2]. Therefore, diagnosing a pediatric patient with an esophageal foreign body can be difficult, not to mention intramural foreign bodies [1]. Fifty percent of cases have an atypical presentation or are asymptomatic [2].

en the ages of 6 months and 3 years [1], [2]. A positive history of ingestion is not always present [2]. Therefore, diagnosing a pediatric patient with an esophageal foreign body can be difficult, not to mention intramural foreign bodies [1]. Fifty percent of cases have an atypical presentation or are asymptomatic [2]. Foreign bodies retained for more than 24 h are associated with a 14.1 times greater risk of complications [1]. Examples include esophageal perforation, mediastinitis, and esophago-aortic fistula [1]. Miller et al described chronic esophageal foreign bodies (CEFBs) defined as those retained for at least 1 week. Of 522 children, 8% qualified as having a CEFB. He found that respiratory symptoms were the primary complaint in 76% of cases and gastrointestinal symptoms in 22% of cases. However, dysphagia or odynophagia was the main secondary symptom, present in 47% of cases [3]. Miller et al introduced the concept of technical esophageal perforation, in which “A foreign body that had been walled off in either mucosal or muscular layer of the esophagus” is one of the criteria, similar to our case. Seventeen percent of all esophageal perforation patients in his study had the above mentioned criterion [3].

al introduced the concept of technical esophageal perforation, in which “A foreign body that had been walled off in either mucosal or muscular layer of the esophagus” is one of the criteria, similar to our case. Seventeen percent of all esophageal perforation patients in his study had the above mentioned criterion [3]. Upon reviewing the literature, we found 2 similar cases. The first was reported in 1982 from Hospital for Sick Children, London. They described an 18-month-old boy with a history of long-standing dysphagia. The plain chest X-ray was unremarkable, and the barium swallow showed a narrowing of the esophagus. The provisional diagnosis was a foregut duplication cyst. His esophagoscopy showed no visualized foreign body. During a thoracotomy, a metal cap top was retrieved [4]. The second case was that of a 6-month-old boy who had a chest X-ray for evaluation of cough and was found to have a foreign body. A chest CT revealed an intramural foreign body, similar to our patient. A repeated esophagoscopy of the boy identified a barely visible tail of a coil. It was removed endoscopically [1]. Interestingly, our patient was asymptomatic after 2 sessions of esophageal dilatation, which misleadingly favored the diagnosis of congenital esophageal stenosis. We could not find any reported cases in the literature of asymptomatic patients following the treatment/intervention of their presumed initial diagnosis.

Upon reviewing the literature, we found 2 similar cases. The first was reported in 1982 from Hospital for Sick Children, London. They described an 18-month-old boy with a history of long-standing dysphagia. The plain chest X-ray was unremarkable, and the barium swallow showed a narrowing of the esophagus. The provisional diagnosis was a foregut duplication cyst. His esophagoscopy showed no visualized foreign body. During a thoracotomy, a metal cap top was retrieved [4]. The second case was that of a 6-month-old boy who had a chest X-ray for evaluation of cough and was found to have a foreign body. A chest CT revealed an intramural foreign body, similar to our patient. A repeated esophagoscopy of the boy identified a barely visible tail of a coil. It was removed endoscopically [1]. Interestingly, our patient was asymptomatic after 2 sessions of esophageal dilatation, which misleadingly favored the diagnosis of congenital esophageal stenosis. We could not find any reported cases in the literature of asymptomatic patients following the treatment/intervention of their presumed initial diagnosis. 4 Conclusion Intramural foreign bodies are possible serious conditions that might be masked by unusual symptoms. There should be a high index of suspicion for this possibility for all pediatric patients who present with long-standing and unexplained dysphagia. Conflict of interest No conflict of interest Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Lipoid proteinosis (LP), also referred to as Urbach–Wiethe disease, lipoglycoproteinosis and hyalinosis cutis et mucosae [1], is a very rare, autosomal recessive and inherited genodermatosis (OMIM 247100). It is a poorly understood disease that commonly affects the mucosae and skin. Cutaneous manifestations in LP are constant and characteristic, but they are frequently misdiagnosed at their early erosive vesicular stage, which can mimic many other diseases. Herein we describe a 3.5-year-old female patient with this uncommon disease, which was revealed by a vesiculobullous eruption.

cosae and skin. Cutaneous manifestations in LP are constant and characteristic, but they are frequently misdiagnosed at their early erosive vesicular stage, which can mimic many other diseases. Herein we describe a 3.5-year-old female patient with this uncommon disease, which was revealed by a vesiculobullous eruption. 2 Case report A female child aged 3.5 years old was referred to our department for a chronic and recurrent vesiculobullous skin eruption since early childhood. She was born to consanguineous parents originating from the northwest of Tunisia with no history of other affected family members. The patient had developed hoarseness of the voice during the first few months of life. At the age of one year old, she started to develop recurrent erosions and blisters located on her face, hands, elbows and knees without photosensitivity. No medical advice had been sought during this time. An examination revealed the presence of multiple non-pruritic tense vesicles and erosions on a non-erythematous base on her face, hands and elbows (Figure 1, Figure 2). She also had a diffuse and firm waxy thickening of the skin on her face with multiple varioliform and acneiform scars. The lesions were located on acneogenic and non-acneogenic regions of the skin. The examination of her nails and hair was normal. She had an eversion of her lower lip with multiple carious teeth (Fig. 3). The intraoral examination did not show any infiltrated plaques in the oral cavity. The patient underwent laryngoscopy on account of her dysphonia, which showed thickening of the epiglottis and the aryepiglottic folds. She had no history of frontal headaches, seizures or visual disturbances. Her ophthalmologic, neurological and psychiatric examinations were normal. Routine haematological and biochemical investigations were within normal limits. Skin swab cultures were negative. Results from a porphyrin screen were normal for uroporphyrins and coproporphyrins in the urine and faeces. Protoporphyrins in the erythrocytes were also normal. The clinical features were highly suggestive of lipoid proteinosis. Light microscopic examination of a biopsy of an intact vesicle revealed a subepidermal blister with extensive deposits of homogeneous hyaline-like material in the upper dermis that reacted strongly with the periodic acid–Schiff (PAS) stain. Deposits were also found in the dermis between collagen bundles and near blood vessels (Fig. 4). Direct immunofluorescence of the perilesional skin was negative.

rmal blister with extensive deposits of homogeneous hyaline-like material in the upper dermis that reacted strongly with the periodic acid–Schiff (PAS) stain. Deposits were also found in the dermis between collagen bundles and near blood vessels (Fig. 4). Direct immunofluorescence of the perilesional skin was negative. Hence, a diagnosis of LP was assessed. The patient was then regularly followed in our department for therapy for her disease.Figure 1 Diffuse waxy thickening of the skin on the face with multiple vesicles and acneiform scars with eversion of the lower lip. Figure 2 Erosions and atrophic scars located on the dorsum of the hands. Figure 3 Multiple carious teeth. Figure 4 A: Infiltration of the dermis with amorphous, extracellular, eosinophilic hyaline deposits around the blood vessels. B: PAS-positive hyaline material in the dermis around the blood vessels. 3 Discussion Lipoid proteinosis, or Urbach–Wiethe disease, was first described by the dermatologist E. Urbach and the otolaryngologist C. Wiethe in 1929 [2]. It is a rare and recessively inherited disorder that is characterized by the deposition of hyaline material into the skin, oral cavity and larynx. It occurs with equal frequency in both males and females [3]. Approximately 300 cases of LP have been reported in the literature, predominantly in people of European ancestry. Few cases have been reported from patients originating from North Africa, especially in Tunisia, where only 11 cases have been reported [4].

3 Discussion Lipoid proteinosis, or Urbach–Wiethe disease, was first described by the dermatologist E. Urbach and the otolaryngologist C. Wiethe in 1929 [2]. It is a rare and recessively inherited disorder that is characterized by the deposition of hyaline material into the skin, oral cavity and larynx. It occurs with equal frequency in both males and females [3]. Approximately 300 cases of LP have been reported in the literature, predominantly in people of European ancestry. Few cases have been reported from patients originating from North Africa, especially in Tunisia, where only 11 cases have been reported [4]. The exact pathogenesis is unknown, but LP can be the result of either a lysosomal storage disorder, as suggested by Bauer et al, who demonstrated the presence of inclusions within the fibroblasts [5], or from a disturbance in collagen synthesis. Other authors have suspected that a metabolic deficiency in the degradation pathway of glycolipids or sphingolipids could lead to the storage of ceramide or more complex lipids [6]. Recent studies have shown that LP is the result of the reduced expression of the extracellular-matrix-protein (ECM1) gene mapped to chromosome 1 in fibroblasts. This discovery improves diagnostic accuracy and makes carrier screening and DNA based prenatal diagnosis of LP feasible [7].

The exact pathogenesis is unknown, but LP can be the result of either a lysosomal storage disorder, as suggested by Bauer et al, who demonstrated the presence of inclusions within the fibroblasts [5], or from a disturbance in collagen synthesis. Other authors have suspected that a metabolic deficiency in the degradation pathway of glycolipids or sphingolipids could lead to the storage of ceramide or more complex lipids [6]. Recent studies have shown that LP is the result of the reduced expression of the extracellular-matrix-protein (ECM1) gene mapped to chromosome 1 in fibroblasts. This discovery improves diagnostic accuracy and makes carrier screening and DNA based prenatal diagnosis of LP feasible [7]. Clinically, the first sign of LP is a hoarseness of the voice due to vocal infiltration, which remains throughout the patient's life. Cutaneous lesions appear shortly afterwards, usually during the first two years of life. They occur in two overlapping stages. The first stage is represented by vesicles, bullae and haemorrhagic crusts that appear spontaneously and resolve with scar formation. In the second stage, diffuse thickening of the skin occurs along with the development of yellowish and waxy infiltrated papules and nodules on the face because of the increasing deposition of hyaline material in the skin [8], [9]. Hyperkeratotic or verrucous lesions resembling xanthoma may be seen on the elbows, knees and buttocks. The infiltration of the eyelids gives rise to a beaded appearance, also called moniliform blepharosis, which is characteristic of the disease. This feature was absent in our patient because of her young age [6]. Scalp involvement may lead to hair loss [7]. Nail dystrophy with haemorrhagic blisters on the wrists, fingers and nailbed is a common finding [1]. The mucosae of the pharynx, tongue, soft palate, tonsils and lips are also infiltrated and this may lead to respiratory difficulty [3]. Carious teeth and poor dental hygiene are frequently seen in LP and may result from dryness of the mouth associated with the infiltration and obstruction of the parotid duct by hyaline material [6].

the pharynx, tongue, soft palate, tonsils and lips are also infiltrated and this may lead to respiratory difficulty [3]. Carious teeth and poor dental hygiene are frequently seen in LP and may result from dryness of the mouth associated with the infiltration and obstruction of the parotid duct by hyaline material [6]. Extracutaneous features may include epilepsy, mental retardation, memory loss, schizophrenic behavior and neuropsychiatric abnormalities, sometimes in association with calcifications in the temporal lobes or hippocampi, which were absent in our patient (Fig. 5) [6], [3]. Hyaline deposits have also been described in the conjunctiva, cornea, trabeculum and retina. Corneal opacities or secondary glaucoma due to infiltration in the trabeculum may appear later [1].Figure 5 The absence of calcifications in the temporal lobes assessed by the CT scan of the brain. The diagnosis is confirmed by histopathological findings that show extensive deposits of homogeneous hyaline-like material in the upper dermis that reacts strongly with the PAS stain. Hyaline deposits are also found in the dermis between collagen bundles surrounding blood vessels and around sweat glands. The hyaline material is eosinophilic, PAS+ and diastase–resistant, indicating the presence of glycoproteins [1].

us hyaline-like material in the upper dermis that reacts strongly with the PAS stain. Hyaline deposits are also found in the dermis between collagen bundles surrounding blood vessels and around sweat glands. The hyaline material is eosinophilic, PAS+ and diastase–resistant, indicating the presence of glycoproteins [1]. Vesiculobullous eruptions represent the early erosive stage of LP and can mimic many other diseases. Thus, LP is rarely diagnosed at the early stages. In fact, the recurrent vesicles and erosions in LP could mimic other infectious processes, such as impetigo. LP could even mimic other childhood blistering dermatoses, such as epidermolysis bullosae, when the blistering is severe and diffuse [10]. The lesson to draw from our case is that vesicles and crusted lesions may occur in the early stage of LP, especially in the first two years of life, as observed in our case. Thus, a high index of suspicion is required to diagnose LP when the characteristic moniliform blepharosis and verrucous lesions have not yet developed [11]. We should therefore consider that the association of hoarseness of voice, vesiculobullous eruption and evidence of dermal hyaline material to be the key for the diagnosis of LP at early stages.

n is required to diagnose LP when the characteristic moniliform blepharosis and verrucous lesions have not yet developed [11]. We should therefore consider that the association of hoarseness of voice, vesiculobullous eruption and evidence of dermal hyaline material to be the key for the diagnosis of LP at early stages. The condition most closely resembling LP is erythropoietic protoporphyria (EP). It displays similar skin symptoms, but without oral lesions. Increased values of protoporphyrins in erythrocytes in EP are the key for differentiation. Clinical differentiation can be achieved by the absence of photosensitivity and the presence of skin lesions in non-sun-exposed areas in LP [1], [12], [13]. Histologically, EP has a deposition of PAS positive material that is less dense around blood vessels and never occurs around sweat coils [6]. The disease could be easily differentiated from xanthomatosis, amyloidosis, papular mucinosis and colloid milia, especially in consideration of the histological findings [9], [13].

stologically, EP has a deposition of PAS positive material that is less dense around blood vessels and never occurs around sweat coils [6]. The disease could be easily differentiated from xanthomatosis, amyloidosis, papular mucinosis and colloid milia, especially in consideration of the histological findings [9], [13]. Regarding treatment, there is no effective and clear-cut treatment regimen for LP [1]. Usually, treatment for this disease is unsatisfactory and has been helpful in only limited cases [12]. Sustained benefits were reported in only a limited number of patients. Wong and Lin reported a remarkable response with dimethyl sulfoxide therapy in one patient [14], which they attributed to its solvent properties and its ability to dissolve collagen. Limited success has been found with oral steroids, chloroquine phosphate and etretinate [15]. Facial lesions have been treated successfully by dermabrasion, chemical peeling, blepharoplasty and a CO2 laser. Kaya et al even suggested D penicillamine as a promising agent, even at low doses, for the treatment of LP because of its ability to temporarily relieve symptoms [15]. A recent study conducted in Turkey reported that treatment with acitretin in 10 patients affected with lipoid proteinosis was quite effective [16]. Currently, the identification of the ECM1 mutation in LP provides a basis for the development of more rational forms of treatment, including trials of recombinant ECM1 protein and the development of somatic gene therapy for the skin and respiratory mucosa [7].

Regarding treatment, there is no effective and clear-cut treatment regimen for LP [1]. Usually, treatment for this disease is unsatisfactory and has been helpful in only limited cases [12]. Sustained benefits were reported in only a limited number of patients. Wong and Lin reported a remarkable response with dimethyl sulfoxide therapy in one patient [14], which they attributed to its solvent properties and its ability to dissolve collagen. Limited success has been found with oral steroids, chloroquine phosphate and etretinate [15]. Facial lesions have been treated successfully by dermabrasion, chemical peeling, blepharoplasty and a CO2 laser. Kaya et al even suggested D penicillamine as a promising agent, even at low doses, for the treatment of LP because of its ability to temporarily relieve symptoms [15]. A recent study conducted in Turkey reported that treatment with acitretin in 10 patients affected with lipoid proteinosis was quite effective [16]. Currently, the identification of the ECM1 mutation in LP provides a basis for the development of more rational forms of treatment, including trials of recombinant ECM1 protein and the development of somatic gene therapy for the skin and respiratory mucosa [7]. This condition may compromise quality of life due to its disfiguring scars and multisystemic involvement and especially because of neurological impairment and respiratory obstruction [1]. However, LP usually follows a benign and slow progressive course. Finally, the course of the disease and the therapeutic possibilities are still being debated.

se quality of life due to its disfiguring scars and multisystemic involvement and especially because of neurological impairment and respiratory obstruction [1]. However, LP usually follows a benign and slow progressive course. Finally, the course of the disease and the therapeutic possibilities are still being debated. 4 Conclusion In summary, the lesson to draw from our case is that LP is rare and can easily be misdiagnosed. The diagnosis is easy when combining the early onset of hoarseness and characteristic cutaneous manifestations with evidence of dermal hyaline deposition. LP should be considered in the differential diagnosis of vesiculobullous lesions in children. In these patients, long-term follow-up and a detailed examination to determine the extent of involvement should be performed. Conflict of interest None. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Urinary tract infections (UTIs) occur in 1–3% of girls and 1% of boys. In girls, the first UTI usually occurs by the age of 5 years, with peaks during infancy and toilet training. In boys, most UTIs occur during the 1st year of life. The prevalence of UTIs varies with age. During the 1st year of life, the male: female ratio is 2.8–5.4: 1. Beyond 1–2 years, there is a female preponderance, with a female: male ratio of 10: 1 [1]. The association between urinary nitrite and UTIs was first reported in 1914 and has frequently been the object of investigation [2]. The advantages of utilizing urinary nitrites are its low cost, the rapidity with which the results are available, and its ability to categorize patients into two distinct groups, nitrite positive or negative [3], [4]. Knowledge of the spectrum of pathogens and their patterns of resistance in the population allows the clinician to empirically select an effective agent [5]. Whether the absence of urine nitrites predicts resistance to common antibiotics that are used for the treatment of uncomplicated UTIs has been poorly investigated. Furthermore, the results from the few studies that have investigated this correlation are conflicting [6], [7], [8], [9]. 2 Materials and methods 2.1 Setting Woodhull Medical Health and Mental Center is an inner city community hospital in New York, NY that is affiliated with NYU, School of Medicine.

Knowledge of the spectrum of pathogens and their patterns of resistance in the population allows the clinician to empirically select an effective agent [5]. Whether the absence of urine nitrites predicts resistance to common antibiotics that are used for the treatment of uncomplicated UTIs has been poorly investigated. Furthermore, the results from the few studies that have investigated this correlation are conflicting [6], [7], [8], [9]. 2 Materials and methods 2.1 Setting Woodhull Medical Health and Mental Center is an inner city community hospital in New York, NY that is affiliated with NYU, School of Medicine. 2.2 Study design This is a retrospective, descriptive, and analytical study that was conducted in an urban inner city community hospital in New York City (NYU Woodhull Medical and Mental Health Center). Charts were reviewed for all patients seen in the Emergency Department and Pediatric Unit who had a diagnosis of a UTI during a 3-year period (Jan 2010–Dec 2012). Urine cultures were sent either by urine catheterization or clean mid-stream catch depending on whether the patient was toilet trained or not. As a general practice in our institution, a culture obtained by a urinary bag is not sent due to the high likelihood of contamination. This study received approval from our Institutional Review Board of NYU Langone Medical Center before chart review commenced.

depending on whether the patient was toilet trained or not. As a general practice in our institution, a culture obtained by a urinary bag is not sent due to the high likelihood of contamination. This study received approval from our Institutional Review Board of NYU Langone Medical Center before chart review commenced. 2.3 Data storage and statistical analysis The chart numbers were obtained from the medical record department at Woodhull Medical and Mental Health Center. All of the charts were reviewed through the use of the electronic medical record system QUADRAMED to obtain demographic, clinical, and laboratory information from the patients. The data were stored on NYU REDCap (secure data base on NYU Onsite) on a secured computer in Woodhull Medical Center. Each subject was entered into the REDcap database as a subject number (1, 2,3, etc.). We used SSPS statistical software, version 20, to analyze our data. Chi-square and Fisher Exact tests were used. P value < .05 was considered statistically significant. 3 Inclusion and exclusion criteria We collected the records of all pediatric patients aged 1 day to 18 years of age who had a final discharge diagnosis of UTI, cystitis, or pyelonephritis. Only patients who had a single urine pathogen of >105 colony-forming units (CFU) per milliliter were included. Patients who had a diagnosis of UTI, pyelonephritis, or cystitis were excluded if no urine culture was sent, if the culture was negative, or grew more than a single pathogen.

UTI, cystitis, or pyelonephritis. Only patients who had a single urine pathogen of >105 colony-forming units (CFU) per milliliter were included. Patients who had a diagnosis of UTI, pyelonephritis, or cystitis were excluded if no urine culture was sent, if the culture was negative, or grew more than a single pathogen. 4 Measurements The following information was collected from the medical records: demographic information (age and sex), history of subjective or documented fever, urinalysis (UA) findings (urine white blood cell [WBC], leukocyte esterase [LE], and nitrite), leukocytosis in the complete blood count (CBC), causative organism, and susceptibility pattern to antibiotics. For the purpose of the study, leukocytosis was defined as a WBC in the complete blood count of more than 15,000 regardless of the subject's age. Positive WBCs in the urine was defined as the presence of >5 WBC/power field. Sensitivity information was gathered for each bacterium. A bacterium was considered to be resistant to a specific antibiotic if the report read either resistance or intermediate. 5 Results We studied the sensitivity pattern to the following antibiotics: ampicillin, ampicillin/sulbactam, cefazolin, cefuroxime, cefotaxim, ceftazidim, cefepime, ciprofloxacin, nitrofurantoin, gentamicin, piperacillin/tazobactam, trimethoprim/sulfamethoxazole, and imipenem.

4 Measurements The following information was collected from the medical records: demographic information (age and sex), history of subjective or documented fever, urinalysis (UA) findings (urine white blood cell [WBC], leukocyte esterase [LE], and nitrite), leukocytosis in the complete blood count (CBC), causative organism, and susceptibility pattern to antibiotics. For the purpose of the study, leukocytosis was defined as a WBC in the complete blood count of more than 15,000 regardless of the subject's age. Positive WBCs in the urine was defined as the presence of >5 WBC/power field. Sensitivity information was gathered for each bacterium. A bacterium was considered to be resistant to a specific antibiotic if the report read either resistance or intermediate. 5 Results We studied the sensitivity pattern to the following antibiotics: ampicillin, ampicillin/sulbactam, cefazolin, cefuroxime, cefotaxim, ceftazidim, cefepime, ciprofloxacin, nitrofurantoin, gentamicin, piperacillin/tazobactam, trimethoprim/sulfamethoxazole, and imipenem. Between January 2010 and December 2012, a total of 378 patients had a diagnosis of UTI. Seventy-five (19.8%) were males, and 303 (80.2%) were females. Fifty (36.8%) males and 86 (63.2%) females were less than 2 years of age. In the 2–13 years of age group, there were 23 males (13.1%) and 153 (86.9%) females. Of those older than 13 years of age, 2 (3%) were males and 64 (97%) were females. The age distribution of the isolates differed significantly by gender (P value < .0005).

.8%) males and 86 (63.2%) females were less than 2 years of age. In the 2–13 years of age group, there were 23 males (13.1%) and 153 (86.9%) females. Of those older than 13 years of age, 2 (3%) were males and 64 (97%) were females. The age distribution of the isolates differed significantly by gender (P value < .0005). With regard to the UA results, nitrite was positive in 38% and negative in 62% of patients. Negative nitrite results were more common in patients less than 2 years of age (P value of .034). Bacteria were positive in 86.2% and negative 13.8% of patients. LE was positive 82.7% and negative 17.3% of patients. CBC was obtained in 37.6% of patients. Leukocytosis was present in 44.4% of patients.

n 62% of patients. Negative nitrite results were more common in patients less than 2 years of age (P value of .034). Bacteria were positive in 86.2% and negative 13.8% of patients. LE was positive 82.7% and negative 17.3% of patients. CBC was obtained in 37.6% of patients. Leukocytosis was present in 44.4% of patients. Of the 378 patients with a diagnosis of UTI, the most common isolated pathogen was Escherichia coli, which was detected in 283 (74.9%) isolates. Other bacteria included Klebsiella spp 30 (7.9%), Proteus 21 (5.6%), Enterococcus 14 (3.7%), and others 30 (7.9%). Urine nitrite was tested in 371 patients and was positive in 141(38%) and negative in 230 (62%). WBCs in the urine were evaluated in 307 samples and were positive in 247 (80.4%) and negative in (19.6%). LE was positive in 307 (82.7%) and negative in 64 (17.3%) samples. Bacteria was identified in the UA in 263 (86.2%) and was negative in 42 (13.8%) patients. A CBC was obtained in 142 (37.6%) patients, while 236 (62.4%) patients had no CBC results. Among the patients who had results from a CBC, 63 (44.4%) had leukocytosis and 79 (55.6%) had no leukocytosis. Fever was present in 148 (45.4%) patients and was absent in 178 (54.6%). Fig. 1 shows the sensitivity pattern to all of the isolated pathogens.Figure 1 Sensitivity pattern for all isolated pathogens. The correlation between the nitrite results and resistance patterns to common antibiotics that may be used to treat UTI is shown in Table 1.Table 1 The correlation between nitrite results and resistant patterns to common antibiotics that may be used to treat UTIs.

Fig. 1 shows the sensitivity pattern to all of the isolated pathogens.Figure 1 Sensitivity pattern for all isolated pathogens. The correlation between the nitrite results and resistance patterns to common antibiotics that may be used to treat UTI is shown in Table 1.Table 1 The correlation between nitrite results and resistant patterns to common antibiotics that may be used to treat UTIs. Antibiotic Sensitive Resistant P Value Ampicillin Positive Urine Nitrite 44 (31.4%) 96 (68.6%) .007 Negative Urine Nitrite 103 (45.8%) 122 (54.2%) Ampicillin/Sulbactam Positive Urine Nitrite 60 (42.9%) 80 (57.1%) .012 Negative Urine Nitrite 122 (56.5%) 94 (43.5%) Cefazolin Positive Urine Nitrite 106 (80.3%) 26 (19.7%) .46 Negative Urine Nitrite 176 (83.4%) 35 (16.6%) Cefuroxime Positive Urine Nitrite 105 (92.1%) 9 (7.9%) .38 Negative Urine Nitrite 176 (94.6%) 10 (5.4%) Cefotaxime Positive Urine Nitrite 129 (92.8%) 10 (7.2%) .79 Negative Urine Nitrite 202 (93.5%) 14 (6.5%) Ceftazidime Positive Urine Nitrite 131 (92.9%) 10 (7.1%) .44 Negative Urine Nitrite 204 (94.9%) 11 (5.1%) Cefepime Positive Urine Nitrite 124 (93.2%) 9 (10%) .52 Negative Urine Nitrite 204 (94.9%) 11 (5.1%) Ciprofloxacin Positive Urine Nitrite 125 (93.3%) 9 (6.7%) .51 Negative Urine Nitrite 200 (91.3%) 19 (8.7%) Nitrofurantoin Positive Urine Nitrite 114 (91.9%) 10 (8.1%) .16 Negative Urine Nitrite 187 (87%) 28 (13%) Gentamicin Positive Urine Nitrite 122 (91%) 12 (9%) .68 Negative Urine Nitrite 200 (89.7%) 23 (10.3%) Impinem Positive Urine Nitrite 131 (98.5%) 2 (1.5%) .63 Negative Urine Nitrite 212 (98.6%) 3 (1.4%) Piperacillin/Tazobactam Positive Urine Nitrite 129 (97%) 4 (3%) .36 Negative Urine Nitrite 211 (98.1%) 4 (1.9%) TM/SMX Positive Urine Nitrite 81 (60.4%) 53 (39.6%) .005 Negative Urine Nitrite 163 (74.8%) 55 (25.2%)

0.3%) Impinem Positive Urine Nitrite 131 (98.5%) 2 (1.5%) .63 Negative Urine Nitrite 212 (98.6%) 3 (1.4%) Piperacillin/Tazobactam Positive Urine Nitrite 129 (97%) 4 (3%) .36 Negative Urine Nitrite 211 (98.1%) 4 (1.9%) TM/SMX Positive Urine Nitrite 81 (60.4%) 53 (39.6%) .005 Negative Urine Nitrite 163 (74.8%) 55 (25.2%) The correlation between the LE results and resistance patterns is shown in Table 2.Table 2 The correlation between leukoesterase results and resistant patterns.

0.3%) Impinem Positive Urine Nitrite 131 (98.5%) 2 (1.5%) .63 Negative Urine Nitrite 212 (98.6%) 3 (1.4%) Piperacillin/Tazobactam Positive Urine Nitrite 129 (97%) 4 (3%) .36 Negative Urine Nitrite 211 (98.1%) 4 (1.9%) TM/SMX Positive Urine Nitrite 81 (60.4%) 53 (39.6%) .005 Negative Urine Nitrite 163 (74.8%) 55 (25.2%) The correlation between the LE results and resistance patterns is shown in Table 2.Table 2 The correlation between leukoesterase results and resistant patterns. Antibiotic Sensitive Resistant P Value Ampicillin Positive Urine Leukoesterase 123 (40.6%) 180 (59.4%) .73 Negative Urine Leukoesterase 24 (38.7%) 38 (61.3%) Ampicillin/Sulbactam Positive Urine Leukoesterase 148 (49.8%) 149 (50.2%) .27 Negative Urine Leukoesterase 34 (57.6%) 25 (42.4%) Cefazolin Positive Urine Leukoesterase 241 (84.3%) 45 (15.7%) .026 Negative Urine Leukoesterase 41 (71.9%) 16 (28.1%) Cefuroxime Positive Urine Leukoesterase 243 (94.6%) 14 (5.4%) .12 Negative Urine Leukoesterase 38 (88.4%) 5 (1.6%) Cefotaxime Positive Urine Leukoesterase 281 (94%) 18 (6%) .2 Negative Urine Leukoesterase 50 (89.3%) 6 (10.7%) Ceftazidime Positive Urine Leukoesterase 281 (94.6%) 16 (5.4%) .36 Negative Urine Leukoesterase 54 (91.5%) 5 (8.5%) Cefepime Positive Urine Leukoesterase 275 (94.5%) 16 (5.5%) .65 Negative Urine Leukoesterase 53 (93%) 4 (7%) Ciprofloxacin Positive Urine Leukoesterase 271 (91.9%) 24 (8.1%) .75 Negative Urine Leukoesterase 54 (93.1%) 4 (6.9%) Nitrofurantoin Positive Urine Leukoesterase 255 (90.1%) 28 (9.9%) .084 Negative Urine Leukoesterase 46 (82.1%) 10 (17.9%) Gentamicin Positive Urine Leukoesterase 268 (90.5%) 28 (9.5%) .63 Negative Urine Leukoesterase 54 (88.5) 7 (11.5%) Impinem Positive Urine Leukoesterase 288 (99%) 3 (1%) .15 Negative Urine Leukoesterase 55 (96.5%) 2 (3.5%) Piperacillin/Tazobactam Positive Urine Leukoesterase 285 (97.9%) 6 (2.1%) .51 Negative Urine Leukoesterase 55 (96.5%) 2 (3.5%) TM/SMX Positive Urine Leukoesterase 202 (68.5%) 93 (31.5%) .44 Negative Urine Leukoesterase 42 (73.7%) 15 (26.3%)

oesterase 288 (99%) 3 (1%) .15 Negative Urine Leukoesterase 55 (96.5%) 2 (3.5%) Piperacillin/Tazobactam Positive Urine Leukoesterase 285 (97.9%) 6 (2.1%) .51 Negative Urine Leukoesterase 55 (96.5%) 2 (3.5%) TM/SMX Positive Urine Leukoesterase 202 (68.5%) 93 (31.5%) .44 Negative Urine Leukoesterase 42 (73.7%) 15 (26.3%) The correlation between the urine nitrite results and different age groups is shown in Table 3.Table 3 Comparing urinary nitrite results in different age groups. Age groups Urinary Nitrite Negative Positive Total <2 Years 76 (65%) 41 (35%) 117 2–13 Years 115 (61%) 74 (39%) 189 >13 Years 39 (60%) 26 (40%) 65 Total 230 (62%) 141 (38%) 371 P Value .034 6 Discussion Urine culture is the gold standard for the diagnosis of UTI. However, the result of the culture is not readily available to the clinician in the Emergency Department. Thus, this study was conducted to determine whether the initial UA and urine nitrite results could serve as a guide in choosing the most appropriate empirical antibiotic. Several uropathogens, such as E. coli, Klebsiella, and Proteus, can reduce nitrate to nitrite, whereas others do not have this ability.

y Department. Thus, this study was conducted to determine whether the initial UA and urine nitrite results could serve as a guide in choosing the most appropriate empirical antibiotic. Several uropathogens, such as E. coli, Klebsiella, and Proteus, can reduce nitrate to nitrite, whereas others do not have this ability. Several factors can lead to a false negative nitrite result, including a short time between urine collection and testing, the amount of bacteriuria, a urine pH less than 6.0, organisms that further reduce nitrites to ammonia and dilute urine, and the presence of blood, urobilinogen, medications, or ascorbic acid [5]. A nitrite test is not a sensitive marker for children, particularly infants, who empty their bladders frequently. Therefore, a negative nitrite test result has little value in ruling out a UTI. Moreover, not all urinary pathogens reduce nitrate to nitrite [6].

of blood, urobilinogen, medications, or ascorbic acid [5]. A nitrite test is not a sensitive marker for children, particularly infants, who empty their bladders frequently. Therefore, a negative nitrite test result has little value in ruling out a UTI. Moreover, not all urinary pathogens reduce nitrate to nitrite [6]. Very few studies have investigated the relationship between urinary nitrite results and the selection of initial antibiotics. Weiz and his colleagues [6] suggested that a negative urine nitrite test is a possible indicator that a microorganism is resistant to the first and third-generation of cephalosporins. However, Grant et al [8] concluded that the detection of urine nitrites should not influence the use of first-generation cephalosporins for urinary tract infections. Larson et al [9] reported that no significant difference was observed between the rates of TMP-SMX resistance in both negative and positive nitrite groups. Mahyar et al [7] studied a large number of antibiotics, such as gentamycin, amikacin, nalidixic acid, ampicillin, and nitrofurantoin, in addition to first and third-generation cephalosporin. However, they found no correlation between urinary nitrite results and bacterial resistance to antimicrobial drugs. In our study, we evaluated the significance of urine nitrites in relation to a larger group of antimicrobial agents, some of which have not previously been studied.

rst and third-generation cephalosporin. However, they found no correlation between urinary nitrite results and bacterial resistance to antimicrobial drugs. In our study, we evaluated the significance of urine nitrites in relation to a larger group of antimicrobial agents, some of which have not previously been studied. In the past, sulphonamides were the drug of choice for outpatient management of UTIs. However, most hospitals switched to a first or a third generation cephalosporin due to the emerging resistance to sulphonamides. Unfortunately, resistance to first and now even third generation cephalosporins is increasingly reported in the literature, especially in developing countries. This mandates local evaluations of susceptibility patterns to common oral antibiotics used in the treatment of UTIs [10], [11], [12], [13]. Consistent with the vast majority of studies, we found that E. coli was the most commonly isolated bacteria (74.9%). This supports the fact that most UTIs are ascending infections. The bacteria arise from the faecal flora, colonize the perineum, and enter the bladder via the urethra [1], [5], [10], [14]. Based on expert opinion, the threshold of 20% as the resistance prevalence at which the agent is no longer recommended for empirical treatment of UTI is a widely accepted practice [15]. 7 Bacterial susceptibility pattern In our institution, we generally use cephalexin as an empirical antibiotic for the treatment of most uncomplicated UTIs diagnosed in the ED.

Consistent with the vast majority of studies, we found that E. coli was the most commonly isolated bacteria (74.9%). This supports the fact that most UTIs are ascending infections. The bacteria arise from the faecal flora, colonize the perineum, and enter the bladder via the urethra [1], [5], [10], [14]. Based on expert opinion, the threshold of 20% as the resistance prevalence at which the agent is no longer recommended for empirical treatment of UTI is a widely accepted practice [15]. 7 Bacterial susceptibility pattern In our institution, we generally use cephalexin as an empirical antibiotic for the treatment of most uncomplicated UTIs diagnosed in the ED. In our study, the resistance rate was higher in the nitrite positive group for TMP/SMX and ampicillin with or without sulbactam. However, because the resistance rate was >20%, even in the nitrite negative group, these above mentioned antibiotics are not appropriate for empirical treatment in our institution. In all of the studied cephalosporins, the resistance rate was lower in nitrite negative group (0.7–5.1), but these differences are not significant. However, for nitrofurantoin, gentamicin, ciprofloxasin, and piperacillin/tazobactam, the resistance rates were higher in the nitrite negative group (1.3–4.9), although these differences were not significant. No difference was found with imipenem. Thus, urinary nitrite results are not helpful in choosing an initial antibiotic to treat a UTI.

ntoin, gentamicin, ciprofloxasin, and piperacillin/tazobactam, the resistance rates were higher in the nitrite negative group (1.3–4.9), although these differences were not significant. No difference was found with imipenem. Thus, urinary nitrite results are not helpful in choosing an initial antibiotic to treat a UTI. No significant correlation was found between the LE and resistance patterns in all of studied antibiotics, except for cefazolin, which had a resistance rate of 16% in the LE positive group that was much higher (28.1%) in the LE negative group. Thus, if LE is negative in initial UA, a first generation cephalosporin should not be used as an empirical therapy in our population. No correlation was found between the presence of fever or leukocytosis and resistance patterns. In our patients, bacteria were highly resistant to TMP/SMX, reaching a rate of 30.1%. However, first generation cephalosporins (we used cefazolin as a proxy for first generation cephalosporin) are still acceptable as a first line empirical therapy, with an overall resistance rate of 18.3%. Consistent with previous studies, nitrofurantoin was very effective among other oral antibiotics, with a resistance rate of 11.9%, The American Academy of Pediatrics recommends that ciprofloxacin be limited to urinary tract infections caused by Pseudomonas aeruginosa or other multidrug-resistant and Gram-negative bacteria (the FDA licensed ciprofloxacin for complicated E. coli urinary tract infections and pyelonephritis attributable to E. coli in patients 1–17 years of age) (evidence grade II-2) [16].

ofloxacin be limited to urinary tract infections caused by Pseudomonas aeruginosa or other multidrug-resistant and Gram-negative bacteria (the FDA licensed ciprofloxacin for complicated E. coli urinary tract infections and pyelonephritis attributable to E. coli in patients 1–17 years of age) (evidence grade II-2) [16]. Nitrofurantoin is an oral antibiotic that is used in the treatment and prevention of lower UTIs. Nitrofurantoin only achieves antibiotic concentrations in the urine with low circulating blood levels and poor tissue penetration making it unsuitable for the treatment of upper UTIs. Other contraindications are renal failure and neonates and children with G6PD deficiency [17]. 8 Limitations A potential selection bias arises from our definition of a positive culture as > 100 K CFUs of bacteria. Some other studies have used lower thresholds. However, we focused on a pediatric population with incontrovertible UTIs. Reducing the CFU threshold may have included some patients without UTIs. Another limitation is that we studied in vitro susceptibility, which may not always reflect in vivo susceptibility. In addition, this was a retrospective study, which has known limitations.

sed on a pediatric population with incontrovertible UTIs. Reducing the CFU threshold may have included some patients without UTIs. Another limitation is that we studied in vitro susceptibility, which may not always reflect in vivo susceptibility. In addition, this was a retrospective study, which has known limitations. 9 Conclusion Due to the high resistance of bacteria to TMP/SMX and ampicillin with or without sulbactam, urinary nitrite results were not helpful in predicting bacterial resistance. LE, leukocytosis in blood or urine and fever were also of little value in the prediction of bacterial resistance. We recommend the use of nitrofurantoin or cephalexin in the treatment of cystitis. If LE is negative, nitrofurantoin is preferable to cephalexin. Second or third generation cephalosporins are appropriate antibiotics in the management of complicated UTI or when pyelonephritis is highly suspected. Funding None. Conflict of interest The authors have no conflicts of interest relevant to this article to disclose. Financial disclosure The authors have no financial relationships relevant to this article to disclose. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Recent advances in perinatal and neonatal medicine and the broader use of antenatal steroids, exogenous surfactants, sophisticated incubators and ventilator support modalities have resulted in a remarkable increase in the survival of preterm infants. Despite these advances, extremely low birth weight (ELBW) preterm infants remain at significant risk for the most frequent life-threatening complications of prematurity, such as intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP) and anaemia of prematurity (AOP) [1]. Preterm infants, particularly those with a birth weight less than 1500 g, are at high risk of requiring at least one, and often, multiple red blood cell (RBC) transfusions [2]. The mean number of transfusions in the two largest studies ranged from 3.3 to 5.7, depending on whether restrictive or liberal transfusion guidelines were used [3], [4]. Nearly 50% of ELBW infants (or infants born at or before 29 weeks of gestation) receive their first transfusion during the first 2 weeks of age, and 80% receive at least one additional blood transfusion by the end of their hospitalization [5].

on whether restrictive or liberal transfusion guidelines were used [3], [4]. Nearly 50% of ELBW infants (or infants born at or before 29 weeks of gestation) receive their first transfusion during the first 2 weeks of age, and 80% receive at least one additional blood transfusion by the end of their hospitalization [5]. Although RBC transfusions are a critical part of neonatal intensive care unit (NICU) stays and can be life saving for premature infants with severe anaemia or haemorrhage, they also convey risks and are costly and not easy to utilize, especially in resource-limited settings [6]. Therefore, preventive strategies to start life with higher haemoglobin levels have become popular during the last few decades [7]. This article reviews preventive strategies for AOP, giving particular emphasis to the enhancement of placental transfusion in the delivery room. 2 Anaemia of prematurity Anaemia of prematurity is a pathological condition unlike physiologic anaemia in newborns [8]. The pronounced decline in the haemoglobin (Hb) concentration that occurs in ELBW infants is usually associated with abnormal clinical signs and requires allogeneic RBC transfusions [8], [9]. AOP is characterized by reduced endogenous erythropoietin (EPO), reduced RBC lifespan and hypo-regenerative bone marrow [7]. Non-physiologic factors related to prematurity, such as phlebotomy losses for laboratory evaluations and nosocomial infections resulting in oxidative haemolysis, also contribute to high transfusion preterm infants [10].

reduced endogenous erythropoietin (EPO), reduced RBC lifespan and hypo-regenerative bone marrow [7]. Non-physiologic factors related to prematurity, such as phlebotomy losses for laboratory evaluations and nosocomial infections resulting in oxidative haemolysis, also contribute to high transfusion preterm infants [10]. When tissue hypoxia occurs, the transcription and expression of EPO mRNA increases, followed by an increase in erythropoiesis. Hypoxia-induced EPO expression is controlled by an enhancer element called hypoxia inducible factor-1 (HIF-1). Induction of HIF-1 binding in hypoxic cells requires RNA and protein synthesis, as well as protein phosphorylation. Sustained hypoxia is required for increasing EPO production. EPO production occurs primarily in the liver before 30 weeks of gestation (and is produced primarily in the kidney thereafter), and hypoxia is a less effective isolated stimulus for EPO production and erythropoiesis. The switch in hypoxia responsiveness and in the site of EPO production may contribute to AOP [2]. Suboptimal erythropoiesis appears to be the result of the inadequate synthesis of EPO in response to hypoxia [11]. EPO deficiency is greater in smaller premature infants compared to less mature infants [12]. Iron, folate, vitamin B12, or vitamin E deficiencies can also contribute to inadequate erythropoiesis [11].

[2]. Suboptimal erythropoiesis appears to be the result of the inadequate synthesis of EPO in response to hypoxia [11]. EPO deficiency is greater in smaller premature infants compared to less mature infants [12]. Iron, folate, vitamin B12, or vitamin E deficiencies can also contribute to inadequate erythropoiesis [11]. Traditionally, AOP has been treated with frequent packed RBC transfusions [13]. Among all age groups, the need for allogenic packed RBCs is common in newborns. Furthermore, preterm infants are among the most heavily transfused patient populations [3], [4]. The goal of packed RBC transfusions in infants with AOP is to restore or maintain oxygen delivery without increasing oxygen consumption [11]. However, according to the UK Serious Hazards of Transfusion (SHOT) National Haemovigilance Scheme, an increased number of adverse events related to RBC transfusion occur in children compared to adults, more so in neonates [14]. There are recognized potential adverse associations related to RBC transfusions unique to neonates. For example, associations between RBC transfusions and NEC, IVH, and chronic lung disease (CLD) as well as mortality have also been described [15], [16], [17], [18], [19], [20], [21], [22].

lts, more so in neonates [14]. There are recognized potential adverse associations related to RBC transfusions unique to neonates. For example, associations between RBC transfusions and NEC, IVH, and chronic lung disease (CLD) as well as mortality have also been described [15], [16], [17], [18], [19], [20], [21], [22]. In recent years, most institutes have implemented more restrictive transfusion guidelines to reduce the number of transfusions and donor exposures [3], [4]. Two larger RCTs (the Iowa and PINT trials) have examined the transfusion criteria in the ELBW population. Both trials compared restrictive with liberal transfusion criteria for clinically relevant outcomes. Both trials developed transfusion algorithms based on the need for oxygen and the level of respiratory support in conjunction with Hb or haematocrit (Hct) levels [3], [4]. Both studies found that neonates in the restrictive group had fewer RBC transfusions, without an increase in mortality or morbidity. However, one critical discrepancy was present. Bell et al [3] described increases in apnoea, severe IVH and periventricular leukomalacia in infants transfused with restrictive guidelines, but the trial was not designed to study these end points. Although the rates of serious outcomes were fairly high in both groups of the Kirpalani et al [4] trial, they found no differences in the rates of serious outcomes between infants in the restrictive vs. liberal groups.

nts transfused with restrictive guidelines, but the trial was not designed to study these end points. Although the rates of serious outcomes were fairly high in both groups of the Kirpalani et al [4] trial, they found no differences in the rates of serious outcomes between infants in the restrictive vs. liberal groups. 3 Preventive strategies for anaemia of prematurity 3.1 Recombinant human EPO Prevention and treatment of AOP with recombinant human EPO (r-HuEPO) has been the subject of many randomized controlled studies for over 20 years among over 3000 infants [2]. Although the role of EPO in the pathophysiology of AOP is well known, neither early (2–14 days of life) nor late (2–3 weeks of life) r-HuEPO therapy, nor co-treatment with iron, vitamin B12 and folate, alters the number or volume of RBC transfusions [7]. The combination of early r-HuEPO and iron does not reduce the RBC transfusion requirements in infants below 1250 g of birth weight, although the reticulocyte counts and Hct values are higher in the treatment group [23]. The use of early r-HuEPO does not significantly reduce the use of one or more RBC transfusions or the number of RBC transfusions per infant compared with late r-HuEPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage ≥3 with early EPO treatment is of great concern [24]. Due to the limited benefits and the possibly increased risk of ROP, the administration of EPO is not recommended [25].

ed with late r-HuEPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage ≥3 with early EPO treatment is of great concern [24]. Due to the limited benefits and the possibly increased risk of ROP, the administration of EPO is not recommended [25]. The preventive strategies for AOP are summarized in Fig. 1.Figure 1 Therapeutic and preventive strategies for anaemia of prematurity. 3.2 Reduction of phlebotomy losses Iatrogenic anaemia due to the repeated removal of blood for laboratory testing is common in premature infants [11]. During the first postnatal weeks, when severe neonatal cardiorespiratory illness is at its peak and frequent laboratory testing is most intense, phlebotomy loss among preterm infants is typically the most important contributor to AOP and is the reason that a transfusion is required [26].

mmon in premature infants [11]. During the first postnatal weeks, when severe neonatal cardiorespiratory illness is at its peak and frequent laboratory testing is most intense, phlebotomy loss among preterm infants is typically the most important contributor to AOP and is the reason that a transfusion is required [26]. Strategies for reducing phlebotomy losses include micro-sampling, batching blood labs, cord blood sampling for immediate postnatal labs (i.e., blood type and cross-match), ordering only necessary labs, careful monitoring of phlebotomy losses, and use of blood-testing devices operated at the bedside or point of care (POC) devices [27]. Madan et al [28] suggested that after the use of the POC analyzer in their NICU, the number of RBC transfusions and the mean volume of RBC transfusions decreased by 43% and 46%, respectively, in infants with birth weights less than 1 kg. Widness et al [29] found that infants who were examined with an in-line umbilical artery catheter analyser received a significantly lower amount of RBCs than infants who were examined according to regular laboratory use during the first week of life. However, these strategies, which are dependent on a sophisticated device, are limited by economic conditions, especially in developing countries.

lical artery catheter analyser received a significantly lower amount of RBCs than infants who were examined according to regular laboratory use during the first week of life. However, these strategies, which are dependent on a sophisticated device, are limited by economic conditions, especially in developing countries. 3.3 Enhancing placental transfusion In animal studies, it was found that immediate cord clamping after birth results in the accumulation of approximately 30%–50% of the feto-placental blood volume in the placental unit and leaves the newborn with the same amount of reduced blood volume [30], [31]. Approximately one-half of the feto-placental blood volume (nearly 110 ml/kg) remains outside the newborn infant's circulation at 30 weeks of gestation if the umbilical cord is clamped immediately [31], [32]. Aladangady et al [31] were the first group that demonstrated that the blood volume of ELBW preterm newborns could be increased by delayed cord clamping (DCC) for 30–90 s in both vaginal and CS deliveries. The placental transfusion via DCC was more marked after vaginal deliveries and seemed to be more apparent for preterm infants with lower gestational ages [31].

hat demonstrated that the blood volume of ELBW preterm newborns could be increased by delayed cord clamping (DCC) for 30–90 s in both vaginal and CS deliveries. The placental transfusion via DCC was more marked after vaginal deliveries and seemed to be more apparent for preterm infants with lower gestational ages [31]. Delayed cord clamping and umbilical cord milking (UCM) are the main methods for enhancing placental transfusion. The key difference between DCC and UCM is the mechanism of cord blood transfer to the infant. In DCC, a passive transfer of additional blood volume occurs at a slow rate, mostly by uterine contractions, whereas in UCM, an active transfer of additional blood volume occurs at a rapid rate and within a short time [33].

n. The key difference between DCC and UCM is the mechanism of cord blood transfer to the infant. In DCC, a passive transfer of additional blood volume occurs at a slow rate, mostly by uterine contractions, whereas in UCM, an active transfer of additional blood volume occurs at a rapid rate and within a short time [33]. 3.4 Delayed cord clamping A recent Cochrane meta-analysis of data from 15 randomized trials with a total of 738 infants who were born between 24 and 36 weeks' gestation found that DCC for 30–120 s, rather than immediate clamping, seems to be associated with less need for transfusion, better circulatory stability, less IVH and a lower risk for NEC [34]. Concerns about polycythaemia and hyperbilirubinemia as well as delays in transition were not included in the review due to the heterogeneity of the trials [34]. In December 2012, the American College of Obstetricians and Gynecologists (ACOG) recommended a 30–60 s delay in umbilical cord clamping for all preterm deliveries because of the associated neonatal benefits, including increased blood volume, reduced need for RBC transfusion, and decreased incidence of IVH in preterm infants [35]. The “European Consensus Guidelines on Resuscitation of the Preterm Infant” also recommended a delay of 30–60 s before clamping the umbilical cord [36]. In a clinical trial on neurodevelopmental outcomes in preterm infants by Mercer et al [37], 58 infants who were randomized to DCC (30–45 s) had similar Bayley II scores with the control group of infants at seven months of age. A regression model of the effects of DCC on motor scores controlling for gestational age, IVH, bronchopulmonary dysplasia, sepsis, and male gender suggested higher motor scores in male infants with DCC [38]. More recently, Andersson et al [38] found that DCC compared with immediate cord clamping improved scores in the fine-motor and social domains at 4 years of age, especially in boys who were born at term gestation.

hopulmonary dysplasia, sepsis, and male gender suggested higher motor scores in male infants with DCC [38]. More recently, Andersson et al [38] found that DCC compared with immediate cord clamping improved scores in the fine-motor and social domains at 4 years of age, especially in boys who were born at term gestation. Although DCC has been adopted by many centers in Canada and Europe, especially in preterm populations, it has not gained wide acceptance in the United States [39]. Some researchers have noted that DCC may lead to delayed resuscitation and heat loss in infants who have a lower birth weight or a shorter gestational age [34], [40]. However, it is already known that neonates who require resuscitation also need a placental transfusion as much or more so than do healthy newborns [41]. More recently, Mercer and Erickson-Owens [41] suggested that an intrapartum care provider can achieve a placental transfusion for a distressed neonate by UCM several times or can resuscitate the neonate at the perineum with an intact cord. Bringing the resuscitation to the mother's bedside is a novel concept and supports an intact cord. Adopting resuscitation with an intact umbilical cord in a hospital setting will take concentrated effort and teamwork by midwifery, obstetric, pediatric, and nursing staff [41]. They also suggested that UCM can be performed quickly by any intrapartum care provider within the current Neonatal Resuscitation Program guidelines [41]. Furthermore, a recent Cochrane review concluded that larger multi-center studies are essential and demand international collaboration to provide a scientific rationale for improving the delivery and resuscitation of the preterm infant [34]. However, more recently, the 2015 ILCOR systematic review for the neonatal resuscitation program suggested that DCC after 30 s is reasonable for both term and preterm infants who do not require resuscitation at birth. They did not recommend the routine use of UCM for ELBW infants due to concerns regarding the safety of rapid changes in blood volume by UCM for extremely preterm infants [42].

l resuscitation program suggested that DCC after 30 s is reasonable for both term and preterm infants who do not require resuscitation at birth. They did not recommend the routine use of UCM for ELBW infants due to concerns regarding the safety of rapid changes in blood volume by UCM for extremely preterm infants [42]. 3.5 Umbilical cord milking An alternative to DCC is UCM, in which the unclamped umbilical cord is grasped and blood is pushed toward the infant several times before it is clamped to auto-infuse blood into a preterm neonate [43]. Although Beck [44] proposed this procedure for premature babies in 1941, the first randomized controlled trial on UCM in premature babies was published by Hosono et al [40] in 2008. Hosono et al [40] were able to demonstrate reductions in both the need for RBC transfusion during the first 3 weeks of life and the total length of NICU hospitalization with UCM. They reported that the percentage of infants who had no RBC transfusions was significantly higher in the UCM group (65% vs. 30%) [40]. This study showed that UCM is a simple and cost free method that can reduce the number of RBC transfusions in preterm infants born at less than 29 weeks' gestation [40].

ation with UCM. They reported that the percentage of infants who had no RBC transfusions was significantly higher in the UCM group (65% vs. 30%) [40]. This study showed that UCM is a simple and cost free method that can reduce the number of RBC transfusions in preterm infants born at less than 29 weeks' gestation [40]. A second randomized controlled trial to compare UCM with ICC was published by March et al [45] in 2013. They showed that preterm infants whose cords were milked had higher Hb levels at birth and had significantly fewer transfusions in the first 14 days of life. Although the difference in the incidence of the neonatal transfusions did not reach statistical significance in their study, a 14.1% decrease was observed in the UCM group during the first 28 days of life [45]. Katheria et al [46] designed a randomized controlled trial including 60 preterm infants to investigate the effect of UCM on systemic blood flow. They found that preterm infants randomized to UCM had greater measures of superior vena cava flow and right ventricular output in the first 6 and 30 h of life. In addition, neonates receiving UCM also had greater serum Hb levels, received fewer blood transfusions, had fewer days on oxygen therapy, and had less frequent use of oxygen at 36 weeks' corrected postmenstrual age [46]. Our study group [47] previously demonstrated that UCM resulted in higher Hb levels in very low birth-weight preterm infants within the first day of life. However, the number and volume of RBC transfusions was nearly equal between the UCM and ICC groups by the end of 14 and 35 days of life and during the total length of NICU stay in our study, probably due to excessive phlebotomy losses.

her Hb levels in very low birth-weight preterm infants within the first day of life. However, the number and volume of RBC transfusions was nearly equal between the UCM and ICC groups by the end of 14 and 35 days of life and during the total length of NICU stay in our study, probably due to excessive phlebotomy losses. More recently, Kilicdag et al [48] found that the absolute neutrophil counts (ANCs) were lower and the frequency of neutropenia was higher in the UCM group in their RCT. In contrast to former RCTs, they did not find any difference between the UCM and ICC groups in terms of the Hb and Hct levels [48].

her Hb levels in very low birth-weight preterm infants within the first day of life. However, the number and volume of RBC transfusions was nearly equal between the UCM and ICC groups by the end of 14 and 35 days of life and during the total length of NICU stay in our study, probably due to excessive phlebotomy losses. More recently, Kilicdag et al [48] found that the absolute neutrophil counts (ANCs) were lower and the frequency of neutropenia was higher in the UCM group in their RCT. In contrast to former RCTs, they did not find any difference between the UCM and ICC groups in terms of the Hb and Hct levels [48]. In addition to the trials that compared UCM with ICC, there are two RCTs that aim to compare UCM with DCC [43], [49]. Rabe et al [49] designed a RCT including 58 preterm infants who were randomized either to UCM or DCC for 30 s and found that the number of infants who did not need a RBC transfusion was not significantly different between the 2 intervention groups (52% for DCC and 37% for UCM). Katheria et al [43] found that UCM provides higher initial Hb levels, higher blood pressure, and improved systemic blood flow and urine output in preterm infants delivered by caesarean delivery. However, they did not find any difference in these parameters in infants delivered by vaginal delivery and speculated that more blood remained in the placenta when a neonate was delivered by caesarean section because the anaesthetic and surgical interventions interfered with the active contraction of the uterine muscles to expel the placenta [43]. Katheria et al [43] also suggested that UCM might be preferable in preterm infants delivered by caesarean delivery, particularly in newborns when immediate resuscitation is needed.

ecause the anaesthetic and surgical interventions interfered with the active contraction of the uterine muscles to expel the placenta [43]. Katheria et al [43] also suggested that UCM might be preferable in preterm infants delivered by caesarean delivery, particularly in newborns when immediate resuscitation is needed. In total, umbilical cord milking has been studied in 8 RCTs and 4 controlled trials over the past two decades in preterm infants (n = 968) [39], [40], [43], [45], [46], [47], [48], [49], [50], [51], [52], [53]. These trials are summarized in Table 1. The heterogeneity of the methodologies, primary outcomes and UCM techniques of these trials is remarkable. Furthermore, the local guidelines for RBC transfusions were not specified in most of these trials, except for the studies by Hosono et al [40], Rabe et al [49] and Alan et al [47]. Hosono et al [40] and Rabe et al [49] used more restrictive guidelines for RBC transfusion than the guideline Alan et al [47] utilized. In addition, phlebotomy losses were also not specified in most of these trials, except the trials performed by Hosono et al [40], Rabe et al [49] and Alan et al [47] (Table 1).Table 1 A summary of the studies on the effect of umbilical cord milking in preterm infants.

fusion than the guideline Alan et al [47] utilized. In addition, phlebotomy losses were also not specified in most of these trials, except the trials performed by Hosono et al [40], Rabe et al [49] and Alan et al [47] (Table 1).Table 1 A summary of the studies on the effect of umbilical cord milking in preterm infants. Population Randomization Blindness UCM technique Mode of delivery Control condition Phlebotomy Guidelines for RBC transfusion Primary outcomes 1 Katheria et al [39], 2015 154 infants, 23–32 wk Yes Yes 20 cm in 2 s, 4 times CD DCC with 45 s Not reported Not reported Superior vena cava flow and right ventricular output 2 Hosono et al [48], 2015 40 infants, <29 wk No No 20 cm within 2 s, 1 time CD, NSVD UCM with 20 cm within 2 s, 2–3 times The number of RBC transfusions and the probability of not needing a RBC transfusion 3 Kilicdag et al [46], 2015 54 infants, ≤32 wk Yes No 20 cm in 2 s, 4 times CD ICC Not reported Not reported Impact of UCM on Absolute neutrophil counts 4 Patel et al [33], 2014 318 infants, <30 wk No No 20 cm within 2 s, 2–3 times CD, NSVD ICC Not reported Not reported Severe IVH, NEC, death before discharge 5 Katheria et al [40], 2014 60 infants, 23 wk–31 wk 6 d Yes Yes 20 cm in 2 s, 3 times CD, NSVD ICC Not reported Not reported Systemic blood flow (superior vena cava flow) 6 Alan et al [43], 2014 44 infants, ≤32 wk Yes No 25–30 cm, 5 cm in 1 s, 3 times CD, NSVD ICC The median of 38 ml/kg in UCM and 38 ml/kg in ICC groups during the first 35 days of life Yes the number and volume of RBC transfusions 7 Katheria et al [49], 2014 41 infants, 23 wk–31 wk 6 d Yes Yes (Partial) 20 cm in 2 s, 3 times CD, NSVD ICC Not reported Not reported HR, SpO2, MAP, and FiO2 in the delivery room 8 Christensen et al [50], 2014 First: 32 infants, 23–40 wk.

s during the first 35 days of life Yes the number and volume of RBC transfusions 7 Katheria et al [49], 2014 41 infants, 23 wk–31 wk 6 d Yes Yes (Partial) 20 cm in 2 s, 3 times CD, NSVD ICC Not reported Not reported HR, SpO2, MAP, and FiO2 in the delivery room 8 Christensen et al [50], 2014 First: 32 infants, 23–40 wk. Second: 20 infants, <32 wk No No In 10–15 s, 2–4 times CD, NSVD ICC Not reported Not reported Hyperviscosity in preterm infants 9 March et al [42], 2013 75 infants, 24–28 completed wks Yes No 20 cm, 3 times CD, NSVD ICC Not reported Not reported The need for RBC transfusion 10 Takami et al [51], 2012 50 infants, <29 wk No No 20 cm in a s, 2–3 times CD, NSVD ICC Not reported Not reported Cerebral and systemic perfusion 11 Rabe et al [41], 2011 58 infants, 24 wk–32 wk 6 d Yes No 20 cm in 2 s, 4 times CD, NSVD DCC with 30 s The median of 19 ml in UCM group 23 ml in DCC group during the first 42 d of life Yes To compare two strategies for enhancing placental transfusion 12 Hosono et al [38], 2008 40 infants, 24-28 wk Yes No 20 cm in 2 s, 2–3 times CD, NSVD ICC 16 ± 3 ml/kg in the UCM group and 16.7 ± 4.8 ml/kg in the control group during first 4 wk of life Yes The need for RBC transfusion and morbidities Abbreviations: CD: Caesarean delivery, HR: Heart rate, ICC: Immediate cord clamping, NSVD: Normal spontaneous vaginal delivery, RBC: Red blood cell, IVH: Intraventricular haemorrhage, MAP: Mean arterial pressure, UCM: Umbilical cord milking, wk: week.

first 4 wk of life Yes The need for RBC transfusion and morbidities Abbreviations: CD: Caesarean delivery, HR: Heart rate, ICC: Immediate cord clamping, NSVD: Normal spontaneous vaginal delivery, RBC: Red blood cell, IVH: Intraventricular haemorrhage, MAP: Mean arterial pressure, UCM: Umbilical cord milking, wk: week. To our knowledge, there are three meta-analyses concerning UCM in preterm infants. A meta-analysis by Al-Wassia and Shah [33] evaluating the safety and efficacy of UCM at birth concluded that there was a lower risk for an oxygen requirement at 36 weeks and IVH of all grades, but no difference in the risk of mortality. A recent meta-analysis by Dang et al [54] found that UCM at preterm birth was comparatively safe and associated with a lower RBC exposure and lower incidence of IVH, NEC and death. An additional meta-analysis by Backes et al [55] concluded that enhanced placental transfusion (DCC or UCM) at birth provided better neonatal outcomes (reductions in overall mortality, lower risk of IVH, and decreased RBC transfusion incidence) in very preterm neonates. Although the data on neurodevelopmental outcomes in premature infants are limited, some authors strongly suggest that UCM should no longer be considered experimental; rather, it is a proven intervention that ensures that premature newborns receive an adequate placental transfusion at birth [44].

To our knowledge, there are three meta-analyses concerning UCM in preterm infants. A meta-analysis by Al-Wassia and Shah [33] evaluating the safety and efficacy of UCM at birth concluded that there was a lower risk for an oxygen requirement at 36 weeks and IVH of all grades, but no difference in the risk of mortality. A recent meta-analysis by Dang et al [54] found that UCM at preterm birth was comparatively safe and associated with a lower RBC exposure and lower incidence of IVH, NEC and death. An additional meta-analysis by Backes et al [55] concluded that enhanced placental transfusion (DCC or UCM) at birth provided better neonatal outcomes (reductions in overall mortality, lower risk of IVH, and decreased RBC transfusion incidence) in very preterm neonates. Although the data on neurodevelopmental outcomes in premature infants are limited, some authors strongly suggest that UCM should no longer be considered experimental; rather, it is a proven intervention that ensures that premature newborns receive an adequate placental transfusion at birth [44]. 4 Conclusion Due to the increased survival of ELBW infants, AOP has become a common and serious problem for all NICUs. RBC transfusion is the only proven treatment strategy for AOP. However, there are no physiological or laboratory markers for accurate indicators of requiring RBC transfusion other than Hb values. Placental/umbilical cord blood was an untapped resource for premature infants until the last few decades. After the results and recommendations of the trials and meta-analyses failed to demonstrate that neither prevention nor treatment of AOP with r-HuEPO was effective and safe, the issue of enhanced placental transfusion has been raised. The methods for enhancing placental transfusion have many proven beneficial effects in preterm infants. This strategy clearly results in higher Hb levels at birth and a reduced need for RBC transfusions, as well as creating a better haemodynamic status during the initial hours of life. To date, the enhancement of placental transfusion in the delivery room either by DCC or UCM seems to be the best preventive measure for AOP. The effects of placental transfusion probably vary in vaginal deliveries and caesarean sections. Although the safety of rapid changes in blood volume via UCM for preterm infants remains a concern, there are no data for haemodynamic adverse effects up to now. Furthermore, studies assessing neurodevelopmental outcomes are insufficient. However, resuscitation events are not reported consistently, precluding the determination of the optimal cord clamping practice among neonates born severely depressed or requiring immediate resuscitation. Large-scale, randomized clinical trials of enhanced placental transfusion strategies to assess long-term neurodevelopmental and neurologic sequelae are needed.

ed consistently, precluding the determination of the optimal cord clamping practice among neonates born severely depressed or requiring immediate resuscitation. Large-scale, randomized clinical trials of enhanced placental transfusion strategies to assess long-term neurodevelopmental and neurologic sequelae are needed. One should also keep in mind that blood elements other than red blood cells are transfused via DCC or UCM and that the clinical results of the transfusion of these blood elements have not been evaluated. 5 Recommendations • Enhancing placental transfusion by DCC (at least for 30 s) or UCM (2–4 times) during delivery seems to be the best approach for preterm infants who do not require resuscitation. Sufficient data for performing resuscitation with intact cords are still lacking. • Cord blood should be used for initial laboratory tests. • Phlebotomy losses should be reduced. • Nutrition support with vitamins (folate, B12 and vitamin E) and iron should be optimized. • Individual transfusion guidelines should be established and utilized. Conflict of interest The authors declare no conflict of interest. Ethical approval No need to obtain ethical approval for this review Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Foreign body injuries (FBIs) in the auditory canal, nasopharynx, and oropharynx of pediatric patients represent substantial causes of morbidity and mortality in young children. Foreign body exposure is one of the five most common hazardous pediatric exposures, and 4100 deaths were attributed to FBIs in the oropharynx and trachea in 2006 [1], [2]. The current body of literature suggests that FBI is associated with the male gender, a young age, and medical and psychiatric comorbidities [3], [4], [5]. The combined rate of death and anoxic brain injury associated with pediatric foreign bodies is approximately 4% [1], [4]. Furthermore, FBI represents a large financial burden. The annual overall inpatient cost associated with pediatric oropharyngeal FBI is approximately $12.8 million. The current body of evidence suggests that foreign bodies are most commonly found in the auditory canal followed by the nasopharynx and oropharynx, and oropharyngeal injury results in the greatest mortality [1]. The population that is at the greatest risk is young children; studies have reported increased risk among children ranging in age from under 18 months to less than 10 years [3], [4], [5], [6]. Furthermore, male children appear to be at a greater risk of FBI [3]. The most common objects of injury include beads, toys, and seeds [3]. More recent studies have linked FBI vulnerability with different populations. A study by Shlizerman et al identified young male Arab patients as a population in the area that is more vulnerable to FBI [6]. Furthermore, medical comorbidities, such as developmental delays, have long been established as risk factors, and recent literature has identified links between FBI and psychiatric and behavioral conditions such as ADHD (Attention Deficit Hyperactivity Disorder).

pulation in the area that is more vulnerable to FBI [6]. Furthermore, medical comorbidities, such as developmental delays, have long been established as risk factors, and recent literature has identified links between FBI and psychiatric and behavioral conditions such as ADHD (Attention Deficit Hyperactivity Disorder). Although previous studies have identified age, male gender, and medical and psychiatric comorbidities as risk factors for FBI, the roles of other demographic factors, including urban neighborhood, number of children in the household, parental education, and socioeconomic status (SES), are unclear [3], [4], [7], [8], [9], [10], [11], [12], [13]. The primary objective of the present study was to investigate the associations of household demographics, parental education level and socioeconomic status with and foreign body injuries in a pediatric population [14]. We hypothesized that the risk of FBI would increase with increases in the number of children in the household, lower parental educational level and lower socioeconomic status and decrease with the number of adults in the household. The clinical goals of this study were to establish specific and effective protocols of anticipatory guidance for families to prevent injuries such as FBI that are associated with potentially high mortality and morbidity. 2 Patients and methods This study was approved by the St. Christopher's Hospital for Children and the Drexel University College of Medicine institutional review boards.

The clinical goals of this study were to establish specific and effective protocols of anticipatory guidance for families to prevent injuries such as FBI that are associated with potentially high mortality and morbidity. 2 Patients and methods This study was approved by the St. Christopher's Hospital for Children and the Drexel University College of Medicine institutional review boards. 2.1 Participants and data collection The hospital records of 650 patients between the ages of 2 and 10 years who were seen at the St. Christopher's Hospital for Children Emergency Room with FBI beginning in 2010 were obtained through a retrospective electronic medical record review. St. Christopher's Hospital is a level 1 trauma center with approximately 75,000 visits per year. Patients with documented developmental delays were excluded. The remaining 250 patients were contacted by telephone, and demographic parameters, including household members, caregivers, highest level of education in the household, and income, were collected via surveys conducted by research personnel. Two hundred twenty-three of those contacted agreed to participate. Once the data were collected, the study was expanded to include matched controls. Another 250 patients between the ages of 2 and 10 years who were seen at St. Christopher's Emergency Room for reasons other than FBI were identified and contacted for phone survey. Of these patients, 250 agreed to participate, and the same demographic information was collected. Of the 250 controls, the three most common diagnoses were otitis media (n = 66), acute upper respiratory infection (n = 49), and viral infection (n = 39). In total, there were 473 participants aged 2–10 years, and the mean age was 3.4 years.

250 agreed to participate, and the same demographic information was collected. Of the 250 controls, the three most common diagnoses were otitis media (n = 66), acute upper respiratory infection (n = 49), and viral infection (n = 39). In total, there were 473 participants aged 2–10 years, and the mean age was 3.4 years. 2.2 Predictor variables The investigated predictor variables included household members, caregivers, level of education, and household income. The participants were asked to list all of the people living in their household, their relationships, and the total number of children cared for. The participants were asked to specify the primary caregiver, which was defined as the individual who spent the greatest portion of time caring for the child outside of teaching professionals. Education levels were tabulated in the following categories: some high school, high school graduate or equivalent, some college, and college graduate. Yearly income levels were categorized as follows: $0–20,000, $21,000–$40,000, $41,000–60,000, $61,000–90,000, and greater than $90,000. These intervals were modeled after the categorization for state benefits of the Pennsylvania Department of Health and Human Services. Other collected information included the neighborhood of residence, patient age, FBI site, and final diagnosis from the St. Christopher's Emergency Room.

0,000, and greater than $90,000. These intervals were modeled after the categorization for state benefits of the Pennsylvania Department of Health and Human Services. Other collected information included the neighborhood of residence, patient age, FBI site, and final diagnosis from the St. Christopher's Emergency Room. 2.3 Statistical analyses Descriptive analyses were performed on both the outcome and predictor variables to identify differences in FBI based on demographic factors. Statistical significance was defined as P < .05. Initially, univariate analyses in which each possible risk factor was independently evaluated in terms of its relationship with the occurrence of FBI were performed. The statistically significant risk factors identified in the univariate analyses (i.e., father as caregiver, number of children in the household, and income) were evaluated in combination to determine their relationships with FBI in a multivariate analysis. The number of children per household, the father as the caregiver, and income were further analyzed with univariate and multivariate analyses in terms of the relations of these factors with specific FBI (i.e., auditory canal, nasopharynx, and oropharynx injuries).

heir relationships with FBI in a multivariate analysis. The number of children per household, the father as the caregiver, and income were further analyzed with univariate and multivariate analyses in terms of the relations of these factors with specific FBI (i.e., auditory canal, nasopharynx, and oropharynx injuries). 3 Results 3.1 Sample characteristics 3.1.1 Households Of the 233 patients with FBI, 38% had auditory canal injuries (n = 89), 39% had nasopharyngeal injuries (n = 92), and 23% had oropharyngeal injuries (n = 51). All 233 participants lived in urban settings, which was consistent with the control population. Sixteen percent reported that the patient was an only child (n = 37), 36% reported having two children in the household (n = 84), and 48% reported having more than three children (n = 112). Overall, 84% of the participants had more than two children in the household (n = 196). Eighty-six percent reported the mother as the primary caregiver (n = 201), 12% reported the father as the primary caregiver (n = 28), and 2% reported a primary caregiver other than the mother or father, and these findings were consistent with the corresponding findings from the controls.

ren in the household (n = 196). Eighty-six percent reported the mother as the primary caregiver (n = 201), 12% reported the father as the primary caregiver (n = 28), and 2% reported a primary caregiver other than the mother or father, and these findings were consistent with the corresponding findings from the controls. 3.1.2 Income and education Twenty-three percent of the participants reported some high school as the highest level of education (n = 53), 50% reported being high school graduates (n = 116), 8% had some college education (n = 19), and 19% were college graduates (n = 45). Among the families with FBI, 14% reported yearly incomes of $0–20,000 (n = 32), 44% reported $21,000–40,000 (n = 102), 21% reported $41,000–60,000 (n = 49), 4% reported $61,000–90,000 (n = 9), 3% reported incomes greater than $90,000 (n = 7), and 22% did not disclose their incomes (n = 51). The income and education data were consistent between the patient and control populations. Table 1 presents all of the sample characteristics with comparisons with the control data.Table 1 Socioeconomic characteristics of study participants. The children who presented to the ED with foreign body injury (FBI) and those who presented for different medical reasons are compared.

patient and control populations. Table 1 presents all of the sample characteristics with comparisons with the control data.Table 1 Socioeconomic characteristics of study participants. The children who presented to the ED with foreign body injury (FBI) and those who presented for different medical reasons are compared. Variable With FBI (n = 223) Without FBI (n = 250) Children in household Only child 16% 63% 2 children 36% 23% 3 or more 48% 14% >1 84% 36% Highest level of education in household Some high school 23% 10% High school graduate 50% 49% Some college education 8% 24% College graduate 19% 17% Caregiver Mother 86% 87% Father 12% 7% Other 2% 6% Income 0–20,000 14% 18% 21,000–40,000 44% 23% 41,000–60,000 21% 19% 61,000–90,000 4% 10% >90,000 3% 7% Below poverty line (2014) 60% 41% Did not disclose 22% 23% 3.2 Descriptive analyses The univariate and multivariate analyses revealed statistically significant relationships of FBI with the number of children in the household, the number of caregivers, the father as the primary caregiver, and income stratification. With each increment in the number of children, the risk of FBI increased by 1.44-fold (OR = 1.442). With each increase in the number of caregivers, the risk of a FBI decreased 33% (OR = 0.673). Furthermore, the father as the caregiver was associated with a 2-fold increase in the risk of FBI (OR = 2). With each increase in income level, the risk of FBI decreased 59% (OR = 0.413). The other investigated demographic factors were not predictive of FBI.

of caregivers, the risk of a FBI decreased 33% (OR = 0.673). Furthermore, the father as the caregiver was associated with a 2-fold increase in the risk of FBI (OR = 2). With each increase in income level, the risk of FBI decreased 59% (OR = 0.413). The other investigated demographic factors were not predictive of FBI. Further univariate and multivariate analyses of the predictors in terms of the site of FBI demonstrated that the number of children in the household and income level were significantly related to all three of the sites of injury. For each increase in the number of children, the risks of FBI increased by 1.42-fold in the auditory canal (OR = 1.416), 1.35-fold in the nasopharynx and 1.67-fold in the oropharynx. With each increase in income, the risks of FBI decreased by 64% in the auditory canal, 56% in the nasopharynx, and 55% in the oropharynx. The father as the primary caregiver was associated with 3.9- and 2.6-fold increases in the risks of auditory and nasopharyngeal FBIs, respectively, but this factor was not significantly related to oropharyngeal FBI. Table 2 presents the results of the univariate and multivariate analyses of all of the investigated predictors.Table 2 Multivariate analysis of the data with P-values and CIs. The number of caregivers, number of children in the household, income and father as the caregiver factors that significantly influenced presentation with foreign body injury.

f the univariate and multivariate analyses of all of the investigated predictors.Table 2 Multivariate analysis of the data with P-values and CIs. The number of caregivers, number of children in the household, income and father as the caregiver factors that significantly influenced presentation with foreign body injury. Predictor P Value Odds ratio Confidence interval (95%) Number of caregivers .0215 0.673 0.48–0.943 Number of children .0014 1.44 1.152–1.804 Mother as caregiver .1136 1.66 0.886–3.108 Father as caregiver .0139 1.994 1.151–3.456 Education .8821 <0.001 <0.001–>999.999 Income <.001 0.413 0.325–0.525 4 Discussion Our data suggest that FBIs are significantly associated with the number of children in the household, the father as the main caregiver, and lower income.

Predictor P Value Odds ratio Confidence interval (95%) Number of caregivers .0215 0.673 0.48–0.943 Number of children .0014 1.44 1.152–1.804 Mother as caregiver .1136 1.66 0.886–3.108 Father as caregiver .0139 1.994 1.151–3.456 Education .8821 <0.001 <0.001–>999.999 Income <.001 0.413 0.325–0.525 4 Discussion Our data suggest that FBIs are significantly associated with the number of children in the household, the father as the main caregiver, and lower income. As noted, each increase in number of children significantly increased the risk of FBI by 1.44-fold (P < .05). This finding is consistent with our initial hypothesis that the second and third children are at a greater risk of FBI than the first child. This phenomenon could be the result of false parental impressions of adequate supervision of the younger children by the older siblings. Consequently, caregivers may provide less directed supervision for younger children, which increases the risk of FBI. Furthermore, it is possible that older siblings, many of whom may also be young, may increase the risk of FBI in their younger siblings through play. The role of age differences between siblings was not examined in our study and represents a potential research question. Second, our results suggest the father as the primary caregiver doubled the risk of FBI. While this finding may also be related to decreased targeted supervision of the children, this finding may be limited to our population, and further studies are needed.

ned in our study and represents a potential research question. Second, our results suggest the father as the primary caregiver doubled the risk of FBI. While this finding may also be related to decreased targeted supervision of the children, this finding may be limited to our population, and further studies are needed. Finally, we found that each increase in income level decreased the risk of FBI by 59% (OR = 0.41). This finding may highlight the role of monetary resources in eliciting appropriate childcare. Families with lower SESs may not be able to afford childcare in which the caregiver-to-child ratio is high, and thus directed child supervision may be inadequate and result in an increased risk for and incidence of FBI. The remaining investigated predictors, including education level, were not significantly associated with the risk of FBI. The challenges for our study included having the patients agree to the phone survey and communicating with the non-English speaking population. There was also the risk of recall bias because the study was based on phone surveys; however, we attempted to minimize this risk by cross-checking the reported information with the information documented in the patients' charts.

ients agree to the phone survey and communicating with the non-English speaking population. There was also the risk of recall bias because the study was based on phone surveys; however, we attempted to minimize this risk by cross-checking the reported information with the information documented in the patients' charts. Our results have not been replicated in other studies. As cited earlier, the associations between FBI and demographic factors have been limited to age, gender, and medical comorbidity. Thus, our results are the first to suggest that the number of children in the household, the father as a caregiver, and low SES are associated with increases in the risk of FBI. One limitation of this study is the congruent population; i.e., all participants were from an urban neighborhood. Further studies involving multiple neighborhoods and variable education levels would strengthen the identified associations. The relationships of FBI with the number of children per household, the father as the caregiver, and income level highlight the importance of psychosocial context in pediatric injury. Understanding demographic risk factors for FBI can enable appropriate primary injury prevention measures. Our results emphasize the importance of directed supervision and the potential of play-related injuries as avenues for the prevention of FBI. Disclosure No financial assistance was received to support this study. Conflict of interest The authors declare that there are no known conflicts of interest.

The relationships of FBI with the number of children per household, the father as the caregiver, and income level highlight the importance of psychosocial context in pediatric injury. Understanding demographic risk factors for FBI can enable appropriate primary injury prevention measures. Our results emphasize the importance of directed supervision and the potential of play-related injuries as avenues for the prevention of FBI. Disclosure No financial assistance was received to support this study. Conflict of interest The authors declare that there are no known conflicts of interest. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Purpose of the guidelines To standardize a clinical practice for classification and management of BCG related lymphadenitis in children, extrapolated from the relevant literature besides our accumulative experience in this field, through evaluation of benefits and harms of alternative care options. These guidelines intended to provide an outcome with maximum benefits and minimum risks, reduce the inappropriate variation in clinical practice, eliminate the unnecessary interventions, promote efficient use of resources and support the decision making processes for the best interest of children presenting with BCG related lymphadenitis. 2 Introduction BCG vaccine developed by Albert Calmette and Camille Guerin in France between 1908 and 1921 contained a live attenuated Mycobacterium bovis. Currently, there are multiple strains of BCG vaccines in use around the world produced by different manufacturers. BCG is now used worldwide in childhood immunization programs with approximately 100 million newborns being vaccinated each year [1]. In Saudi Arabia, BCG was introduced initially for population at risks in 1964 and later for all newborns in 1970 [2].

2 Introduction BCG vaccine developed by Albert Calmette and Camille Guerin in France between 1908 and 1921 contained a live attenuated Mycobacterium bovis. Currently, there are multiple strains of BCG vaccines in use around the world produced by different manufacturers. BCG is now used worldwide in childhood immunization programs with approximately 100 million newborns being vaccinated each year [1]. In Saudi Arabia, BCG was introduced initially for population at risks in 1964 and later for all newborns in 1970 [2]. Efficacies of BCG vaccines ranges from 0 to 80% in studies of different populations throughout the world [3]. The main role of the BCG vaccines is to protect vaccinees, especially infants and children against disseminated TB and tuberculous meningitis with an estimated efficacy of 78% and 64% respectively [4], [5]. The current estimated incidence of TB in Saudi Arabia is 14/100,000 [6]. Globally the incidence of BCG adverse reaction differs between regions, ranging between 0.5–100 per 1000 vaccinations [7], [8], [9] with the most common presentation is regional lymphadenitis, mainly non-suppuartive lymphadenitis. A rare complication is a disseminated disease, in less than one in a million of vaccinated individuals [7], [10].

f BCG adverse reaction differs between regions, ranging between 0.5–100 per 1000 vaccinations [7], [8], [9] with the most common presentation is regional lymphadenitis, mainly non-suppuartive lymphadenitis. A rare complication is a disseminated disease, in less than one in a million of vaccinated individuals [7], [10]. In Saudi Arabia, a raised incidence in BCG related lymphadenitis from zero to 10.4 per 1000 vaccinations was linked to the introduction of the Danish strain(SSI 1331), currently in use since November 2005 [11], leading to more awareness about this complication [12] and raising the need to establish national guidelines with the best management approach and outcome. 3 Classification of BCG related lymphadenitis The term BCG lymphadenitis applies when lymph node(s) have become large enough to be easily palpable and a cause of concern for the parents [13], [14], likely with a diameter greater than or equal to 1 cm. 3.1 Regional BCG related lymphadenitis The term regional lymphadenitis may apply when there is a BCG vaccine at one arm with ipsilateral regional lymph node(s) involvement. Laboratory and radiological investigations are not routinely recommended in a thriving child with unremarkable physical examination and no evidence of immunodeficiency in the family history. The flowing features are in favor of regional BCG related lymphadenitis rather than other pathology [14], [15], [16]:1) BCG vaccination at the ipsilateral arm. 2) Onset between 2 weeks and 6 months, most patients present within 2–4 months after BCG vaccination. 3) Child age not more than 2 years

in the other). The authors mentioned that these complications were not directly related to the use of factor VII [13]. We recommend that patients with hepatic vein thrombosis who require major surgery should not be administered high doses of recombinant activated factor VII, as this can induce further thrombosis (14). The findings of the present case report show that fever and liver mass in children can be manifestations of a rare disease such as IPT, which should be considered in the differential diagnosis when all investigations are inconclusive. Based on the literature review, surgical excision seems to be the best treatment strategy for this condition. However, the imaging findings, especially the size and location of the mass, must be carefully discussed with the surgical team before the operation. Further studies are required to determine the safest dose of recombinant activated factor FVII in patients with liver disease-related coagulopathy. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

3.1 Regional BCG related lymphadenitis The term regional lymphadenitis may apply when there is a BCG vaccine at one arm with ipsilateral regional lymph node(s) involvement. Laboratory and radiological investigations are not routinely recommended in a thriving child with unremarkable physical examination and no evidence of immunodeficiency in the family history. The flowing features are in favor of regional BCG related lymphadenitis rather than other pathology [14], [15], [16]:1) BCG vaccination at the ipsilateral arm. 2) Onset between 2 weeks and 6 months, most patients present within 2–4 months after BCG vaccination. 3) Child age not more than 2 years 4) Absence of systemic manifestations such as fever and weight loss. 5) Absence of tenderness over the lymph node(s). 6) Axillary lymph node is mostly involved, although supraclavicular or cervical may be involved in isolation or association with axillary lymphadenopathy. 7) Unremarkable physical examination, e.g. no distant lymphadenopathy or organomegaly. 3.1.1 Non suppurative lymphadenitis This form represents the majority of BCG related lymphadenitis. Its typically develops 2 weeks to 6 months post immunization and tends to affect the axillary lymph node(s). Supraclavicular and cervical lymph nodes can be involved, in isolation or in addition to the axillary lymph node(s) [17], [18], usually it regress with time and some may progress to suppuration.

3.1.1 Non suppurative lymphadenitis This form represents the majority of BCG related lymphadenitis. Its typically develops 2 weeks to 6 months post immunization and tends to affect the axillary lymph node(s). Supraclavicular and cervical lymph nodes can be involved, in isolation or in addition to the axillary lymph node(s) [17], [18], usually it regress with time and some may progress to suppuration. 3.1.2 Suppurative lymphadenitis The suppurative form is marked by the progressive enlargement of regional lymph node(s) with collection of suppurative material and fluctuation associated with erythema and edema. If untreated, suppurative lymphadenitis frequently ruptures with sinus formation, resulting in prolonged course of illness and scaring sequels [14], [15]. 3.2 Disseminated BCG infectio The term disseminated BCG infection considered when there is involvement of distant anatomical site(s) beyond BCG administration site and ipsilateral lymph node(s) [19]. Synonyms of disseminated BCG infection are disseminated/systemic BCG disease or BCGosis.

3.1.2 Suppurative lymphadenitis The suppurative form is marked by the progressive enlargement of regional lymph node(s) with collection of suppurative material and fluctuation associated with erythema and edema. If untreated, suppurative lymphadenitis frequently ruptures with sinus formation, resulting in prolonged course of illness and scaring sequels [14], [15]. 3.2 Disseminated BCG infectio The term disseminated BCG infection considered when there is involvement of distant anatomical site(s) beyond BCG administration site and ipsilateral lymph node(s) [19]. Synonyms of disseminated BCG infection are disseminated/systemic BCG disease or BCGosis. Disseminated BCG infection is the most serious complication of BCG vaccination. Fatal infection has occurred at a rate of 0.06–1.56 cases per million doses [12]; these deaths occurred primarily among immunocompromised persons. Immune response to Mycobacterial infection starts with macrophages through phagocytosis and followed by cell mediated immunity. A granuloma formation is associated with production of chemokines and cytokines. Both tumor necrosis factor (TNF) and interferon gamma (IFN-γ) are the cornerstone cytokines involved in activation of macrophage host defense mechanisms [1].

rts with macrophages through phagocytosis and followed by cell mediated immunity. A granuloma formation is associated with production of chemokines and cytokines. Both tumor necrosis factor (TNF) and interferon gamma (IFN-γ) are the cornerstone cytokines involved in activation of macrophage host defense mechanisms [1]. The disseminated BCG infection has been reported in immunocompromised children with primary immunodeficiency (PID), including severe combined immunodeficiency (SCID) [12], [20], complete Di George syndrome (cDGS), chronic granulomatous diseases (CGD), the Mendelian susceptibility to mycobacterial disease (MSMD) (e.g. IFN-γ receptor 1/2 deficiencies, IL-12/23 receptor β1 chain deficiency, IL-12p40 deficiency, S TAT1 deficiency and NEMO deficiency and acquired immune deficiency syndrome (AIDS) [12], [21]. 3.2.1 Clinical presentation of disseminated BCG infection The following findings may indicate disseminated BCG infection:1) Systemic manifestations: fever, anemia, loss or poor weight gain. 2) Distant lymph node(s) enlargement, beyond the ipsilateral lymph node(s) such as right axillary or inguinal. 3) Cutaneous lesions or abscesses beyond the region of vaccination [22]. 4) Hepatosplenomegaly. 5) Bone tenderness or swelling reflecting underlying osteomyelitis [23], [24]. 6) Signs of meningeal involvement, such as seizures [20].

2) Distant lymph node(s) enlargement, beyond the ipsilateral lymph node(s) such as right axillary or inguinal. 3) Cutaneous lesions or abscesses beyond the region of vaccination [22]. 4) Hepatosplenomegaly. 5) Bone tenderness or swelling reflecting underlying osteomyelitis [23], [24]. 6) Signs of meningeal involvement, such as seizures [20]. 3.2.2 Investigations for disseminated BCG infection The investigations should be obtained with guidance of pediatric immunology and infectious diseases specialists. These may include identification of the M. bovis from the patient's organs by culture and/or standard PCR, as well as typical histopathological changes with granulomatous inflammation, in addition to identifying the specific underlying immunodeficiency status. Radiological investigations such as bone scan and abdominal Computed Tomography (CT) scan may be beneficial in evaluating the site(s) and extent of dissemination. 4 Factors associated with increased BCG lymphadenitis incidence 4.1 Vaccine related factors 1) Residual virulence of the BCG strain: BCG strains from different pharmaceutical manufacturers are known to have different reactogenicity profile [12], [14], [25], [26]. 2) Viability of final vaccine product: This is related to the quality of the administered vaccine and is affected by storage conditions such as the cold chain [14], [25]. Live particles concentration in the vaccines ranges from 50,000 to 3 million per dose, according to the BCG strain [1].

4 Factors associated with increased BCG lymphadenitis incidence 4.1 Vaccine related factors 1) Residual virulence of the BCG strain: BCG strains from different pharmaceutical manufacturers are known to have different reactogenicity profile [12], [14], [25], [26]. 2) Viability of final vaccine product: This is related to the quality of the administered vaccine and is affected by storage conditions such as the cold chain [14], [25]. Live particles concentration in the vaccines ranges from 50,000 to 3 million per dose, according to the BCG strain [1]. 4.2 Administration related factors 1) Subcutaneous injection: Subcutaneous administration has been associated with a higher frequency of BCG vaccine complications in comparison with correctly administered intradermal injection [14], [25]. 2) Dose of BCG injection: The higher the dose of BCG injection the more risk of developing vaccine adverse effects including lymphadenitis [14], [25], [27]. 4.3 Host related factors 1) Age: neonates have a higher risk of regional lymphadenitis [14], [25], [26]. 2) Immune status: Immunocompromised patients such as those suffering from SCID or IFN-γ/IL-12 pathway defects, have increased rates of local complications as well as disseminated BCG infection [12], [14], [21], [28]. 5 Management of BCG related lymphadenitis 5.1 Management of BCG related lymphadenitis algorithm i failed initial aspiration, failed repeated aspiration or re-accumulation after ≥2 aspirations ii persistent ≥ 6–9 months, with size ≥3 cm

2) Immune status: Immunocompromised patients such as those suffering from SCID or IFN-γ/IL-12 pathway defects, have increased rates of local complications as well as disseminated BCG infection [12], [14], [21], [28]. 5 Management of BCG related lymphadenitis 5.1 Management of BCG related lymphadenitis algorithm i failed initial aspiration, failed repeated aspiration or re-accumulation after ≥2 aspirations ii persistent ≥ 6–9 months, with size ≥3 cm 5.2 Management of non-suppurative lymphadenitis The non suppurative form is a relatively benign clinical course where most of the nodes resolve spontaneously within 4–6months. Antimycobacterial therapy generally have no effect on the course [29], rather reassurance and regular follow up are needed. The following are recommended clues for the initial assessment and subsequent evaluation with follow up visits:1. Detailed clinical history to rule out immunodeficiency. 2. Growth and development assessment. 3. Size and consistency of the lymph node(s). 4. Symptoms or signs of dissemination (e.g. distant lymphadenopathy, hepatosplenomegaly, skin lesions etc.) 5. Address family concerns and emphasize on importance to proceed with vaccination schedule (unless specific contraindications). If the node(s) show no signs of regression and remained persistently enlarged for more than 6–9 months with a size of 3 cm or more, it is unlikely to regress spontaneously [18], [28], [30], [31], therefore surgical excision may be considered [16], [29], [31].

5. Address family concerns and emphasize on importance to proceed with vaccination schedule (unless specific contraindications). If the node(s) show no signs of regression and remained persistently enlarged for more than 6–9 months with a size of 3 cm or more, it is unlikely to regress spontaneously [18], [28], [30], [31], therefore surgical excision may be considered [16], [29], [31]. 5.3 Management of suppurative lymphadenitis 5.3.1 Role of antimicrobial therapy Antimycobacterial drugs cannot prevent suppuration nor shorten the duration of healing, therefore are not recommended [16], [20], [29], [32]. Antibiotic therapy is indicated for treatment of pyogenic lymphadenitis, as a result of secondary infection with pyogenic bacteria such as Streptococcus pyogenes or Staphylococcus aureus. 5.3.2 Needle aspiration When suppurative BCG lymphadenitis left untreated, it will progress to spontaneous rupture/drainage and sinus formation. This leads to slow healing over several months and probable keloid formation. Moreover, it is associated with an unpleasant cosmetic outcome. In contrast, needle aspiration can shorten the duration of healing, and lessens the complications [8], [14], [16], [29], [30], [33], [34], [35], [36]. Sometimes repeated aspirations are required for optimal management. For ease of evacuation of thick inflammatory materials, a wider bore needles are preferred [35].

5.3.2 Needle aspiration When suppurative BCG lymphadenitis left untreated, it will progress to spontaneous rupture/drainage and sinus formation. This leads to slow healing over several months and probable keloid formation. Moreover, it is associated with an unpleasant cosmetic outcome. In contrast, needle aspiration can shorten the duration of healing, and lessens the complications [8], [14], [16], [29], [30], [33], [34], [35], [36]. Sometimes repeated aspirations are required for optimal management. For ease of evacuation of thick inflammatory materials, a wider bore needles are preferred [35]. Needle aspiration is considered to be a safer option when compared with surgical excision, which likely will require general anesthesia in young infants. Incision and drainage should be avoided due to the risk of persistent draining wound, delayed wound healing and unpleasant cosmetic outcome with scar formation [14], [35], [36]. Generally it's not recommended to send the aspirated fluid for bacterial or mycobacterial examination unless expecting a pyogenic infection or suspecting an associated disseminated disease to help in antimicrobial selection. 5.3.3 Surgical excision Surgical excision should be considered for children who failed needle aspiration or failed to respond to repeated needle aspirations more than twice, after balancing the risks of general anesthesia and potential surgical complications [14], [16], [33], [36].

Generally it's not recommended to send the aspirated fluid for bacterial or mycobacterial examination unless expecting a pyogenic infection or suspecting an associated disseminated disease to help in antimicrobial selection. 5.3.3 Surgical excision Surgical excision should be considered for children who failed needle aspiration or failed to respond to repeated needle aspirations more than twice, after balancing the risks of general anesthesia and potential surgical complications [14], [16], [33], [36]. 5.4 Management of disseminated BCG infection 5.4.1 Immunology workup to rule out immunodeficiency and optimizing treatment Health care provider should suspect immunodeficiency in all cases with disseminated disease, therefore pediatric immunology service should be consulted to rule out any underlying immunodeficiency disease (e.g. SCID, CGD and IFN-γ/IL-12 pathway defects) and to help in optimizing treatment of the underlying immunodeficiency status e.g. Hematopoietic stem cell transplantation (HSCT) in patients with SCID [28], [37], [38]. 5.4.2 Antimycobacterial treatment Antimycobacterial therapy should be started in consultation with pediatric infectious diseases specialists. Which agents, number and duration of antimycoabcetrial drugs depends on the microbiological susceptibility testing, underlying immunodeficiency, degree of dissemination and clinical response. Generally a minimum of four medications are required, with duration of therapy vary from months to years depending on the response and underlying immune defects.

of antimycoabcetrial drugs depends on the microbiological susceptibility testing, underlying immunodeficiency, degree of dissemination and clinical response. Generally a minimum of four medications are required, with duration of therapy vary from months to years depending on the response and underlying immune defects. M. bovis are intrinsically resistant to pyrazinamide. BCG strains have different susceptibility patterns [39], an example is the Danish strain (SSI 1331), currently used in Saudi Arabia, have low-level resistance to isoniazid that may not be of clinical significance [39], [40] on the other hand it is resistant to ethionamide [39]. These differences should be taken into consideration when selecting empirical therapy 6 Conclusions 1) Non suppuartive lymphadenitis is a clinical diagnosis that requires close observation and follow-up. Antimycobactrial therapy are not recommended while surgical excision may be considered if the node remained persistently enlarged more than 6–9 months with a size of 3 cm or more. 2) Suppurative lymphadenitis is a clinical diagnosis that requires needle aspiration while incision and drainage is not recommended. Surgical excision is considered upon failed aspiration(s). Sending aspirated fluid for microbiological examination is generally not indicated unless expecting a disseminated or pyogenic infection. 3) Disseminated BCG infection requires consultation with pediatric immunology and infectious diseases specialists for the optimum management.

2) Suppurative lymphadenitis is a clinical diagnosis that requires needle aspiration while incision and drainage is not recommended. Surgical excision is considered upon failed aspiration(s). Sending aspirated fluid for microbiological examination is generally not indicated unless expecting a disseminated or pyogenic infection. 3) Disseminated BCG infection requires consultation with pediatric immunology and infectious diseases specialists for the optimum management. 4) Based on available data on the BCG vaccine with a low efficacy, serious complications and the high incidence of primary immunodeficiency disorders among Saudi children, it is wise to consider delay the timing of BCG vaccination in our community. Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

1 Introduction Inflammatory pseudo tumor (IPT) is a rare benign lesion that can occur in any organ in the body [1]. IPT is histologically characterized by the presence of inflammatory cells, especially, plasma cells, spindle-shaped cells, and myofibroblasts. The exact etiology is unknown, but in some cases, IPT has arisen after trauma, infection, immune-autoimmune condition, low grade fibro sarcoma with inflammatory surgery or the removal of a malignancy, e.g., Wilms tumor [2], [3]. Although IPT is a rare benign tumor, cases of IPT recurrence and metastasis have been reported. In addition, this tumor can cause symptoms such as biliary obstruction, portal hypertension, vascular thrombosis, cirrhosis, and hepatic failure. IPT most commonly involving the lung and orbit, but it can affect any organ, including the liver, spleen and lymph nodes. The diagnosis is difficult owing to the non-specific clinical, laboratory and imaging features [4]. Many cases of IPTs affecting multiple organs in both adults and children have been documented in the literature. Fifty-five cases of hepatic IPTs have been reported in children [4], [5], and all of them were managed by surgical resection. Limited data are available on IPTs in Arabs. In Saudi Arabia, a few cases have been reported of IPTs in adults, involving the orbit and lungs, and occurring following hip replacement surgery with metal-on-metal implants [6], [7]. To our knowledge, no cases of hepatic IPTs in Saudi children have been documented.

ection. Limited data are available on IPTs in Arabs. In Saudi Arabia, a few cases have been reported of IPTs in adults, involving the orbit and lungs, and occurring following hip replacement surgery with metal-on-metal implants [6], [7]. To our knowledge, no cases of hepatic IPTs in Saudi children have been documented. Our aim was to report the case of an 8-year-old Saudi boy who was referred to our hospital with fever of unknown origin since 3 months with associated weight loss and a hepatic mass. He was found to have an IPT of the liver which was found after surgical resection.

ection. Limited data are available on IPTs in Arabs. In Saudi Arabia, a few cases have been reported of IPTs in adults, involving the orbit and lungs, and occurring following hip replacement surgery with metal-on-metal implants [6], [7]. To our knowledge, no cases of hepatic IPTs in Saudi children have been documented. Our aim was to report the case of an 8-year-old Saudi boy who was referred to our hospital with fever of unknown origin since 3 months with associated weight loss and a hepatic mass. He was found to have an IPT of the liver which was found after surgical resection. 2 History and physical examination An 8-year-old Saudi boy who was previously healthy presented to a local Saudi hospital in June 2014 with right hip joint pain and difficulty in walking. Hip joint aspiration was performed, and the results were inconclusive. He was treated for septic arthritis with a full course of intravenous antibiotics. His condition improved with this treatment, and he was then sent home. A few days after discharge, he started to have daily spikes of fever, which reached 39 °C and only partially responded to antipyretics. He had no other clinical symptoms at this time. He was again admitted to a local hospital for 6 weeks. A physical examination revealed a palpable, tender liver, 4–5 cm below the costal margin, with no other abnormal findings. During his hospital stay, several laboratory investigations were performed to rule out infectious and inflammatory conditions, but all of them yielded inconclusive results. He was empirically treated with antibiotics, without any change in the fever spikes. Radiological studies, including chest x-ray, were normal. An ultrasound examination revealed a non-homogenous liver mass measuring 4 × 4 cm, which was possibly a solid or vascular tumor. The child was then referred to King Faisal Specialist Hospital and Research Centre, Riyadh for further evaluation and management.

es. Radiological studies, including chest x-ray, were normal. An ultrasound examination revealed a non-homogenous liver mass measuring 4 × 4 cm, which was possibly a solid or vascular tumor. The child was then referred to King Faisal Specialist Hospital and Research Centre, Riyadh for further evaluation and management. Upon admission, he continued to be febrile (range, 38°C–39 °C) with no specific pattern of fever. His appetite was poor, and he was losing weight. A clinical examination showed that the child was pale and had tenderness in the upper right quadrant of the abdomen. No other abnormal findings were detected.

es. Radiological studies, including chest x-ray, were normal. An ultrasound examination revealed a non-homogenous liver mass measuring 4 × 4 cm, which was possibly a solid or vascular tumor. The child was then referred to King Faisal Specialist Hospital and Research Centre, Riyadh for further evaluation and management. Upon admission, he continued to be febrile (range, 38°C–39 °C) with no specific pattern of fever. His appetite was poor, and he was losing weight. A clinical examination showed that the child was pale and had tenderness in the upper right quadrant of the abdomen. No other abnormal findings were detected. 3 Laboratory investigations Laboratory investigations showed leukocytosis with microcytic hypochromic anemia. Raised levels of inflammatory markers (C-reactive protein, 170–240 mg/l; erythrocyte sedimentation rate, 106–140 mm/h). Liver enzymes and bilirubin levels were mildly elevated (alanine transaminase, 40–58 U/l; alkaline phosphatase, 129–250 U/l; aspartate transaminase, 50–144 U/l; gamma-glutamyl transpeptidase, 50–70 U/l; total bilirubin, 45–70 μmol/l; and direct bilirubin, 15 μmol/l). Coagulation profiles showed persistently high international normalized ratio (1.3–1.9 HI), prothrombin time (PT; 18–21 s), partial thromboplastin time (PTT; 40–58 s), factor VIII (>2 IU/ml), factor IX (1.17 IU/ml) and D-dimer levels (110–165 μg/l), and coagulation level was not corrected after mixing study (PT, 16 s; PTT, 50 s). Tests for infections also yielded negative results; the work-up for infections included blood culture, fungi tell (fungitell), fungal cultures, tests for ova and parasites, tuberculosis skin test, quantiFERON TB test. Serologic tests for hepatitis A, B and C, schist soma (Shistosoma) antibody titers, malarial serology, Q fever serology, Echinococcus antibody titers, Brucella antibody titers, Epstein–Barr virus serology, cytomegalovirus antibodies, human immunodeficiency virus antibodies and amoeba antibodies. Immunological work-up, to rule out chronic granulomatous disease, hyper IgE and lymphocyte adhesion defect and hemophagocytic syndrome, was negative. Inflammatory disease work-up included tests for antinuclear, anti-cardiolipin and anti-phospholipid antibodies, all of which were negative. Tumor markers, including alpha-fetoprotein, CA 19-9, CA 15-3, CA 12-5, carcinoembryonic antigen and procalcitonin, were tested for to rule out malignancy; all of these tests produced normal results.

se work-up included tests for antinuclear, anti-cardiolipin and anti-phospholipid antibodies, all of which were negative. Tumor markers, including alpha-fetoprotein, CA 19-9, CA 15-3, CA 12-5, carcinoembryonic antigen and procalcitonin, were tested for to rule out malignancy; all of these tests produced normal results. 4 Radiological investigations Radiological investigation was repeated to assess the tumor size and confirm the primary findings. Ultrasonography of the abdomen showed a well-defined, heterogenic mass, measuring 4 × 6 cm, in the right upper quadrant with complete thrombosis of the right hepatic vein (Fig. 1). The initial impression was a vascular tumor or malignancy. For this reason, magnetic resonance imaging was performed, and it showed a heterogeneous solitary lesion in the right hepatic lobe with nonspecific radiological appearance (Fig. 2).Figure 1 Ultrasound examination of the upper abdomen showing a heterogeneous mass, measuring 4 × 6 cm, in the right hepatic lobe. Figure 2 T2-weighted MRI of the abdomen showing a solitary, moderate-sized, complex mass occupying the right lobe of the liver. The differential diagnosis included liver malignancy with extension to the right hepatic vein.

4 Radiological investigations Radiological investigation was repeated to assess the tumor size and confirm the primary findings. Ultrasonography of the abdomen showed a well-defined, heterogenic mass, measuring 4 × 6 cm, in the right upper quadrant with complete thrombosis of the right hepatic vein (Fig. 1). The initial impression was a vascular tumor or malignancy. For this reason, magnetic resonance imaging was performed, and it showed a heterogeneous solitary lesion in the right hepatic lobe with nonspecific radiological appearance (Fig. 2).Figure 1 Ultrasound examination of the upper abdomen showing a heterogeneous mass, measuring 4 × 6 cm, in the right hepatic lobe. Figure 2 T2-weighted MRI of the abdomen showing a solitary, moderate-sized, complex mass occupying the right lobe of the liver. The differential diagnosis included liver malignancy with extension to the right hepatic vein. Our patient underwent multiple ultrasound-guided core and fine needle liver biopsies. The liver mass located in the right lobe was aspirated using a 25-gauge needle and stained with Diff-Quik stain. The aspirate showed a small amount of cellular yield with benign liver cells mixed with benign-looking histiocytes (Fig. 3A and B). The recommendation was to perform a Tru-Cut needle biopsy for the appropriate staining and immunohistochemical studies. The Tru-Cut needle biopsy was obtained under imaging guidance and tissues were sent for appropriate staining and immunohistochemical studies; the results showed a mixture of chronic inflammatory cells and sheets of histiocytes with abundant cytoplasm. Acid-fast bacilli and fungal infection were excluded by special stains. The biopsy showed no obvious pathological or immunohistochemical features of inflammatory myofibroblastic tumor (negative smooth muscle actin and activin receptor-like kinase 1). The other differential diagnosis was dendritic sarcoma, but the biopsy specimen was negative for both CD21 and CD23. Inflammatory bowel disease was also raised as a possible diagnosis, and so, an endoscopic intestinal biopsy was performed, but the findings were negative.Figure 3 A and B. Smears containing a mixture of benign hepatocytes and histiocytes (Diff-Quik stain, ×40).

t the biopsy specimen was negative for both CD21 and CD23. Inflammatory bowel disease was also raised as a possible diagnosis, and so, an endoscopic intestinal biopsy was performed, but the findings were negative.Figure 3 A and B. Smears containing a mixture of benign hepatocytes and histiocytes (Diff-Quik stain, ×40). After a multidisciplinary team meeting and discussion with a liver pathologist, the decision was made to perform an excisional biopsy to obtain a better tissue sample for diagnosis. Because of the size and location of the mass, the excisional biopsy was performed by a liver transplant surgeon in August 2014. Under general anesthesia, an L-shaped incision was made in the right subcostal region with an upper midline extension, and a Hampson–Farley self-retaining abdominal retractor was used to enter the abdomen via this incision. Then, exploration of the abdomen was performed, and no tumor extension or metastasis was found in the omentum or peritoneum. The lesion was confined to the right lobe of the liver, as previously seen on the imaging studies, and had a diameter of approximately 5 cm. Therefore, transection of the hepatic parenchyma of the right lobe of the liver, followed by removal of the right hepatic lobe was performed. After the removal of the mass, fever subsided, and antibiotic therapy was stopped after completing the postoperative course. The postoperative laboratory investigation, including complete blood count, tests for inflammatory markers and coagulation profile, showed normal findings. The patient was then sent home, and regularly followed up by the hepatology and liver transplant teams.

erapy was stopped after completing the postoperative course. The postoperative laboratory investigation, including complete blood count, tests for inflammatory markers and coagulation profile, showed normal findings. The patient was then sent home, and regularly followed up by the hepatology and liver transplant teams. 5 Pathological findings The resected right lobe of the liver showed two lesions separated by 1.5 cm. The largest mass measured 8 × 6 × 5 cm, and had a white fleshy cut surface. The mass was surrounded by a well-demarcated thin capsule (Figure 4, Figure 5). Microscopic examination showed similar morphology to that of the needle biopsy specimen, with a mixture of inflammatory cells and sheets of histiocytic. The inflammatory cells mainly consisted of plasma cells and mature lymphocytes, and were largely concentrated in the sub capsular area and around the blood vessels (Figs. 6 and 7A, B). No granuloma or necrosis was seen. All special stains and immunohistochemical studies were repeated on the resected nodule, with mostly negative results. The histiocytic were positive for the histiocytic marker CD68 (Fig. 7A and B). The plasma cell infiltrate was stained for IgG4, but the number of positively stained cells was insufficient for a diagnosis of IgG4-related disease (Fig. 8).Figure 4 Cross-section of the mass is well demarcated and has a white–yellow, fleshy cut surface. Figure 5 The mass is separated from the surrounding tissue by a thick fibrous capsule.

5 Pathological findings The resected right lobe of the liver showed two lesions separated by 1.5 cm. The largest mass measured 8 × 6 × 5 cm, and had a white fleshy cut surface. The mass was surrounded by a well-demarcated thin capsule (Figure 4, Figure 5). Microscopic examination showed similar morphology to that of the needle biopsy specimen, with a mixture of inflammatory cells and sheets of histiocytic. The inflammatory cells mainly consisted of plasma cells and mature lymphocytes, and were largely concentrated in the sub capsular area and around the blood vessels (Figs. 6 and 7A, B). No granuloma or necrosis was seen. All special stains and immunohistochemical studies were repeated on the resected nodule, with mostly negative results. The histiocytic were positive for the histiocytic marker CD68 (Fig. 7A and B). The plasma cell infiltrate was stained for IgG4, but the number of positively stained cells was insufficient for a diagnosis of IgG4-related disease (Fig. 8).Figure 4 Cross-section of the mass is well demarcated and has a white–yellow, fleshy cut surface. Figure 5 The mass is separated from the surrounding tissue by a thick fibrous capsule. Figure 6 A and B. Lymphoplasmocytic cell infiltration is concentrated in the subcapscular area and around the blood vessels (hematoxylin and eosin, ×40). Figure 7 A and B. All the histiocytes in the tissue specimen are positive for CD68 (hematoxylin and eosin, CD68; ×40). Figure 8 A few plasma cells are positive for IgG4 (IgG4, ×40).

Figure 6 A and B. Lymphoplasmocytic cell infiltration is concentrated in the subcapscular area and around the blood vessels (hematoxylin and eosin, ×40). Figure 7 A and B. All the histiocytes in the tissue specimen are positive for CD68 (hematoxylin and eosin, CD68; ×40). Figure 8 A few plasma cells are positive for IgG4 (IgG4, ×40). 6 Discussion A review of the literature revealed a few reports of IPTs in patients belonging to different age groups. In most of the reported cases, surgical resection was required to treat the symptoms [1]. The recurrence rates of IPT are 3%–10% in adults and 14% in children [8]. The risk factors for IPT recurrence are irregularity of tumor margins, failure to resect the whole tumor and extension beyond the involved organ or the involvement of many organs [8]. Hepatic tumors are rare, affecting men more than women. They mostly present with fever and abdominal pain. In literature, review most of the cases are treated by resection [9]. In our patient, fever was completely resolved following tumor resection. The inflammatory marker levels returned to normal in a couple of months, and the patient was followed up by the liver transplant and hepatology teams.

6 Discussion A review of the literature revealed a few reports of IPTs in patients belonging to different age groups. In most of the reported cases, surgical resection was required to treat the symptoms [1]. The recurrence rates of IPT are 3%–10% in adults and 14% in children [8]. The risk factors for IPT recurrence are irregularity of tumor margins, failure to resect the whole tumor and extension beyond the involved organ or the involvement of many organs [8]. Hepatic tumors are rare, affecting men more than women. They mostly present with fever and abdominal pain. In literature, review most of the cases are treated by resection [9]. In our patient, fever was completely resolved following tumor resection. The inflammatory marker levels returned to normal in a couple of months, and the patient was followed up by the liver transplant and hepatology teams. Before the right hepatic lobectomy, the hepatology team recommended a liver biopsy of the normal liver tissue to rule out any systemic illness that could have caused recurrence. This precaution was very important in our patient, given the large size of the tissue to be removed. The patient may require a liver transplant in the future, if systemic disease had been present. The tumor was large, measuring around 5 × 5 cm, occupying most of the right hepatic lobe and causing vascular compression. This is why the best treatment option was resection.

iven the large size of the tissue to be removed. The patient may require a liver transplant in the future, if systemic disease had been present. The tumor was large, measuring around 5 × 5 cm, occupying most of the right hepatic lobe and causing vascular compression. This is why the best treatment option was resection. Our patient had a prolonged PT (range and unit) and elevated factor VIII level (range and unit), which were most likely a result of liver dysfunction. Liver biopsy is an invasive procedure that can be complicated with life-threatening bleeding [10], which was a distinct possibility in our patient. Therefore, we administered fresh frozen plasma and factor VII prior to the biopsy and total excision of the mass.

it), which were most likely a result of liver dysfunction. Liver biopsy is an invasive procedure that can be complicated with life-threatening bleeding [10], which was a distinct possibility in our patient. Therefore, we administered fresh frozen plasma and factor VII prior to the biopsy and total excision of the mass. Factor VII can be used as an exogenous source to augment the coagulation cascade [11]. There are limited data on the use of factor VII in liver disease-related coagulation dysfunction, and many doses have been reported in the literature. In one study, four different doses (5, 20, 80, and 120 μg/kg) were used in patients with liver cirrhosis prior to laparoscopic liver biopsy, and transient normalization of PT was achieved in all four groups [12]. There was no difference in the amount of hepatic bleeding after the procedure in the four groups, and only two patients developed complications (disseminated intravascular coagulation in one patient and portal vein thrombosis in the other). The authors mentioned that these complications were not directly related to the use of factor VII [13]. We recommend that patients with hepatic vein thrombosis who require major surgery should not be administered high doses of recombinant activated factor VII, as this can induce further thrombosis (14).

1 Introduction Aneurysm of the right atrial appendage is a rare cardiac anomaly that most commonly diagnosed during adulthood. It is much rarer in the pediatric population, with less than 10 reported cases in the literature [1]. It can be identified during prenatal period or incidentally thereafter during routine neonatal clinical examinations and can be associated with other complex cardiac anomalies [2], [3], [4]. It is important to distinguish this diagnosis from Ebstein's anomaly, which is a more common cause of right atrial enlargement in this age group [5], [6], [7]. 2 Case report A 1-day-old female infant was admitted to the pediatric ward as a case of neonatal jaundice to receive phototherapy treatment. The baby was born by normal spontaneous vaginal delivery at term, with a birth weight of 3.74 kg (just above the 50th percentile). There were no natal complications. On physical examination, the patient was jaundiced but otherwise in good general health. Cardiac auscultation revealed a systolic murmur. The chest x-ray showed an enlarged cardiac shadow with a prominent right atrial contour (Fig. 1).Figure 1 Chest X-ray, anteroposterior projection showing cardiomegaly with enlarged right atrial contour. Figure 1