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Thrombotic microangiopathies (TMAs) are a diverse group of disorders presenting with non–immune-mediated hemolytic anemia and thrombocytopenia.1 Treatment of the underlying cause in such cases is crucial for controlling the TMA. However, once all other causes are excluded, physicians face the diagnostic challenge of determining which one of the life-threating TMAs it is: hereditary or autoimmune thrombotic thrombocytopenic purpura (iTTP), Escherichia coli–induced hemolytic uremic syndrome (HUS), or atypical HUS (aHUS). Classic HUS is caused by Shiga toxin–producing organisms; aHUS is associated with complement dysregulation due to mutations in CD46, complement factor (CF) I, CFB, complement component 3, CFH-related (CFHR) 5, CFH, and thrombomodulin or secondary to CFH autoantibodies.2 On the other hand, TTP is characterized by congenital or autoimmune-related deficiency of the von Willebrand factor cleaving protein ADAMTS13 (disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13).3 The case series reported herein illustrates an unusual clinical entity in 3 patients with an acute TMA syndrome with clinical and laboratory features of refractory iTTP associated with genetic mutations typically seen in aHUS as well. All the genetic mutation tests were performed by Machaon Diagnostics.

Classic HUS is caused by Shiga toxin–producing organisms; aHUS is associated with complement dysregulation due to mutations in CD46, complement factor (CF) I, CFB, complement component 3, CFH-related (CFHR) 5, CFH, and thrombomodulin or secondary to CFH autoantibodies.2 On the other hand, TTP is characterized by congenital or autoimmune-related deficiency of the von Willebrand factor cleaving protein ADAMTS13 (disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13).3 The case series reported herein illustrates an unusual clinical entity in 3 patients with an acute TMA syndrome with clinical and laboratory features of refractory iTTP associated with genetic mutations typically seen in aHUS as well. All the genetic mutation tests were performed by Machaon Diagnostics. Case Reports Patient 1 A 24-year-old African American man with Klinefelter syndrome had recently started working at a new job in a poultry processing facility, where he was in direct contact with meat. He initially presented with bloody diarrhea, diffuse abdominal pain, and acute renal failure, with a creatinine level up to 7 mg/dL (to convert to μmol/L, multiply by 88.4). An E coli infection was ruled out. ADAMTS13 activity was less than 5%, with inhibitor titers of 5 Bethesda units (BU). Treatment of TTP is outlined in Figure 1. Initially, the patient had a good response to treatment, and his creatinine level improved, down to 3 mg/dL, for a few weeks only and thereafter started to climb again to the point where hemodialysis was required. As a result of the severe renal injury and lack of lasting response to therapeutic plasma exchange (TPE), corticosteroids, rituximab, cyclophosphamide, and vincristine, aHUS genetic mutation testing was performed. He was found to have a large homozygous deletion in CFHR1 and CFHR3 genes. Skin biopsy performed at this time showed focal C5b-9 deposition within vessels, including the superficial vascular plexus (Figure 2). Antibodies against CFH were detectable. Therefore, eculizumab treatment was added to TPE (Figure 1). We noted the inadequate response to eculizumab, without clearance of ADAMTS13 inhibitor, and so eculizumab administration was with held until serial testing showed loss of the inhibitor. Reinstitution of eculizumab after clearance of the ADAMTS13 inhibitor led to improvement in renal function such that dialysis could be stopped and he maintained his platelet count in the reference range.Figure 1 Treatment timelines for the 3 study patients with thrombotic thrombocytopenic purpura showing ADAMTS13 (disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity and inhibitor levels. The first 2 patients illustrate the importance of eliminating the ADAMTS13 inhibitor before starting treatment with eculizumab. The ADAMTS13 test is sent to an outside laboratory and has a few days' turnaround time. This principle was applied to the treatment of the third patient with good clinical response.

or levels. The first 2 patients illustrate the importance of eliminating the ADAMTS13 inhibitor before starting treatment with eculizumab. The ADAMTS13 test is sent to an outside laboratory and has a few days' turnaround time. This principle was applied to the treatment of the third patient with good clinical response. BU = Bethesda units; CFHR1-3 = complement factor H–related 1-3; K = thousand; MRI = magnetic resonance imaging; TPE = therapeutic plasma exchange. Figure 2 A, A biopsy sample of the normal skin did not show any conspicuous light microscopic abnormalities (hematoxylin-eosin, ×400). B, Although the routine hematoxylin-eosin–stained material was unremarkable, fairly striking deposits of C5b-9 were noted in the capillaries and venules of the skin, corroborating the diagnosis of atypical hemolytic uremic syndrome (C5b-9 diaminobenzidene, ×400).

ght microscopic abnormalities (hematoxylin-eosin, ×400). B, Although the routine hematoxylin-eosin–stained material was unremarkable, fairly striking deposits of C5b-9 were noted in the capillaries and venules of the skin, corroborating the diagnosis of atypical hemolytic uremic syndrome (C5b-9 diaminobenzidene, ×400). Patient 2 A 35-year-old African American woman presented with slurred speech and left-sided numbness; her renal function was within the reference range. Testing revealed less than 5% ADAMTS13 activity and anti-ADAMTS13 antibody titers of 2.2 BU. Corticosteroid therapy and TPE were initiated without an adequate response. Rituximab and vincristine were added, but the response was still inadequate (Figure 1). Genetic mutation testing for complement-related genes showed multiple genetic mutations (Table). Eculizumab administration was started before clearance of ADAMTS13 inhibitor, without an adequate response to treatment. The decision was made to hold eculizumab until the ADAMTS13 inhibitor had been cleared. One year after her diagnosis, the patient continues to do well, and she receives eculizumab every 2 weeks.Table Genetic Mutations Found by Machaon Diagnostics in Patient 2

AMTS13 inhibitor, without an adequate response to treatment. The decision was made to hold eculizumab until the ADAMTS13 inhibitor had been cleared. One year after her diagnosis, the patient continues to do well, and she receives eculizumab every 2 weeks.Table Genetic Mutations Found by Machaon Diagnostics in Patient 2 Mutation Location Significance, frequency (1000 Genomes Project database) Heterozygous missense variant (c.1246A>C,p.lle416Leu) Exon 11 of CFI Linked to aHUS,4 0.0028 (c.1135 G>C, p.Val379leu) Exon 7 of CFHR5 Linked to aHUS,4 0.005 (c.3019G>T, p.Val1007Leu) Exon 19 of CFH Linked to aHUS,4 0.2553 in AA population (c.2669G>T, p.Ser890lle) Exon 17 of CFH Benign mutation,5 0.1893 in AA population (c.3207T>C, p.Ser1069Ser) Exon 20 or CFH Unknown significant, 0.0018 Intronic deletion (chr1:207932961,T A>T) Upstream of exon 4 of MCP/CD46 Unknown significant, 0.0042 (c.40G>A, p.Gly14Ser) Exon 1 of THBD Unknown significant, 0.0068 Nonsence variant (c.1704T>A,p.Cys568Stop) Exon 10 of CFHR5 Unknown significant, 0.01 Heterozygous polymorphism (IVS9-78 G>A) Intron in MCP/CD46 Common in the AA population up to 44% Heterozygous large deletion CFHR1-CFHR3 Only homozygous deletion is strongly associated with CFH antibodies Found in up to 33% in the AA population AA = African American; aHUS = atypical hemolytic uremic syndrome; CF = complement factor; CFHR = complement factor H–related.

MCP/CD46 Common in the AA population up to 44% Heterozygous large deletion CFHR1-CFHR3 Only homozygous deletion is strongly associated with CFH antibodies Found in up to 33% in the AA population AA = African American; aHUS = atypical hemolytic uremic syndrome; CF = complement factor; CFHR = complement factor H–related. Patient 3 A 64-year-old African American woman presented with mouth droop and left arm weakness. ADAMTS13 activity was less than 5%, with an inhibitor level of 1.1 BU. Renal function was mildly decreased (creatinine clearance, 30 mL/min per 1.73 m2 [to convert to mL/s per m2, multiply by 0.0167]). Daily TPE and corticosteroid therapy were initiated for acquired TTP. This resulted in complete clearance of the ADAMTS13 inhibitor; however, her condition continued to deteriorate and right-sided weakness, bilateral cerebral infarcts on magnetic resonance imaging, and seizure-like activity developed. Hence, complement-related genetic testing was ordered and showed a large homozygous deletion in CFHR1-CFHR3. Treatment with eculizumab was instituted, and an improvement in the platelet count was seen after the first dose (Figure 2). Six months after inititating treatment with eculizumab, treatment was discontinued. Two years later, she has not had a recurrence of her TMA. Further details about this patient can be found in a recently published report.6 Baseline testing for CFH antibodies at diagnosis is not available. However, antibodies to CFH were undetectable during treatment with eculizumab.

izumab, treatment was discontinued. Two years later, she has not had a recurrence of her TMA. Further details about this patient can be found in a recently published report.6 Baseline testing for CFH antibodies at diagnosis is not available. However, antibodies to CFH were undetectable during treatment with eculizumab. Discussion Severe ADAMTS13 deficiency has been considered the unique pathognomonic event of TTP. Initially, Furlan et al3 reported normal ADAMTS13 activity in approximately 85% of patients with HUS. The finding that patients with HUS have normal ADAMTS13 activity was classically used as the definitive criteria to differentiate patients with HUS from those with TTP. However, these findings have been challenged by reports of the coexistence of iTTP and aHUS. The first report described a patient with clinical deterioration despite TPE; a skin biopsy confirmed the presence of heavy perivascular CF depositions and triggered successful treatment with eculizumab.7 The second report described 3 of 4 patients with TMA due to ADAMTS13 inhibitors approximately 2.4 to 4 weeks after starting treatment with ticlopidine. Renal disease in these patients responded poorly to TPE, although hematologic parameters sometimes normalized. Patients had CFH mutations.8 Complement regulatory factor mutations represent another independent susceptibility factor, and their presence in addition to ADAMTS13 deficiency may be required for the onset of disease.9

sease in these patients responded poorly to TPE, although hematologic parameters sometimes normalized. Patients had CFH mutations.8 Complement regulatory factor mutations represent another independent susceptibility factor, and their presence in addition to ADAMTS13 deficiency may be required for the onset of disease.9 The lack of clinical recovery in the present patients prompted us to look for complement pathway defects. The aHUS mutation testing in the first and third patients showed CFHR1-CFHR3 homozygous deletion. Despite the fact that CFHR1-3 deletions are seen in approximately 33% of the healthy African population, homozygous deletions in CFHR1-CFHR3 have been reported to be strongly associated with the presence of CFH autoantibodies.10, 11, 12, 13 However, only 4% to 14% of patients with aHUS may have CFH autoantibodies. In fact, CFH antibodies in patient 1 were within the reference range. A random skin biopsy may be helpful in demonstrating the presence of extensive microvascular deposition of C5b-9, which supports the diagnosis of aHUS or a subset of TTP with concomitant complement dysregulation.7 Such depositions are not diagnostic of aHUS. However, in confirmed cases of aHUS, the presence of significant vascular C5b-9 deposition may predict clinical responsiveness to eculizumab.14

rovascular deposition of C5b-9, which supports the diagnosis of aHUS or a subset of TTP with concomitant complement dysregulation.7 Such depositions are not diagnostic of aHUS. However, in confirmed cases of aHUS, the presence of significant vascular C5b-9 deposition may predict clinical responsiveness to eculizumab.14 The second patient has multiple genetic mutations (Table). The lack of response to traditional TTP treatment in patients 2 and 3 prompted us to look for complement dysregulation despite the absence of severe renal injury. Both patients had an excellent response to eculizumab treatment. This finding is consistent with previous reports on the use of eculizumab for refractory TTP.7 Conclusion Herein we presented our experience in treating 3 African American patients with diagnostic features of iTTP and genetic mutations consistent with complement dysregulation. The simultaneous presence of inhibitor-related ADAMTS13 deficiency and complement dysregulation may blur the distinction between aHUS and TTP. Finally, response to treatment was facilitated by clearance of ADAMTS13 inhibitor levels before the institution of anticomplement therapy. Acknowledgments We thank Dr Cynthia Magro, Weill Cornell College of Medicine, for her help with reading and preparing the skin biopsy samples in Figure 2. Potential Competing Interests: The authors report no competing interests.

The role of endothelial dysfunction (ED) in the natural history of cardiovascular disease is well-known and is acknowledged as one of the earliest stages in the physiopathologic continuum of atherosclerosis.1 Thus, ED is an important cardiovascular risk marker, with significant prognostic implications.2, 3, 4, 5, 6, 7 To date, flow-mediated dilation (FMD) is recognized as the reference method for assessing endothelial function (EF) noninvasively. The percentage increase in brachial artery diameter after reactive hyperemia (RH) defines the FMD and relates to the endothelium's ability to release and respond to nitric oxide, thus indicating its functional health.7 Although this technique has strong advantages, it also has some important disadvantages, such as being highly operator-dependent, which could determine unacceptable variability unless a dedicated technician and adequate equipment are present.8 As an alternative to the conventional FMD technique, pulse wave velocity (PWV) could offer a much easier and more reproducible methodological alternative to studying EF. In fact, the Moens-Korteweg equation links PWV to the arterial radius, as follows: PWV=E·hD·δ, where E is the elastic modulus; h, the wall thickeness; D, the arterial diameter; and δ, the blood density.9 The theoretical consequence of this is that if the arterial radius R increases after RH, a decrease in PWV is expected to occur. If this assumption is true, then the deceleration of PWV over the brachial artery (what we designate as flow-mediated slowing [FMS]) should be an equivalent signal of EF during a conventional RH procedure. Because PWV is a validated method, easy to perform, highly reproducible, and low cost, the demonstration of its usefulness for evaluating ED should be of major interest.8 To date, just a few studies have explored this hypothesis.10, 11

wing [FMS]) should be an equivalent signal of EF during a conventional RH procedure. Because PWV is a validated method, easy to perform, highly reproducible, and low cost, the demonstration of its usefulness for evaluating ED should be of major interest.8 To date, just a few studies have explored this hypothesis.10, 11 Based on this premise, we present the preliminary results of an ongoing project that aims to appraise the clinical usefulness of FMS for the evaluation of ED, particularly focusing on the comparision between FMS and FMD after RH in healthy individuals. Methods We conducted a cross-sectional study aimed at comparing FMS and FMD estimations of EF in 25 clinically healthy participants (18 women [72%]) with a mean ± SD age of 21.12±0.73 years.

Based on this premise, we present the preliminary results of an ongoing project that aims to appraise the clinical usefulness of FMS for the evaluation of ED, particularly focusing on the comparision between FMS and FMD after RH in healthy individuals. Methods We conducted a cross-sectional study aimed at comparing FMS and FMD estimations of EF in 25 clinically healthy participants (18 women [72%]) with a mean ± SD age of 21.12±0.73 years. Evaluations were conducted in a laboratory with controlled luminosity, temperature, and humidity. All the evaluations took place in the morning, with participants fasting and deprived from smoking, exercise, alcohol, and cafeine for 12 hours before the study. Demographic data were collected for each participant. The participants were then placed in the supine position, and after a 10-minute rest period, brachial blood pressure was measured using an automatic and clinically validated sphygmomanometer (ri-champion N; Rudolf Riester GmbH) with a cuff that adjusted for the arm diameter. Afterward, FMD was obtained, complying with the methodological recommendations.8, 12 A Vivid 3 echograph (General Electric) equipped with a linear probe (frequency range, 7-12 MHz) was used. A basal measurement of the diameter of the right brachial artery in a linear plane was made, approximately 2 to 3 cm off the antecubital fossa. Baseline carotid-radial PWV was then acquired in the same arm using the Complior Analyse device (Alam Medical). For this, a probe with piezoelectric crystals was placed on the right radial artery and another on the ipsilateral carotid artery. The probes were adjusted to ensure the acquisition of pulse waves with suitable reproducible, stability, and amplitude. The distance between the 2 points was measured directly. The brachial PWV corresponded to the distance (d) divided by the pulse wave transit time (PTT) between the 2 arterial territories considered (carotid-radial), where PWV = d/PTT (m/s).

cquisition of pulse waves with suitable reproducible, stability, and amplitude. The distance between the 2 points was measured directly. The brachial PWV corresponded to the distance (d) divided by the pulse wave transit time (PTT) between the 2 arterial territories considered (carotid-radial), where PWV = d/PTT (m/s). Subsequently, a cuff was placed on the forearm, distal to the site of the ultrasound assessment, and was inflated into a suprasystolic pressure (∼50 mm Hg above the previously measured systolic blood pressure), keeping the ischemia for a 5-minute period, after which the cuff was deflated. Approximately 1 minute after complete deflation of the cuff, the diameter of the brachial artery and the brachial PWV were simultaneously measured. The FMD was calculated as the percentage increase in brachial diameter after RH. The FMS was calculated using the baseline PWV and the PWV after RH, as ΔPWV, quantifying the absolute difference between the 2 moments of PWV, and as %PWV, quantifying the percentage of variation. All measurements were performed in the right arm. All the tests were performed by the same experienced operator (T.P.) to ensure the necessary reproducibility conditions. All the participants agreed voluntarily to participate in the study and gave their informed consent.

Subsequently, a cuff was placed on the forearm, distal to the site of the ultrasound assessment, and was inflated into a suprasystolic pressure (∼50 mm Hg above the previously measured systolic blood pressure), keeping the ischemia for a 5-minute period, after which the cuff was deflated. Approximately 1 minute after complete deflation of the cuff, the diameter of the brachial artery and the brachial PWV were simultaneously measured. The FMD was calculated as the percentage increase in brachial diameter after RH. The FMS was calculated using the baseline PWV and the PWV after RH, as ΔPWV, quantifying the absolute difference between the 2 moments of PWV, and as %PWV, quantifying the percentage of variation. All measurements were performed in the right arm. All the tests were performed by the same experienced operator (T.P.) to ensure the necessary reproducibility conditions. All the participants agreed voluntarily to participate in the study and gave their informed consent. IBM SPSS Statistics for Windows, version 23.0 (IBM Corp), was used. Simple descriptive statistic was used to characterize the population. Data are presented as mean ± SD for continuous variables and as absolute frequency (percentage) for categorical variables. Continuous variables were compared using the independent t test, and categorical variables were compared using the Fisher exact test. The correlations between continuous variables were determined using the Pearson R correlation test. A P≤.05 was set as the criterion for statistical significance for a 95% CI.

variables. Continuous variables were compared using the independent t test, and categorical variables were compared using the Fisher exact test. The correlations between continuous variables were determined using the Pearson R correlation test. A P≤.05 was set as the criterion for statistical significance for a 95% CI. Results The Table presents the characteristics of the population (N=25), with a mean ± SD age of 21.12±0.73 years and a mean ± SD body mass index (calculated as the weight in kilograms divided by the height in meters squared) of 22.10±3.19. Men (n=7) were taller and heavier, had higher systolic and pulse pressures, and had greater baseline brachial diameters. No participant had cardiovascular risk factors or a history of cardiovascular disease. Only 1 man was a recent smoker. All the participants referred a sporadic recreational alcohol drinking pattern. Regarding family history of cardiovascular disease, 48% of the study population claimed to have direct relatives with a history of cardiovascular disease. No participant was under any long-term medication intake, except for the use of oral contraceptives, seen in most of the female participants.Table Demographic Characteristics of the Study Populationab

ascular disease, 48% of the study population claimed to have direct relatives with a history of cardiovascular disease. No participant was under any long-term medication intake, except for the use of oral contraceptives, seen in most of the female participants.Table Demographic Characteristics of the Study Populationab Characteristic Total (N=25) Men (n=7) Women (n=18) P value Age (y) 21.12±0.73 21.00±10 21.17±0.62 .62 Height (m) 1.68±0.10 1.80±0.05 1.63±0.06 <.001 Weight (kg) 62.10±10.47 72.42±9.59 58.06±7.81 .001 BMI 22.10±3.19 22.30±2.62 22.04±3.45 .86 SBP (mm Hg) 114.20±10.80 121.57±8.12 111.33±10.50 .03 DBP (mm Hg) 66.72±8.48 65.43±6.45 67.22±9.27 .65 PP (mm Hg) 47.48±11.11 56.14±10.19 44.11±9.74 .01 MBP (mm Hg) 88.55±7.70 84.14±5.16 81.93±8.55 .53 HR (beats/min) 70.92±8.79 68.14±9.94 72.00±8.35 .34 Basal diameter (mm) 3.46±0.59 4.17±0.43 3.12±0.22 <.001 Basal carotid-radial PWV (m/s) 8.58±1.16 9.23±1.33 8.33±1.02 .08 a BMI = body mass index; DBP = diastolic blood pressure; HR = heart rate; MBP = mean blood pressure; PP = pulse pressure; PWV = pulse wave velocity; SBP = systolic blood pressure. b Data are presented as mean ± SD.

Characteristic Total (N=25) Men (n=7) Women (n=18) P value Age (y) 21.12±0.73 21.00±10 21.17±0.62 .62 Height (m) 1.68±0.10 1.80±0.05 1.63±0.06 <.001 Weight (kg) 62.10±10.47 72.42±9.59 58.06±7.81 .001 BMI 22.10±3.19 22.30±2.62 22.04±3.45 .86 SBP (mm Hg) 114.20±10.80 121.57±8.12 111.33±10.50 .03 DBP (mm Hg) 66.72±8.48 65.43±6.45 67.22±9.27 .65 PP (mm Hg) 47.48±11.11 56.14±10.19 44.11±9.74 .01 MBP (mm Hg) 88.55±7.70 84.14±5.16 81.93±8.55 .53 HR (beats/min) 70.92±8.79 68.14±9.94 72.00±8.35 .34 Basal diameter (mm) 3.46±0.59 4.17±0.43 3.12±0.22 <.001 Basal carotid-radial PWV (m/s) 8.58±1.16 9.23±1.33 8.33±1.02 .08 a BMI = body mass index; DBP = diastolic blood pressure; HR = heart rate; MBP = mean blood pressure; PP = pulse pressure; PWV = pulse wave velocity; SBP = systolic blood pressure. b Data are presented as mean ± SD. Regarding the relationship between the estimates of EF derived from the conventional FMD technique and those from the innovative FMS procedure, significant correlation coefficients were obtained by bivariate correlation analysis (Figure), even when adjusting for potential confounding variables, thus indicating a significant and moderate correlation between FMD and ΔPWV (R=−0.42; P=.04) and between FMD and %PWV (R=0.46; P=.02). As depicted in the Figure, a greater PWV slowing effect was depicted for participants showing a greater increase in the brachial diameter after RH, according to the predictions of the Moens-Korteweg equation.9Figure Relationship of pulse wave velocity (PWV) absolute difference (ΔPWV) and PWV percentage variation (%PWV) with flow-mediated dilation (FMD).

r PWV slowing effect was depicted for participants showing a greater increase in the brachial diameter after RH, according to the predictions of the Moens-Korteweg equation.9Figure Relationship of pulse wave velocity (PWV) absolute difference (ΔPWV) and PWV percentage variation (%PWV) with flow-mediated dilation (FMD). An additional cluster analysis was performed to explore individual differences, and 2 main groups of participants were extracted in terms of the consistency in the estimates of EF with the comparing methods: group 1 comprised participants with a consistent relationship between FMD and FMS, and group 2 comprised participants with little concordant or even discordant results. Based on this definition, significant differences were identified mainly in the basal brachial diameters between the 2 groups (P=.02), implying that the correlation between the 2 methods seems to be diameter dependent so that FMS tends to be lower in individuals with smaller baseline arteries. Discussion The importance of ED has been widely established as a starting point in the continuum of the most significant cardiovascular diseases. Therefore, efforts to develop accurate noninvasive methods for use in clinical practice are of utmost importance. Currently, the echo-based FMD procedure is widely acknowledged as the reference method for this purpose, although some important limitations are identified, chiefly in terms of reproducibility, cost, and expertise requirements.6, 10

lop accurate noninvasive methods for use in clinical practice are of utmost importance. Currently, the echo-based FMD procedure is widely acknowledged as the reference method for this purpose, although some important limitations are identified, chiefly in terms of reproducibility, cost, and expertise requirements.6, 10 Simpler, cheaper, and more reproducible alternatives should, thus, be considered, and the proposed concept of FMS could be an interesting hypothesis to explore. These preliminary results pinpoint a significant correlation between FMD and FMS in a healthy and young population. In fact, larger FMD values were followed by a greater deceleration of the pulse wave in the carotid-radial area, as would be expected from the knowledge that the bigger the vessel, the lower the resistance, and, therefore, less will be the velocity, and also following the predictions in the Moens-Korteweg equation, by which PWV is directly proportional to the arterial wall thickness and its elastic modulus and is inversely proportional to vessel diameter and blood viscosity.11, 13 Curiously, women had smaller baseline brachial artery diameters, in line with previous research,14 but showed a trend for lower baseline brachial PWV compared with men, pinpointing the influence of other physiologic regulation vectors as relevant modulators for propagation of the pulse wave, from which the elastic modulus may play a quite important role.11 Similar results were previously reported15 comparing the brachial PWV response with different durations of ischemia, demonstrating greater reductions in PWV to increasing ischemia durations, peaking at 5 minutes of RH.

for propagation of the pulse wave, from which the elastic modulus may play a quite important role.11 Similar results were previously reported15 comparing the brachial PWV response with different durations of ischemia, demonstrating greater reductions in PWV to increasing ischemia durations, peaking at 5 minutes of RH. The results obtained should be envisioned as a preliminary attempt to develop a new concept of noninvasively studying EF, considering the limitations of the study, mainly the small population included (N=25) and the particular clinical features of the participants. The replication of this study in a larger population, including a wider spectrum of clinical subsets, with participants with known risk factors,15 and in a longitudinal design would provide further insight into the usefulness of this method for identifying ED and discriminating cardiovascular risk profiles. In conclusion, FMS seems to be a promising indirect method for the assessment of ED, although further research is needed to better characterize its validity and clinical usefulness. Potential Competing Interests: The authors report no competing interests.

Since the approval of ipilimumab for the treatment of melanoma in 2011, immune checkpoint inhibitors (ICIs) have been changing the landscape of oncology. They up-regulate the body's own antitumor immunity and include anti–cytotoxic T-lymphocyte antigen 4, anti–programmed death-1 (PD-1), and anti–programmed death-ligand 1 (PD-L1) monoclonal antibodies. The toxicity profile of ICIs is unique in that they often trigger the development of immune-related adverse effects (irAEs). Commonly reported irAEs include colitis, hepatitis, endocrinopathies, dermatitis, thyroiditis, and pneumonitis; however, virtually all organ systems can develop immune toxicities.1, 2 Neurologic irAEs include neuropathy, myelopathy, Guillain-Barré syndrome, meningitis, myasthenia gravis, and encephalitis and occur in less than 1% of patients.1, 3 Immune-mediated encephalitis is especially uncommon and occurs in less than 0.2% of patients.4 We describe a case of anti–PD-1 antibody-related immune-mediated cerebellar encephalitis. To our knowledge, this is the first described case of ICI-associated immune-mediated cerebellar encephalitis in the literature.

ts.1, 3 Immune-mediated encephalitis is especially uncommon and occurs in less than 0.2% of patients.4 We describe a case of anti–PD-1 antibody-related immune-mediated cerebellar encephalitis. To our knowledge, this is the first described case of ICI-associated immune-mediated cerebellar encephalitis in the literature. Case Study A 20-year-old white man with stage IVB primary refractory Hodgkin lymphoma that progressed despite 3 previous therapies (doxorubicin-bleomycin-vinblastine-dacarbazine [ABVD], ifosfamide-carboplatin-etoposide [ICE], and brentuximab vedotin) was treated with nivolumab 3 mg/kg every 2 weeks. He presented 13 days after his third cycle of nivolumab to an emergency department with 1 day of bilateral stabbing headache, diplopia, confusion, nausea, and vomiting. He did not have any history of infection. On examination he was afebrile and hemodynamically stable. Neurologic examination was notable for ataxia and dysmetria. Meningeal signs were absent. Initial head computed tomography showed cerebellar edema. Brain magnetic resonance imaging (MRI) showed a diffusely edematous cerebellum with patchy enhancement, signs of early tonsillar herniation, and early hydrocephalus. Antibiotics were initiated for possible meningitis. Initial lumbar puncture was unsuccessful. After consultation with his primary oncologist, high-dose dexamethasone (8 mg every 6 hours) was initiated because of a high possibility of immune-mediated encephalitis.

of early tonsillar herniation, and early hydrocephalus. Antibiotics were initiated for possible meningitis. Initial lumbar puncture was unsuccessful. After consultation with his primary oncologist, high-dose dexamethasone (8 mg every 6 hours) was initiated because of a high possibility of immune-mediated encephalitis. By day 6, his nausea and vomiting had resolved. He continued to have mild residual ataxia of his extremities (left greater than right), mild dysmetria, and dizziness. Repeated MRI on day 6 showed persistent but improved bilateral cerebellar hemispheric edema with mild cerebellar leptomeningeal enhancement (Figure 1). Later, cerebrospinal fluid (CSF) examination revealed normal glucose (73 mg/dL), elevated protein (161 mg/dL), and lymphocytic pleocytosis (white blood cells, 31/μL; 94% lymphocytes, 6% monocytes). Cryptococcal antigen studies, herpes simplex virus polymerase chain reaction, and routine CSF cultures yielded negative results. The CSF flow cytometry results were normal. The patient was discharged on day 8 and dexamethasone was tapered over 4 weeks. At 6-week follow-up, the patient's symptoms had essentially resolved except for mild diplopia. The brain MRI at 6-week follow-up showed near resolution of cerebellitis with subtle persistent enhancement within the cerebellar sulci (Figure 2). Positron emission tomography at 6-week follow-up showed a partial response. The cerebellitis was believed to represent an immune-mediated encephalitis related to anti–PD-1 therapy; therefore, nivolumab was discontinued with a plan to begin an alternative therapy at next follow-up.Figure 1 Axial T2 FLAIR MRI of patient on day 6 of hospitalization and day 4 of dexamethasone therapy. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.

phalitis related to anti–PD-1 therapy; therefore, nivolumab was discontinued with a plan to begin an alternative therapy at next follow-up.Figure 1 Axial T2 FLAIR MRI of patient on day 6 of hospitalization and day 4 of dexamethasone therapy. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging. Figure 2 Axial T2 FLAIR MRI of patient 6 weeks after presentation, 2 weeks after completion of dexamethasone therapy. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.

phalitis related to anti–PD-1 therapy; therefore, nivolumab was discontinued with a plan to begin an alternative therapy at next follow-up.Figure 1 Axial T2 FLAIR MRI of patient on day 6 of hospitalization and day 4 of dexamethasone therapy. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging. Figure 2 Axial T2 FLAIR MRI of patient 6 weeks after presentation, 2 weeks after completion of dexamethasone therapy. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging. Discussion We describe a case of acute cerebellar encephalitis that developed after exposure to nivolumab used to treat primary refractory Hodgkin lymphoma. Although causality cannot be proven without biopsy, several clinical features suggest that his presentation was related to ICI exposure, including the timing of his symptoms, his rapid improvement with corticosteroids, and negative results of infectious work-up. Etiologies that must be considered in the differential diagnosis of ICI-related immune-mediated cerebellar encephalitis include paraneoplastic cerebellar degeneration (PCD), acute infectious cerebellitis, postinfectious cerebellitis, gliadin-associated cerebellar ataxia, glutamic acid decarboxylase (GAD)–associated cerebellar ataxia, thiamine deficiency, alcohol abuse, and cerebellar metastases.5 Thiamine deficiency and alcohol abuse were excluded on the basis of history. Brain metastases were excluded on the basis of absence of localized lesion on brain MRI and normal findings on CSF flow cytometry. Paraneoplastic cerebellar degeneration, gliadin- and GAD-associated cerebellar ataxia, and infectious and postinfectious cerebellitis were all considerations in our patient's case.

history. Brain metastases were excluded on the basis of absence of localized lesion on brain MRI and normal findings on CSF flow cytometry. Paraneoplastic cerebellar degeneration, gliadin- and GAD-associated cerebellar ataxia, and infectious and postinfectious cerebellitis were all considerations in our patient's case. Paraneoplastic cerebellar degeneration has been well described in Hodgkin lymphoma, as well as breast, ovarian, and small cell lung cancer.6 It is associated with several antibodies, most commonly anti-Yo in ovarian and breast cancer, anti-Hu and anti-Zic4 in small cell lung cancer, and anti-Tr and anti-mGluR1 in Hodgkin lymphoma.5 Antibodies associated with autoimmune cerebellitis that can occur in the absence of malignancy include anti-GAD and antigliadin antibodies.5 Neither presence nor absence of these antibodies could definitively diagnose or exclude ICI-related immune-mediated cerebellar encephalitis in our patient's case. On initial MRI, our patient had significant cerebellar edema in contrast to most cases of PCD in which patients more commonly have an initially normal MRI result. Nonetheless, some patients with PCD do demonstrate diffuse cerebellar enlargement with cortical-meningeal enhancement early in their disease course.5 In most cases, PCD does not respond well to immunosuppressive therapy, which is also in contrast to our patient's case.7

ore commonly have an initially normal MRI result. Nonetheless, some patients with PCD do demonstrate diffuse cerebellar enlargement with cortical-meningeal enhancement early in their disease course.5 In most cases, PCD does not respond well to immunosuppressive therapy, which is also in contrast to our patient's case.7 Acute infectious cerebellitis has been associated with Epstein-Barr virus, varicella-zoster virus, influenza, enterovirus, dengue virus, JC virus, and Listeria monocytogenes.8 Acute postinfectious cerebellar ataxia presents similar to infectious cerebellitis except that infectious testing results are negative, with symptoms beginning approximately 2 weeks after a febrile illness. The most common antecedent infection is varicella-zoster virus infection in young children and Epstein-Barr virus infection in young adults. Initial MRI results can range from normal findings to significant cerebellar edema with obstructive hydrocephalus in both infectious and postinfectious cerebellitis.8 The results of CSF examination are notable for a lymphocytic pleocytosis and elevated protein. Viral polymerase chain reaction testing for the above etiologies was not done in our patient's case because he lacked a convincing history for these etiologies.

drocephalus in both infectious and postinfectious cerebellitis.8 The results of CSF examination are notable for a lymphocytic pleocytosis and elevated protein. Viral polymerase chain reaction testing for the above etiologies was not done in our patient's case because he lacked a convincing history for these etiologies. Immune-mediated encephalitis related to ICI therapy is still not well described, with only 13 cases in the literature (Supplemental Table, available online at http://mcpiqojournal.org/).4, 7, 9, 10, 11, 12, 13, 14, 15 It is considered a grade 3 or 4 irAE and warrants immediate and permanent discontinuation of ICI therapy. Cases have been reported in patients with various cancer types: non–small cell lung cancer, small cell lung cancer, advanced melanoma, and prostate cancer. Nivolumab, ipilimumab, and pembrolizumab have all been associated with the syndrome. There are no reported cases with anti–PD-L1 therapy. Signs and symptoms are variable and can include headache, weakness, confusion, aphasia, ataxia, bradykinesia, somnolence, and seizures. Time from initiation of ICI therapy to symptom development varies widely from 4 days to 11 months. Time from corticosteroid initiation to symptom resolution is also widely variable from 1 day to 6 months. Initial MRI findings are usually normal but can demonstrate T2-weighted fluid-attenuated inversion recovery (FLAIR) hyperintensities in the affected areas. The results of CSF studies usually show a lymphocytic pleocytosis and elevated protein but can be normal. Most who develop immune-mediated encephalitis have a positive tumor response to ICI therapy but about a fifth of patients experience progressive disease. In a sixth of cases symptoms persisted despite high-dose glucocorticoids, and further immunosuppressive therapy (intravenous immunoglobulin and/or rituximab) was needed to achieve a durable response.4, 9 Paraneoplastic and autoimmune antibody testing results were positive in only a fourth of cases in which testing was performed.9

of cases symptoms persisted despite high-dose glucocorticoids, and further immunosuppressive therapy (intravenous immunoglobulin and/or rituximab) was needed to achieve a durable response.4, 9 Paraneoplastic and autoimmune antibody testing results were positive in only a fourth of cases in which testing was performed.9 Conclusion For patients receiving ICI therapy with evidence of immune-mediated cerebellitis, prompt recognition and early initiation of high-dose corticosteroids is essential for symptom resolution and treatment success, including the prevention of hydrocephalus and tonsillar herniation. Currently, no evidence-based guidelines are available to guide the initial dose, type, or duration of corticosteroids. Because dexamethasone has good penetration and efficacy in the central nervous system, we favor it in these cases. Any patient with probable ICI-induced cerebellitis should have prompt and permanent discontinuation of ICI therapy and prolonged corticosteroid treatment until resolution of symptoms and imaging abnormalities. Supplemental Online Material Supplemental Table Supplemental material can be found online at http://mcpiqojournal.org/. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data. Potential Competing Interests: The authors report no competing interests.

Behavioral health disorders (mental health problems and substance use disorders) are highly prevalent, negatively impact chronic medical illness, and raise the overall cost of health care from increased emergency department utilization, hospital readmission rates, and occupational disability.1, 2, 3 Psychiatrists make up a scarce and expensive resource needed to address the demand for treatment of patients with behavioral health disorders. Patients in rural areas are even more in need as problems with access and capacity persist, particularly as psychiatrists are located primarily in major cities and urban areas.4 Primary care practices are the only resource in these rural towns and feel inadequately equipped to manage these conditions, not just because of knowledge gaps but also because of the nature of business practices. Integrated care has been shown as a new business practice that can improve care, stabilize cost, and foster positive patient and provider experiences.5, 6 However, implementing this model is challenging and difficult to disrupt the current business practice.7 It is important to understand integrated care through the framework of disruptive innovation theory to provide insight into how practices can be disrupted to extend affordable and accessible psychiatric expertise to primary care.

menting this model is challenging and difficult to disrupt the current business practice.7 It is important to understand integrated care through the framework of disruptive innovation theory to provide insight into how practices can be disrupted to extend affordable and accessible psychiatric expertise to primary care. Clayton Christensen defines disruptive innovation as “the process of coupling cost- reducing technologies with innovative business models to deliver increasingly affordable and accessible products and services.”8 Overall, a business model has 4 components, though its strength lies in its value proposition, which is defined as a service or product that helps customers do something they want to do effectively, conveniently, and affordably.9 The other 3 components are (1) the resources needed to deliver the value proposition; (2) the processes, which stipulate the way of working together to address a recurrent task in a consistent way; and (3) the profit formula, which keeps the business in practice. Three types of business models are possible in health care and can be combined with technologies to either sustain or disrupt the psychiatric practice.9 These business models have been called solution shops, value adding process model, and facilitated user network, with the latter being the most disruptive. It is important to understand these business models and how they can be tailored to extend psychiatric expertise to deliver the value proposition of improved well-being for behavioral health patients in primary care.

s, value adding process model, and facilitated user network, with the latter being the most disruptive. It is important to understand these business models and how they can be tailored to extend psychiatric expertise to deliver the value proposition of improved well-being for behavioral health patients in primary care. Like most specialists in health care and consultants in other industries, psychiatrists are solution shop experts. By solution shop, it means that they use expert knowledge and the intuition gained from years of training and treating many patients to address complex unstructured problems that patients present with.8 In the psychiatric practice, resources (staff, technologies) are put together, and a process of care is devised to deliver the value proposition (diagnosis, treatment recommendation) for patients, with the intention of obtaining a profit margin, which keeps the practice in business to continue to provide care. The financial compensation for these services follows a fee-for-service model, either time- or complexity- based reimbursement. In keeping with other specialties in health care, innovative efforts are appropriately focused on improving diagnosis (Diagnostic and Statistical Manual of Mental Disorders, biomarkers) and treatments (medication, pharmacogenomic testing, and psychotherapy) but may end up increasing the cost without necessarily improving access and affordability.

lties in health care, innovative efforts are appropriately focused on improving diagnosis (Diagnostic and Statistical Manual of Mental Disorders, biomarkers) and treatments (medication, pharmacogenomic testing, and psychotherapy) but may end up increasing the cost without necessarily improving access and affordability. In rural areas, access to these solution shop experts is limited and attempts to use cost-lowering technologies such as telepsychiatry only end up sustaining the same practices without necessarily reducing the cost or reaching more people, because patients can be seen only one at a time, and this magnifies the cry for more psychiatrist to be trained or relocated to rural areas.10 However, the bigger problem with treating behavioral health disorders is that most of them are chronic in nature and a solution shop model, though required for diagnosis and treatment recommendation, does not necessarily enable patients to maintain wellness. Patients are tasked with implementing the recommendations from solution shops but making the required behavior change is difficult. This predicament also applies to other chronic medical illnesses that are dependent on health behavior change such as diet, exercise, medication compliance, smoking cessation, appropriate alcohol intake, and avoidance of recreational drug use. It is clear that a different model to address the value proposition of maintaining wellness is required and to extend psychiatric expertise across a larger population. Herein lie the benefits of integrated care.

edication compliance, smoking cessation, appropriate alcohol intake, and avoidance of recreational drug use. It is clear that a different model to address the value proposition of maintaining wellness is required and to extend psychiatric expertise across a larger population. Herein lie the benefits of integrated care. Integrated care uses a value adding process model to enable psychiatric expertise to be converted into simpler and affordable ones and help patients implement recommendations from solution shops to achieve wellness goals. A value adding process business model derives its strength from optimizing process efficiency.9 The focus is to repackage the resources used to streamline the processes of care to deliver the value proposition of wellness while operating on different profit margin rules. The core processes in integrated care have been defined as team driven, population focused, measurement guided, and evidence based.11 The resources used include the addition of a care manager (CM) with behavioral health expertise who works with the primary care provider (PCP) and patient and is supervised by a consulting psychiatrist in a team-based approach that can be collocated in primary care or virtual.12 The care process is initiated when a PCP sees a patient with behavioral health needs and liaises with a CM who adds the patient to the caseload of patients they track within a population registry. The registry contains important patient data that provide the basis of systematic case review each week with the care team.13 These data typically include symptom measures (eg, Patient Health Questionnaire-9), process measures (eg, access), experience measures (patient and provider), and utilization measures (eg, emergency department visits). The CM interacts with patients on a regular basis and uses evidenced-based approaches suited to primary care such as motivational interviewing, problem-solving therapy, and behavior activation to move patients toward wellness.14

easures (patient and provider), and utilization measures (eg, emergency department visits). The CM interacts with patients on a regular basis and uses evidenced-based approaches suited to primary care such as motivational interviewing, problem-solving therapy, and behavior activation to move patients toward wellness.14 The consulting psychiatrist working in this model wears many hats including clinical leader, caseload consultant, curbside consultant, direct consultant, clinical educator, and coach.15 The psychiatrist consults indirectly through the care team on a defined caseload of primary care patients to shape their behavioral health. It is estimated that the amount of time required by the psychiatrist to make substantial impact on a population of patients is 2 to 3 hours every week.15 They also consult directly by seeing selected patients who are not improving, hence maintaining a solution shop market too. Ensuring fidelity to the value adding processes in integrated care is critical for the success of this model of care and delivering the improved clinical outcomes that have been demonstrated in randomized controlled trials.16 Reimbursement for these nontraditional services (CM role, indirect consults by psychiatrist) requires value-based payment schemes such as bundled payments for a predetermined group of services that are typically not billable under traditional insurance schemes.17 Since 2017, Medicare has implemented payment codes to pay for this model though it remains stringent and private insurance schemes are lagging.18

st) requires value-based payment schemes such as bundled payments for a predetermined group of services that are typically not billable under traditional insurance schemes.17 Since 2017, Medicare has implemented payment codes to pay for this model though it remains stringent and private insurance schemes are lagging.18 Despite overwhelming evidence of improved clinical outcomes16 and cost-effectiveness19, 20, 21 of integrated care, translating the new practice into the real world is challenging as shown in the Depression Improvement Across Minnesota Offering a New Direction (DIAMOND) study. Solberg et al22 evaluated the DIAMOND study and found no considerable improvement in clinical outcomes but admitted to having no specific way to measure and ensure fidelity to the model, which is critical for effectiveness. Kathol et al23 argue that models of integrated care that embed behavioral health professionals with expertise in evidence-based therapies ensure improved clinical outcomes. A blend of models24 may be needed in practice to ensure the success of integrated care in primary care. Nevertheless, the evaluation of the DIAMOND study demonstrates difficulty in translating evidence into practice despite the support of insurance companies to use bundled payments. Miller et al25 believe that capitated payment models that reimburse for a predetermined per person rate to primary care practices regardless of whether the care is for behavioral health or medical conditions will better support the sustainability of integrated care. Health policy initiatives on payment reform to support integrated care certainly lack the pace of practice innovation.26

for a predetermined per person rate to primary care practices regardless of whether the care is for behavioral health or medical conditions will better support the sustainability of integrated care. Health policy initiatives on payment reform to support integrated care certainly lack the pace of practice innovation.26 The true disruptive power of integrated care can be realized only when it transitions from a value adding process to a facilitated user network business model that thrives from efficient management of a technological platform. For example, a centralized virtual telehub using telepsychiatry and Web-based registry platforms can further extend psychiatric expertise across a wider population by building the capacity of PCPs to treat behavioral health condition.27 In these learning networks, aggregated sparse and distributed anonymized data from process and outcome measures allow for the identification of trends in delivery system gaps and the insights gained can be used to foster business-to-business practices and/or business-to-customer offerings.13 Some business-to-business practices aimed at building the capacity of PCPs to treat behavioral health conditions include the use of psychiatrist specialist hub and multiple primary care spokes for didactics, consultative, and case-based learning to foster continuous professional development.28, 29 In addition, the insights gained from the large amount of data stored within these platforms can create new clinical support tools for point-of-care decision making for PCPs.27, 30 On the business-to-consumer side of the platform, direct evaluation of a patient at an originating site by a psychiatrist at a distant site via telepsychiatry can be done for difficult-to-reach areas. Digital and mobile technologies/apps to support patient self-management, under the guidance of a CM, can also be incorporated within these platforms.27

of the platform, direct evaluation of a patient at an originating site by a psychiatrist at a distant site via telepsychiatry can be done for difficult-to-reach areas. Digital and mobile technologies/apps to support patient self-management, under the guidance of a CM, can also be incorporated within these platforms.27 A number of studies, as summarized in a metanalysis,31 suggest that telepsychiatry is equivalent to face-to-face assessments in diagnostic accuracy and patient satisfaction. However, when telepsychiatry is embedded within an integrated care model it has been shown to be better than usual care. Fortney et al32 conducted a randomized controlled trial to study whether telepsychiatry-enhanced integrated care was better than usual primary care in depression treatment in Veterans Affair’s community-based outpatient clinics and demonstrated positive results. Evidence-based psychotherapy delivered virtually was also found to have contributed to another telepsychiatry-based integrated care leading to positive results in patients with posttraumatic stress disorder.33 In another study, Fortney et al12 demonstrated that telepsychiatry-based integrated care was better than practice-based integrated care for depression treatment with improved cost-effectiveness.34 By coupling these technological advances with appropriately matched business models such as integrated care, disruptive innovation has the potential to bring affordability and accessibility to a wider population.

was better than practice-based integrated care for depression treatment with improved cost-effectiveness.34 By coupling these technological advances with appropriately matched business models such as integrated care, disruptive innovation has the potential to bring affordability and accessibility to a wider population. Extending psychiatric expertise to primary care does not mean replacement of traditional specialty behavioral health services. What it does is help distribute resources by using a stepped care model to ensure that only patients with complex behavioral health problems are referred to specialty behavioral health services such as long-term psychotherapy, pharmacotherapy, partial hospitalization programs, traditional case management services, and community treatment teams. In conclusion, though the implementation of integrated care is difficult and varied models may be needed to ensure sustainability of the model, the theory of disruptive innovation suggests that integrated care, enabled by technological platform, has the potential to increase access and capacity to rural primary care sites for treatment of behavioral health conditions. In this way, integrated care can disrupt current practice to reach a market that has been ignored and allow patients to get the job they want done, more effectively, conveniently, and affordably. Potential Competing Interests: The author reports no competing interests.

To the Editor: Physician burnout is prevalent among 50% of students, residents, and practicing physicians. Interventions to combat burnout can be on an individual level as well as on the level of antecedent factors that lead to burnout. In 2016, Shanafelt and Noseworthy1 stressed the importance of leadership training on individual and institutional levels to specifically combat burnout. There is a lack of proper leadership training to combat burnout in medicine.2 The art and science of medicine are taught through the old dictum of “see one, do one, teach one.” A qualitative research was designed to study the sustainable effects of a 2-day coaching workshop using leadership training, emotional intelligence, and self-care on burnout among 6 program directors from the Houston area. The theory is that this workshop will help them understand, recognize, combat, and prevent physician burnout. The directors will be better able to self-care, improve their leadership skills, and feel more equipped to guide, train, and lead others.

There is a lack of proper leadership training to combat burnout in medicine.2 The art and science of medicine are taught through the old dictum of “see one, do one, teach one.” A qualitative research was designed to study the sustainable effects of a 2-day coaching workshop using leadership training, emotional intelligence, and self-care on burnout among 6 program directors from the Houston area. The theory is that this workshop will help them understand, recognize, combat, and prevent physician burnout. The directors will be better able to self-care, improve their leadership skills, and feel more equipped to guide, train, and lead others. The approach was defined as the Awareness, Acknowledgement, Action approach. The science of emotional intelligence and wellness and self-care coaching principles based on total wellness along its 6 dimensions (mental, physical, emotional, spiritual, financial/occupational, and social) were used. Each participant, before the workshop, underwent an emotional intelligence survey using the Emotional Quotient Inventory administered by MHS3 as well as the Maslach Burnout Inventory.4 During the workshop, group scores of burnout and emotional intelligence were reviewed. Furthermore, directors listed their top institutional problems and roadblocks in managing those problems.

onal intelligence survey using the Emotional Quotient Inventory administered by MHS3 as well as the Maslach Burnout Inventory.4 During the workshop, group scores of burnout and emotional intelligence were reviewed. Furthermore, directors listed their top institutional problems and roadblocks in managing those problems. The 6 female directors were from different ethnicities. Their age groups ranged from early 30s to mid-50s. Coaching enhances self-awareness and promotes self-growth. It uses innate strengths and abilities and helps individuals maximize them to reach their true potential. Group coaching is an effective and cost-saving approach that targets several individuals simultaneously.5 Using coaching techniques that focus on improving self-awareness, self-care, self-compassion, and boundary setting have led to behavioral changes among physician and improved patient care. There were preintervention and postintervention questionnaires. Discussion of the 9- month follow-up questionnaire is shown. The questionnaire reflects degree of subjective improvement. The scale ranges from 1 (least) to 5 (most) (Table).Table Nine-month Questionnaire Feedback

The 6 female directors were from different ethnicities. Their age groups ranged from early 30s to mid-50s. Coaching enhances self-awareness and promotes self-growth. It uses innate strengths and abilities and helps individuals maximize them to reach their true potential. Group coaching is an effective and cost-saving approach that targets several individuals simultaneously.5 Using coaching techniques that focus on improving self-awareness, self-care, self-compassion, and boundary setting have led to behavioral changes among physician and improved patient care. There were preintervention and postintervention questionnaires. Discussion of the 9- month follow-up questionnaire is shown. The questionnaire reflects degree of subjective improvement. The scale ranges from 1 (least) to 5 (most) (Table).Table Nine-month Questionnaire Feedback PDA PDB PDC PDD PDE AVG 1. I am able to enjoy more my experience/interaction with my patients. 5 5 4 4 5 4.6 2. I am better able to detect my burnout symptoms. 5 4 5 5 5 4.8 3. I feel more equipped to handle burnout and decrease its effects on myself and my patients. 5 4 5 4 5 4.6 4. I am more aware of my emotions and those of my patients and others around me. 5 5 5 4 5 4.8 5. I feel more engaged in my practice of medicine. 5 4 4 4 4 4.2 6. I understand the importance of self-care and am doing a better job at it. 5 4 4 5 5 4.6 7. I am getting improved feedback from my patients and my coworkers. 4 3 3 4 4 3.6 8. I am happier and more relaxed at work now. 5 4 4 4 5 4.4 9. My work-life balance has improved. 5 3 4 4 4 4 10. I feel I am better able to perform my duties as a leader/director. 5 3 5 5 5 4.6 11. I am more aware of the resident’s/fellow’s burnout symptoms. 5 4 5 5 5 4.8 12. I feel more confident in managing the resident’s/fellow’s burnout symptoms. 5 4 5 5 5 4.8 13. I would recommend such an intervention for program directors. 5 5 5 5 5 5 14. I would recommend such an intervention for other physicians. 5 5 5 5 5 5 15. I would recommend such an intervention to other health care professionals. 5 5 5 5 5 5 AVG = average; PDA = Program Director A; PDB = Program Director B; PDC = Program Director C; PDD = Program Director D; PDE = Program Director E.

5 5 5 5 14. I would recommend such an intervention for other physicians. 5 5 5 5 5 5 15. I would recommend such an intervention to other health care professionals. 5 5 5 5 5 5 AVG = average; PDA = Program Director A; PDB = Program Director B; PDC = Program Director C; PDD = Program Director D; PDE = Program Director E. The participants noted the workshop as extremely helpful. It revealed how little the directors knew about burnout, understood its pathophysiology, or were aware of emotional intelligence with its benefits/relationship to burnout, leadership, and wellness. Once awareness of burnout, emotional intelligence, and well-being was increased, there was improvement in understanding burnout and its relationships with emotional intelligence and wellness. Introducing the directors to the different techniques and their practical applications in enhancing emotional intelligence and wellness helped create a change in the way they thought and acted. The researchers helped introduce a 2-day workshop that seemed to have subjectively impactful and sustainable results over a 9-month period. To our knowledge, this is the first approach that combines the sciences of emotional intelligence, self-care, and leadership for one goal: Train the trainers so they are better able to handle the challenges of burnout before them, within them, and others. The personal and professional noticeable results felt by the directors perhaps open the door for larger scale interventions using the sciences of emotional intelligence, wellness, and self-leadership.

l: Train the trainers so they are better able to handle the challenges of burnout before them, within them, and others. The personal and professional noticeable results felt by the directors perhaps open the door for larger scale interventions using the sciences of emotional intelligence, wellness, and self-leadership. Grant Support: The workshop was funded by a grant from the Methodist Health Care System, Houston, TX. Potential Competing Interests: The intervention was done through a grant from Methodist Hospital to Vital Signs Vital Skills, a coaching company based in Texas. The grant helped cover the expenses of data gathering, travel, and the 2-day workshop. There are no financial gains from publishing this article.

To the Editor: Chronic pain (CP) management is a challenging task for primary care physicians, with at least 116 million adult Americans having CP associated with decreased quality of life.1 In 2010, around 9% of the US population older than 12 years were reported to be illicit drug users, with nonmedical use of prescription drugs being the second most commonly used drug.2 Primary care physicians, however, are often concerned when prescribing opioids about abuse, misuse, addiction, and potential prosecution and disciplinary actions.3 In 2012, the American Society of Interventional Pain Physicians (ASIPP) recommended comprehensive assessment and screening for opioid use and implementation of prescription drug monitoring programs (PDMPs) and urine drug screening (UDS) to decrease prescription drug abuse when patients are receiving CP management therapy.4 The ASIPP also recommended that “a robust agreement which is followed by all parties is essential in initiating and maintaining opioid therapy as such agreements reduce overuse, misuse, abuse, and diversion.”4 Similar use of PDMPs and UDS with annual urine drug testing has been recommended by the Centers for Disease Control and Prevention when prescribing opioids for CP.5

ich is followed by all parties is essential in initiating and maintaining opioid therapy as such agreements reduce overuse, misuse, abuse, and diversion.”4 Similar use of PDMPs and UDS with annual urine drug testing has been recommended by the Centers for Disease Control and Prevention when prescribing opioids for CP.5 In 2007, the internal medicine residency clinic at Western Michigan University Homer Stryker M.D. School of Medicine initiated a policy for opioid prescription for CP management requiring pain contracts, PDMPs via the Michigan Automated Prescription System (MAPS), and random UDS. We report the results of a study undertaken to analyze the experience of the clinic with pain management policy and to identify demographic parameters associated with violation of pain contracts. Patients and Methods We conducted a retrospective cohort study of all adult patients who participated in a program of long-term opioid therapy (defined as longer than 4 weeks) and a pain contract at our residency clinic between March 1, 2007, and June 30, 2013. Patients were identified as currently compliant with the pain contract (group 1), those weaned from opioid analgesics (group 2), and those who violated the pain contract (group 3). Intergroup comparison was done to determine high-risk demographic parameters associated with violation of pain contracts. Statistical analysis was performed using the χ2 test and SPSS statistical software, version 17.0 for Windows (SPSS Inc).

oid analgesics (group 2), and those who violated the pain contract (group 3). Intergroup comparison was done to determine high-risk demographic parameters associated with violation of pain contracts. Statistical analysis was performed using the χ2 test and SPSS statistical software, version 17.0 for Windows (SPSS Inc). Results Of the 325 patients who initiated the program of long-term opioid therapy and a pain contract, 106 (32.6%) were compliant with the contract (group 1), 47 (14.5%) were successfully weaned from opioids (group 2), and 172 (52.9%) violated the pain contract (group 3) (Table). Patients who violated the contract were younger (mean ± SD age, 49.5±11.2 years) compared with patients in group 2 (56.8±14.7 years) and group 1 (56.3±13.5 years) (P<.001). Patients who violated the contract were more likely to be current smokers (P<.001) and have an underlying psychiatric disorder (P=.023). Female sex was associated with successful weaning from opiates (P=.032). There was no significant difference in the 3 groups with respect to underlying diagnosis (P=.44), employment (P=.35), marital status (P=.56), or ethnicity (P=.13). For the 106 patients compliant with the pain contract, 104 patients (98.1%) had random UDS, and all 106 patients had MAPS review with 104 patients (98.1%) having their last MAPS review within the preceding 12 months.Table Distribution of Demographic Parameters in the 325 Study Patientsa,b

(P=.56), or ethnicity (P=.13). For the 106 patients compliant with the pain contract, 104 patients (98.1%) had random UDS, and all 106 patients had MAPS review with 104 patients (98.1%) having their last MAPS review within the preceding 12 months.Table Distribution of Demographic Parameters in the 325 Study Patientsa,b Variable Patients maintained on opioid analgesics (n=106) Patient weaned from opioid analgesics (n=47) Patients violating the pain contract (n=172) P value Age (y) <.001 Mean ± SD 56.3±13.5 56.8±14.7 49.5±11.2 Range 20-93 24-87 18-88 Sex .032 Male 52 (49.1) 15 (31.9) 92 (53.5) Female 54 (50.9) 32 (68.1) 80 (46.5) Ethnicity .13 African American 26 (24.5) 5 (10.6) 23 (13.4) White 73 (68.87) 37 (78.7) 62 (36.0) Unknown 5 (4.72) 0 85 (49.4) Other 2 (1.89) 5 (10.6) 2 (1.2) Relationship status .56 Single 43 (40.6) 23 (48.9) 76 (44.2) Married 35 (33.0) 11 (23.4) 43 (25.0) Other (divorced, widowed, legally separated) 28 (26.4) 12 (25.5) 33 (19.2) Unknown 0 1 (2.1) 20 (11.6) Employment status .35 Employed 8 (7.5) 2 (4.2) 17 (9.9) Unemployed 88 (83.0) 40 (85.1) 128 (74.4) Unknown 10 (9.4) 5 (10.6) 27 (15.7) Smoking <.001 Current 44 (41.5) 17 (36.2) 95 (55.2) Former 33 (31.1) 15 (31.9) 16 (9.3) Never 27 (25.5) 11 (23.4) 16 (9.3) Unknown 2 (1.9) 4 (8.5) 45 (26.2) Diagnosis .44 Abdominal pain 3 (2.8) 1 (2.1) 5 (2.9) Back pain 63 (59.4) 23 (48.9) 111 (64.5) Cancer 6 (5.7) 3 (6.4) 5 (2.9) CPS/fibromyalgia 5 (4.7) 2 (4.2) 4 (2.3) Degenerative joint disease 15 (14.2) 6 (12.8) 25 (14.5) Miscellaneous 14 (13.2) 12 (25.5) 22 (12.8) Presence of psychiatric disorder 39 (36.8) 17 (36.2) 89 (51.7) .023 a CPS = chronic pain syndrome.

5 (2.9) Back pain 63 (59.4) 23 (48.9) 111 (64.5) Cancer 6 (5.7) 3 (6.4) 5 (2.9) CPS/fibromyalgia 5 (4.7) 2 (4.2) 4 (2.3) Degenerative joint disease 15 (14.2) 6 (12.8) 25 (14.5) Miscellaneous 14 (13.2) 12 (25.5) 22 (12.8) Presence of psychiatric disorder 39 (36.8) 17 (36.2) 89 (51.7) .023 a CPS = chronic pain syndrome. b Data are presented as No. (percentage) of patients unless indicated otherwise. Percentages may not total 100 because of rounding. Discussion Our study indicated that a significant proportion of patients violated their pain contract. Younger age, associated psychiatric disorders, and current smoking were associated with violation of the pain contract. Previously, Chakrabortty et al6 reported middle age, obesity, and unmarried males to be associated with a breach in the narcotic use contract. Our study also highlights the high compliance of our residency clinic with ASIPP/Centers for Disease Control and Prevention guidelines. Although our study is limited because it is a single-center experience and a retrospective review, it highlights the high rate of violations/noncompliance among patients despite the use of structured guidelines and points toward the unmet need for development of alternative strategies for safe prescription of opioid analgesics.

Erdheim-Chester disease (ECD) is a rare form of non–Langerhans cell histiocytosis characterized by xanthogranulomatous infiltration of multiple organs by lipid-laden histiocytes. It is classified within the histiocytic neoplasms in the revised 2016 World Health Organization Classification. Histiocytes in this disease are characteristically CD68+ and CD1a−. Erdheim-Chester disease has a wide-ranging, nonspecific clinical spectrum and multiorgan involvement. The central nervous system (CNS) is commonly involved, with more than one-third of patients presenting with CNS lesions.1, 2 Conventionally, experience-based management of ECD involves the use of tumor necrosis factor–blocking agents, interleukin 1 antagonists, interferon alfa (IFN-α), corticosteroids, surgery, chemotherapy, and radiation.2 Molecular analysis of ECD samples has demonstrated a high prevalence of somatic BRAF V600E mutations in ECD, as high as 54% in one study.3 Currently, 2 United States Food and Drug Administration (FDA)–approved inhibitors of the mutant BRAF V600E kinase have been developed through structure-guided drug discovery approach: vemurafenib and dabrafenib.4 Accordingly, recent studies have demonstrated efficacy of vemurafenib and dabrafenib in the treatment of BRAF V600E–positive multisystem ECD as well as other BRAF V600E–positive malignancies.1, 5, 6, 7, 8, 9, 10, 11, 12, 13 This has led to recent FDA approval of vemurafenib for the treatment of ECD.14

and dabrafenib.4 Accordingly, recent studies have demonstrated efficacy of vemurafenib and dabrafenib in the treatment of BRAF V600E–positive multisystem ECD as well as other BRAF V600E–positive malignancies.1, 5, 6, 7, 8, 9, 10, 11, 12, 13 This has led to recent FDA approval of vemurafenib for the treatment of ECD.14 Both these inhibitors have been shown through in vitro melanoma and in vivo murine models to have limited blood-brain barrier penetration due to active efflux. However, both BRAF V600E kinase inhibitors have been shown to have efficacy in melanoma metastatic to the brain.5, 15 In addition, there is growing evidence that both vemurafenib and dabrafenib have activity against BRAF V600E–positive mutated ECD with CNS involvement.9, 16 Both BRAF V600E kinase inhibitors are known to cause considerable cutaneous adverse effects, as well as headaches and arthralgias, but only vemurafenib is known to frequently cause photosensitivity.17 Between the 2 drugs, dabrafenib has been shown to have greater brain distribution in comparison to vemurafenib.18, 19 In combination with the mitogen-activated protein kinase inhibitor trametinib, dabrafenib has demonstrated a substantial increased overall survival and lower rate of cutaneous neoplasms in comparison to vemurafenib alone in the treatment of metastatic melanoma.16

r brain distribution in comparison to vemurafenib.18, 19 In combination with the mitogen-activated protein kinase inhibitor trametinib, dabrafenib has demonstrated a substantial increased overall survival and lower rate of cutaneous neoplasms in comparison to vemurafenib alone in the treatment of metastatic melanoma.16 Report of Case We describe a 44-year-old female patient who has been under our care from August of 2015 through November 2017. The patient presented with a 2-year history of light-headedness and fatigue, ataxia, and dysarthria who was responsive to systemic treatment with a BRAF inhibitor. The patient's medical history was notable for anxiety and depression. In addition, the patient had been evaluated by magnetic resonance imaging (MRI) for an episode of vertigo 3 years before presentation, which showed a focal T2 signal abnormality and enhancement in the pons and thickening of the pituitary stalk (Supplemental Figure 1, available online at http://mcpiqojournal.org/). However, the patient did not receive initial treatment or follow-up and the etiology of the lesion was unclear. The patient was an unemployed librarian, with both parents living in good health. Her personal family history was unremarkable. She did not smoke, drink alcohol, or use illicit drugs.

The patient's medical history was notable for anxiety and depression. In addition, the patient had been evaluated by magnetic resonance imaging (MRI) for an episode of vertigo 3 years before presentation, which showed a focal T2 signal abnormality and enhancement in the pons and thickening of the pituitary stalk (Supplemental Figure 1, available online at http://mcpiqojournal.org/). However, the patient did not receive initial treatment or follow-up and the etiology of the lesion was unclear. The patient was an unemployed librarian, with both parents living in good health. Her personal family history was unremarkable. She did not smoke, drink alcohol, or use illicit drugs. On examination, the patient was oriented, with cranial nerves intact and symmetric. Sensation was intact in upper and lower extremities, but she was diffusely hyperreflexic in the bilateral upper and lower extremities. The patient had dysmetria of her upper and lower extremities with preserved motor strength. The patient had moderate dysmetria on finger-to-nose testing and heel-to-shin testing bilaterally. She had a wide-based gait but was able to maintain balance. She also had gross dysarthria and nystagmus on horizontal gaze bilaterally.

tient had dysmetria of her upper and lower extremities with preserved motor strength. The patient had moderate dysmetria on finger-to-nose testing and heel-to-shin testing bilaterally. She had a wide-based gait but was able to maintain balance. She also had gross dysarthria and nystagmus on horizontal gaze bilaterally. A lumbar puncture was performed to analyze the patient's cerebrospinal fluid (CSF). Flow cytometry of CSF revealed cells that were mostly CD56+CD3−. Her glucose level was 66 mg/dL (to convert to mmol/L, multiply by 0.0555), red blood cell count was 4 cells/μL, and total protein level was 26 mg/dL (to convert to g/L, multiply by 10.0). Pathologic analysis of the CSF was negative for malignant cells but showed few small mature lymphocytes. Venereal Disease Research Laboratory test results were negative and no cryptococcal antibodies were detected. The CSF cultures were negative for any fungi or viruses.

26 mg/dL (to convert to g/L, multiply by 10.0). Pathologic analysis of the CSF was negative for malignant cells but showed few small mature lymphocytes. Venereal Disease Research Laboratory test results were negative and no cryptococcal antibodies were detected. The CSF cultures were negative for any fungi or viruses. The MRI showed a more extensive area of increased T2/fluid-attenuated inversion recovery signal in the brain stem, persistent enhancement in the pons, thickening of the pituitary stalk, and a new enhancing lesion in the midbrain (Figure 1). Positron emission tomography/computed tomography (PET/CT) showed intense symmetrically increased radiotracer uptake involving the distal femur and tibia bilaterally (Supplemental Figure 2, available online at http://mcpiqojournal.org/).Figure 1 The MRI at presentation. A, Axial FLAIR image demonstrates progression of the brain-stem lesion (arrow). B and D, Axial and sagittal T1-weighted postcontrast images show irregular heterogeneous enhancement in the pons and thickening of the pituitary stalk (arrows). C, Axial T1-weighted postcontrast image shows new enhancing lesion in the midbrain. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.

nd D, Axial and sagittal T1-weighted postcontrast images show irregular heterogeneous enhancement in the pons and thickening of the pituitary stalk (arrows). C, Axial T1-weighted postcontrast image shows new enhancing lesion in the midbrain. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging. On December 28, 2015, a right tibial bone biopsy was performed (Supplemental Figure 3, available online at http://mcpiqojournal.org/). Immunohistochemical staining demonstrated an abundant population of histiocytes among the CD45-positive chronic inflammatory cells. Immunohistochemical staining for S100, Pax-8, keratin, and the BRAF V600E (VE-1 antibody) mutation was negative. However, next-generation sequencing analysis of the same bone tissue in January 2016 demonstrated the presence of a BRAF V600E mutation. Shortly afterward, the patient underwent whole-body technetium Tc99m bone scintigraphy, which showed bilateral symmetric increased activity involving the long bones, predominantly of the lower extremities (Figure 2).Figure 2 Whole-body technetium Tc99m bone scintigraphy performed before treatment shows bilateral symmetric increased activity involving the long bones, predominantly of the lower extremities.

which showed bilateral symmetric increased activity involving the long bones, predominantly of the lower extremities (Figure 2).Figure 2 Whole-body technetium Tc99m bone scintigraphy performed before treatment shows bilateral symmetric increased activity involving the long bones, predominantly of the lower extremities. In April 2016 (2 years after initial presentation), the patient was formally diagnosed with ECD and placed on combination therapy with dabrafenib and trametinib. Trametinib was added to prevent the development of squamous cell carcinoma of the skin.20 The patient was started on 2 mg of trametinib daily by mouth and her dabrafenib dose was gradually increased from 75 mg twice daily to 150 mg twice daily. She developed a rash on the torso and extremities, requiring a short course of corticosteroids and multiple dose adjustments of dabrafenib and trametinib. Her final regimen was dabrafenib at 75 mg twice daily and trametinib at 1 mg every evening. In August 2016, her dysarthria and gait had remarkably improved. The PET/CT at 4 months and 9 months after the initiation of treatment demonstrated remarkable interval improvement in the hypermetabolic skeletal lesions and resolution of the increased metabolic activity in the right hepatic lobe. No new hypermetabolic lesions were seen.

er dysarthria and gait had remarkably improved. The PET/CT at 4 months and 9 months after the initiation of treatment demonstrated remarkable interval improvement in the hypermetabolic skeletal lesions and resolution of the increased metabolic activity in the right hepatic lobe. No new hypermetabolic lesions were seen. The PET/CT (Figure 3) and MRI of the brain (Figure 4) showed response to treatment, with resolved signal abnormality and enhancement in the brain and decreased bone uptake.Figure 3 The FDG-PET scan demonstrates a symmetrical radiotracer uptake in the diaphysis and metaphysis of the long bones of legs (A). Response to treatment in the long bones assessed by FDG-PET scan performed after 4 (B), 10 (C), and 16 months (D) of treatment shows a marked reduction in tracer uptake especially in long bones of the tibias and the femurs. FDG-PET = fluorodeoxyglucose-positron emission tomography. Figure 4 Response to treatment. A, FLAIR axial image shows complete resolution of brain-stem signal abnormality. B, Postcontrast T1 sagittal image shows resolved brain-stem enhancement and normal pituitary stalk. FLAIR = fluid-attenuated inversion recovery.

The PET/CT (Figure 3) and MRI of the brain (Figure 4) showed response to treatment, with resolved signal abnormality and enhancement in the brain and decreased bone uptake.Figure 3 The FDG-PET scan demonstrates a symmetrical radiotracer uptake in the diaphysis and metaphysis of the long bones of legs (A). Response to treatment in the long bones assessed by FDG-PET scan performed after 4 (B), 10 (C), and 16 months (D) of treatment shows a marked reduction in tracer uptake especially in long bones of the tibias and the femurs. FDG-PET = fluorodeoxyglucose-positron emission tomography. Figure 4 Response to treatment. A, FLAIR axial image shows complete resolution of brain-stem signal abnormality. B, Postcontrast T1 sagittal image shows resolved brain-stem enhancement and normal pituitary stalk. FLAIR = fluid-attenuated inversion recovery. She was evaluated 10 months after continuous treatment. Although she had minor neurological deficits, her dysarthria had improved considerably. Finger-to-nose and heel-to-shin test results remained mildly abnormal on the left side but much improved. Her gait was steady and she was able to pivot without difficulty. Performance on the Romberg test was improved from previous examinations and demonstrated only minor instability. Her speech pattern had normalized, with minimal residual slurring. She continued to have minimal nystagmus on horizontal gaze bilaterally. Muscle tone and sensory examinations were normal and symmetric.

lty. Performance on the Romberg test was improved from previous examinations and demonstrated only minor instability. Her speech pattern had normalized, with minimal residual slurring. She continued to have minimal nystagmus on horizontal gaze bilaterally. Muscle tone and sensory examinations were normal and symmetric. Discussion Erdheim-Chester disease is marked by bilaterally symmetric bone infiltration composed of foamy histiocytes causing granulomatous and fibrotic changes. Neurologic involvement in ECD is not infrequent, as this patient exemplified through her mild cerebellar findings and pronounced dysarthria. Oftentimes, ECD is associated with soft-tissue sheathing of the thoracic or abdominal aorta, as seen on the PET/CT for this patient.1, 2 In a retrospective multicenter analysis of 53 patients with ECD, Arnaud et al21 demonstrated that CNS involvement is an independent factor for increased mortality while treatment with IFN-α was identified as an independent predictor of survival. In a phase 2 trial, Hyman et al10 investigated the efficacy of vemurafenib in nonmelanoma cancers with the BRAF V600E mutations in a study that included a cohort of 14 patients with ECD or Langerhans'-cell histiocytosis. In this study, 6 patients responded including 1 complete response and 5 patients who responded partially. The extensive CNS disease and presence of the BRAF V600E mutation in this patient's ECD steered the treatment of choice from IFN-α toward BRAF inhibitors.8, 9

14 patients with ECD or Langerhans'-cell histiocytosis. In this study, 6 patients responded including 1 complete response and 5 patients who responded partially. The extensive CNS disease and presence of the BRAF V600E mutation in this patient's ECD steered the treatment of choice from IFN-α toward BRAF inhibitors.8, 9 Although there are more reports in the literature demonstrating the efficacy of BRAF inhibitor vemurafenib in treating BRAF V600E–positive ECD, we chose the alternative BRAF inhibitor dabrafenib on the basis of improved overall survival without increased toxicity demonstrated in clinical trials of melanoma treatment, as well as improved CNS penetrance relative to vemurafenib.5, 6, 7, 9, 10, 13 A recent study following 51 patients with ECD treated with BRAF inhibitors demonstrated disease regression in all patients, with 1 patient treated with dabrafenib monotherapy from the beginning and 3 patients switched to dabrafenib from vemurafenib because of adverse effects.22

elative to vemurafenib.5, 6, 7, 9, 10, 13 A recent study following 51 patients with ECD treated with BRAF inhibitors demonstrated disease regression in all patients, with 1 patient treated with dabrafenib monotherapy from the beginning and 3 patients switched to dabrafenib from vemurafenib because of adverse effects.22 Conclusion Recently, the FDA approved the use of vemurafenib in patients with ECD who carry the BRAF V600E mutation.14 There is currently no standard accepted regimen to treat ECD. Of the various treatments for this disease, IFN-α is the most often tried but there are Serious adverse effects and the response rate is unclear. In this case report, we demonstrate a progressive and sustained response of a combination therapy with dabrafenib, a BRAF inhibitor, and trametinib, a mitogen-activated protein kinase inhibitor. In a patient presenting with brain-stem disease, the presence of BRAF V600E mutation presents unique opportunities for targeted treatment. We believe that a clinical trial comparing the efficacy of dabrafenib to vemurafenib is warranted, possibly leading the way for the FDA approval for another treatment option for this orphan disease. Currently, there is a phase 2 clinical trial sponsored by the Cancer Therapy Evaluation Program that is enrolling new patients with ECD with BRAF V600E mutations and treating with dabrafenib and trametinib (www.clinicaltrials.gov #NCT02281760). Supplemental Online Material Supplementary Figures 1-3

Conclusion Recently, the FDA approved the use of vemurafenib in patients with ECD who carry the BRAF V600E mutation.14 There is currently no standard accepted regimen to treat ECD. Of the various treatments for this disease, IFN-α is the most often tried but there are Serious adverse effects and the response rate is unclear. In this case report, we demonstrate a progressive and sustained response of a combination therapy with dabrafenib, a BRAF inhibitor, and trametinib, a mitogen-activated protein kinase inhibitor. In a patient presenting with brain-stem disease, the presence of BRAF V600E mutation presents unique opportunities for targeted treatment. We believe that a clinical trial comparing the efficacy of dabrafenib to vemurafenib is warranted, possibly leading the way for the FDA approval for another treatment option for this orphan disease. Currently, there is a phase 2 clinical trial sponsored by the Cancer Therapy Evaluation Program that is enrolling new patients with ECD with BRAF V600E mutations and treating with dabrafenib and trametinib (www.clinicaltrials.gov #NCT02281760). Supplemental Online Material Supplementary Figures 1-3 Supplemental material can be found online at http://mcpiqojournal.org/. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data. Potential Competing Interests: The authors report no competing interests.

Heart failure (HF) is a commonly seen complication in patients with acute myocardial infarction (AMI), with an incidence ranging from 19% to 45%.1, 2, 3, 4, 5, 6, 7 Clearly, HF adversely affects survival, hospital readmissions, and quality of life of patients with AMI.1, 5, 6, 8, 9, 10 During the past decade, substantial improvements in AMI revascularization and medical therapies have occurred, along with tremendous increases in the burden of cardiovascular (CV) and non-CV comorbidities.11 Recent data describing national trends in the incidence, management, and clinical outcomes of HF-complicated ST-segment elevation myocardial infarction (STEMI) hospitalizations in a US population are limited. Note that previous studies have been limited to single community-based settings, smaller sample sizes, and descriptions of events from the 1970s to the early 2000s. In addition, the results are controversial.2, 4, 5, 12, 13 Hence, we studied a large sample to examine the national temporal trends in the incidence, CV interventions, and in-hospital outcomes associated with HF-complicated STEMI hospitalization using the 2003 through 2010 Nationwide Inpatient Sample (NIS) databases.

. In addition, the results are controversial.2, 4, 5, 12, 13 Hence, we studied a large sample to examine the national temporal trends in the incidence, CV interventions, and in-hospital outcomes associated with HF-complicated STEMI hospitalization using the 2003 through 2010 Nationwide Inpatient Sample (NIS) databases. Patients and Methods We performed this study using 2003 through 2010 data from the NIS, the largest publicly available all-payer database of US hospital inpatient stays. The NIS is an administrative data set sponsored by the Agency for Healthcare Research and Quality as a part of the Healthcare Cost and Utilization Project.14 The NIS includes all discharge records for the sampled hospitals and data for approximately 8 million inpatient stays from approximately 1000 hospitals in all participating states (n=45 in 2010). It is approximately a 20% stratified sample of all US hospitals, defined as “all non-Federal, short-term, general, and other specialty hospitals, excluding hospital units of institutions.”14 Each hospital visit is treated as an individual entry and is coded with 1 principal diagnosis, up to 24 secondary diagnoses, and 15 procedural diagnoses associated with that stay. Discharge weights, provided for each patient discharge record, were used to obtain national estimates for each year. The NIS database provides statistical sampling weights as a variable “DISCWT” that can be used to calculate expected hospitalization rates in the United States.14 The internal and external validity of the NIS database are maintained through annual data quality assessments and comparison with other databases, such as the National Hospital Discharge Survey and MedPAR (Medicare Provider and Analysis Review). These reports are published on the NIS website (http://www.hcup-us.ahrq.gov/db/nation/nis/nisrelatedreports.jsp).

he NIS database are maintained through annual data quality assessments and comparison with other databases, such as the National Hospital Discharge Survey and MedPAR (Medicare Provider and Analysis Review). These reports are published on the NIS website (http://www.hcup-us.ahrq.gov/db/nation/nis/nisrelatedreports.jsp). We used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (410.xx) listed as the primary diagnosis to identify patients with AMI from January 1, 2003, through December 31, 2010. Patients with the principal diagnosis of STEMI were then identified using ICD-9-CM codes 410.x1, except code 410.71, as used in other studies.15 We chose the principal diagnosis because it is considered the primary reason for hospital admission. All patients with a diagnostic code of 410.7x (non-STEMI) in any of the diagnostic fields were completely excluded to limit analysis to only STEMI hospitalizations. In administrative databases, the AMI diagnosis identified using ICD-9-CM codes has been found to have specificity of 99.5%, sensitivity of 72.4%, a negative predictive value of 96.1%, and a positive predictive value of 95.9%.16 Patients with HF-complicated STEMI hospitalization were then defined as patients with STEMI without a history of HF but with HF at the time of discharge identified using ICD-9-CM codes 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, and 428.x listed anywhere except the primary diagnosis. These ICD-9-CM codes have been previously validated and also used in administrative database studies to accurately identify patients with HF.16, 17, 18, 19, 20 We then identified patients with cardiogenic shock to create 2 groups: HF-complicated STEMI with and without cardiogenic shock. Coronary interventions were identified as percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), and diagnostic coronary angiography (dCA).

s with HF.16, 17, 18, 19, 20 We then identified patients with cardiogenic shock to create 2 groups: HF-complicated STEMI with and without cardiogenic shock. Coronary interventions were identified as percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), and diagnostic coronary angiography (dCA). We initially studied the overall trends in the proportion of HF-complicated STEMI hospitalizations. Then an analysis was conducted for the HF with cardiogenic shock and HF without cardiogenic shock subgroups. We also examined the trends in cardiac interventions (PCI, CABG, and dCA). The primary outcome of interest was all-cause in-hospital mortality, defined as “died” during the hospitalization encounter in the NIS database. We used the median length of stay (LOS) and the consumer price index (CPI)–adjusted median hospital cost (in 2010 US dollars) as secondary outcomes. Costs were inflation adjusted using the US Bureau of Labor Statistics' CPI, with 2010 as the index base.

s “died” during the hospitalization encounter in the NIS database. We used the median length of stay (LOS) and the consumer price index (CPI)–adjusted median hospital cost (in 2010 US dollars) as secondary outcomes. Costs were inflation adjusted using the US Bureau of Labor Statistics' CPI, with 2010 as the index base. Baseline patient characteristics used included demographic characteristics (age, sex, race, primary expected payer, weekday vs weekend admission, and median household income for patient zip code), clinical comorbidities (such as diabetes mellitus with and without complications, smoking, dyslipidemia, hypertension, obesity, alcohol abuse, atrial fibrillation, known coronary artery disease, previous AMI, carotid artery disease, peripheral vascular disease, liver disease, acute renal failure, and chronic pulmonary disease); and in-hospital procedures (PCI, CABG, and dCA). A list of ICD-9-CM and Clinical Classifications Software codes used to identify comorbidities and in-hospital procedures is provided in the Supplemental Table (available online at http://www.mcpiqojournal.org). Hospital characteristics, such as hospital region (northeast, midwest, south, and west), bed size (small, medium, and large), location (rural, urban), and teaching status, were also included.

morbidities and in-hospital procedures is provided in the Supplemental Table (available online at http://www.mcpiqojournal.org). Hospital characteristics, such as hospital region (northeast, midwest, south, and west), bed size (small, medium, and large), location (rural, urban), and teaching status, were also included. For trend analysis, we used the Mantel-Haenszel χ2 test of linear association for categorical variables and linear regression for continuous variables. To determine whether there was temporal variability from year to year in the incidence of HF-complicated STEMI, coronary intervention, and in-hospital mortality, we used unadjusted and multivariable-adjusted logistic regression models to determine the odds of developing HF complication, undergoing coronary intervention, or dying during hospitalization each year relative to 2003. We used 2 types of regression models. Model 1 was adjusted for all the demographic characteristics, hospital characteristics, and clinical comorbidities, and model 2 was adjusted for all the covariates (as in model 1) along with coronary intervention. Model 2 was used everywhere to obtain adjusted odds ratios (AORs) except when mentioned otherwise. In both models, we entered calendar year as a continuous variable to obtain unadjusted ORs and AORs (per year) for the overall temporal trend and then as a categorical variable (with 2003 as the reference year) to determine whether there was temporal variability from year to year. Temporal trends in median LOS and median CPI-adjusted hospital charges were also examined.

uous variable to obtain unadjusted ORs and AORs (per year) for the overall temporal trend and then as a categorical variable (with 2003 as the reference year) to determine whether there was temporal variability from year to year. Temporal trends in median LOS and median CPI-adjusted hospital charges were also examined. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23.0 (IBM Corp). All P values were 2 sided, with a significance threshold of P<.001. A lower-than-usual P value threshold was selected to correct for the effects of a large sample size as well as inflation of type I error because of repeated testing using a large number of variables. Categorical variables are expressed as percentages and continuous variables as mean ± SD or median (interquartile range [IQR]) as appropriate. The OR and 95% CI are used to report the results of logistic regression.

size as well as inflation of type I error because of repeated testing using a large number of variables. Categorical variables are expressed as percentages and continuous variables as mean ± SD or median (interquartile range [IQR]) as appropriate. The OR and 95% CI are used to report the results of logistic regression. Results From January 1, 2003, through December 31, 2010, 1,990,002 STEMI hospitalizations with a primary diagnosis of STEMI in patients 18 years and older were identified. The overall incidence of HF complication in patients admitted with STEMI across 8 years was 23.7% (n=471,525), with a decrease in the proportion of patients from 25.4% in 2003 to 20.7% in 2010 (AOR [per year], 0.987; 95% CI, 0.985-0.989; P<.001) (Figure 1). In patients with HF-complicated STEMI, the incidence of cardiogenic shock was 16.5% (n=77,627), and the proportion of these patients increased from 13.9% (95% CI, 13.6%-14.1%) in 2003 to 22.6% (95% CI, 22.2%-23.0%) in 2010 (AOR [per year], 1.093; 95% CI, 1.088-1.098; P<.001) (Figure 2).Figure 1 Trends in the incidence rates of heart failure–complicated ST-segment elevation myocardial infarction (STEMI). Heart failure (%) was calculated as the number of patients with HF complication divided by the number of patients with STEMI per year × 100 (P trend<.001).

093; 95% CI, 1.088-1.098; P<.001) (Figure 2).Figure 1 Trends in the incidence rates of heart failure–complicated ST-segment elevation myocardial infarction (STEMI). Heart failure (%) was calculated as the number of patients with HF complication divided by the number of patients with STEMI per year × 100 (P trend<.001). Figure 2 Trends in the incidence of cardiogenic shock complication in heart failure (HF)–complicated ST-segment elevation myocardial infarction (STEMI). Cardiogenic shock (%) was calculated as the number of patients with cardiogenic shock divided by the number of patients with HF-complicated STEMI per year × 100 (P trend<.001). Baseline demographic characteristics, hospital characteristics, and clinical comorbidities are presented in Table 1 for patients who experienced acute HF while hospitalized for STEMI during the study period. The mean ± SD age decreased from 73.4±13.4 years to 71.5±14.2 years (P trend<.001). From 2003 through 2010, there was an increase in the proportion of men; white individuals constituted the highest proportion of patients; and the prevalence of all comorbidities increased, except chronic pulmonary disease and atrial fibrillation, for which the prevalence decreased (all P trend<.001).Table 1 Baseline Demographic Characteristics, Hospital Characteristics, and Comorbidities of Patients With Heart Failure–Complicated ST-Segment Elevation Myocardial Infarctiona Variable 2003 2004 2005 2006 2007 2008 2009 2010 Overall Demographic characteristics No.

Baseline demographic characteristics, hospital characteristics, and clinical comorbidities are presented in Table 1 for patients who experienced acute HF while hospitalized for STEMI during the study period. The mean ± SD age decreased from 73.4±13.4 years to 71.5±14.2 years (P trend<.001). From 2003 through 2010, there was an increase in the proportion of men; white individuals constituted the highest proportion of patients; and the prevalence of all comorbidities increased, except chronic pulmonary disease and atrial fibrillation, for which the prevalence decreased (all P trend<.001).Table 1 Baseline Demographic Characteristics, Hospital Characteristics, and Comorbidities of Patients With Heart Failure–Complicated ST-Segment Elevation Myocardial Infarctiona Variable 2003 2004 2005 2006 2007 2008 2009 2010 Overall Demographic characteristics No. of cases (weighted) 78,845 76,901 67,023 62,870 52,839 48,588 44,111 40,348 471,525 Age (y), mean ± SD 73.4±13.4 73.6±13.2 73.9±13.5 73.2±13.8 72.9±14.1 72.5±14.2 71.7±14.2 71.5±14.2 73.0±13.8 Female sex (%) 49.1 48.4 48.3 47.2 46.8 46.2 44.9 43.5 47.2 Race (%) White 77.9 79.6 81.1 80.7 78.5 79.6 77.5 76.9 79.1 African American 8.3 8.5 6.7 7.4 8.2 7.5 8.1 8.8 7.9 Hispanic 8.4 6.6 7.1 6.9 7.2 5.8 6.7 7.6 7.1 Asian or Pacific Islander 2.8 2.1 1.9 1.9 2.2 2.7 2.7 2.8 2.4 Native American 0.1 0.3 0.3 0.6 0.8 1.0 0.8 0.8 0.5 Other 2.5 2.9 2.9 2.4 3.0 3.4 4.2 3.1 3.0 Primary expected payer (%) Medicare 73.5 72.5 72.5 71.3 68.7 67.7 65.7 63.9 70.2 Medicaid 4.5 4.3 4.6 4.5 5.0 5.1 5.5 6.8 4.9 Private insurance 17.2 17.7 17.5 17.7 19.6 19.6 21.0 20.8 18.6 Self-pay 2.9 3.4 3.3 3.9 3.8 4.6 5.2 5.5 3.9 No charge 0.2 0.3 0.4 0.3 0.4 0.4 0.3 0.4 0.3 Other 1.7 1.8 1.8 2.3 2.4 2.6 2.3 2.6 2.1 Median household income (%) 0-25th percentile 27.8 29.9 29.3 28.8 30.1 30.1 29.1 29.0 29.2 26th-50th percentile 29.0 28.9 27.4 28.0 26.9 29.5 28.2 28.0 28.3 51st-75th percentile 24.7 21.7 24.1 23.6 23.0 21.9 23.2 24.4 23.3 76th-100th percentile 18.4 19.5 19.2 19.6 20.0 18.5 19.4 18.5 19.1 Weekend admission (%) 26.3 26.0 25.3 26.1 26.9 26.9 27.3 28.0 26.4 Elective admission (%) 8.6 7.7 7.8 7.6 7.6 6.6 5.9 6.6 7.5 Hospital characteristics Region (%) Northeast 14.2 18.0 18.5 17.2 19.6 18.2 18.4 19.1 17.7 Midwest 26.7 24.2 24.1 24.7 25.3 23.1 22.6 24.7 24.6 South 39.6 38.8 39.3 39.5 36.4 39.6 39.8 35.6 38.7 West 19.5 19.0 18.1 18.6 18.7 19.0 19.2 20.6 19.0 Bed size (%) Small 11.2 12.0 11.3 15.7 12.5 14.6 11.5 12.3 12.6 Medium 25.0 24.1 24.1 24.3 25.9 22.9 22.4 20.3 23.9 Large 63.8 63.9 64.7 59.9 61.5 62.4 66.1 67.3 63.5 Urban location (%) 80.3 83.6 82.5 83.7 83.3 84.1 86.9 86.6 83.5 Teaching hospital (%) 40.1 40.3 34.7 41.3 43.8 40.9 44.8 43.9 40.8 Clinical comorbidities (%)b Smoking 14.6 14.6 15.9 17.5 20.1 23.2 28.9 29.3 19.3 Alcohol abuse 1.8 2.1 2.1 2.2 2.8 2.6 2.8 3.1 2.3 Hypertension 50.7 50.9 52.4 54.0 56.5 60.7 62.6 63.5 55.3 Dyslipidemia 23.5 25.9 28.5 31.0 36.1 40.2 46.6 49.2 33.1 Diabetes (uncomplicated) 27.7 27.5 27.2 27.6 28.9 29.2 29.5 30.5 28.3 Diabetes (complicated) 6.1 6.1 6.1

ing 14.6 14.6 15.9 17.5 20.1 23.2 28.9 29.3 19.3 Alcohol abuse 1.8 2.1 2.1 2.2 2.8 2.6 2.8 3.1 2.3 Hypertension 50.7 50.9 52.4 54.0 56.5 60.7 62.6 63.5 55.3 Dyslipidemia 23.5 25.9 28.5 31.0 36.1 40.2 46.6 49.2 33.1 Diabetes (uncomplicated) 27.7 27.5 27.2 27.6 28.9 29.2 29.5 30.5 28.3 Diabetes (complicated) 6.1 6.1 6.1 6.1 6.3 5.7 7.1 6.7 6.2 Obesity 5.1 5.2 5.8 6.3 6.7 9.0 10.5 11.0 7.0 Atrial fibrillationc 23.5 24.3 25.2 24.6 23.8 21.7 22.7 23.5 23.8 Previous myocardial infarction 7.3 7.4 7.2 7.8 8.7 8.6 10.5 10.6 8.2 Coronary artery disease 67.8 68.5 70.2 73.0 74.3 77.4 79.8 80.4 67.8 Carotid artery disease 0.9 0.8 0.9 1.0 1.2 1.4 1.9 2.0 1.2 Peripheral vascular disease 8.6 8.9 8.8 9.3 10.6 11.5 12.9 11.6 9.9 Chronic pulmonary disease 25.1 25.8 27.9 27.2 26.1 24.2 25.1 24.6 25.9 Fluid and electrolyte disorder 22.4 23.2 23.9 25.6 26.2 27.2 29.5 30.2 25.4 Renal failure (chronic) 11.1 11.6 14.1 20.7 22.4 21.0 22.4 23.3 17.3 Liver disease 0.7 0.8 0.8 0.9 1.1 1.0 1.0 1.1 0.9 a The Mantel-Haenszel χ2 test of linear association was used for categorical variables, and linear regression was used for continuous variables. All P values are <.001. b Comorbidities were extracted using the International Classification of Diseases, Ninth Revision, Clinical Modification and Clinical Classifications Software codes. c The exact values were 23.52% in 2003 and 23.51% in 2010.

6.1 6.3 5.7 7.1 6.7 6.2 Obesity 5.1 5.2 5.8 6.3 6.7 9.0 10.5 11.0 7.0 Atrial fibrillationc 23.5 24.3 25.2 24.6 23.8 21.7 22.7 23.5 23.8 Previous myocardial infarction 7.3 7.4 7.2 7.8 8.7 8.6 10.5 10.6 8.2 Coronary artery disease 67.8 68.5 70.2 73.0 74.3 77.4 79.8 80.4 67.8 Carotid artery disease 0.9 0.8 0.9 1.0 1.2 1.4 1.9 2.0 1.2 Peripheral vascular disease 8.6 8.9 8.8 9.3 10.6 11.5 12.9 11.6 9.9 Chronic pulmonary disease 25.1 25.8 27.9 27.2 26.1 24.2 25.1 24.6 25.9 Fluid and electrolyte disorder 22.4 23.2 23.9 25.6 26.2 27.2 29.5 30.2 25.4 Renal failure (chronic) 11.1 11.6 14.1 20.7 22.4 21.0 22.4 23.3 17.3 Liver disease 0.7 0.8 0.8 0.9 1.1 1.0 1.0 1.1 0.9 a The Mantel-Haenszel χ2 test of linear association was used for categorical variables, and linear regression was used for continuous variables. All P values are <.001. b Comorbidities were extracted using the International Classification of Diseases, Ninth Revision, Clinical Modification and Clinical Classifications Software codes. c The exact values were 23.52% in 2003 and 23.51% in 2010. Figure 3 describes the temporal changes in the use of dCA, PCI, and CABG in patients with acute HF with STEMI and subgroups based on cardiogenic shock as a coexisting complication. Use of dCA and PCI increased from 44.3% in 2003 to 62.1% in 2010 (unadjusted OR [per year], 1.116; 95% CI, 1.113-1.119; P<.001) and from 25.0% in 2003 to 48.1% in 2010 (unadjusted OR [per year], 1.164; 95% CI, 1.161-1.167; P<.001), respectively, whereas CABG procedures decreased from 9.7% in 2003 to 8.9% in 2010 (unadjusted OR [per year], 1.000, 95% CI, 0.996-1.004; P=.99). Even after adjustment for demographic characteristics, hospital characteristics, and comorbidities, a similar trend in the utilization rates of PCI (AOR [per year], 1.174; 95% CI, 1.170-1.178; P<.001), dCA (AOR [per year], 1.126; 95% CI, 1.122-1.130; P<.001), and CABG procedures (AOR [per year], 0.979; 95% CI, 0.974-0.984; P<.001) was observed (Table 2). Similar trends were present in the subgroups with and without cardiogenic shock for the use of invasive coronary interventions.Figure 3 Trends in procedure use (percutaneous coronary intervention [PCI], diagnostic coronary angiography [dCA], and coronary artery bypass graft [CABG]) in patients with heart failure (HF)–complicated ST-segment elevation myocardial infarction (STEMI) (A), patients with HF-complicated STEMI with cardiogenic shock (B), and patients with HF-complicated STEMI without cardiogenic shock (C) (left y-axis). Procedure use (%) was calculated as the number of patients who underwent the procedure (PCI, dCA, CABG) divided by the number of patients with HF-complicated STEMI, HF-complicated STEMI with cardiogenic shock, or HF-complicated STEMI without cardiogenic shock, respectively, per year × 100 (all P trend<.001). Trends in in-hospital mortality in patients with HF-complicated STEMI, HF-complicated STEMI with cardiogenic shock, or HF-complicated STEMI without cardiogenic shock, respectively (right y-axis).

with cardiogenic shock, or HF-complicated STEMI without cardiogenic shock, respectively, per year × 100 (all P trend<.001). Trends in in-hospital mortality in patients with HF-complicated STEMI, HF-complicated STEMI with cardiogenic shock, or HF-complicated STEMI without cardiogenic shock, respectively (right y-axis). In-hospital mortality (%) was calculated as the number of patients who died in the hospital divided by the number of patients with HF-complicated STEMI, HF-complicated STEMI with cardiogenic shock, or HF-complicated STEMI without cardiogenic shock, respectively, per year × 100 (all P trend<.001). Table 2 In-hospital Cardiovascular Interventions and Mortalitya

In-hospital mortality (%) was calculated as the number of patients who died in the hospital divided by the number of patients with HF-complicated STEMI, HF-complicated STEMI with cardiogenic shock, or HF-complicated STEMI without cardiogenic shock, respectively, per year × 100 (all P trend<.001). Table 2 In-hospital Cardiovascular Interventions and Mortalitya Variable Odds ratio (per year) (95% CI) P value Overall HF-complicated STEMI hospitalizations PCI UOR 1.164 (1.161-1.167) <.001 AORb 1.174 (1.170-1.178) <.001 CABG UOR 1.000 (0.996-1.004) .99 AORb 0.979 (0.974-0.984) <.001 dCA UOR 1.116 (1.113-1.119) <.001 AORb 1.126 (1.122-1.130) <.001 In-hospital mortality UOR 0.970 (0.967-0.973) <.001 AOR-1b 0.992 (0.988-0.997) <.001 AOR-2c 1.012 (1.008-1.017) <.001 HF-complicated STEMI hospitalizations without cardiogenic shock PCI UOR 1.133 (1.126-1.140) <.001 AORb 1.172 (1.168-1.177) <.001 CABG UOR 0.986 (0.981-0.991) <.001 AORb 0.966 (0.960-0.972) <.001 dCA UOR 1.109 (1.106-1.112) <.001 AORb 1.124 (1.119-1.128) <.001 In-hospital mortality UOR 0.957 (0.953-0.961) <.001 AOR-1b 0.977 (0.971-0.982) <.001 AOR-2c 1.001 (.996-1.007) .63 HF-complicated STEMI hospitalizations with cardiogenic shock PCI UOR 1.160 (1.156-1.163) <.001 AORb 1.138 (1.129-1.147) <.001 CABG UOR 1.003 (0.994-1.011) .50 AORb 0.992 (0.982-1.003) .16 dCA UOR 1.098 (1.091-1.106) <.001 AORb 1.097 (1.087-1.106) <.001 In-hospital mortality UOR 0.922 (0.916-0.928) <.001 AOR-1b 0.931 (0.923-0.938) <.001 AOR-2c 0.955 (0.949-0.963) <.001 a AOR = adjusted odds ratio; CABG = coronary artery bypass graft; dCA = diagnostic coronary angiography; HF = heart failure; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; UOR = unadjusted odds ratio.

<.001 AOR-1b 0.931 (0.923-0.938) <.001 AOR-2c 0.955 (0.949-0.963) <.001 a AOR = adjusted odds ratio; CABG = coronary artery bypass graft; dCA = diagnostic coronary angiography; HF = heart failure; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; UOR = unadjusted odds ratio. b Model 1 is adjusted for patient demographic characteristics, hospital characteristics, and clinical comorbidities. c Model 2 is adjusted for patient demographic characteristics, hospital characteristics, clinical comorbidities, and invasive coronary intervention. Trends for In-hospital Mortality In-hospital mortality in the overall cohort of patients with acute HF-complicated STEMI was 16.9%. A decreasing trend for in-hospital mortality was seen from 18.1% in 2003 to 15.1% in 2010 (unadjusted OR [per year], 0.970; 95% CI, 0.967-0.973; P <.001) (Figure 3A). When adjusted for demographic characteristics, hospital characteristics and comorbidities, there was a declining trend in in-hospital mortality from 2003 to 2010 in patients with STEMI (AOR [per year], 0.992; 95% CI, 0.988-0.997; P<.001). After additional adjustment for cardiac intervention, the effect of year on death was significantly attenuated (AOR [per year], 1.012; 95% CI, 1.008-1.017; P<.001) (Table 2). Similar results were present in the subgroup without cardiogenic shock, and the AOR for the cardiogenic shock subgroup did not change significantly after adjustment (Table 2).

r cardiac intervention, the effect of year on death was significantly attenuated (AOR [per year], 1.012; 95% CI, 1.008-1.017; P<.001) (Table 2). Similar results were present in the subgroup without cardiogenic shock, and the AOR for the cardiogenic shock subgroup did not change significantly after adjustment (Table 2). Median LOS and Hospitalization Costs Table 3 represents median LOS and CPI-adjusted hospitalization cost for the overall cohort and subgroups. The median (IQR) LOS and CPI-adjusted hospital cost for the overall cohort with acute HF–complicated STEMI were 5 (3-9) days and $39,717 ($16,646-$82,184), respectively. Both median LOS and hospitalization cost for the subgroup with HF-complicated STEMI with cardiogenic shock were significantly higher than for those without cardiogenic shock (P<.001). Although the median LOS remained constant for the overall group and the individual subgroups, CPI-adjusted hospitalization cost increased across 8 years (2003-2010) (Table 3).Table 3 Median Length of Stayand Consumer Price Index-Adjusted Cost of Hospitalization

higher than for those without cardiogenic shock (P<.001). Although the median LOS remained constant for the overall group and the individual subgroups, CPI-adjusted hospitalization cost increased across 8 years (2003-2010) (Table 3).Table 3 Median Length of Stayand Consumer Price Index-Adjusted Cost of Hospitalization Year Median length of stay (d), median (IQR) Consumer Price Index-adjusted cost of hospitalization (2010 USD), median (IQR) Overall HF-complicated STEMI hospitalizations 2003 5 (3-9) 34,810 (15674-73,800) 2004 5 (3-9) 37,874 (16,684-79,994) 2005 5 (3-9) 38,051 (16,096-83,149) 2006 5 (3-9) 43,034 (17,728-86,537) 2007 5 (3-9) 45,051 (19,673-89,965) 2008 5 (3-8) 48,144 (21,114-93060) 2009 5 (3-9) 56,499 (25,117-109,714) 2010 5 (3-8) 61,899 (27,422-119,511) HF-complicated STEMI hospitalizations with cardiogenic shock 2003 8 (3-13) 74,927 (32,346-140,144) 2004 8 (3-13) 83,637 (37,656-148,923) 2005 7 (3-13) 85,184 (37,732-154,984) 2006 8 (4-13) 88,727 (47,150-157,856) 2007 7 (3-13) 90,330 (47,218-161,475) 2008 7 (3-12) 92,867 (48,108-163,252) 2009 8 (4-14) 112,209 (60,694-204,285) 2010 8 (4-13) 116,976 (60,590-200,649) HF-complicated STEMI hospitalizations without cardiogenic shock 2003 5 (3-9) 31,196 (14,540-64,601) 2004 5 (3-8) 33,811 (15,647-68,717) 2005 5 (3-8) 33,569 (14,949-70,910) 2006 5 (3-8) 37,181 (16,011-74,208) 2007 5 (3-8) 38,976 (17,395-76,218) 2008 5 (3-8) 41,990 (18,814-78,382) 2009 5 (3-8) 48,003 (20,987-87,968) 2010 4 (3-7) 51,292 (23,029-96,054) HF = heart failure; IQR = interquartile range; STEMI = ST-segment elevation myocardial infarction.

,717) 2005 5 (3-8) 33,569 (14,949-70,910) 2006 5 (3-8) 37,181 (16,011-74,208) 2007 5 (3-8) 38,976 (17,395-76,218) 2008 5 (3-8) 41,990 (18,814-78,382) 2009 5 (3-8) 48,003 (20,987-87,968) 2010 4 (3-7) 51,292 (23,029-96,054) HF = heart failure; IQR = interquartile range; STEMI = ST-segment elevation myocardial infarction. Discussion In this large real-world US population–based observational study, we found decreasing rates of HF complication in STEMI hospitalizations from 2003 through 2010 despite a significant increase in the CV and non-CV comorbidity burden. The proportion of patients with HF-complicated STEMI with cardiogenic shock increased significantly. There was a temporal increase in PCI and dCA use, in-hospital survival, and median hospital charges in patients with STEMI with acute HF complication. The temporal changes in cardiac interventions likely played an important role in mediating the secular decrease in in-hospital mortality of patients with STEMI with acute HF complication.

al increase in PCI and dCA use, in-hospital survival, and median hospital charges in patients with STEMI with acute HF complication. The temporal changes in cardiac interventions likely played an important role in mediating the secular decrease in in-hospital mortality of patients with STEMI with acute HF complication. Previous studies have reported incidence rates of HF-complicated AMI hospitalization ranging from 19% to 40%.2, 4, 5, 6, 12, 13 The results with respect to temporal trends from different studies are controversial. A report from the National Registry of Myocardial Infarction-2 (NRMI-2) reported an overall incidence of 19.1% of HF complication in 190,518 STEMI admissions from 1994 to 1998.6 Researchers from the Worcester Heart Attack Study reported an overall incidence of 32.4% in 11,061 patients with AMI, with a decline in the incidence of HF complication from 35.4% in 1975 to 25.8% in 2005.5 Gerber et al21 also observed a temporal declining trend in HF complication (in person-years) in 2596 patients with AMI from 10.8 in 1990 to 1996 to 9.8 in 2004 to 2010. In contrast, other studies, such as those from Olmsted County and the Framingham Heart Study, have reported conflicting data on events from the 1970s to the early 2000s.2, 4, 12, 13 Although the Framingham Heart Study reported increases in post-MI HF incidence at both 30 days (from 10% in 1970-1979 to 23.1% in 1990-1999) and 5 years (from 27.6% in 1970-1979 to 31.9% in 1990-1999), a study from Olmsted County reported a reduction in the incidence at 28 days (from 27% in 1979-1984 to 23% in 1990-1994) and 5 years (from 40% in 1979-1984 to 33% in 1990-1994). Potential reasons for these dissimilarities from the present study can be attributed to differences in the study sample size, patient characteristics, regional differences, HF definitions, different timelines for HF inclusion (admission only vs in-hospital vs 30 days or 5 years), inclusion of all patients with AMI (non-STEMI and STEMI vs STEMI only in the present study), and the advancements in invasive and medical interventions for both AMI and HF in recent years.

, regional differences, HF definitions, different timelines for HF inclusion (admission only vs in-hospital vs 30 days or 5 years), inclusion of all patients with AMI (non-STEMI and STEMI vs STEMI only in the present study), and the advancements in invasive and medical interventions for both AMI and HF in recent years. During the past 2 decades, we have witnessed tremendous improvements in the secondary prevention and management of coronary heart disease. The increased awareness for the modification of CV disease risk factors through healthy lifestyle changes and use of medications, such as aspirin, statins (including at intensive doses), β-blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, and dual antiplatelet therapies, has resulted in regression of the incidence and severity of acute ischemic coronary events.22, 23 In addition, clear guidelines with respect to triage, interfacility transfer, reperfusion strategies, protocols (such as door-to-balloon time), and use of invasive coronary interventions have led to infarct size reductions, cardiac function improvements, and improvements in overall clinical outcomes in patients with STEMI.24, 25 All of the previously mentioned factors might have contributed to the reduction in the incidence and mortality of patients with STEMI with acute HF complication. Although information related to medications, hospital transfers, and time variables, such as door-to-balloon time, are unavailable in this study, we observed a significant decrease in acute HF-complicated STEMI, from 25.4% in 2003 to 20.7% in 2010, even after broad adjustments for multiple factors, such as patient demographic characteristics, hospital characteristics, clinical comorbidities, and coronary intervention. Notably, we also found increasing rates of cardiogenic shock complication in patients with HF-complicated STEMI. Although given the administrative nature of the database, exact description behind this surprising trend is not possible, but we believe it can possibly be related to reimbursement issues, early and increased recognition of cardiogenic shock, along with increasing use of medical interventions such as β-blockers, opioids, ACE inhibitors, diuretics, and PCI, as highlighted in previous studies.26, 27, 28, 29

surprising trend is not possible, but we believe it can possibly be related to reimbursement issues, early and increased recognition of cardiogenic shock, along with increasing use of medical interventions such as β-blockers, opioids, ACE inhibitors, diuretics, and PCI, as highlighted in previous studies.26, 27, 28, 29 The overall incidence of acute mortality in patients with HF-complicated STEMI was 16.9%, with a temporal decline in mortality from 2003 to 2010, similar to those reported by earlier research.5, 6, 30 Previous studies based on the Global Registry of Acute Coronary Events (GRACE), the NRMI-2, and the Worcester Heart Attack Study have reported in-hospital mortality rates in such patient populations of 12% to 21%. Interestingly, despite encouraging survival trends in the study, patients with acute HF-complicated STEMI had markedly higher hospital mortality than rates reported in the general STEMI population.24, 31 Likewise, patients with HF-complicated AMI have previously been found to be significantly undertreated with lifesaving therapies, such as aspirin, statins, β-blockers, heparin, PCI, and dCA, at the time of initial presentation or during hospitalization.5, 6, 30, 32 Even in the present study, the utilization rates of PCI (33.5%), CABG (9.7%), and dCA (50.1%) were much lower in patients with STEMI with acute HF diagnosis than those reported in overall patients with STEMI.31 The undertreatment of patients with HF-complicated AMI has been plausibly attributed to the older age and higher comorbidity burden compared with patients who did not develop acute HF complication.5, 33 Also, although the present findings of underuse of invasive interventions are consistent with those reported by others, note that we were unable to stratify the medical facilities based on their invasive procedure capacity and, hence, the numbers might be an underrepresentation than for accredited “chest pain” centers.5

lso, although the present findings of underuse of invasive interventions are consistent with those reported by others, note that we were unable to stratify the medical facilities based on their invasive procedure capacity and, hence, the numbers might be an underrepresentation than for accredited “chest pain” centers.5 It is critical to emphasize that enough literature exists supporting the role of therapies such as β-blockers, reperfusion strategies, and revascularization in improving clinical outcomes in patients with HF-complicated AMI.24, 30, 32, 34 At the same time, the increasing trend of cardiogenic shock in patients with HF-complicated STEMI in the present study highlights the need for clinical presentation–specific guidelines for the use of medications such as ACE inhibitors, opioids, and diuretics, as addressed for β-blocker use in HF-complicated STEMI in the most recent guidelines.24 In the present study, the declining trend of mortality in patients with HF-complicated STEMI became significantly attenuated after adjustment for temporal changes of invasive coronary intervention, possibly reflecting their critical role in mortality reduction, as reported previously by Shah et al35 in an overall STEMI population. The fact that HF-complicated AMI has markedly higher mortality but is surprisingly undertreated deserves special attention, as is also highlighted in studies from the NRMI-2 and GRACE investigators.6, 30 This has been emphasized in the most recent 2013 American College of Cardiology/American Heart Association STEMI guidelines that recommend performing emergency revascularization and dCA as a class I (level of evidence: B) recommendation for the treatment of patients with severe acute HF after STEMI, irrespective of the time delay from onset of AMI, which is a major change from previous guidelines.24, 36 Because the present study is limited to 2010 and earlier, it will be interesting to study the changes in the management and outcomes of patients with HF-complicated STEMI after guideline introduction.

after STEMI, irrespective of the time delay from onset of AMI, which is a major change from previous guidelines.24, 36 Because the present study is limited to 2010 and earlier, it will be interesting to study the changes in the management and outcomes of patients with HF-complicated STEMI after guideline introduction. This study has certain limitations secondary to the retrospective observational nature of the study and being based on an administrative-type database. Therefore, this study lacks certain potentially important clinical information, such as angiographic details, ejection fraction, medication use, biomarkers, HF phenotypic expression and subcategories (ie, systolic vs diastolic), and door-to-balloon times, and is prone to coding errors. The NIS database does not allow defining the temporal relationship of the development of HF, ie, present on admission, with that developing during hospitalization. Given that the NIS database consists of approximately 20% of all US hospitalizations and the national estimates are created using discharge weight estimates, it may not fully reflect all national hospitalizations. Another important limitation was the inability to assess the transfer status of patients because this information was missing in most patients (60% for transfer in and 90% for transfer out). Also, observations in the NIS are at the level of the hospitalization rather than the individual. Hence, addressing individual-specific issues, such as underuse of invasive coronary interventions, is not possible. Last, outcomes are limited to in-hospital events, and the exact cause of death is not available. Nevertheless, the NIS provided an unequaled statistical power and important insight into the real-world data to study the changes in incidence and management related to this critically ill subgroup of patients with STEMI. Hence, this analysis should also be seen as a call out for further research based on databases such as the ACTION Registry–Get With The Guidelines, which provide more details to account for the effects of medications, accreditation status of “chest pain” centers, clinical parameters, and time variables.

nts with STEMI. Hence, this analysis should also be seen as a call out for further research based on databases such as the ACTION Registry–Get With The Guidelines, which provide more details to account for the effects of medications, accreditation status of “chest pain” centers, clinical parameters, and time variables. Conclusion In this large nationwide study, we observed a temporal decline in the overall adjusted incidence of acute HF complication in US STEMI hospitalizations. There have been favorable trends in the use of PCI and dCA, with an overall decline in mortality in this high-risk patient group. Supplemental Online Material Supplemental Table Supplemental material can be found online at http://www.mcpiqojournal.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data. Potential Competing Interests: The authors report no competing interests.

Correlation Between IP Activity and Psoriasis Activity Interstitial pneumonia activity was evaluated by chest radiography, CT, and serum KL-6 periodically in patients with psoriasis with IP. Psoriasis activity was evaluated by PASI scores. Five of the 8 patients were treated with anti–interleukin (IL) 12/IL-23p40 antibodies; UST or anti–IL-17 antibodies; SEC or anti–IL-17 receptor antibodies; or brodalumab, and disease activity decreased in 3 patients (cases 6, 7, and 8) and was stable in 2 patients. Details on the clinical course of cases 6, 7, and 8 are as follows. In case 6, UST induction treatment improved not only skin lesions but also IP lesions.7 After the recurrence of skin lesions during UST maintenance treatment, IP became worse. An increased dose of UST ameliorated both skin and lung lesions (Figure 2). The IP became worse again with further relapse of psoriasis, which was improved by treatment with SEC (data not shown). In case 7, lung lesions (ground-glass and irregular linear [reticular] opacity) on chest CT regressed with UST treatment, which was effective for psoriasis skin lesions (Figure 3). In case 8, both lung and skin lesions regressed with UST treatment. Both lesions were exacerbated after the discontinuation of UST (Figure 4). In these 3 patients, IP activity was aligned with psoriasis activity. Intriguingly, patients who were treated with biologic agents other than an IL-23/IL-17 axis blocker showed no clear association between IP activity (assessed by CT and KL-6) and psoriasis activity (PASI score).

Psoriasis is a chronic inflammatory skin disease.1 Inflammation in psoriasis is not limited to the skin as surplus proinflammatory cytokines from inflamed skin affect systemic organs.1 Almost all blood flows into the pulmonary circulation, suggesting that the lung parenchyma is susceptible to systemic inflammation in psoriasis. However, no large studies demonstrating a link between psoriasis and interstitial pneumonia (IP) have been conducted. Patients with psoriasis are routinely screened for prevalent well-known comorbidities, including cardiovascular diseases and diabetes mellitus.2, 3, 4, 5 However, lung involvement, including IP, is not intensively investigated unless respiratory symptoms are obvious. Chest computed tomography (CT) is a useful tool for finding mild IP that is not detectable on chest radiography; however, CT is not routinely performed in all patients with psoriasis. Hence, asymptomatic, mild IP associated with psoriasis may have been underdiagnosed so far. In our hospital, chest CT is routinely performed in patients with psoriasis who need biologic agents to exclude latent and active lung tuberculosis because tuberculosis is highly prevalent in Japan. We retrospectively evaluated lung lesions in these patients. We also evaluated IP activity in relation to psoriasis activity by chest CT and serum Krebs von den Lungen-6 (KL-6) assay. The aims of this study were to determine the prevalence of IP and to reveal the clinical and radiographic characteristics of IP in patients with psoriasis.

evaluated lung lesions in these patients. We also evaluated IP activity in relation to psoriasis activity by chest CT and serum Krebs von den Lungen-6 (KL-6) assay. The aims of this study were to determine the prevalence of IP and to reveal the clinical and radiographic characteristics of IP in patients with psoriasis. Patients and Methods Study Population Five hundred twelve patients with psoriasis were treated with biologic agents at Jikei University Hospital from June 1, 2008, to June 30, 2017. Chest CT was performed in 392 patients, and the images were evaluated by 2 specialists of the Japanese Respiratory Society (H.H. and H.K.). Interstitial pneumonia was detected in 8 patients. The clinical characteristics of patients with IP and those without IP were compared. In the 8 patients with IP, the radiographic characteristics of IP were evaluated. The psoriasis area severity index (PASI) score and type of psoriasis were determined by specialists of the Japanese Dermatological Association. This study was approved by the Ethics Committee of Jikei University (29-078 [8694]). Statistical Analyses Clinical indices were compared between patients with psoriasis with IP and those without IP using Welch t test, Fisher exact test, Mann-Whitney U test, and χ2 test. A 2-sided P value of less than .05 was considered statistically significant.

This study was approved by the Ethics Committee of Jikei University (29-078 [8694]). Statistical Analyses Clinical indices were compared between patients with psoriasis with IP and those without IP using Welch t test, Fisher exact test, Mann-Whitney U test, and χ2 test. A 2-sided P value of less than .05 was considered statistically significant. All statistical analysis was performed with EZR (Saitama Medical Center), which is a graphical user interface for R (The R Foundation for Statistical Computing). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.6 Results Clinical Characteristics of Patients With Psoriasis With or Without IP Lung involvement of the 392 patients with psoriasis who were treated with biologic agents was evaluated by chest CT before starting biologic therapy. Interstitial pneumonia was detected in 8 patients (2.0%). The clinical characteristics of patients with psoriasis with IP and those without IP are summarized in Table 1.Table 1 Characteristics of Patients With Psoriasis With or Without IP

with biologic agents was evaluated by chest CT before starting biologic therapy. Interstitial pneumonia was detected in 8 patients (2.0%). The clinical characteristics of patients with psoriasis with IP and those without IP are summarized in Table 1.Table 1 Characteristics of Patients With Psoriasis With or Without IP Characteristic With IP (n=8) Without IP (n=384) P value Age (y) 72±5.98 53.5±15.3 <.001 Sex: male (%) 6 (75) 271 (70.6) >.99 Disease duration (y) 11±8.49 13.9±10.4 .21 Ex-smoker (%) 5 (62.5) 221 (57.9) Unknown: n=2 >.99 BI 832±455 551±478 .13 Family history of psoriasis 0 (0) 21 (5.5) Unknown: n=2 >.99 PASI score 12.1±9.93 12.2±8.48 .76 KL-6 (U/mL) 504±149 261±172 .003 Type of psoriasis .003 PsV 4 (50%) 290 (75.52%) PsA 1 (12.5%) 81 (21.09%) GPP 2 (25 %) 9 (2.34%) PsE 1 (12.5%) 1 (0.26%) PsG 0 (0%) 1 (0.26%) PPP 0 (0%) 2 (0.52%) BI = Brinkman index; GPP = generalized pustular psoriasis; IP = interstitial pneumonia; KL-6 = Krebs von den Lungen-6; PASI = psoriasis area severity index; PPP = palmoplantar pustulosis; PsA = psoriatic arthritis; PsE = erythrodermic psoriasis; PsG = guttate psoriasis; PsV = psoriasis vulgaris.

%) PPP 0 (0%) 2 (0.52%) BI = Brinkman index; GPP = generalized pustular psoriasis; IP = interstitial pneumonia; KL-6 = Krebs von den Lungen-6; PASI = psoriasis area severity index; PPP = palmoplantar pustulosis; PsA = psoriatic arthritis; PsE = erythrodermic psoriasis; PsG = guttate psoriasis; PsV = psoriasis vulgaris. Patients with psoriasis with IP were significantly older than those without IP (P<.01). The serum sialylated carbohydrate antigen KL-6 levels in patients with psoriasis with IP were higher than those in patients without IP (P=.003). Generalized pustular psoriasis, the most severe type of psoriasis, was frequent in patients with psoriasis with IP. Sex, smoking status, family history of psoriasis, PASI scores, and underlying diseases were not different between the 2 groups. It is highly likely given the small sample size in the psoriasis with IP group that there is not sufficient statistical power to detect meaningful differences between the psoriasis with IP group and the psoriasis without IP group. The coexistence of any other connective tissue diseases that might cause IP was excluded by clinical evaluation and laboratory tests including autoantibodies. Biologic agents were used in 392 patients (infliximab in 88 cases, adalimumab in 129 cases, ustekinumab [UST] in 141 cases, secukinumab [SEC] in 33 cases, and brodalumab in 1 case).

Patients with psoriasis with IP were significantly older than those without IP (P<.01). The serum sialylated carbohydrate antigen KL-6 levels in patients with psoriasis with IP were higher than those in patients without IP (P=.003). Generalized pustular psoriasis, the most severe type of psoriasis, was frequent in patients with psoriasis with IP. Sex, smoking status, family history of psoriasis, PASI scores, and underlying diseases were not different between the 2 groups. It is highly likely given the small sample size in the psoriasis with IP group that there is not sufficient statistical power to detect meaningful differences between the psoriasis with IP group and the psoriasis without IP group. The coexistence of any other connective tissue diseases that might cause IP was excluded by clinical evaluation and laboratory tests including autoantibodies. Biologic agents were used in 392 patients (infliximab in 88 cases, adalimumab in 129 cases, ustekinumab [UST] in 141 cases, secukinumab [SEC] in 33 cases, and brodalumab in 1 case). Detailed characteristics of the 8 patients with psoriasis with IP are presented in Table 2. Of the eight patients, 6 were men and 2 were women (age range, 61-81 years; median age, 73.5 years). Psoriasis disease duration was 1 to 26 years, with a median of 11 years. Five patients were former smokers, and the other 3 were nonsmokers. One patient had respiratory symptoms, whereas the others had no symptoms. Four patients had a PASI score higher than 10 (average, 12.1; range, 0.6-20.4), and KL-6 levels were elevated in 4 patients (3 of the 4 patients with a PASI score of >10) (average, 504; range, 307-770). Of the 8 patients, 5 patients were treated with UST, 2 were treated with adalimumab, and 1 was treated with infliximab.Table 2 Clinical Characteristics of Patients With Psoriasis With Interstitial Pneumonia

levels were elevated in 4 patients (3 of the 4 patients with a PASI score of >10) (average, 504; range, 307-770). Of the 8 patients, 5 patients were treated with UST, 2 were treated with adalimumab, and 1 was treated with infliximab.Table 2 Clinical Characteristics of Patients With Psoriasis With Interstitial Pneumonia Case Age (y) Sex Disease duration (y) Smoking status PASI score KL-6 (U/mL) Type of psoriasis Treatment 1 61 M 3 Ex 6.2 352 GPP ADA 2 67 M 2 Ex 0.6 507 PsA ADA 3 68 M 1 Ex 32 530 PsE IFX 4 75 M 26 Never 10.4 467 PsV UST 5 75 M 16 Never 2.7 407 PsV UST 6 72 M 15 Ex 18 770 PsV UST/SEC 7 77 F 18 Ex 6.6 307 GPP UST 8 81 F 7 Never 20.4 688 PsV UST ADA = adalimumab; GPP = generalized pustular psoriasis; F = female; IFX = infliximab; KL-6 = Krebs von den Lungen-6; M = male; PASI = psoriasis area severity index; PsA = psoriatic arthritis; PsE = erythrodermic psoriasis; PsV = psoriasis vulgaris; SEC = secukinumab; UST = ustekinumab.

T 8 81 F 7 Never 20.4 688 PsV UST ADA = adalimumab; GPP = generalized pustular psoriasis; F = female; IFX = infliximab; KL-6 = Krebs von den Lungen-6; M = male; PASI = psoriasis area severity index; PsA = psoriatic arthritis; PsE = erythrodermic psoriasis; PsV = psoriasis vulgaris; SEC = secukinumab; UST = ustekinumab. Radiographic Findings in Patients With Psoriasis With IP Chest CT scans of the patients with psoriasis with IP are shown in Figure 1, Figure 2, Figure 3, Figure 4. A summary of the radiographic findings is presented in Table 3.Figure 1 A, Ground-glass and irregular linear (reticular) opacity was distributed along the bronchial vascular bundle in the lower lobes on chest computed tomography (CT) of case 1 (61-year-old man). Chest CT in case 2 (67-year-old man) (B) and case 5 (75-year-old man) (E) showed subpleural ground-glass and irregular linear (reticular) opacity distributed in the lower lobes. Subpleural linear opacity was shown on CT in case 3 (68-year-old man) (C) and case 4 (75-year-old man) (D).

(CT) of case 1 (61-year-old man). Chest CT in case 2 (67-year-old man) (B) and case 5 (75-year-old man) (E) showed subpleural ground-glass and irregular linear (reticular) opacity distributed in the lower lobes. Subpleural linear opacity was shown on CT in case 3 (68-year-old man) (C) and case 4 (75-year-old man) (D). Figure 2 The relationship between IP activity and psoriasis activity in case 6, a 72-year-old man.7 Interstitial pneumonia activity was evaluated by chest CT and serum KL-6, and psoriasis activity was assessed by PASI scores. Chest CT showed subpleural ground-glass and irregular linear (reticular) opacity distributed in the lower lobes. Interstitial pneumonia activities fluctuated in accordance with psoriasis activity. Used with permission of Eur J Dermatol.7 CT = computed tomography; IP = interstitial pneumonia; KL-6 = Krebs von den Lungen-6; PASI = psoriasis area severity index; UST = ustekinumab. Figure 3 The chest CT, KL-6 levels, and PASI score of case 7 (77-year-old man) are shown. Ground-glass opacities along the bronchial vascular bundle were ameliorated by treatment with UST with decreased KL-6 levels and PASI scores. CT = computed tomography; KL-6 = Krebs von den Lungen-6; PASI = psoriasis area severity index; UST = ustekinumab.

-6 levels, and PASI score of case 7 (77-year-old man) are shown. Ground-glass opacities along the bronchial vascular bundle were ameliorated by treatment with UST with decreased KL-6 levels and PASI scores. CT = computed tomography; KL-6 = Krebs von den Lungen-6; PASI = psoriasis area severity index; UST = ustekinumab. Figure 4 The chest CT, KL-6 levels, and PASI score of case 8 (81-year-old man) are shown. Subpleural ground-glass and irregular linear (reticular) opacity distributed in the lower lobes improved with UST treatment temporarily. Discontinuation of the treatment worsened both IP and psoriasis. CT = computed tomography; IP = interstitial pneumonia; KL-6 = Krebs von den Lungen-6; PASI = psoriasis area severity index; UST = ustekinumab. Table 3 Radiographic Characteristics of IP in Patients With Psoriasis Case Abnormal chest radiography findings Distribution GGO Reticular opacity Emphysema IP activity during psoriasis treatment Respiratory failure due to IP 1 Yes Bilateral lower lobe Yes Yes No Stable No 2 Yes Bilateral lower lobe Yes Yes No Stable Yes 3 Yes Bilateral lower lobe No Yes Yes Stable No 4 No Bilateral lower lobe No Yes No Stable No 5 No Bilateral lower lobe Yes Yes No Stable No 6 No Bilateral lower lobe Yes Yes Yes Improved No 7 No Bilateral lower lobe Yes Yes No Improved No 8 Yes Bilateral lower lobe Yes Yes No Improved No GGO = ground-glass opacity; IP = interstitial pneumonia.

No Yes Yes Stable No 4 No Bilateral lower lobe No Yes No Stable No 5 No Bilateral lower lobe Yes Yes No Stable No 6 No Bilateral lower lobe Yes Yes Yes Improved No 7 No Bilateral lower lobe Yes Yes No Improved No 8 Yes Bilateral lower lobe Yes Yes No Improved No GGO = ground-glass opacity; IP = interstitial pneumonia. Lung lesions could be detected by chest radiography in 4 patients. Bilateral ground-glass and/or irregular linear (reticular) opacity was the most common CT finding in these patients. These opacities predominantly involved the lower lung zone in both lungs. Correlation Between IP Activity and Psoriasis Activity Interstitial pneumonia activity was evaluated by chest radiography, CT, and serum KL-6 periodically in patients with psoriasis with IP. Psoriasis activity was evaluated by PASI scores. Five of the 8 patients were treated with anti–interleukin (IL) 12/IL-23p40 antibodies; UST or anti–IL-17 antibodies; SEC or anti–IL-17 receptor antibodies; or brodalumab, and disease activity decreased in 3 patients (cases 6, 7, and 8) and was stable in 2 patients.

Details on the clinical course of cases 6, 7, and 8 are as follows. In case 6, UST induction treatment improved not only skin lesions but also IP lesions.7 After the recurrence of skin lesions during UST maintenance treatment, IP became worse. An increased dose of UST ameliorated both skin and lung lesions (Figure 2). The IP became worse again with further relapse of psoriasis, which was improved by treatment with SEC (data not shown). In case 7, lung lesions (ground-glass and irregular linear [reticular] opacity) on chest CT regressed with UST treatment, which was effective for psoriasis skin lesions (Figure 3). In case 8, both lung and skin lesions regressed with UST treatment. Both lesions were exacerbated after the discontinuation of UST (Figure 4). In these 3 patients, IP activity was aligned with psoriasis activity. Intriguingly, patients who were treated with biologic agents other than an IL-23/IL-17 axis blocker showed no clear association between IP activity (assessed by CT and KL-6) and psoriasis activity (PASI score). Discussion In this study, we demonstrated that IP was detected in patients with psoriasis who needed biologic agents (8 of 392 [2%]). Bilateral ground-glass and irregular linear (reticular) opacity in the lower lobes was the most common chest CT finding in these patients. Most of the IPs were mild without respiratory symptoms, and half of the IPs were not detectable by chest radiography. The activities of IP were aligned with the activities of psoriasis in 3 of 5 patients treated with anti–IL-12/IL-23 or IL-17 antibodies, suggesting an intimate link between psoriasis and IP.

e patients. Most of the IPs were mild without respiratory symptoms, and half of the IPs were not detectable by chest radiography. The activities of IP were aligned with the activities of psoriasis in 3 of 5 patients treated with anti–IL-12/IL-23 or IL-17 antibodies, suggesting an intimate link between psoriasis and IP. Increasing evidence suggests that psoriasis has systemic effects and is associated with several systemic comorbidities, including cardiometabolic diseases.1, 3, 4, 5 Although the high prevalence of chronic obstructive pulmonary disease8, 9 and pneumonia10 in psoriasis has been demonstrated by population-based studies, the association between psoriasis and IP remains to be determined. Indeed, there are only a few case reports demonstrating the simultaneous existence of psoriasis and IP,11, 12, 13, 14, 15 including case 6 in this report.7 No epidemiologic studies searching for comorbidities in psoriasis have revealed a high prevalence of IP in psoriasis, indicating that clinically relevant IP might be rare in patients with psoriasis. However, in this study, we showed that IP was involved in 2% of patients with psoriasis who needed biologic agents. Considering that the prevalence of idiopathic pulmonary fibrosis, one of the most common idiopathic forms of IP, is 0.01% in the general population in Japan,16 the prevalence of IP in psoriasis in this study seems high.

s study, we showed that IP was involved in 2% of patients with psoriasis who needed biologic agents. Considering that the prevalence of idiopathic pulmonary fibrosis, one of the most common idiopathic forms of IP, is 0.01% in the general population in Japan,16 the prevalence of IP in psoriasis in this study seems high. The high prevalence of IP in patients with psoriasis in this study is partly due to the high detection rate of asymptomatic and subclinical IP by chest CT. In previous studies, chest CT would not be performed in most patients because IP has not been recognized as a comorbidity in psoriasis. Subclinical IP associated with psoriasis might be underdiagnosed in those studies. Intriguingly, Scherak et al17 reported that lymphocytes in the bronchoalveolar lavage fluid of asymptomatic seronegative patients with arthritis (8 patients with psoriasis of a total of 13 patients were included) increased.17 The lung might be affected insidiously in psoriasis. Another reason for the high prevalence of IP in this study was that the study population included patients with severe psoriasis who needed biologic agents. In particular, generalized pustular psoriasis, the most severe type of psoriasis,18 was more frequent in patients with psoriasis with IP than in those without IP. The severity of psoriasis is associated with the high prevalence of comorbidities of psoriasis.19 A large surplus of proinflammatory cytokines from inflamed skin might have affected the lungs in the patients with severe psoriasis in this study.

more frequent in patients with psoriasis with IP than in those without IP. The severity of psoriasis is associated with the high prevalence of comorbidities of psoriasis.19 A large surplus of proinflammatory cytokines from inflamed skin might have affected the lungs in the patients with severe psoriasis in this study. In this study, we investigated the radiographic characteristics of IP associated with psoriasis. Most of the IPs associated with psoriasis were mild and affected only a small part of the lung; hence, half of the IPs were not detectable by chest radiography. Bilateral ground-glass and/or irregular linear (reticular) opacity in the lower lung zone on CT scans was a characteristic radiographic finding.

ith psoriasis. Most of the IPs associated with psoriasis were mild and affected only a small part of the lung; hence, half of the IPs were not detectable by chest radiography. Bilateral ground-glass and/or irregular linear (reticular) opacity in the lower lung zone on CT scans was a characteristic radiographic finding. Increasing evidence suggests that the IL-23/IL-17 axis plays central roles in the pathogenesis of psoriasis,1, 20 and clinically available anti–IL-23 or IL-17 antibodies improve psoriasis skin lesions.21, 22, 23 In this study, we showed that the disease activities of IP were aligned with the activities of psoriasis in 3 of 5 patients treated with anti–IL-12/IL-23 or IL-17 antibodies. Inhibition of the IL-23/IL-17 axis ameliorated not only psoriasis skin lesions but also IP, indicating that this signaling pathway is involved in the development of both psoriasis and IP. In addition to the 3 patients in this report, Miyachi et al13 recently reported a case showing the improvement in IP during psoriasis by IL-23/IL-17 inhibition. Inhibition of this pathway with biologic agents may be effective for IP associated with psoriasis, although biologic agents also potentially induce IP.24, 25 Intriguingly, inhibition of the IL-23/IL-17 axis also ameliorated inflammation-induced lung fibrosis in mouse models through several mechanisms.26, 27, 28 The IL-23/IL-7 axis is also up-regulated in many autoimmune diseases, including rheumatoid arthritis and inflammatory bowel diseases,29 although the pathogenetic roles of the IL-23/IL-17 axis remain unknown. Rheumatoid arthritis and inflammatory bowel diseases frequently affect the lungs,30, 31 suggesting that the IL-23/IL-17 axis may play some roles in the development of lung involvement in these diseases. The precise mechanisms of the intimate relationship between IP and autoimmune diseases, including psoriasis, need further studies.

thritis and inflammatory bowel diseases frequently affect the lungs,30, 31 suggesting that the IL-23/IL-17 axis may play some roles in the development of lung involvement in these diseases. The precise mechanisms of the intimate relationship between IP and autoimmune diseases, including psoriasis, need further studies. This study has several limitations. First, this study was retrospectively designed and performed in a single center. In addition, the sample size was small. Larger studies are necessary to confirm our results. Second, psoriasis affects 2% to 3% of the general population in Europe, whereas it affects 0.34% in Japan.32 The genetic background may differ between patients in Japan and those in other countries. Hence, our conclusions might not be applicable to patients in other countries. Finally, our study population consisted of patients with severe psoriasis who needed the biologic agents described. The prevalence of IP in psoriasis will be lower in patients with mild or topical psoriasis than in patients with severe psoriasis in this study.

ons might not be applicable to patients in other countries. Finally, our study population consisted of patients with severe psoriasis who needed the biologic agents described. The prevalence of IP in psoriasis will be lower in patients with mild or topical psoriasis than in patients with severe psoriasis in this study. Conclusion Mild asymptomatic IP was detected in 2% of patients with psoriasis who needed biologic agents. Ground-glass and/or irregular linear (reticular) opacity in the bilateral lower lobes was characteristic of IP with psoriasis. Individuals with severe psoriasis should be counseled and screened for IP by chest CT and serum KL-6. The intimate relationship between psoriasis and IP indicated that common pathways were involved in the development of both psoriasis and IP. The IL-23/IL-17 axis may play important roles in the pathogenesis of both psoriasis and IP although a direct role for this pathway in the IP observed in the patients with psoriasis remains to be elucidated. Inhibition of this pathway may be effective treatment for IP associated with psoriasis. Additional therapy for IP with immunosuppressants can be avoided in some cases. Acknowledgments Drs Kawamoto and Hara contributed equally to this work. Potential Competing Interests: H. Nakagawa is a consultant and/or has received research grants and/or speaker honoraria from Kyowa Hakko Kirin, AbbVie, Mitsubishi Tanabe, Janssen, Eli Lilly, Leo Pharma, Maruho, and MSD.

Conclusion Mild asymptomatic IP was detected in 2% of patients with psoriasis who needed biologic agents. Ground-glass and/or irregular linear (reticular) opacity in the bilateral lower lobes was characteristic of IP with psoriasis. Individuals with severe psoriasis should be counseled and screened for IP by chest CT and serum KL-6. The intimate relationship between psoriasis and IP indicated that common pathways were involved in the development of both psoriasis and IP. The IL-23/IL-17 axis may play important roles in the pathogenesis of both psoriasis and IP although a direct role for this pathway in the IP observed in the patients with psoriasis remains to be elucidated. Inhibition of this pathway may be effective treatment for IP associated with psoriasis. Additional therapy for IP with immunosuppressants can be avoided in some cases. Acknowledgments Drs Kawamoto and Hara contributed equally to this work. Potential Competing Interests: H. Nakagawa is a consultant and/or has received research grants and/or speaker honoraria from Kyowa Hakko Kirin, AbbVie, Mitsubishi Tanabe, Janssen, Eli Lilly, Leo Pharma, Maruho, and MSD. A. Asahina is a consultant and/or has received speaker honoraria from Kyowa Hakko Kirin, AbbVie, Mitsubishi Tanabe, Taiho, Torii, Janssen, Eli Lilly, Leo Pharma, and Maruho.

Potential Competing Interests: H. Nakagawa is a consultant and/or has received research grants and/or speaker honoraria from Kyowa Hakko Kirin, AbbVie, Mitsubishi Tanabe, Janssen, Eli Lilly, Leo Pharma, Maruho, and MSD. A. Asahina is a consultant and/or has received speaker honoraria from Kyowa Hakko Kirin, AbbVie, Mitsubishi Tanabe, Taiho, Torii, Janssen, Eli Lilly, Leo Pharma, and Maruho. K. Kuwano is a consultant and has received consulting fees and research grants from ONO Pharmaceutical Co., LTD; he also has received research grants from Astellas Pharma Inc., KYORIN Pharmaceutical Co., LTD, and Nippon Boehringer Ingelheim Co., LTD. The rest of the authors report no competing interests.

A 67-year-old woman presented to a local emergency department with abdominal pain and hematochezia that developed after she attended an agricultural state fair where she ate local products. Her medical history was notable for well-controlled type 2 diabetes and hypertension, and over 1 year previously, she had undergone matched unrelated donor allogenic peripheral blood stem cell transplant for the treatment of high-risk acute myeloid leukemia. The posttransplant course was complicated by the development of biopsy-proven grade 2 lower gastrointestinal graft-vs-host disease (GvHD) on day 39 that was successfully treated with tacrolimus and corticosteroids. At the time of current presentation, she was taking tacrolimus, 0.5 mg daily, and prednisone, 5 mg daily.

The posttransplant course was complicated by the development of biopsy-proven grade 2 lower gastrointestinal graft-vs-host disease (GvHD) on day 39 that was successfully treated with tacrolimus and corticosteroids. At the time of current presentation, she was taking tacrolimus, 0.5 mg daily, and prednisone, 5 mg daily. Two days before this presentation, she started experiencing loose bowel movements associated with abdominal pain that rapidly progressed to frequent episodes of bloody diarrhea, severe abdominal pain, nausea, and vomiting on the day of presentation. She was admitted to a local hospital for further management. At the time of admission, she reported no fever, chills, night sweats, or respiratory or urinary symptoms. She had eaten crepes and nutty bars at the fair 3 days before admission as well as drinking from a water fountain. She denied any sick contacts and had no relevant travel history. After admission, she underwent a diagnostic colonoscopy with random biopsies. Pathological examination revealed extensive hemorrhage within the lamina propria, extensive surface erosions, prominent crypt dropout, and foci of hyalinization within the lamina propria, suggesting severe mucosal inflammation. She was transferred to our institution the next day for further management. On arrival, she continued to report considerable abdominal pain, nausea, and diarrhea.

Two days before this presentation, she started experiencing loose bowel movements associated with abdominal pain that rapidly progressed to frequent episodes of bloody diarrhea, severe abdominal pain, nausea, and vomiting on the day of presentation. She was admitted to a local hospital for further management. At the time of admission, she reported no fever, chills, night sweats, or respiratory or urinary symptoms. She had eaten crepes and nutty bars at the fair 3 days before admission as well as drinking from a water fountain. She denied any sick contacts and had no relevant travel history. After admission, she underwent a diagnostic colonoscopy with random biopsies. Pathological examination revealed extensive hemorrhage within the lamina propria, extensive surface erosions, prominent crypt dropout, and foci of hyalinization within the lamina propria, suggesting severe mucosal inflammation. She was transferred to our institution the next day for further management. On arrival, she continued to report considerable abdominal pain, nausea, and diarrhea. Computed tomography of the abdomen and pelvis demonstrated markedly thickened and edematous colon, extending from the cecum to the splenic flexure. Findings were consistent with severe colitis (Figure 1).Figure 1 Computed tomography on admission. Markedly thickened and edematous colon extending from the cecum to the splenic flexure. Findings consistent with colitis, most likely infectious vs inflammatory. The arrows show the marked thickening of the colon.

lexure. Findings were consistent with severe colitis (Figure 1).Figure 1 Computed tomography on admission. Markedly thickened and edematous colon extending from the cecum to the splenic flexure. Findings consistent with colitis, most likely infectious vs inflammatory. The arrows show the marked thickening of the colon. Initial laboratory evaluation revealed leukocytosis, new-onset thrombocytopenia, and an elevated creatinine level. Hemoglobin on admission was within normal limits. Stool studies demonstrated positivity to Shiga toxin–producing Escherichia coli O157 serotype. At the time of transfer, she was receiving metronidazole, doxycycline, and cephalexin (initiated for a presumed diagnosis of infectious colitis), which were discontinued because of potential increased risk for transformation to hemolytic uremic syndrome (HUS). Prophylactic acyclovir and posaconazole were continued.

pe. At the time of transfer, she was receiving metronidazole, doxycycline, and cephalexin (initiated for a presumed diagnosis of infectious colitis), which were discontinued because of potential increased risk for transformation to hemolytic uremic syndrome (HUS). Prophylactic acyclovir and posaconazole were continued. Supportive management with intravenous fluids was initiated. Neurological evaluation was performed every 4 hours. Hemolysis parameters were monitored with daily peripheral blood smear and haptoglobin, lactate dehydrogenase (LDH), and reticulocyte measurements. Three days after admission, mild confusion was reported overnight, and examination revealed a somnolent patient who was disoriented to time and place. The patient continued to experience diarrhea. In addition, schistocytes were identified on peripheral smear for the first time that morning (Figure 2). Laboratory values over the course of a few days continued to show deterioration with new-onset anemia, worsening thrombocytopenia, increasing creatinine levels, LDH elevation, and haptoglobin decrease. Total complement, factor B and H complement assay, and complement C3 and C4 were within normal limits, SC5b-9 complement was elevated (348 ng/mL [<251 ng/mL]), and ADAMTS13 activity was normal at 71%, consistent with the development of microangiopathy and HUS. Because of the concern for drug-induced microangiopathy, tacrolimus was withheld at the time of admission. Because of the patient’s continued decline in renal function, the multidisciplinary team decided to administer eculizumab (Soliris). Eculizumab is a monoclonal antibody against complement C5 and therefore is associated with increased risk of meningococcal infection. It is therefore recommended that patients receive meningococcal vaccination at least 2 weeks before eculizumab therapy. However, there is concern that administration of meningococcal vaccine at that time may increase complement activity and potentially worsen HUS. As a result, the decision was made to initiate azithromycin beginning 12 hours after eculizumab infusion at a dose of 500 mg intravenously daily for meningococcal prophylaxis. The decision to use azithromycin was made after considering the risks and benefits including the possibility that introducing an antibiotic could increase the risk of toxin production and worsen HUS.Figure 2 Peripheral smear at at the time of eculizumab administration.

intravenously daily for meningococcal prophylaxis. The decision to use azithromycin was made after considering the risks and benefits including the possibility that introducing an antibiotic could increase the risk of toxin production and worsen HUS.Figure 2 Peripheral smear at at the time of eculizumab administration. During the 3 days following the eculizumab infusion, the patient’s neurological status continued to worsen, with reports of visual hallucinations and agitation. Microangiopathic parameters continued to worsen, with hemoglobin decreasing to 7.8 g/dL, platelet count decreasing to 12 × 109/L, LDH increasing to 804 U/L, and creatinine increasing to 2.6 mg/dL (Table). Interestingly, the patient’s hematochezia improved and her diarrhea resolved.Table Blood Markers Before and After Eculizumab Blood marker 3 mo before admission Admission Day before eculizumab administration (day 0) Morning before second eculizumab dose (day 13) 1 mo after first dose 12 mo after eculizumab Plasma creatinine (mg/dL) 1.1 1.29 2.09 3.5 5.2 3.3 Platelet count (×103/μL) 152 77 26 23 92 210 Lactate dehydrogenase (U/L) 239 410 596 574 478 196 Hemoglobin (g/dL) 12.69 13.89 9.39 8.2 7.7 12.7 Absolute reticulocytes (×109/L) 83.69 85.80 203 Haptoglobin (mg/dL) <14 <14 <14 <14 Peripheral blood smear No schistocytes Slight schistocytes and helmet cells Moderate polychromasia, moderate schistocytes, and helmet cells

tate dehydrogenase (U/L) 239 410 596 574 478 196 Hemoglobin (g/dL) 12.69 13.89 9.39 8.2 7.7 12.7 Absolute reticulocytes (×109/L) 83.69 85.80 203 Haptoglobin (mg/dL) <14 <14 <14 <14 Peripheral blood smear No schistocytes Slight schistocytes and helmet cells Moderate polychromasia, moderate schistocytes, and helmet cells Six days after the eculizumab infusion, the patient’s neurological status improved. She was alert and oriented on examination. She continued to have borderline renal function. Diuretics were administered because of evidence of hypervolemia. A second dose of eculizumab was administered 7 days after the initial dose. Creatinine continued to rise, and there was ongoing evidence of hemolysis, requiring a total of 5 units of packed red blood cell transfusions over a period of 15 days (transfusion threshold of <7 g/dL). Platelets remained at less than 20 × 109/L, with subsequent increase to 78 × 109/L 15 days after the second infusion. No platelet transfusion was required. The patient's serum creatinine level peaked at 5.5 mg/dL at 20 days after admission. She experienced volume overload and hyperkalemia, managed only with diuretics. Dialysis was never required during the disease course; interestingly, persistent polychromasia, moderate schistocytes, and helmet cells remained present (Figure 3).Figure 3 Peripheral blood smear 14 days after.

dL at 20 days after admission. She experienced volume overload and hyperkalemia, managed only with diuretics. Dialysis was never required during the disease course; interestingly, persistent polychromasia, moderate schistocytes, and helmet cells remained present (Figure 3).Figure 3 Peripheral blood smear 14 days after. She was discharged from the hospital 23 days after admission with close outpatient follow-up. She continued to experience borderline renal function and required monitoring of her hemoglobin with periodic red blood cell transfusions. Two weeks after hospitalization, she received immunizations with the Menomune meningococcal polysaccharide vaccine, BEXSERO meningococcal group B vaccine, pneumococcal vaccine series, and Haemophilus influenzae vaccination. Seven months after her initial presentation to the emergency department with hematochezia, the patient’s renal function remained stable, no signs of GvHD were identified, her energy level improved significantly, and dialysis has not been required.

She was discharged from the hospital 23 days after admission with close outpatient follow-up. She continued to experience borderline renal function and required monitoring of her hemoglobin with periodic red blood cell transfusions. Two weeks after hospitalization, she received immunizations with the Menomune meningococcal polysaccharide vaccine, BEXSERO meningococcal group B vaccine, pneumococcal vaccine series, and Haemophilus influenzae vaccination. Seven months after her initial presentation to the emergency department with hematochezia, the patient’s renal function remained stable, no signs of GvHD were identified, her energy level improved significantly, and dialysis has not been required. Discussion This case highlights a rare but important differential diagnosis for the development of microangiopathic hemolysis in an allogeneic transplant recipient—Shiga toxin–producing Escherichia coli (STEC)–associated HUS. It also presents the current challenges in the management of STEC-HUS, the role of antibiotics and complement-directed therapy. Our patient presented with bloody diarrhea accompanied by abdominal cramps. Symptoms progressed to encephalopathy, microangiopathy, and renal failure. After a multidisciplinary discussion, a decision was made to use eculizumab. Encephalopathy improved over a period of 2 weeks, hemolysis ceased after 4 months, and kidney function stabilized without any requirement for dialysis.1

dominal cramps. Symptoms progressed to encephalopathy, microangiopathy, and renal failure. After a multidisciplinary discussion, a decision was made to use eculizumab. Encephalopathy improved over a period of 2 weeks, hemolysis ceased after 4 months, and kidney function stabilized without any requirement for dialysis.1 Shiga toxin–producing Escherichia coli–associated HUS is defined as the triad of hemolytic anemia with erythrocyte fragmentation, thrombocytopenia, and acute kidney injury that occurs after a prodromal infection by a Shiga toxin–producing strain of bacteria.2 This results from a direct binding of the potent Shiga cytotoxin to cell membrane glycolipid Gb3. The incidence of STEC-HUS ranges from 6 in 100,000 children younger than 5 years to 2 in 100,000 in the overall population including adults. Escherichia coli O157:H7 remains the most common bacterial strain associated with STEC-HUS.2, 3 Common vehicles of transmission include ground beef, unpasteurized milk, and municipal or swimming water. Shiga toxin–associated HUS is a main cause of acute renal failure in young children; in contrast, in adults, the HUS with prodromal diarrhea, indicating an infectious cause, is a rare event.1, 4 The reported mortality is up to 5%, as demonstrated in the wide German outbreak.5

ized milk, and municipal or swimming water. Shiga toxin–associated HUS is a main cause of acute renal failure in young children; in contrast, in adults, the HUS with prodromal diarrhea, indicating an infectious cause, is a rare event.1, 4 The reported mortality is up to 5%, as demonstrated in the wide German outbreak.5 Although the association between bone marrow transplant (BMT) and thrombotic microangiopathy (TMA) is a well-documented and potentially lethal complication, the outcomes of STEC-HUS after allogeneic transplant are unknown. The overall incidence of postallogeneic transplant TMA is reported to be between 0.5% and 63.6%.6 Since its first description in 1978,6 numerous cases of transplant-associated TMA have been reported. A number of pathogenic factors have been implicated in post-BMT TMA, including immunosuppressive agents such as calcineurin inhibitors, muromonab-CD3,7 total body irradiation, and acute GvHD as well as systemic viral infections, including cytomegalovirus, parvovirus, adenovirus, and influenza A virus.

ve been reported. A number of pathogenic factors have been implicated in post-BMT TMA, including immunosuppressive agents such as calcineurin inhibitors, muromonab-CD3,7 total body irradiation, and acute GvHD as well as systemic viral infections, including cytomegalovirus, parvovirus, adenovirus, and influenza A virus. In early May 2011, northern Germany was the principal site of a massive HUS epidemic caused by a single clone of a strain of enterohemorrhagic E coli classified as O104:H4. This represents the largest reported case series in the literature. The outbreak involved 298 adults in 23 hospitals, and more than 50% of patients required dialysis. The reported mortality rate was 4%.1 More than 20% of patients received eculizumab treatment. Although there was no considerable improvement in outcomes in patients receiving eculizumab, a small group of patients that received antimicrobials and eculizumab had improved outcomes (lower rates of seizures and improved mortality). Notably, the use of plasma exchange did not improve outcomes either.

zumab treatment. Although there was no considerable improvement in outcomes in patients receiving eculizumab, a small group of patients that received antimicrobials and eculizumab had improved outcomes (lower rates of seizures and improved mortality). Notably, the use of plasma exchange did not improve outcomes either. Another outbreak of STEC-HUS was reported in Bordeaux, France, in June 2011.8 This involved 24 cases, of which 9 developed HUS. Although the report is limited by the small sample size, patients who received early treatment with eculizumab (day 0-4) had rapid improvement in symptoms.8 The association between the initiation of eculizumab therapy and platelet count recovery in the French outbreak may also be a coincidental finding. On the basis of the reported experience in the German outbreak, patients treated with best supportive care had worsening of disease activity 6 to 8 days after diarrhea, followed by improvement. Therefore, the observed improvement after eculizumab might be the natural course, and no concrete conclusions can be drawn on eculizumab-specific efficacy for STEC-HUS.8 On the basis of these reports and after a multidisciplinary discussion that involved hematology, nephrology, and infectious disease services, we elected to treat our patient with eculizumab on day 3 of her presentation.

Another outbreak of STEC-HUS was reported in Bordeaux, France, in June 2011.8 This involved 24 cases, of which 9 developed HUS. Although the report is limited by the small sample size, patients who received early treatment with eculizumab (day 0-4) had rapid improvement in symptoms.8 The association between the initiation of eculizumab therapy and platelet count recovery in the French outbreak may also be a coincidental finding. On the basis of the reported experience in the German outbreak, patients treated with best supportive care had worsening of disease activity 6 to 8 days after diarrhea, followed by improvement. Therefore, the observed improvement after eculizumab might be the natural course, and no concrete conclusions can be drawn on eculizumab-specific efficacy for STEC-HUS.8 On the basis of these reports and after a multidisciplinary discussion that involved hematology, nephrology, and infectious disease services, we elected to treat our patient with eculizumab on day 3 of her presentation. The use of antimicrobial therapy is generally controversial in patients with STEC-HUS. Several studies showed that it did not affect outcomes.8 Furthermore, some studies reported that antibiotic treatment triggered the development of HUS.7 On that basis, antibiotics were discontinued at the time of admission in our patient and the initiation of prophylactic azithromycin was delayed until 12 hours after eculizumab use.

s showed that it did not affect outcomes.8 Furthermore, some studies reported that antibiotic treatment triggered the development of HUS.7 On that basis, antibiotics were discontinued at the time of admission in our patient and the initiation of prophylactic azithromycin was delayed until 12 hours after eculizumab use. It is well established that patients undergoing allogeneic transplant have a substantially increased risk of bacterial, fungal, and viral infections due to continued immunosuppression and due to the development of GvHD in most patients.9, 10 However, it is unclear whether there is an increased susceptibility to STEC. In 2012, Eriguchi et al11 described that in mice, damage to Paneth cells by GvHD resulted in dramatically reduced expression of α-defensins in the small intestines and perturbed the normal intestinal environment. The diversity of the intestinal microflora was lost with overwhelming expansion of specific bacteria, such as E coli, which are normally a very small proportion of the intestinal microbial communities. This study confirms and further extends a recent study showing the intestinal flora change, with an increase in gram-negative Enterobacteriaceae family members including E coli after allogeneic BMT in mice.11 In summary, we report a case of STEC-HUS as a differential diagnosis for the development of microangiopathy in an allogeneic transplant recipient and discuss important treatment decisions in an immunocompromised host, including the controversial role of eculizumab and antimicrobial therapy.

It is well established that patients undergoing allogeneic transplant have a substantially increased risk of bacterial, fungal, and viral infections due to continued immunosuppression and due to the development of GvHD in most patients.9, 10 However, it is unclear whether there is an increased susceptibility to STEC. In 2012, Eriguchi et al11 described that in mice, damage to Paneth cells by GvHD resulted in dramatically reduced expression of α-defensins in the small intestines and perturbed the normal intestinal environment. The diversity of the intestinal microflora was lost with overwhelming expansion of specific bacteria, such as E coli, which are normally a very small proportion of the intestinal microbial communities. This study confirms and further extends a recent study showing the intestinal flora change, with an increase in gram-negative Enterobacteriaceae family members including E coli after allogeneic BMT in mice.11 In summary, we report a case of STEC-HUS as a differential diagnosis for the development of microangiopathy in an allogeneic transplant recipient and discuss important treatment decisions in an immunocompromised host, including the controversial role of eculizumab and antimicrobial therapy. Grant Support: The study was supported by a grant (N.L.) from Omeros. Potential Competing Interests: Dr Leung has board membership with Takeda and BTG and is a consultant for Prothena. The rest of the authors report no competing interests.

by quantitative observational studies based on larger sample sizes; second, because consequences for patient care were based on participants' perceptions, we cannot assess the true impact of these conflict stories, and thus we prefer to speak of potential consequences, possibilities of something affecting patient care. Taking the above into account, we can say that a non-negligible proportion of team conflict stories was perceived by professionals to have potentially negative consequences on patient quality of care. It is possible that this proportion may have been underestimated in our study; indeed, during interviews, some participants had difficulty assessing the consequences of team conflict on patient care. While waiting for more studies on this topic, our results led us to believe that when addressing team conflicts, patient care should be taken into consideration and that quality management of acute care hospitals should consider team conflicts as a potential threat for the quality of patient care. Improvement programs may need to strengthen health care professionals' ability to identify and respond to team conflicts.

Workplace conflicts among professionals are frequent in health care. A majority of health care professionals has witnessed disruptive behaviors1 or perceived conflicts on a weekly basis.2, 3 In the United States, 20% of residents reported serious conflicts with other staff members,4 and 43% of surgeons reported experiencing conflicts about postoperative goals of care with intensivists either sometimes or always.5 Conflicts within teams can involve harsh language (threats, yelling, profanity), blaming, breakdown in communication, or disruptive conduct.6, 7 Whereas team conflicts may be viewed constructively when used to clarify misunderstandings and disagreements about roles and tasks,8, 9 they can alter team dynamics and communication, decrease trust and team performance,10, 11 and lead to poor mental health among professionals.12, 13, 14 Team conflicts may draw health care professionals' attention away from patient care and drain their personal resources,3, 6, 15, 16 posing a threat to the team safety climate17 and, ultimately, the quality of patient care.4, 18

st and team performance,10, 11 and lead to poor mental health among professionals.12, 13, 14 Team conflicts may draw health care professionals' attention away from patient care and drain their personal resources,3, 6, 15, 16 posing a threat to the team safety climate17 and, ultimately, the quality of patient care.4, 18 Two qualitative studies specifically analyzed the consequences of conflicts for patient care.19, 20 The study of Walrath et al used focus groups to explore disruptive behaviors observed or experienced by 96 registered nurses in an acute care hospital in the Northeastern United States. The authors noted that disruptive behaviors affected the nurses, the nurses' practice settings, and the patients. The impact on patient care could take 2 forms: first, nurses could be distracted from patient care; second, the patient could become the witness of disruptive behaviors from health care professionals. Nurses also expressed the general concern that disruptive behaviors could decrease the quality of care and create risks to patient safety.19 The study of Aberese-Ako et al used ethnographic methods to explore the influence of conflicts among health care professionals working in the departments of obstetrics and gynecology of a referral hospital in Ghana. They found that team conflicts could affect quality of care in 2 ways: directly (delays in provision of health care, not providing “essential care” to patients) and indirectly (health care professionals feeling demotivated and exhibiting negative attitudes toward patients). The authors also found that conflicts may have positive effects on quality of care,by preventing “medical complacency and negligence.”20 However, these studies had 2 main limitations. First, they mainly discussed the consequences of conflicts for patients care by considering quality as a general concept. Quality of care is, however, not a single dimension,21 and which of the multifaceted nature of quality of care (safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity)22 are affected by team conflicts remains, until now, an unexplored area.

ents care by considering quality as a general concept. Quality of care is, however, not a single dimension,21 and which of the multifaceted nature of quality of care (safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity)22 are affected by team conflicts remains, until now, an unexplored area. Second, these studies focused on team conflicts in general, disregarding the fact that conflicts are not similar in their form.23 For example, team conflicts differ depending on whether the protagonists (the health care professionals involved in a conflict) belong to the same profession or not.24 Interprofessionality of care can lead to team conflict as a result of areas of overlapping competencies and shared responsibilities,25, 26 such as when determining the goals of care.5 Interprofessional conflicts may affect the safety climate17 and lead to medical errors.4 Team conflicts also differ in their form when involving protagonists within a professional group but with different statuses (nurse vs nurse manager, resident vs chief resident, etc).27 In acute care hospitals, hierarchy is often inherent to medical and clinical decision making and health care professional cultures have fostered a hierarchical power structure that is now challenged by the interprofessional processes of patient care.28 Few studies have looked at the interplay between hierarchical differences and conflicts.29 We therefore know little about how it might affect aspects of quality of care.

h care professional cultures have fostered a hierarchical power structure that is now challenged by the interprofessional processes of patient care.28 Few studies have looked at the interplay between hierarchical differences and conflicts.29 We therefore know little about how it might affect aspects of quality of care. Given this gap in the literature, the objective of this study was to explore health care professionals' experiences of team conflicts and their perceptions of whether and how conflicts affected the multifaceted quality of patient care. We also sought to understand whether different forms of conflicts (intraprofessional vs interprofessional and same vs different levels of hierarchy) might affect different aspects of quality of care. Methods Design and Setting This study reports on a large-scale qualitative research project on health care professionals' experiences of team conflicts.23 The study was conducted at the University Hospitals of Geneva, Switzerland, a 1700-bed tertiary care hospital. The study was approved by the Regional Research Ethics Committee of Geneva. Given the sensitivity of the topic, chief medical officers and chairs of the departments involved in the study independently reviewed and approved the project.

the University Hospitals of Geneva, Switzerland, a 1700-bed tertiary care hospital. The study was approved by the Regional Research Ethics Committee of Geneva. Given the sensitivity of the topic, chief medical officers and chairs of the departments involved in the study independently reviewed and approved the project. Recruitment and Interviews Between October 2014, and March 2016, we invited a randomly selected sample of professionals involved in first-line patient care to participate in a semistructured interview: residents, chief residents, certified nursing assistants, nurses, and nurse supervisors. We did not include attending physicians because they represent second-line physicians in the process of care at our hospital, whereas chief residents are involved in direct supervision. We selected participants from 4 clinical departments with different levels of acuity, types of patients, and work organization to have a range of experiences (internal medicine, family medicine, pediatrics, and 2 surgical units). An approximately equal number of physicians and nurses were invited from each department. Four social scientists conducted the interviews (N.Bo., V.M.J., P.H., S.C.). Two of these scientists worked at the University of Geneva, and 2 worked at the University Hospitals of Geneva; none was involved with the participants' hospital department.

al number of physicians and nurses were invited from each department. Four social scientists conducted the interviews (N.Bo., V.M.J., P.H., S.C.). Two of these scientists worked at the University of Geneva, and 2 worked at the University Hospitals of Geneva; none was involved with the participants' hospital department. After accepting to participate in the study, each participant received a written description of the research project, with instructions to think about conflict stories they had experienced or witnessed with coworkers. The definition of conflict stories was left up to the participants. The interview guide, available elsewhere,23 was informed by a previous study on professional conflicts in health care.30 During the interviews, participants were invited to recount 1 or more conflict stories. We also asked about the sources, consequences, and responses to conflicts. At the beginning of the interview, we gave participants time to sign consent forms and to ask questions. Participants could withdraw from the study at any time; we also gave them the opportunity to read and request removal of any content from their interview transcript. Average duration of interviews was 38 minutes (minimum 23, maximum 69).

e interview, we gave participants time to sign consent forms and to ask questions. Participants could withdraw from the study at any time; we also gave them the opportunity to read and request removal of any content from their interview transcript. Average duration of interviews was 38 minutes (minimum 23, maximum 69). Analysis Interviews were audio-taped, transcribed verbatim, and anonymized. Transcripts were analyzed using a thematic approach.31 All authors read 6 interviews to familiarize themselves with the interviews, discussed codes that were derived from the data, and developed an initial list of codes. This list of codes was inductively grounded in the data and deductively derived from the literature on work conflicts.15, 32, 33 The codes were then tested on a sample of 15 interviews and refined. For each conflict story, we coded protagonists' characteristics (gender, professional group and status, specialty) and the form of the conflict story (intraprofessional vs interprofessional conflict, hierarchical differences among professionals involved in the conflict, and whether or not the conflicts had been solved). Hierarchical levels (same vs different) were defined based on whether protagonists had, or not had, a management role in our hospital such as nurse manager (vs nurse and certified nurse) or chief resident (vs resident). Although we had not specifically prompted participants to talk about interprofessionality and professional hierarchies, these were spontaneously mentioned in their conflict stories, and therefore we included these dimensions in our analyses. All data were then coded (N.Bo.) using Atlas.ti Scientific Software Development (version 7.5).

not specifically prompted participants to talk about interprofessionality and professional hierarchies, these were spontaneously mentioned in their conflict stories, and therefore we included these dimensions in our analyses. All data were then coded (N.Bo.) using Atlas.ti Scientific Software Development (version 7.5). Potential consequences of conflict stories for patient care were based on what participants reported. In the interview guide, 1 questioner asked: “What were the consequences of this situation?” We selected conflict situations in which participants reported consequences for patient care and analyzed these responses using the 6 dimensions of quality of care defined by the Institute of Medicine Committe on Quality of Health Care in America: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity.10 We adapted the 6 attributes and their definitions for this study (Table 1). Two of the interviewers (N.Bo., S.C.) independently coded the reported consequences of conflict stories for patient care, assigning either 1 or several dimensions of quality of care to each situation. They then met to compare their coding and reach a consensus in case of discrepancy. When more than 1 quality-of-care dimension was coded in a conflict story, we distinguished between the primary dimension and secondary dimensions. The primary dimension was the main consequence in participants' discourses, and secondary dimensions were less important. The current analyse focused on the primary dimension. Two nurse supervisors and 2 physicians (F.M., T.L., P.C., M.N.) reviewed all coded data. Discrepancies were solved by consensus.Table 1 Dimensions of Quality of Carea

was the main consequence in participants' discourses, and secondary dimensions were less important. The current analyse focused on the primary dimension. Two nurse supervisors and 2 physicians (F.M., T.L., P.C., M.N.) reviewed all coded data. Discrepancies were solved by consensus.Table 1 Dimensions of Quality of Carea Dimension Characteristics Safety “First do no harm” (individual caregiver responsibility and property of the system). Effectiveness Neither underuse nor overuse the best available techniques, treatment, or care. Patient-centeredness Be attentive to patient's culture, social context, and specific needs, encourage patient participation in decision making, and avoid patient witnessing conflicts between professionals. Timeliness Minimize delays in patient care. Efficiency Minimize the waste of supplies, equipment, space, ideas, and opportunities. Equity Ensure high-quality care for all patients, regardless of their gender, ethnicity, income, social support, social life and unhealthy health behaviors. a Adapted from The Institute of Medicine Committee on Quality of Health Care in America. Crossing the Quality Chasm, Washington, DC: National Academies Press; 2001.

quity Ensure high-quality care for all patients, regardless of their gender, ethnicity, income, social support, social life and unhealthy health behaviors. a Adapted from The Institute of Medicine Committee on Quality of Health Care in America. Crossing the Quality Chasm, Washington, DC: National Academies Press; 2001. Results Characteristics of Health Care Professionals and of Team Conflict Stories A total of 82 semistructured interviews with health care professionals (participants' characteristics are reported in Table 2) provided 130 team conflict stories. Of the 82 interviewees, 41 shared 1 story, 34 shared 2 stories, and 7 shared 3 stories. Seventy-five percent (98 of 130) of conflicts stories were experienced first-hand, whereas others were witnessed; 84% (109 of 130) referred to specific situations, whereas 16% (21 of 130) were generic situations; 67% (87 of 130) involved protagonists at the same level of hierarchy, and 33% (43/130) involved different levels of hierarchy among protagonists. Fifty-seven percent (74 of 130) involved intraprofessional conflicts, whereas 43% (56 of 130) were interprofessional.Table 2 Characteristics of the 82 Health Care Professionals

% (87 of 130) involved protagonists at the same level of hierarchy, and 33% (43/130) involved different levels of hierarchy among protagonists. Fifty-seven percent (74 of 130) involved intraprofessional conflicts, whereas 43% (56 of 130) were interprofessional.Table 2 Characteristics of the 82 Health Care Professionals Characteristics Age: Mean (range) 41 (29-62) Sex (Women:Men) 50:32 Profession Certified Nursing Assistant 6 (7.3%) Nurse 27 (32.9%) Nurse Manager 6 (7.3%) Resident 22 (26.8%) Chief Resident 21 (25.6%) Clinical Department Pediatrics 21 (25.6%) Surgical Units 21 (25.6%) Internal Medicine 20 (24.4%) Family Medicine 20 (24.4%) Number of years of experience: median (range) 11 (1-35) Country of education until diploma (Switzerland:Other) 36:46 Consequences of Conflict Stories on Quality of Care Health care professionals were asked about the consequences of conflict stories they reported. Based on their assessment, 59% (77 of 130) of team conflict stories had no consequences for patient care and 41% (53 of 130) had potential consequences for patient care.

Characteristics Age: Mean (range) 41 (29-62) Sex (Women:Men) 50:32 Profession Certified Nursing Assistant 6 (7.3%) Nurse 27 (32.9%) Nurse Manager 6 (7.3%) Resident 22 (26.8%) Chief Resident 21 (25.6%) Clinical Department Pediatrics 21 (25.6%) Surgical Units 21 (25.6%) Internal Medicine 20 (24.4%) Family Medicine 20 (24.4%) Number of years of experience: median (range) 11 (1-35) Country of education until diploma (Switzerland:Other) 36:46 Consequences of Conflict Stories on Quality of Care Health care professionals were asked about the consequences of conflict stories they reported. Based on their assessment, 59% (77 of 130) of team conflict stories had no consequences for patient care and 41% (53 of 130) had potential consequences for patient care. We categorized these consequences into the 6 dimensions of quality of care: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity (Table 3). Among the 53 conflict stories that involved potential consequences for patient care, 28 (53%) had a single consequence on quality of care (1 quality dimension), whereas 25 (47%) had multiple consequences (several quality dimensions). Among conflict stories with multiple consequences, we distinguished the primary (reported above and in Table 4, column A) and other consequences. We reported the primary consequence in order of frequency (highest to lowest). The main dimension involved in conflict stories was care not being provided in a timely manner (34% of the 53 stories that had consequences for patient care): participants reported delays in providing medical treatment or performing surgical interventions.We try to provide good patient care, we don't want to do anything that could harm patients; that's obvious. If I think of my family, I wouldn't want anyone to be anesthetised longer just because the surgeon is poorly organized. So, even if I don't know our patients, I don't think they should just be lying down in the OR for no reason.

e good patient care, we don't want to do anything that could harm patients; that's obvious. If I think of my family, I wouldn't want anyone to be anesthetised longer just because the surgeon is poorly organized. So, even if I don't know our patients, I don't think they should just be lying down in the OR for no reason. (Nurse, Surgical Units)Table 3 Quality Dimensions Involved in the Consequences of Team Conflicts on Patient Care, as Reported by Participants

e good patient care, we don't want to do anything that could harm patients; that's obvious. If I think of my family, I wouldn't want anyone to be anesthetised longer just because the surgeon is poorly organized. So, even if I don't know our patients, I don't think they should just be lying down in the OR for no reason. (Nurse, Surgical Units)Table 3 Quality Dimensions Involved in the Consequences of Team Conflicts on Patient Care, as Reported by Participants Quality Dimensionsa Illustrative Quotes Timeliness The patient had been feeling worse for a couple of days, so if we had been able to better discuss the case, we might have been able to take him to the OR a day earlier. (Resident, Pediatrics) There are delays because I need to look for nurses, I need to wait for them to be available to come with me, so it's not always easy. (Certified Nursing Assistant, Pediatrics) Patient-centeredness I clearly wasn't feeling very calm when I went to see the patients right after the conflict occurred. I should have had a break to talk it through with my coworkers instead of going straight to see my patients as if nothing had happened. (Nurse, Family Medicine) It was very difficult for us to work with that intern, and once she became aggressive with one of our patient's wives. The wife did not speak French, but the intern talked to her in French, rather violently, and she made the wife cry. (Nurse Supervisor, Internal Medicine) Efficiency When I'm on call in this specialty, I have to round to see my patients, and I'm on call at the same time. So if I get paged, I have to leave, go check what's going on, and come back, which creates discontinuities in my rounds. (Resident, Pediatrics) We can't work well. In fact, the work we do is pretty poor because of working conditions that just aren't adapted to our situation here. (Chief Resident, Pediatrics) Effectiveness For that situation, I'm convinced that patient care was suboptimal. We should have given adrenaline to our patient. But I guess the resident was stressed [because of two chief residents] before he even started taking care of the patient, which contributed to suboptimal patient care. (Chief Resident, Surgical Units) Safety It was entirely our fault if this patient had a completely abnormal cardiac rhythm. Our care had been iatrogenic; she had very few comorbidities. (Resident, Internal Medicine) The surgeon wasn't listening to us, and it got really stressful because we could hear the patient's cardiac rhythm slowing down on the monitor; we got scared. (Nurse, Surgical Units) Equity I asked the respiratory therapist to come remove the patient's secretions.

d very few comorbidities. (Resident, Internal Medicine) The surgeon wasn't listening to us, and it got really stressful because we could hear the patient's cardiac rhythm slowing down on the monitor; we got scared. (Nurse, Surgical Units) Equity I asked the respiratory therapist to come remove the patient's secretions. My patient was in the ICU and it was an end-of-life situation. I wanted my patient to be comfortable, but the RT refused to come because he didn't see the point of it with a dying patient. (Nurse, Pediatrics, talking about when she worked in an adult ICU) a Institute of Medicine Committee on Quality of Health Care in America. Crossing the Quality Chasm. Washington, DC: National Academies Press; 2001. Table 4 Frequency of Quality Dimensions Involved in 53 Team Conflict Storiesa Quality Dimensionsb All Forms of Team Conflict Intra-professional Inter-professional Same Level of Hierarchy Different Levels of Hierarchy A B C N (%) N (%) N (%) N (%) N (%) Timeliness 18 (34%) 7 (39%) 11 (61%) 14 (78%) 4 (22%) Patient-centeredness 16 (30%) 10 (63%) 6 (38%) 11 (69%) 5 (31%) Efficiency 13 (25%) 7 (54%) 6 (46%) 8 (62%) 5 (39%) Effectiveness 3 (6%) 2 (67%) 1 (33%) 2 (67%) 1 (33%) Safety 2 (4%) 1 (50%) 1 (50%) 1 (50%) 1 (50%) Equity 1 (2%) - 1 (100%) 1 (100%) - a Primary consequence of the conflict on patient care. b Institute of Medicine Committee on Quality of Health Care in America. Crossing the Quality Chasm. Washington, DC: National Academies Press; 2001.

Quality Dimensionsb All Forms of Team Conflict Intra-professional Inter-professional Same Level of Hierarchy Different Levels of Hierarchy A B C N (%) N (%) N (%) N (%) N (%) Timeliness 18 (34%) 7 (39%) 11 (61%) 14 (78%) 4 (22%) Patient-centeredness 16 (30%) 10 (63%) 6 (38%) 11 (69%) 5 (31%) Efficiency 13 (25%) 7 (54%) 6 (46%) 8 (62%) 5 (39%) Effectiveness 3 (6%) 2 (67%) 1 (33%) 2 (67%) 1 (33%) Safety 2 (4%) 1 (50%) 1 (50%) 1 (50%) 1 (50%) Equity 1 (2%) - 1 (100%) 1 (100%) - a Primary consequence of the conflict on patient care. b Institute of Medicine Committee on Quality of Health Care in America. Crossing the Quality Chasm. Washington, DC: National Academies Press; 2001. Lack of patient-centeredness was the second most mentioned consequence for care (30% of the situations): Teams did not fully meet patient and family needs; they failed to listen to patient requests because they were distracted by conflicts.Of course, it affected patients! I work night shifts, and as I got to work one evening, people told me that the schedule for the Christmas break was up. I checked it, and it drove me mad. I was in for a bad night, and obviously all the patients had bad nights, too. (…) I was really upset, so I was less available for my patients. I was not able to focus on their needs as much as usual. (Nurse, Internal Medicine)

Lack of patient-centeredness was the second most mentioned consequence for care (30% of the situations): Teams did not fully meet patient and family needs; they failed to listen to patient requests because they were distracted by conflicts.Of course, it affected patients! I work night shifts, and as I got to work one evening, people told me that the schedule for the Christmas break was up. I checked it, and it drove me mad. I was in for a bad night, and obviously all the patients had bad nights, too. (…) I was really upset, so I was less available for my patients. I was not able to focus on their needs as much as usual. (Nurse, Internal Medicine) The third most mentioned consequence was a lack of efficiency (25%). Teams did not communicate in an optimal way, resulting in a loss of information, counter-orders, and a lack of consistency in decisions, team disorganization, and deteriorated communication regarding medical orders.We keep having to look for nurses when we have questions about our patients, and when we ask someone, they always say: “Oh, she just left to go get lunch.” “Okay, so who is in charge of her patients while she's away?” “Well, I don't know.” So we waste a huge amount of time. (Resident, Pediatrics)

The third most mentioned consequence was a lack of efficiency (25%). Teams did not communicate in an optimal way, resulting in a loss of information, counter-orders, and a lack of consistency in decisions, team disorganization, and deteriorated communication regarding medical orders.We keep having to look for nurses when we have questions about our patients, and when we ask someone, they always say: “Oh, she just left to go get lunch.” “Okay, so who is in charge of her patients while she's away?” “Well, I don't know.” So we waste a huge amount of time. (Resident, Pediatrics) The other 3 dimensions were less frequently mentioned in our interviews (see quotes in Table 3). Less effective care (3 conflict stories) was related to surgical interventions performed by inexperienced and unsupervised surgeons or failure to use best available techniques. In terms of safety (2 conflict stories), participants described environments in which errors had occurred (or were more likely to occur) because of conflicts. Finally, lack of equitable care (1 conflict story) was mentioned in an end-of-life situation. Because of the patient's state, a respiratory therapist refused to perform what had been asked to alledgely make the patient more comfortable. Of note, during the interviews, some participants reported difficulty in assessing whether the conflict story had had consequences for the patient:I do not think this conflict changed anything in the patient's care, but it's hard to say. Yeah, I would say that we probably managed to keep it among ourselves without affecting our patient.

e interviews, some participants reported difficulty in assessing whether the conflict story had had consequences for the patient:I do not think this conflict changed anything in the patient's care, but it's hard to say. Yeah, I would say that we probably managed to keep it among ourselves without affecting our patient. (Resident, Internal Medicine) Forms of Team Conflicts and Quality of Patient Care Distribution of conflict stories across the 2 forms of conflicts (intraprofessional vs interprofessional conflict, same vs different levels of hierarchy) is reported in Table 5. Distribution of consequences for quality of care with respect to these 2 forms of conflicts is provided in Table 4.Table 5 Forms of Team Conflict Stories With and Without Consequences for Patient Care Forms 53 Conflict Stories With Consequences for Patient Care 77 Conflict Stories With No Consequences for Patient Care N (%) N (%) Intra-/Interprofessional Intraprofessional 27 (50.9) 47 (61.0) Interprofessional 26 (49.1) 30 (39.0) Hierarchical levels Same level 37 (69.8) 50 (64.9) Different levels 16 (30.2) 27 (35.1) Timeliness and patient-centredness consequences differed by form of conflicts (Table 4, columns B and C). Timeliness consequences were mostly linked with interprofessional conflicts (61%) and with conflicts among protagonists at the same level of hierarchy (78%): patient-centeredness consequences with intraprofessional conflicts (63%) and with conflicts among protagonists having the same hierarchical level (69%).

B and C). Timeliness consequences were mostly linked with interprofessional conflicts (61%) and with conflicts among protagonists at the same level of hierarchy (78%): patient-centeredness consequences with intraprofessional conflicts (63%) and with conflicts among protagonists having the same hierarchical level (69%). Efficiency consequences were linked with conflicts among protagonists at the same level of hierarchy (62%) and were roughly similar between intraprofessional vs interprofessional conflicts (54% and 46%, respectively). Effectiveness, safety, and equity of care consequences also differed by form of conflicts; however, sample sizes across strata were too small to draw conclusions.

Efficiency consequences were linked with conflicts among protagonists at the same level of hierarchy (62%) and were roughly similar between intraprofessional vs interprofessional conflicts (54% and 46%, respectively). Effectiveness, safety, and equity of care consequences also differed by form of conflicts; however, sample sizes across strata were too small to draw conclusions. Discussion Through interviews with a random sample of physicians, nurses, and certified nursing assistants working at a teaching hospital, we have examined whether and how team conflicts could affect quality of patient care. Our study illustrates how conflicts among health care professionals are not circumscribed in teams and may lead to suboptimal patient care. This result is in line with previous studies19, 20; however, our study goes further by identifying which aspects of quality of care were affected by team conflicts. We used the framework of the Institute of Medicine Committee on Quality of Health Care in America as a template to go beyond general statements about quality of care.10 The most common consequences were failure to provide care in both a timely and a patient-centered manner and less efficient care. This finding is comforting, as it suggests that when team conflicts spill over to patient care, safety may be affected only rarely. Nevertheless, our results suggest that team conflicts are detrimental to patient-centeredness. This result echoes an ethnographic study of morning interprofessional rounds in intensive care, which showed that conflicts prevented teams from involving patients in their own care.34

are, safety may be affected only rarely. Nevertheless, our results suggest that team conflicts are detrimental to patient-centeredness. This result echoes an ethnographic study of morning interprofessional rounds in intensive care, which showed that conflicts prevented teams from involving patients in their own care.34 Our study assessed whether forms of team conflicts can be linked with different dimensions of quality of care. We observed that intraprofessional conflicts were linked with impaired patient-centered care and that interprofessional conflicts were related with more delays. These results are new and would need further—in particular, quantitative— studies to better understand these phenomenons and to determine the impact of these problems. However, they may help attending physicians, nurse managers, and quality management programs identifying the domains in which quality of patient care may be threatened by team conflicts and implement appropriate counter-measures more efficiently. How can we explain the effect of team conflicts on quality of patient care? The provision of safe patient care rests on good clinical knowledge but also on good communication and collaboration skills. More specifically, effective collaborative practice and teamwork represent cornerstones for high quality of care.35, 36, 37, 38 However, conflicts can lead health care professionals to exhibiting poor collaborative attitudes.20 Failure to communicate within a team may mean that decisions for patient care are made in isolation and do not include all team members' perspectives on patients.39

nt cornerstones for high quality of care.35, 36, 37, 38 However, conflicts can lead health care professionals to exhibiting poor collaborative attitudes.20 Failure to communicate within a team may mean that decisions for patient care are made in isolation and do not include all team members' perspectives on patients.39 Finally, based on participants' assessments of 130 conflicts stories, we showed that more than 4 of 10 (41%) team conflicts stories had potential consequences for quality of care. To our knowledge, this is the first study to document the proportion of team conflicts potentially affecting quality of patient care. Two caveats must, however, be emphasized: First, the observed proportion (4 of 10) is indicative and should be confirmed by quantitative observational studies based on larger sample sizes; second, because consequences for patient care were based on participants' perceptions, we cannot assess the true impact of these conflict stories, and thus we prefer to speak of potential consequences, possibilities of something affecting patient care.

m conflicts, patient care should be taken into consideration and that quality management of acute care hospitals should consider team conflicts as a potential threat for the quality of patient care. Improvement programs may need to strengthen health care professionals' ability to identify and respond to team conflicts. Limitations This study has several limitations. First, the data-collection technique (semistructured interviews) may have favored information bias, and we did not triangulate data from interviews with field observations or hospital records. Second, team conflict stories were selected using participants' self-assessment, allowing selection bias in identifying conflicts stories. Third, during interviews, some participants had difficulties evaluating whether and how conflicts had affected patient care; even if interviewers helped participants identifying these consequences, we may have missed some patient-care consequences. Fourth, we interviewed a limited number of health care professions. Integrating additional professions (midwives, physiotherapists, for example) may enrich our description of team conflict stories, but we cannot assert whether it would enrich the description of consequences of team conflict on patient care. Fifth, based on participants' discourses, it was not always entirely clear whether quality of care was the consequence or the cause of conflict stories. Some participants referred to the chicken-and-egg conundrum to describe how distinguishing what had started a conflict from its consequences could be tricky, as unaddressed conflicts can lead to further tensions.23 Despite multiple reviews of these ambiguous situations by all co-authors, we cannot avoid the possibility that some conflicts stories may have been misclassified as cause of impaired quality of care or as cause of team conflict.

its consequences could be tricky, as unaddressed conflicts can lead to further tensions.23 Despite multiple reviews of these ambiguous situations by all co-authors, we cannot avoid the possibility that some conflicts stories may have been misclassified as cause of impaired quality of care or as cause of team conflict. Despite these limitations, we feel confident in the robustness of our results. We conducted a significant number of interviews in different clinical settings, increasing confidence in our capacity to capture sufficient heterogeneity in conflict stories. Random sampling allowed a smooth recruitment of participants, avoiding participants' concerns with the reasons of their selection for the study. Finally, interviews were conducted by social scientists to minimize barriers related to peer interviewing. Conclusion In a tertiary hospital, conflicts among health care professionals can potentially affect patient care. When team conflicts have consequences for patient care, they mostly influence timeliness, patient-centeredness, and efficiency. Quality managers of care hospitals should consider team conflicts as potential barriers to quality care. Quality management should consider preventive actions and support programs for management of conflicts. Acknowledgments The authors wish to thank all participants who agreed to share their stories and experiences as well as the heads of departments who supported this project. They also extend their gratitude to Ms. Nuria Scherly for her transcription work.

Conclusion In a tertiary hospital, conflicts among health care professionals can potentially affect patient care. When team conflicts have consequences for patient care, they mostly influence timeliness, patient-centeredness, and efficiency. Quality managers of care hospitals should consider team conflicts as potential barriers to quality care. Quality management should consider preventive actions and support programs for management of conflicts. Acknowledgments The authors wish to thank all participants who agreed to share their stories and experiences as well as the heads of departments who supported this project. They also extend their gratitude to Ms. Nuria Scherly for her transcription work. Grant Support: This study was funded in part by funds from the University of Geneva. Potential Competing Interests: The authors report no competing interests.

Cardiovascular disease (CVD) is recognized as the number one cause of morbidity and mortality globally, with coronary heart disease (CHD) being the major contributor. This issue is of growing concern in low- and middle-income countries1, 2 in addition to wealthy Western countries, where it has long been recognized that diet and lifestyle contribute to 80% of CHD.3 However, the role of dietary carbohydrate is unclear, it may not even be mentioned in major articles4 or media,2 and it may be concluded to have negligible impact5 even when considering the glycemic index (GI) and glycemic load (GL).6 Meanwhile, Halton et al7 reported a modest increase in incident CHD of 22% from the 10th to the 90th percentile of carbohydrate intake in women nurses in the United States. Dwarfing this finding, they reported a 90% higher risk for CHD from GL, strong enough to suggest a role for this marker in carbohydrate food quality. Whether the risk relations (RR) between CHD and dietary GL and GI are sufficiently strong (threshold RR >1.20 with a lower bound >1.10) to support risk reduction via nutrition guidance is unclear. Methodological problems in original studies and existing systematic and meta-analytic reviews prevent an understanding of whether this threshold is met. Therefore, we reexamined the available evidence, aiming to avoid pitfalls in the existing literature.

.10) to support risk reduction via nutrition guidance is unclear. Methodological problems in original studies and existing systematic and meta-analytic reviews prevent an understanding of whether this threshold is met. Therefore, we reexamined the available evidence, aiming to avoid pitfalls in the existing literature. A number of extreme-quantile meta-analyses (EQMs) have supported that a higher risk for CHD arises among women consuming diets of higher GL, by 69% in 5 studies,8 55% in 6 studies,9 and 49% in 5 studies while representing 1 study of high RR twice.10 Each meta-analysis combined mostly the same studies, and they reported CHD-GI RRs approximately half that for GL and that RRs were lower in men than women. Unfortunately, each meta-analysis combined results having different definitions for GL or GI (across tertile or quartile or quintile ranges) and with different ranges per quantile. Also, none of the studies adjusted GL to a common energy intake before analysis. None asked whether the size of these RRs was dependent on the quality of the dietary instrument or selected to use only those studies using truly validated dietary instruments to assess GI and GL intakes. Also not addressed was whether the RRs were independent of macronutrient intakes.

on energy intake before analysis. None asked whether the size of these RRs was dependent on the quality of the dietary instrument or selected to use only those studies using truly validated dietary instruments to assess GI and GL intakes. Also not addressed was whether the RRs were independent of macronutrient intakes. Another EQM with problems similar to those noted previously had additionally undertaken dose-response meta-analyses (DRMs) combining studies on men and women.10 Dose-response meta-analysis helps to avoid combining studies of different definitions of exposure. However, DRM depends on the dietary assessment systems not resulting in overdispersion of the exposure variable, which results in bias toward the null.11 The authors of the EQM10 tabulated the CHD RR to be higher by only 5% per 50-U increment in GL (11 studies), which is hard to reconcile with results from other EQMs.8, 9, 10 Moreover, a graphical presentation in their article shows a pattern of confidence intervals inconsistent with the method of DRM indicated.

null.11 The authors of the EQM10 tabulated the CHD RR to be higher by only 5% per 50-U increment in GL (11 studies), which is hard to reconcile with results from other EQMs.8, 9, 10 Moreover, a graphical presentation in their article shows a pattern of confidence intervals inconsistent with the method of DRM indicated. Mente et al12 reported evidence supporting a causal link between dietary factors and CHD, indicating a 32% greater risk among persons consuming higher GI and GL diets, a combined value as if the risk was the same from GI and GL. The approach to assessment of causality was that of Bradford-Hill,13 although only the first 4 of the 9 criteria were used, and for GI and GL, none of the criteria were independent of the prospective cohort studies analyzed. Micha et al14 reported some evidence on the CHD-GL RR, although they did address all Bradford-Hill criteria. However, although they reported use of an appropriate DRM, the value for the CHD-GL RR they provided was from an earlier publication,9 which was based on EQM having the problems noted previously.

udies analyzed. Micha et al14 reported some evidence on the CHD-GL RR, although they did address all Bradford-Hill criteria. However, although they reported use of an appropriate DRM, the value for the CHD-GL RR they provided was from an earlier publication,9 which was based on EQM having the problems noted previously. Usually, relevant studies have assessed the CHD-GL and GI RRs in prospective cohort studies as noted previously. Notably, Jakobsen et al15 adopted a different approach by investigating the CHD-carbohydrate RR, finding this relation was “dependent” on the GI of the carbohydrate, although they did not quantify the “dependence.” Others have also provided estimates of the CHD-carbohydrate RR for dietary carbohydrate of known mean GI.16, 17, 18, 19, 20 To our knowledge, there are no published meta-analyses of these data, which we provide. Also to our knowledge, there is no published quantitative DRM of the CHD-GL and GI RRs across the global (worldwide) range of dietary GL and GI intakes as large as 235 g/d GL and 30 U GI, and just one exists for half these ranges,10 with the attendant problems noted. We aimed to rectify this absence since observations are now available to cover the wider ranges.16, 17, 19, 20, 21, 22, 23, 24 We further explored whether the size of the CHD-GL and GI RRs depends on the absence of study-level adjustments for each specific macronutrient. Finally, in discussion, we address causality.

d. We aimed to rectify this absence since observations are now available to cover the wider ranges.16, 17, 19, 20, 21, 22, 23, 24 We further explored whether the size of the CHD-GL and GI RRs depends on the absence of study-level adjustments for each specific macronutrient. Finally, in discussion, we address causality. Methods Protocol and Guidelines The study protocol was registered with PROSPERO (CRD42013004504). It was to investigate CHD-GI and GL and type 2 diabetes–GL and GI RRs with control for the validity of the dietary instrument, potential sex differences, and macronutrient adjustments (among others). The present article concerns CHD only. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)25 and MOOSE (Meta-analyses of Observational Studies in Epidemiology)26 guidelines for reporting were used.

Methods Protocol and Guidelines The study protocol was registered with PROSPERO (CRD42013004504). It was to investigate CHD-GI and GL and type 2 diabetes–GL and GI RRs with control for the validity of the dietary instrument, potential sex differences, and macronutrient adjustments (among others). The present article concerns CHD only. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)25 and MOOSE (Meta-analyses of Observational Studies in Epidemiology)26 guidelines for reporting were used. Literature Searches and Sources MEDLINE and EMBASE were searched simultaneously using ProQuest LLC via the Royal Society of Medicine, London, United Kingdom. A highly efficient protocol was developed in collaboration with the Royal Society of Medicine LitSearch and adapted to CHD. The search period was January 1, 2000, to June 5, 2018 (Supplemental Figure S1a, available online at http://mcpiqojournal.org). The search included identification of Cochrane studies and was for prospective cohort studies (the most reliable epidemiological design) that investigated the association of CHD (first incidence and deaths) with GI and/or GL and carbohydrate characterized by GI in ostensibly heathy adult populations without selection by age, sex, race/ethnicity, or region.

Cochrane studies and was for prospective cohort studies (the most reliable epidemiological design) that investigated the association of CHD (first incidence and deaths) with GI and/or GL and carbohydrate characterized by GI in ostensibly heathy adult populations without selection by age, sex, race/ethnicity, or region. Inclusion and Exclusion Criteria For inclusion in our analyses, studies had to meet the following criteria: (1) prospective cohort study, (2) relevant to adult public health, (3) investigated the association between confirmed first nonfatal myocardial infarction (MI) or fatal CHD (collectively, CHD) and GI and/or GL, (4) used at least 2 defined categories of exposure (by quantiles and/or range such as standard deviation of intakes) and (5) included estimates of relative risk (risk ratio, hazard ratio, odds ratios, relative risk) with (6) measures of uncertainty (standard errors or confidence intervals) (7) relative to a referent exposure, (8) used study-level adjustments for major confounding factors, (9) had a follow-up duration of 4 or more years (when there were multiple publications from a study, the longest duration of follow-up was used unless there was a prohibitive reason [eg, insufficient information]), (10) ascertained MI or CHD by clinical record, (11) reported the sex of the participants, and (12) used either food records or a dietary instrument with validation for the investigated population. Validity was accepted by us when the instrumental measure of carbohydrate (or carbohydrate food) intakes correlated (>0.55) with intakes obtained using objective food records (see Exclusions). Adults of any age, sex, race/ethnicity from any region worldwide in a report published at any time during the study paramenters were included without language restriction. External to the registered protocol, we included observations on the CHD-carbohydrate RR when the GI of the carbohydrate was reported.

Exclusions). Adults of any age, sex, race/ethnicity from any region worldwide in a report published at any time during the study paramenters were included without language restriction. External to the registered protocol, we included observations on the CHD-carbohydrate RR when the GI of the carbohydrate was reported. Studies were excluded if they (1) were not observational, longitudinal, or prospective studies, (2) used self-reported disease ascertainment only, (3) included patients with MI, CHD, or type 2 diabetes at baseline, (4) reported observations other than from fully adjusted models, (5) reported observations including stroke or other CVD, and (6) used invalid dietary instuments (defined as those with energy-adjusted correlation coefficients [Corr] of 0.55 or less for carbohydrate or carbohydrate foods vs objective food records27, 28, 29 unless there was reason to do otherwise).

ly adjusted models, (5) reported observations including stroke or other CVD, and (6) used invalid dietary instuments (defined as those with energy-adjusted correlation coefficients [Corr] of 0.55 or less for carbohydrate or carbohydrate foods vs objective food records27, 28, 29 unless there was reason to do otherwise). Data Extraction and Calculation Data were extracted by 2 reviewers independently (G.L., H.L.), and disparities were resolved by agreement. Data included the following: (1) carbohydrate, GI, and GL by quantiles (means, medians), (2) the reference standard used (glucose or white bread)—to adjust to a common glucose metric (GI glucose = 100, GI white bread = 70), (3) relative risks for first incidence of MI and CHD deaths (risk ratios, hazard ratios, or odds ratios) and their 95% confidence limits by quantiles or by linear relations if not provided by quantiles, (4) energy intake by quantiles and the intake of energy to which GL, GI, and carbohydrate were adjusted, (5) cohort average alcohol intakes, (6) whether RR had received study-level adjustments for intakes of energy, carbohydrate, fat (or fats), protein, fiber, folate, supplemental multivitamins, and alcohol, (7) whether RR had received study-level adjustments for nonnutrient factors—baseline hypertension, hypercholesterolemia, menopausal state and related hormone use, level of education, body mass index, age, physical activity, family history of MI or diabetes, smoking, occupation, income, and marital status, (8) whether studies had excluded CVD other than (in addition to) MI and CHD at baseline, (9) population region, (10) participants’ sex (fraction of men), (11) population race/ethnicity, (12) the number of followed up participants, cases, and person-years of follow-up, (13) follow-up in years, (14) attrition rates during follow-up, (15) whether the dietary instrument was validated and the level of validity, and (16) the method used for ascertainment of MI or CHD. Information not reported directly was calculated when possible or sought from corresponding dietary instrument validation publications (for validity), related publications with dietary details, or correspondence with authors (Supplemental Tables S1, S2, and S3, available online at http://mcpiqojournal.org).

MI or CHD. Information not reported directly was calculated when possible or sought from corresponding dietary instrument validation publications (for validity), related publications with dietary details, or correspondence with authors (Supplemental Tables S1, S2, and S3, available online at http://mcpiqojournal.org). Study Quality The Newcastle-Ottawa Quality Assessment score for prospective cohort studies was used to generate a score from 0 to 9 “stars” based on criteria for selection of participants, comparability of subcohorts, and study-level outcomes.30 We deducted one star from comparability for those studies using a dietary instrument with an energy-adjusted carbohydrate correlation of 0.55 or less. Meta-analyses/Synthesis Analyses used Stata/SE statistical software, version 11.2 (StataCorp) with “mais” (Meta-Analysis in Stata) installation.31 Two-step meta-analysis was used for quantitative DRM for doses within jurisdictions or nationwide exposures. Step 1 used the generalized least squares method for trend estimation of summarized dose-response data of Geenland and Longnecker32 as implemented by Osini et al33 (glst v9.2), which provided individual study dose-response RR values. Step 2 combined the RR values by meta-analysis without covariates (metan v3.03) or with covariates—meta-regression (metareg v6.1) using method of moments and random effects,34 which resolved to fixed effects when results from different studies were consistent (I2=0). Eligible studies providing only extreme quantile RR values or providing dose-response results directly were introduced at step 2.

3) or with covariates—meta-regression (metareg v6.1) using method of moments and random effects,34 which resolved to fixed effects when results from different studies were consistent (I2=0). Eligible studies providing only extreme quantile RR values or providing dose-response results directly were introduced at step 2. Global DRM examined the dose response across the global population (sampled worldwide exposures) and used cubic spline (nonlinear) meta-regression analysis placing knots at the 10th, 50th, and 90th percentile of global exposures. For this purpose, the procedure of Geenland and Longnecker32 was used to combine eligible studies in one repeating step (from the second to the last study) using at each repeat the pooling procedure with random effects.33 The repeating steps introduced studies one at a time beginning with the study with the lowest referent exposure to enable prediction from prior studies of the graphical location of the subsequently added study observations. Each study introduced resulted in a third error term equal to the forecast standard error (σfi) for the placement of results from each additional study, the combined square of which (σf2) was additive with heterogeneity (τ2) and the combined within-study variance estimate (σ2). Thus, the usual τ2 + σ2 for random effects became τ2 + σ2 + σf2 in the global analysis (only), in which τ2 was zero for fixed effects. I2 was calculated as 100 · τ2/(τ2 + σ2 + σf2), although it was also calculated as 100 · τ2/(τ2 + σ2) to assess whether inclusion of σf2 made an important difference.

ance estimate (σ2). Thus, the usual τ2 + σ2 for random effects became τ2 + σ2 + σf2 in the global analysis (only), in which τ2 was zero for fixed effects. I2 was calculated as 100 · τ2/(τ2 + σ2 + σf2), although it was also calculated as 100 · τ2/(τ2 + σ2) to assess whether inclusion of σf2 made an important difference. Additional Analyses Small-study effects were assessed by nonparametric trim-and-fill funnel plots (metatrim in Stata) and by a Galbraith-like regression (Log RRi · Ni on Ni, where RRi was the study-level dose-response RR and Ni was the number of persons followed up).35, 36 Because epidemiological studies have potential to generate precise but spurious results, the possibility of an outlying result (P<.05) was examined by meta-regression using an indicator variable for a suspected study (one for which confidence intervals were not overlapping the combined studies mean RR). Difference in RR between two subgroups was assessed using meta-regression using an indicator variable for one of the subgroups. Statistical Tests The z test was used for combined means, covariates, and outliers, the t test for small-study effects, and the χ2 test for heterogeneity. I2 can be interpreted only approximately.37 Bradford-Hill Rating All 9 Bradford-Hill criteria38 were used. We limited the ratings to either probable or less than probable for each criterion, with total possible scores of 0 to 9. This procedure involved less subjectivity in decision making (G. Livesey, R. Taylor, H. Livesey, et al, unpublished data, 2018) than 3 categories per criterion.39

Bradford-Hill criteria38 were used. We limited the ratings to either probable or less than probable for each criterion, with total possible scores of 0 to 9. This procedure involved less subjectivity in decision making (G. Livesey, R. Taylor, H. Livesey, et al, unpublished data, 2018) than 3 categories per criterion.39 Results Search Outcomes The search of MEDLINE and EMBASE (including Cochrane studies) for prospective cohort studies on the CHD-GL and GI RRs (Supplemental Figure S1a) identified 176 potentially relevant records without duplicates. After examination of titles and abstracts, 30 were potentially relevant and were retrieved (Supplemental Figure S1a). On examination of the full publications, 16 did not meet the inclusion criteria: an early commentary40; a narrative review on diet and CHD41; a systematic review of randomized controlled trials (RCTs)42; 2 systematic reviews of potentially relevant studies10; 2 cross-sectional studies43, 44; 1 case-control study45; 4 prospective cohort studies examining dietary factors other than GI or GL5, 46, 47, 48; a prospective cohort study on nondietary factors49; a conference report of an otherwise later study report50; a prospective cohort study that focused on the CHD-carbohydrate score RR and reported on relations with GI and GL but without quantitative information on exposures by categories of exposure7; and a conference report of CHD-GI and GL RRs, again with too little quantitative information on GI and GL.51

ter study report50; a prospective cohort study that focused on the CHD-carbohydrate score RR and reported on relations with GI and GL but without quantitative information on exposures by categories of exposure7; and a conference report of CHD-GI and GL RRs, again with too little quantitative information on GI and GL.51 Among the retrieved publications, 14 included prospective cohort studies reporting on one or more of either the CHD-GL or CHD-GI or the CHD-carbohydrate RRs. Thirteen reported on the CHD-GL RR16, 17, 18, 19, 20, 21, 22, 23, 24, 52, 53, 54, 55 including 19 studies. Twelve reported on the CHD-GI risk RR16, 17, 18, 19, 20, 21, 22, 23, 24, 52, 53, 55 including 17 studies. Six reported on the CHD-carbohydrate RR for carbohydrate with specified GI values15, 16, 17, 18, 19, 20 including 12 studies (Supplemental Figure S1a).

, 19, 20, 21, 22, 23, 24, 52, 53, 54, 55 including 19 studies. Twelve reported on the CHD-GI risk RR16, 17, 18, 19, 20, 21, 22, 23, 24, 52, 53, 55 including 17 studies. Six reported on the CHD-carbohydrate RR for carbohydrate with specified GI values15, 16, 17, 18, 19, 20 including 12 studies (Supplemental Figure S1a). Among the 19 studies on the CHD-GL RR, 7 studies from 4 publications18, 53, 54, 55 were not eligible because they had invalid dietary instruments by our criterion (Supplemental Figure S1b). Similarly, among the 17 studies on the CHD-GI RR, 5 studies from 3 publications18, 53, 55 were not eligible because of invalid dietary instruments by our criterion (Supplemental Figure S1c). Among the 12 studies on the CHD-carbohydrate RR with known GI, 5 studies from 2 publications15, 18 were not eligible because of invalid dietary instruments by our criterion (Supplemental Figure S1d). This left 12, 12, and 7 studies eligible for DRM of the CHD-GL, CHD-GI, and CHD-carbohydrate characterized by GI. These inclusions were provided that results would not prove to be significant outliers (P<.05) (Supplemental Figure S1a-d).

because of invalid dietary instruments by our criterion (Supplemental Figure S1d). This left 12, 12, and 7 studies eligible for DRM of the CHD-GL, CHD-GI, and CHD-carbohydrate characterized by GI. These inclusions were provided that results would not prove to be significant outliers (P<.05) (Supplemental Figure S1a-d). Characteristics of the Study Participants Eligible studies included only men (6 studies) or only women (6 studies). They included adults with a mean ± SD age at baseline of 51±12 years (range, 26-71 years) and mean ± SD body mass index (calculated as weight in kilograms divided by height in meters squared) of 25±1.0 kg/m2 (range, 23-26 kg/m2). All were ostensibly healthy persons free of prior MI (or CHD) and diabetes at baseline. Participants lived in the United States (1 study), Europe (9 studies), and China (2 studies). Occupations were considered representative of these populations in 8 studies, and 1 study focused on nurses. Urban dwelling was included in 2 studies, and smokers were included in 1. Race/ethnicities were largely European/white (9 studies), European American (1 study), and East Asian (2 studies).

and China (2 studies). Occupations were considered representative of these populations in 8 studies, and 1 study focused on nurses. Urban dwelling was included in 2 studies, and smokers were included in 1. Race/ethnicities were largely European/white (9 studies), European American (1 study), and East Asian (2 studies). Nutritional Characteristics Nutritional characteristics were collected for the 12 studies that used valid dietary instruments by our criterion. Population mean ± SD values were as follows: energy intake, 2367±280 kcal/d (range, 1930-2617 kcal/d) (1 kcal = 4.184 kJ) in men (6 studies) and 1792±120 kcal/d (range, 1674-1984 kcal/d) in women (6 studies); alcohol consumption (reported in 11 of the 12 eligible studies), 12.5±7 g/d (range, 2-24 g/d) in men (5 studies) and 6.2±2 g/d (range, 2-9 g/d) in women (6 studies); dietary fiber intake (or cereal fiber in 2 studies) (reported in 10 of 12 eligible studies), 24±3.6 g/d (range, 19-29 g/d) in men (5 studies) and 20±3.6 g/d (range, 15-23 g/d) in women (5 studies); protein intake (reported in 10 of the 12 eligible studies), 69±8 g/2000 kcal (range, 57-79 g/2000 kcal) in men (5 studies) and 79±5 g/2000 kcal (range, 73-86 g/2000 kcal) in women (5 studies); carbohydrate intake (reported in 12 of 12 eligible studies), 236±66 g/2000 kcal (range, 185-366 g/2000 kcal) in men (6 studies) and 271±58 g/2000 kcal (range, 190-369 g/2000 kcal) in women (6 studies); GI (reported in all 12 eligible studies), 62±19 on the glucose scale (range, 55-82) in men (6 studies) and 59±10 (range, 47-82) on same scale in women (6 studies); GL (reported in all 12 eligible studies), 166±63 g/2000 kcal (range, 119-290 g/2000 kcal) in men (6 studies) and 170±59 g/2000 kcal (range, 125-286 g/2000 kcal) in women (6 studies).

gible studies), 62±19 on the glucose scale (range, 55-82) in men (6 studies) and 59±10 (range, 47-82) on same scale in women (6 studies); GL (reported in all 12 eligible studies), 166±63 g/2000 kcal (range, 119-290 g/2000 kcal) in men (6 studies) and 170±59 g/2000 kcal (range, 125-286 g/2000 kcal) in women (6 studies). The 10th to 90th percentile range of carbohydrate intakes in populations of men and women combined and relevant to the CHD-carbohydrate RR was 98±24 g/d (range 78-144 g/d) (adjusted to 2000 kcal/d) (11 studies). That relevant to the CHD-GL RR was 65±13 g/d (range, 46-83 g/d) (adjusted to 2000 kcal/d) (12 studies), and that relevant to the CHD-GI RR was 10±3.2 (range, 5.7-13.8) (glucose scale) (12 studies). Study Quality Newcastle-Ottawa quality scores (from 0-9) for the CHD-GL RRs were 8.1 (range, 7-9) for inlying studies with valid dietary instrument (correlation >0.55), 7 for an outlying study,54 and 7.3 (range, 6-8) for those studies with a correlation of 0.55 or less (Supplemental Figure S2, available online at http://mcpiqojournal.org). Corresponding scores for the CHD-GI RR were 8.1 (range, 7-9), 7.5 (range, 7-8),24, 54 and 7.0 (range, 6-8) (Supplemental Figure S3, available online at http://mcpiqojournal.org). For the CHD-carbohydrate RR, corresponding results were 8.3 (range, 8-9), 7 (range, 7-7), and 7.4 (range, 7-8) (Supplemental Figure S4, available online at http://mcpiqojournal.org).

re 8.1 (range, 7-9), 7.5 (range, 7-8),24, 54 and 7.0 (range, 6-8) (Supplemental Figure S3, available online at http://mcpiqojournal.org). For the CHD-carbohydrate RR, corresponding results were 8.3 (range, 8-9), 7 (range, 7-7), and 7.4 (range, 7-8) (Supplemental Figure S4, available online at http://mcpiqojournal.org). Study Characteristics Study characteristics were collected for the 12 studies that used valid dietary instruments by our criterion. Dietary intakes were mostly assessed using food frequency questionnaires (9 studies); 1 study each used a combination of food records and diet history interview, food records, and diet history questionnaire. Studies using food frequency questionnaires as their dietary instrument were validated using energy-adjusted Pearson (otherwise Spearmen) Corr comparing the dietary instrument values with food records for carbohydrate (9 studies) or for high-carbohydrate foods (1 study). Studies using food records directly (2 studies) were assigned an arbitrary but high value for Corr of 0.8. The mean Corr value for the 12 eligible studies was 0.72 (range, 0.64-0.80). The mean ± SD value was 0.71±0.05 (range, 0.64-0.8) in men (6 studies) and 0.73±0.05 (range, 0.66-0.8) in women (6 studies).

(1 study). Studies using food records directly (2 studies) were assigned an arbitrary but high value for Corr of 0.8. The mean Corr value for the 12 eligible studies was 0.72 (range, 0.64-0.80). The mean ± SD value was 0.71±0.05 (range, 0.64-0.8) in men (6 studies) and 0.73±0.05 (range, 0.66-0.8) in women (6 studies). Categories of intakes were presented by tertiles in 1 study, quartiles in 5 studies, and quintiles in 6 studies. The mean ± SD follow-up duration for the 12 studies was 11.4±4.6 years (range, 5-19 years). The median study size was 22,400 persons (range, 646-75,521 persons), and the total number of persons entering the studies was 350,000. The median number of events per study (cases) of first MI and CHD deaths was 614 (range, 114-4379), totaling 10,400 events. Excluded at baseline were MI, CHD, and type 2 diabetes in all 12 studies. All 12 studies ascertained cases from medical records. The 12 eligible studies made study-level adjustments to relative risks for variance in nutrient intakes: energy (12 studies), alcohol (12 studies), dietary fiber (5 studies, including 1 for cereal fiber alone), protein (9 studies), fat or individual groups of fats (saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids) (10 studies), and carbohydrate for the CHD-GI RRs only (7 studies).

t intakes: energy (12 studies), alcohol (12 studies), dietary fiber (5 studies, including 1 for cereal fiber alone), protein (9 studies), fat or individual groups of fats (saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids) (10 studies), and carbohydrate for the CHD-GI RRs only (7 studies). Study-level adjustments made for nonnutritive factors were as follows: smoking (12 studies), body mass index (12 studies), age of participants (12 studies), physical activity (12 studies), history of hypertension (8 studies) and systolic blood pressure (2 studies), level of education (8 studies), hypercholesterolemia (total cholesterol or high-density lipoprotein [HDL] cholesterol) (6 studies), family history of MI or CHD (12 studies), aspirin use (3 studies), income (2 studies), marital status (2 studies), multivitamin use (1 study), and menopausal state and related hormone use in women (3 studies).

studies), hypercholesterolemia (total cholesterol or high-density lipoprotein [HDL] cholesterol) (6 studies), family history of MI or CHD (12 studies), aspirin use (3 studies), income (2 studies), marital status (2 studies), multivitamin use (1 study), and menopausal state and related hormone use in women (3 studies). Risk of Bias Assessment All 12 studies were judged to have adequate dietary assessment tools (Corr >0.55), had objective outcome assessment (medical records), had adequate follow-up (>4 years), had been reported with no competing interests, generally had low attrition rates (1%-8% in 9 studies, 20% in 1 study,17 and not reported but seemingly <1% in 2 studies22, 23), and had probable adequate adjustment for confounding (nutrient and nonnutrient factors). From the outset, therefore, there was no appreciable evidence of study-level risk of bias other than what may arise from confounding factors (see Sensitivity of RRs to Study-Level Adjustments section, subsections Macronutrient and Folate Intakes and Nonnutrient Factors) and occurrence of small-study effects (see subsequent results).

t, therefore, there was no appreciable evidence of study-level risk of bias other than what may arise from confounding factors (see Sensitivity of RRs to Study-Level Adjustments section, subsections Macronutrient and Folate Intakes and Nonnutrient Factors) and occurrence of small-study effects (see subsequent results). Coronary Heart Disease–Glycemic Load RR Of 19 studies on the CHD-GL RR, 12 were eligible with dietary instruments having a correlation for carbohydrate greater than 0.55 (Supplemental Figure S1b). Meta-analysis of these valid studies yielded a combined dose-response RR (relative to the lowest dose) that increased in 11 studies by 1.44 (95% CI, 1.25-1.65; P<.001) per 65 g/d GL (adjusted to 2000 kcal/d) with nonsignificant inconsistency among studies (I2=18%; P=.27) (Figure 1). The study of Similä et al52 in men was dropped from the meta-analysis as a significant outlier (P=.005) and remained significantly outlying among the subgroup of men (P=.02).Figure 1 Forest plot of the coronary heart disease (CHD)–glycemic load (GL) risk relation (RR). The plot shows for each prospective cohort study the relative risk associated with a higher exposure. Risk relations shown were generated by quantitative dose-response meta-analysis. Box sizes are proportional to the weight contributed by a study to the combined study mean. Horizontal lines span the individual study 95% CIs. Arrowheads indicate truncations. Diamonds represent the combined studies mean RR values and its 95% CI values.

shown were generated by quantitative dose-response meta-analysis. Box sizes are proportional to the weight contributed by a study to the combined study mean. Horizontal lines span the individual study 95% CIs. Arrowheads indicate truncations. Diamonds represent the combined studies mean RR values and its 95% CI values. As expected, studies that were less reliable because they used dietary instruments that performed less well (Corr ≤0.55)18, 56, 57, 58 gave a lower mean relative risk of 1.30 (95% CI, 1.13-1.50) (P<.001) per 65 g/d GL (adjusted to 2000 kcal/d) (Table 1).Table 1 Sensitivity of the CHD-GL and GI Risk Relations to Dietary Instrument Correlation for Carbohydrate and to Sex of the Study Populationa,b

ents that performed less well (Corr ≤0.55)18, 56, 57, 58 gave a lower mean relative risk of 1.30 (95% CI, 1.13-1.50) (P<.001) per 65 g/d GL (adjusted to 2000 kcal/d) (Table 1).Table 1 Sensitivity of the CHD-GL and GI Risk Relations to Dietary Instrument Correlation for Carbohydrate and to Sex of the Study Populationa,b Variable n Risk relation I2 (%) τc P value Mean (95% CI) P value Corr ≤0.55 (low or nonvalid studies),d men and women combined Glycemic loade 7 1.30 (1.13-1.50) <.001 0 0 .66 Glycemic indexf 5 1.18 (1.03-1.34) .016 0 0 .64 Corr >0 .55 (valid studies),c men and women combined Glycemic loade 11 1.44 (1.25-1.65) <.001 18 0.10 .27 Glycemic indexf 10 1.24 (1.12-1.38) <.001 10 0.05 .35 Men, Corr >0.55d Glycemic loade 5 1.43 (1.15-1.78) .001 21 0.12 .28 Glycemic indexf 4 1.04 (0.88-1.23) .62 0 0 .96 Women, Corr >0.55d Glycemic loade 6 1.44 (1.17-1.78) <.001 30 0.14 .21 Glycemic indexf 6 1.35 (1.20-1.52) <.001 0 0 .62 a CHD = coronary heart disease morbidity (myocardial infarction) and mortality; GI = glycemic index; GL = glycemic load; I2 = inconsistency among study-level risk relation values, ie, the variance among studies expressed as a percentage of the sum of the variance within and among studies; n = number of prospective cohort studies; P = probability values for risk relation, τ, and I2; τ2 = heterogeneity, ie, the variance among studies. b Risk relations obtained by random-effects dose-response meta-analysis. c τ, the square root of τ2, is the standard error among studies and has the same units as risk relation (footnotes e and f).

Variable n Risk relation I2 (%) τc P value Mean (95% CI) P value Corr ≤0.55 (low or nonvalid studies),d men and women combined Glycemic loade 7 1.30 (1.13-1.50) <.001 0 0 .66 Glycemic indexf 5 1.18 (1.03-1.34) .016 0 0 .64 Corr >0 .55 (valid studies),c men and women combined Glycemic loade 11 1.44 (1.25-1.65) <.001 18 0.10 .27 Glycemic indexf 10 1.24 (1.12-1.38) <.001 10 0.05 .35 Men, Corr >0.55d Glycemic loade 5 1.43 (1.15-1.78) .001 21 0.12 .28 Glycemic indexf 4 1.04 (0.88-1.23) .62 0 0 .96 Women, Corr >0.55d Glycemic loade 6 1.44 (1.17-1.78) <.001 30 0.14 .21 Glycemic indexf 6 1.35 (1.20-1.52) <.001 0 0 .62 a CHD = coronary heart disease morbidity (myocardial infarction) and mortality; GI = glycemic index; GL = glycemic load; I2 = inconsistency among study-level risk relation values, ie, the variance among studies expressed as a percentage of the sum of the variance within and among studies; n = number of prospective cohort studies; P = probability values for risk relation, τ, and I2; τ2 = heterogeneity, ie, the variance among studies. b Risk relations obtained by random-effects dose-response meta-analysis. c τ, the square root of τ2, is the standard error among studies and has the same units as risk relation (footnotes e and f). d Corr, dietary instrument correlation for carbohydrate intake (energy adjusted and deattenuated) measured by food frequency questionnaire vs diet records; values ≤0.55 were deemed invalid instruments. e Units: higher risk relation per 65 g/d GL adjusted to 2000 kcal (8400 kJ) of energy intake per day. f Units: higher risk relation per 10 U dietary GI.

d Corr, dietary instrument correlation for carbohydrate intake (energy adjusted and deattenuated) measured by food frequency questionnaire vs diet records; values ≤0.55 were deemed invalid instruments. e Units: higher risk relation per 65 g/d GL adjusted to 2000 kcal (8400 kJ) of energy intake per day. f Units: higher risk relation per 10 U dietary GI. The CHD-GL RR was not different in men and women for studies with Corr greater than 0.55 (Table 1). In women-only studies, it was 1.44 (95% CI, 1.17-1.78) (6 studies; P<.001) with nonsignificant inconsistency (I2=30%; P=.21), while in men it was 1.43 (95% CI, 1.15-1.78) (5 studies; P=.001) with nonsignificant inconsistency (I2=21%; P=.28).

different in men and women for studies with Corr greater than 0.55 (Table 1). In women-only studies, it was 1.44 (95% CI, 1.17-1.78) (6 studies; P<.001) with nonsignificant inconsistency (I2=30%; P=.21), while in men it was 1.43 (95% CI, 1.15-1.78) (5 studies; P=.001) with nonsignificant inconsistency (I2=21%; P=.28). Potentially, the low RR in the study of men by Similä et al52 may in part be due to relatively higher alcohol consumption. The population alcohol consumption in studies with a mean of less than 15 g/d was known in 9 studies with Corr greater than 0.55 (from 8 publications).16, 17, 19, 20, 21, 22, 23, 52 Meta-regression using alcohol as a continuous covariate in the low to moderate range of intakes (<15 g/d or approximately 1 drink per day) indicated that at the lowest level of consumption (2 g/d for the present studies), the CHD-GL RR was 1.90 (95% CI, 1.25-2.89; P=.003). By contrast, at a higher level of alcohol consumption (10.9 g/d), this RR was only 1.09 (95% CI, 0.88-1.36; P=.44). Thus, alcohol may significantly attenuate the CHD-GL RR (9 studies; P=.04). However, meta-regression analysis with only 9 studies should be regarded cautiously. Inconsistency was not absent, although it was nonsignificant (I2=27%; P=.20). From this model perspective, the study of Similä et al52 ceased to be significantly outlying (P=.14).

gnificantly attenuate the CHD-GL RR (9 studies; P=.04). However, meta-regression analysis with only 9 studies should be regarded cautiously. Inconsistency was not absent, although it was nonsignificant (I2=27%; P=.20). From this model perspective, the study of Similä et al52 ceased to be significantly outlying (P=.14). The men and women combined studies RR of 1.44 (95% CI, 1.25-1.65) (11 studies; P<.001) (Figure 1) was sensitive to individual studies. The lowest combined RR of 1.34 (95% CI, 1.18-1.51; P<.001) (I2=0%; P=.06) arose when dropping the study in women by Liu et al,16 and the highest RR of 1.48 (95% CI, 1.29-1.68; I2=4%; P=.40) arose when the study in women by Grau et al24 was dropped. The Egger test indicated no significant small-study effects (11 studies; P=.61). Trim-and-fill analysis funnel plots indicated symmetry (ie, no trimming or filling to attain this state) (Supplemental Figure S5, available online at http://mcpiqojournal.org).

The men and women combined studies RR of 1.44 (95% CI, 1.25-1.65) (11 studies; P<.001) (Figure 1) was sensitive to individual studies. The lowest combined RR of 1.34 (95% CI, 1.18-1.51; P<.001) (I2=0%; P=.06) arose when dropping the study in women by Liu et al,16 and the highest RR of 1.48 (95% CI, 1.29-1.68; I2=4%; P=.40) arose when the study in women by Grau et al24 was dropped. The Egger test indicated no significant small-study effects (11 studies; P=.61). Trim-and-fill analysis funnel plots indicated symmetry (ie, no trimming or filling to attain this state) (Supplemental Figure S5, available online at http://mcpiqojournal.org). For eligible studies across the globe, GL intakes ranged from 55 to 290 g/d (span 235 g/d), which was more than 3 times wider than the study average range of intakes (65 g/d GL) and reached higher RR values (Figure 2 Inset). The CHD-GL relative risk across the lowest 65 g/d GL range of intakes was 1.32 (1.21-1.45) (Figure 2 and Table 2 [row 9]). The CHD-GL relative risk across the sampled Western populations range of GL intakes (110 g/d) was 1.78 (1.57-2.02), and across the full range of GL intakes (235 g/d) was 5.5 (3.1-9.8). Heterogeneity and inconsistency among study RR values was absent (I2 and τ = 0 by each method of derivation (see Methods section).Figure 2 Glycemic load (GL) and estimates of risk relation (RR) for coronary heart disease (CHD) in men and women combined. Bubbles show results for each cohort from a common referent at 55 g/d GL. Observations were from Beulens et al,17 Burger et al,19 Grau et al,24 Levitan et al,22, 23 Liu et al,16 van Dam et al,21 and Yu et al20 (11 studies from 8 publications). Curves show estimates from a global cubic spline (nonlinear) quantitative dose-response meta-analysis. Bubble areas increase with increasing precision of observation. Blue dashed lines show the 95% confidence limits based on random effects alone. Orange dashed lines show wider 95% CIs based an additional error from forecasting the graphical position of results for each added study. Inset shows the unlogged dose-response curve (blue line), its lower confidence limit (dashed line), and an unlogged log-linear analysis (red line) for comparison.

ndom effects alone. Orange dashed lines show wider 95% CIs based an additional error from forecasting the graphical position of results for each added study. Inset shows the unlogged dose-response curve (blue line), its lower confidence limit (dashed line), and an unlogged log-linear analysis (red line) for comparison. Table 2 Summary of the CHD-Carbohydrate, Glycemic Load, and Glycemic Index Risk Relations in Men and Women Combinedab

ndom effects alone. Orange dashed lines show wider 95% CIs based an additional error from forecasting the graphical position of results for each added study. Inset shows the unlogged dose-response curve (blue line), its lower confidence limit (dashed line), and an unlogged log-linear analysis (red line) for comparison. Table 2 Summary of the CHD-Carbohydrate, Glycemic Load, and Glycemic Index Risk Relations in Men and Women Combinedab Variable n Risk relation (95% CI) and unit of measurement P value I2 (%) P value CHD-carbohydrate risk relation by GIc 1 Over eligible studies,d GI = 50 U 11b 1.11 (0.86-1.42) Per 98 g CHO .42 18 .28 2 Over eligible studies,d GI = 80 U 5.10 (2.39-10.9) Per 98 g CHO <.001 CHD-GI risk relation derived from CHD-carbohydrate risk relations per 98 g/d carbohydrate at different glycemic indices (thus avoiding attenuation due to study-level adjustment for carbohydrate intake)e 3 Over eligible studiesd 11 1.66 (1.23-2.25) Per 10 U GI <.001 16 .30 4 Over the 50-80 U GId 11 4.57 (1.86-11.4) Per 30 U GI <.001 16 .30 CHD-glycemic index risk relations (not avoiding potential attenuation due to study-level adjustment for carbohydrate intake) 5 Over eligible studiesf 10 1.24 (1.12-1.38) Per 10 U GI <.001 10 .35 6 Lowest range of GI valuesg 10b 1.26 (1.15-1.38) Over 10 U GI <.001 0 .98 7 Full range of GI valuesg 2.71 (1.47-4.40) Over 35 U GI <.001 CHD-glycemic load risk relations (avoiding attenuation due to study-level adjustment for carbohydrate) 8 Over eligible studiesh 11 1.44 (1.25-1.65) Per 65 g/d GL <.001 18 .27 9 Lowest range of GL valuesi 11b 1.32 (1.21-1.45) Over 65 g/d GL <.001 0 .41 10 Full range of GL valuesi 5.5 (3.1-9.8) Over 235 g/d GL <.001 a CHD = coronary heart disease; CHO = carbohydrates; DRM = dose-response meta-analysis; GI = glycemic index; GL = glycemic load; I2= inconsistency; n = number of prospective cohort studies; P = probability values for risk relation and τ (and I2); RR = risk relation.

nge of GL valuesi 5.5 (3.1-9.8) Over 235 g/d GL <.001 a CHD = coronary heart disease; CHO = carbohydrates; DRM = dose-response meta-analysis; GI = glycemic index; GL = glycemic load; I2= inconsistency; n = number of prospective cohort studies; P = probability values for risk relation and τ (and I2); RR = risk relation. b Adjacent rows sharing common values for n, I2 (and its P-value) shared common inputs and common meta-regression models of analysis but differed in the outputs for the relative risk dependent on the question asked related to GL, GI, and CHO and to the level of exposure or range of exposures addressed. c Two-stage quantitative DRM, obtained by centering GI at 50 U and 80 U, respectively, rather than using the noncentered GI as in Figure 7. d Excluding one outlying study (P<.001). e Two-stage quantitative DRM: estimating RR per 98 g/d CHO (adjusted to 2000 kcal) followed by meta-regression (Figure 7). f Two-stage quantitative DRM: estimating RR per 10 U GI followed by meta-analysis without covariates (Figure 3). g One-stage cubic-spline pool-first quantitative DRM (Figure 4). h Two-stage quantitative DRM: estimating RR per 65 g/d GL intake (adjusted to 2000 kcal/d), followed by meta-analysis (Figure 1). i One-stage cubic-spline pool-first quantitative global DRM (Figure 2).

f Two-stage quantitative DRM: estimating RR per 10 U GI followed by meta-analysis without covariates (Figure 3). g One-stage cubic-spline pool-first quantitative DRM (Figure 4). h Two-stage quantitative DRM: estimating RR per 65 g/d GL intake (adjusted to 2000 kcal/d), followed by meta-analysis (Figure 1). i One-stage cubic-spline pool-first quantitative global DRM (Figure 2). Coronary Heart Disease–Glycemic Index RR Of 17 studies reporting on the CHD-GI RRs, 12 were eligible with dietary instruments correlation for carbohydrate greater than 0.55 (Supplemental Figure S1c), of which 2 proved to be outliers (see subsequent discussion). Meta-analysis gave a combined studies mean CHD-GI RR of 1.24 (95% CI, 1.12-1.38) (P<.001) per 10 U GI (Figure 3). Inconsistency of results among studies was nonsignificant (10 studies; I2=10%; P=.35). As expected, studies that were less reliable because they used a dietary instrument with Corr of 0.55 or less18, 53, 55 gave a lower RR of 1.18 (95% CI, 1.03-1.34) (P=.02) per 10 U GI (5 studies; I2=0%; P=.64) (Table 1).Figure 3 Forest plot of the coronary heart disease (CHD)–glycemic index (GI) risk relation (RR). For explanation of symbols see legend to Figure 1.

cause they used a dietary instrument with Corr of 0.55 or less18, 53, 55 gave a lower RR of 1.18 (95% CI, 1.03-1.34) (P=.02) per 10 U GI (5 studies; I2=0%; P=.64) (Table 1).Figure 3 Forest plot of the coronary heart disease (CHD)–glycemic index (GI) risk relation (RR). For explanation of symbols see legend to Figure 1. The CHD-GI RR was higher in women than in men (4 studies; P=.01) for studies with Corr of greater than .055 (Figure 3 and Table 1). In women-only studies, RR was 1.35 (95% CI, 1.20-1.52) (P<.001) with no inconsistency (6 studies; I2=0%; P=.62). However, in men-only studies, this relation was small and nonsignificant at 1.04 (95% CI, 0.88-1.23) (P=.62) (4 studies; I2=0%; P=.96). This difference should be regarded cautiously because it may not be an inherent sex difference. Among studies with Corr greater than 0.55, the men-only study of Grau et al24 was a significantly low outlier (P<.001) and therefore not included. Among the remaining studies, the men-only study of Similä et al52 was also a significant outlier (P<.001). Low values of RR for men were therefore not due to these low outlying studies, although they may be related to alcohol consumption.

Grau et al24 was a significantly low outlier (P<.001) and therefore not included. Among the remaining studies, the men-only study of Similä et al52 was also a significant outlier (P<.001). Low values of RR for men were therefore not due to these low outlying studies, although they may be related to alcohol consumption. Meta-regression with population average alcohol intake as a covariate in the low to moderate range of intakes (<15 g/d or approximately 1 drink per day) indicated that at low consumption (2 g/d) the CHD-GI RR was 1.51 (95% CI, 1.17-1.94) (10 studies; P=.001) (I2=10%; P=.35). By contrast, at the higher population average alcohol consumption (10.9 g/d), a CHD-GI RR was not evident because RR was 0.95 (95% CI, 0.86-1.06) (10 studies; P=.38) (I2=10%; P=.35). The study of Similä et al52 remained outlying (P=.02) even with alcohol as a covariate, while the study of women from Grau et al24 became outlyingly high (P=.01). The men and women combined studies RR without covariates of 1.24 (95% CI, 1.12-1.38) (10 studies; P<.001) (Figure 3) was sensitive to dropping of individual studies. The lowest combined RR of 1.18 (95% CI, 1.07-1.32) (9 studies; P=.002) (I2=0%; P=.70) arose when the study in women from Grau et al24 was dropped, and a highest RR of 1.30 (95% CI, 1.17-1.44) (9 studies; P<.001) (I2=0%; P=.64) arose when the study in men by Levitan et al23 was dropped.

o dropping of individual studies. The lowest combined RR of 1.18 (95% CI, 1.07-1.32) (9 studies; P=.002) (I2=0%; P=.70) arose when the study in women from Grau et al24 was dropped, and a highest RR of 1.30 (95% CI, 1.17-1.44) (9 studies; P<.001) (I2=0%; P=.64) arose when the study in men by Levitan et al23 was dropped. A Galbraith-type plot with Egger test indicated no significant small-study effects (10 studies; P=.26). Trim-and-fill analysis of the funnel plot indicated symmetry (no trimming or filling to attain this state) (Supplemental Figure S6, available online at http://mcpiqojournal.org).

o dropping of individual studies. The lowest combined RR of 1.18 (95% CI, 1.07-1.32) (9 studies; P=.002) (I2=0%; P=.70) arose when the study in women from Grau et al24 was dropped, and a highest RR of 1.30 (95% CI, 1.17-1.44) (9 studies; P<.001) (I2=0%; P=.64) arose when the study in men by Levitan et al23 was dropped. A Galbraith-type plot with Egger test indicated no significant small-study effects (10 studies; P=.26). Trim-and-fill analysis of the funnel plot indicated symmetry (no trimming or filling to attain this state) (Supplemental Figure S6, available online at http://mcpiqojournal.org). Across the globe, the range of GI values in men and women was 47 to 82 U GI (glucose scale), which covered a range more than 3 times wider than the average range of 10 U GI within study population samples. By global DRM (Figure 4 Inset), the CHD-GI RR over the lowest 10 units range of GI (from 47-57 GI) was 1.26 (95% CI, 1.15-1.38) (Table 2 [row 6]). Across the sampled Western populations range of GI intakes (lowest 16 U GI), the RR was 1.44 (95% CI, 1.28-1.63), and across sampled global population range of GI intakes (35 U GI), the RR was 2.71 (95% CI, 1.47-4.40). No inconsistency or heterogeneity was evident (I2 and τ = 0), and these relations were significant (P<.001).Figure 4 Glycemic index (GI) and estimates of the risk relation (RR) for coronary heart disease (CHD) in men and women. Bubbles show results for each cohort from a common referent at 47 U GI. Observations were from Beulens et al,17 Burger et al,19 Grau et al,24 Levitan et al,22, 23 Liu et al,16 van Dam et al,21 and Yu et al20 (10 studies from 8 publications). For explanation of symbols see legend to Figure 2.

ase (CHD) in men and women. Bubbles show results for each cohort from a common referent at 47 U GI. Observations were from Beulens et al,17 Burger et al,19 Grau et al,24 Levitan et al,22, 23 Liu et al,16 van Dam et al,21 and Yu et al20 (10 studies from 8 publications). For explanation of symbols see legend to Figure 2. In women (Figure 5 Inset), the global DRM for the CHD-GI RR across the lowest range of 10 U GI (47-57 U GI) was 1.35 (95% CI, 1.21-1.50) per 10 U GI. Across the sampled Western populations range of GI intakes (lowest 16 U GI), the RR was 1.64 (95% CI, 1.38-1.94), and across the sampled global population range of GI intakes (35 U GI), the RR was 3.78 (95% CI, 1.51-9.42). No inconsistency or heterogeneity among observations was evident (I2 and τ = 0), and all 3 RRs were statistically significant (P<.001).Figure 5 Glycemic index (GI) and estimates of the risk relation (RR) for coronary heart disease (CHD) in women. Bubbles show results for each cohort from a common referent at 47 U GI. Observations were from Beulens et al,17 Burger et al,19 Grau et al,24 Levitan et al,22 Liu et al,16 and Yu et al20 (6 studies from 6 publications). For explanation of symbols, see legend to Figure 2.

(RR) for coronary heart disease (CHD) in women. Bubbles show results for each cohort from a common referent at 47 U GI. Observations were from Beulens et al,17 Burger et al,19 Grau et al,24 Levitan et al,22 Liu et al,16 and Yu et al20 (6 studies from 6 publications). For explanation of symbols, see legend to Figure 2. Sensitivity of RRs to Study-Level Adjustments Macronutrient and Folate Intakes Where study-level adjustments had been made for intakes of energy, alcohol, fiber, protein, fats, or folate, the CHD-GL RR in men and women combined remained greater than 1.20 with a lower confidence limit (LCL) greater than 1.10. Prudently, no study adjusted for carbohydrate intake (Supplemental Table S4, available online at http://mcpiqojournal.org). To avoid possible confounding by an apparently low risk in men (Table 1), the CHD-GI RR was examined for women alone. Where study-level adjustments had been made for intakes of the aforementioned factors and carbohydrate or folate, the CHD-GI RR also remained greater than 1.20 with a LCL greater than 1.10 (Supplemental Table S4, available online at http://mcpiqojournal.org).

n men (Table 1), the CHD-GI RR was examined for women alone. Where study-level adjustments had been made for intakes of the aforementioned factors and carbohydrate or folate, the CHD-GI RR also remained greater than 1.20 with a LCL greater than 1.10 (Supplemental Table S4, available online at http://mcpiqojournal.org). Nonnutrient Factors Where study-level adjustments had been made to the CHD-GL and GI RRs for smoking, body mass index, age of participants, physical activity, family history of MI, diabetes status, hypertension, hypercholesterolemia, menopausal state and related hormone use (in women), level of education, and exclusion of other CVD in addition to MI or CHD at baseline, these relations remained greater than 1.20 with an LCL greater than 1.10 (Supplemental Table S4). Aspirin use was associated with variable results. Potentially, it lowered the CHD-GI RR, although nonsignificantly (P=.26), and the RR remained greater than 1.20 for both GL and GI but with an LCL of less than 1.10 for GI (Supplemental Table S5).

greater than 1.20 with an LCL greater than 1.10 (Supplemental Table S4). Aspirin use was associated with variable results. Potentially, it lowered the CHD-GI RR, although nonsignificantly (P=.26), and the RR remained greater than 1.20 for both GL and GI but with an LCL of less than 1.10 for GI (Supplemental Table S5). Coronary Heart Disease–Carbohydrate RR The CHD-carbohydrate RR when using valid dietary instruments (Corr >0.55) was reported in 6 single-sex studies with apparent inconsistency (I2=47%; P=.09) (Figure 6). No study reported on this RR for a GI of less than 50 U on the glucose scale. Carbohydrate with GI of less than 56 U showed no clear association, while at the highest GI, the RR was high at 4.46 (95% CI, 1.53-12.9) per 98 g/d carbohydrate (adjusted to 2000 kcal diet).Figure 6 Forest plot of the coronary heart disease (CHD)–carbohydrate risk relation (RR) by population sample mean glycemic index. Observations were from Liu et al,16 Beulens et al,17 Burger et al,19 and Yu et al.20 For explanation of symbols, see legend to Figure 1.

per 98 g/d carbohydrate (adjusted to 2000 kcal diet).Figure 6 Forest plot of the coronary heart disease (CHD)–carbohydrate risk relation (RR) by population sample mean glycemic index. Observations were from Liu et al,16 Beulens et al,17 Burger et al,19 and Yu et al.20 For explanation of symbols, see legend to Figure 1. Meta-regression requires more than the 6 studies presented in Figure 6. Therefore, we reintroduced the 3 studies by Jakobsen et al15 and the 2 studies by Sieri et al18 with Corr of 0.55 or less to assess the rate of change in RR with GI (Figure 7). The RR was high at 1.66 (95% CI, 1.23-2.25) per 10 U GI on the glucose scale (P<.001) (Table 2 [row 6]). Inconsistency was low (I2=16%; P=.30). While the funnel plot for studies in Figure 6 was asymmetrical (Supplemental Figure S7), adjustment for differences in GI (Figure 7) removed 85% of the inconsistency and resulted in a symmetrical funnel plot (Supplemental Figure S8, available online at http://mcpiqojournal.org). Among these studies, the observations from Similä et al52 were excluded as statistically significant outliers (P<.001) both for high and medium GI categories of carbohydrate.Figure 7 The log-linear relation between the coronary heart disease (CHD)–carbohydrate risk relation (RR) and the population or cohort average glycemic index. The unlogged slope was 1.66 (1.23-2.25) per 10 units higher GI (P<.001). Observations were from Beulens et al,17 Burger et al,19 Jakobsen et al,15 Liu et al,16 Sieri et al,18 and Yu et al.20 For explanation of symbols, see legend to Figure 2.

drate risk relation (RR) and the population or cohort average glycemic index. The unlogged slope was 1.66 (1.23-2.25) per 10 units higher GI (P<.001). Observations were from Beulens et al,17 Burger et al,19 Jakobsen et al,15 Liu et al,16 Sieri et al,18 and Yu et al.20 For explanation of symbols, see legend to Figure 2. Discussion Risk Relations To our knowledge no prior meta-analysis on the dependence of the CHD-carbohydrate RR on GI has been undertaken. Carbohydrate with a GI of greater than 50 U on the glucose scale was a strong risk factor for CHD and reached 4.46 (95% CI, 1.53-12.9) (Figure 6) and 5.1 (95% CI, 2.39-10.9) (Figure 7) each per 98 g/d carbohydrate, increasing by 1.66 (95% CI, 1.23-2.25) per 10 U GI. The quantities 98 g/d carbohydrate and 10 U GI each were combined studies mean ranges of intake, from the 10th to the 90th percentile of the study populations. To put this into further context, the ranges of GI values within major food categories (eg, whole-grain, vegetable, fruit) are approximately 60 U for each category.56 This implies that “healthy foods” of extreme high GI for their food category might be a 20 times greater risk to heart health than foods of extreme low GI from the same food category when assuming the increment remains truly log-linear, ie, exp(ln[1.66] · 60/10) = 21. This strong RR on the global scale was supported by high RR values for GL at 5.5 (95% CI, 3.1-9.8) (Figure 2 Inset; Table 2, row 10) and for GI at 2.71 (95% CI, 1.47-4.40) (Figure 4 Inset; Table 2, row 7). It seems worrysome, therefore, that the general public receives little authoritative guidance leading toward the consumption of lower rather than higher GI carbohydrate foods within food groups.

(95% CI, 3.1-9.8) (Figure 2 Inset; Table 2, row 10) and for GI at 2.71 (95% CI, 1.47-4.40) (Figure 4 Inset; Table 2, row 7). It seems worrysome, therefore, that the general public receives little authoritative guidance leading toward the consumption of lower rather than higher GI carbohydrate foods within food groups. Whether addressing GI or GL of carbohydrate characterized by GI, all 3 associated strongly globally for a nutrient relation with CHD risk. In general, however, harmful RRs greater than 1.20 with a lower 95% CL greater than 1.10 within sample population ranges of intakes have been regarded as sufficient to consider a nutrient for inclusion in nutrition guidance12 (G. Livesey, R. Taylor, H. Livesey, et al, unpublished data, 2018) when sufficiently supported by an assessment such as Bradford-Hill ratings12 (G. Livesey, R. Taylor, H. Livesey, et al, unpublished data, 2018). These within-population RR criteria were clearly met, both for all eligible studies on GL combined (Table 2, row 8) and over the lowest 65 g/d GL range within the global range of GL (Table 2, row 9). These criteria were less clearly met by the CHD-GI RR for all eligible studies (Table 2, row 5) and for the lowest 10 units range of GI within the global range (Table 2, row 6). Avoiding possible attenuation by adjustment for carbohydrate, this RR was possibly stronger (Table 2, RRs in row 3 vs rows 5 or 6).

2, row 9). These criteria were less clearly met by the CHD-GI RR for all eligible studies (Table 2, row 5) and for the lowest 10 units range of GI within the global range (Table 2, row 6). Avoiding possible attenuation by adjustment for carbohydrate, this RR was possibly stronger (Table 2, RRs in row 3 vs rows 5 or 6). A strength of our analyses was that eligible studies showed no significant study-level risk of bias (see the Results section, Risk of Bias Assessment). Newcastle-Ottawa study quality scores were high (see Results section, Study Quality), and only studies applying truly valid dietary instruments were used, as first suggested,27 first used in relation to GI and GL,28 and first shown to be a significant determinant of the type 2 diabetes–GL RR.29 A further strength was that we used DRM, which makes use of more of the available observational information than is used by EQM, accounts for different definitions of exposure in respect to the number of quantiles reported, and allows global DRM to be undertaken. In addition, for carbohydrate and GL, which are adjusted within the original studies to different energy intakes, we readjusted to a common energy intake of 2000 kcal/d for each study. Another strength was that DRM as performed obtains efficient estimates of RR by accounting for nonindependence of observations within studies32 and in global DRM additionally took account of the error introduced by the placement of observations graphically. A further strength is that none of the primary relations (Figures 1, 3, and 7 and Table 2, rows 3, 5, and 8) had significant Egger test results for small-study effects (eg, publication bias) or had asymmetric funnel plots (Supplemental Figures S5, S6, and S8, available online at http://mcpiqojournal.org). Further still, all primary RRs had low levels of inconsistency (I2<20%), which for GI and GL were reduced to zero when accounting for curvature in the global dose-response analysis (I2=0%).

lication bias) or had asymmetric funnel plots (Supplemental Figures S5, S6, and S8, available online at http://mcpiqojournal.org). Further still, all primary RRs had low levels of inconsistency (I2<20%), which for GI and GL were reduced to zero when accounting for curvature in the global dose-response analysis (I2=0%). A weakness of our study is that residual confounding can never be excluded. Also, weaknesses existed in original reporting of results for eligible studies at the study level. In particular, some studies did not report values of exposure, energy intakes to which exposures were adjusted, number of cases, and number of persons followed up, each by categories of exposure. However, sufficient information was available from related publications, by correspondence with the authors, by calculation from related published data (exposures and energy intakes for exposure adjustments), or approximated (number of persons and cases per quantile) as described study by study (footnotes to Supplemental Tables S1, S2, and S3). For the present purpose, the approximated values contribute negligible error (<3%) to an individual study’s estimated log dose-response RR (see Supplemental Table S1 footnotes d and e).

approximated (number of persons and cases per quantile) as described study by study (footnotes to Supplemental Tables S1, S2, and S3). For the present purpose, the approximated values contribute negligible error (<3%) to an individual study’s estimated log dose-response RR (see Supplemental Table S1 footnotes d and e). Bradford-Hill Ratings Bradford-Hill ratings aim to assess the probability of RRs being causal.38 The ratings fall under 9 headings or viewpoints: strength of association (from meta-analyses when possible), consistency of association, specificity, temporality, biological gradient (dose dependency), plausibility, experimental evidence, analogy, and coherence with the natural history and biology of disease. Ratings increase from 0 to 9 with increasing probability of causality. The ratings provide guidance in the absence of convincing proof from large long-term RCTs or when RCTs might be judged to be unrepresentative of real-world circumstances assessed within prospective cohort studies.

ral history and biology of disease. Ratings increase from 0 to 9 with increasing probability of causality. The ratings provide guidance in the absence of convincing proof from large long-term RCTs or when RCTs might be judged to be unrepresentative of real-world circumstances assessed within prospective cohort studies. 1. Strength of Association This factor is important for public health when RR is greater than 1.20 and its lower confidence limit is greater than 1.10 from the 10th to 90th percentile of nutrient intake12 (G. Livesey, R. Taylor, H. Livesey, et al, unpublished data, 2018). This criterion was met for the CHD-carbohydrate RR for high GI carbohydrate, the CHD-GL RR, and the CHD-GI RR for men and women combined (Table 2). The last two were examined for the influence of alcohol, finding stronger relations when population average alcohol intake was small (2 g/d), RR then being 1.90 (95% CI, 1.25-2.89) per 65 g/d GL and 1.51 (95% CI, 1.17-1.94) per 10 U GI (see Results section, Coronary Heart Disease–Glycemic Load RR, paragraph 4, and Coronary Heart Disease–Glycemic Index RR, paragraph 4).

ohol, finding stronger relations when population average alcohol intake was small (2 g/d), RR then being 1.90 (95% CI, 1.25-2.89) per 65 g/d GL and 1.51 (95% CI, 1.17-1.94) per 10 U GI (see Results section, Coronary Heart Disease–Glycemic Load RR, paragraph 4, and Coronary Heart Disease–Glycemic Index RR, paragraph 4). 2. Consistency of Association This criterion refers to inconsistency (I2<50%)57 when the lower confidence limit is greater than 1.10 for a harmful relation12 (G. Livesey, R. Taylor, H. Livesey, et al, unpublished data, 2018). National (or local) DRM (Figures 1, 3, and 7) indicated little inconsistency in these relations (I2≤20%), in part attributable to differences in alcohol consumption and/or a sex difference in study-level results and to curvature in the dose responses (when in the latter, I2=0%). The direction of these relations was the same in 100% of eligible studies on GL (Figure 1), 90% of studies on G1 (Figure 3), and 80% of studies on the CHD-carbohydrate on GI RR (Figure 7). Thus, all 3 relations met the consistency criterion for men and women combined.

in the dose responses (when in the latter, I2=0%). The direction of these relations was the same in 100% of eligible studies on GL (Figure 1), 90% of studies on G1 (Figure 3), and 80% of studies on the CHD-carbohydrate on GI RR (Figure 7). Thus, all 3 relations met the consistency criterion for men and women combined. 3. Specificity Diverse health effects of nutrients are possible (see Coherence section) so that the original definition for this criterion (relating to a single specified disease38) is not possible. To meet this criterion, therefore, the specified association for the disease incidence must be related to the exposure variable hypothesized. Potentially confounding risk factors (see below), both dietary and nondietary, must therefore be adjusted for at the study level or assessed by relevant sensitivity analysis during meta-analyses—finding, RR greater than 1.20 with LCL greater than 1.10 for harmful relations where adjustments were made. This criterion was met for adjustments for energy, fiber, alcohol, protein, and fats or fats and folate for both GI and GL (Supplemental Table S4) and for hypertension, hypercholesterolemia, menopausal state (in women), educational status, and exclusion of other CVD at baseline for both GL and GI (Supplemental Table S5). Other adjustments made at the study level for all eligible studies were smoking, body mass index, age of participants, physical activity, family history of MI, and diabetes status (in addition to exclusion of diabetes at baseline). When these adjustments were made, the CHD-GL and GI RRs were greater than 1.20 with LCL greater than 1.10. An exception was for aspirin consumption (Supplemental Table S5) when the LCL greater than 1.10 criterion was met for neither GL nor GI; however, differences in RR with vs without aspirin use were not statistically significant (P=.78 and P=.16, respectively) (Supplemental Table S5).

han 1.20 with LCL greater than 1.10. An exception was for aspirin consumption (Supplemental Table S5) when the LCL greater than 1.10 criterion was met for neither GL nor GI; however, differences in RR with vs without aspirin use were not statistically significant (P=.78 and P=.16, respectively) (Supplemental Table S5). 4. Temporality Exposure must precede incidence of disease. This criterion is met by design in all prospective cohort studies (see also Experimental and Analogy sections, which refer to intervention studies). 5. Biological Gradient (Dose Response) In prospective cohort studies, this criterion is met when the combined studies dose-response RR is statistically significant, as was the case for GL (Figures 1 and 2), GI (Figures 2 and 4), and carbohydrate meta-regressed on GI (Figures 6 and 7).

4. Temporality Exposure must precede incidence of disease. This criterion is met by design in all prospective cohort studies (see also Experimental and Analogy sections, which refer to intervention studies). 5. Biological Gradient (Dose Response) In prospective cohort studies, this criterion is met when the combined studies dose-response RR is statistically significant, as was the case for GL (Figures 1 and 2), GI (Figures 2 and 4), and carbohydrate meta-regressed on GI (Figures 6 and 7). 6. Plausibility This criterion is met when at least one credible mechanism can explain the association. The GL and GI are major food and dietary markers predictive of a food’s (or diet’s) ability once ingested to both elevate postprandial blood glucose58 and determine longer-term fasting blood glucose and HbA1c concentrations in the nondiabetic and diabetic states.59 Elevated HbA1c and blood glucose concentrations, including postprandial glucose, each are major risk factors for CVD,60, 61 for which CHD is the major contributor.2, 62 This includes elevation of glucose and HbA1c in the normal range in addition to the elevation that occurs in diabetes.60, 61, 63, 64, 65 Further, observations in the general population have shown that HbA1c and blood glucose are better markers of cardiovascular and CHD risk than either HDL cholesterol or total cholesterol66, 67 (see also Experimental section).

1c in the normal range in addition to the elevation that occurs in diabetes.60, 61, 63, 64, 65 Further, observations in the general population have shown that HbA1c and blood glucose are better markers of cardiovascular and CHD risk than either HDL cholesterol or total cholesterol66, 67 (see also Experimental section). 7. Experimental Intervention trials that show either reduction of the specified disease incidence or reduction in markers of disease are needed to meet this criterion. (For trials, see Analogy section.) Several pathogenic pathways from high GL and GI lead to a conclusion that “modern dietary guidelines for patients at risk of CHD should reflect…[the] danger of consuming a HGL [high GL] diet.”68 Further evidence comes from a primary care setting. A study by Unwin et al69, 70 found that lowering the GL of the diet by advice to avoid high GI foods for 13 months in 69 at-risk persons with either prediabetes or diabetes lowered several parameters, including body weight (−9 kg; P<.001), waist circumference (−15 cm; P<.001), HbA1c (−19%; P<.001), total cholesterol (−6%; P<.001), and cholesterol to HDL cholesterol ratio (−9%; P=.001). The study concluded that this dietary approach was a practical alternative to drug therapy (for prediabetes and diabetes, ie, patients at risk for CHD) and had considerable cost savings for general medical practice. Consistently, the present analyses support high GI carbohydrate as a major nutritional risk factor for CHD among general populations.

dietary approach was a practical alternative to drug therapy (for prediabetes and diabetes, ie, patients at risk for CHD) and had considerable cost savings for general medical practice. Consistently, the present analyses support high GI carbohydrate as a major nutritional risk factor for CHD among general populations. 8. Analogy Lower GI and GL diets can be achieved using inhibitors of carbohydrate digestion.71 Treatment with acarbose (an α-glucosidase inhibitor) has the same pattern of effect on markers of metabolic disease as does treatment with lower GI or lower GL diets.58 Further, reducing the GI and GL of the diet by use of acarbose has reduced the incidence of any cardiovascular event by 49% (5%-72%) and CHD (as MI) by 91% (28%-99%).71

arbose (an α-glucosidase inhibitor) has the same pattern of effect on markers of metabolic disease as does treatment with lower GI or lower GL diets.58 Further, reducing the GI and GL of the diet by use of acarbose has reduced the incidence of any cardiovascular event by 49% (5%-72%) and CHD (as MI) by 91% (28%-99%).71 9. Coherence To meet this criterion, a disease-exposure association should not conflict with the natural history of disease. Evidence of coherence arises in part from the interventional studies supporting plausibility, experimental, and analogy criteria (see preceding sections). Further evidence comes from the association of one disease with another, each of which is linked to higher blood glucose and insulin concentrations; thus, excess body weight72 and CHD, diabetes, and certain cancers.73, 74 Meta-analysis has revealed that lower GL diets, achieved using lower GI carbohydrate foods, result in a dose-dependent reduction in body weight among persons with varied glycemic control from normal to the diabetic state.59 Further, avoidance of high GI foods to achieve a lower GL diet has proved effective in improving body weight and glycemic and lipidemic parameters over a mean of 13 months in prediabetic and diabetic patients.69, 70 Beneficial effects of low GI and GL have become evident in long-term primary prevention of obesity-associated diseases.75 In longitudinal trials, lower GI and GL due to ingestion of α-glucosidase inhibitors lowers not only the risk of CHD72 but also the risk of diabetes76, 77, 78 and colorectal cancer.79 Likewise, lower GI and GL diets also prospectively associate with a lower risk for type 2 diabetes,28, 29, 80, 81, 82 a disease that increases the risk of subsequent CHD83, 84, 85 and subsequent diagnosis of colon cancer.58

wers not only the risk of CHD72 but also the risk of diabetes76, 77, 78 and colorectal cancer.79 Likewise, lower GI and GL diets also prospectively associate with a lower risk for type 2 diabetes,28, 29, 80, 81, 82 a disease that increases the risk of subsequent CHD83, 84, 85 and subsequent diagnosis of colon cancer.58 In summary, all 9 of Bradford-Hill’s criteria for probable causality were met in our study. In application of GI and GL to food and dietary guidance, it should be noted that food group–based dietary guidelines would be insufficient because each food group contains foods having a very wide range of GI and GL values56, 86 and that prospective cohort studies have shown that even within beneficial food patterns, such as the Mediterranean diet and the healthy or vegetarian diet in the United Kingdom, there was evidence of added benefits of lower GI and GL.87, 88, 89 Conclusion Among healthy persons from Europe, North America, and East Asia, strong (RR >1.20, LCL >1.10 within jurisdictions) and probably causal (Bradford-Hill ratings) RRs occur between incident CHD and dietary GI and GL. The CHD-carbohydrate of high GI, the CHD-GL, and the CHD-GI RRs each are markedly greater across the globe than within jurisdictions. The evidence presented supports the use of these markers of carbohydrate food quality in dietary guidelines for general populations. Supplemental Online Material Supplemental Material

Conclusion Among healthy persons from Europe, North America, and East Asia, strong (RR >1.20, LCL >1.10 within jurisdictions) and probably causal (Bradford-Hill ratings) RRs occur between incident CHD and dietary GI and GL. The CHD-carbohydrate of high GI, the CHD-GL, and the CHD-GI RRs each are markedly greater across the globe than within jurisdictions. The evidence presented supports the use of these markers of carbohydrate food quality in dietary guidelines for general populations. Supplemental Online Material Supplemental Material Supplemental material can be found online at http://mcpiqojournal.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data. Acknowledgments The funding organizations had no role in the design and execution of the study, in the collection, analyses, and interpretation of the data, or in the preparation, review, or approval of the submitted manuscript. Grant Support: This work was funded by BENEO GmbH.

Supplemental material can be found online at http://mcpiqojournal.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data. Acknowledgments The funding organizations had no role in the design and execution of the study, in the collection, analyses, and interpretation of the data, or in the preparation, review, or approval of the submitted manuscript. Grant Support: This work was funded by BENEO GmbH. Potential Competing Interests: Dr Geoffrey Livesey hold shares in Independent Nutrition Logic Ltd, a consultancy, and has received research grants, travel funding, consultant fees, and honoraria, from the American Association for the Advancement of Science, the All-Party Parliamentary Group for Diabetes, the Almond Board of California, BENEO GmbH, Biotechnology and Biological Sciences Research Council, British Nutrition Foundation, Calorie Control Council, Cantox, Colloides Naturel International, Coca-Cola Company, Danisco, Diabetes Nutrition Study Group, Diabetes UK, Elsevier Inc, European Commission, European Polyol Association, EUREKA, Food and Agriculture Organization of the United Nations, Granules India, General Maills Inc, Health Canada, Institute of Food Research, International Carbohydrate Quality Consortium, Institute of Medicine, International Life Sciences Institute, Life Sciences Research Office, Federation of American Societies for Experimental Biology, Kellogg Company, Knights Fitness, Nutrition Society of Australia, Leatherhead Food Research, LighterLife, Matsutani, Inc, Medical Research Council, MSL Group, Porter Novelli, Südzuker, Sugar Nutrition/World Sugar Research Organisation, Tate & Lyle, The Food Group, Weight Watchers, Wiley-Blackwell, and World Health Organization. Ms Helen Livesey holds shares in Independent Nutrition Logic Ltd and has benefitted from the aforementioned organizations.

To the Editor: A few years ago, I contemplated the decision to shift my career path from a practicing physician to a full-time academic researcher. I reflected on the things I knew I would miss: the daily-interactions with patients; and the immense joy of healing and/or improving the quality of their lives. Among the main reasons leading to this early career-changing decision were my compromised sense of joy in practicing medicine, and burnout resulting from challenging healthcare system structure. I could not find the motivation to be part of these seemingly-flawed systems, in my humble opinion, leaving me feeling ambivalent. After reflective prayers and conversations with my family, colleagues-friends, and mentors, I decided to support the collective mission-of-caring for our patients through an equally significant path—research. My mission is to help in transforming health care to an evidence-based, expert-guided, minimally disruptive, and careful and thoughtful system where the goals of the patients, indeed, come first.1 Concurrently, not at the expense of those who willingly and selflessly support those goals of caring; clinician burnout should not be the yield of this mission.2

health care to an evidence-based, expert-guided, minimally disruptive, and careful and thoughtful system where the goals of the patients, indeed, come first.1 Concurrently, not at the expense of those who willingly and selflessly support those goals of caring; clinician burnout should not be the yield of this mission.2 Clinicians encounter multidimensional, long-past, and well-documented challenges while delivering health care, making burnout a prevalent syndrome, which may lead patients to experience lower quality of care and less favorable outcomes.2, 3 The impact does not just stop there; it affects clinicians personally as well as their milieu—family, friends and other aspects of their lives.3 Friends and peers in healthcare from across the globe experience burnout. While each has unique challenges, there is consensus that the mission of medicine has been dramatically and sadly compromised by clinician burnout.

s clinicians personally as well as their milieu—family, friends and other aspects of their lives.3 Friends and peers in healthcare from across the globe experience burnout. While each has unique challenges, there is consensus that the mission of medicine has been dramatically and sadly compromised by clinician burnout. So, when did we veer off the noble path of care? How do we get back on it? While the evidence suggests that burnout is mainly a system-driven challenges, I believe that all of us, as individuals, may contribute to finding solutions to minimizing burnout and increasing well-being.4, 5 Despite these challenges, there is still a concurrent clinician-led movement of hope; a change shall come. This poses the need to advocate shifting health care towards a minimally disruptive care that accounts for the capacity and workload encompassed by all stakeholders: patients, caregivers, clinicians, and health care systems.1 This is a sincere invitation to all of us to pause, to think, reassess, mobilize, collaborate, and move forward together. I am privileged to work within a supportive and enjoyable work environment that empowers me and my colleagues to lift each other up through personal and professional growth, as we continue exploring solutions to better health care delivery5; yet as a physician-researcher, I experience my own challenges, including, sometimes, burnout. I admire the strength and resilience fellow clinicians, researchers, and health care allies muster while facing daily challenges in an overly-regulated environment as they serve our patients. Recently, I was profoundly saddened by the news of losing a past colleague who had struggled silently, and sadly found no escape but through suicide. Enough is enough. We need to find the way-forward; we ought to speak up; to kindly and thoughtfully work together; soon, now, and not until we lose our sanity or anymore lives.

ly, I was profoundly saddened by the news of losing a past colleague who had struggled silently, and sadly found no escape but through suicide. Enough is enough. We need to find the way-forward; we ought to speak up; to kindly and thoughtfully work together; soon, now, and not until we lose our sanity or anymore lives. Potential Competing Interests: The author reports no competing interests.

To the Editor: In 2001, Crossing the Quality Chasm reported a gap of 17 years between discovery and implementation of improvements. This recognition led to a surge in quality improvement and the new field of “knowledge translation.” Since then, a body of literature focuses on different approaches.1 Yet, implementation of best practices across care teams and geographic regions remains dauntingly challenging despite advances in the science of improvement and solid models for replicating best practices. The challenge lies with the complex interrelationships between clinical processes, work settings, and system changes which generate both intended and unintended consequences.2, 3 The current environment dictates accelerated, if imperfect, solutions. To address the need for opioid stewardship, we reviewed industrial models for performance evaluation.4 Nonhealth care enterprises have successfully maintained common standards despite differences in local environments. We then applied these principles through a series of iterative questions for performance needs assessment. The figure outlines the result; a model designed to accelerate Mayo Clinic’s response to the US opioid public health crisis, but applicable to nearly any large problem.Figure Conceptual framework for needs assessment for improving large problems in health care. CDS = clinical decision support; CME = continuing medical education; EMR = electronic medical record.

igned to accelerate Mayo Clinic’s response to the US opioid public health crisis, but applicable to nearly any large problem.Figure Conceptual framework for needs assessment for improving large problems in health care. CDS = clinical decision support; CME = continuing medical education; EMR = electronic medical record. To confront crises in health care, problems and goals for successful improvement need to be defined first. Identifying improvable gaps for individual, manageable projects is an imprecise science. For opioid stewardship, the question, “Are expectations clear?” proved a useful starting point. Guideline development and deployment improves clarity. However, while prescribing guidelines provide clarity, simply defining best practice cannot ensure change. Human, environmental, and systems factors significantly influence successful implementation and improvement.4 This model provides a path to accelerate improvements. Each step outlines the need for individual projects to improve gaps. Additionally, as the overall problem is improved, the process can be iteratively reexamined for further opportunities. While this framework is useful for identifying gaps both for overarching problems and individual projects, it doesn’t specifically define metrics or implementation and control strategies, but reserves those actions for specific projects. Those projects can then deploy problem solving assignments as required. As an iterative model, consideration of each factor in the framework doesn’t preclude simultaneous work, allowing flexibility in pace and workload.

metrics or implementation and control strategies, but reserves those actions for specific projects. Those projects can then deploy problem solving assignments as required. As an iterative model, consideration of each factor in the framework doesn’t preclude simultaneous work, allowing flexibility in pace and workload. In our example on opioid prescribing, this framework offered a useful way to tackle a mammoth problem. We know that patients and health care providers alike are aware of the overprescribing of opioids and genuinely want to do the “right thing.” Still, opioid prescribing has not decreased significantly despite that widespread awareness and buyin.5 Put simply, we don’t know why we still prescribe so many opioids. That makes crafting effective interventions nearly impossible, and many efforts have failed to progress, languishing in attempts to define the complex problem as it affects nearly all aspects of clinical care. By using this framework for needs assessment, organizations can systematically identify actionable interventions based on needs as they are recognized. Potential Competing Interests: The authors report no competing interests.

Low ankle brachial index (ABI) has been consistently associated with increased cardiovascular (CV) and all-cause mortality in several epidemiologic studies in a wide variety of populations.1, 2, 3, 4, 5, 6 However, the prognostic significance of a high ABI is less clear. Various studies have yielded conflicting results, with some showing a strong association with CV and all-cause mortality, others showing no association, and still others showing an association with CV events but not mortality.4,7, 8, 9, 10 The reasons for these discrepant findings are not well understood. One hypothesis is that obesity may itself contribute to a high ABI measurement and thus influence the prognostic significance of ABI in obese individuals.11,12 However, the impact of BMI on the association between abnormal ABI (either low or high ABI) and both all-cause and CV mortality has not been previously examined. We hypothesized that the prognostic significance of an abnormal ABI (especially high ABI) is significantly affected by BMI. The objective of this study was to examine the association of ABI with CV and all-cause mortality according to BMI (in both obese and nonobese individuals) in the general US population using the National Health and Nutrition Examination Survey (NHANES) sample from 1999 to 2002.

gh ABI) is significantly affected by BMI. The objective of this study was to examine the association of ABI with CV and all-cause mortality according to BMI (in both obese and nonobese individuals) in the general US population using the National Health and Nutrition Examination Survey (NHANES) sample from 1999 to 2002. Patients and Methods Study Population We used data from NHANES, which is a cross-sectional study of US residents.13 The NHANES design consisted of a multistage, stratified, clustered probability dataset providing a representative sample of the noninstitutionalized civilian population of the United States. The study protocol was approved by the National Center for Health Statistics of the Centers for Disease Control and Prevention institutional review board. All participants gave written informed consent for the study. We queried the NHANES population database between January 1, 1999, and December 31, 2002. All subjects with available BMI and ABI data were included. We excluded those with missing data on any of the key variables outlined herein. The final sample size for the study was 4614 subjects.

en informed consent for the study. We queried the NHANES population database between January 1, 1999, and December 31, 2002. All subjects with available BMI and ABI data were included. We excluded those with missing data on any of the key variables outlined herein. The final sample size for the study was 4614 subjects. Data Collection The methodology used for data collection by NHANES has been described in detail elsewhere.13 In brief, data including past medical history, medication use, demographics, education level, alcohol consumption, and smoking status were collected using a standardized questionnaire. Using a mobile examination center, a detailed physical examination was completed for each participant. Blood pressure was measured 3 times during the visit. For the purpose of the study, hypertension was defined as a systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or receipt of antihypertensive therapies. Diabetes mellitus was defined as a fasting plasma glucose level ≥126 mg/dL, a nonfasting plasma glucose ≥200 mg/dL, or ongoing use of oral hypoglycemic agents for diabetes treatment.

sion was defined as a systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or receipt of antihypertensive therapies. Diabetes mellitus was defined as a fasting plasma glucose level ≥126 mg/dL, a nonfasting plasma glucose ≥200 mg/dL, or ongoing use of oral hypoglycemic agents for diabetes treatment. The NHANES ABI measurement protocol is detailed elsewhere.14 In brief, the right arm blood pressure (BP) and the posterior tibial artery BP were used to calculate the ABI. For patients whose right arm BP could not be recorded (for various reasons listed in the NHANES protocol), left arm BP was used. The size of the arm cuff was based on the arm circumference, with a larger cuff used for larger circumference. The lower extremity cuff used for each patient was the same size as that used for his or her upper arm. Thus, the study accounted for patient size in choosing the cuff. Categories for ABI were defined as <0.9 (low), 0.9 to 1.3 (normal, reference range), and >1.3 (high). Height and weight were measured, and BMI was calculated as weight in kilograms divided by height in meters squared. BMI categories were <30 kg/m2 (nonobese) and ≥30 kg/m2 (obese).

for patient size in choosing the cuff. Categories for ABI were defined as <0.9 (low), 0.9 to 1.3 (normal, reference range), and >1.3 (high). Height and weight were measured, and BMI was calculated as weight in kilograms divided by height in meters squared. BMI categories were <30 kg/m2 (nonobese) and ≥30 kg/m2 (obese). For the purposes of our investigation, a single measurement of ABI, as obtained in the NHANES cohort, was thought to be adequate for analysis, given that several previous epidemiologic studies have used single ABI measurements to predict CV outcomes with consistent results.15, 16, 17 The inter- and intraobserver variability of ABI measurements has been shown to be quite small, especially in relatively healthy populations such as the NHANES cohort.18, 19, 20, 21, 22, 23 The factor that may most significantly affect the accuracy of ABI measurements is use of an appropriately sized cuff, which was well standardized in the NHANES protocol. Outcomes All participants were followed up from their entry into the NHANES study (baseline) to December 31, 2011. Outcomes assessed for this study were all-cause and CV mortality. Vital status and assignment of cause of death were based upon probabilistic matching of NHANES data with National Death Index records. CV mortality was defined based on reported cause of death on death certificate records. For deaths between 1988 through 1998, International Classification of Diseases, 10th Revision (ICD-10) was used (ICD-10 codes I00-I99), as has been used in previous studies from NHANES.13

ANES data with National Death Index records. CV mortality was defined based on reported cause of death on death certificate records. For deaths between 1988 through 1998, International Classification of Diseases, 10th Revision (ICD-10) was used (ICD-10 codes I00-I99), as has been used in previous studies from NHANES.13 Statistical Analysis Sampling weights were used to account for the complex survey design. Descriptive statistics were reported as mean and standard deviation for continuous variables and percentages for categorical variables. Baseline characteristics were compared using analysis of variance (ANOVA) and χ2 tests in pairwise analyses when appropriate. We presented 10-year predicted incidence rates, adjusted for demographic characteristics and CV risk factors, for all-cause and CV mortality for each ABI category in both obese and nonobese participants. Kaplan-Meier survival curves were presented for the outcome of interest for each category of ABI according to BMI. Cox proportional hazards models were used to estimate hazards ratios (HRs) for mortality. We used 2 different models with Model 1 adjusting for age, race, gender, income (<$20,000 vs ≥$20,000), and education (<12 years vs >12 years) and Model 2 further adjusting for history of diabetes, systolic blood pressure, total cholesterol, HDL cholesterol, history of CV disease, and current smoking. Interaction between ABI and BMI for all-cause and CV mortality was examined from the fully adjusted model using the Wald test. We used continuous net reclassification index to test if risk stratification for all-cause and CV mortality improved with the addition of ABI to conventional CV risk factors for both obese and nonobese individuals. P values <.05 were considered statistically significant. All statistical analyses were done using STATA 12 (StataCorp, College Station, TX).

tion index to test if risk stratification for all-cause and CV mortality improved with the addition of ABI to conventional CV risk factors for both obese and nonobese individuals. P values <.05 were considered statistically significant. All statistical analyses were done using STATA 12 (StataCorp, College Station, TX). Results The study cohort was composed of 4614 subjects, among whom 52% were female. Mean age was 56±12 years. Subjects were followed up for a median period of 10.3 years (IQR: 9.3 to 11.4 years) from enrollment. Baseline characteristics of the study population by ABI and BMI are displayed in Table 1. Seven percent (n=325) had low ABI (<0.9), whereas 8% (n=358) had high ABI (>1.3). The population was predominantly white (n=3583, 78%), and 52% were women. In the nonobese group, there were significant differences in age (P<.001), female sex (P<.001), and the percentage of white subjects (P=.03). Similar findings were seen in nonobese patients with respect to education, household income, smoking status, systolic blood pressure, and prevalent CV disease (P<.001 for all). In obese subjects, significant differences in baseline characteristics were also observed for age, female sex, percentage of white subjects, education, income, and prevalent CV disease. Obese subjects demonstrated differences in prevalence of diabetes (P=.01), as well as total cholesterol and HDL cholesterol concentrations (P<.001), which were not observed in the nonobese subjects. Finally, in contrast to the nonobese group, obese subjects did not have significant differences in smoking status (P=.4) or systolic blood pressure (P=.1) between ABI groups. Other factors—such as level of education, household income, blood pressure, diabetes, and incident CV disease—were not significantly different at baseline among the ABI groups, regardless of obesity status.Table 1 Baseline Characteristics of the Study Population

.4) or systolic blood pressure (P=.1) between ABI groups. Other factors—such as level of education, household income, blood pressure, diabetes, and incident CV disease—were not significantly different at baseline among the ABI groups, regardless of obesity status.Table 1 Baseline Characteristics of the Study Population Overall sample BMI <30 kg/m2 P BMI ≥ 30 kg/m2 P ABI <0.9 ABI 0.9 to 1.3 ABI >1.3 ABI <0.9 ABI 0.9 to 1.3 ABI >1.3 n 4,614 232 2653 227 NA 93 1278 131 NA Age 56 (12) 69 (14) 55 (12) 55 (12) <.001 64 (14) 55 (11) 55 (11) <.001 Female % 2380 (52) 52 54 33 <.001 55 64 40 .01 White % 3583 (78) 80 77 85 .03 77 76 77 .01 African Americans % 404 (9) 11 8 3 18 11 5 Mexican Americans % 208 (5) 3 4 6 3 5 2 Hispanics % 240 (5) 5 6 3 2 5 2 Education ≥12 years % 3641 (79) 64 80 84 <.001 63 78 80 .02 Income ≥$20,000 % 3829 (83) 67 84 90 <.001 70 81 88 .02 Current smoker % 962 (21) 34 23 9 <.001 21 17 12 .4 Diabetes % 692 (15) 18 12 10 .08 42 21 20 .01 Systolic BP mm Hg 127 (19) 141 (28) 126 (19) 121 (17) <.001 137 (27) 130 (18) 125 (15) .1 Prevalent cardiovascular disease % 508 (11) 28 9 9 <.001 30 12 16 .006 Cholesterol mg/dL 212 (41) 216 (51) 212 (41) 205 (35) .08 198 (41) 214 (41) 202 (34) <.001 HDL cholesterol mg/dL 52 (16) 54 (21) 55 (17) 53 (14) .26 49 (16) 47 (13) 47 (11) <.001 BMI (kg/m2) 28 (6) 25 (4) 25 (3) 25 (3) .07 35 (6) 35 (4) 35 (5) .8 Continuous variables reported as mean (standard deviation), whereas categorical variables are reported as n (%) in the overall sample column and percentages in subsequent columns with corresponding n values included in the first row.

(13) 47 (11) <.001 BMI (kg/m2) 28 (6) 25 (4) 25 (3) 25 (3) .07 35 (6) 35 (4) 35 (5) .8 Continuous variables reported as mean (standard deviation), whereas categorical variables are reported as n (%) in the overall sample column and percentages in subsequent columns with corresponding n values included in the first row. P values were computed using ANOVA or χ2 tests where indicated. Values <.05 were considered statistically significant. ABI = ankle-brachial index; BMI = body mass index; HDL = high density lipoprotein; BP = blood pressure. To assess the outcomes of all-cause and CV mortality in subjects stratified by ABI and BMI, survival curves were constructed using the Kaplan-Meier method, as depicted in the Figure (A and B, respectively). A significantly lower probability of survival from all-cause mortality was observed for low ABI subjects with both normal and high BMI, compared with all other groups (log rank test P<.001). This survival difference was detectable at 2 years, and its magnitude continued to increase throughout the duration of follow-up. Similar trends were seen for survival from cardiovascular mortality (Figure [B]), with worse survival in the low ABI groups for both normal and high BMI (P<.001).Figure (A) Survival estimates for all-cause mortality using Kaplan-Meier analysis. (B) Survival estimates for cardiovascular mortality using Kaplan-Meier analysis.

ar trends were seen for survival from cardiovascular mortality (Figure [B]), with worse survival in the low ABI groups for both normal and high BMI (P<.001).Figure (A) Survival estimates for all-cause mortality using Kaplan-Meier analysis. (B) Survival estimates for cardiovascular mortality using Kaplan-Meier analysis. The association of ABI with risk of all-cause and cardiovascular mortality stratified by BMI is presented in Table 2. After adjustment for demographic variables and traditional cardiovascular risk factors, low ABI was associated with increased risk of all-cause and cardiovascular mortality in both normal BMI (HR 1.5, 95% confidence interval [CI], 1.1-2.1 for all cause and 3.0 (1.8-5.1) for cardiovascular mortality) and high BMI 1.8 (1.2-2.7) for all-cause and 2.5 (1.2-5.6) for cardiovascular mortality) compared with those with ABI 0.9-1.3. We also observed that those with high ABI had a higher risk of cardiovascular mortality compared with ABI 0.9-1.3 in the nonobese individuals (2.2 [1.1-4.5]) but not in the obese group (0.6 [0.2-1.7]). High ABI was not associated with all-cause mortality when stratified by body mass. Adjusted incidence rates for all-cause and cardiovascular mortality according to ABI and BMI are shown in Table 3 to convey absolute risk.Table 2 Association of Ankle-Brachial Index With All-Cause and Cardiovascular Mortality According to Body Mass Index

associated with all-cause mortality when stratified by body mass. Adjusted incidence rates for all-cause and cardiovascular mortality according to ABI and BMI are shown in Table 3 to convey absolute risk.Table 2 Association of Ankle-Brachial Index With All-Cause and Cardiovascular Mortality According to Body Mass Index ABI BMI <30 kg/m2 BMI ≥30 kg/m2 Overall Model 1a Model 2b Model 1a Model 2b Model 1a Model 2b All-Cause Mortality 0.9-1.3 Reference Reference Reference Reference Reference Reference <0.9 1.8 (1.3-2.5) 1.5 (1.1-2.1) 2.0 (1.3-3.1) 1.8 (1.2-2.7) 1.8 (1.4-2.5) 1.6 (1.2-2.1) >1.3 0.9 (0.6-1.4) 1.1 (0.8-1.6) 1.0 (0.5-2.0) 1.1 (0.6-2.3) 1.0 (0.7-1.4) 1.1 (0.8-1.6) Cardiovascular Mortality 0.9-1.3 Reference Reference Reference Reference Reference Reference <0.9 3.4 (2.0-5.8) 3.0 (1.8-5.1) 3.2 (1.3-7.9) 2.5 (1.2-5.6) 3.2 (2.0-5.5) 2.9 (1.8-4.7) >1.3 1.9 (0.9-4.1) 2.2 (1.1-4.5) 0.5 (0.2-1.4) 0.6 (0.2-1.7) 1.3 (0.7-2.6) 1.5 (0.8-2.8) Interaction P=.8 for all-cause and 0.09 for cardiovascular mortality. Net reclassification index P<.05 for both all-cause and cardiovascular mortality with addition of ankle-brachial index to conventional cardiovascular risk factors for both obese and nonobese individuals. ABI = ankle-brachial index; BMI = body mass index. a Model 1 adjusted for age, race, gender, income (< $20,000 vs ≥ $20,000), and education (<12 years vs ≥12 years). b Model 2 further adjusted for history of diabetes, systolic blood pressure, total cholesterol, HDL cholesterol, history of cardiovascular disease, and current smoking.

ABI = ankle-brachial index; BMI = body mass index. a Model 1 adjusted for age, race, gender, income (< $20,000 vs ≥ $20,000), and education (<12 years vs ≥12 years). b Model 2 further adjusted for history of diabetes, systolic blood pressure, total cholesterol, HDL cholesterol, history of cardiovascular disease, and current smoking. Table 3 Incidence Rates for All-Cause and Cardiovascular Mortality by Ankle-Brachial Index and Body Mass Index Categories ABI Total (n) Total deaths Cardiovascular deaths Mortality ratea Cardiovascular mortality ratea BMI <30 kg/m2 0.9-1.3 2653 508 67 16.7 (14.8-18.5) 2.1 (1.5-2.8) <0.9 232 129 38 24.7 (18.8-30.6) 6.2 (3.6-8.7) >1.3 227 48 10 19.4 (12.8-26.0) 4.8 (1.9-7.6) BMI ≥30 kg/m2 0.9-1.3 1278 215 37 16.1 (14.0-18.2) 2.9 (1.2-4.6) <0.9 93 42 11 26.2 (17.3-35.0) 6.2 (1.6-10.7) >1.3 131 22 3 18.2 (6.5-29.8) 1.7 (0.4-3.7) ABI = ankle-brachial index; BMI = body mass index a 10-year predicted incidence rates per 100 person-years. All rates adjusted for age, race, gender, income (< $20,000 vs ≥ $20,000) and education (<12 years vs ≥12 years), history of diabetes, systolic blood pressure, total cholesterol, HDL cholesterol, history of cardiovascular disease, and current smoking.

ABI Total (n) Total deaths Cardiovascular deaths Mortality ratea Cardiovascular mortality ratea BMI <30 kg/m2 0.9-1.3 2653 508 67 16.7 (14.8-18.5) 2.1 (1.5-2.8) <0.9 232 129 38 24.7 (18.8-30.6) 6.2 (3.6-8.7) >1.3 227 48 10 19.4 (12.8-26.0) 4.8 (1.9-7.6) BMI ≥30 kg/m2 0.9-1.3 1278 215 37 16.1 (14.0-18.2) 2.9 (1.2-4.6) <0.9 93 42 11 26.2 (17.3-35.0) 6.2 (1.6-10.7) >1.3 131 22 3 18.2 (6.5-29.8) 1.7 (0.4-3.7) ABI = ankle-brachial index; BMI = body mass index a 10-year predicted incidence rates per 100 person-years. All rates adjusted for age, race, gender, income (< $20,000 vs ≥ $20,000) and education (<12 years vs ≥12 years), history of diabetes, systolic blood pressure, total cholesterol, HDL cholesterol, history of cardiovascular disease, and current smoking. We found no significant multiplicative interaction between ABI and BMI for either all-cause or cardiovascular mortality (P=.8 and P=.09 for all-cause and cardiovascular mortality, respectively). In our risk prediction analysis, we found that risk prediction for both all-cause and cardiovascular mortality improved significantly when BMI was added to the fully adjusted model with ABI for both obese and nonobese individuals (P<.05).

tality (P=.8 and P=.09 for all-cause and cardiovascular mortality, respectively). In our risk prediction analysis, we found that risk prediction for both all-cause and cardiovascular mortality improved significantly when BMI was added to the fully adjusted model with ABI for both obese and nonobese individuals (P<.05). Discussion This study provides a comprehensive examination of the influence of BMI on the association of ABI and both all-cause and cardiovascular mortality in a nationally representative sample of United States residents. A key finding of the study is that high ABI (>1.3) was not associated with an increased risk of all-cause mortality irrespective of BMI, although a high ABI was associated with increased risk of cardiovascular mortality in nonobese but not obese individuals (there was no association in the overall group, however). The study also found that low ABI is associated with a significantly increased risk of both all-cause and cardiovascular mortality in both obese and nonobese individuals. A number of large-scale epidemiologic studies have previously associated low ABI with adverse cardiovascular outcomes and mortality.4,7,16,17,24 In a meta-analysis including 44,590 patients from 11 epidemiologic studies representing 6 national populations, Heald et al.1 found that ABI <0.9 conferred a higher risk of both all-cause mortality (pooled risk ratio [RR] 1.60, 95% CI, 1.32-1.95) and CV mortality (pooled RR 1.96, 95% CI, 1.46-2.64) after adjustment for conventional cardiovascular risk factors.

ts from 11 epidemiologic studies representing 6 national populations, Heald et al.1 found that ABI <0.9 conferred a higher risk of both all-cause mortality (pooled risk ratio [RR] 1.60, 95% CI, 1.32-1.95) and CV mortality (pooled RR 1.96, 95% CI, 1.46-2.64) after adjustment for conventional cardiovascular risk factors. Although many of the cited studies adjusted for BMI when estimating the association between ABI and their outcomes of interest, the risk conferred by abnormal ABI stratified by BMI has not been previously examined, to our knowledge. Despite the well-known association of obesity with all-cause mortality,25,26 the validity of ABI-based risk assessment in an obese population is less clear. We found that low ABI was associated with a similarly elevated risk of all-cause and CV mortality in both obese and nonobese patients.

examined, to our knowledge. Despite the well-known association of obesity with all-cause mortality,25,26 the validity of ABI-based risk assessment in an obese population is less clear. We found that low ABI was associated with a similarly elevated risk of all-cause and CV mortality in both obese and nonobese patients. Beyond the associations between abnormal ABI and all-cause and CV mortality, our study sought to examine the impact of ABI on CV risk prediction in this population. Fowkes et al. found significant associations between low ABI and cardiovascular mortality after adjusting for the Framingham Risk Score (FRS).2 In the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, Criqui et al. found the association between abnormal ABI and CV disease events remained significant following adjustment for other known measures of subclinical atherosclerosis.4 In the NHANES cohort, we also found that there was a significant improvement in risk prediction for both all-cause and CV mortality when ABI was added to the model while adjusting for most conventional CV risk factors. This relationship remained true for both obese and nonobese patients, a finding that has not been clearly demonstrated previously.

found that there was a significant improvement in risk prediction for both all-cause and CV mortality when ABI was added to the model while adjusting for most conventional CV risk factors. This relationship remained true for both obese and nonobese patients, a finding that has not been clearly demonstrated previously. The association of high ABI and CV outcomes is less well established. Most—although not all—studies showing an association of high ABI with adverse outcomes have been in populations with a high underlying cardiovascular risk. The Strong Heart Study (SHS) was among the first to show an association between high ABI (>1.4) and CV outcomes.7 In that study, Resnick et al. examined 4393 American Indian patients over an 8-year follow-up period.7 In patients with high ABI, the relative risk ratio was 1.77 (95% CI, 1.48-2.13) for all-cause mortality and 2.09 (95% CI, 1.49-2.94) for CV mortality.7 SHS featured a high-risk population with diabetes present in more than half the subjects and a relatively high prevalence of high ABI at 9.2%. Similarly, in another study of high-risk patients on hemodialysis in Japan, Ono et al. noted a higher risk of all-cause and CV mortality with ABI >1.3.27 A Dutch study of 7538 patients with prevalent CV disease or risk factors found that an ABI ≥1.4 was associated with an increased risk of myocardial infarction.10 High ABI has traditionally been thought to result from noncompressibility of lower extremity (LE) arteries related to medial arterial calcification (MAC). MAC does portend a poor prognosis in diabetic patients and in at least 1 study in patients with type 1 diabetes, subjects with ABI >1.3 had a higher likelihood of having MAC on x-ray.28, 29, 30

een thought to result from noncompressibility of lower extremity (LE) arteries related to medial arterial calcification (MAC). MAC does portend a poor prognosis in diabetic patients and in at least 1 study in patients with type 1 diabetes, subjects with ABI >1.3 had a higher likelihood of having MAC on x-ray.28, 29, 30 It is likely that the association of high ABI with adverse CV outcomes in high-risk populations is related to MAC being an etiologic factor in causing high ABI readings. In these high-risk populations, the relationship of high ABI and adverse CV outcomes is quite consistent across studies. However, in more general populations, the findings have been discrepant. The Atherosclerosis Risk in Communities (ARIC) investigators assessed the clinical significance of high ABI in their general population cohort from 4 US communities,9,31 They found high ABI was not associated with an increased CV event rate, compared with normal ABI. In this general population, in which the incidence of diabetes and MAC is expected to be lower than SHS, for example, there may be other factors that result in high ABI. The MESA investigators showed an independent, positive, and graded association with increasing obesity and prevalent high ABI.12 Furthermore, they found that indicators of general obesity, such as BMI, were a stronger predictor of high ABI than measures of visceral adiposity. This observation is supported by previous work assessing the relationship between LE soft tissue composition and ABI. Tabara et al. used computed tomography to measure trunk and LE soft tissue composition in relation to ABI.11 After adjustment for CV risk factors, the study found LE muscle mass and not visceral or femoral fat or femoral circumference was independently associated with high ABI. The authors hypothesized that increased LE muscle mass confers resistance to compression in LE arteries, leading to higher ABI. This could explain the lack of association of high ABI and CV events seen in the general risk populations such as the ARIC cohort, in which BMI was significantly higher in the high ABI group.

The authors hypothesized that increased LE muscle mass confers resistance to compression in LE arteries, leading to higher ABI. This could explain the lack of association of high ABI and CV events seen in the general risk populations such as the ARIC cohort, in which BMI was significantly higher in the high ABI group. Furthermore, it has been shown that for the same BMI, racial and ethnic differences exist in body fat and muscle content. This has been observed in comparisons of several ethnicities including European, African, and Asian populations.32, 33, 34 These differences in BMI and body fat/mass content and distribution may—to some degree—explain differences in various population-based studies examining outcomes with high ABI. The MESA study showed high ABI was associated with elevated CV risk in persons free of known CV disease.4 The high ABI group was significantly different from the normal ABI group in terms of BMI (30.1 vs 28.3 kg/m2) and ethnic distribution (Caucasians 48.2% vs 38.2%, Chinese 2.7% vs 12.7%). It is possible that these factors also exert influence on the prognostic significance of high ABI.

persons free of known CV disease.4 The high ABI group was significantly different from the normal ABI group in terms of BMI (30.1 vs 28.3 kg/m2) and ethnic distribution (Caucasians 48.2% vs 38.2%, Chinese 2.7% vs 12.7%). It is possible that these factors also exert influence on the prognostic significance of high ABI. Similar to the ARIC study, in the NHANES cohort we found—looking at the overall study population—high ABI (>1.3) was not associated with an increased risk of all-cause or CV mortality. However, when stratified according to BMI, in those with BMI < 30, a high ABI was associated with increased CV mortality, although not all-cause mortality. In those with BMI ≥ 30, high ABI was not associated with increased CV or all-cause mortality. It is likely that, in a population with a low prevalence of diabetes, CV disease and, by extension, a low likelihood of MAC, high ABI measured in obese individuals is related to poor compressibility of the LE arteries due to such factors as LE muscle mass, rather than arterial disease. Another issue is that of accurate cuff sizing when measuring ABI. Unlike the upper extremity, where there are recommendations for appropriate cuff sizing, no recommendations or guidelines are available for adequate cuff sizing based on calf circumference for the LE.6,35 In the NHANES protocol, there is a detailed description of cuff-sizing methodology based on BMI, and thus cuff sizing is likely not a significant factor to be considered when interpreting the findings of the current study.14

r guidelines are available for adequate cuff sizing based on calf circumference for the LE.6,35 In the NHANES protocol, there is a detailed description of cuff-sizing methodology based on BMI, and thus cuff sizing is likely not a significant factor to be considered when interpreting the findings of the current study.14 Limitations The main limitations of our study include the potential for residual confounding not accounted for in our analyses, particularly with regard to associations between high ABI and mortality for which there is a need for further investigation to better elucidate the underlying mechanisms leading to high ABI. The NHANES data set does not include peripheral arterial disease symptoms for consideration with ABI measurements, a potentially useful discriminator in determining whether high ABI is reflective of noncompressible vessels or artifact related to body habitus. A cutoff value of 1.3 was used to define high ABI, based on previous studies of the ARIC and MESA populations,9,36 although a more recent societal guideline suggests using a value of 1.4.37 A sensitivity analysis to assess for changes in outcome using an ABI cutoff of 1.4 for high ABI in our study population was not possible because of low numbers of subjects and events in this higher ABI group. For the ankle pressure, only the posterior tibialis (PT) measurement was obtained in the NHANES protocol, without an assessment of the dorsalis pedis site for comparison and potential incorporation into ABI calculation. Although the latter approach is preferable, previous studies have established the relationship between the ABI calculated with a PT measurement only and CV outcomes.6,17 Only a single measure of ABI and BMI was obtained at baseline, which may have affected the accuracy of our findings, although considering the large cohort and multiple patient sites in NHANES, a significant impact on the outcomes measured seems unlikely. Furthermore, there was no serial assessment of BMI in the NHANES data set, which would have provided additional valuable insights regarding the relationship between BMI, ABI, and CV outcomes.

considering the large cohort and multiple patient sites in NHANES, a significant impact on the outcomes measured seems unlikely. Furthermore, there was no serial assessment of BMI in the NHANES data set, which would have provided additional valuable insights regarding the relationship between BMI, ABI, and CV outcomes. Conclusions In a nationally representative US cohort, obesity significantly influenced the prognostic significance of high ABI. High ABI is associated with an increased risk of CV mortality in nonobese but not in obese patients. Low ABI is associated with an increased risk of all-cause and CV mortality in both nonobese and obese patients. Acknowledgments Drs Gupta and Waheed were responsible for the study conception and design of this report. Dr Waheed acquired the data, and Drs Waheed, Jazayeri, and Gupta analyzed and interpreted the data. Dr Jazayeri drafted the manuscript. All authors were responsible for the critical revision and final approval of the manuscript. The authors wish to thank Dr Heather Gornik, Department of Cardiovascular Medicine, Cleveland Clinic; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, for her critical review of the manuscript and excellent suggestions for its improvement. Grant Support: This article was supported by The University of Kansas (KU) One University Open Access Author Fund sponsored jointly by the KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research and managed jointly by the Libraries at the Medical Center and KU - Lawrence.

The authors wish to thank Dr Heather Gornik, Department of Cardiovascular Medicine, Cleveland Clinic; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, for her critical review of the manuscript and excellent suggestions for its improvement. Grant Support: This article was supported by The University of Kansas (KU) One University Open Access Author Fund sponsored jointly by the KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research and managed jointly by the Libraries at the Medical Center and KU - Lawrence. Potential Competing Interests: The authors report no competing interests.

Health care–associated infections have steadily increased over the last several decades. The annual cost of such infections is more than 25 billion dollars.1 While gloves and hand hygiene have prevented spreading of infections from physical contact, stethoscope still exists as a potential vector.2, 3, 4 There have been several articles which concluded that stethoscopes are known vectors of transmitting infections such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and various other micro-organisms that respond to only a narrow spectrum of antibiotics.4, 5, 6 For nearly the last century, stethoscopes continue to be of prime importance in making patient care decisions, especially in fast-paced settings such as the emergency department and intensive care units.7 These settings require heavy decision making from clinical exams. The use of the stethoscope is vital in such situations. For example, the stethoscope can be used to determine if a patient in respiratory distress is breathing fast because of a pneumothorax, pneumonia, or congestive heart failure. If the patient who had been involved in a recent motor vehicle crash has pneumothorax or hemothorax, the use of a stethoscope would add useful information beneficial to immediate management for that patient. Being a physician’s companion around their neck and more readily available than x-rays, computed tomography scans, and ultrasound machines, stethoscopes will continue to be the mainstay in critical care situations.

he use of a stethoscope would add useful information beneficial to immediate management for that patient. Being a physician’s companion around their neck and more readily available than x-rays, computed tomography scans, and ultrasound machines, stethoscopes will continue to be the mainstay in critical care situations. Except for the introduction of digital stethoscopes, not a lot has been modified in the basic design of stethoscopes. Some physicians opt for disposable stethoscopes and some prefer sanitizing their personal stethoscopes with alcohol wipes or Oxivir wipes, but the vast majority have been unable to clean their stethoscope between every patient evaluation. Centers for Disease Control and Prevention guidelines recommend using a US Environmental Protection Agency–registered disinfectant for stethoscopes not contaminated with blood and for a tuberculocidal agent or a 1:100 dilution of a hypochlorite solution for stethoscopes with visible contamination of blood; however, these solutions still require a few minutes to clean the stethoscope.8,9

a US Environmental Protection Agency–registered disinfectant for stethoscopes not contaminated with blood and for a tuberculocidal agent or a 1:100 dilution of a hypochlorite solution for stethoscopes with visible contamination of blood; however, these solutions still require a few minutes to clean the stethoscope.8,9 Although a few authors in the past have suggested diaphragm covers in scientific literature, most of those studies lacked a robust design and methodology.10 A potential solution to the problem has been suggested by Vasudevan et al in their manuscript, where a disposable aseptic diaphragm barrier was noted to remain sterile at 24 hours. The authors concluded that barriers prevented the growth of anaerobes, antibiotic-resistant bacteria, yeasts, and body samples. Since the diaphragm is the main part of the stethoscope that comes in contact with the patient, the ease of application and removal of aseptic barriers on the diaphragm offers a ray of hope to this unresolved problem. Potential Competing Interests: The authors report no competing interests.

From the vantage point of the 21st century, it is very easy to overlook the fact that when Mayo Clinic practice began in 1864, Minnesota was still part of the Old West (Figure 1). In fact, when Dr William Worrall Mayo brought his family to Rochester in 1863, Jesse James had not yet robbed the Northfield Bank, Billy the Kid was still shooting his way through the West, and Calamity Jane was only 11 years old. When Saint Marys Hospital opened its doors in 1889, the Coca-Cola Company was incorporated, Vincent Van Gogh painted The Starry Night, the first issue of the Wall Street Journal was published, and Charlie Chaplin and Adolph Hitler were born just days apart from each other. In Rochester, streets were unpaved, the horse was still the main mode of transportation, and the city’s first municipally owned power plant would not generate electricity until 1894.1 On the medical front, cocaine, heroin, morphine, and laudanum were everyday ingredients in medical “remedies,” peddled for toothaches, coughs, and fussing, teething babies.2Figure 1 Downtown Rochester, Minnesota, circa 1868. Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota.

From the vantage point of the 21st century, it is very easy to overlook the fact that when Mayo Clinic practice began in 1864, Minnesota was still part of the Old West (Figure 1). In fact, when Dr William Worrall Mayo brought his family to Rochester in 1863, Jesse James had not yet robbed the Northfield Bank, Billy the Kid was still shooting his way through the West, and Calamity Jane was only 11 years old. When Saint Marys Hospital opened its doors in 1889, the Coca-Cola Company was incorporated, Vincent Van Gogh painted The Starry Night, the first issue of the Wall Street Journal was published, and Charlie Chaplin and Adolph Hitler were born just days apart from each other. In Rochester, streets were unpaved, the horse was still the main mode of transportation, and the city’s first municipally owned power plant would not generate electricity until 1894.1 On the medical front, cocaine, heroin, morphine, and laudanum were everyday ingredients in medical “remedies,” peddled for toothaches, coughs, and fussing, teething babies.2Figure 1 Downtown Rochester, Minnesota, circa 1868. Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota. Similarly, medical education was waiting for the next advancement. When the first officially recognized otolaryngology resident at Mayo Clinic, Dr Margaret I. Smith (Figure 2), started training in 1908, US medical schools were mainly private, for-profit, and not affiliated with a university.3,4 On average nationwide, the ratio of patients per doctor was 568:1,4 what Abraham Flexner would describe in his 1910 report on the state of medical education in the United States as an “over-production of uneducated and ill trained medical practitioners.”4 There were few requirements of medical schools, and likewise few requirements to qualify as a medical doctor, much less a medical student. There was no specialized medical training beyond completing medical school and working side-by-side with a physician, often performing little more than “scut work” to gain experience and start a practice. Perhaps the most valuable post–medical school training up to World War I consisted of traveling to Europe to observe in operating theaters.5 This certainly was a large part of Drs William J. (Will) and Charles H. (Charlie) Mayo’s education after they completed medical school and throughout their lives.Figure 2 Margaret I. Smith, MD, is the first officially recognized otology and rhinology trainee at Mayo Clinic, starting her training in 1908 and leaving Mayo Clinic in 1911. She went on to practice medicine in Minneapolis, Minnesota, and become the director of clinical/pathology laboratories at Northwestern Hospital there.6

2 Margaret I. Smith, MD, is the first officially recognized otology and rhinology trainee at Mayo Clinic, starting her training in 1908 and leaving Mayo Clinic in 1911. She went on to practice medicine in Minneapolis, Minnesota, and become the director of clinical/pathology laboratories at Northwestern Hospital there.6 In some ways, the Mayo brothers were actually the first surgical residents at Mayo Clinic, working alongside their father, William W. Mayo, MD (Figure 3). While they were growing up, apprenticeships were the norm for training physicians, but they recognized early that physicians and surgeons on the whole were not fully sharing their knowledge and that trainees were mired in drudge work. After visiting a medical school in the East, Dr Will noted, “[The residents] seemed to spend their days in subservient yessir-ing, in being flunkie for the permanent staff.”7 Drs Will and Charlie learned from their father’s teaching method—which included nonmedical lessons, such as sending his young inexperienced sons to wrangle an ill-tempered cow he had bought from a patient8—that hands-on experience and open communication were the best methods for learning (Figure 4). Dr Will, in an address to the Mayo Alumni Association in 1919, reflected on the reason for the growth of Mayo Clinic and its educational shield: “the desire to advance in medical education by research, by diligent observation, and by the application of knowledge gained from others; and most important of the desire to pass on to others the scientific candle this spirit has lighted.”9Figure 3 Dr William W. Mayo, circa 1904.

Mayo Clinic and its educational shield: “the desire to advance in medical education by research, by diligent observation, and by the application of knowledge gained from others; and most important of the desire to pass on to others the scientific candle this spirit has lighted.”9Figure 3 Dr William W. Mayo, circa 1904. Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota.Figure 4 Educational articles published by Drs Will and Charlie Mayo in 1927 and 1919, respectively.10,11 The Harold I. Lillie Era Preaccreditation Mayo Clinic originated before the establishment of the National Confederation of State Medical Examining and Licensing boards in 1890, and medical school graduates traveled to Mayo Clinic for training long before standards or regulations for graduate medical training were published.

arold I. Lillie Era Preaccreditation Mayo Clinic originated before the establishment of the National Confederation of State Medical Examining and Licensing boards in 1890, and medical school graduates traveled to Mayo Clinic for training long before standards or regulations for graduate medical training were published. The nationwide need for standards and regulations was made glaringly evident in 1910, when Abraham Flexner and the Carnegie Foundation released Medical Education in the United States and Canada: A Report to the Carnegie Foundation for the Advancement of Teaching, a pivotal report that analyzed the state of medical education and ultimately changed the face of medical education in the United States. The Flexner report only peripherally addressed postgraduate education and therefore did not affect Mayo Clinic directly, because at the time Mayo Clinic did not have a medical school as such but rather took on medical graduates for further training. It would, however, have an eventual impact on the quality and variety of graduates who came to Mayo to train,12,13 particularly regarding the unintended consequences of the Flexner report on female and black medical students who were heavily impacted by medical school closures, setting medical training opportunities for such students back decades.12, 13, 14 Relevant to the state of Minnesota, the Flexner report congratulated the University of Minnesota for “absorbing all other medical schools in the state.”4

male and black medical students who were heavily impacted by medical school closures, setting medical training opportunities for such students back decades.12, 13, 14 Relevant to the state of Minnesota, the Flexner report congratulated the University of Minnesota for “absorbing all other medical schools in the state.”4 In 1915, the Mayo Foundation for Medical Education and Research was established, which included an integral partnership with the University of Minnesota. The University of Minnesota conferred graduate medical degrees for Mayo Clinic until 1983.5,15 In total, by 1922 more than 1000 prospective candidates sought positions for graduate medical training at Mayo Clinic.16 Of course, since Dr Charlie himself was keenly interested in head and neck surgery, otorhinolaryngology (ENT) fellows (Mayo Clinic training programs used the term fellows until the 1970s for both residents and fellows, reminiscent of European terminology5) had been training at Mayo Clinic long before then, with the training program established in 1908 with fellow Margaret I. Smith, MD. By 1923, as a specialty ENT-ophthalmology, or “eye-ears-nose-throat” was nationwide the most popular specialty to practice, followed by general surgery and distantly by internal medicine. Unfortunately, this was also the era of ENT specialty training that otolaryngologist George E. Shambaugh described as producing “carpenters in oto-laryngology,”7 certainly not a flattering description of the state of otolaryngology education in the United States during this boom of popularity.

tly by internal medicine. Unfortunately, this was also the era of ENT specialty training that otolaryngologist George E. Shambaugh described as producing “carpenters in oto-laryngology,”7 certainly not a flattering description of the state of otolaryngology education in the United States during this boom of popularity. Throughout the 1920s, the primary teaching method in otolaryngology continued to be the apprenticeship model—the traditional teaching method since the beginning of medical education in the United States. However, in a 1924 report to the Mayo Clinic Board of Governors, department chair Dr Harold I. Lillie refined the definition of the apprenticeship model (Figure 5). Instead of the traditional one-on-one relationship between master and apprentice in which learning relied almost exclusively on direct observation and was limited by the abilities and teaching inclinations of the master,17 apprenticeship in otolaryngology at Mayo Clinic meant “being made responsible for a patient and his care under the direction of the consultant’s advice,”18 thus establishing the backbone of ENT training to the present time and giving a nod to the hands-on learning directly advocated by the Mayo brothers.19Figure 5 Harold I. Lillie, MD, served as the department chair from 1919 to 1953, not only overseeing the formation of the early Otolaryngology Section but also laying the foundation of the otolaryngology residency program. Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota.

Throughout the 1920s, the primary teaching method in otolaryngology continued to be the apprenticeship model—the traditional teaching method since the beginning of medical education in the United States. However, in a 1924 report to the Mayo Clinic Board of Governors, department chair Dr Harold I. Lillie refined the definition of the apprenticeship model (Figure 5). Instead of the traditional one-on-one relationship between master and apprentice in which learning relied almost exclusively on direct observation and was limited by the abilities and teaching inclinations of the master,17 apprenticeship in otolaryngology at Mayo Clinic meant “being made responsible for a patient and his care under the direction of the consultant’s advice,”18 thus establishing the backbone of ENT training to the present time and giving a nod to the hands-on learning directly advocated by the Mayo brothers.19Figure 5 Harold I. Lillie, MD, served as the department chair from 1919 to 1953, not only overseeing the formation of the early Otolaryngology Section but also laying the foundation of the otolaryngology residency program. Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota. At the time, the arrangement between staff and their fellows was symbiotic—the fellows benefited from graduated educational experiences and faculty mentorship: “The men are gradually allowed to assume responsibilities under surveillance commensurate with their ability to do so.”18 However, equally so, the faculty benefited from the fellows’ execution of menial service tasks so that they might have more time for “thought, study, and preparation of articles for publication.”18 Thus, although there was no question about the dedication of faculty to the education of their trainees, the driving force behind the number of fellows accepted each year closely paralleled clinical volume and the need for assistance with routine work.

or “thought, study, and preparation of articles for publication.”18 Thus, although there was no question about the dedication of faculty to the education of their trainees, the driving force behind the number of fellows accepted each year closely paralleled clinical volume and the need for assistance with routine work. It was not until 1938 that a curriculum beyond case work was mentioned in the annual departmental report to the Board of Governors: “Individual case demonstrations [have] proven to be the most satisfactory of teaching the fellowship men. Courses of reading are suggested. Seminars will be inaugurated this year.”18 The inauguration of seminars in 1938 may have been a reaction to outside pressure throughout the 1920s and 1930s for accountability and standardization. In 1924, the National Board of Examiners in Otolaryngology was established in part to “produce a safe and sane man to practice in the specialty.”7 Graduates now had to demonstrate competence before they were allowed to practice independently. On the program side, in 1928, the American Medical Association published “Essentials of Approved Residencies and Fellowships”20—the first published standard for residency and fellowship programs. Later, in 1939, the American College of Surgeons (ACS) published “Graduate Training for General Surgery and the Surgical Specialties,”21 spelling out what was or should be required of both hospitals and the residents to make a successful residency.

”20—the first published standard for residency and fellowship programs. Later, in 1939, the American College of Surgeons (ACS) published “Graduate Training for General Surgery and the Surgical Specialties,”21 spelling out what was or should be required of both hospitals and the residents to make a successful residency. Interestingly, the focus of the ACS requirements was quite different from today’s accreditation requirements. In particular, they did not address what the program was supposed to provide for the trainee. Rather, even when discussing what the program should consist of, the ACS addressed the trainee directly and pointedly: it is the trainee’s responsibility to provide everything they need to succeed, including keeping a record of their progress and periodically submitting “for the consideration of their preceptors a prescribed summary of their work.”21 In contrast, once accreditation became a requirement, the onus was put fully on the program to not only provide requisite resources but to also ensure that the residents made full use of them.

of their progress and periodically submitting “for the consideration of their preceptors a prescribed summary of their work.”21 In contrast, once accreditation became a requirement, the onus was put fully on the program to not only provide requisite resources but to also ensure that the residents made full use of them. The road to accreditation was not newly paved in the 1920s and 1930s. Solid steps had been taken as early as 1896 when what is now named the American Academy of Otolaryngology-Head and Neck Surgery was established, which led to the first specialty boards—ophthalmology in 1916 and otolaryngology in 1924.22 Furthermore, individual states enacted legislation requiring licensure of physicians beginning in the late 1800s. In 1887, Minnesota was the first to enact a law requiring a minimum of medical education prior to practicing.23 With licensure came examinations and the boards, and accreditation would follow. The Road to Accreditation The Mayo Clinic otolaryngology residency program was first accredited in 1952 by what would eventually become the Accreditation Council for Graduate Medical Education. To reach accreditation, however, the program had to traverse declining interest, turf battles, radical changes in otolaryngology as a practice, and a devastating world war.

aryngology residency program was first accredited in 1952 by what would eventually become the Accreditation Council for Graduate Medical Education. To reach accreditation, however, the program had to traverse declining interest, turf battles, radical changes in otolaryngology as a practice, and a devastating world war. Throughout the early 1940s, the annual reports to the Mayo Clinic Board of Governors were filled with roll calls of able-bodied otolaryngologists and fellows who were already commissioned by the military and contingency plans if they were all called to duty. The worst-case scenario saw one surgeon, Dr H. I. Lillie, who would do surgery all day and one medical otolaryngologist, Dr B. E. Hempstead, who would consult in the office all day, noting, “It is certain, however, that the service to the patients in general will suffer greatly because it will be physically impossible for two consultants adequately to perform the duties of six consultants.”24 The report continued, “It may be difficult to obtain physicians on the fellowship services unless certain ones who [cannot] meet the physical requirements of the military services apply.” Thus, by 1943, it was noted that all fellows except for one were exempt from military service “due to physical defects,” and the one who would meet the military’s physical requirements was not a naturalized citizen.

ervices unless certain ones who [cannot] meet the physical requirements of the military services apply.” Thus, by 1943, it was noted that all fellows except for one were exempt from military service “due to physical defects,” and the one who would meet the military’s physical requirements was not a naturalized citizen. During this stressful time, Dr H. I. Lillie noted, “For some unknown reason, perhaps the general nervous tension, there has crept into the service a spirit of rivalry never previously encountered.” He continued, “Under the present stress of the national emergency I do not propose to make any radical changes in the personnel, but if the relationship does not change, a change may be urged.” In the same report, he lamented that the fellowship left “much to be desired and there seems no way immediately in the future to correct the situation.” By the end of the war, however, a “notable improvement in the esprit de corps” came with a salary adjustment and a return to regular vacation time.24 Not only was the department able to stay staffed throughout the war, but patient and surgical counts did not plummet as originally projected. The training program continued throughout the war even when Drs H. L. Williams, K. M. Simonton, H. A. Brown, and O. E. Hallberg were called to service in 1940.

r vacation time.24 Not only was the department able to stay staffed throughout the war, but patient and surgical counts did not plummet as originally projected. The training program continued throughout the war even when Drs H. L. Williams, K. M. Simonton, H. A. Brown, and O. E. Hallberg were called to service in 1940. World War II was not the only strain on attracting “suitable men…applying for training in ear, nose, and throat.” This time, the deficiency was due to the changing nature of the otolaryngology practice, as well as the changing landscape of medical education on the whole. For one thing, there was more competition for fellows “because of the influence of American Examination Board [sic]” and more “available opportunities for training more men in the field.”24 Furthermore, because other otolaryngology programs across the United States were aggressively expanding specialty jurisdiction through turf battles with rivaling specialties, the most “suitable men” were seeking their education at other programs with greater training opportunities (H. B. Neel III, MD, written communication, undated). It was during this time that a turf contest between otolaryngology and neurosurgery developed in the years prior to the United States joining World War II, climaxing in 1939-1940 when Dr H. I. Lillie declared that “the attitude of the chief of neural surgery is unreasonable.”24 A year later, the controversy had not been resolved:

ng this time that a turf contest between otolaryngology and neurosurgery developed in the years prior to the United States joining World War II, climaxing in 1939-1940 when Dr H. I. Lillie declared that “the attitude of the chief of neural surgery is unreasonable.”24 A year later, the controversy had not been resolved: No disposition has been made of the controversy between the ear, nose and throat staff and the neural surgical staff. The matter has been brought to the attention of [the Board of Governors] on previous occasions. The relationship is not too cordial and there is always evident some restraint which may be detrimental to the patient’s welfare. If credit could be given where credit might belong, it might make possible a better service to the patient. Unjust criticism of technical procedures in which there is no unanimity of opinion among the profession is not conducive to cordiality.24

evident some restraint which may be detrimental to the patient’s welfare. If credit could be given where credit might belong, it might make possible a better service to the patient. Unjust criticism of technical procedures in which there is no unanimity of opinion among the profession is not conducive to cordiality.24 Thereafter, when discussing “Relationship to Other Departments, Hospitals, and Institutions” (a regular section in the report to the Board of Governors), Dr Lillie repeated the same paragraph each year word-for-word: “There has been no interruption in the hospital consultation services. Every effort is made to co-operate with other services. We are in turn deeply appreciative of the fine co-operation that has been extended to this service. It is my feeling that all extramural relationships are cordial.”24 No mention of an actual solution was ever made; however, it was clear in subsequent reports that otolaryngology and neurosurgery reestablished a clear and mutually beneficial clinical partnership.

ine co-operation that has been extended to this service. It is my feeling that all extramural relationships are cordial.”24 No mention of an actual solution was ever made; however, it was clear in subsequent reports that otolaryngology and neurosurgery reestablished a clear and mutually beneficial clinical partnership. The otolaryngology section at Mayo Clinic was slow in responding to the need to grow subspecialties and consolidate regardless of turf wars. While today otolaryngology-head and neck surgery as a specialty is generally divided into 7 subspecialties—otology/neurotology, rhinology, laryngology, head and neck surgery, pediatric otolaryngology, facial plastic reconstruction, and sleep surgery—in the first half of the 20th century at Mayo Clinic only a few physicians aligned themselves with a subspecialty now linked to otolaryngology, and they were in different sections apart from otolaryngology. The 1941 Board of Governors report appears to be the first to mention a “gradual splitting off from the service of certain borderline types of conditions.” Certainly, trends foreshadowing this split, not just at Mayo Clinic but within otolaryngology as a whole, had been in sight for several years, starting with the advent of sulfonamides and penicillin, which by curing infections without surgery, reduced the surgical volume for otolaryngology residents and consultants alike.19 Throughout the 1940s, concerns were raised that fellows had insufficient surgical experience in cases such as mastoidectomies because of new medical rather than surgical treatment. Indeed, by 1949, the consensus was that “outstanding men in the field will need to have very broad medical background training and the borderline surgical fields will be included in the scope of the specialty.”24

surgical experience in cases such as mastoidectomies because of new medical rather than surgical treatment. Indeed, by 1949, the consensus was that “outstanding men in the field will need to have very broad medical background training and the borderline surgical fields will be included in the scope of the specialty.”24 At this point in time, programs at other institutions, such as the universities of Iowa, Michigan, Illinois, and Pennsylvania, were already transitioning, broadening the scope of their training. At Mayo Clinic, Dr Lillie was fighting the tendency to confine specialty surgical fields “to structures within the mucocutaneous margin of the involved anatomic structures,” declaring it “too arbitrary and actually a very short-sighted and silly position to take.” Specialists, he argued, required the same medical education and training as general surgeons. Thus, the focus after World War II was “centered on arranging the teaching of fellowship men on a curriculum which will conform to that suggested by the American Board of Otolaryngology,” and research work for the consultants was suspended while they worked at reorganizing the program. Such a narrow definition of the practice, he argued, would result in a decline in the number of future physicians going into otolaryngology and thus future fellows, a possibility “looked upon with increasing apprehension by the older staff members.”24

ultants was suspended while they worked at reorganizing the program. Such a narrow definition of the practice, he argued, would result in a decline in the number of future physicians going into otolaryngology and thus future fellows, a possibility “looked upon with increasing apprehension by the older staff members.”24 Certainly, in Dr Lillie’s last report to the Board of Governors in 1950 before Dr H. L. Williams became the department chairman, he wondered why so few graduates were seeking training in otolaryngology. The demand, he noted, was there. Salaries were $9000 to $15,000, and the “auspices are all that could be desired.” Still, at the time there was only one fellow on board, and he would be completing his training the following October. Dr Lillie admitted that “the glamor of the surgery has lessened, as it has in all training centers,” but he noted the way the specialty had developed to interrelate general medical problems with otolaryngological disorders made training in otolaryngology “well-rounded…‘doctors’ first and ‘specialists’ secondarily.”24 No longer regarding the fellows as “filler-ins,”18 a second pair of hands for the consultant, the focus was now on their training, noting that required case presentations, examinations by the American Board, library work, and editing their “literary efforts” were all beneficial for their education.24

s’ secondarily.”24 No longer regarding the fellows as “filler-ins,”18 a second pair of hands for the consultant, the focus was now on their training, noting that required case presentations, examinations by the American Board, library work, and editing their “literary efforts” were all beneficial for their education.24 Throughout the 1940s, suggested reading schedules and didactic seminars—sometimes with extramural speakers and including instruction in anatomy and pathology—supplemented traditional clinical and surgical hands-on training, and by 1952, the program was accredited. Having accomplished this noteworthy feat, Dr H. I. Lillie retired from Mayo Clinic in 1953 after serving 34 years as department chair and died at home in 1957.25

and including instruction in anatomy and pathology—supplemented traditional clinical and surgical hands-on training, and by 1952, the program was accredited. Having accomplished this noteworthy feat, Dr H. I. Lillie retired from Mayo Clinic in 1953 after serving 34 years as department chair and died at home in 1957.25 Glimmers of the Future Accreditation Another era of change was upon the otolaryngology residency program after Dr H. I. Lillie stepped down. The 1950s and 1960s swirled with challenges and threats, as well as possibility and promise. In the 1950s, the ENT department was solidly split into 2—a consequence of events that can be traced to the beginnings of Mayo Clinic. Approximately a decade after the doors of Saint Marys Hospital officially opened, a number of physicians were hired to manage conditions that overlapped with the modern otolaryngology practice: Drs J. Matthews and Gordon B. New, laryngology and rhinology; Dr Carl Fisher, ophthalmology and otology; Dr Henry S. Plummer, upper aerodigestive endoscopy and thyroid disease; and Drs Edward Starr Judd and Walter E. Sistrunk, head and neck tumors.19 Although this increase in staff would seem to be the start of a cohesive, modern ENT department, in fact these surgeons were instead divided between surgical specialties. At the time, there was really no way to anticipate how the ENT specialty would come together, encompassing otology, rhinology, laryngology, head and neck surgery, and more. The only permanent separation in this group would eventually be ophthalmology.

ct these surgeons were instead divided between surgical specialties. At the time, there was really no way to anticipate how the ENT specialty would come together, encompassing otology, rhinology, laryngology, head and neck surgery, and more. The only permanent separation in this group would eventually be ophthalmology. In 1917, ENT was further transformed after the affiliation between Mayo Clinic and the University of Minnesota was made permanent and with the formal establishment of a separate Section on Laryngology, Oral and Plastic Surgery headed by Dr G. B. New, while Dr Lillie was appointed otolaryngology section head. At this point, it was stipulated that two-thirds of laryngology cases would go to the new laryngology section with the remainder going to otolaryngology and rhinology. However, the other third often did not carry over.19 Indeed, in 1937, Dr Lillie reinforced the division: “This understanding has never been insisted upon because as the work developed it was found that the paranasal sinus and the ear work so greatly increased that it was impossible to consider doing any operative laryngology. Operative laryngology is done so well in the other section this understanding has been overlooked.”18

s understanding has never been insisted upon because as the work developed it was found that the paranasal sinus and the ear work so greatly increased that it was impossible to consider doing any operative laryngology. Operative laryngology is done so well in the other section this understanding has been overlooked.”18 Unfortunately, this division would prove severely detrimental to the residency training program. In Dr Williams’ first report to the Board of Governors in 1952, he noted a “waning spirit of co-operation between the two sections as far as the training program for fellowship men in our specialty was concerned.”24 The Section on Laryngology, Oral and Plastic Surgery had developed their own fellowship program in plastic surgery, and the time the otolaryngology residents spent in that section was cut from 1 year to 6 months. Opportunities for the otolaryngology residents for observation and training during that 6 months were limited, and, Dr Williams noted, “it seemed to me at times that the Section on Laryngology, Oral and Plastic Surgery was attempting to deny their share of the responsibility for the fellowship in otology, rhinology and laryngology.” At the same time in other institutions, the specialty was expanding to include areas that were divided at Mayo Clinic, such as skull base surgery, head and neck surgery, and facial trauma. Otolaryngology at Mayo Clinic was, in Dr Williams’ words, “deteriorating not only relatively to [other institutes’ training programs] but absolutely.”18

ther institutions, the specialty was expanding to include areas that were divided at Mayo Clinic, such as skull base surgery, head and neck surgery, and facial trauma. Otolaryngology at Mayo Clinic was, in Dr Williams’ words, “deteriorating not only relatively to [other institutes’ training programs] but absolutely.”18 After negotiations with the Section on Laryngology, Oral and Plastic Surgery, including a vetoed suggestion that the 2 fellowships be combined under the Section on Otolaryngology and Rhinology, the situation remained virtually status quo except that fellows were able to spend a full year in laryngology, and assurances were given that the otolaryngology fellows would have the same learning opportunities as the fellows in plastic surgery.

ellowships be combined under the Section on Otolaryngology and Rhinology, the situation remained virtually status quo except that fellows were able to spend a full year in laryngology, and assurances were given that the otolaryngology fellows would have the same learning opportunities as the fellows in plastic surgery. Despite the division, the otolaryngology residency program made do with the resources available. At this time, training encompassed a year in the Section on Laryngology, Oral and Plastic Surgery, 6 months of training in pathology, regular Tuesday evening seminars consisting of case presentations by the residents and lectures by staff, dissections in the Anatomy Laboratory including cadaver surgery and practice with surgical flaps, suturing, and knot tying, and training in medical otolaryngology and allergy treatments. While the Section on Laryngology, Oral and Plastic Surgery focused on and advanced treatments for sinus, pharynx, and larynx malignancies and other surgeries, the Section on Otolaryngology and Rhinology was tackling deafness and vestibular disorders, a patient population that had few, if any, options prior to this era and was regularly turned away from Mayo Clinic. The rise of this field kept a portion of the specialty in the operating room with canal fenestrations, mastoidectomies, and labyrinthectomies. At the same time, relationships with otology and neurosurgery had improved enough that they were able to collaborate on certain conditions, such as Bell palsy and hemifacial spasm.24

ise of this field kept a portion of the specialty in the operating room with canal fenestrations, mastoidectomies, and labyrinthectomies. At the same time, relationships with otology and neurosurgery had improved enough that they were able to collaborate on certain conditions, such as Bell palsy and hemifacial spasm.24 Unfortunately, this richness in education was precariously dependent on interdepartmental cooperation, especially with what could be viewed as competing fellowships, so while Dr Williams declared in 1953, “The future of otology, rhinology, and laryngology…never seemed brighter,” he followed quickly with: It is very important that the associations between the Sections on Otolaryngology and Rhinology and of Plastic Surgery and Laryngology be maintained at the present cordial level or even better strengthened. With the opportunities for fellowship training that are offered elsewhere, we will not be able to obtain the most desirable type of man for our fellowship unless we are able to offer them training in the surgical care of malignancies of the head and neck, otolaryngologic plastic surgery, repair of injuries in the region of the head and neck and bronchoscopy commensurate with that received elsewhere.24 As soon as the following year, the Council on Medical Education and Hospitals of the American Medical Association made “inquiries in regard to the actual amount of surgery done by our fellows.”24 Thus began a threat to program accreditation.

It is very important that the associations between the Sections on Otolaryngology and Rhinology and of Plastic Surgery and Laryngology be maintained at the present cordial level or even better strengthened. With the opportunities for fellowship training that are offered elsewhere, we will not be able to obtain the most desirable type of man for our fellowship unless we are able to offer them training in the surgical care of malignancies of the head and neck, otolaryngologic plastic surgery, repair of injuries in the region of the head and neck and bronchoscopy commensurate with that received elsewhere.24 As soon as the following year, the Council on Medical Education and Hospitals of the American Medical Association made “inquiries in regard to the actual amount of surgery done by our fellows.”24 Thus began a threat to program accreditation. In 1954, Dr Williams frankly noted that “all of our fellows are not equally competent,” that cadaver studies could be a partial solution, but it was “impossible to obtain the necessary anatomic material.”24 Furthermore, he cited the decline in resident surgical experience as stemming from a “continued attrition in the numbers of surgical patients” with the introduction of antibiotics. Furthermore, he noted that surgical numbers were divided between “too many individuals so that it is difficult for one man to develop outstanding skill.” This then affected referrals (and eventually surgical experience for the fellows), which had also declined, because none of their individual surgeons were “well-known” enough: “It is possible that the levelling process in our section has been carried too far.” He went on to cite a lack of control in distributing surgical cases and an “unusual amount of unused time” or overstaffing in the department. Again, he suggested the consolidation of the 2 sections, to which one of the reviewers from the Board of Governors responded in the margin, “This seems so logical, I wonder it has not been accomplished long ago.”24

in distributing surgical cases and an “unusual amount of unused time” or overstaffing in the department. Again, he suggested the consolidation of the 2 sections, to which one of the reviewers from the Board of Governors responded in the margin, “This seems so logical, I wonder it has not been accomplished long ago.”24 The next few years are a testament to increasing pressure from the Board of Otolaryngology and competition from other medical institutions that were expanding their training programs to 4 and 5 years. Dr Williams remarked in his 1956 report, “I fear that some time in the near future the Board of Otolaryngology will pronounce our training program inadequate.” He defended the training program, although revealing his own innate prejudices at the same time: “[Other institutions] are training head and neck surgeons rather than otorhinolaryngologists. These men must sit around their offices until someone refers them a malignancy and would prove inadequate in general practice of the specialty.”24 The noose tightened the following year when the American Board of Otolaryngology required that candidates for board certification would need to be prepared in otology, rhinology, laryngology, bronchoscopy, and surgery for nose, sinus, and pharyngeal malignancies. The following year, a fourth year in general surgery would be required.24

ed the following year when the American Board of Otolaryngology required that candidates for board certification would need to be prepared in otology, rhinology, laryngology, bronchoscopy, and surgery for nose, sinus, and pharyngeal malignancies. The following year, a fourth year in general surgery would be required.24 When Dr K. M. Simonton took over the chairmanship from Dr Williams in 1958, he acknowledged a core deficiency in the training program to the Board of Governors: “Our surgical training is considered by the fellows to be one of the weak points of the program. This is the result of the nature of our practice.” However, Dr Simonton pointed out that cadaver dissection and a program for teaching microsurgery of the ear were instituted just a few years before to help bolster surgical training and asserted that the “surgical competence of the men who have finished the training course in the past” was an indication of the success of the program.24

ton pointed out that cadaver dissection and a program for teaching microsurgery of the ear were instituted just a few years before to help bolster surgical training and asserted that the “surgical competence of the men who have finished the training course in the past” was an indication of the success of the program.24 Perhaps a little paradoxically, it was during this rather austere time in the Mayo ENT residency program that a slow but significant practice change was happening, which would affect the residency for years to come. Otorhinolaryngology as a specialty, it seemed, was deemed desirable because of the varied surgical experience, and physicians who had been trained in ENT were interested in practicing the full breadth of the evolving specialty. The division in the department meant the ENT side was limited with few, if any, laryngology, head and neck, facial trauma, and other procedures. As late as 1958, Dr Williams was bemoaning the limitations put on the practices of ENT residents at Mayo, thus limiting recruitment. However, just a year later, Dr Simonton noted a “gradual division of surgical work” taking place in the department. Otorhinolaryngology surgeons were subspecializing into rhinologists, laryngologists, and otologists.24 This trend had been gathering momentum for many years—for example with Dr J. Lillie specializing in laryngologic surgery—but the value of subspecialization was just being recognized. With this shift, Mayo ENT surgeons were able to carve out a name for themselves within their subspecialty, thereby increasing referrals and recognition of the ENT department at Mayo Clinic. In turn, the residency program was able to take advantage of this depth of knowledge and change its system of rotations. Starting in 1960, fellows would work with one staff member per quarter. In this way, the fellow would gain experience working among the staff members throughout the department, an innovation on the preceptorship style of education that removed the risk of limited experience for the fellow who worked with a single mentor throughout training.24 This system of rotations has carried through to the present day, with residents training in each of the subspecialities by working one-on-one with a physician in that subspeciality for 3 months at a time throughout their residency and getting multiple perspectives on a wide array of cases.

mentor throughout training.24 This system of rotations has carried through to the present day, with residents training in each of the subspecialities by working one-on-one with a physician in that subspeciality for 3 months at a time throughout their residency and getting multiple perspectives on a wide array of cases. Unfortunately, back in the 1960s, this innovation was not enough. After a review of the training program in 1961 by the Residency Review Committee (RRC), concern was officially raised about the amount of hands-on surgical training offered in the program. With that concern raised, the American Board of Otolaryngology “insisted that we broaden the scope of our training.”24 By 1962, the program was on probation.

ning program in 1961 by the Residency Review Committee (RRC), concern was officially raised about the amount of hands-on surgical training offered in the program. With that concern raised, the American Board of Otolaryngology “insisted that we broaden the scope of our training.”24 By 1962, the program was on probation. Probation Although formal accreditation was initiated in 1952, the Mayo Foundation appeared on the list of “Approved Residencies and Fellowships” for some time before that. In the 1942-1943 edition, “Mayo Foundation Fellowships—The Mayo Foundation for Medical Education and Research, Rochester, Minn., under the direction of D. C. Balfour” offered approved, 3-year fellowships in coordination with the University of Minnesota. These fellowships were in anesthesia, dermatology and syphilology, internal medicine, neurology and psychiatry, neurosurgery, obstetrics and gynecology, ophthalmology, orthopedic surgery, otolaryngology, pathology, pediatrics, physical medicine, plastic surgery, proctology, radiology, surgery, and urology with a stipend of $900 per year.26 The listings of approved residencies at Mayo Clinic changed little over time, even when the residency program went on probation for 5 years.

logy, orthopedic surgery, otolaryngology, pathology, pediatrics, physical medicine, plastic surgery, proctology, radiology, surgery, and urology with a stipend of $900 per year.26 The listings of approved residencies at Mayo Clinic changed little over time, even when the residency program went on probation for 5 years. After the warning in 1961, it was official: “Our program has been placed on probation by the Residency Review Committee. The reason for the probation is that we have not been providing surgical experience that is comparable to other institutions.” Dr Simonton cited 2 distinct reasons for the probation in a letter to the Board of Governors. First, unlike today when institutions like Mayo Clinic are clearly teaching institutes and patients understand up front that they will be working with fellows and residents under a consultant’s supervision, there was a hesitancy to turn patients over to residents for surgery because Mayo Clinic was a private practice. Interestingly, this was counter to previous concerns throughout the 1920s that patients would consider the fellows to be their doctors, which at the time was considered detrimental to Mayo Clinic. Second, as always, the division of labor between the ENT section and the general surgery section (neck dissection and salivary gland surgery), the Department of Plastic Surgery (head and neck tumor surgery), the medical chest section (peroral endoscopy), and the allergy section clearly reduced hands-on experience in the operating room.

, the division of labor between the ENT section and the general surgery section (neck dissection and salivary gland surgery), the Department of Plastic Surgery (head and neck tumor surgery), the medical chest section (peroral endoscopy), and the allergy section clearly reduced hands-on experience in the operating room. Measures were put in place to mitigate the dissatisfaction of the RRC. In 1964, the fourth-year fellows were assigned to outside institutions as far away as Shreveport, Louisiana, for a 6-month rotation to get training and experience in neck dissection and head and neck oncology. Furthermore, “certain selected fellows with above-average ability” would get “some improvement” in neck dissection with Dr O. H. Beahrs in general surgery.24 However, even when the fellows were receiving the required training in all areas of ENT by placement with other institutes and other departments within Mayo Clinic, the probationary status remained intact because “a relatively small proportion of the training required for certification in Otolaryngology” was being managed by the otolaryngology section itself. Dr Simonton noted that reorganizing the otolaryngology section would require “some change in the basic philosophy of the Clinic which has been to have one area of work done entirely by one group.” He also revealed that a plan from the previous year to reassure the RRC had failed. Placing Dr Devine’s and Dr Lillie’s names on otolaryngology departmental letterhead “was recognized for what it is…‘lip service.’ ”24

he basic philosophy of the Clinic which has been to have one area of work done entirely by one group.” He also revealed that a plan from the previous year to reassure the RRC had failed. Placing Dr Devine’s and Dr Lillie’s names on otolaryngology departmental letterhead “was recognized for what it is…‘lip service.’ ”24 By 1967, changes were under way. Leadership of the department was about to change from Dr Simonton to Dr Thane Cody. Drs K. Devine and J. Lillie were moving into the Department of Otorhinolaryngology, leaving the Department of Plastic Surgery. In addition, Dr Beahrs agreed to allow the department to approach “a promising general surgical resident” for a combined training program in general surgery and otolaryngology, which would lead to a position in otolaryngology with the express purpose of performing radical neck dissections and salivary gland procedures.24 The following year, Dr L. DeSanto joined ENT. In addition, a Chief Residency Program was well under way, opening up patients’ willingness to be treated by residents. In 1968, the ENT residency program averted the threatened shutdown, instead receiving the “full approval of the Residency Review Committee.”

procedures.24 The following year, Dr L. DeSanto joined ENT. In addition, a Chief Residency Program was well under way, opening up patients’ willingness to be treated by residents. In 1968, the ENT residency program averted the threatened shutdown, instead receiving the “full approval of the Residency Review Committee.” Later accounts of how the section overcame probation are varied. One account even goes so far as to state that neither the ENT department nor Mayo Clinic was aware of the residency’s probationary status (T. J. McDonald, MD, written communication, June 17, 2002).19 In truth, the Board of Governors was notified before probation and given updates as the department worked through the problem. In Dr K. M. Simonton’s unpublished memoir of his time at Mayo Clinic, he credits incoming chair Dr Cody with bringing the department together and recruiting the needed faculty.27 However, a careful reading of the 1967 report to the Board of Governors indicates that Dr Simonton, still the chair of the department, would have played a large part in the process. Undoubtedly, he and Dr Cody worked together with the other members of the education committee, but another hint comes in 1973 with Dr Cody’s Biennial Department Review, which begins with a retrospective of the history of the ENT department and indicates that the Board of Governors “determined that it was advisable that at least some of the traditional areas of Otorhinolaryngology such as laryngology and head and neck oncology return to the Department of Otorhinolaryngology.” Thus, it may have been the intervention of the Board of Governors itself that finally pulled the section into a distinct, recognizable Department of Otorhinolaryngology.

some of the traditional areas of Otorhinolaryngology such as laryngology and head and neck oncology return to the Department of Otorhinolaryngology.” Thus, it may have been the intervention of the Board of Governors itself that finally pulled the section into a distinct, recognizable Department of Otorhinolaryngology. The Mayo Clinic ENT residency program had made it into the Space Age, but not without hitches. Ten years after coming off its near-terminal probation, the residency program had another brush with the RRC. Being located in a relatively rural area of the country, residents in Rochester were not receiving sufficient surgical education in facial trauma. Otorhinolaryngology was able to establish a practice at Saint Marys Hospital, but because the cases were too few and far between, the partnership with the University of Minnesota, which still conferred the graduate medical degrees from Mayo Clinic, was expanded so that Mayo residents would spend a month at Hennepin County Medical Center to gain that experience. This is a partnership that has lasted to the present day, even after the original agreement with the university was terminated.

nnesota, which still conferred the graduate medical degrees from Mayo Clinic, was expanded so that Mayo residents would spend a month at Hennepin County Medical Center to gain that experience. This is a partnership that has lasted to the present day, even after the original agreement with the university was terminated. Mayo Clinic was expanding, and the medical field itself was booming beyond medical advancements with the rise of pharmaceutical giants and the reign of powerful insurance companies. The regulation and standardization of graduate medical education solidified with the formation of the Accreditation Council for Graduate Medical Education. The ENT residency program at Mayo Clinic expanded from 15 residents per year to a maximum of 25 per year, from 9 teaching staff members in 1970 to 18 in 2018, from 4 years of training to 5 years and encompassing all elements of ENT, from 100 applications per year for residency to over 350. In 1987, Dr H. B. Neel III, was able to note that the residency program had grown to include residents from across the country: “Finally, we have a ‘national’ residency program, I believe.” Graduated Responsibility Throughout the 1970s and 1980s, the Department of Otolaryngology saw department chairs Drs D. T. Cody and H. B. Neel continuing the difficult process of consolidating the ENT practice and recruiting faculty into each of the subspecialties, which significantly broadened the scope of learning for residents.

esponsibility Throughout the 1970s and 1980s, the Department of Otolaryngology saw department chairs Drs D. T. Cody and H. B. Neel continuing the difficult process of consolidating the ENT practice and recruiting faculty into each of the subspecialties, which significantly broadened the scope of learning for residents. By the end of the 1980s, the rotation schedule was set, and with this focused training, residents were able to take on more responsibility for patient care earlier in their residency, which prepared them for their fifth year of residency when they were promoted to Chief Resident Associate in addition to Clinical Instructor and given their own semiautonomous clinic to run side-by-side with faculty. Besides caring for patients in the clinic and achieving near autonomy in the operating room, the chief resident gained enough experience and knowledge to step into the educator role with weekly Chief Resident Associate Grand Rounds and supervising junior residents in the operating room.

o run side-by-side with faculty. Besides caring for patients in the clinic and achieving near autonomy in the operating room, the chief resident gained enough experience and knowledge to step into the educator role with weekly Chief Resident Associate Grand Rounds and supervising junior residents in the operating room. Historically, not all residency structures functioned like this. From the start, the ENT residency program at Mayo Clinic was built on a rectangle system,5,28,29 a system that was formally recognized in 1937 as developed by Edward Delos Churchill but practiced at Mayo Clinic from its initiation.28,30 In contrast, most other institutes across the country practiced the traditional pyramidal (Halsted) system, in which residencies began with a full complement of trainees and then each year trainees would be eliminated until eventually at the end of the residency only the very “best” resident would have completed the program in its entirety.31,32 Although residents who were eliminated from the program were still capable and able to find positions,29 the pyramidal system compounded the already incredible stress and competition of the residency. Arguably, trainees’ concentration was not on patient care; it was on survival. In a rectangular system, all trainees who succeeded and persisted would be assured of the opportunity to complete the residency in its entirety and thus have a full range of prospects after graduation, whether to private practice, academic otolaryngology, or research, which was a late addition to the residency.

rvival. In a rectangular system, all trainees who succeeded and persisted would be assured of the opportunity to complete the residency in its entirety and thus have a full range of prospects after graduation, whether to private practice, academic otolaryngology, or research, which was a late addition to the residency. At the start, residents were generally not involved in research projects at all. Occasionally a “volunteer student” would join the group for a limited time to work on research,33 rather like today’s research fellows. Research was always acknowledged as a benefit both to patient care and to establish Mayo Clinic’s and its physicians’ reputations, but until the arrival of Dr Thane Cody in 1961, research and writing were relegated to physicians’ spare time after clinic hours, which makes the extensive research of early Mayo physicians such as H. I. Lillie, H. F. Wilkinson, and W. B Stark all the more impressive. The only exception to this restriction was granted to Dr Williams, who was allowed to use a portion of his mornings and not report to the clinic on his surgical days so he could work on projects.24 Dr Cody was the first to be hired with the understanding that he would have dedicated research time twice a week, with time funded by grants rather than the department.24 At the same time, he was immediately able to draw residents into his projects, thus opening the residency to fully embrace the research shield, and by the early 1980s, residents were taking significant national honors in research.34

ed research time twice a week, with time funded by grants rather than the department.24 At the same time, he was immediately able to draw residents into his projects, thus opening the residency to fully embrace the research shield, and by the early 1980s, residents were taking significant national honors in research.34 Today, although the residency program is significantly different from more than 100 years ago and while oversight of residencies in the United States has grown into an industry unto itself, many of today’s challenges echo days past (Figure 6). As in the 1920s, great effort is made to recruit the most competent residents, although now concern is primarily recognizing and recruiting talent beyond the “fellow men” of the 20s. As in the 1950s, branding the residency program through recognition of the faculty’s and residents’ accomplishments not just clinically but also in research and education takes effort. In addition, the timeworn frustration of today’s burgeoning administrative duties required of faculty and residents was echoed more than 45 years ago by Dr Cody:Figure 6 Teaching in the operating room now (A) and then (B; circa 1913, Dr Charlie pictured on the right). Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota.

Today, although the residency program is significantly different from more than 100 years ago and while oversight of residencies in the United States has grown into an industry unto itself, many of today’s challenges echo days past (Figure 6). As in the 1920s, great effort is made to recruit the most competent residents, although now concern is primarily recognizing and recruiting talent beyond the “fellow men” of the 20s. As in the 1950s, branding the residency program through recognition of the faculty’s and residents’ accomplishments not just clinically but also in research and education takes effort. In addition, the timeworn frustration of today’s burgeoning administrative duties required of faculty and residents was echoed more than 45 years ago by Dr Cody:Figure 6 Teaching in the operating room now (A) and then (B; circa 1913, Dr Charlie pictured on the right). Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota. Although it is recognized that the committee system is democratic and desirable, anything can be done in excess…. It is my own personal opinion that this Biennial Department Report is an excellent example of how a consultants [sic] time can be wasted by the demands of a committee. Everything in this report…has been presented to various committees or subcommittees, or appeared in annual reports, residency review reports or grant applications. I hope that the committee will see fit to either discontinue the annual report or the biennial review.34

] time can be wasted by the demands of a committee. Everything in this report…has been presented to various committees or subcommittees, or appeared in annual reports, residency review reports or grant applications. I hope that the committee will see fit to either discontinue the annual report or the biennial review.34 Administration of residencies is no longer reliant on the annual departmental report to the sponsoring institution; now there are annual program evaluations, self-studies, site visits, and periodic reviews, as well as monthly reports to maintain oversight, thus opening the door to the education program coordinator role. The ENT residency program at Mayo Clinic found its first official program coordinator in Ms Barbara Chapman, who was in that position for 37 years. In 2019, the residency got a new name, Otolaryngology-Head and Neck Surgery, reflecting the change in the now-called American Board of Otolaryngology-Head and Neck Surgery. Those long familiar initials, ABOto, are now replaced by ABO-HNS, signaling not only the future direction of the residency but also the future of ENT as a specialty.

ency got a new name, Otolaryngology-Head and Neck Surgery, reflecting the change in the now-called American Board of Otolaryngology-Head and Neck Surgery. Those long familiar initials, ABOto, are now replaced by ABO-HNS, signaling not only the future direction of the residency but also the future of ENT as a specialty. Today the “clinic in the cornfield” has grown out of the cornfield, from a home in the Masonic Temple to stretching between more than 65 clinics, warehouses, office buildings, electrical plants, and historical sites throughout the Rochester area, and, of course, beyond Rochester, Minnesota, to Arizona and Florida. As a school of graduate medicine, Mayo has trained more than 23,000 residents and fellows,16 more than 300 of whom have gone through the otolaryngology residency program. Of course, the city of Rochester has grown with Mayo Clinic and all its residency programs and fellowships. The streets are paved, electricity flows, and a bucket and shovel are no longer required to clean up after traffic (Figure 7).Figure 7 A, Downtown Rochester, Minnesota, circa 1902 and present day. B, Saint Marys Hospital, circa 1898 and present day. Reproduced with permission of the W. Bruce Fye Center for the History of Medicine, Mayo Clinic, Rochester, Minnesota. Potential Competing Interests: The authors report no competing interests.