Diversity in Clinical Trials: A Complicated Issue, Not a Simple Solution.

This article is adapted from a speech Ms. Brown-Friday delivered in June 2023 as President, Health Care & Education, of the American Diabetes Association. She delivered her address at the Association's 83rd Scientific Sessions in San Diego, CA. A webcast of this speech is available for viewing on the DiabetesPro website (https://events.diabetes.org/live/25/page/186).

Emotional Distress Predicts Reduced Type 2 Diabetes Treatment Adherence in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: We examined longitudinal associations between emotional distress (specifically, depressive symptoms and diabetes distress) and medication adherence in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing four glucose-lowering medications added to metformin in adults with relatively recent-onset type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The Emotional Distress Substudy assessed medication adherence, depressive symptoms, and diabetes distress in 1,739 GRADE participants via self-completed questionnaires administered biannually up to 3 years. We examined baseline depressive symptoms and diabetes distress as predictors of medication adherence over 36 months. Bidirectional visit-to-visit relationships were also examined. Treatment satisfaction, beliefs about medication, diabetes care self-efficacy, and perceived control over diabetes were evaluated as mediators of longitudinal associations. RESULTS: At baseline, mean ± SD age of participants (56% of whom were White, 17% Hispanic/Latino, 18% Black, and 66% male) was 58.0 ± 10.2 years, diabetes duration 4.2 ± 2.8 years, HbA1c 7.5% ± 0.5%, and medication adherence 89.9% ± 11.1%. Higher baseline depressive symptoms and diabetes distress were independently associated with lower adherence over 36 months (P < 0.001). Higher depressive symptoms and diabetes distress at one visit predicted lower adherence at the subsequent 6-month visit (P < 0.0001) but not vice versa. Treatment assignment did not moderate relationships. Patient-reported concerns about diabetes medications mediated the largest percentage (11.9%-15.5%) of the longitudinal link between emotional distress and adherence. CONCLUSIONS: Depressive symptoms and diabetes distress both predict lower adherence to glucose-lowering medications over time among adults with T2DM. Addressing emotional distress and concerns about anticipated negative effects of taking these treatments may be important to support diabetes treatment adherence.

Study Protocol Using Cohort Data and Latent Variable Modeling to Guide Sampling Women With Type 2 Diabetes and Depressive Symptoms.

BACKGROUND: Depression affects one in three women with Type 2 diabetes, and this concurrence significantly increases the risks of diabetes complications, disability, and early mortality. Depression is underrecognized because of wide variation in presentation and the lack of diagnostic biomarkers. Converging evidence suggests inflammation is a shared biological pathway in diabetes and depression. Overlapping epigenetic associations and social determinants of diabetes and depression implicate inflammatory pathways as a common thread. OBJECTIVES: This article describes the protocol and methods for a pilot study aimed to examine associations between depressive symptoms, inflammation, and social determinants of health among women with Type 2 diabetes. METHODS: This is an observational correlational study that leverages existing longitudinal data from the Women's Interagency HIV Study (WIHS), a multicenter cohort of HIV seropositive (66%) and HIV seronegative (33%) women, to inform purposive sampling of members from latent subgroups emergent from a prior retrospective cohort-wide analysis. Local active cohort participants from the Bronx study site are then selected for the study. The WIHS recently merged with the Multicenter Aids Cohort Study (MACS) to form the MACS/WIHS Combined Cohort Study. Latent subgroups represent distinct symptom trajectories resultant from a growth mixture model analysis of biannually collected depressive symptom data. Participants complete surveys (symptom and social determinants) and provide blood samples to analyze plasma levels and DNA methylation of genes that encode for inflammatory markers (CRP, IL-6, TNF-α). Correlation and regression analysis will be used to estimate the effect sizes between depressive symptoms and inflammatory markers, clinical indices (body mass index, hemoglobin A1C, comorbidities), and social determinants of health. RESULTS: The study began in January 2022, and completed data collection is estimated by early 2023. We hypothesize that depressive symptom severity will associate with higher levels of inflammation, clinical indices (e.g., higher hemoglobin A1C), and exposure to specific social determinants of health (e.g., lower income, nutritional insecurity). DISCUSSION: Study findings will provide the basis for future studies aimed at improving outcomes for women with Type 2 diabetes by informing the development and testing of precision health strategies to address and prevent depression in populations most at risk.

Emotional distress, self-management, and glycemic control among participants enrolled in the glycemia reduction approaches in diabetes: A comparative effectiveness (GRADE) study.

OBJECTIVE: We examined emotional distress in relation to metformin adherence, overall diabetes self-management, and glycemic control among adults with early type 2 diabetes (T2DM) enrolled in the GRADE study. METHODS: Linear regression models examined cross-sectional associations of baseline depression symptoms and diabetes distress with adherence to metformin, self-management, and HbA1c, adjusting for covariates. Cognitive-affective (e.g., sadness) and somatic (e.g., sleep/appetite disturbance) depression symptoms and diabetes distress subscales were also examined. RESULTS: This substudy of 1,739 GRADE participants (56 % Non-Hispanic White, 18 % Non-Hispanic Black, 17 % Hispanic, 68 % male, mean[SD] age = 57.96[10.22] years, diabetes duration = 4.21[2.81] years, and HbA1c = 7.51[0.48]) found that the prevalence of clinically significant depression and diabetes distress was 8.7 % and 25 %, respectively. Fully adjusted models showed that depression symptoms were associated with lower self-management (p < 0.0001); this effect was only significant for somatic symptoms. Diabetes distress was associated with lower adherence (p = 0.0001) and self-management (p < 0.0001); effects were significant for all subscales, except physician-related distress. No significant relationships of total depression symptom severity or diabetes distress with HbA1c were found. CONCLUSIONS: Depression symptoms and diabetes distress were robustly associated with problematic diabetes self-management among participants in GRADE. These findings highlight the need for routine assessment of depression symptoms and diabetes distress early in T2DM care.

Resilience and Optimism as Moderators of the Negative Effects of Stigma on Women Living with HIV.

Resilience and optimism may not only have main effects on health outcomes, but may also moderate and buffer negative effects of stressors. We examined whether dispositional resilience and optimism moderate the associations between HIV-related stigma in health care settings and health-related outcomes (trust in HIV health care providers and depression symptoms) among women living with HIV (WLHIV). One thousand four hundred five WLHIV in nine US cities completed validated questionnaires for cross-sectional analyses. Higher self-reported experienced and anticipated stigma and lower resilience and optimism were associated with higher depression symptoms and with lower trust in HIV providers. Importantly, resilience moderated the effects of experienced stigma (but not of anticipated stigma): When resilience was high, the association of experienced stigma with higher depression symptoms and lower trust in HIV providers was weaker compared with when resilience was low. Further, significant moderation effects suggested that when optimism was high, experienced and anticipated stigma was both less strongly associated with depression symptoms and with lower trust in one's HIV care providers compared with when optimism was low. Thus, the effects of experienced stigma on depression symptoms and provider trust were moderated by both resilience and optimism, but the effects of anticipated stigma were moderated only by optimism. Our findings suggest that in addition to their main effects, resilience and optimism may function as buffers against the harmful effects of stigma in health care settings. Therefore, optimism and resilience may be valuable intervention targets to reduce depression symptoms or improve trust in providers among populations that experience or anticipate stigma, such as WLHIV.

Predictors of sustained reduction in energy and fat intake in the Diabetes Prevention Program Outcomes Study intensive lifestyle intervention.

BACKGROUND: Few lifestyle intervention studies examine long-term sustainability of dietary changes. OBJECTIVE: To describe sustainability of dietary changes over 9 years in the Diabetes Prevention Program and its outcomes study, the Diabetes Prevention Program Outcomes Study, among participants receiving the intensive lifestyle intervention. DESIGN: One thousand seventy-nine participants were enrolled in the intensive lifestyle intervention arm of the Diabetes Prevention Program; 910 continued participation in the Diabetes Prevention Program Outcomes Study. Fat and energy intake derived from food frequency questionnaires at baseline and post-randomization Years 1 and 9 were examined. Parsimonious models determined whether baseline characteristics and intensive lifestyle intervention session participation predicted sustainability. RESULTS: Self-reported energy intake was reduced from a median of 1,876 kcal/day (interquartile range [IQR]=1,452 to 2,549 kcal/day) at baseline to 1,520 kcal/day (IQR=1,192 to 1,986 kcal/day) at Year 1, and 1,560 kcal/day (IQR=1,223 to 2,026 kcal/day) at Year 9. Dietary fat was reduced from a median of 70.4 g (IQR=49.3 to 102.5 g) to 45 g (IQR=32.2 to 63.8 g) at Year 1 and increased to 61.0 g (IQR=44.6 to 82.7 g) at Year 9. Percent energy from fat was reduced from a median of 34.4% (IQR=29.6% to 38.5%) to 27.1% (IQR=23.1% to 31.5%) at Year 1 but increased to 35.3% (IQR=29.7% to 40.2%) at Year 9. Lower baseline energy intake and Year 1 dietary reduction predicted lower energy and fat gram intake at Year 9. Higher leisure physical activity predicted lower fat gram intake but not energy intake. CONCLUSIONS: Intensive lifestyle intervention can result in reductions in total energy intake for up to 9 years. Initial success in achieving reductions in fat and energy intake and success in attaining activity goals appear to predict long-term success at maintaining changes.

10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.

BACKGROUND: In the 2.8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term. METHODS: All active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5.7 years (IQR 5.5-5.8). 910 participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group (850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00038727. FINDINGS: During the 10.0-year (IQR 9.0-10.5) follow-up since randomisation to DPP, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years (95% CI 4.1-5.7) in the intensive lifestyle intervention group, 7.8 (6.8-8.8) in the metformin group, and 11.0 (9.8-12.3) in the placebo group. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5.9 per 100 person-years (5.1-6.8) for lifestyle, 4.9 (4.2-5.7) for metformin, and 5.6 (4.8-6.5) for placebo. Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo. INTERPRETATION: During follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Ibuprofen provides analgesia equivalent to acetaminophen-codeine in the treatment of acute pain in children with extremity injuries: a randomized clinical trial.

OBJECTIVES: This study compared the analgesic effectiveness of acetaminophen-codeine with that of ibuprofen for children with acute traumatic extremity pain, with the hypothesis that the two medications would demonstrate equivalent reduction in pain scores in an emergency department (ED) setting. METHODS: This was a randomized, double-blinded equivalence trial. Pediatric ED patients 5 to 17 years of age with acute traumatic extremity pain received acetaminophen-codeine (1 mg/kg as codeine, maximum 60 mg) or ibuprofen (10 mg/kg, maximum 400 mg). The patients provided Color Analog Scale (CAS) pain scores at baseline and at 20, 40, and 60 minutes after medication administration. The primary outcome measured was the difference in changes in pain score at 40 minutes, compared to a previously described minimal clinically significant change in pain score of 2 cm. The difference was defined as (change in ibuprofen CAS score from baseline) - (change in acetaminophen-codeine CAS score from baseline); negative values thus favor the ibuprofen group. Additional outcomes included need for rescue medication and adverse effects. RESULTS: The 32 acetaminophen-codeine and the 34 ibuprofen recipients in our convenience sample had indistinguishable pain scores at baseline. The intergroup differences in pain score change at 20 minutes (-0.6, 95% confidence interval [CI] = -1.5 to 0.3), 40 minutes (-0.4, 95% CI = -1.4 to 0.6), and 60 minutes (0.2, 95% CI = -0.8 to 1.2) were all less than 2 cm. Adverse effects were minimal: vomiting (one patient after acetaminophen-codeine), nausea (one patient after ibuprofen), and pruritus (one after acetaminophen-codeine). The three patients in each group who received rescue medications all had radiographically demonstrated fractures or dislocations. CONCLUSIONS: This study found similar performance of acetaminophen-codeine and ibuprofen in analgesic effectiveness among ED patients aged 5-17 years with acute traumatic extremity pain. Both drugs provided measurable analgesia. Patients tolerated them well, with few treatment failures and minimal adverse effects.

Alcohol consumption and diabetes risk in the Diabetes Prevention Program.

BACKGROUND: Moderate alcohol consumption is associated with a decreased risk of type 2 diabetes in the general population, but little is known about the effects in individuals at high risk of diabetes. OBJECTIVES: The objectives were to determine associations between alcohol consumption and diabetes risk factors and whether alcohol consumption was a predictor of incident diabetes in individuals enrolled in the Diabetes Prevention Program (DPP). DESIGN: DPP participants (n = 3175) had impaired glucose tolerance (2-h glucose: 7.8-11.1 mmol/L), elevated fasting glucose (5.3-7.0 mmol/L), and a body mass index (in kg/m(2)) > or =24. Participants were randomly assigned to placebo, metformin, or lifestyle modification and were followed for a mean of 3.2 y. Alcohol intake was assessed at baseline and year 1 by using a semiquantitative food-frequency questionnaire. Diabetes was diagnosed by annual oral-glucose-tolerance testing and semiannual fasting plasma glucose measurement. RESULTS: Participants who reported higher alcohol consumption tended to be male, older, white, and less obese and to have a higher calorie intake and a higher HDL-cholesterol concentration. Higher alcohol consumption was associated with lower insulin secretion at any level of insulin sensitivity. We found lower incidence rates of diabetes with higher alcohol consumption in the metformin (P < 0.01 for trend) and lifestyle modification (P = 0.02 for trend) groups, which remained significant after adjustment for multiple baseline covariates. No similar association was observed in the placebo group. CONCLUSIONS: Despite overall low rates of alcohol consumption, there was a reduced risk of incident diabetes in those who reported modest daily alcohol intake and were assigned to metformin or lifestyle modification. Moderate daily alcohol intake is associated with lower insulin secretion-an effect that warrants further investigation. This trial was registered at clinicaltrials.gov as NCT00038727.

Evaluating the accuracy of an aneroid sphygmomanometer in a clinical trial setting.

BACKGROUND: The mercury sphygmomanometer, the "gold" standard for blood pressure measurements, has been gradually phased out in many institutions because of environmental concerns. Our on-going clinical trial compared the use of mercury vs. aneroid sphygmomanometers, before implementing a study-wide transition to the aneroid sphygmomanometer. METHODS: The Diabetes Prevention Program Outcomes Study (DPPOS) studied the accuracy of the Welch Allyn Tycos 767-Series Mobile aneroid sphygmomanometer from 20 March 2006 to 21 June 2006 at multiple clinic centers. We compared readings from 997 participants in 24 clinic centers using both mercury and aneroid sphygmomanometers. RESULTS: The study found no statistically significant difference for systolic blood pressure (SBP) (P > 0.05) and a small but significantly (P < 0.0001) lower (0.8 mm Hg) reading for diastolic blood pressure (DBP) using the aneroid sphygmomanometer. Regression analysis of aneroid vs. mercury showed regression lines (Y = 4.8 + 0.96X for SBP, Y = 3.1 + 0.95X for DBP) slightly but statistically significantly different from the line of equality (P < 0.001). Participants' age, sex, race/ethnicity, body mass index, blood pressure, and clinical center together explain about 8-10% of the variation of the difference between readings from the two sphygmomanometers. Based on the above result, on 1 August 2006, DPPOS clinics began the conversion from mercury to aneroid sphygmomanometers. CONCLUSIONS: The Welch Allyn Tycos 767-Series Mobile Aneroid model 7670-04 tested in this validation study can be used to replace mercury model in clinical trials.

Update on appendicitis: diagnosis and presurgical management.

PURPOSE OF REVIEW: Practitioners who see pediatric patients with acute complaints are commonly faced with making the diagnosis of appendicitis. While sometimes the history and physical examination are sufficient, frequently some diagnostic confirmation will be necessary. While diagnostic imaging is frequently useful, it may not be easily obtained. Blood tests are more readily available, with less cost and risk, but unclear diagnostic accuracy. Other questions for the initial examiner are when to consult the surgeon and if analgesia administration will obscure the diagnosis. RECENT FINDINGS: Abdominal computed tomography scans and ultrasound scans have been shown to be accurate in the diagnosis of acute appendicitis. The literature has begun to focus on which patients should undergo imaging studies. Several clinical decision rules that may be helpful in identifying low-risk patients have been derived. Analgesia given before establishing a diagnosis does not appear to change outcomes. SUMMARY: A careful history and physical examination will identify a minority of pediatric appendicitis cases. When diagnostic testing is needed, computed tomography scanning has the best test performance, but also carries the risk of radiation. Elimination of a portion of low-risk patients may reduce unnecessary imaging.

A comparison of pediatric emergency medicine and general emergency medicine physicians' practice patterns: results from the Future of Pediatric Education II Survey of Sections Project.

BACKGROUND: This survey was conducted to obtain information about career and practice issues facing pediatric emergency medicine (PEM) physicians and general emergency medicine (GEM) physicians. We hypothesized that PEM physicians work fewer clinical hours and perform more teaching and research in their positions than GEM physicians. METHODS: Two surveys sponsored by the Future of Pediatric Education II Project were sent to 1545 emergency physicians identified by the American Board of Pediatrics, the American Academy of Pediatrics, and the American College of Emergency Physicians between October 1997 and February 1998. Data on demographics, job description, recent job changes, and career expectations were obtained and analyzed using Student t test or Welch analysis of variance for continuous variables and chi2 for categorical data. P values less than 0.05 were considered significant. Comparisons between PEM and GEM physicians were adjusted using analysis of covariance to control for the effect of medical school affiliation. RESULTS: Effective response rate was 934 (64%) of 1451. A total of 705 (75%) respondents identified themselves as a PEM physician, and 229 (25%) identified as a GEM physician. PEM physicians were younger (41.0 y vs 45.1 y) and more likely to be women (44% vs 15%, P < 0.0001 for both). Children younger than 18 years made up 80.9% and 28.6% of patients seen by PEM and GEM physicians, respectively (P < 0.001). Seventy-nine percent of PEM physicians and 42% of GEM physicians held an academic appointment (P < 0.0001). No differences were found for full-time equivalents per physician group (9.7 vs 9.1) or clinical hours spent in the emergency department (ED) (31.5 vs 32.7) when means were adjusted for academic appointment. During ED clinical activities, PEM physicians reported more time spent supervising trainees (34% vs 16%, P < 0.0001), and GEM physicians reported more time spent in direct patient care (77% vs 57%, P < 0.0001). Total clinical hours worked per week were greater for GEM physicians (37.9 vs 35.3, P < 0.05). PEM physicians spent more time than GEM physicians teaching (12% vs 8%, P < 0.005) and conducting clinical research (5% vs 2%, P < 0.0003). Of PEM and GEM physicians combined, 26% reported a job change in the past 3 years. Extended reduction of ED clinical duties occurred most commonly because of child care issues and was reported more commonly by women than men (53% vs 6%, P < 0.0001) irrespective of PEM or GEM practice. The likelihood of leaving emergency medicine practice within 5 years increased with age for both groups: 10% of PEM and GEM physicians under 40 years old anticipated leaving practice versus 30% of those older than 50 years (P < 0.0001). PEM physicians were more likely than GEM physicians to predict an increased need for additional pediatric subspecialists in general (60% vs 26%, P < 0.001) and for pediatric subspecialists in their discipline (54% vs 17%, P < 0.001). PEM subspecialists were twice as likely as GEM specialists to perceive competition in their subspecialty (60% vs 31%, P < 0.001). CONCLUSIONS: According to our sample, GEM and PEM physicians worked the same number of clinical hours in the ED but reported significant differences in how those hours are spent. Job changes and extended leaves were common in both groups. These results suggest that PEM and GEM physicians face similar vocational challenges, especially in the areas of balancing of family time, clinical hours, and academic productivity. These data also have important implications for workforce projection for the PEM physician supply, given the current estimated attrition rate, frequency of leave from clinical duties, and projection for increased need for PEM physicians in the future.