Publications

BACKGROUND: There is limited data on the associations of (glycated hemoglobin A1C [HbA1C], fasting plasma glucose, and 2-hour postload glucose) and insulin resistance (fasting plasma insulin, insulin-to-glucose ratio, homeostasis model assessment of insulin resistance, and quantitative insulin sensitivity check index) markers with arterial stiffness.

METHODS: We included 6617 Framingham Heart Study participants (53.8% women; 6.9% diabetes, mean age: 48±14 years). Arterial stiffness measures included natural log (Ln)-transformed carotid-femoral pulse wave velocity, augmentation index (AIx), central pulse pressure, carotid-brachial pulse wave velocity, carotid-radial pulse wave velocity, and brachial pulse pressure. Estimates of associations were adjusted for several clinical characteristics.

RESULTS: Adjusted means of log (Ln)-transformed carotid-femoral pulse wave velocity, AIx, and carotid-brachial pulse wave velocity were increasingly abnormal with higher HbA1C (all P<0.05). Each 1% higher HbA1C was associated with elevated CFPWV (odds ratio [OR], 1.24 [95% CI, 1.11-1.39]) and lower AIx (OR, 0.86 [95% CI, 0.78-0.95]). Each 10-mg/dL higher fasting plasma glucose was associated with elevated CFPWV (OR, 1.09 [95% CI, 1.05-1.13]), but lower AIx (OR, 0.91 [95% CI, 0.87-0.94]). Each 10-mg/dL higher 2-hour postload glucose was associated with elevated CFPWV (OR, 1.04 [95% CI, 1.01-1.07]), central pulse pressure (OR, 1.04 [95% CI, 1.02-1.06]), brachial pulse pressure (OR, 1.04 [95% CI, 1.02-1.06]), but lower AIx (OR, 0.94 [95% CI, 0.91-0.96]). Higher fasting plasma insulin, insulin-to-glucose ratio, homeostasis model assessment of insulin resistance, and lower quantitative insulin sensitivity check index were associated with higher CFPWV and lower AIx (all P<0.05).

CONCLUSIONS: In community-dwelling individuals, worse glycemia and insulin sensitivity were associated with abnormal arterial stiffness.

Regression to the mean (RTM) can inflate apparent placebo response in epilepsy trials, but its mechanisms are often conflated. Using CHOCOLATES, we simulated 1,000,000 patients with 36 months of daily seizure counts and simulated placebo trials: 2-month baselines followed by 3-month test periods without treatment effects. Transient worsening (RTM type 1), stricter eligibility thresholds (RTM type 2), reduced sensitivity, and false alarms (RTM type 3) each increased RTM and apparent response. These findings show that placebo-arm improvement can arise from temporary illness, natural variability, measurement error, or mixtures thereof, informing epilepsy trial design and endpoint interpretation.

BACKGROUND: Placebos have historically been used as comparative tools in randomised controlled trials (RCTs), but their therapeutic effect, particularly in psychiatric conditions, warrant a more detailed exploration to improve research design and clinical practice.

AIMS: This systematic review and meta-analysis examines the factors influencing placebo treatment effects across major psychiatric disorders, including depression, anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).

METHOD: This PROSPERO registered systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify RCTs with at least one placebo and one medication arm (citalopram or escitalopram), across four major groups of psychiatric conditions. Data extraction focused on study characteristics, methodology, target condition, participant demographics and outcome measurements. Cohen's d effect sizes for placebo and medication groups were calculated, with random-effects model meta-analyses performed to assess heterogeneity and their correlates.

RESULTS: The review included 80 studies with 312 outcome measures, involving 19 776 participants (7 to 91 years old). A large placebo response was observed (effect size: 1.01; 95% CI: 0.93-1.10) with significant heterogeneity (I2: 99.61%). Significant differences in placebo responses were noted across clinical conditions, independent of the medication type. PTSD and depressive disorders exhibited the highest placebo effect size (1.14 and 1.02, respectively), whereas OCD showed the lowest (effect size: 0.62, P < 0.01). Anxiety disorders displayed a moderately large placebo effect size (0.86), with significant variability among anxiety disorder subclasses, specifically noting the lowest placebo effect size in specific phobia (0.23, P < 0.01). The medication effect size (1.43) also demonstrated considerable heterogeneity (I2: 99.76%) but was not significantly different across psychiatric conditions (P = 0.61). Placebo response magnitude was larger in studies with more study arms (b: 0.181, P < 0.01) and younger mean age of the participant (b: -0.010, P < 0.01). Moreover, clinician-rated outcomes versus patient self-reports (effect size: 1.07 v. 0.76, P < 0.01), multicentre studies (p < 0.01) and using intention-to-treat data (effect size: 1.08 v. 0.86, P = 0.01) were associated with larger placebo effect size.

CONCLUSIONS: This study used a unique approach to examine placebo responses from the same interventions across multiple major psychiatric disorders. We found substantial placebo responses across psychiatric conditions and significant heterogeneity, influenced by a range of study-related and demographic factors. The findings underscore the complexity of placebo responses and highlight the importance of considering these variances in both research design and clinical translation.

UNLABELLED: Automated seizure detection devices are increasingly plausible tools for epilepsy trials, but no device is perfect. We used CHOCOLATES, a realistic seizure diary simulator, to examine how device sensitivity and false alarm rate (FAR) affect regression-to-the-mean (RTM) and placebo median percentage change (MPC) in a simulated randomized trial design. For each device condition, 100,000 potential participants were generated; eligibility was assessed during a 2-month baseline, followed by a 3-month test period. With FAR fixed at 0, reducing sensitivity from 100% to 10% increased the fraction of eligible participants exhibiting RTM from 38.2% to 64.8% and increased placebo MPC from 14.7% to 48.1%. With sensitivity fixed at 100% and expected FAR correction, increasing FAR from 0 to 1 alarm/day increased RTM from 38.2% to 53.2% and placebo MPC from 14.7% to 31.3%. Imperfect seizure detection can therefore change the apparent placebo response expected from RTM.

SHORT SUMMARY FOR TABLE OF CONTENTS: In simulated epilepsy trials, imperfect seizure detection altered regression to the mean and placebo median percentage change. Trial planning should model detector sensitivity and false alarm rate before device-derived seizure counts are used as endpoints.

AIMS: Exercise cardiovascular magnetic resonance (Ex-CMR) assesses cardiac function under physiological stress. Imaging during continuous in-bore exercise reflects peak physiology but is challenging, prone to motion artefacts and patient discomfort. Exercise performed outside the scanner followed by rapid post-exercise imaging improves feasibility and image quality, but the time course of ventricular volume recovery after exercise cessation remains poorly defined. We compared biventricular Ex-CMR measurements during steady-state peak exercise with those acquired sequentially after exercise termination.

METHODS AND RESULTS: Ten healthy adults [24 (21-31) years; 8 female] underwent Ex-CMR on a 3T system. Biventricular volumes were assessed using a free-breathing, electrocardiogram-triggered, highly accelerated multi-slice cine sequence with compressed sensing and deep learning-based reconstruction. Short-axis stacks were acquired at rest, during two steady-state peak exercise acquisitions, and at three sequential post-exercise timepoints, with the first recovery scan beginning 10-15 s after cessation. Linear mixed-effects models evaluated recovery categorically and as a function of elapsed time. Differences between repeated peak acquisitions were small [left ventricular (LV) end-diastolic volume +1 ± 3 mL; LV end-systolic volume -4 ± 7 mL]. Immediately after cessation (13 ± 2 s), biventricular volumes remained unchanged vs. peak (all P = 1.00). Significant recovery-related changes emerged by 54 ± 9 s and were present for all parameters by 99 ± 18 s. Linear modelling showed LV stroke volume declining 2.1 mL (-1.9%) per 10 s, with similar right-ventricular trends. Post-exercise acquisitions showed higher diagnostic quality and fewer artefacts than in-bore imaging.

CONCLUSION: Biventricular volumes measured immediately after exercise closely approximate peak physiology, whereas recovery changes occur rapidly and linearly thereafter. Rapid post-exercise acquisition offers a practical surrogate for peak measurements while improving image quality.

Diabetes and hypertension frequently coexist, greatly increasing cardiovascular and mortality risk. The optimal dietary strategies for blood pressure (BP) control in people with diabetes remain uncertain. This report details the rationale and design of the Dietary Approaches to Stop Hypertension for Diabetes (DASH4D) trial, a randomized, controlled, crossover feeding study designed to evaluate the effects of the DASH4D dietary pattern and sodium content on BP among adults with type 2 diabetes. The DASH4D dietary pattern was developed by adapting the DASH diet, an effective diet for BP lowering, to maximize efficacy and safety in a diabetes population. The DASH4D trial randomized participants to a sequence of four 5-week feeding periods testing the following diets: 1) DASH4D diet with lower sodium, 2) DASH4D diet with higher sodium, 3) comparison (typical US) diet with lower sodium, and 4) comparison diet with higher sodium (primary contrast: 1 vs. 4). Diets were tailored to meet specific nutrient targets, and calories were adjusted to maintain stable weight. The primary outcome was systolic BP, and the secondary outcome was diastolic BP. Key additional outcomes included measures of glycemia, lipids, proteinuria, and diet acceptability. The study design addressed multiple challenges including conducting controlled feeding in a medically complex population, maximizing dietary adherence, and implementation during the COVID-19 pandemic. This design provides a road map to rigorously evaluate the efficacy of nutritional interventions in people with diabetes, and generates critical evidence to inform guidelines and clinical practice around the optimal dietary strategies to control diabetes and hypertension.

BACKGROUND: General medicine (GM) research fellowships facilitate health care professionals to obtain the skills and mentored research experience needed for a research career. Yet, little is known about the experience and outcomes of recent graduates of GM fellowships.

OBJECTIVE: To survey (1) GM research fellows and recent graduates and (2) program directors to learn about the opportunities and challenges facing GM research fellowships.

DESIGN: Cross-sectional retrospective survey study.

PARTICIPANTS: Individuals who were enrolled in or completed a GM research fellowship (identified through prior fellow lists, advertising from the Society of General Internal Medicine, and fellowship program directors) between 2012 and 2022 in which ≥ 50% of effort was devoted to training and conducting research; 2022 program directors were recruited separately.

MAIN MEASURES: Respondents were asked to rate factors motivating them to pursue a research fellowship and their experiences during fellowship and to report their professional outcomes. Program directors were asked to rate how challenging different fellowship activities were to them.

KEY RESULTS: A total of 160 (42.2%) current/former fellows and 27 (67.5%) program directors completed surveys. Fellowship training was considered essential to obtain the skills necessary to become a GM researcher. Fellows were highly productive (median of 4 papers [IQR 3-6] published from fellowship work); the majority obtained research faculty positions. Gaps in training included negotiation skills, team management, and grant writing. Trainees and graduates sought more cross-institutional collaboration during fellowship. Approximately 1/3 reported at least one symptom of burnout. Fellowship outcomes generally did not vary by gender or under-represented in medicine status. Program directors (88%) found fellowship recruitment challenging.

CONCLUSIONS: Research fellowships play a critical role in cultivating GM investigators. Consistent investment in GM research fellowships is needed to ensure a pipeline of researchers with the skills necessary to improve general medicine, especially during an ongoing crisis in primary care.

BACKGROUND: Persistent post-surgical pain, a chronic pain syndrome with few effective treatments, has spiked in recent years due to the increase in life expectancy and the number of surgical procedures performed. Studies have shown that non-pharmacological interventions, such as yoga, may help manage chronic pain, reducing pain severity and interference. Despite emerging evidence of the efficacy of yoga in managing chronic pain symptoms, rigorous studies evaluating its use in patients with persistent post-surgical pain have not been conducted. This study describes protocols used in Persistent Relief, an ongoing pilot randomized controlled trial comparing yoga to chronic pain health education. Results from a modified Delphi validation process used to adapt a yoga program for chronic low back pain to the unique needs of this patient population are also included.

METHODS/DESIGN: Fifty patients aged ≥18 with persistent post-surgical pain for at least 3 months and a mean pain severity of 4/10 on the Brief Pain Inventory are randomized to a 12-week yoga program (12, 75-minute sessions) or a chronic pain health education program (12, 15-30-minute sessions), followed by a 12-week follow-up period. Results of an iterative Delphi validation process led by an interdisciplinary expert panel indicated strong endorsement of the Yoga Program (across 7 experts and 9 questions; mean=6.7 [SD=0.64] on a 7-point Likert scale). Primary outcomes include pre-specified feasibility and acceptability metrics. Secondary outcomes include a battery of biopsychosocial measures, with the Brief Pain Inventory as the primary clinical outcome for a future fully powered trial.

DISCUSSION: Results will provide preliminary data to inform modifications for a future fully powered study evaluating the efficacy of yoga integrated into the management of persistent post-surgical pain. Findings will also inform the design of future studies examining the biological mechanisms underlying the integrative use of yoga to prevent or resolve chronic pain syndromes.

CLINICALTRIALSGOV IDENTIFIER: NCT06949007.

BACKGROUND: Prediabetes is common among adults with hypertension, but its contribution to heart failure (HF) risk, particularly in the presence of subclinical myocardial abnormalities, remains uncertain.

OBJECTIVES: The objective of the study was to assess whether prediabetes combined with malignant left ventricular hypertrophy (LVH)-defined as LVH accompanied by subclinical myocardial injury or stress-is associated with increased HF risk in hypertensive adults without diabetes.

METHODS: This prospective cohort analysis included 8,131 hypertensive adults without diabetes or prior HF from the SPRINT (Systolic Blood Pressure Intervention Trial). LVH was defined using the Cornell voltage product. Subclinical myocardial injury was defined as high-sensitivity cardiac troponin I ≥6 ng/L (men) or ≥4 ng/L (women), and subclinical myocardial stress as N-terminal pro-B-type natriuretic peptide ≥125 pg/mL. Cox proportional hazards models estimated adjusted HRs and 95% CIs for HF.

RESULTS: During a median 3.3-year follow-up, 115 HF events occurred. Compared with normoglycemic adults without malignant LVH, those with both prediabetes and malignant LVH had higher HF risk (adjusted HR: 3.55; 95% CI: 1.98-6.36). Similar patterns were observed for prediabetes with LVH plus myocardial injury (HR: 4.02; 95% CI: 2.21-7.30) or stress (HR: 4.04; 95% CI: 2.22-7.34). Prediabetes alone was not associated with HF (adjusted HR: 1.24; 95% CI: 0.80-1.91).

CONCLUSIONS: Among hypertensive adults, the coexistence of prediabetes and malignant LVH identifies a subgroup at substantially elevated HF risk. Integrating glycemic status, ECG findings, and cardiac biomarkers may enhance HF risk stratification and inform preventive strategies.