Research

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.

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.