Nevin Manimala

Trials. 2025 Dec 8. doi: 10.1186/s13063-025-09324-5. Online ahead of print.

ABSTRACT

BACKGROUND: Parallel-group multi-arm trials are randomised controlled trials (RCTs) where participants are allocated to three or more concurrent treatment groups. Multiplicity occurs when several statistical tests are conducted within the same study. Statistical adjustments to the design and analysis of multi-arm trials can be used to control the study-wise type I error rate. There is no clear guidance or consensus on the necessity of multiplicity adjustment in multi-arm trials, nor on which methods are most appropriate. This comprehensive review aimed to investigate the design, analysis and reporting of publicly funded parallel-group multi-arm trials and to report the approach to multiplicity in these trials with respect to sample size and statistical analysis.

METHODS: We searched the United Kingdom’s National Institute for Health and Care Research (NIHR) online Journals Library, from 1 January 1997 to 31 December 2024 for reports of multi-arm RCTs. Information on the trial characteristics, the sample size estimation and analysis of the primary outcome was extracted. Two researchers conducted the search and selected reports for inclusion. Data from each report was independently extracted by two reviewers, and any disagreement was resolved by discussion.

RESULTS: A total of 2452 reports, published online in the NIHR Journals Library, were screened for eligibility; 97 reports of multi-arm parallel-group trials met the inclusion criteria. Of these, 90 included the results of a multi-arm efficacy analysis. In the review, 35% (34/97) of the trials did adjust for multiplicity in the sample size calculation; in 84% (76/90), the potential between-arm comparisons were described in the methods, and 37% (33/90) made a multiplicity adjustment in the analysis. A further 86% (77/86) reported 95% confidence intervals. For the minority of multi-arm trials that did adjust for multiplicity, the most common adjustment method was Bonferroni.

CONCLUSIONS: The majority of the publicly funded multi-arm trials did not adjust for multiplicity in the sample size, statistical analysis, or estimation of confidence intervals. Researchers should follow the Consolidated Standards of Reporting Trials guidelines for multi-arm trials and clearly state in protocols and trial reports whether a multiplicity adjustment was made or provide a reason if no adjustment was made.

PMID:41361478 | DOI:10.1186/s13063-025-09324-5

BMC Nurs. 2025 Dec 8;24(1):1471. doi: 10.1186/s12912-025-04112-7.

ABSTRACT

BACKGROUND: Nurses play a crucial role as essential healthcare providers, and their health-promoting lifestyle behaviors (HPLB) can significantly influence patients’ attitudes toward health promotion. Despite their importance, limited research has been conducted on HPLB among clinical nurses in Mogadishu. This study aims to examine the HPLB of clinical nurses in Mogadishu and identify key factors influencing these behaviors.

METHODOLOGY: A descriptive cross-sectional study was conducted from September to November 2024, involving 423 nurses from public and private hospitals in Mogadishu. Cluster random sampling was used, and data were collected using self-administered questionnaires based on the modified Health-Promoting Lifestyle Profile II (HPLP-II). Data analysis was performed using descriptive statistics, independent t-tests, ANOVA, and categorical regression with SPSS version 27.

RESULTS: A total of 423 nurses participated in the study. The mean scores for self-actualization, health responsibility/physical activity, nutrition, job security, interpersonal support, and overall health-promoting lifestyle were 25.87 ± 4.99, 26.70 ± 5.71, 10.16 ± 2.48, 18.73 ± 4.09, and 17.68 ± 3.95, respectively, with an overall mean score of 99.14 ± 16.1 out of 152. Nurses demonstrated moderate levels of health-promoting behaviors, with self-actualization reflecting frequent engagement in personal growth, while nutrition and interpersonal support indicated moderate adherence to recommended practices. Categorical regression analysis identified monthly income, employment sector, number of children, educational qualification, working department, gender, and years of work experience as predictors of overall health-promoting lifestyle behaviors (p < 0.001), with adjusted R² values ranging from 0.023 to 0.094 across the six subscales.

CONCLUSION: Nurses in Mogadishu demonstrated moderate health-promoting lifestyle behaviors. Key predictors included income, employment sector, working department, gender, and work experience. Interventions that promote healthy habits and supportive work environments are essential to enhance nurses’ well-being and quality of care.

PMID:41361464 | DOI:10.1186/s12912-025-04112-7

Lipids Health Dis. 2025 Dec 9. doi: 10.1186/s12944-025-02825-x. Online ahead of print.

ABSTRACT

BACKGROUND: Brown adipose tissue (BAT) regulates metabolic homeostasis, yet its role in tumor presence remains undefined. This study investigates the associations among BAT, body mass index (BMI), and tumor presence in a large Chinese cohort.

METHODS: We retrospectively analyzed 1,736 adults who underwent ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (¹⁸F-FDG PET/CT) at Shanghai East Hospital (2016-2024). Patients were grouped by BAT status with propensity score matching and sex stratification. BAT was identified by FDG uptake at typical depots with CT density criteria. Statistical analyses included chi-square tests, regression models, and mediation analysis (structural equation modeling with bootstrapping) to assess the role of BMI in the BAT-tumor presence association.

RESULTS: The presence of BAT was associated with younger age, female sex, and lower BMI. In multivariable logistic regression, age (p < 0.001) and BMI (p = 0.014) were independently associated with tumor presence. After propensity score matching (PSM), sex-stratified mediation analysis showed that in females, BAT was indirectly associated with a lower likelihood of tumor presence (Natural Indirect Effect OR = 0.88, 95% CI 0.72-0.98), whereas no significant mediation effect was observed in males. Among cancer patients, individuals with BAT had a significantly lower BMI compared to individuals without BAT (overall: 21.08 vs. 23.34; females: 21.33 vs. 22.97; males: 19.65 vs. 24.68).

CONCLUSIONS: Our findings indicate that BAT and tumor presence are statistically associated in a sex-specific manner, with BMI potentially playing a mediating role in females. The consistently lower BMI among BAT(+) cancer patients further indicates a plausible link between BAT and body weight regulation. These observations warrant further investigation to elucidate the underlying mechanisms.

PMID:41361455 | DOI:10.1186/s12944-025-02825-x

BMC Public Health. 2025 Dec 9. doi: 10.1186/s12889-025-25859-3. Online ahead of print.

ABSTRACT

BACKGROUND: The World Health Organization recommends adopting smoke-free campuses (SFCs), and in 2024, the European Council has urged Member States to implement smoke-free policies on educational premises. However, unlike North America, Australia and New-Zealand, Europe has been slow to adopt SFCs. In France, the EHESP School of Public Health became the first SFC in 2018. This research assessed students’ support for this SFC policy since its implementation and examined associated factors.

METHODS: An online cross-sectional study was conducted annually from 2018 to 2025. The dependent variable was students’ support for the SFC policy, measured using a four-point Likert scale ranging from strong opposition to strong support. Explanatory variables included tobacco use behaviors, knowledge of tobacco’s dangers, and sociodemographic characteristics. An ordered logit regression model was applied to account for the ordinal nature of the outcome variable. Explanatory variables were introduced sequentially to evaluate their incremental contribution.

RESULTS: The sample comprised 2,532 students with a 56.97% overall response rate. Support for the SFC policy was nearly universal (96.7% – 91.4% among students who smoked), exceeding levels reported outside Europe. Smoking status, demographic factors, and time were significantly associated with it. Current smoking or vaping, or ever smoking were negatively associated with support. Support increased between 2018 and 2025. Being a woman, an aspiring public servant, or older in age positively influenced it. Knowledge of tobacco’s dangers showed no significant association with support.

CONCLUSIONS: Most research on SFC policies has been conducted in settings with low smoking prevalence where SFCs are typical. Our study is the first to assess support in a country where SFC policies were not yet widespread. The high level of support observed should encourage the broader implementation of SFCs in France and across other European countries.

PMID:41361437 | DOI:10.1186/s12889-025-25859-3

Cardiovasc Diabetol. 2025 Dec 8;24(1):455. doi: 10.1186/s12933-025-02942-y.

ABSTRACT

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing global health challenge. Conventional diagnostic tools have limited sensitivity and specificity for early-stage disease. In this context, long non-coding RNAs (lncRNAs) have emerged as promising biomarkers for T2DM risk. However, studies exploring their predictive value remain limited. This study aimed to evaluate the potential of circulating lncRNAs in T2DM development and to assess their interaction with dietary interventions.

METHODS: The study included 462 non-diabetic participants from the CORDIOPREV study, followed for 5 years under Mediterranean or low-fat diet interventions. Expression levels of 22 circulating lncRNAs were quantified by qPCR. A series of statistical and machine learning methods were applied.

RESULTS: Random forest analysis identified four lncRNAs (XIST, LINC01116, CASC2, LINC01370) as predictive of T2DM incidence. The combination of these lncRNAs with clinical variables significantly improved prediction performance (AUC = 0.730) compared to models with Hb1Ac (p = 0.015) or clinical variables alone (p < 0.001). Regarding the constructed lncRNA score from the previous model, a lower lncRNA score was associated with a reduced risk of developing T2DM (HR 0.37 (0.24-0.59), p < 0.001), and showed an inverse correlation with the disposition index among individuals following a Mediterranean diet (r = – 0.18, p = 0.009).

CONCLUSION: Circulating lncRNAs, particularly integrated into an epigenetic score, represent promising predictive biomarkers for T2DM development. The interaction with dietary intervention-especially the Mediterranean diet-supports their potential use in guiding personalized dietary strategies for T2DM prevention in high-risk populations.

PMID:41361433 | DOI:10.1186/s12933-025-02942-y

JAMA Intern Med. 2025 Dec 8. doi: 10.1001/jamainternmed.2025.6566. Online ahead of print.

ABSTRACT

IMPORTANCE: The 2007 US Food and Drug Administration (FDA) Amendments Act (FDAAA) expanded its safety-related regulatory authorities, including enhanced postmarketing safety surveillance and new clinical study requirements. However, whether FDAAA has been associated with differences in the frequency and timing of postmarket safety-related actions remains poorly understood.

OBJECTIVES: To assess whether FDAAA was associated with differences in time to first FDA postmarket drug safety-related action, and to assess whether therapeutic and regulatory characteristics were associated with differences in time to these actions post-FDAAA implementation.

DESIGN AND SETTING: This was a cross-sectional study of all novel therapeutics approved by FDA between January 1, 2001, and December 31, 2019, and followed up through December 31, 2024. Approvals were categorized as pre- or post-FDAAA (before or after March 25, 2008). Post-FDAAA therapeutic and regulatory characteristics included drug class, therapeutic area, orphan status, special regulatory pathway, and presence of a boxed warning or FDAAA-mandated postmarket study requirement at approval.

MAIN OUTCOMES AND MEASURES: Time to first FDA postmarket drug safety-related action, a composite of withdrawals due to safety concerns, incremental boxed warnings, and safety-related communications.

RESULTS: Of the 560 novel therapeutics approved, FDA took postmarket safety-related actions for 130 (23.2%) during a median (IQR) follow-up of 12.1 (7.8-18.2) years. These comprised actions within 5 years of approval for 34 of 164 therapeutics (20.7%) approved pre-FDAAA, and 57 of 396 (14.4%) approved post-FDAAA (rate ratio, 0.69; 95% CI, 0.47-1.02; P = .06). Compared to pre-FDAAA approvals, after accounting for therapeutic and regulatory characteristics, there was no statistically significant difference in time to first postmarket safety-related action for post-FDAAA approvals (time ratio, 0.40; 95% CI, 0.15-1.07; P = .07). However, among therapeutics with postmarket safety-related actions within 5 years of approval, median time to first action was shorter post-FDAAA (median [IQR], 3.1 (2.0-4.2) years for pre-FDAAA vs 1.8 [1.3-2.5] years post-FDAAA; P = .004). Among 260 novel therapeutics approved post-FDAAA, after the October 2013 enactment of breakthrough therapy designation, the following therapeutic and regulatory characteristics were associated with time to first postmarket safety-related action: small molecule type (time ratio, 0.24; 95% CI, 0.07-0.81; P = .02), orphan designation (time ratio, 8.29; 95% CI, 2.43-28.27; P < .001), fast track (time ratio, 0.22; 95% CI, 0.08-0.64; P = .005), breakthrough therapy designation (time ratio, 0.10; 95% CI, 0.03-0.32; P < .001), prolonged regulatory review time (>400 days; time ratio, 0.16; 95% CI, 0.03-0.73; P = .02), and FDAAA-mandated postmarket study requirements at approval (time ratio, 0.35; 95% CI, 0.15-0.80; P = .01).

CONCLUSIONS AND RELEVANCE: This cross-sectional analysis found that the enhanced safety-related regulatory authorities of FDAAA were not associated with differences in time to first postmarket safety-related action. However, among therapeutics with postmarket safety-related actions within 5 years of approval, median time to first action was shorter post-FDAAA implementation.

PMID:41359349 | DOI:10.1001/jamainternmed.2025.6566

JAMA Netw Open. 2025 Dec 1;8(12):e2543062. doi: 10.1001/jamanetworkopen.2025.43062.

ABSTRACT

IMPORTANCE: The US Department of Veterans Affairs (VA) aims to ensure all veterans have access to emergency care, whether at VA or community facilities. However, the factors influencing where veterans seek care remain poorly understood.

OBJECTIVE: To assess factors associated with veterans use of community vs VA EDs.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study included all veterans aged 18 years or older with at least 1 VA or community ED visit across the contiguous US and Puerto Rico between October 1, 2021, and September 30, 2022. Data were analyzed from October 3, 2024, to March 10, 2025.

EXPOSURES: Patient demographics, clinical characteristics, prior VA and community health care use, differential distance to the nearest VA and community EDs, and facility complexity.

MAIN OUTCOMES AND MEASURES: Community or VA ED visit. Logistic regression models were used to assess factors associated with community ED use compared with VA ED use.

RESULTS: The sample included 2 777 564 ED visits by 1 359 850 veterans (mean [SD] age, 61.9 [16.1] years; 1 202 964 [88.5%] male). Of these visits, 1 000 437 (36.0%) occurred at community EDs. Community ED use was associated with greater differential ED distance (>64.0 km: adjusted odds ratio [AOR], 16.20; 95% CI, 15.96-16.44), prior community ED use (≥5 prior visits: AOR, 17.87; 95% CI, 17.14-18.63), and high-acuity diagnoses (eg, cardiac arrest and ventricular fibrillation: AOR, 84.57, 95% CI, 65.47-109.25). Prior VA ED visits (1 prior visit: AOR, 0.28; 95% CI, 0.28-0.28) and primary care use (AOR, 0.78; 95% CI, 0.77-0.79) were associated with lower odds of community ED use. Racial and ethnic minority veterans were consistently less likely to use community EDs compared with White veterans (Asian veterans: AOR, 0.64 [95% CI, 0.61-0.67]; Black veterans: AOR, 0.76 [95% CI, 0.76-0.77]; and Hispanic veterans: AOR, 0.73 [95% CI, 0.72-0.74]).

CONCLUSIONS AND RELEVANCE: In this cross-sectional study, community ED use among veterans was associated with geographic access, prior care patterns, and diagnosis acuity. Targeted strategies appear to be needed to strengthen care coordination and ensure equitable emergency care access.

PMID:41359338 | DOI:10.1001/jamanetworkopen.2025.43062

JAMA Netw Open. 2025 Dec 1;8(12):e2546556. doi: 10.1001/jamanetworkopen.2025.46556.

ABSTRACT

IMPORTANCE: Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies.

OBJECTIVE: To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD.

DESIGN, SETTING, AND PARTICIPANTS: This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate.

INTERVENTION: Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up.

MAIN OUTCOMES AND MEASURES: The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging.

RESULTS: Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale-cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study-Activities of Daily Living (-0.55; 95% CI, -0.89 to -0.21; P = .02), and Face-Name Association Test (-1.14; 95% CI, -1.66 to -0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale-cognitive subscale (-0.59; 95% CI, -1.02 to -0.16; P = .007), Alzheimer Disease Cooperative Study-Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05643326.

PMID:41359335 | DOI:10.1001/jamanetworkopen.2025.46556

JAMA Netw Open. 2025 Dec 1;8(12):e2547455. doi: 10.1001/jamanetworkopen.2025.47455.

ABSTRACT

IMPORTANCE: Racial and ethnic disparities in postpartum readmission (PPR) remain a critical public health concern, with non-Hispanic Black individuals experiencing rates up to 3 times as high as non-Hispanic White individuals. PPR is often associated with mental health disorders (MHDs) and substance use disorders (SUDs), and barriers to care are particularly acute in rural communities.

OBJECTIVE: To investigate intersections in the associations of individual residential rurality and race and ethnicity with all-cause, MHD-, and SUD-related PPR throughout 1 year post partum.

DESIGN, SETTING, AND PARTICIPANTS: This statewide retrospective cohort study used data from birth certificates linked to all-payer hospital data for individuals 15 to 50 years of age who gave birth and were discharged from South Carolina hospitals between January 1, 2018, and December 31, 2021. Data analyses were completed August 17, 2025.

EXPOSURES: Individual race and ethnicity and individual residential location at time of birth.

MAIN OUTCOMES AND MEASURES: Cumulative incidence of all-cause, MHD-, and SUD-related PPR at 42, 90, 180, and 365 days post partum. Cox proportional hazards models estimated adjusted hazard ratios (AHRs) and 95% CIs for 1-year follow-up, adjusting for individual characteristics.

RESULTS: Of 190 645 births to 166 330 unique individuals (mean [SD] age, 28.2 [5.8] years; 4.9% Hispanic, 30.9% non-Hispanic Black, and 57.1% non-Hispanic White), the highest percentage (30.4%) included individuals between 25 and 29 years of age; 27 961 (14.7%) of births were to women residing in rural areas and 162 684 (85.3%) of births were to women residing in urban areas. Up to 1 year post partum, 4.7% of birthing individuals had all-cause PPR, 1.5% had MHD-related PPR, and 0.8% had SUD-related PPR. In adjusted models, non-Hispanic Black individuals had higher risk of all-cause PPR compared with non-Hispanic White individuals in urban areas (AHR, 1.38 [95% CI, 1.31-1.45]), whereas Hispanic individuals had lower risk (AHR, 0.83 [95% CI, 0.74-0.93]). Rural residence was associated with increased all-cause PPR risk overall (AHR, 1.15 [95% CI, 1.06-1.25]) but was also associated with reduced racial and ethnic disparities in all-cause PPR (interaction AHR, 0.86 [95% CI, 0.77-0.97] for non-Hispanic Black compared with non-Hispanic White, and interaction AHR, 0.55 [95% CI, 0.34-0.89] for Hispanic compared with non-Hispanic White). Similar patterns were observed for MHD- and SUD-related PPR, although rural interactions were not statistically significant.

CONCLUSIONS AND RELEVANCE: In this cohort study of individuals giving birth in South Carolina, racial and ethnic disparities associated with PPR were pronounced among urban residents and attenuated in rural areas, suggesting that geographic context may modify these disparities.

PMID:41359333 | DOI:10.1001/jamanetworkopen.2025.47455

Stat Methods Med Res. 2025 Dec 8:9622802251403279. doi: 10.1177/09622802251403279. Online ahead of print.

ABSTRACT

Longitudinal data are often available in cohort studies and clinical settings, such as covariates collected at cohort follow-up visits or prescriptions captured in electronic health records. Such longitudinal information, if correlates with the health event of interest, may be incorporated to dynamically predict the probability of a health event with better precision. Landmarking is a popular approach to dynamic prediction. There are well-established methods for landmarking using full cohort data, but collecting data on all cohort members may not be feasible when resource is limited. Instead, one may select a subset of the cohort using subsampling designs, and only collect data on this subset. In this work, we present conditional likelihood and inverse-probability weighted methods for landmarking using data from cohort subsampling designs, and discuss considerations for choosing a particular method. Simulations are conducted to evaluate the applicability of the methods and their predictive performance in different scenarios. Results show that our methods have similar predictive performance to the full cohort analysis but only use small fractions of the full cohort data. We use real nested case-control data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial to illustrate the methods.

PMID:41359305 | DOI:10.1177/09622802251403279