Tag: nevin manimala

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

Insights Imaging. 2025 Dec 8;16(1):274. doi: 10.1186/s13244-025-02135-x.

ABSTRACT

INTRODUCTION: RADUCATION – a digital platform for radiological postgraduate training by the German Young Radiology Forum – provides learning content structured according to the German Training Curriculum, including original board exam questions. This is the first study to evaluate user statistics, experience, and preferences.

MATERIALS AND METHODS: Data were collected through webpage analytics and surveys. User statistics were analyzed for four periods: initial usage (05/2022-05/2023), post-introduction of theoretical board exam questions (05-11/2023), post-introduction of image-based board exam questions (12/2023-05/2024), and ongoing usage (03-12/2024). User perception surveys were conducted before (05/2023-01/2024) and after (06-08/2024) implementation of image-based board exam questions. Analyses included descriptive statistics and multivariable logistic regressions.

RESULTS: User numbers increased steadily, with board exam questions becoming the most accessed feature. Mean monthly active user numbers increased from 372 between 05/2022-05/2023 (total users 4468), to 613 between 03/2024-12/2024 (total 15,828). Survey respondents (n = 243) consistently rated RADUCATION as valuable for board exam preparation (88.6%), for night/weekend shifts (75.6%), and for clinical routine (73.4%). Board exam preparation was more beneficial for 4th/5th-year residents (odds ratio (OR) 1.35 (95% confidence interval (95% CI): 1.15-1.59)), while shift preparation was less critical for senior than for junior residents (OR 0.77 (95% CI: 0.59-0.99)). Video- and image-based learning content were preferred, with users rating the platform highly user-friendly (86.0%) and clearly structured (88.0%).

CONCLUSIONS: RADUCATION is a valuable, widely used digital learning tool for radiology residents. Board exam questions substantially increased engagement. Its structured, peer-developed design offers a scalable model for digital postgraduate medical education across specialties and countries.

CRITICAL RELEVANCE STATEMENT: This is the first comprehensive evaluation of RADUCATION, a peer-developed, competency-based digital learning platform for the radiology residency. Integrating original board exam questions significantly increases engagement and perceived educational value, offering a scalable model for modern postgraduate medical education.

KEY POINTS: RADUCATION, a peer-developed, competency-based learning platform for radiology residents, is a highly valued, scalable model for postgraduate medical training. Users prefer video- and image-based content, while engagement and perceived educational value increase when integrating original board exam questions. RADUCATION is perceived as user-friendly and well-structured, and is considered particularly valuable for exam preparation by senior residents.

PMID:41359302 | DOI:10.1186/s13244-025-02135-x

Gen Thorac Cardiovasc Surg. 2025 Dec 8. doi: 10.1007/s11748-025-02236-w. Online ahead of print.

ABSTRACT

OBJECTIVES: Few physiological assessments are available for patients who undergo mitral valve repair for severe mitral regurgitation (symptomatic or asymptomatic). The aim of the study was to evaluate change in exercise tolerance as a means of physiological assessment following mitral valve repair.

METHODS: We studied 41 consecutive patients who received elective isolated mitral valve repair for severe mitral regurgitation in a minimally invasive manner via a completely endoscopic platform and who underwent cardiopulmonary exercise testing in our institution between February 2018 and August 2019. There were 21 asymptomatic (group A) and 20 symptomatic (group S) patients. Physiological assessment was performed by cycle ergometer cardiopulmonary exercise testing pre-operatively and at approximately 6 months post-operatively.

RESULTS: Mean age was 59 ± 11.6 years and 24 patients were male (58.5%). Overall, there was no significant change in peak oxygen consumption or anaerobic threshold after surgical repair. There were no intergroup differences in terms of peak oxygen consumption, anaerobic threshold, ventilation/carbon dioxide production, or gas exchange ratio. There were no intergroup differences in any transthoracic echocardiographic variable except for post-operative left atrial dimension (group A: 35.2 ± 5.9 vs. group S: 39.8 ± 6.2, p = 0.01).

CONCLUSIONS: There was no statistically discernible change in functional capacity at 6-12 months after endoscopic mitral valve repair. The physiological assessment found no improvements in cardiopulmonary exercise testing values post-operatively despite improvement of the symptoms.

PMID:41359257 | DOI:10.1007/s11748-025-02236-w

J Clin Monit Comput. 2025 Dec 8. doi: 10.1007/s10877-025-01392-x. Online ahead of print.

ABSTRACT

The Mean flow index (Mxa) is widely used to assess dynamic cerebral autoregulation in different clinical populations. This calculation is based on defined characteristics, including blocks, overlap periods, and epochs of the whole recordings. This study aimed to investigate the reproducibility of different Mxa calculations, using variable blocks, overlap periods, and epochs. We retrospectively analyzed 50 transcranial Doppler recordings from septic shock patients, acquired within 48 h of ICU admission. Mxa was computed using eight signal-processing strategies that varied by block duration (5-10 s), overlap percentage (20%, 50%, 80%), and epoch length (3-5 min), as well as a continuous approach without epochs. Each configuration was labeled using the format epoch-block-overlap. Mxa values were compared using repeated measures analyses, intraclass correlation coefficients (ICC), Bland-Altman plots, and polychoric correlation heatmaps. Median Mxa values ranged from 0.36 to 0.45 across configurations, with no statistically significant differences in within-patient comparisons (p > 0.05). ICCs demonstrated excellent agreement (ICC > 0.90) between approaches using the same epoch duration. Agreement declined modestly when comparing configurations with different epoch lengths (e.g., ICC = 0.782 between 3-10-50 and 5-10-50). Fixed-effects analysis did not identify any individual segmentation parameter as a significant source of variability. Mxa values calculated using different combinations of block, overlap, and epoch duration were consistent within patients, particularly when epoch length was maintained. These findings support the reproducibility of Mxa and suggest flexibility in processing strategies, provided methodological consistency is maintained. Further validation is warranted.

PMID:41359245 | DOI:10.1007/s10877-025-01392-x

J Interv Card Electrophysiol. 2025 Dec 8. doi: 10.1007/s10840-025-02206-5. Online ahead of print.

ABSTRACT

BACKGROUND: Pulsed-field ablation (PFA) has emerged as a potentially safer alternative to radiofrequency ablation (RFA). However, recent studies have raised concerns that PFA may induce hemolysis, which could contribute to the development of acute kidney injury (AKI).

METHODS: The PubMed, Embase, Scopus, and Cochrane databases were searched for randomized clinical trials (RCTs) and non-RCTs that reported AKI incidence and hemolysis biomarkers after PFA. Random-effects models were used to calculate pooled odds ratio (OR) and mean differences (MDs) with 95% confidence intervals (CIs). Substantial heterogeneity was defined as I² > 25%.

RESULTS: Ten studies, including one RCT, comprising a total of 3,843 patients, were included, with 1,859 in the PFA group and 1,994 in the RFA group. In the primary endpoint analysis related to AKI and renal function, no significant differences were found between the PFA and RFA groups, with PFA having a total prevalence of 2.1% (95% CI [0.90; 4.84]). The leave-one-out analysis, specifically the exclusion of one outlier study, led to the comparative results having statistical significance statistical significance (OR 3.70, 95% CI [2.49; 5.51], p = 0.0019; I² = 0%), indicating no heterogeneity, and with the total prevalence increasing to 2.4% (95% CI [0.96; 5.93]). Regarding hemolysis, all evaluated biomarkers were significantly elevated in the PFA group, although with high heterogeneity.

CONCLUSION: PFA appears to be associated with a slightly higher risk of AKI than RFA. Renal injury is mostly mild-degree and transient. PFA is associated with significant peri-procedural hemolysis.

PMID:41359232 | DOI:10.1007/s10840-025-02206-5

J Assist Reprod Genet. 2025 Dec 8. doi: 10.1007/s10815-025-03770-5. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate how the timing of oocyte denudation (DN) and intracytoplasmic sperm injection (ICSI) affects embryological and clinical outcomes in highly standardized oocyte donation cycles.

METHODS: This retrospective cohort study included 1538 donor stimulation cycles from a single IVF center between January 2019 and July 2023. Timing intervals between human chorionic gonadotropin (hCG) administration, oocyte pick-up (OPU), DN, and ICSI were recorded. Outcomes included oocyte maturation (MII rate), fertilization, embryo quality, and clinical results. Statistical analyses included linear and logistic regression models, and chi-square tests, adjusting for donor and recipient age and BMI.

RESULTS: Longer hCG-DN intervals (> 39 h) were significantly associated with increased MII rates and decreased proportions of MI and discarded oocytes (P < 0.05). However, hCG-DN timing had no effect on fertilization rates, embryo quality, or pregnancy outcomes. Shorter DN-ICSI intervals (< 90 min) were associated with a higher proportion of top-quality blastocysts and fewer medium-quality embryos (P < 0.05). DN-ICSI timing did not influence clinical outcomes. Recipient BMI was the strongest predictor of pregnancy, clinical pregnancy, and live birth (P < 0.001).

CONCLUSIONS: Extended incubation prior to denudation improves oocyte maturation but does not affect fertilization or pregnancy. Short DN-ICSI intervals favor top-quality blastocyst formation without altering clinical results. Recipient BMI significantly impacts reproductive success. These findings support timing optimization in ART and highlight the influence of patient-specific factors.

PMID:41359227 | DOI:10.1007/s10815-025-03770-5