Category: Statistics

Epileptic Disord. 2025 Oct 3. doi: 10.1002/epd2.70112. Online ahead of print.

ABSTRACT

OBJECTIVE: Progressive myoclonic epilepsy type 1 (EPM1) is a neurodegenerative disease caused by biallelic variants in the cystatin B (CSTB) gene. Despite a progressive course, phenotype severity varies among patients, even within families. We studied the potential role of APOE ε4 in modifying phenotypic diversity in EPM1, given its established association with neurodegeneration, particularly in Alzheimer’s disease.

METHODS: APOE genotypes were determined for 65 genetically verified EPM1 patients homozygous for the CSTB expansion mutation. The Unified Myoclonus Rating Scale (UMRS), Quality of Life in Epilepsy Inventory-31 questionnaire (QOLIE-31), intellectual ability (WAIS-R), clinical data, and quantitative neuroimaging data were compared between APOE ε4 carriers and noncarriers to assess potential correlations with EPM1 severity. Volumetric analysis was performed on MRI data, while diffusion tensor imaging (DTI) was analyzed using Tract-Based Spatial Statistics (TBSS) and atlas-based white matter (WM) tract region of interest (ROI) analysis.

RESULTS: The cohort included 20 ε4 carriers (16 ε3/ε4 and 4 ε4/ε4) and 45 ε4 noncarriers (36 ε3/ε3, 8 ε2/ε3, and 1 ε2/ε2). No significant differences were found in UMRS or disease duration. Carriers had better QOLIE-31 scores in emotional well-being (p = .047), energy/fatigue (p = .048), and medical effects (p = .024). In volumetric analysis, carriers exhibited greater preservation of bilateral hippocampal and amygdalar volumes but demonstrated more pronounced cortical thinning in the left lingual gyrus, right lateral occipital gyrus, and right posterior cingulate (p < .05). Carriers exhibited more widespread WM degeneration in DTI, characterized by reduced fractional anisotropy (FA) and increased mean diffusivity (MD).

SIGNIFICANCE: Despite greater white matter degeneration and reduced cortical thickness, APOE ε4 carriers exhibited preserved deep brain volumes and better self-reported well-being. This study highlights the complex interplay between genetic factors and neurodegenerative processes. Our future research aims to provide more natural history data of EPM1 and correlate long-term phenotypic data with additional geno-phenotypic analyses.

PMID:41042579 | DOI:10.1002/epd2.70112

Endocr Connect. 2025 Oct 3:EC-25-0290. doi: 10.1530/EC-25-0290. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the clinical spectrum, ARMC5 mutation distribution, and metabolic/cardiovascular risks in patients with radiologically suspected primary bilateral macronodular adrenal hyperplasia (PBMAH).

DESIGN: Cross-sectional study.

METHODS: We analyzed clinical characteristics and germline ARMC5 mutations in patients meeting radiologic criteria for PBMAH (bilateral adrenal nodules ≥1 cm), excluding non-adrenocortical lesions or bilateral adenomas with adrenal atrophy.

RESULTS: The subgroup distribution among 485 patients with radiologically suspected PBMAH was as follows: nonfunctional adrenal tumors (NFAT, 30.1%), mild autonomous cortisol secretion (MACS, 41%), overt Cushing’s syndrome (CS, 14.4%), primary aldosteronism (PA, 8.9%), and coexisting PA and MACS (PA+MACS, 5.6%). Imaging revealed a higher proportion of multiple confluent adrenal nodules in the MACS and CS groups compared to others (P<0.05). Cortisol-related comorbidities (hypertension, diabetes, etc.) showed no statistically significant differences between MACS and NFAT. Germline ARMC5 testing in 62 unrelated patients identified 7 novel pathogenic variants. Pathogenic mutations were detected only in MACS and CS groups, with no significant difference observed between them (P>0.05). Multiple confluent nodules were present in all ARMC5-mutated patients (16/16) but in fewer ARMC5 wild-type patients (20/44), with high sensitivity and negative predictive value for the prediction of germline pathogenic mutations.

CONCLUSION: No significant cortisol-related comorbidity differences were observed between radiologically suspected PBMAH patients with NFAT and MACS. Germline ARMC5 screening should prioritize patients with radiological findings of multiple confluent macronodules.

SIGNIFICANCE STATEMENT: Our work provides new insights into the management of primary bilateral macronodular adrenal hyperplasia (PBMAH): 1) MACS and NFAT patients with radiologically suspected PBMAH (i.e., bilateral benign adrenal macronodules) may require equal clinical attention; 2) We identified 7 novel ARMC5 pathogenic variants; 3) Multiple confluent adrenal nodules on imaging demonstrate predictive value for ARMC5 pathogenic mutations, refining genetic screening criteria.

PMID:41042544 | DOI:10.1530/EC-25-0290

JAMA Health Forum. 2025 Oct 3;6(10):e253479. doi: 10.1001/jamahealthforum.2025.3479.

ABSTRACT

IMPORTANCE: Persistent disparities in mortality across countries suggest uneven improvements in living standards and access to life-extending health technologies, as well as context-specific obstacles. Studies have analyzed cross-country inequality in mortality but have not widely contextualized those disparities in terms of developmental progress relative to a frontier representing a level of mortality achievable with broad access to the best health-enhancing technology and living standards available.

OBJECTIVE: To examine probability of premature death (PPD)-defined as probability of dying before 70 years of age-across countries and regions, benchmarking progress as years behind the lowest country-level PPD (the frontier).

DESIGN AND SETTING: This cross-sectional study used aggregate-level data from the 2024 United Nations World Population Prospects and Human Mortality Database to calculate PPD across 7 global regions and the 30 most populous countries. Data were analyzed from May to September 2025.

MAIN OUTCOME AND MEASURES: The primary outcomes were PPD and the number of years behind the lowest country-level PPD.

RESULTS: The frontier PPD fell from 57% to 12% from 1900 to 2019. Sub-Saharan Africa’s PPD in 2019 was 52%, corresponding to the 1916 frontier PPD. However, sub-Saharan Africa had converged toward the frontier by over 40 years since 2000, when it had a 65% PPD. China has been converging toward the frontier since 1970, having been 93 years behind the frontier PPD in 1970 (with a 60% PPD) and 35 years behind in 2019 (21% PPD). The US has diverged away from the frontier, having been 29 years behind in 1970 (38% PPD) and 38 years in 2019 (22% PPD). Of the regions included, the North Atlantic (Western Europe and Canada) was the closest to the frontier, being 13 years behind in 2019 (15% PPD). The US, Central and Eastern Europe, and sub-Saharan Africa were the furthest above the 2019 PPD Preston curve (ie, they had a greater PPD than predicted by their per capita gross domestic product).

CONCLUSIONS AND RELEVANCE: In this cross-sectional study, disparities in PPD were likely to reflect major inequality in access to health-enhancing technologies and living standards, as well as context-specific obstacles. Technological and medical advancements leading to universal health benefits need to be rapidly and fairly disseminated.

PMID:41042526 | DOI:10.1001/jamahealthforum.2025.3479

JAMA Health Forum. 2025 Oct 3;6(10):e253871. doi: 10.1001/jamahealthforum.2025.3871.

ABSTRACT

IMPORTANCE: The US has faced persistent antibiotic shortages over the past decade, compromising patient care, public health, and national security. Understanding the global sources of US antibiotic imports is critical to inform policies to improve supply chain resilience.

OBJECTIVE: To identify the global sources of US antibiotic imports, focusing on finished dosage forms (FDFs) and active pharmaceutical ingredients (APIs) between 1992 and 2024.

DESIGN AND SETTING: This cross-sectional study of US antibiotic importation records used data from USA Trade Online from January 1992 to July 2024. Data included import volumes, costs, and the originating country.

MAIN OUTCOMES AND MEASURES: Trends in annual import volumes for antibiotic FDFs and APIs (metric tons), spending and price per kilogram (inflation-adjusted dollars), and market concentration measured by the Herfindahl-Hirschman Index (HHI). An HHI less than 1500 indicates an unconcentrated (ie, competitive) market, 1500 to 2500 indicates a moderate concentration, and greater than 2500 indicates high concentration.

RESULTS: The final sample included 50 FDF-originating countries and 52 API-originating countries. Compared with the annual volume of US antibiotic FDF imports in 1992, the annual volume in 2024 increased 2595.0%, while the annual volume of API imports remained relatively stable. Mean inflation-adjusted importation prices for FDFs decreased from $1836.03 per kg in 1992 to $177.44 per kg in 2024. For APIs, mean prices decreased from $351.74 per kg in 2003 to $65.69 per kilogram in 2024. From 2020 to 2024, India was the leading originating country for FDFs (31.9% of the total imported volume and 18.2% of the total imported cost), followed by Italy (13.4% of the total volume and 22.4% of the total cost). China was the leading originating country for APIs (62.6% of the total imported volume and 28.7% of the total cost), followed by Bulgaria (16.1% of the total volume and 3.8% of the total cost). Italy was the originating country for 2.6% of API imported volume but accounted for 27.9% of the importation costs. HHI revealed that FDF importation has become unconcentrated since 2020 (HHI, 1500-2500), while API importation markets are highly concentrated (2024 HHI, >5000).

CONCLUSIONS AND RELEVANCE: This study found that US antibiotic importation relies on diversified global sources for FDFs but primarily on China for APIs. Policies to strengthen domestic production and diversify sourcing are critical to mitigate supply chain vulnerabilities. Improved traceability and targeted strategies for specific antibiotics are recommended to safeguard public health and national security.

PMID:41042525 | DOI:10.1001/jamahealthforum.2025.3871

JAMA Netw Open. 2025 Oct 1;8(10):e2535137. doi: 10.1001/jamanetworkopen.2025.35137.

ABSTRACT

IMPORTANCE: Hospital-acquired venous thromboembolism (HA-VTE) remains a leading cause of preventable death among hospitalized adults in the US. Despite numerous attempts to prognosticate HA-VTE with risk models, no single model has outperformed the rest, and the effectiveness of such models to drive prophylaxis decisions is unknown. Testing such systems in urban and rural settings may inform their generalizability.

OBJECTIVE: To conduct a randomized clinical trial to assess the effectiveness of artificial intelligence (AI)-driven clinical decision support (CDS) in reducing HA-VTE incidence in adults across urban and rural hospital settings.

DESIGN, SETTING, AND PARTICIPANTS: This parallel-group, single-blind, pragmatic randomized clinical trial is planned to be conducted from October 1, 2025, through September 30, 2027, by the Vanderbilt University Medical Center, a major academic health system in Tennessee. The study population will include adult (aged ≥18 years) patients admitted to medical, surgical, and intensive care units who may be at high risk for VTE and with no active or contraindication to deep vein thrombosis prophylaxis at Vanderbilt Adult Hospital in urban Nashville and 3 affiliated hospitals serving rural communities in Middle Tennessee.

INTERVENTION: Patients will be randomized 1:1 within the electronic health record to receive either VTE-AI-driven CDS (nudge practice alert [intervention arm]) or standard care using traditional risk assessment (control arm).

MAIN OUTCOME AND MEASURES: The primary outcome will be incidence of HA-VTE. Secondary trial outcomes will be process metrics, including length of stay, readmission rates, safety, and bleeding events. Outcomes will be analyzed using descriptive statistics and compared using Poisson regression.

DISCUSSION: Using a validated prognostic model, this study is one of the first to provide insights into whether AI-driven CDS can effectively reduce HA-VTE incidence without increasing adverse events. This study also is intended to provide insights into the usefulness of the same AI model implemented across urban and rural settings. The study’s findings and statistical code will be shared with the public through peer-reviewed publication and ClinicalTrials.gov.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06939803.

PMID:41042513 | DOI:10.1001/jamanetworkopen.2025.35137

JAMA Netw Open. 2025 Oct 1;8(10):e2535200. doi: 10.1001/jamanetworkopen.2025.35200.

ABSTRACT

IMPORTANCE: It is unclear whether performing surgery for most patients with an acute subdural hematoma (ASDH) and traumatic brain injury (TBI) is superior to conservative treatment.

OBJECTIVE: To compare the effectiveness of a strategy preferring acute surgical ASDH evacuation with one preferring initial conservative treatment.

DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study used data from February 1, 2014, to July 31, 2018, from the prospective observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study, conducted at 18 Level 1 trauma centers in the US. The study included patients with nonpenetrating TBI presenting to the emergency department and admitted within 24 hours after injury with ASDH detected on acute head computed tomography scan. Statistical analysis was performed from December 1, 2022, to December 20, 2024.

EXPOSURES: Acute surgical hematoma evacuation vs initial conservative treatment, comparing outcomes between centers according to treatment preferences, measured by the case mix-adjusted probability of undergoing acute surgery (vs conservative treatment) per center.

MAIN OUTCOMES AND MEASURES: Functional disability at 6 months was assessed with the Glasgow Outcome Scale-Extended at 6 months, analyzed with ordinal logistic regression adjusted for prespecified confounders, quantified with a common odds ratio (OR). Variation in center preference was quantified with a median OR (MOR).

RESULTS: Of 2697 included patients, 711 (mean [SD] age, 46.5 [19.4] years; 539 men [76%]) had an ASDH, of whom 148 (21%) underwent acute cranial surgery and 563 (79%) underwent initial conservative treatment. The acute surgery cohort had lower mean (SD) Glasgow Coma Scale scores (6.8 [4.4] vs 11.4 [4.6]), more pupil abnormalities (both pupils unreacting: 43 of 133 [32%] vs 41 of 477 [9%]), and fewer isolated ASDHs (eg, more with concurrent intracranial lesions; 92 of 133 [69%] vs 297 of 563 [53%%]) compared with the conservative treatment cohort. In the surgical cohort, 129 of 148 patients (87%) underwent decompressive craniectomy (DC), and 17 of 148 (11%) underwent craniotomy. In the conservative treatment cohort, 67 of 563 patients (12%) underwent delayed cranial surgery (DC or craniotomy). The proportion of patients undergoing acute surgery ranged from 0% to 86% (median, 17% [IQR, 5%-27%]) between centers, with up to a 3-fold higher probability of prognostically similar patients receiving acute surgery in one center compared with another random center (MOR, 2.95 [95% CI, 1.79-7.47]; P = .06). Center preference for acute surgery over initial conservative treatment was not associated with a better outcome (OR, 1.05 [95% CI, 0.88-1.26] per 22% [IQR, 5%-27%] increase in acute surgery at a given trauma center).

CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study, similar patients with traumatic ASDH were treated differently due to center-specific treatment preferences. Outcomes were similar in centers preferring surgical evacuation and those preferring initial conservative treatment. This study suggests that, for a patient with ASDH for whom a neurosurgeon experiences clinical equipoise between acute surgery vs (initial) conservative treatment, conservative treatment may be considered.

PMID:41042512 | DOI:10.1001/jamanetworkopen.2025.35200

JAMA Netw Open. 2025 Oct 1;8(10):e2535330. doi: 10.1001/jamanetworkopen.2025.35330.

ABSTRACT

IMPORTANCE: Mammography screening is essential for the early detection of breast cancer; however, delayed detection among screen-detected breast cancers (SDBCs) is rarely studied.

OBJECTIVES: To investigate whether women diagnosed with SDBC who missed the screening round immediately before the diagnostic round experience clinically significant delays in detection and whether tumor characteristics vary.

DESIGN, SETTING, AND PARTICIPANTS: This prospective register-based cohort study included all women diagnosed with SDBC in Stockholm, Sweden, between January 1, 1995, and February 28, 2020, with a follow-up until December 31, 2022. Data were analyzed from November 5, 2023, to May 27, 2024.

EXPOSURE: Nonparticipation in the screening immediately prior to the diagnostic round.

MAIN OUTCOMES AND MEASURES: Tumor characteristics and breast cancer-specific survival.

RESULTS: Among 8602 women with SDBC (median age at diagnosis, 61 [IQR, 55-66] years), 1482 (17.2%) did not attend the immediate past screening. Nonparticipants in the past screening were more likely to have larger tumors (adjusted odds ratio [AOR], 1.55 [95% CI, 1.37-1.76] for a tumor size ≥20 mm), lymph node involvement (AOR, 1.28 [95% CI, 1.12-1.45), and distant metastasis (AOR, 4.64 [95% CI, 2.10-10.29]) and less likely to have estrogen receptor-negative breast cancer (AOR, 0.74 [95% CI, 0.60-0.92]); however, there were no differences in progesterone receptor status (AOR, 0.96 [95% CI, 0.83-1.11]) or ERBB2 (formerly HER2 or HER2/neu) status (AOR, 1.00 [95% CI, 0.81-1.24]). In addition, these women experienced poorer breast cancer-specific survival, with an adjusted hazard ratio (AHR) of 1.33 (95% CI, 1.08-1.65). There was no association after adjusting for tumor characteristics (AHR, 1.11 [95% CI, 0.89-1.38]). Additionally, no association was found between nonparticipation in the second-to-last screening and tumor characteristics among those with screen-detected breast cancers (AHR, 0.98 [95% CI, 0.80-1.19] for stage II tumors or higher).

CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that some women with SDBC experience delayed detection and have clinically relevant worse outcomes. Future research is needed to investigate whether advancing the next mammography screening invitation date could enhance early detection and improve breast cancer outcomes in this population.

PMID:41042510 | DOI:10.1001/jamanetworkopen.2025.35330

JAMA Netw Open. 2025 Oct 1;8(10):e2535408. doi: 10.1001/jamanetworkopen.2025.35408.

ABSTRACT

IMPORTANCE: Medicare enrollees with low income report challenges affording out-of-pocket costs for health care. Although the Medicare Savings Programs (MSPs) were established to provide financial support, recent patterns in program take-up are understudied.

OBJECTIVES: To provide national and state-level estimates of take-up of the MSPs from 2018 to 2020 and describe the profile of enrolled and unenrolled individuals eligible for the MSPs.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis used data from the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of community-dwelling Medicare beneficiaries. Respondents from 2018 to 2020 who completed the income and assets questionnaire, which allowed assessment of MSP eligibility, were analyzed. Data were analyzed in July 2024.

EXPOSURES: Eligibility for the MSPs.

MAIN OUTCOMES AND MEASURES: The take-up rate of the MSPs, defined as the proportion of eligible beneficiaries enrolled in the program. The MCBS survey weights were applied to create a subsample that was nationally representative of the community-dwelling Medicare population.

RESULTS: The primary sample included 26 240 respondent-year observations, representing 179 221 355 beneficiary-years (14.0% [95% CI, 13.4%-14.5%] of respondents were <65 years, 55.1% [95% CI, 54.1%-56.0%] were female, and 37.7% [95% CI, 36.0%-39.4%] had a high school education or lower). A total of 20.9% (95% CI, 19.8%-22.0%) of the primary sample was eligible for the MSPs. Of those eligible, 56.7% (95% CI, 54.5%-59.0%) were enrolled. Take-up rates varied widely across states, ranging from 41.5% (95% CI, 25.7%-57.3%) in Ohio to 72.9% (95% CI, 67.6%-78.2%) in California. Take-up among Medicare Advantage beneficiaries was higher than among those in traditional Medicare (61.3% vs 52.9%; difference, 8.4 percentage points [pp] [95% CI, 3.5-13.2 pp]). Compared with eligible beneficiaries who were not enrolled, enrolled individuals had greater economic insecurity, including being 30.0 pp (95% CI, 25.4-34.6 pp) more likely to report income below 100% of the federal poverty level and 16.4 pp (95% CI, 13.2-19.6 pp) more likely to report assets less than $3000.

CONCLUSIONS AND RELEVANCE: This cross-sectional study of Medicare beneficiaries suggests that MSP take-up remains incomplete and varied across states despite policy efforts. A policy to encourage participation in the MSPs among eligible populations that target less socially and financially vulnerable-although still with low income and eligible for the MSPs-individuals may be more likely to be associated with gains in the MSP take-up.

PMID:41042507 | DOI:10.1001/jamanetworkopen.2025.35408

Ir J Med Sci. 2025 Oct 3. doi: 10.1007/s11845-025-04108-x. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: This study investigated the relationship between preoperative Modified 5-item Frailty Score (mFI-5) and long-term survival as well as 30-day postoperative complications in patients who underwent radical cystectomy for bladder cancer.

METHODS: Patients who underwent radical cystectomy between 2012-2023 were analyzed and divided into two groups based on their mFI-5 scores: low-risk (≤ 1) and high-risk (≥ 2). Overall survival (OS), cancer-specific survival (CSS), and 30-day postoperative complications were compared between these groups. Additionally, Cox proportional hazards regression analysis was used to examine the impact of the mFI-5 score on OS and CSS.

RESULTS: Our study included 288 patients with an average age of 63.8 ± 9.1 years at the time of surgery. Patients with a low mFI-5 score comprised 77.4% (n = 223) of the cohort, while 22.6% (n = 65) had a high mFI-5 score. The majority of patients had advanced-stage disease (pT3-pT4 for 53.8% (n = 155)). Patients with a high mFI-5 score demonstrated significantly worse OS and CSS compared to those with a low mFI-5 score (p = 0.002 and p = 0.007, respectively). Although 30-day mortality rates were significantly higher in the high mFI-5 score group (p = 0.002), the difference in overall complication rates was not statistically significant (p = 0.120). In multivariate Cox proportional hazards analysis, the mFI-5 score was identified as an independent predictor for both OS and CSS (p = 0.001 and p = 0.003, respectively).

CONCLUSION: mFI-5 score can provide valuable prognostic information regarding survival after radical cystectomy in bladder cancer patients, based on preoperative findings. It is an independent predictor of long-term survival.

PMID:41042491 | DOI:10.1007/s11845-025-04108-x

Infection. 2025 Oct 3. doi: 10.1007/s15010-025-02644-3. Online ahead of print.

ABSTRACT

BACKGROUND: Sepsis survivors are affected by a broad spectrum of long-term impairments, which overlap with Long-Covid and sequelae after influenza in their clinical presentation. However, we lack comparative assessments on the burden of long-term outcomes, particularly with patients being recruited from the same, contemporary patient population. Therefore we compared long-term outcomes after respiratory sepsis (RS), SARS-CoV-2-associated sepsis (SS) and influenza-associated sepsis (IS).

METHODS: Retrospective, population-based cohort study. We included patients > 15 years hospitalized with RS, SS and IS between 01/2020 and 12/2020 in Germany, who received intensive care unit treatment. We compared mortality, readmissions, prevalence of diagnoses in the cognitive, psychological or medical domain, and the number of impaired domains in the 12 months post-discharge between the three survivor cohorts, adjusting for between-group differences in relevant covariates by inverse propensity score weighting based on generalized propensity scores.

RESULTS: Our study included 12,854 patients, of which 8,201 were RS, 3,964 SS and 689 IS survivors. RS survivors had a considerably higher risk for 12-month mortality compared to SS and IS survivors (relative risk, 1.77 [95% CI, 1.54-2.03]; P < 0.001 and relative risk, 1.37 [95% CI, 1.14-1.65]; P = 0.001, respectively). They were more often rehospitalized, affected by multiple domain impairments, cognitive decline and impairments related to the severity of acute disease, e.g. complications of the tracheostoma, compared to survivors after SS and IS. RS survivors had a lower risk for being affected by medical diagnoses compared to SS. Risks for psychological diagnoses did not differ between RS and the other survivor groups.

CONCLUSIONS: Although respiratory sepsis survivors seem to be affected by more severe long-term impairments, the overall burden of post-acute sequelae among all survivor groups is high. This warrants efforts to provide targeted aftercare for all survivor populations after life-threatening infections.

PMID:41042487 | DOI:10.1007/s15010-025-02644-3