To explore the clinical phenotype and genetic etiology for a Chinese pedigree affected with Hereditary coagulation factor Ⅴ deficiency (FⅤD). A 47-year-old female who visited the First Affiliated Hospital of Wenzhou Medical University in July 2025 and her family members (husband, mother, younger brother and younger brother's wife, elder sister, second elder sister, daughter, son, elder niece, and second niece) were selected as study subjects. Clinical data and family history were retrospectively collected. Peripheral blood samples were collected from the proband and her family members. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), coagulation factor Ⅱ activity (FⅡ:C), coagulation factor Ⅶ activity (FⅦ:C), coagulation factor Ⅷ activity (FⅧ:C), coagulation factor Ⅹ activity (FⅩ:C), and FⅤ activity (FⅤ:C) were measured in all participants using the one-stage clotting assay. FⅤ antigen (FⅤ:Ag) levels in plasma were determined with enzyme-linked immunosorbent assay (ELISA). Genomic DNA was extracted from peripheral blood samples of all participants, and the coding regions of the F5 gene were amplified by PCR and subjected to Sanger sequencing. Candidate variants were verified with multiple online tools to predict their pathogenicity and impact on splicing. Based on guidelines formulated by the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was evaluated. Coagulation function of all participants was evaluated using thrombin generation assay and thromboelastography. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: KY2022-R193). The proband's peripheral blood PT and APTT were 25.6 s and 58.3 s, respectively, while FⅤ:C and FⅤ:Ag were 7% and 6%, respectively, which was in keeping with a phenotype of type I FⅤD. Her brother also showed significantly decreased FⅤ:C and FⅤ:Ag levels. The proband's mother, eldest sister, second sister, daughter, son, eldest niece, second niece had FⅤ:C and FⅤ:Ag approximately 50% of those of normal controls, whereas her husband and sister-in-law showed no obvious abnormality in such indices. Genetic testing revealed that the proband and her brother both harbored compound heterozygous variants of the F5 gene, namely c.6528+3A>T (IVS24+3A>T) and c.6665A>G (p.Asp2222Gly), for which other family members with reduced FⅤ:C and FⅤ:Ag were heterozygous carriers, and those with normal coagulation indices were of the wild-type. Bioinformatics analyses using multiple software indicated that the IVS24+3A>T variant is located at a splice donor site and can significantly weaken the strength of the splice site, potentially leading to exon skipping. Based on the ACMG guidelines, the novel variant is classified as likely pathogenic (PM2_Moderate+PM3_Moderate+PP1_Supporting+PP3_Supporting+PP4_Supporting). Results of thrombin generation assay indicated reduced thrombin generation capacity in the proband, whilst thromboelastography results showed abnormal coagulation characteristics manifested as prolonged coagulation initiation time. Ultimately, both the proband and her younger brother were diagnosed with hereditary type I FⅤD. The IVS24+3A>T and p.Asp2222Gly compound heterozygous variants of the F5 gene probably underlay the pathogenesis of FⅤD in this pedigree. Above finding has enriched the mutational spectrum of the F5 gene and provided a basis for genetic counseling and molecular diagnosis.
The growing involvement of private equity in the health care sector raises important questions about its effect on cost, quality, access, and the physician workforce. Private equity investment in health care is associated with increased costs and, in some settings, adverse effects on care delivery and outcomes. Rising costs, administrative burdens, workforce shortages, and declining reimbursement have made independent practice increasingly difficult, contributing to physician transitions to corporate ownership models. Physicians employed by private equity-owned health care organizations may also experience challenges due to the evolving dynamics of their work environment. State and federal regulators, as well as lawmakers, should consider implementing policy interventions to address these challenges. Although corporate investment may improve efficiency and, in limited instances, care delivery, private equity in this sector raises important questions about its role and effects. This American College of Physicians (ACP) position paper builds on the previous ACP position paper on financial profit in medicine, which explored the growing influence of corporate interests and private equity investment in the health care industry. This paper examines the effect of private equity investment on clinical autonomy, health care costs, quality, access, equity, and innovation. It emphasizes the need for more vigorous enforcement of regulatory measures and policy solutions to preserve the quality of patient care and protect the physician workforce. It also offers recommendations to strengthen oversight, transparency, and accountability related to private equity's effects on clinical autonomy, care delivery, and organizational decision making. Finally, it discusses the potential opportunities and challenges associated with private equity investment in health care, including increased consolidation and corporatization.
Road injuries are a leading cause of mortality and morbidity worldwide. Years of international efforts have aimed to strengthen policy engagement, including the 2020 UN General Assembly's proclamation of the Second Decade of Action for Road Safety (2021-30), targeting a 50% reduction in road traffic deaths and serious injuries by 2030. The aim of this study is to provide estimates to monitor progress and identify intervention gaps. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2023, we estimated incidence, mortality, and morbidity of road injuries for 204 countries and territories from 1990 to 2023. Four road injury types and 47 nature-of-injury categories were examined. Morbidity and mortality data from clinical records, vital registration, and police reports were harmonised using meta-analytic techniques to ensure consistency and correct for systematic bias. Incidence was modelled with the meta-regression tool Disease Modelling-Meta-Regression version 2.1 and cause-specific mortality with the Cause of Death Ensemble model, both incorporating location-specific covariates to support interpolation. Years of life lived with disability (YLDs) were estimated from the prevalence and severity of the nature of road injury, and years of life lost (YLLs) from the number of cause-specific deaths multiplied by the standard life expectancy at the age of death. Disability-adjusted life-years (DALYs) were the sum of YLLs and YLDs. All metrics were calculated with 95% uncertainty intervals (UIs). In 2023, there were 50·9 million (95% UI 46·1-56·1) road injury incident cases, 1·34 million (1·04-1·58) deaths, and 75·3 million (59·8-89·2) DALYs globally. Road injuries were the leading global cause of death among males aged 10-39 years. Between 1990 and 2023, age-standardised incidence decreased by 38·3% (95% UI 36·9-39·7) and mortality decreased by 32·3% (6·1-49·0), but progress varied widely by World Bank income group. Mortality in low-income countries (43·8 [95% UI 31·7-56·0] deaths per 100 000 population) was approximately six times higher than in high-income countries (7·5 [7·1-7·9] deaths per 100 000), despite the high-income countries showing the highest age-standardised incidence rates (858·1 [95% UI 781·9-947·1] cases per 100 000). In the past decade, many countries achieved notable reductions in road injuries, but others, including Ghana and the USA, saw increases. More severe injuries tended to occur in low-income and middle-income countries. Although global incidence, mortality, and DALY rates from road injuries have declined, progress remains uneven, with pronounced disparities across income groups reflecting systemic inadequacies in infrastructure, vehicle standards, enforcement, and post-crash care. Strengthening emergency response, improving road design, enforcing safety measures, and adapting policies to the evolving demographics remain essential. Gates Foundation.
Mild traumatic brain injury (mTBI) is common among older adults but challenging to diagnose due to symptoms that overlap with age-related changes. Blood biomarkers are proposed to complement diagnostic criteria, but older adults are underrepresented in existing studies, leaving performance and thresholds uncertain. To determine the diagnostic accuracy of 4 plasma biomarkers-glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), brain-derived tau (BD-tau), and neurofilament light (NfL)-for identifying mTBI and to explore the utility of these biomarkers for discriminating clinically ambiguous suspected mTBI in older adults. This cross-sectional study was conducted between June 27, 2024, and August 5, 2025. Participants were individuals 60 years of age or older who visited a tertiary adult trauma center in Melbourne, Australia, within 72 hours of a suspected head injury or community-dwelling volunteers at least 60 years of age with no recent head injury or bodily trauma (controls). Clinical diagnosis of mTBI within 72 hours of injury based on 2023 American Congress of Rehabilitation Medicine criteria. Glasgow Coma Scale score, ranging from 3 to 15, with higher values indicating milder injury, collected during enrollment. Diagnostic performance of each plasma biomarker quantified by age- and sex-adjusted area under the (receiver operating characteristic) curve (AAUC). Participants (n = 89) ranged in age from 60.0 to 84.0 years (mean [SD], 70.8 [6.6] years; 48 [54%] male). Among them, 35 were healthy controls, 45 were diagnosed with mTBI, and 9 had suspected mTBI. The majority of the group diagnosed with mTBI presented with a Glasgow Coma Scale score of 15 (n = 34 [76%]). All 4 biomarkers were significantly elevated in participants with diagnosed mTBI vs controls (B = 129.36 [95% CI, 86.66-172.06]; P < .001 for GFAP; B = 5.61 [95% CI, 3.99-7.24]; P < .001 for BD-tau; B = 4.63 [95% CI, 1.53-7.74]; P = .005 for NfL; and B = 16.52 [95% CI, 5.96-27.07]; P < .001 for UCH-L1). GFAP demonstrated excellent diagnostic accuracy (AAUC = 0.93 [95% CI, 0.86-0.98]), and BD-tau showed good accuracy (AAUC = 0.72 [95% CI, 0.54-0.95]). UCH-L1 and NfL showed fair accuracy (AAUC = 0.68 [95% CI, 0.487-0.93] and AAUC = 0.67 [95% CI, 0.54-0.79], respectively). Optimal diagnostic thresholds for biomarkers were age-dependent (eg for GFAP, 94-108 pg/mL at age 60 years to 194-208 pg/mL at age 84 years) and sex-dependent (eg for UCH-L1, approximately 9.6 pg/mL for females and approximately 2.3 pg/mL for males across the age range). The suspected mTBI group had elevated GFAP (B = -87.04 [95% CI, -151.38 to -22.70]; P = .01) and BD-tau (B = -5.59 [95% CI, -8.83 to -2.36]; P = .001) concentrations vs controls, with 6 participants (67%) to 8 participants (89%) exceeding their personalized diagnostic cutoffs, for GFAP and BD-tau, respectively. In this cross-sectional study of older adults presenting within 72 hours of injury, the plasma GFAP concentration demonstrated excellent diagnostic accuracy for mTBI. GFAP was elevated in the majority of clinically suspected mTBI cases using age- and sex-adjusted thresholds, supporting its potential to improve diagnostic certainty in mTBI, particularly in diagnostically ambiguous presentations, in older adults.
Machine learning (ML) has become a transformative force in clinical research, offering predictive precision and data-driven decision-making across diverse medical domains. Despite this rapid adoption, a comprehensive informatic-based synthesis of ML applications in clinical trials remains lacking. This study systematically maps the scientific landscape, thematic evolution, and emerging directions of ML-related clinical trial research. The analysis was conducted on PubMed-indexed clinical trials (1995-2025) using Bibliometrix R package, VOSviewer, and Microsoft Excel 2021 (Microsoft Corp., USA). Temporal trends were modeled using ARIMA(5,1,0) forecasting and additive time-series decomposition. Collaboration networks, productivity patterns (Lotka's Law), journal dispersion (Bradford's Law), keyword co-occurrence, and thematic mapping (Walktrap clustering, Callon's centrality/density) were analyzed to identify conceptual structures and research frontiers. A total of 1,195 publications across 563 journals were identified, showing exponential growth after 2018 and a forecasted stabilization by 2030. The USA (24.8%) and China (19.5%) led global output, reflecting strong North American-Asian collaboration. Keyword co-occurrence revealed eight clusters centered on machine learning, artificial intelligence, and radiomics, transitioning toward deep learning, precision medicine, and mHealth. Bradford's Law identified 36 core journals, including Scientific Reports, BMJ Open, and PLOS ONE. Thematic evolution showed a shift from algorithmic and retrospective studies to clinically grounded themes such as cognitive behavioral therapy and telemedicine. Emerging topics emphasized translational and patient-centered applications. This study delineates the dynamic evolution of ML in clinical trials, highlighting its growing integration into precision medicine. Future research should prioritize inclusivity, real-world implementation, and ethical frameworks to sustain equitable and clinically impactful innovation.
Digital health tools are increasingly used in mental health care to passively collect patient data and analyze health status outside of clinical settings. While technologies such as digital phenotyping, affective computing, and computational behavioral analysis offer new insights into symptom manifestation in daily life, they generate large volumes of potentially sensitive data that raise significant data privacy concerns, requiring high levels of patient awareness and consent. Empirical research is lacking on stakeholder understandings toward the sensitivity of these data and expectations for data stewardship, perspectives that are critical for developing robust informed consent and data protection policies for digital health data use. This study aimed to explore key stakeholder perspectives on the sensitivity of computer perception (CP) data, trust in existing data protections, willingness to share CP data externally, and desire for transparency of CP data transactions outside of the clinical space. As part of a larger, multisite study, we conducted qualitative interviews (n=40) via Zoom (Zoom Communications, Inc) with 20 adolescents (aged 12-17 years) familiar with CP tools and their caregivers (n=20). Interviews consisted of a series of open-ended questions regarding stakeholders' perspectives on privacy, data security, and the use and exchange of CP data. We developed a qualitative codebook to identify and label thematic patterns in responses to questions addressing the topics above, using thematic content analysis to identify themes inductively. Each interview was coded by merging work from at least two separate coders, and several team members contributed to qualitative analysis. Most adolescents and caregivers viewed CP data as highly sensitive and expressed a reluctance to share these data beyond their clinical teams. While many participants expressed trust in existing data protections to protect CP data, they often misunderstood or overestimated the extent of protections to safeguard CP data. Our findings underscore the critical need for clear and effective patient communication and education about the risks, benefits, and protections associated with CP data through informed consent protocols. To promote greater transparency, understanding, and trust, we recommend 5 strategies: educating patients about data protection; studying secondary data exchange and reidentification risks; strengthening transparency regulations; improving data traceability mechanisms, such as distributed ledger technologies, to enhance data traceability and auditability; and adopting dynamic consent models.
To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.
Small, dense low-density lipoprotein (sdLDL) particles are considered a highly atherogenic subfraction of LDL. Automated biochemical measurement of sdLDL cholesterol (sdLDL-C) has good fidelity to gold-standard measurements. We evaluated relationships of sdLDL-C and LDL-C to risk of major adverse cardiovascular events (MACE) and treatment benefit of the PCSK9-directed monoclonal antibody alirocumab in patients with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins despite optimized statin treatment. Analyses comprised 11,837 participants in the ODYSSEY OUTCOMES trial randomized to receive alirocumab or placebo. sdLDL-C was measured using the Denka method; baseline LDL-C was calculated with the Friedewald formula. In the placebo group (n = 5920), cubic splines depicted relationships of sdLDL-C, LDL-C, and their ratio to risk of MACE (cardiovascular death, non-fatal myocardial infarction, ischemic stroke, hospitalization for unstable angina, and ischemia-driven coronary revascularization). Treatment hazard ratio (HR) was calculated across sdLDL-C and LDL-C ranges. Over 2.8 years median follow-up, risk of MACE in the placebo group increased with higher baseline sdLDL-C or LDL-C with nearly superimposable splines and without variation according to sdLDL-C/LDL-C. Findings were similar in patients with greater or lesser degrees of insulin resistance. Alirocumab reduced risk of MACE (HR 0.87, 95% CI 0.79, 0.95). Treatment HR did not vary significantly across the range of LDL-C or sdLDL-C. In patients with recent ACS on optimized statin treatment, sdLDL-C and LDL-C similarly predict risk of MACE and benefit of alirocumab treatment. Measurement of sdLDL-C does not appear to provide additional prognostic or predictive information in this population.
Since the 1970s, the World Health Organization (WHO) has advanced "traditional medicine" as a global policy category for culturally grounded health care. In South America, this framework has encountered a distinct political landscape in which traditional peoples have emerged as collective subjects mobilizing around rights, territorial claims, and expanding conceptions of citizenship. This paper examines how the codification of "tradition" from an identity category into a health regulatory term reconfigures the conditions under which difference can be expressed, claimed, and sustained. Drawing on archival research across 10 South American countries, as well as WHO and United Nations documentation, the study traces how the global framework has been incorporated, requalified, or displaced across distinct national contexts. The analysis reveals a spectrum of regulatory arrangements in which institutional incorporation and the political force of collective difference are not commensurate, ranging from frameworks that engage with the political projects through which traditional peoples have sought to reshape citizenship to those in which "tradition" operates as a market authorization criterion detached from the subjects who sustain it. The codification of tradition into governable categories does not simply extend recognition to those who bear it; it reconfigures the terms under which they can act as political subjects.
The credibility of nutritional research is dependent on the rigor with which studies are conducted and the ability for independent assessment to be performed. Despite the importance of these, more work is needed in the field of nutrition to buttress the trustworthiness of nutrition research. To develop and apply a process for evaluating the rigor, reproducibility, and verifiability of nutritional research, using the relationship between potato consumption and Colorectal Cancer (CRC) as a case study. We updated existing systematic reviews to include studies on potatoes and CRC, assessing their design, execution, and reporting quality. We attempted to reproduce and verify the results of included studies by requesting raw data from authors and following statistical methods as described in the publications. Rigor was evaluated using four different tools: ROBINS-E, STROBE-Nut, Newcastle-Ottawa scale, and additional criteria related to transparency. Eighteen studies were included, none of which publicly share data. We managed to access data for only two studies, successfully reproducing and verifying the results for one. The majority of studies exhibited a high risk of bias, with significant limitations in reporting quality and methodological rigor. Research on the relationship between potato consumption and CRC risk is insufficiently reproducible and verifiable, undermining the trustworthiness of its findings. This study highlights the need for improving transparency, data sharing, and methodological rigor in nutritional research. Our approach provides a model for assessing the credibility of research in other areas of nutrition.
Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Recent reductions in global health funding have threatened TB control, making comprehensive assessment of TB, HIV-related TB, and drug-resistant TB burdens before these disruptions essential for shaping effective responses. The WHO End TB Strategy sets targets of a 95% reduction in TB deaths and a 90% reduction in TB incidence between 2015 and 2035. Using results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, this study aims to assess the burden of TB and multidrug-resistant TB (MDR-TB) across 204 countries and territories, and to evaluate progress towards the WHO End TB incidence and mortality targets. We quantified TB mortality using the Cause of Death Ensemble modelling platform with global vital registration, surveillance, verbal autopsy, and minimally invasive tissue sampling data. For TB morbidity estimation, we simultaneously modelled incidence, prevalence, and mortality by age and sex using DisMod-MR 2.1. A population attributable fraction (PAF) approach was applied to stratify morbidity and mortality estimates by HIV and drug-resistance status. We also calculated disability-adjusted life-years (DALYs) as the sum of years of life lost and years lived with disability. For the risk factor analysis, a comparative risk assessment framework was used and PAFs were derived for alcohol use, smoking, and high fasting plasma glucose to determine the proportion of TB burden associated with these risk factors. In 2023, there were an estimated 9·11 million (95% uncertainty interval 8·04-10·3) incident cases of all-form TB, 1·22 million (0·98-1·49) deaths, and 54·6 million (43·8-65·5) DALYs globally. HIV-related TB comprised 781 000 (690 000-879 000) incident cases and 210 000 (142 000-279 000) deaths, contributing 11·0 million (7·56-14·3) DALYs. MDR-TB accounted for 466 000 (198 000-1 080 000) incident cases, 102 000 (31 700-238 000) deaths, and 3·96 million (1·31-9·01) DALYs. From 2015 to 2023, global all-form TB incidence rates declined by 19·2% (17·8-20·5) and deaths declined by 22·6% (4·7-35·7); declines were larger for drug-susceptible TB than for MDR-TB. Sub-Saharan Africa and south Asia had the highest mortality burdens in 2023; reductions in all-form TB incidence and mortality were uneven between 2000 and 2023, with limited progress in both measures in Latin America and the Caribbean. Removing smoking, alcohol use, and high fasting plasma glucose would reduce global TB deaths to 768 000 (592 000-970 000) and DALYs to 34·9 million (27·8-43·8) in 2023; MDR-TB deaths would decrease to 77 200 (23 400-183 000) and DALYs to 3·12 million (1·03-7·29). Global progress towards WHO End TB targets is disparate and fragile. Although many regions achieved meaningful gains, others have stagnated in recent years. The complexity of TB prevention is amplified by divergent MDR-TB trends, the persistent burden of HIV, and growing exposure to modifiable risk factors. Recent volatility in global health financing threatens to further destabilise this vulnerable epidemiological landscape; concerted action is urgently needed to temper disruptions and preserve progress. Gates Foundation.
This article argues that biobanks are best conceptualized as fiduciaries of biospecimens and associated data. Building on fiduciary legal theory and Anglo-American fiduciary jurisprudence, it explains how long-term discretionary control, informational asymmetry, and donors' limited ability to monitor downstream uses justify duties of care and loyalty, even though legal recognition and enforceability remain jurisdiction-dependent. The argument is situated within earlier trust-based and fiduciary accounts of biobank governance and is connected to international governance standards, including ISO 20387 (which frames the biobank as a legal entity) and the International Society for Biological and Environmental Repositories Best Practices, treating them as practical specifications of fiduciary stewardship rather than sources of binding law. The fiduciary framework reconceives broad consent as an ongoing governance commitment rather than a one-time authorization, justifies cost recovery as reimbursement for professional stewardship, and subjects intellectual property and benefit-allocation arrangements to loyalty-based constraints. It also situates this fiduciary approach alongside EU General Data Protection Regulation principles of accountability, purpose limitation, and transparency. It argues that public trust is a condition of sustainable biobank governance and that fiduciary governance supports proactive, accountable promotion of research uses of samples and data.
Disclosure of conflict of interest (COI) is important for surgical societies to minimize bias. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) requires committee members to disclose potential COI to promote full transparency. This study investigates compliance with this requirement and quantifies the actual dollar amounts that ineligible companies, collectively "industry", give to committee members. All SAGES committee members were queried in the Centers for Medicare & Medicaid Services Open Payments database (OPD). The query results for 2023 and 2024 were compared to the actual self-reported disclosure statements submitted to SAGES in the spring of 2025. Due to the nature of the database, only US-based physicians were included. Only payments of $500 or more were recorded. Only committees whose rosters were available online were utilized. Incorrect disclosure was defined as a mismatch between the OPD and the member's disclosure. There were 930 individual committee members and 185 were excluded by OPD. Only 51% (382/745) of OPD queries matched disclosures. Correct disclosure occurred in 104/467 who had disclosable COI. Industry paid over $18,000,000 to committee members; one-third came from Intuitive Surgical. Members who received payments received an average of $38,992. The largest total amount to one individual was over $2,500,000. There was no difference in average payments received or appropriate disclosure rate by committee members on one committee versus those on multiple committees. Chair/co-chairs (n = 114) did not differ from other members (n = 631) in percent of appropriate disclosures (59 vs. 50%). However, chairs/co-chairs did receive larger payments ($37,501 vs. $22,021; p < 0.0035). SAGES has set policies for disclosing COI. Enforcement of these policies is challenging. Many committee members receive large payments from industry; thus the actual dollar amount should also be reported. Full and accurate reporting will allow for full transparency and reduce perception of bias.
Inclisiran is a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 messenger RNA, that effectively reduces low-density lipoprotein cholesterol (LDL-C) levels. The effect of inclisiran on cardiovascular (CV) outcomes has not been formally tested. VICTORION-2 Prevent (NCT05030428) is an ongoing, Phase 3 randomized, double-blind, placebo-controlled, international trial assessing the efficacy and safety of inclisiran in preventing CV events in patients with established atherosclerotic cardiovascular disease (ASCVD) receiving high-intensity statin therapy. Patients with established ASCVD (history of myocardial infarction [MI], ischemic stroke, or symptomatic peripheral artery disease), and fasting plasma LDL-C ≥ 1.8 mmol/L (70 mg/dL) despite high-intensity statin therapy (≥ 20 mg rosuvastatin or ≥ 40 mg atorvastatin daily) will be enrolled. Patients will be treated with inclisiran sodium 300 mg or placebo, administered subcutaneously at Day 1, Day 90, and every 6 months thereafter. The primary outcome will include time to first occurrence of 3-point major adverse CV events (3P-MACE; composite of CV death, MI, or ischemic stroke). Secondary outcomes will include time to occurrence of CV death, time to first occurrence of 4P-MACE (composite of 3P-MACE and urgent revascularization), and major adverse limb event (all adjudicated outcomes), time to occurrence of all-cause death, and long-term safety of inclisiran. Safety will be monitored using a selective safety data collection strategy. VICTORION-2 Prevent will provide robust data on CV benefits and safety of inclisiran in patients with established ASCVD and not at guideline-recommended LDL-C goals despite high-intensity statin treatment. https://clinicaltrials.gov/study/NCT05030428.
Use of the US Food and Drug Administration's Accelerated Approval pathway assumes that patients are willing to accept uncertainty about clinical benefit in exchange for faster access to new cancer drugs. However, little is known about how patients view this trade-off or the circumstances under which they consider it acceptable. To explore patients' views on the trade-off between faster approval and evidentiary certainty regarding the clinical benefit of new cancer drugs in the US. This qualitative study used semistructured interviews conducted online between January 27 and April 1, 2025, with patients aged 18 years or older diagnosed with breast cancer. Purposive sampling was used to achieve maximum variation in cancer stage, treatment status, age, and sociodemographic background. The primary outcome was patients' views on the trade-off between faster drug approval and evidentiary certainty. Interview transcripts were thematically analyzed to identify key patterns in understanding, experiences of uncertainty, attitudes toward waiting, treatment priorities, and views on regulatory decision-making. A total of 125 individuals registered their interest and met eligibility criteria to participate. After purposive sampling, 30 participated in this study (10 aged 20-39 years [33.3%], 12 aged 40-59 years [40.0%], and 8 aged >60 years [26.7%]; all female), representing 17 US states (9 Northeast, 12 Midwest, 4 South, 5 West). A total of 13 participants (43.3%) had metastatic disease, 21 (70.0%) were receiving active treatment, and 27 (90.0%) had received at least 1 systemic therapy. Faster approval at the expense of certainty about the clinical benefit of new cancer drugs was considered most acceptable when no alternative treatments existed or when the anticipated benefits were transformative. When clinical benefit was uncertain, participants emphasized the importance of survival and quality of life as priority treatment outcomes, the added risks of adverse effects, and the burden of intensive treatment. Many viewed broader access to clinical trials, rather than faster regulatory approval, as an effective way to address unmet needs while facilitating evidence generation for approval. In this qualitative study of patients diagnosed with breast cancer, there was a mismatch between when patients considered trading evidentiary certainty for faster approval as acceptable and the conditions under which many new cancer drugs are approved by the Food and Drug Administration. To better align regulatory approvals with patient values, use of accelerated approval may be most appropriate for drugs that are likely to address genuine treatment gaps or offer meaningful improvements in clinical outcomes over existing alternatives.
Glomerular diseases are a leading cause of chronic kidney disease (CKD) and kidney failure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the risk of kidney function loss in CKD, but its effects in individuals with CKD due to glomerular diseases are uncertain. To evaluate the efficacy and safety of finerenone in patients with glomerular diseases. Prespecified exploratory subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled trial conducted across 24 countries and regions, focusing on participants with an investigator-reported glomerular disease diagnosis. The overall trial enrolled adults with nondiabetic CKD and an estimated glomerular filtration rate (eGFR) of either (1) at least 25 to less than 60 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 200 mg/g to less than 500 mg/g or (2) an eGFR of at least 25 to less than 90 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 500 mg/g to less than 3500 mg/g. Finerenone 10 mg or 20 mg taken orally once daily (n = 446) vs matching placebo (n = 457). Annualized rate of eGFR decline (total eGFR slope) from baseline to month 32 (primary outcome of the main trial); percent change in albuminuria to 12 months; and a composite outcome of kidney failure or sustained 40% or more decline in eGFR (prespecified exploratory outcomes). Of 1584 participants, 903 (57.0%) had investigator-reported glomerular disease, including 416 (46.1%) with immunoglobulin A nephropathy, 215 (23.8%) with focal segmental glomerulosclerosis, and 90 (10.0%) with membranous nephropathy. Participants with glomerular disease (mean [SD] age, 51.1 [13.6] years; 362 female [40.1%]; 558 Asian [61.9%]) had a mean eGFR of 48.8 mL/min/1.73 m2 and median urinary albumin to creatinine ratio of 839.6 mg/g. The total eGFR slope up to 32 months was -3.50 mL/min/1.73 m2 per year with finerenone and -4.23 mL/min/1.73 m2 per year with placebo (0.73 mL/min/1.73 m2 per year difference; 95% CI, 0.22-1.24). Finerenone reduced albuminuria at month 12 by 42% (95% CI, 35%-48%) and lowered the risk of kidney failure or 40% or more eGFR decline (7.42 vs 9.60 events per 100 patient-years; hazard ratio, 0.74; 95% CI, 0.57-0.97). In this exploratory analysis, treatment with finerenone slowed kidney function decline, reduced albuminuria, and lowered the risk of kidney failure or substantial loss of kidney function in patients with glomerular diseases. These findings suggest an important role for finerenone in preserving kidney function in this population. ClinicalTrials.gov Identifier: NCT05047263.
Smoking represents a significant public health problem and exploring the factors that may influence its development in youth is of major importance. The research on adolescent populations that addresses the impact of posttraumatic stress on smoking over time, especially using ethnicity and gender perspectives, remains limited. The study was conducted on a representative sample of predominantly ethnic minority youth (N = 2596; 53.5% female; age 11-16 years old (M(SD) = 12.75(1.27)); 58.8% African-American, 25.5% Hispanic American, 13.6% White). Self-reported information was obtained on smoking, symptoms of posttraumatic stress and depression in year 1 and on smoking in year 2. Generalised Linear Models were used to explore the association between posttraumatic stress in year 1 and smoking in year two in youth from the different ethnic groups, while controlling for their baseline levels of smoking, depressive symptoms, age and socio-economic status. Posttraumatic stress was related to smoking one year later, and the association remained significant while also adjusting for the baseline variables. Sensitivity analyses indicated that the association was primarily driven by smoking frequency rather than smoking quantity. The association between posttraumatic stress and smoking did not differ by gender or ethnicity, although more females than males reported smoking both at baseline and one year later, and fewer African American adolescents reported smoking, as compared to White and Hispanic American adolescents. The findings emphasize the importance of the timely recognition of traumatic exposure and may inform targeted prevention and early interventions.
The authors analyze the 2024 US Court Case concerning a civil action brought by the mother of an American adolescent affected by Asperger syndrome who, after developing an emotional dependency on an artificial intelligence-based chatbot, died by suicide using his stepfather's firearm. The action was brought against the software developer on grounds related to the design and deployment of the application. The case highlights the correlation between psychological risk factors and insufficient protective measures in the context of neurodivergent autism spectrum conditions and excessive, unregulated internet use. The analysis considers the interaction between the minor's psychological vulnerability in engaging with the software and the lack of adequate control and safety mechanisms within the technological device. Parental responsibility also emerges, in relation to the mother's failure to supervise her son's digital activities and the stepfather's breach of the legal duty to properly secure a firearm. A comparative perspective between the United States and Italy allows consideration of regulatory similarities and converging legal principles.
Between 2018 and 2024, 14 US states sought or obtained Section 1115 waivers to condition Medicaid expansion coverage on community engagement requirements, with medically frail exemptions determined from claims-based administrative data; the One Big Beautiful Bill Act of 2025 (Public Law 119-21) codified these requirements nationally, with state implementation due by January 2027. Using American Community Survey Public Use Microdata Sample data from 75 043 Medicaid-enrolled adults aged 19-64 across 17 states, we simulated frailty identification under each state's existing algorithm via a 3-channel Monte Carlo microsimulation incorporating algorithm design, claims visibility, and documentation burden. Existing algorithms identified a mean of 31.4% of adults with functional disability as medically frail (range: 14.3% [Florida, Arizona] to 45.4% [New York]). An evidence-based redesigned algorithm incorporating expanded diagnostic criteria, health information exchange integration, ex parte determination, and elimination of physician certification requirements increased mean identification to 45.6% (+14.3% points), with gains across all 17 states. In multi-dimensional equity evaluation, the redesigned algorithm narrowed the American Indian/Alaska Native-White sensitivity gap by 46% (from 11.6% to 6.3% points) and the Black-White gap by 10% (from 12.8% to 11.5% points); within-race rural-urban sensitivity differences of 3%-5% points persisted under both algorithms. Adoption of the redesigned algorithm would identify an estimated 3.8 million additional medically frail adults and avert approximately 253 000 coverage losses under full implementation. These findings support minimum algorithmic design standards for state frailty determination systems.
To investigate hospital-level variation in the supplementation of calcium, magnesium, phosphate, and potassium in critically ill patients. Retrospective cohort study. Premier Healthcare Database of inpatients from the USA. Adults (age ≥ 18 years) admitted to an intensive care unit (ICU) on hospital day 1 between October 1, 2022 and July 31, 2024, who had at least one calcium (total or ionized), magnesium, phosphate, or potassium level measured in an ICU between day 2 and 28. We excluded patients with renal failure, a pregnancy-related diagnosis, and intracranial bleeding on admission. Calcium, magnesium, phosphate, or potassium supplementation. We included 47,988 patients from 67 ICUs across 52 hospitals, totaling 167,621 patient-days with a measurement of one of the studied electrolytes. Median age was 64 years (interquartile range [IQR] 52-74) and 46% (22,057) were female. There were 38,621 patients (80.5%) with a minimum value below a lower limit of normal, and 33,626 (70.1%) patients who received supplementation. Across hospitals, the median (IQR) percentages receiving supplementation per day were: calcium 9.4% (6.7-12.2); magnesium 28.6% (22.6-35.0); phosphate 19.1% (15.9-23.2); potassium 28.9% (25.8-34.6). From a multilevel model, the median relative odds of supplementation, comparing any two hospitals, ranged from 1.51 (95% confidence interval [CI] 1.48-1.55) for potassium to 2.09 (95% CI 1.99-2.19) for magnesium. At most hospitals, there were no calcium or phosphate levels at which the percentage receiving supplementation exceeded 50%. At 75% of hospitals there was a magnesium level at which the percentage receiving magnesium supplementation was 50% or more (range: 1.5-2.1 mg/dL), and at 96% of hospitals there was an analogous potassium level (range: 3.3-3.9 mmol/L). Supplementation of calcium, magnesium, phosphate, or potassium is common in critically ill patients and varies across hospitals, suggesting a need for randomized trials to clarify optimal supplementation practices.