Pediatric migrant health has been identified by the World Health Organization as a critical area for interdisciplinary research to improve care for children and adolescents with migration experience. Nevertheless, research agendas have rarely been shaped systematically by individuals with lived and professional experience, limiting relevance and impact. To identify and prioritize the most important unanswered research questions in pediatric migrant health in Europe through a structured, participatory priority-setting process. This multiphase survey study (April 2024 to June 2025), led by migrants and clinicians using the James Lind Alliance participatory priority-setting methodology, comprised 2 online consultations informed by Delphi procedures and a final in-person consensus workshop using a modified nominal group technique. Participants residing in multiple European countries included migrant caregivers, former migrant children and adolescents, health care workers in pediatric migrant health, and double experts with combined lived and professional experience. They were recruited via professional networks, community organizations, and open calls. The final in-person consensus workshop convened in Basel, Switzerland, in June 2025. The primary outcome was a ranked list of the top 10 unanswered research priorities in pediatric migrant health based on participant-generated questions and consensus methods. In consultation 1, 256 participants (156 [61.0%] with lived migration experience; 25 countries of residence, 41 countries of origin; 115 aged <35 years [44.9%], 138 aged ≥35 years [53.9%]; 158 female [61.7%]) submitted 1589 questions and comments, which were consolidated into 53 unanswered summary questions after qualitative content analysis and evidence checking. In consultation 2, rankings from 576 participants (214 [37.2%] with lived migration experience; 31 countries of residence, 50 countries of origin; 193 aged ≤35 years [33.5%], 364 aged ≥35 years [63.2%]; 412 female [71.5%]) yielded a short list of 25 questions. During the final consensus workshop, participants selected the top 10 research priorities. The 3 highest ranked priorities focused on universal access to health care, the health impact of racism and discrimination, and barriers to accessing care. Remaining priorities addressed health effects of migration, social determinants of health, needs of at-risk groups (including unaccompanied or undocumented minors and children with medical complexities), professional language support, training of health care workers, and family involvement in care. The research priorities identified in this survey study could provide a roadmap for future multidisciplinary and participatory research to improve health equity for pediatric migrants in Europe.
A contemporary standard of care for patients with metastatic androgen pathway modulator-naive/sensitive (APMN/S) prostate cancer (also known as metastatic hormone-sensitive prostate cancer) is androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) until progression. PSMAddition aimed to evaluate the efficacy and safety of [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) combined with ADT plus ARPI in prostate-specific membrane antigen (PSMA)-positive metastatic APMN/S prostate cancer. PSMAddition is an ongoing, randomised, controlled, phase 3 superiority trial conducted at 169 sites across 20 countries, including hospitals, medical centres, and specialist cancer centres. Eligible male patients had treatment-naive or minimally treated metastatic APMN/S prostate cancer diagnosed by CT, MRI, or bone scan and one or more PSMA-positive metastatic lesion on centrally read baseline [68Ga]Ga-PSMA-11 PET. Patients were randomly assigned 1:1 to open-label, intravenous 177Lu-PSMA-617 (7·4 GBq [200 mCi] ±10% every 6 weeks for up to six cycles) with ADT plus ARPI (177Lu-PSMA-617 arm) or ADT plus ARPI (control arm). ADT and ARPI were investigator-chosen according to local authorisation and administered per local product labelling. Control arm patients with centrally confirmed radiographic progression could cross over to 177Lu-PSMA-617. The primary endpoint was radiographic progression-free survival (centrally assessed per Prostate Cancer Clinical Trials Working Group 3-modified RECIST 1.1 or death); secondary endpoints included safety and tolerability. We report the second interim analysis of radiographic progression-free survival in the intention-to-treat population (all randomly assigned participants; data cutoff Jan 13, 2025). Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04720157, and is ongoing. From June 15, 2021, to July 25, 2023, 1529 patients were screened and 1144 were randomly assigned (n=572 per arm; 1144 [100%] male, 572 [50%] with de novo metastatic APMN/S prostate cancer, 779 [68%] with high-volume disease; median age 68·0 years [IQR 62·0-73·0]). Baseline characteristics were balanced between arms. At second interim analysis for radiographic progression-free survival (median time from randomisation to data cutoff 23·6 months [IQR 20·3-29·2]; median radiographic progression-free survival follow-up time 19·6 months [IQR 14·0-24·1]), 139 (24%) of 572 participants in the 177Lu-PSMA-617 arm and 172 (30%) of 572 participants in the control arm had radiographic disease progression or death. Radiographic progression-free survival was significantly improved in the 177Lu-PSMA-617 arm versus the control arm, with a 28% reduction in the relative risk of radiographic progression or death (HR 0·72 [95% CI 0·58-0·90]; p=0·0021; median radiographic progression-free survival not reached in either arm). The primary endpoint was thus met. Grade 3 or worse adverse events occurred in 286 (51%) of 564 patients in the 177Lu-PSMA-617 arm and 243 (43%) of 565 patients in the control arm. Serious adverse events occurred in 180 (32%) of 564 patients in the 177Lu-PSMA-617 arm and 162 (29%) of 565 in the control arm; of which 17 (3%) in the 177Lu-PSMA-617 arm were 177Lu-PSMA-617-related. The most common adverse event was dry mouth, in 258 (46%) patients in the 177Lu-PSMA-617 arm and 21 (4%) patients in the control arm; all were grade 1 or 2 and none were serious. Other common adverse events with higher incidence in the 177Lu-PSMA-617 arm included cytopenias and gastrointestinal disturbances. Combining 177Lu-PSMA-617 with ADT plus ARPI prolonged radiographic progression-free survival in patients with PSMA-positive metastatic APMN/S prostate cancer. Although adverse events were more frequent, there were no unexpected safety findings associated with the drug combination. Therefore, combining 177Lu-PSMA-617 with ADT plus ARPI might be a new treatment option in metastatic APMN/S prostate cancer. Novartis.
暂无摘要（点击查看详情）
Large-bore mechanical thrombectomy (LBMT) is a catheter-directed therapy for acute pulmonary embolism (PE). The relationship between aspirated thrombus weight and volume with outcomes remains unclear. The aim was to evaluate the impact of aspirated thrombus weight and volume on outcomes after LBMT. This prospective, open-label, single-arm, single-center registry study included 48 patients undergoing LBMT using the FlowTriever system (Inari Medical/Stryker, Irvine, CA, USA). Thrombus weight and volume were quantified, and clot composition assessed. Associations between thrombus characteristics and clinical, invasive hemodynamics, echocardiographic parameters, and biomarkers were evaluated immediately after the procedure, at hospital discharge, and at 3-month follow-up. Thrombus material was available in 48 patients (31% women), of which 41 presented with intermediate-risk and 7 with high-risk PE. LBMT resulted in significant reductions in systolic pulmonary artery pressures (sPAP) intraprocedurally (- 12.8 ± 8.3 mmHg, p < 0.001), with a further invasively measured decrease through 3 months (- 9.6 ± 10.6 mmHg, p < 0.001). From baseline to discharge, right ventricular coupling improved (+ 0.24, p < 0.001) and right ventricle (RV)/left ventricle (LV) ratio decreased (- 0.23, p < 0.001). NT-proBNP and high-sensitivity cardiac troponin T declined significantly. Neither thrombus weight nor volume correlated with acute changes in sPAP (ρvolume = 0.06; ρweight = 0.10), RV-uncoupling (ρvolume = 0.47; ρweight = 0.46), and RV/LV ratio (ρvolume = - 0.02; ρweight = - 0.005) (p for all > 0.05), nor with outcomes at 3 months. Aspirated thrombus weight and volume were not associated with improvements after LBMT, suggesting that, beyond mechanical obstruction, additional mechanisms potentially including paracrine and endocrine effects of thrombus material may contribute to acute and chronic PE-related cardiopulmonary dysfunction.
HIV-associated tuberculosis is a leading cause of mortality. Mycobacterium tuberculosis bloodstream infection (MTB-BSI) is complicated by diagnostic difficulty and severe illness. We assessed whether MTB-BSI continues to be common in the era of widespread antiretroviral therapy and whether it continues to result in increased risk of early mortality. We enrolled inpatients from medical wards irrespective of tuberculosis symptoms and outpatients with tuberculosis symptoms. All participants had HIV and were ≥18 years old, and all were recruited from 7 countries: Malawi, South Africa, Tanzania, Thailand, Uganda, Vietnam, and Zambia. Participants also had <3 doses of antituberculosis treatment in the past 60 days and no isoniazid preventive therapy in the past 6 months. We estimated the prevalence of MTB-BSI. In Bayesian survival models, we estimated the hazards of mortality for inpatients with MTB-BSI vs those without. Between 2019 and 2021, 1703 participants were included: 44% were hospitalized, the median CD4 count was 361 cells/μL, and 77% reported using antiretroviral therapy. Crude prevalence of MTB-BSI varied by country but was 4.4% (32/723) among all inpatients, 22.5% (32/142) among inpatients with microbiologically confirmed TB, and 0.2% (2/913) among all outpatients. Among all inpatients, those with MTB-BSI had 2.65-times (95% credible interval, 1.06-5.01) increased hazard of death by 30 days and 1.79-times (95% credible interval, .81-3.11) increased hazard by 70 days. Lower CD4 and older age were strongly associated with mortality. MTB-BSI is far more common for inpatients than outpatients with HIV. Across multiple settings with high tuberculosis prevalence, MTB-BSI was strongly associated with heightened risk of early mortality in PWH. Novel optimized diagnostic and treatment strategies are still needed for HIV-associated MTB-BSI.
Background/Objectives: Among the most common medical conditions of pregnancy, nausea and vomiting of pregnancy (NVP) and its severe form hyperemesis gravidarum (HG) represent a clinically significant and increasingly researched area of maternal health. However, the global evolution, structural organization, and thematic development of this literature remain insufficiently characterized. This bibliometric study maps five decades of global research on therapeutic and supportive interventions for NVP and HG. Methods: Web of Science Core Collection records were searched on 10 May 2026, restricted to English-language articles and reviews published up to 2025, and deduplicated to 1182 unique documents. A secondary thematic filter was subsequently applied to generate a refined obstetric subset for the country collaboration, keyword co-occurrence, and thematic evolution analyses. Bibliometric performance, collaboration networks, source impact, institutional output, PELT-based changepoint detection, metadata completeness, keyword co-occurrence, and thematic evolution were analyzed using VOSviewer, Bibliometrix/Biblioshiny, and custom Python scripts. Results: Publication output increased markedly after 2010 and reached its maximum in 2025. PELT sensitivity analysis localized the principal transitions to the mid-1990s and early 2010s, informing three broad analytical macroperiods: 1975-1994, 1995-2009, and 2010-2025. The United States dominated cumulative output and collaboration intensity, while Canada, England, Australia, Italy, Germany, and China showed substantial scientific influence. Core publication venues were concentrated in obstetrics, gynecology, reproductive safety, and pregnancy-focused clinical medicine. Keyword and thematic analyses showed a transition from early vomiting, Bendectin, exposure, and pregnancy-safety concerns toward pharmacological treatment, complementary interventions, controlled clinical evaluation, maternal-fetal outcomes, and supportive management. Metadata-completeness analysis identified a major pre-1991 indexing discontinuity, requiring caution when interpreting long-range keyword-based trends. Conclusions: These findings outline the trajectory of the field and highlight priorities for future research, including stronger comparative evidence for pharmacological, complementary, and supportive-care strategies, broader international collaboration, and prospective studies to strengthen the evidence base for managing NVP and HG.
Hierarchical composite end points (HCEs) are a promising tool used in randomized clinical trials (RCTs) to integrate multiple outcomes of varying clinical relevance into a single measure. To describe how often HCEs are used as primary outcomes in RCTs, and how they are constructed, analyzed, and reported. MEDLINE, Embase, CENTRAL, and Web of Science were searched on December 9, 2024, complemented by a forward citation search of methodological papers on HCEs. RCTs that used an HCE as their primary outcome were included, defined either by self-declaration (hierarchical composite or outcome ranking) or through use of an HCE-specific analytical approach (win ratio, win odds, probabilistic index, or generalized pairwise comparison). Pilot studies, post hoc analyses, and hierarchically tested coprimary end points were excluded. Data were independently screened and extracted in duplicate. Trial characteristics, end point composition, hierarchy justification, and analytical methods were summarized descriptively. Among 5188 screened records, 92 RCTs were included, with 79 567 planned participants. The use of an HCE as a primary end point has increased, with 72 trials (78.3%) initiating recruitment within the past decade. Most RCTs were drug trials (43.5% [40 of 92]), in cardiology (43.5% [40 of 92]), multicenter (91.3% [84 of 92]), and non-industry sponsored (67.4% [62 of 92]). The 92 HCEs had a median (IQR) of 4 (3-5) components and the highest ranked component was usually mortality (80.4% [74 of 92]). The last hierarchical component was most often a continuous component (64.1% [59 of 92]). The majority of RCTs did not report any information on how the hierarchy was established (82.2% [60 of 73]; excluding RCTs where only information from registries was available). Generalized pairwise comparison was the most frequent analysis approach (57.3% [26 of 45]) among the 45 published RCTs, yet no standardized way for presenting results was observed. This scoping systematic review of 92 RCTs using HCEs found that their use has increased across medical fields, but their construction, analytical approaches, and reporting of results remained highly heterogeneous. By systematically mapping how HCEs are currently implemented, further review is essential for the development of much needed methodological and reporting standards.
To explore the experiences and challenges associated with genetic testing decisions among untested individuals from hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) families. Qualitative descriptive study. Semi-structured telephone interviews were conducted between 2022 and 2024 with 56 untested at-risk relatives drawn from the Israeli CASCADE cohort of HBOC and LS families, which comprises carriers of pathogenic/likely pathogenic variants, true negatives (non-carriers) and untested individuals. Interview narratives were analysed using thematic analysis. Two overarching themes were generated. (1) Illusion of Mastery, encompassing four categories reflecting internal coping strategies participants employed to maintain perceptions of control, resulting in avoidance of genetic testing: choosing uncertainty as a psychological shield; avoiding anxiety; controlling health through lifestyle; and protecting life stages. (2) Lost in the System, encompassing five categories across two subthemes: (2.1) perceived deficiencies in informational, emotional and familial guidance from the healthcare system; and (2.2) active withdrawal from the system to avoid medical entrapment and preserve personal values, both resulting in avoidance of genetic testing. Findings suggest avoidance rather than denial or outright refusal of genetic testing, reflecting active decision-making. This avoidance was shaped by a convergence of personal,familial and systemic factors, centered on autonomy, uncertainty management and psychological self-protection, in the context of inadequate informational and emotional support. These findings highlight nurses' potential to support informed, person- and family-centered genetic testing decision-making. Given their accessibility to at-risk families across diverse clinical settings, nurses can address emotional needs, provide clear guidance and acknowledge the psychological complexity underlying testing avoidance. Future studies should explore nurse-led interventions that facilitate informed decision-making while respecting individual autonomy. This study adhered to the Consolidated Criteria for Reporting Qualitative Studies (COREQ) guidelines. No patient or public contribution.
Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation. To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA). This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements). Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months. Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC). The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively. In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.
暂无摘要（点击查看详情）
Opisthorchis viverrini (OV) is a liver fluke endemic to the Lower Mekong Basin. Infections often begin in childhood and are causally linked to cholangiocarcinoma, an often-fatal bile duct cancer. Anthelmintic treatment is the primary control strategy, but infection can recur. Therefore, additional strategies are needed. This study assessed the impact of "The Magic Glasses Opisthorchiasis" (MGO), a cartoon-based intervention, on schoolchildren's OV-related knowledge, attitudes and practices (KAP). A cluster (school)-randomised controlled trial was conducted in Cambodia, Laos and Thailand. Clusters were randomised into either school health education only or with MGO. OV KAP was measured using a standardised questionnaire. FGDs and interviews were also conducted in intervention schools with schoolchildren, parents, and teachers. Cambodia intervention knowledge and attitude scores improved by 19.2 (p < 0.001) and 25.3 (p < 0.001) percentage points, respectively, relative to the control. Laos intervention knowledge and attitude scores improved by 19.0 (p < 0.001) and 14.2 (p < 0.001) percentage points. However, Thailand's intervention knowledge and attitude scores declined by 23.3 (p < 0.001) and 15.8 percentage points (p < 0.001). There were no improvements in behaviour scores in any country, but parents and schoolchildren in Cambodia and Laos reported improved fish preparation practices, suggesting positive spillover effects from MGO. The findings support MGO as an effective tool for school-based health education.
The quadriceps tendon has gained significant momentum as a graft source for knee ligament reconstruction, with the isolated harvest of its superficial layer-the rectus femoris tendon-rapidly emerging as a popular technical refinement. This shift has been driven largely by practical considerations: the cost and limited availability of proprietary instrumentation promoted for partial quadriceps tendon harvesting, combined with the appeal of a familiar, hamstring-like workflow using standard tendon strippers. As a result, numerous surgical technique descriptions have appeared in recent years. However, the enthusiasm surrounding this graft has outpaced the evidence supporting it. This narrative review critically appraises the current state of knowledge regarding the rectus femoris tendon autograft by evaluating its anatomical basis, biomechanical properties and the first available clinical outcomes. Anatomical studies confirm the rectus femoris tendon as a consistent superficial layer separated from the deep vastus intermedius by a distinct cleavage plane, facilitating reproducible harvest. Biomechanically, the isolated graft demonstrates ultimate stress comparable to the patellar tendon, yet exhibits significantly higher elasticity, raising unresolved questions about long-term graft creep and laxity. Early clinical comparative studies report functional outcomes equivalent to hamstring tendon autografts in primary anterior cruciate ligament reconstruction, and folded soft-tissue quadriceps grafts show promising re-rupture rates in the revision setting. Despite these encouraging findings, the existing literature is predominantly Level III and IV evidence with short-term follow-up, and the heterogeneous definitions of 'quadriceps tendon graft' across studies preclude any formal meta-analysis of this specific graft entity. While the rectus femoris tendon autograft holds considerable potential as a versatile option for primary, revision and complex multi-ligament reconstruction, high-powered randomized controlled trials with long-term follow-up are needed to determine whether it truly represents a paradigm shift or merely a technical variation. LEVEL OF EVIDENCE: Level V, narrative review.
Evidence increasingly shows close, bidirectional links between infectious diseases (IDs) and non-communicable diseases (NCDs). However, research, health policy, and prevention practices still largely address them in separate frameworks. This scoping review summarises the current evidence on the interconnections between IDs and NCDs and explores integrated strategies for their prevention and management. This scoping review systematically searched PubMed, Web of Science, and Scopus for English-language systematic reviews and meta-analyses published between Jan 1, 2000, and April 20, 2026. Two reviewers independently screened eligible studies and extracted effect estimates for associations between IDs and NCDs. Evidence was grouped into two themes: associations between infectious agents and cancer, and the effects of NCDs on susceptibility to or severity of IDs. From 5799 records identified, 41 meta-analyses or systematic reviews met the inclusion criteria. The included reviews showed associations between pathogen infections and specific cancers, including hepatitis B and C virus infections with liver cancer, human papillomavirus infection with cervical cancer, and Helicobacter pylori infection with gastric cancer. IDs were also associated with an increased risk or burden of NCDs, as illustrated by the association between tuberculosis and chronic obstructive pulmonary disease. Conversely, NCDs could affect susceptibility to and outcomes of IDs; patients with diabetes or cardiovascular disease had higher risks of severe disease or adverse outcomes following tuberculosis, influenza, or COVID-19 infection. IDs and NCDs can interact through shared mechanisms, overlapping risk factors, and bidirectional pathways, underscoring the need for integrated strategies that combine prevention, early detection, treatment, and long-term management. At the public health level, this calls for health policies and financing mechanisms to move beyond disease-specific silos towards systemic frameworks that support integrated prevention and control, coordinated management, and cross-sectoral action.
Spinal metastases may progress to debilitating pain, spinal instability, and neurological deficits. Timely referral is essential, yet delays are common because patients often first present to non-spine clinicians where red flags rarely expedite referral and guidelines primarily target spine specialists. We aimed to develop a staging-based referral tool to support non-spine clinicians in recognizing progression and guiding referral urgency. We defined the Spinal Metastasis Staging (SMS) system as four stages: SMS I, asymptomatic; SMS II, inflammatory pain; SMS III, mechanical pain and/or spinal instability; and SMS IV, neurological deficits and/or high-grade spinal cord compression. Stages were translated into a referral algorithm organized by urgency and presented as a pocket map. The tool was refined through regional and international multidisciplinary expert panels, and feasibility was evaluated in an international survey. Panels endorsed the four-stage SMS system and referral algorithm. Among all survey respondents (n = 120), high acceptability was reported. Among non-spine clinicians (n = 32), 94% found the tool easy to understand, 91% considered the format suitable for clinical use, and 91% anticipated improved referrals. Overall, 88% would use the tool at least occasionally, including 55% who would use it frequently or always. The SMS staging system and referral tool (link) was rated feasible by expert panels and survey respondents. However, only 32 of 120 survey respondents (27%) were non-spine clinicians, so findings in this group are preliminary and may overstate acceptance. The tool should be considered provisional: prospective studies are needed to validate effects on referral and patient outcomes.
Recent meta-analyses of randomized controlled trials have raised concerns that treatment with omega-3 fatty acids may increase the risk of atrial fibrillation (AF). However, these meta-analyses included at most 8 trials. The aim of this current meta-analysis was to expand the search by including other eligible omega-3 randomized controlled trials with AF incidence data, incorporating both published and unpublished data. Eligible studies were randomized controlled trials investigating daily doses of ≥500 mg/d of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Additional inclusion criteria included ≥12 months of treatment with EPA/DHA, participants ≥50 years of age, and, where possible, the absence of known AF/atrial flutter at baseline. The primary outcome was the occurrence of new-onset AF. Our primary hypothesis was that risk for AF would simultaneously depend on both omega-3 dose (above or below 1500 mg/d) and background cardiovascular disease risk status, and that their combined impact on AF risk would be synergistic. A total of 35 randomized controlled trials (37 data sets; n=114 592) were included in this meta-analysis. Only studies including patients at high-risk for cardiovascular disease who were treated with high-doses of EPA/DHA (>1500 mg/d) showed a statistically significant increase in AF risk with a pooled odds ratio (OR) of 1.43 (95% CI, 1.14-1.79) and an absolute risk difference of 0.8% (0.40%-1.1%). None of the other 3 groups showed statistically significant levels of AF risk (odds ratios, 1.07 [high risk-low dose], 1.06 [low risk-low dose], and 1.03 [low risk-high dose]). This meta-analysis suggests that high-dose EPA/DHA treatment is associated with an increased risk of AF in patients at high cardiovascular disease risk, whereas low-dose EPA/DHA does not appear to increase AF risk, even in high-risk populations. Further prospective studies are needed to evaluate any potential increased risk of higher doses balanced against potential benefits.
Background: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), differ in etiology but share several convergent pathological mechanisms. Pterostilbene (PTR) is a natural stilbene with reported antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to prioritize putative PTR-associated targets and biological processes potentially relevant to shared neurodegenerative mechanisms. Methods: An integrative in silico workflow combining network pharmacology, protein-protein interaction (PPI) analysis, GO Biological Process (GO BP) enrichment, molecular docking, and molecular dynamics (MD) simulations was applied. GO BP terms were filtered, focused on neurodegeneration- and neuroprotection-related processes, and subjected to REVIGO-based redundancy reduction. Selected targets were further evaluated by docking and 500 ns MD simulations. Results: A total of 181, 165, 128, and 109 shared PTR-disease targets were identified for AD, PD, HD, and ALS, respectively. Redundancy-reduced GO BP analysis indicated associations with neuroinflammation, oxidative stress and reactive oxygen species-related responses, programmed cell death, MAPK/ERK- and PI3K/AKT-related signaling, ion and calcium transport, and lipid-, steroid-, or hormone-associated regulation. PPI topology prioritized SRC, ESR1, and HSP90AA1 as recurrent hub-bottleneck proteins, whereas MD-based structural interpretation focused on ESR1 and HSP90AA1. MD analyses indicated stable PTR interactions with both proteins, with ESR1 showing the most favorable predicted interaction profile. Conclusions: These findings suggest that PTR may interact with shared neurodegeneration-relevant molecular systems, particularly through ESR1- and HSP90AA1-associated mechanisms. However, the results are exclusively computational and should be interpreted as hypothesis-generating, requiring further experimental validation.
Understanding the concomitant evolution of bleeding vs ischemic risk after percutaneous coronary intervention (PCI) in patients at high bleeding risk (HBR) treated with 1-month dual antiplatelet therapy (DAPT) would help optimize dynamic treatment strategies. The aim of this study was to describe the timing of bleeding and ischemic events during 1 year after PCI in this population. Timings of major bleeding events and of major adverse cardiovascular events (MACE) were analyzed in patient-level data from 7 prospective studies including HBR patients treated with PCI and 1-month DAPT. Among 7,266 patients (mean age 76 ± 9.0 years, 31.5% women), Bleeding Academic Research Consortium (BARC) types 3 to 5 bleeding occurred in 284 (4.0%), with 73 (1.0%) occurring ≤30 days after and 211 (2.9%) >30 days after index PCI. MACE occurred in 433 patients (6.0%), among which 64 (0.9%) occurred ≤30 days after index PCI and 369 (5.1%) after 30 days. During the first 30 days, there was no significant difference between rates of MACE and BARC types 3 to 5 bleeding events (22.3% vs 25.7%; P = 0.407). However, MACE rates were significantly higher than rates of BARC types 3 to 5 bleeding between 31 and 90 days (7.2% vs 4.9%; P = 0.024) and between 91 and 365 days (5.3% vs 3.1%; P < 0.001) CONCLUSIONS: Among HBR patients undergoing PCI treated with 1-month DAPT, the risk for major bleeding and MACE is highest in the first 30 days. MACE remain consistently more frequent than bleeding after the first month, when event rates stabilize over time while on single antiplatelet therapy.
Functional secondary hypogonadism is frequent in men with obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), but whether testosterone replacement therapy (TRT) produces clinically relevant metabolic benefits remains uncertain. This systematic review evaluated double-blind randomized placebo-controlled trials of TRT in obese men with functional secondary hypogonadism and either T2DM or metabolic syndrome. PubMed and Scopus were searched up to May 2026. Eligible studies enrolled adult men with biochemical hypogonadism and T2DM or metabolic syndrome, compared TRT with placebo, and reported metabolic outcomes. Open-label, single-blind, and non-randomized studies were excluded. Risk of bias was assessed with the Cochrane RoB 2 framework and certainty of evidence with GRADE. Eight trials were included. The most consistent signal was improvement in body composition, mainly increased lean mass and reduced fat mass. Effects on insulin resistance were favorable in several trials but heterogeneous. GRADE certainty was low for fat mass, lean mass, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and it was very low for clamp-derived insulin sensitivity, HbA1c, fasting glucose, lipid outcomes, inflammatory and vascular surrogate markers, and long-term safety. Low-certainty evidence suggests that TRT may improve body composition and HOMA-IR in carefully selected men with functional secondary hypogonadism and metabolic disease, whereas effects on glycemic and lipid outcomes remain very uncertain. TRT should not be regarded as an antidiabetic or lipid-lowering intervention. Larger phenotype-specific trials with longer follow-up are needed.
Clonal hematopoiesis (CH), defined by the expansion of hematopoietic cells with somatic mutations in leukemogenic genes (CH of indeterminate potential (CHIP)) or with mosaic chromosomal alterations (mCAs), is associated with aging and adverse health outcomes in the general population. CHIP prevalence is higher in People with HIV (PWH) than in controls. However, the full spectrum, prevalence, and clinical consequences of CH in PWH remain incompletely understood. We assessed CHIP and mCAs in a large sample of PWH (N∼2,500) from the Swiss HIV Cohort Study. Using high-depth targeted sequencing of CHIP genes and genome-wide genotyping to call mCAs, we quantified the prevalence and clone size of both CH types and investigated an association of CH with clinical variables. CHIP (25% of individuals) and mCAs (16% of individuals) were common, positively correlated with age, often co-occurring (OR=1.7, p=0.02 for autosomal mCAs), and associated with various clinical outcomes, including all-cause mortality (HR=1.3, p=0.02 for CHIP) and hematologic malignancies (HR=9.4, p=0.01 for the effect of CHIP on the risk of myeloid cancer; HR>20, p<0.001 for the effect of co-occurring CHIP and mCAs on the risk of lymphoid cancer). We also observed associations of CH with several proxies of inflammatory status (CD4:CD8 ratio, HIV viral load, late initiation of antiretroviral therapy, and toxicity of antiretroviral drugs). The study provides a comprehensive assessment of the CH landscape in PWH, highlighting potential causes and consequences in this population and suggesting an interaction between CH and chronic immune activation.