Citations

Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Unvetted scientific claims about vaccines can spread rapidly and undermine decades of progress in immunization and public trust. A recent non-peer-reviewed analysis, promoted at political hearings, in the documentary “An Inconvenient Study,” and on social media, has been used to suggest that vaccinated children experience higher rates of chronic illness than unvaccinated peers. Despite standard regression models, critical flaws - uncontrolled confounding, exposure misclassification, unequal follow-up, and outcome multiplicity, invalidate causal inference. An independent group of international experts critically appraises this analysis and contrast its claims with the consistent evidence confirming vaccine safety and effectiveness. We also show how poorly designed studies can distort public discourse, amplify misinformation, and fuel vaccine hesitancy. We outline actions to strengthen research integrity, such as transparent data sharing, labeling of non-peer-reviewed content, and evidence-based communication. Safeguarding public health demands that vaccine evidence be methodologically sound, reviewed, and interpreted by qualified experts.

Abstract Introduction Bipolar disorder (BD) has been associated with increased medical burden and accelerated biological aging. Long non-coding RNAs (lncRNAs) regulate molecular pathways related to cellular senescence, inflammation, and telomere maintenance, which are implicated in both BD and aging. This study examined whether aging-related lncRNA expression reflects familial vulnerability or illness-specific effects, and whether childhood trauma and lifestyle factors modulate these signatures within a gene–environment framework. Methods In this cross-sectional study, expression levels of aging-related lncRNAs, including Antisense Non-coding RNA in the INK4 Locus (ANRIL), HOX Transcript Antisense Intergenic RNA (HOTAIR), Nuclear Enriched Abundant Transcript 1 (NEAT1), Taurine Upregulated Gene 1 (TUG1), Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1), Growth Arrest-Specific 5 (GAS5), and Telomerase RNA Component (TERC), were measured in peripheral blood mononuclear cells (PBMCs) from individuals with bipolar disorder (BD) (n=68), siblings without BD diagnosis (SIB) (n=54), and healthy controls (HC) (n=70) using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Childhood trauma and lifestyle were assessed using the Childhood Trauma Questionnaire (CTQ) and the Healthy Lifestyle Profile II (HPLP-II). Principal component analysis generated a composite aging-related lncRNA factor. Results At the individual transcript level, NEAT1 and TERC were elevated, whereas GAS5 was reduced, in both BD and SIB relative to HC. The aging-related lncRNA composite score was higher in BD and SIB than in HC (F = 7.315, p = 0.001). Familial liability to BD (presence vs. absence of familial liability ) showed a significant main effect on the composite score (F(1,182)=8.18, p=0.005) and interacted with childhood trauma (F(1,182)=10.14, p=0.002). In multivariable models, total CTQ and physical neglect were independently associated with lower composite scores, while familial liability remained a positive predictor (all p<0.001). Conclusions Aging-related lncRNA alterations mark familial vulnerability to BD and are shaped by childhood trauma within a gene–environment interaction framework.

The persistent shortage of allogenic donor organs has driven the exploration of xenotransplantation as a viable alternative for patients with end-stage liver disease. This review investigates the progress and challenges in liver xenotransplantation, focusing on the use of genetically engineered animals, particularly pigs, as potential organ donors. This narrative review discusses various sources of xenografts, highlighting their advantages and limitations, and provides a historical overview of liver xenotransplantation, encompassing both clinical and experimental experiences. Key obstacles, such as immunological rejection, coagulation dysfunction, and the risk of zoonotic infections, are analyzed, with emphasis on how these challenges have been addressed through genetic modifications and adjunctive therapies. Recent clinical trials are also reviewed, offering insights into the outcomes and lessons learned from these pioneering efforts. We also explored the regulatory, legal, and ethical considerations critical to advancing liver xenotransplantation into clinical practice, along with future perspectives on the field’s evolution. This comprehensive overview aims to provide a clear understanding of the current state of liver xenotransplantation and the strategies being developed to overcome existing barriers, paving the way for future clinical applications.

Abstract Background Some centres advocate preoperative radiotherapy in patients with pancreatic cancer and arterial involvement despite a lack of Level 1 evidence on survival benefit. Although it has been suggested that preoperative radiotherapy may increase the risk of postpancreatectomy haemorrhage (PPH) and morbidity, evidence is again lacking. This study investigated the association between preoperative radiotherapy and both PPH and major morbidity following arterial divestment/resection during pancreatic adenocarcinoma resection after chemotherapy. Methods Consecutive patients diagnosed with pancreatic adenocarcinoma and &gt; 180° arterial involvement who were treated with preoperative chemotherapy with or without radiotherapy followed by pancreatic resection with arterial divestment/resection were included in the study. Logistic regression analyses including propensity score-based overlap weighting were performed to investigate associations between radiotherapy and in-hospital PPH grade B/C and major morbidity, expressed as adjusted risk differences (aRDs). Results Overall, 246 patients undergoing pancreatic resection with arterial resection (169, 69%) or divestment (77, 31%) were included. Radiotherapy was not associated with PPH (aRD 6%; 95% confidence interval (c.i.) −3 to 14), regardless of arterial divestment (aRD 3%; 95% c.i. −5 to 11) or arterial resection (aRD 12%; 95% c.i. 1 to 23; Pinteraction = 0.189). Radiotherapy was associated with a 14% (95% c.i. 2 to 25) higher risk of major morbidity, especially after arterial resection (aRD 27%; 95% c.i. 11 to 43) compared with arterial divestment (aRD −12%; 95% c.i. −35 to 11; Pinteraction = 0.006) and after external beam radiotherapy (aRD 21%; 95% c.i. 8 to 32) compared with stereotactic body radiotherapy (aRD −12%; 95% c.i. −27 to 6; Pinteraction = 0.0001). Ninety-day mortality was increased, albeit not significantly, after preoperative radiotherapy (10 (8%) versus 3 (3%) deaths with versus without preoperative radiotherapy, respectively; P = 0.067). Conclusions Radiotherapy before resection of pancreatic cancer with &gt; 180° arterial involvement was associated with an increased risk of postoperative major morbidity when arterial resection, but not arterial divestment, was performed. This risk should be taken into account when considering preoperative radiotherapy in patients who may require arterial resection.

ABSTRACT Background and Aims Pruritus is a frequent and debilitating symptom in primary biliary cholangitis (PBC), substantially impairing sleep, mood and quality of life. Peroxisome proliferator‐activated receptor (PPAR) agonists are promising second‐line therapies for patients with an inadequate response to ursodeoxycholic acid (UDCA). We conducted a systematic review and meta‐analysis to evaluate the efficacy of PPAR agonists on pruritus and health‐related quality of life (HRQoL) in PBC. Methods We systematically searched for randomised placebo‐controlled trials (RCTs) of PPAR agonists in PBC through December 2025. Eligible studies reported validated pruritus or HRQoL outcomes. Main outcomes were NRS and PBC‐40 total score. Pooled estimates were calculated using random‐effects models and expressed as mean differences (MD) with 95% confidence intervals (CI). Results Five RCTs evaluating bezafibrate, elafibranor and seladelpar ( n = 660; 390 PPAR agonist; 270 placebo) met the inclusion criteria. For pruritus intensity analyses, data were restricted to participants with moderate‐to‐severe baseline symptoms (NRS ≥ 4) when available. PPAR agonists significantly reduced NRS scores at 3 months (MD, −1.39; 95% CI: −2.49 to −0.29), 6 months (MD, −1.17; 95% CI: −1.96 to −0.38) and 12 months (MD, −1.73; 95% CI, −3.00 to −0.46); in individual agent analyses, bezafibrate and seladelpar reached statistical significance at two or more time points. While improvements were also noted in PBC‐40 itch‐domain and 5D‐itch score, an impact on overall HRQoL as reflected by PBC‐40 total score could not be demonstrated, with a lower level of certainty. Conclusions PPAR agonists, notably bezafibrate and seladelpar, reduce pruritus severity in PBC patients with moderate‐to‐severe symptoms and consistently improve itch‐specific outcomes. However, effects on global HRQoL remain uncertain. These findings underscore the incorporation of validated, symptom‐focused endpoints in future PBC trials.

Metabolic dysfunction-associated steatohepatitis (MASH) is a global health care burden. Appropriate large animal models mimicking the main MASH characteristics of steatosis, inflammation, and hepatocyte damage alongside progression of fibrosis are imperative for robust preclinical studies, especially in the field of hepatobiliary surgery. The present study aimed to characterize a novel model of steatohepatitis in fumarylacetoacetate hydroxylase-deficient ( FAH -/- ) pigs. FAH -/- pigs were generated using a CRISPR/Cas9 system. The animals received a choline-deficient, L-amino acid-defined high-fat diet and subtherapeutic doses of nitisinone and were followed for 3 months. Liver biopsies were obtained at baseline and every month during treatment. Steatosis, inflammation, and fibrosis were assessed by conventional histological scoring systems and by an artificial intelligence (AI) model. Serum liver parameters were analyzed every 2 weeks. Steatosis increased significantly throughout the study, with severe steatosis observed as early as 2 months into treatment. The inflammation score was increased in all animals after 3 months of treatment, whereas the AI-based CD45+ cell count showed region-specific trends in the portal and lobular areas. Collagen content and the corresponding fibrosis stage showed an increase over the 3-month period; however, the difference was not significant. Serum liver parameters did not show any relevant elevations during the study. In summary, we successfully developed and characterized a novel model of steatohepatitis in the FAH -/- pig within 3 months. Further studies with prolonged observation time and/or cycling of nitisinone administration are needed to evaluate whether progressive fibrosis and cirrhosis could be achieved with this model.

Sharing research code in an open access version-controlled repository offers significant benefits for both science as a whole and for individual researchers. In this article, we focus on this practice, which is fully aligned with the NIH’s Gold Standard Science (GSS) program as well as FAIR (findable, accessible, interoperable, reusable) and TRUST (transparency, responsibility, user focus, sustainability, technology) principles. Gold Standard Science supports open science by emphasizing transparency, reproducibility, and the use of best practices that enable others to verify and extend research. Pairing a research article’s cited data snapshot with a versioned, environment-specific code release, deposited in a companion code repository, ensures that, upon submission to a medical journal, readers and reviewers can directly verify results. An executable and updatable companion code repository complements, rather than replaces, established research data repositories. When code underlying medical research results is made openly available, then other scientists can inspect, run, and validate analyses. These activities enhance reproducibility, which is a core aim of GSS. Shared code also facilitates collaborative innovation by allowing researchers to extend the utility of the code to new datasets and applications. For researchers, code sharing can increase visibility, credibility, and citation impact. Demonstrating transparency through shared executable and updatable code builds trust with journal readers, peer reviewers, funders, and peers. Shared code in an open access repository signals adherence to high standards of scientific integrity and attracts opportunities for collaboration. A researcher who shares code receives recognition as a leader in reproducible, trustworthy research consistent with NIH’s GSS principles.