Citations

ABSTRACT Background and Aims It remains unclear whether different factors influence 30‐ and 90‐day readmission rates. We identified predictors of 90‐day mortality in a global cohort of hospitalised patients with cirrhosis. Methods Variables associated with 30‐ and 90‐day post‐discharge readmission, liver transplantation (LT), and mortality were compared in prospectively enrolled, non‐electively hospitalised adult patients with cirrhosis. Results We enrolled 4208 patients from 125 centres across 37 countries. Alcohol‐related liver disease was the most common aetiology of cirrhosis (40%), followed by hepatitis B virus infection (21%); 47% were readmitted, 8% received liver transplantation (LT), and 23% died within 90 days post‐discharge. In multivariable analysis, country income was significantly associated with both 30‐ and 90‐day readmission rates, the receipt of LT, and mortality within 30 and 90 days post‐discharge (all p ‐values < 0.001). Independent predictors of higher rates of 30‐ and 90‐day readmissions, respectively, were disease severity ( p < 0.001, p = 0.003), prior ascites ( p = 0.025, p = 0.016), prior hospitalisation ( p < 0.001), hyponatremia ( p < 0.001, p = 0.008), and in‐hospital vasopressor use ( p = 0.002, p = 0.011). Prior variceal bleeding independently predicted higher 90‐day readmission rates, whereas age, disease severity, mechanical ventilation, and in‐hospital vasopressor use (all, p < 0.001) increased odds of 30‐ and 90‐day post‐discharge death. Additionally, admission ( p = 0.011) and nosocomial ( p = 0.022) infections increased the odds of 90‐day post‐discharge death. Conclusion In a global cohort of hospitalised patients with cirrhosis, patients in high‐income countries exhibited the highest rates of 30‐ and 90‐day readmission, alongside lower mortality rates and a higher incidence of LT. Variables that predict 30‐day readmission also predicted 90‐day readmission. Understanding these disparities is essential for achieving health equity.

Introduction/Objectives The rise in screening for social drivers of health (SDoH) in primary care settings has led to questions about effective intervention design. A large primary care practice at Mayo Clinic developed a model centered on a full-time Health Equity Coordinator (HEC) to facilitate clinic-community partnerships in 2022. The goal of this analysis was to assess the model on process outcomes, resolution of SDoH needs, and changes in healthcare utilization. Methods Using a cohort study design, we identified primary care patients with unmet SDoH needs at the intervention clinic and two comparator clinics from March 2022 to December 2023. We assessed process outcomes descriptively and resolution of SDoH needs and healthcare utilization using multivariable regression. Results The HEC contacted 348 patients and conducted 748 meetings with community-based organization staff. While there were decreases for SDoH needs and missed or late cancelled appointments in intervention group, there were no significant difference in resolution of SDoH and healthcare utilization relative to comparator groups. Conclusions The HEC model for multi-stakeholder coordination showed promise in referring patients to services and engaging key stakeholders in a primary care setting. Longer term follow up may be needed to identify changes in SDoH needs and healthcare utilization.

Background: Itraconazole is the preferred antifungal agent for mild to moderate histoplasmosis and step-down therapy following amphotericin B treatment. Although hydroxy-itraconazole, a major metabolite of itraconazole, displays antifungal activity comparable with that of the parent compound, its role in therapeutic drug monitoring targets for histoplasmosis remains uncertain. Methods: The objective was to compare clinical outcomes and adverse events using itraconazole parent-compound concentrations alone versus combined itraconazole and hydroxy-itraconazole concentrations in patients treated for histoplasmosis. This retrospective cohort study included adults with probable or proven histoplasmosis who received itraconazole and had at least 1 documented serum concentration. The primary outcome was clinical response across 3 groups: (1) parent (itraconazole parent-compound concentration >1.0 mcg/mL), (2) combined (parent-compound concentration <1.0 mcg/mL with combined itraconazole plus hydroxy-itraconazole >1.0 mcg/mL), and (3) subtherapeutic (failure to reach either threshold). Treatment response and adverse events were analyzed using the Fisher exact test. Results: Among 108 patients (parent, n = 40; combined, n = 40; subtherapeutic, n = 28), response rates differed across groups (parent (95%); combined (90%); subtherapeutic (67.9%); P = 0.006). There was no difference between the parent and combined groups. Adverse events did not differ, although drug discontinuation occurred more frequently in the subtherapeutic group (parent (5%); combined (20%); subtherapeutic (25%); P = 0.04). Conclusions: Patients who failed to achieve either an itraconazole concentration >1 mcg/mL or a combined itraconazole plus hydroxy-itraconazole concentration >1 mcg/mL had lower response rates. Similar outcomes among patients achieving the itraconazole target alone and those achieving the combined target suggest that hydroxy-itraconazole concentrations may contribute to therapeutic drug monitoring targets in histoplasmosis.

Introduction: Atherosclerotic lesions preferentially form in arterial regions exposed to disturbed flow (DF), where ECs exhibit mitochondrial (mt) dysfunction, metabolic reprogramming, and senescence. Hippo pathway kinases LATS1/2 maintain EC homeostasis, but how DF–mediated LATS1/2 suppression drives EC metabolic remodeling remains unclear. Hypothesis: We propose that DF activates CD38, leading to mt dysfunction and metabolic reprogramming that promotes EC senescence and aberrant proliferation by LATS1/2 inhibition. Methods: EC-specific Lats1/2 knockout mice were generated using tamoxifen-inducible Cre systems, and DF was induced by partial carotid ligation. Murine and human plaques were analyzed using COMET™ immunofluorescence, and spatial metabolomics. Bioenergetic profiling included Seahorse XF analysis, 13 C-glucose/ 13 C-glutamine tracing, and pharmacologic modulation of CD38, mtROS, and ATP synthase. Results: Complete Lats1/2 deletion caused fatal edema and vascular leakage, while partial loss produced fragile, highly neovascularized plaques. Spatial proteomics revealed a CD38-driven senescence-associated stemness (SAS) phenotype under LATS1/2 deficiency. Metabolomics showed sulfite and taurine accumulation, consistent with SUOX deficiency. Mechanistically, CD38 suppressed SUOX, induced Complex V reverse-mode , increased succinate flux, and accelerated ATP consumption. Despite ATP depletion, glutamate metabolism and TCA cycle flux were enhanced, sustaining EC proliferation under energetic stress. LATS1/2 knockdown reduced mt respiratory capacity (lower OCR peak) without significantly increasing glycolysis, and DF suppressed both OCR and ECAR, indicating impaired energy metabolism under pathological shear stress. CD38 inhibition restored mt respiration and glycolytic capacity by preserving NAD, and rescuing LATS1/2 and DF-mediated defects. Blocking reverse-mode Complex V reduced DF- and LATS1/2-dependent EC senescence and proliferation. Conclusion: Complete LATS1/2 deletion causes fatal vascular leakage, while partial loss drives plaque formation with fragile neovessels through a CD38-dependent SAS phenotype. CD38 suppresses SUOX, induces Complex V reverse-mode , increases succinate flux, and accelerates ATP consumption, enabling EC proliferation despite energy stress. DF and LATS1/2 loss impair mt and glycolytic function, whereas CD38 inhibition restores mt respiration and reduces EC senescence and proliferation to prevent atherothrombosis in DF regions.

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

Abstract Cancer outcomes vary widely between individual patients, each accumulating an irregular record of treatments, diagnoses, measurements, and complications. Current prognostic models reduce this complexity into a single snapshot, focus on narrow clinical settings, and rarely generalize across hospitals. Here we introduce Chronicle , an explainable transformer that learns from entire patient trajectories to predict diverse clinical outcomes throughout the disease course while capturing both short- and long-term temporal dependencies. Trained on 53.7 million longitudinal data points from 51,711 patients spanning 67 cancer types, Chronicle operates natively on irregular data without imputation and jointly predicts eight endpoints within a flexible framework adaptable to additional outcomes. Chronicle outperformed cross-sectional models for overall survival prediction (C-index 0.84 vs 0.76-0.79), stratified patients more accurately than established prognostic systems, including TNM stage, and predicted seven adverse event and transfusion endpoints (AUC 0.80-0.92). Applied without retraining to 69,341 patients in Germany, Switzerland, and the United States, Chronicle generalized across healthcare systems and improved further with local fine-tuning. Integrated explainability traced each risk update to patient-specific clinical factors, revealing distinct temporal persistence of prognostic information, with relevance half-lives ranging from weeks for therapies to nearly one year for baseline characteristics. These findings demonstrate that learning from hospital-wide patient trajectories enables interpretable and continuously updated predictions, providing a scalable framework to support individualized treatment decisions.

Abstract Inflammation is a key driver of coronary syndromes across the continuum from chronic coronary syndromes to acute coronary syndromes. It contributes to atherogenesis, plaque destabilization, and ischaemic events and influences myocardial injury, repair, and remodelling. Inflammatory activity is further amplified by metabolic and autoimmune comorbidities such as diabetes, obesity, and connective tissue diseases, with obesity representing a major driver of chronic low-grade inflammation through adipose tissue dysfunction and cytokine activation, while psychosocial stress and environmental exposures including air pollution serve as additional triggers. Genetic variations, including human leucocyte antigen genotypes, modulate individual susceptibility to vascular inflammation and myocardial injury. This expert consensus from the European Society of Cardiology’s Association for Acute CardioVascular Care summarizes the current understanding of inflammation across the full spectrum of coronary syndromes, including underlying mechanisms, relevant biomarkers, and imaging approaches that characterize vascular inflammation, and integrates insights from experimental and clinical studies. Importantly, this document provides explicit consensus-based guidance on when, how, and in whom inflammation should be assessed and treated in routine clinical practice. While the causal association between inflammation and atherosclerotic cardiovascular disease is well established, pharmacological modification of inflammation has produced conflicting evidence. Some agents, such as low-dose colchicine, have demonstrated modest reductions in cardiovascular events, although results across trials have been inconsistent. Other anti-inflammatory therapies have not shown clinical benefit, whereas selective cytokine inhibition with canakinumab has reduced cardiovascular risk at the cost of increased infection rates. The present manuscript also focuses on the evaluation of inflammatory activity in cardiovascular patients in routine clinical practice. It further discusses criteria for patient selection and clinical decision-making regarding the introduction of anti-inflammatory therapy in individuals with established atherosclerotic cardiovascular disease.

Abstract Background There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions. Methods This international multi-center observational retrospective study included patients with advanced NSCLC with or without pericardial effusions receiving ICIs. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Cox proportional hazards multivariable models assessed the association between survival outcomes and clinicopathologic variables, and an inverse probability of treatment weighting (IPTW) model compared outcomes between the two groups. Results A total of 1248 patients with advanced NSCLC treated with ICIs across 13 institutions were included. Of these, 85 patients (6.8%) had pre-existing pericardial effusions. Compared to controls, patients with pericardial effusions were younger (median age 63 vs 67 years, P = .007), diagnosed more frequently with PD-L1 positive tumors (96% vs 76%, P &lt; .001), and had a higher median number of baseline metastatic sites (3 vs 1, P &lt; .001). IrAEs were similar between both groups (42% vs 38%), and no cardiac irAEs occurred in patients with pericardial effusions. PFS (median 5.6 vs 4.6 months, P = .3) and OS (median 10.2 vs 14.7 months, P = .50) were not statistically different between patients with pericardial effusions and the controls, respectively. In both multivariable and IPTW models, pericardial effusions were not associated with PFS or OS. Conclusions Among patients with NSCLC and pre-existing pericardial effusions, ICIs demonstrate meaningful clinical benefit similar to those without effusions, with no new cardiac or severe toxicities.

Abstract Black/African American populations, globally, bear the greatest prostate cancer (CaP) burden compared to other racial/ethnic groups. Addressing CaP disparities in Black men is complex, requiring a patient-centered, community-centric and comprehensive approach. This study integrates iCCaRE Consortium findings and broader literature to address unmet needs in survivorship care. The iCCaRE Consortium implemented five complementary pilot studies using mixed-methods designs, including feasibility trials, qualitative research, and observational analyses across the United States and sub-Saharan Africa. Descriptive statistics, subgroup analyses, and qualitative thematic analyses were performed across these studies. Collectively, projects addressed multilevel determinants including social, behavioral, and biological drivers of disparities. Project 1 implemented a Virtual Reality Assistant (ViRA) across clinical and community settings, with ongoing evaluation in pragmatic trials. Project 2 showed strong patient preference for home-based cancer care. Project 3 enrolled demonstrated trends toward improved health-related quality of life. Project 4 identified key themes influencing survivorship experiences. Project 5 identified biological mechanisms linking stress, immune modulation, and symptom burden. The iCCaRE pilot projects demonstrate the feasibility and early impact of a consortium-based, transdisciplinary approach to addressing CaP disparities in Black men. These findings highlight the importance of integrating patient-centered interventions, community engagement, and biological insights to inform scalable strategies aimed at improving survivorship outcomes and advancing health equity. The iCCaRE Consortium demonstrates that a transatlantic, patient-centered, and multidisciplinary approach integrating social, clinical, and biological factors can generate scalable strategies to improve survivorship outcomes and advance equity in CaP care for Black men.

Heart rate variability (HRV) is a widely utilized approach for investigating cardiovascular health and human performance. Methodological approaches, analyses, and interpretations of HRV can vary extensively, and scientific debates on HRV reliability and utility remain. These debates have been amplified in recent years by the rapid growth and ubiquity of wearable devices, and their incorporation into scientific research studies. The present guidelines paper takes an evidence-based approach to propose more consistent and rigorous measurement and interpretation of HRV within human cardiovascular research and application. First, HRV has some utility as a cardiovascular risk stratification tool, but is not appropriate to employ as a specific marker of cardiac sympathetic outflow or sympathovagal balance. While time-domain and spectral analysis can more accurately reflect respiratory modulation of cardiac vagal (parasympathetic) activity, caution is necessary to avoid overinterpretation, particularly with respect to the concept of “vagal tone”. Numerous experimental, demographic, and environmental factors influence HRV assessment, interpretation, and reliability. Specifically, it is critical to account for non-modifiable (age, sex, race/ethnicity, etc.) and modifiable (i.e., exercise, physical fitness, etc.) factors within participant samples. Furthermore, technical approaches such as the HRV input signal (e.g., electrocardiography vs. photoplethysmography), length of recording, location of recordings (i.e., laboratory vs. field), respiratory rate and depth, and analytical approaches (i.e., time vs. frequency domain) can all impact rigor, reliability, and study interpretations. Finally, with respect to the rapid advancements of HRV assessment using wearable technology, investigators should interpret and contextualize findings within the limitations outlined in this guideline review.