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Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

ABSTRACT Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in energy metabolism, DNA repair, and cellular signaling. While the effects of acute NAD depletion have been better characterized, the consequences of chronic NAD deficiency remain unclear. Here, we investigated the impact of chronic NAD depletion in cultured cells by removing the availability of nicotinamide (NAM), a key precursor for NAD synthesis, from the culture media. In NIH3T3 fibroblasts, NAM depletion caused a dramatic drop in intracellular NAD levels within 2 days. Remarkably, the cells remained viable even after 7–14 days of NAM depletion, despite NAD + levels falling to less than 10% of control conditions. This chronic NAD depletion led to distinct metabolic alterations. Mitochondrial basal respiration remained unchanged, but cells exhibited reduced spare respiratory and maximal capacities, along with significantly impaired glycolysis. Notably, NAD depletion triggered an interferon‐dependent inflammatory response, resembling viral infections. This was driven by cytosolic leakage of mitochondrial DNA (mtDNA) through voltage‐dependent anion channel 1 (VDAC1), which activated the cGAS‐STING signaling pathway. Inhibition of VDAC oligomerization with VBIT‐4, STING signaling with H‐151, or mtDNA depletion blocked the upregulation of interferon genes induced by NAM depletion. Similar interferon responses triggered by NAD depletion were observed in IMR90 human fibroblasts and HS5 stromal cells. Our findings reveal a novel link between chronic NAD deficiency, VDAC‐mediated mtDNA release to the cytoplasm, and the activation of the inflammatory response, providing new insight into how NAD decline affects cellular metabolic and inflammatory processes.

Introduction Infectious intracranial aneurysms (IIAs) are rare but serious complications of systemic infections, particularly infective endocarditis. These aneurysms are prone to rupture, leading to significant morbidity and mortality. Management strategies lack consensus due to the rarity of the condition and reliance on small case series. This study examines the clinical management of IIAs using data from a large multicenter cohort. Methods A retrospective registry-based cohort study was conducted across 11 tertiary care centers in the USA between 2018 and 2023. Patients with IIAs were identified based on clinical and radiographic criteria. The primary outcome was treatment failure defined as persistence, growth, or rupture of the aneurysm. Secondary outcomes were mortality and the modified Rankin Scale (mRS) score at 90 days and 1 year. Multivariate logistic regressions were used to identify outcome predictors. Results A total of 104 patients with 166 aneurysms were included, with a median age of 43 years. Medical management was successful in 56% of cases, with failure often within 18 days of initiation. Predictors of failure included younger age, larger aneurysm size, and rupture at presentation. Surgical and endovascular interventions achieved higher success rates with better outcomes. At 90 days, 57% of patients achieved functional independence (mRS 0–2), while the mortality rate was 24%. Conclusion This study highlights the limitations of medical management for IIAs and underscores the need for early surgical or endovascular intervention in high-risk patients. Outcome predictors aid clinical decision-making, optimizing patient management. Further research is needed to standardize management guidelines for IIAs.

Heart transplantation is a well-established treatment for end-stage heart failure, but many patients present in poor physical condition, complicating outcomes. The Impella 5.5 device, used in cardiogenic shock, may support pretransplant rehabilitation by stabilizing organ function and promoting functional improvement. This retrospective cohort study assessed the relationship between functional status, measured by standardized Activity Measure for Post-Acute Care Basic Mobility (AM-PAC) scores, and days alive outside the hospital within 30 days post-transplant (DAOH-30). Patients who received Impella 5.5 support before transplantation between January 2019 and October 2023 were included, excluding those without AM-PAC scores within 24 hours pretransplant. Among 65 patients, the median DAOH-30 was 15 days (interquartile range [IQR], 8–19). Higher pretransplant standardized AM-PAC scores correlate with increased DAOH-30 (adjusted coefficient 0.3; 95% confidence interval [CI] = 0.01–0.6; p = 0.04), as did AM-PAC score improvement during rehabilitation (adjusted coefficient 0.35; 95% CI = 0.01–0.6; p = 0.04). Extended rehabilitation was associated with greater functional gains. These findings suggest that better pretransplant functional status and rehabilitation-related improvements were associated with increased DAOH-30. The Impella 5.5 device facilitates rehabilitation and may enhance post-transplant outcomes. Further research should refine strategies to optimize rehabilitation and recovery in this high-risk population.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Background Severe alcohol-associated hepatitis (sAH) is a life-threatening condition with high mortality, where corticosteroid use is the only treatment that has shown short-term benefits. Pentoxifylline, an anti-tumour necrosis factor-alpha agent, has been proposed for its potential to improve outcomes, especially in patients with acute kidney injury (AKI). We aimed to evaluate the impact of pentoxifylline on mortality in patients with sAH and AKI in a well-characterised global cohort. Methods We conducted a retrospective, registry-based study including patients meeting the National Institute on Alcohol Abuse and Alcoholism clinical criteria for sAH and AKI. Mortality was the primary endpoint, with liver transplantation as a competing risk. Statistical analysis included Cox regression and Kaplan-Meier survival estimates. Results We included 525 patients from 20 centres across eight countries. The median age was 48 years, with 26.1% females, and 76.9% had a history of cirrhosis. Multivariable Cox regression models showed that pentoxifylline use was not associated with survival (HR 1.20, 95% CI 0.85 to 1.69, p=0.291). Factors associated with mortality included age (HR 1.23, 95% CI 1.10 to 1.36, p<0.001), Model for End-Stage Liver Disease score at admission (HR 1.06, 95% CI 1.04 to 1.08, p<0.001) and renal replacement therapy use (HR 1.39, 95% CI 1.05 to 1.84, p=0.019). The main causes of death were multiple organ failure (42%), infections (10%), oesophageal varices bleeding (7%) and renal failure (6%). Conclusion Pentoxifylline showed no significant benefit on mortality in patients with sAH and AKI. Further studies are needed to refine treatment strategies for this high-risk group.

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P &lt; 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

Background: Severe alcohol-associated hepatitis (sAH) is a well-characterized disease with high short-term mortality. However, there is limited research on those with a “less severe condition” (moderate AH). This study aims to characterize in-depth patients with moderate AH (mAH), including the performance of mortality scoring systems, key prognostic factors, and survival over time. Methods: A multicenter retrospective cohort study (2009–2019) included patients with mAH (MELD score ≤20 at admission). Cox regression and receiver operating characteristic curves with AUC were used for analysis. Results: We included 1845 patients with AH (20 centers, 8 countries) between 2009 and 2019. mAH was defined as a MELD score ≤20 at admission. Twenty-four percent met the criteria for an mAH episode. Patients with mAH tend to be older and have a higher proportion of females, with a median MELD of 17 (15–19), Maddrey discriminant function (mDF) of 33 (22–40), the trajectory of serum bilirubin of 0.83 (0.60–1.21), and neutrophil-to-lymphocyte ratio (NLR) of 5 (2.96–8.60). The primary causes of death in mAH included multiple organ failure (34.1%) and infections (16.6%). The cumulative survival rates at 30, 90, and 180 days were 94.3%, 90.4%, and 88.2%, respectively. In multivariable analysis, age was the only significant predictor of 30-day mortality (HR 1.49, 95% CI: 1.27–1.76, p <0.001). Mortality prediction models showed poor performance, with AUC for MELD (0.671), mDF (0.726), trajectory of serum bilirubin (0.733), and NLR (0.697). Conclusions: Patients with moderate AH exhibited a mortality of 11.8% at 6 months, primarily driven by multiple organ failure and infections. These patients also exhibit a different clinical profile compared to those with sAH. Tailored models and therapeutic strategies are needed to improve long-term outcomes in mAH.