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Abstract Background Traumatic brain injury (TBI) in older adults is associated with high mortality and poor functional outcomes. However, optimal management remains uncertain, as evidence comparing surgical and medical strategies is limited, heterogeneous, and extrapolated from younger populations. We conducted a systematic review and meta-analysis to compare outcomes between surgical and medical management in this population. Methods PubMed, Embase, and Web of Science were searched from database inception to December 8, 2025. Studies including adults aged ≥60 years with TBI comparing surgical versus medical management were included. The primary outcome was favorable neurological outcome, while secondary outcomes included hospital length of stay (LOS) and mortality. Pooled estimates were calculated as risk ratios (RR) and mean differences (MD) using random-effects models with restricted maximum likelihood and Hartung–Knapp adjustment. Results Sixteen cohort studies comprising 132,823 patients were included. Surgical management was not associated with improved favorable neurological outcomes at discharge, 3, 6, or 12 months. However, it was associated with longer LOS (MD = 6.35 days, 95% CI: 2.55 to 10.14; p < 0.01). No differences were observed in in-hospital, 30-day, 3-month, 12-month, or 24-month mortality. Notably, surgical management was associated with a reduction in 6-month mortality (RR = 0.68, 95% CI: 0.51–0.92; p = 0.02). Conclusions In older adults with TBI, surgical management was associated with reduced 6-month mortality and longer hospital LOS, but not with improved functional outcomes, highlighting a dissociation between survival and recovery. This dissociation has implications for clinical decision-making and patient and family counseling. Individualized decision-making that incorporates frailty, comorbidities, and potential reversibility of injury is essential, rather than relying solely on age. While this study represents the best available comparative evidence to date on surgical versus non-surgical management in older adults with TBI, findings should be interpreted with caution due to heterogeneity and low to very low certainty of the evidence. High-quality randomized controlled trials are needed to better define the role of surgery in this population.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

RELA-related disease is a rare, autosomal-dominant condition presenting with immune dysregulation and immunodeficiency. RELA encodes the p65 subunit, a component of the canonical NFκB pathway. The underlying pathogenesis, at least in part, involves impaired NFκB activation, increased susceptibility to TNFα-induced apoptosis, and hyperinflammation. To date, only a modest number of cases have been documented worldwide, and the full clinical and functional spectrum of disease remains incompletely defined. This study represents a large global cohort identified with RELA variants, comprising 40 patients from 30 institutions, expanding our previous report of a single large kindred (1). The clinical spectrum includes arthritis, mucocutaneous ulcers, uveitis, dermatitis, irritable bowel disease, recurrent infections, lymphopenia, hypogammaglobulinemia, recurrent fevers, and susceptibility to neoplasia. The patients represent 36 kindreds with 28 unique RELA variants, of which 15 are missense, 7 nonsense, and 6 frameshift variants. Fifteen are in the Rel homology domain, 7 in the transcriptional activation domain, and 6 in the C-terminal region proximal to TAD (Fig. 1). Functional studies assessed the canonical NFκB pathway in 27% of the cohort (n = 11; healthy controls = 40). Patient peripheral blood mononuclear cells (PBMCs) were used to quantify total and phosphorylated p65 (ph-p65, Ser529) by flow cytometry after stimulation with PMA (100 ng/ml) and ionomycin (1 uM). In 8 patients, we assessed the kinetics of IκBα degradation, required for p65 phosphorylation and nuclear translocation of p65/p50. All patients tested had decreased total p65, while 64% had decreased ph-p65 with altered phosphorylation kinetics. Nearly 45% had impaired IκBα degradation. One patient (P4) demonstrated increased IκBα degradation and ph-p65, while a related proband (P1) had decreased ph-p65. Additionally, P4 did not have the same mucocutaneous clinical phenotype as P1 despite sharing the same RELA variant. This could reflect the effect of other genetic modifiers, epigenetic, environmental, or stochastic variations, which could lead to variable expressivity and/or incomplete penetrance. All patients appeared to have haploinsufficiency, as none had normal levels of p65. This study expands the clinical and genetic spectrum of RELA-related disease and provides mechanistic insights into the impact of these variants on p65 phosphorylation and downstream function, resulting in variable expressivity. Figure 1. RelA protein structure. Represents unique variant locations and categories, key domains, and phosphorylation sites. Source: UniProt. Adapted from (2). BioRender.

Introduction Asymptomatic individuals with negative Interferon-γ release assay (IGRA) and tuberculin skin test (TST) results are often labeled as tuberculosis-unexposed individuals. We hypothesize that flow cytometric (FC) detection of antigen-stimulated T-cells in peripheral blood can differentiate IGRA(-)/TST(-) individuals with and without prior potential M. tuberculosis (Mtb) exposure. Methods We used FC multiparameter profiling of T-cell activation markers in TST/IGRA-negative individuals at risk for Mtb exposure and in unexposed controls. Results We studied 54 IGRA(-)/TST(-) subjects, including 27 individuals at risk for prior Mtb exposure. While quantitative IGRA results were negative in all patients, FC profiling of CD3/CD4 + IFN-γ + HLA-DR + T-cells after stimulation with a pool of Mtb-specific region of difference-1 (RD1) peptides, mycobacterial (PPD and MTB300), or Candida antigens, statistically differentiated between unexposed and potentially exposed individuals (P&lt;0.05). ROC analysis showed PPD and RD1 peptides responses had AUCs &gt;0.7 (sensitivity of 55.5–74% and specificity of 66.6–85.1%). The presence of a polyfunctional RD1-reactive CD3/CD8 + IFN-γ + TNF-α + T-cell subset also significantly differentiated these groups (AUC 0.66). Other T-cell markers demonstrated no significant differences. Conclusions FC detection of antigen-specific IFN-γ + HLA-DR + CD4+T-cells and IFN-γ + TNF-α + CD8 + T-cells can differentiate IGRA(-)/TST(-) individuals at risk of Mtb exposure from unexposed controls. Further validation is needed to determine whether this immunoprofiling approach can improve detection of Mtb infections and identification of unexposed individuals for future biomarker studies and vaccine trails.

Objective To examine the potential errors of a general large language model (LLM) (ie, Claude 3.5 Sonnet) on data extraction from randomised controlled trials (RCTs). Design and setting An empirical study comparing Claude 3.5 Sonnet extractions against a human-performed verification dataset. The extraction tasks for Claude 3.5 Sonnet were based solely on original RCT portable document format (PDF) files. For PDFs that could not be directly extracted by Claude 3.5 Sonnet, optical character recognition was employed to convert them into text format before extraction. Participants A random sample of 664 trials was selected from a well-established trial bank and a final data pool was established based on rigorous manual cross-checking as a reference standard. Data sources PubMed, EMBASE, Scopus, Web of Science (all databases) and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 2023. Eligibility criteria for selecting studies RCTs on children involving medication and adverse events. Main outcome measures Claude 3.5 Sonnet was applied to extract the basic information (eg, trial design, population information and source of funding) and adverse outcomes (ie, name of adverse events, number of events). Claude 3.5 Sonnet outputs were compared against the final data pool and all errors were recorded. Results are presented as error rates and with 95% CI, estimated using a generalised linear mixed model. Results For the 664 trials, a total of 23 069 data cells were extracted via Claude 3.5 Sonnet, with 10 624 for basic information and 12 445 for adverse outcomes. The overall error rate for data extraction was 6.6% (95% CI 5.4% to 8.2%), with 5.7% (95% CI 5.2% to 6.1%) in basic information and 7.6% (95% CI 4.9% to 11.8%) in adverse outcomes. When stratified the 1542 total errors by error types, misallocation (assigning data to incorrect fields; 57.1%, 881/1542) and missed or omitted data (incomplete extraction of available data; 23.2%, 357/1542) accounted for the two most frequent errors, with misallocation occurring more in basic information (53.3%, 470/881), while missed or omitted data occurred more in adverse outcomes (96.1%, 343/357). Post hoc analysis examining the association between trial reporting quality (assessed using Consolidated Standards of Reporting Trials (CONSORT) 2025 and LLM data extraction error rates indicated that higher CONSORT adherence was associated with lower extraction error rates. Conclusions The data extraction error of Claude was relatively low, but it alerts LLM applications in evidence synthesis. Detailed checking for LLM outputs should be the primary consideration for evidence synthesisers.

Abstract Context Incidental thyroid findings (ITFs) are increasingly detected on imaging performed for non-thyroid indications. Their prevalence, features, and consequences remain undefined. Objective To develop, validate, and deploy a natural language processing (NLP) pipeline to identify ITFs in radiology reports and assess their prevalence, features, and clinical outcomes. Design Retrospective cohort study. Setting Mayo Clinic sites (Rochester, Arizona, Florida, Mayo Clinic Health System). Participants Adults without prior thyroid disease undergoing thyroid-capturing imaging from July 1, 2017, to September 30, 2023. A transformer-based NLP pipeline identified ITFs and extracted nodule characteristics from image reports from multiple modalities and body regions. Outcomes ITF prevalence, downstream thyroid ultrasound, biopsy, thyroidectomy, and cancer diagnosis. Logistic regression identified demographic and imaging-related factors. Results Among 115 683 patients (mean age, 56.8 [SD 17.2]; 52.9% women), 9077 (7.8%) had an ITF (92.9% nodular). ITFs were more likely in women, older adults, higher BMI, and in imaging ordered by specialties different from Emergency Medicine. Compared with chest CT, ITFs were more likely via neck CT, PET, and nuclear medicine scans. Nodule characteristics were poorly documented, with size reported in 44% and other features in fewer than 15%. Compared with patients without ITFs, those with ITFs had higher odds of thyroid nodule diagnosis (OR 45, 95%CI 41.1-49.3), biopsy (OR 46.8, 95%CI 39.0-56.2) thyroidectomy (OR 55.8, 95%CI 31.3-99.3), and thyroid cancer diagnosis (OR 61.7, 95%CI 38.6-98.5). Most cancers were papillary (88.5%) and larger when detected after ITFs (2 cm SD 1.4) vs no ITF (1.3 cm SD 0.8). Conclusion ITFs were common and strongly associated with cascades leading to the detection of small, low-risk cancers, highlighting their role in overdiagnosis and the need for standardized reporting and more selective follow-up.

ABSTRACT Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) exhibits marked heterogeneity in fibrosis progression and liver‐related outcomes. Liver biopsy is not feasible for longitudinal risk stratification at scale, creating a need for validated non‐invasive biomarkers, particularly imaging biomarkers, that can predict clinically meaningful disease progression and liver‐related outcomes. Aims To describe the design and rationale of the GOLDMINE study, established to determine whether non‐invasive imaging biomarkers predict MASLD progression and liver‐related clinical outcomes. Methods GOLDMINE is an investigator‐initiated, multi‐centre, international longitudinal cohort enrolling up to 1000 adults with either biopsy‐proven MASLD or MASLD cirrhosis across the full fibrosis spectrum. Participants are recruited from 15 sites in the US and 4 international sites (Japan, Singapore and France). At baseline, participants undergo clinical phenotyping, vibration‐controlled transient elastography, and advanced magnetic resonance imaging (MRI), including proton‐density‐fat‐fraction and magnetic resonance elastography (MRE). MRI (and biospecimen banking) is repeated at 2‐year intervals (years 2 and 4), with annual follow‐up visits for up to 10 years. Baseline liver histology is centrally processed, digitized and reviewed by a single expert hepatopathologist; all MRI/MREs are centrally interpreted. Results The prespecified clinical outcomes include progression to cirrhosis, clinically significant portal hypertension, major adverse liver‐related outcomes (ascites, hepatic encephalopathy, portal hypertensive bleeding, liver transplantation/qualification), hepatocellular carcinoma, major adverse cardiovascular events, and all‐cause mortality, with independent central adjudication of all events. Conclusions GOLDMINE establishes a rigorously phenotyped MASLD cohort integrating centralized histology, advanced MRI‐based biomarkers, longitudinal biobanking, and adjudicated outcomes, providing a platform to validate imaging and blood‐based prognostic biomarkers in MASLD.

Introduction Blood-based biomarkers offer a promising, minimally invasive approach to Alzheimer’s disease (AD) diagnosis, yet validation in admixed populations remains limited. We investigated whether plasma biomarkers predict CSF-defined AD pathology in a Brazilian cohort. Methods Seventy-eight older adults [including individuals with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and cognitively unimpaired controls] underwent cognitive testing, neuroimaging, and plasma biomarker assessment. CSF data were available for symptomatic participants (MCI and SCD; n = 61), and regression and ROC analyses were performed in the subset with both CSF and APOE genotyping data ( n = 53). Plasma Aβ42, p-Tau181, p-Tau217, t-Tau, and derived ratios were quantified. Multivariable logistic regression and ROC analyses evaluated prediction of abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42, adjusting for age, sex, and APOE ε4 status. Results Approximately 25% of individuals with MCI exhibited abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42 ratios. Moderate correlations were observed between plasma and CSF biomarkers (r &gt; 0.4), particularly for Aβ42/p-Tau217 and p-Tau217. In adjusted models, plasma p-Tau217 and the Aβ42/p-Tau217 ratio independently predicted abnormal CSF pathology. Each one standard deviation increase in p-Tau217 was associated with 3.53–4.83-fold higher odds of abnormal CSF ( p ≤ 0.003). In contrast, higher Aβ42/p-Tau217 ratios were associated with substantially lower odds of pathology, with each one standard deviation increase corresponding to a 91%–93% reduction in risk ( p ≤ 0.002). The ratio showed stronger associations than p-Tau217 alone. ROC analyses demonstrated good discrimination. For CSF p-Tau181/Aβ42, Aβ42/p-Tau217 achieved an AUC of 0.88 (83% sensitivity, 85% specificity), compared with 0.83 for p-Tau217. For CSF t-Tau/Aβ42, both biomarkers yielded AUCs of 0.89. Discussion Plasma Aβ42/p-Tau217 and p-Tau217 effectively identify CSF-defined AD pathology in an admixed cohort. While higher p-Tau217 levels were associated with increased odds of pathology, higher Aβ42/p-Tau217 ratios were associated with lower pathological burden and demonstrated stronger effect sizes, supporting the added value of combining amyloid and tau biomarkers. These findings provide initial evidence for local validation of blood-based AD biomarkers in Brazil.

Abstract Background: In Part 2 of the phase 2 RELATIVITY-104 study of first-line nivolumab (NIVO) plus relatlimab (RELA) with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT in patients with metastatic NSCLC, NIVO + RELA + PDCT demonstrated improved clinical benefit, including overall survival, in the prespecified subgroup of tumor PD-L1 expression ≥ 1%, which was further enriched in NSQ tumor histology. Baseline lymphocyte-activation gene 3 (LAG-3) expression was associated with enriched efficacy for both NIVO + RELA + PDCT and NIVO + PDCT. In a comparative transcriptomic analysis, NSQ and squamous tumors demonstrated distinct immune signatures, with NSQ tumors exhibiting higher expression of LAG-3 ligands and greater enrichment for combination therapy benefit by PD-L1 expression. To further elucidate the mechanism of action of NIVO + RELA + PDCT, we report additional exploratory translational data in the PD-L1 ≥ 1% NSQ subgroup for Part 2 of RELATIVITY-104. Methods: Patients with untreated metastatic NSCLC were randomized 1:1 to NIVO 360 mg + RELA 360 mg + PDCT or NIVO 360 mg + PDCT Q3W. Exploratory endpoints included translational analyses in the PD-L1 ≥ 1% NSQ subgroup. Gene expression data from pretreatment tumor RNA sequencing were normalized and analyzed for associations with clinical outcomes. Pre- and on-treatment peripheral blood samples were collected for high-dimensional flow cytometry immunophenotyping using a validated 24-marker LAG-3-specific panel that used drug-tolerant, noncompeting clones for LAG-3, PD-1, and CTLA-4. Statistical associations between biomarkers and clinical outcomes were assessed using logistic regression and Cox proportional hazards models. Data are from the May 2, 2025, database lock. Results: In the NIVO + RELA + PDCT arm, immune signatures demonstrated a significantly lower hazard ratio (HR) in the PD-L1 ≥ 1% NSQ subgroup, while stromal signatures demonstrated a significantly higher HR. T exhausted progenitor signature subsets, as well as ICOS+ CD4+ T cells, at baseline were shown to enrich for survival with NIVO + RELA + PDCT. Clinical benefit was observed across all baseline LAG-3 expression levels (&lt; 1% and ≥ 1%); however, on-treatment increases in LAG-3+ T cells were associated with longer progression-free survival and a higher objective response rate with NIVO + RELA + PDCT. In the NIVO + PDCT arm, increases in LAG-3 cell populations were associated with lower response. Conclusions: In the RELATIVITY-104 study, the on-treatment immune dynamics of LAG-3+ T cells correlated with the benefit of NIVO + RELA + PDCT vs NIVO + PDCT in patients with PD-L1 expression ≥ 1% and NSQ NSCLC. Immune signatures including progenitor T exhausted signatures associated with improved outcomes with NIVO + RELA + PDCT. These data support the mechanistic rationale for adding anti-LAG-3 to anti-PD-1 + PDCT in PD-L1 ≥ 1% NSQ NSCLC. Citation Format: Jaclyn Neely, Annie Yu, Nicolas Girard, Manuel Cobo-Dols, Mauricio Burotto, Luis Paz-Ares, Vamsidhar Velcheti, Martin Reck, Srijata Samanta, Anila Qureshi, Priyanka Kasbekar, Charlie Garnett-Benson. RELATIVITY-104 Part 2: translational analyses in the programmed death ligand 1 (PD-L1) ≥ 1% and non-squamous (NSQ) non-small cell lung cancer (NSCLC) subgroup [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB418.