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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.

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 Background : Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods : Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results : Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion : TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

ABSTRACT Background Journal clubs provide opportunities for discussion of new and evolving practices and technologies. Objective We sought to evaluate the utility and effectiveness of a monthly web‐based cosmetic dermatology journal club facilitated by faculty, residents, and medical students. Results From May 2025 to September 2025, 16 articles were discussed and 41 responses were recorded (response rate: 60%). Most respondents found the journal club was an appropriate length, engaging, and very useful. Relevance, frequency, and likelihood to participate in the future varied significantly by participant type. Medical students and residents collectively considered the journal club too infrequent ( p = 0.03) and reported it had less relevance to their practice ( p < 0.001). Conclusion A monthly web‐based cosmetic dermatology journal club was generally positively received by respondents.

Abstract Spontaneous coronary artery dissection is an unusual, but increasingly recognized, cause of acute coronary syndrome. It is a potentially fatal disorder that predominantly (&gt;90% of cases) affects women, who are about 20 years younger (age 45–52 years) than those presenting with an acute coronary syndrome due to atherosclerotic coronary artery disease, and is the commonest cause of myocardial infarction associated with pregnancy. With the advent of improved coronary artery imaging modalities, including invasive coronary angiography, intravascular ultrasonography (IVUS), and optical coherence tomography (OCT), spontaneous coronary artery dissection is being increasingly diagnosed. It is typically due to a spontaneous bleed in the tunica media of an epicardial coronary artery, with or without an intimal tear, that results in an intramural haematoma; the latter, in turn causing a separation or dissection of the lamellae formed by the layers of smooth muscle cells of the tunica media, which can propagate longitudinally. Although coronary artery dissection can be due to atherosclerotic disease that may, in fact, present spontaneously, or to trauma, or guidewire-induced intimal injury, the understanding that the entity now known as spontaneous coronary artery dissection is an idiopathic disorder that is not associated with atherosclerosis or trauma, and is not iatrogenic, is one that has emerged only relatively recently (last 10–15 years). This raises the question, what is the provenance of spontaneous coronary artery dissection as it is now defined and understood? Here, this issue is addressed by a detailed consideration of the medical literature from 1800.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.