Citations

Abstract Aims Social isolation (SI) is associated with a higher risk of cardiovascular disease (CVD). One mechanism linking SI and CVD is accelerated biological ageing, which can be assessed using artificial intelligence-enabled electrocardiography (AI-ECG). We investigated whether longitudinal changes in SI status are associated with changes in biological ageing patterns. Methods and results A retrospective longitudinal cohort study including 17 663 individuals without significant CVD who completed ≥2 Berkman and Syme Social Network Index and had paired ECGs within 1 year of each questionnaire. Longitudinal SI status was defined by comparing baseline and follow-up SI status. Ageing trends were assessed using Δage-gap, defined as the change in the gap between AI-ECG-predicted age and chronological age from baseline to follow-up. Linear regression models predicting Δage-gap and survival analyses with Kaplan–Meier and multivariable Cox regression for all-cause mortality were performed. Persistently connected individuals were older [63.1 (52.1, 70.6) years] and had a higher prevalence of hyperlipidaemia and hypertension, yet demonstrated more favourable ageing trajectories. Similarly, those who became connected showed a non-significant attenuation of accelerated ageing. In multivariable linear regression, being persistently isolated [β = +0.412 years, P < 0.001] or becoming isolated [β = +0.438 years, P = 0.012] was associated with accelerated ageing compared to being persistently connected. In survival analyses, becoming isolated (aHR = 1.94, 95% CI = 1.53–2.46, P < 0.001) and being persistently isolated (aHR = 1.66, 95% CI = 1.40–1.96, P < 0.001) were associated with significantly higher all-cause mortality, independent of chronological age and comorbidities. Conclusion Persistent social connection is associated with slower biological ageing and lower mortality. The effects of SI on ageing and survival appear to be potentially reversible, calling for a prospective study to evaluate interventions aimed at improving both the social and biological burden of SI.

BACKGROUND Laser interstitial thermal therapy is a minimally invasive surgical technique commonly used for treating epileptogenic foci in patients with drug-resistant epilepsy. Densely calcified lesions pose a challenge because they prevent the placement of a laser cannula within them and act as a heat shield. A 22-year-old male presented with intractable epilepsy with imaging demonstrating a densely calcified lesion in the right medial occipitotemporal gyrus radiographically consistent with a polymorphous low-grade neuroepithelial tumor of the young. OBSERVATIONS Two laser cannulas were stereotactically positioned to flank the centrally calcified portion of the lesion at its anterior and posterior aspects. Intraoperative MR thermography during each ablation showed that the dense calcification shielded ablative heating from spreading to the other side of the lesion. The sum of the thermal ablation zones covered the entirety of the lesion. Postprocedure MRI demonstrated overlapping peripherally enhancing ablation zones, which subsumed the entirety of the calcified mass. The patient tolerated the procedure well and remained seizure free at the 14-month follow-up. LESSONS Using multiple stereotactically placed laser filaments to flank epileptogenic lesions that are densely calcified is a strategy to effectively encompass the entirety of the lesion within the combined ablation zones. https://thejns.org/doi/10.3171/CASE26184

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

8579 Background: LOH may provide a means to target tumor versus normal cells, to augment the efficacy and safety of MSLN-targeted programs (Hecht et al. JCO . 2022). A2B694 is an autologous, logic-gated, Tmod CAR T therapy designed to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR activator with an HLA-A*02 blocker (Hamburger et al. Mol Imm. 2020). Methods: The first-in-human, open-label, phase 1/2 EVEREST-2 (NCT06051695) study of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose. Results: As of 05 January 2026, 13 patients were enrolled: 8 women/5 men, median age 59 years, 11 non-Hispanic White/2 Hispanic with unknown race. Tumor types included colorectal (n = 4), ovarian (n = 3), pancreatic (n = 3), non–small cell lung adenocarcinoma (NSCLC), gastro-esophageal, and mesothelioma (n = 1 each). A2B694 dose level (DL) groups were: DL1: 1×10 8 cells (n = 3), DL2: 2×10 8 cells (n = 4), DL3: 4×10 8 cells (n = 5), and DL4: 6×10 8 cells plus low-dose IL-2 (n = 1). Lymphodepletion prior to administration of A2B694 was well-tolerated, with expected, transient cytopenias. The only adverse event reported in more than 1 patient was grade 3 neutropenia. One patient had grade 3 ICANS and 1 patient had grade 1 CRS. There were no dose-limiting toxicities or new safety signals after up to 17 months follow-up. All 13 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood. While A2B694 was not detected in tumor biopsies collected in patients treated at DL1 (0/2), all patients treated at DL2-DL4 with available biopsies (3/3) had detectable A2B694 in the tumor microenvironment. A patient with KRAS G12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion per RECIST 1.1 by central review and had a confirmed CR at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease. On D243, the patient had a CNS relapse, with an ongoing non-CNS CR per RANO-BM at D284. At M12, the patient's CT showed no new findings and persistence of A2B694 in the blood was confirmed by ddPCR. Conclusions: We report the first patient with NSCLC to have a CR after CAR T. Overall, A2B694 demonstrated manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The maximum tolerated dose has not been reached; dose-escalation continues. Clinical trial information: NCT06051695 .

8549 Background: Despite two decades of anti-angiogenic therapy in NSCLC, no predictive biomarker identifies which patients benefit. As VEGF-targeted combinations advance in clinical development, patient selection biomarkers remain a critical unmet need. QVT (Quantitative Vessel Tortuosity) Score is an automated imaging biomarker measuring chaotic tumor vasculature from baseline CT scans and has been shown to be associated with immune checkpoint inhibitor (ICI) outcomes. We hypothesized that QVT Score could identify patients with chaotic angiogenesis tumors and greater sensitivity to anti-angiogenic therapy. Methods: We analyzed a subset of 334 patients from the SWOG S0819 (NCT00946712) trial with treatment-naïve stage IV non-squamous NSCLC receiving carboplatin/paclitaxel with (56%) or without (44%) bevacizumab. QVT Scores were derived from baseline CTs based on radiologist-defined tumor annotations and radiomic features of tumor vasculature (e.g. vessel twisting, curvature, and branching). Overall survival (OS) was evaluated as the primary endpoint using Cox proportional hazards models with QVT × bevacizumab interaction terms. Bevacizumab was non-randomized in S0819 (physician/patient discretion): to address this, we employed doubly robust estimation combining inverse probability of treatment weighting (IPTW) with multivariable covariate adjustment for age, performance status, histology, smoking history, and stage. Results: The QVT Score × bevacizumab interaction was significant (p=0.007, doubly robust estimation) and stayed consistent across sensitivity analyses (p=0.017 multivariable; p=0.047 IPTW), suggesting differential treatment benefit based on pre-treatment vascular phenotype. QVT Score was strongly OS-associated without bevacizumab (HR=3.03, p=0.003) but not with bevacizumab (HR=1.71, p=0.079), consistent with mitigation of high-risk biology. Bevacizumab benefit increased across QVT quartiles (Table 1): patients in the highest quartile had a 60% reduction in mortality (HR=0.40, p<0.001), while patients in the lowest quartile showed no OS benefit (HR=0.89, p=0.64). Conclusions: Despite unfavorable prognosis on standard-of-care therapies (chemotherapy, ICIs), we found that patients with elevated baseline QVT Score may benefit from the addition of anti-angiogenic agents. As VEGF-targeted combinations including bispecific antibodies enter development, radiomic biomarkers may play a crucial role in enriching trial populations and enabling mechanistic longitudinal monitoring. These findings warrant prospective validation in independent randomized clinical trials. Bevacizumab treatment effect by QVT score quartile. QVT Score Quartile N Bevacizumab effect (Hazard Ratio) P Q1 84 0.89 (0.56 -1.42) 0.64 Q2 83 0.70 (0.44-1.12) 0.14 Q3 83 0.54 (0.34-0.85) 0.01 Q4 84 0.40 (0.24-0.65) 0.0003

Background Burnout arises from prolonged, unresolved work-related stress and adversely affects professional performance and overall well-being. Resident doctors and medical students are particularly vulnerable because of the demands of balancing clinical, academic and related responsibilities. Aims This study aimed to assess self-reported burnout and related stressors among UK resident doctors and medical students, and estimate the economic impact of burnout-related absenteeism among resident doctors. Method Self-report questionnaires assessing burnout and related stressors were distributed to UK resident doctors and medical students. A total of 2793 responses were received: 1439 (51.5%) from resident doctors and 1354 (48.5%) from medical students. Economic losses from absenteeism were calculated with a human capital approach. Results Burnout was reported by 70% ( n = 1008) of resident doctors and 65.7% ( n = 889) of medical students. Notably, 56.8% ( n = 573) and 79.3% ( n = 705) of resident doctors and medical students affected by burnout, respectively, were unaware of available support services. Relocation stress (85.1% of residents and 62.6% of students), financial stress (53.9% of residents and 57.8% of students) and poor work–life balance (32.1% of residents and 20.7% of students) were commonly reported. The annual economic burden of absenteeism related to burnout among resident doctors was estimated to reach £251.5 million. Conclusions Burnout among UK resident doctors and medical students may reflect a combination of underlying factors, including financial strain, relocation stress and difficulties with work–life balance. These findings underscore the need for targeted interventions that support well-being and address financial and relocation challenges, which may, in turn, help prevent burnout and improve retention within the medical workforce. Reducing burnout and associated stressors may also help lessen its economic impact, allowing resources to be redirected towards patient care.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Background/Objectives: Accurate detection of pulmonary nodules on chest CT is critical for lung cancer screening, yet training robust detectors remains challenging due to the high cost of reliable annotations. In this work, we present a systematic study of curriculum learning for CT-based lung nodule detection on the enhanced LUNA25 benchmark and propose a hybrid curriculum learning framework for data-efficient optimization. Methods: Our approach estimates sample difficulty by fusing clinically interpretable handcrafted factors such as nodule size and count with model-driven signals such as prediction confidence from a teacher model, and constructs a three-stage progressive training curriculum from easy to hard samples. Using YOLOv11s as a strong baseline, the proposed hybrid curriculum is compared against conventional training without curriculum learning and against single-source curricula. Results: On the held-out LUNA25 test set, hybrid curriculum learning increases mAP50 from 0.672 to 0.696, mAP50–95 from 0.369 to 0.385, recall from 0.588 to 0.634, and precision from 0.725 to 0.764. Extensive data-efficiency experiments with proportional reductions (1/2, 1/5, 1/10) and fixed training samples (5000–40,000 slices) further confirm consistent gains across limited-data regimes. Conclusions: These results demonstrate that jointly leveraging intrinsic image complexity and optimization-aware feedback provides effective sample scheduling for robust and data-efficient lung nodule detection.

Abstract Context The clinical relevance of etiologic concordance and temporal presentation in bilateral adrenal masses remains poorly defined, creating uncertainty in diagnostic evaluation and management. Objective To characterize the etiologic spectrum of bilateral adrenal masses, evaluate patterns by concordance and synchronicity, and identify predictors of discordance and malignant or pheochromocytoma contralateral lesions. Design Retrospective cohort study (2010-2025). Setting Tertiary referral center. Participants Adults with bilateral adrenal masses. Main Outcome Measures Etiology, concordance, synchronicity, interval to contralateral lesion, and factors associated with discordance and malignant or pheochromocytoma contralateral lesions. Results Among 1035 patients (median age 59.6 years; 51% women), 85% had concordant and 15% discordant etiologies. Concordant cases were predominantly bilateral benign cortical lesions (76%), whereas discordant cases were heterogeneous (benign 35%, malignant 31%, and indeterminate 34%). Presentation was synchronous in 84% and asynchronous in 16%, with a median interval of 45 months (interquartile range 15-87). Asynchronous disease was associated with higher discordance (23% vs 13%, P = .001) and greater prevalence of malignant lesions (bilateral malignant: 17% vs 7%; discordant malignant: 8% vs 4%; overall P &lt; .001). Among asynchronous cases, shorter interval to contralateral lesion (&lt;2 vs ≥5 years) was independently associated with malignant or pheochromocytoma etiology (adjusted odds ratio [OR] 2.63, 95% CI 1.01-6.85), as was larger tumor size (adjusted OR 1.06 per mm, 95% CI 1.02-1.09). Conclusion Most bilateral adrenal masses are benign and concordant; however, discordant or asynchronous disease identifies a higher-risk subgroup enriched for malignancy. Early contralateral lesion development and larger tumor size are key risk factors.