Citations

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

PURPOSE External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

Abstract Aims Trends in upright seated pulmonary artery pressure (PAP) with synchronous measurement of weight, blood pressure (BP), and heart rate (HR) have not been compared prior to heart failure events (HFE) and other causes of hospitalization during remote monitoring. Methods We analysed 24-month data from patients in the PROACTIVE-HF trial. Participants (N = 456) used the CordellaTM HF daily to measure seated PAP, weight, BP, and HR, all taken and transmitted within minutes. Events that were analysed included HFE, those potentially related to HF treatment (HF-TRE), and others (non-HFE). Parameters were trended from 60-days before (D-60) to 30-days after (D + 30) the day of the event (D = 0), and their concurrent changes were compared between D-60 and D = 0, and D = 0 and D + 30 using a mixed effects model. Results There were 196 HFE, 276 non-HFE, and 66 HF-TRE. Prior to HFE, average mean PAP (mPAP) increased from 27.8 ± 10.9 mmHg at D-60 to 32.6 ± 11.2 mmHg at D = 0 (P < .001), and decreased to 30.0 ± 12.4 mmHg at D + 30 (P = .001). Kinetics of mPAP before HFE differed by left ventricular ejection fraction (LVEF); mPAP rose by 3.4 ± 6.8 mmHg in 2 weeks before HFE in those with LVEF >40%, whereas a similar magnitude (3.1 ± 9.1 mmHg) of mPAP rise occurred over 6-weeks before HFE in those with LVEF ≤40%. No consistent changes in weight, SBP, or HR prior to HFE were observed (P > .05). Changes in vital signs but not mPAP were noted prior to HF-TRE and non-HFE. Conclusion Seated mPAP increased weeks in advance of HFE and vital signs did not change consistently before HFE. Differential kinetics of mPAP prior to HFE by the LVEF suggest that an uptrend in seated mPAP may need to be addressed more rapidly in those with LVEF>40%. Changes in vital signs with non-HFE and HF-TRE need further validation.

Abstract A working group of cIMPACT-NOW evaluated the literature on IDH-mutant gliomas for opportunities to improve pathology-based risk stratification and grading, especially at the interface of CNS WHO grades 2 and 3, since therapeutic decisions depend on risk assessment for clinical management. The group also evaluated newly described IDH-mutant glioma subgroups and considered multidisciplinary aspects of therapeutic decision-making. PDGFRA amplification was associated with highly aggressive clinical behavior of IDH-mutant astrocytomas, consistent with CNS WHO grade 4. Other genetic alterations associated with intermediate risk and most consistent with CNS WHO grade 3 included PIK3 mutations; EGFR alteration; MYCN amplification; and specific retinoblastoma pathway alterations, including CDK4, CDK6, and CCND2 amplification, RB1 homozygous deletion or mutation, and mutation of CDKN2A. DNA methylation signatures of G-CIMP-low or A_IDH_HG were consistent with CNS WHO grade 3 or 4, depending upon other grading criteria. We suggest a mitotic count of ≥3 per 2.4 mm2 could be considered as a CNS WHO grade 3 criterion. Our review did not uncover features to improve the grading of oligodendroglioma, IDH-mutant and 1p/19q-codeleted, although CNS WHO grade 3 tumors with elevated mitotic rates, yet lacking necrosis, microvascular proliferation, CDKN2A/B homozygous deletion, and MRI contrast enhancement, may be associated with extended survival. Implementing evidence-based criteria for risk stratification and grading will improve guidance for clinical decision-making.

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.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Abstract Background and aims Carotid calcification features are readily quantifiable by CTA, yet their relationship with plaque vulnerability and rupture remains controversial. We investigated whether calcium score, volume, density, and residual (volume-normalized) calcium density are associated with carotid plaque vulnerability, symptomatic status, and recurrent ipsilateral ischemic stroke and transient ischemic attack (TIA). Methods Patients with recent TIA or ischemic stroke and ≥2mm carotid plaque with <70% stenosis underwent baseline CTA and MRI. Carotid calcifications were segmented on CTA (≥130 Hounsfield units), yielding calcium score, volume, and density. Volume-normalized residual calcium density was calculated as the standardized residuals from a log-transformed calcium density-volume model (Figure 1). Vulnerable plaque features (intraplaque hemorrhage, thin-or-ruptured fibrous cap, and lipid-rich necrotic core, and ulceration) were linked to calcium metrics. Associations between calcium metrics and recurrent ipsilateral TIA or ischemic stroke were assessed using Cox regression and adjusted for age, sex, stenosis. Results Among 193 patients (mean age 67.8±8.5 years, 144 (75%) men), 26 experienced ipsilateral ischemic stroke or TIA over median 5-year follow-up. Lower calcium density and residual calcium density were independently associated with vulnerable plaques (adjusted ORs: 0.40-0.60; Figure 2). Residual calcium density remained independently associated with symptomatic side (adjusted OR: 0.64, 95%CI: 0.47-0.88) and with recurrent TIA/stroke (adjusted HR: 0.53, 95%CI: 0.29-0.95). Calcium score, volume, and density were not independently associated with symptomatic side or recurrent events (Figure 3). Conclusions Residual calcium density is a robust, independent marker of carotid plaque vulnerability and ipsilateral ischemic stroke and TIA risk in patients with symptomatic carotid artery disease. Conflict of interest Juul Bierens: nothing to disclose; Daniel Bos: nothing to disclose; Paul J. Nederkoorn: nothing to disclose; Pim A. de Jong: nothing to disclose; Robert J. van Oostenbrugge: nothing to disclose; Luc J.M. Smits: nothing to disclose; Jae W. Song: nothing to disclose; Giuseppe Lanzino: nothing to disclose; M. Eline Kooi: nothing to disclose; Luca Saba: nothing to disclose. Figure 1 - belongs to Methods Figure 2 - belongs to Results Figure 3 - belongs to Conclusions

Measles virus (MeV) infection is mediated by two cellular receptors: signaling lymphocytic activation molecule family member 1 (SLAMF1, also known as CD150), expressed by immune cells, and nectin-4, expressed by epithelial cells. Infection of immune cells causes systemic disease and immune suppression, while infection of airway epithelial cells results in efficient transmission. In rare cases, MeV reaches the brain and slowly spreads in cells that do not express bona fide receptors, causing subacute sclerosing panencephalitis (SSPE). In the brains of persons with SSPE, multiple mutations of the MeV membrane fusion apparatus are selected that enable its triggering by host proteins acting as surrogate receptors. These mutations favor cell-to-cell spread, which promotes population-based MeV genome evolution and the formation of collective infectious units (CIUs). CIUs, which can rebalance their components and rapidly adapt to new environments, may support neuropathogenesis of other nonintegrating RNA viruses, in particular those with nonsegmented negative-strand genomes.

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351 ) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD] neg ) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel–treated patients achieving MRD neg . Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRD neg . ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRD neg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.