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Abstract Aims We aimed to assess regression and development rates of ≥moderate secondary mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with heart failure and reduced ejection fraction (HFrEF) receiving contemporary guideline-directed medical therapy (GDMT). Methods Patients with a <1 year diagnosis of HFrEF with mildly (40% ≤ EF < 50%) or moderately (<40%) reduced EF enrolled in GDMT titration programme 2019–2024 were identified. Regression rates of ≥moderate MR/TR to ≤mild and development rates of incident ≥moderate MR/TR were calculated. Results Among 844 patients [median age 64; 68% men; 26% mildly reduced EF; 24% New York Heart Association (NYHA) Class III/IV], 28% had ≥moderate MR and 14% had ≥moderate TR. Over median 7.1 months, 171 (75%) patients with ≥moderate MR and 87 (75%) of patients with ≥moderate TR experienced regression to no/mild MR and TR, respectively. Conversely, over median 13 months, incident ≥moderate MR and TR developed in 5% and 6%, respectively, of patients with no/mild baseline MR and TR. Number of GDMT medications at follow-up was less in patients who did not have MR/TR regression (vs who did) and in patients who developed MR/TR (vs who did not). Patients with NYHA Class I/II received a similar number of GDMT and had a similar rate of MR and TR regression and development vs patients with NYHA Class III/IV. However, patients with mildly reduced EF received less GDMT medications vs patients with moderately reduced EF and experienced less MR regression. Conclusion In patients with a recent diagnosis of HFrEF receiving contemporary GDMT, the majority with ≥moderate secondary MR and TR achieved regression of MR/TR, and the minority without significant baseline MR/TR developed ≥moderate regurgitation at follow-up.

Background Increased chronological age correlates with reduced relapse rates and increased disability in multiple sclerosis (MS). Biological age may better capture ageing’s impact on MS and might accelerate due to MS itself. Establishing accelerated biological ageing in adults is complicated by normal ageing and comorbidities. Telomere length, a well-recognised biological ageing marker, is shortened in adults with MS and associated with disability. Demonstrating accelerated biological ageing in paediatric-onset MS (POMS) would strengthen the hypothesis that MS drives premature biological ageing. This study aimed to determine if telomere length differs in POMS compared to age-similar healthy controls. Methods We performed a cross-sectional case-control study of whole blood samples and clinical data from The US Network of Pediatric MS Centers. Real-time quantitative PCR measured telomere length, expressed as a telomere to somatic DNA ratio (T/S ratio). T/S ratio was compared between cases and age-similar healthy controls using multivariate regression analysis adjusting for chronological age, sex, race, ethnicity, tobacco exposure, socioeconomic status and body mass index. Results We analysed 300 POMS cases and 200 controls. The unadjusted mean T/S ratios were 1.66 (SD 0.32) for cases and 1.71 (SD 0.29) for controls (mean difference –0.05, 95% CI –0.10 to 0.01, p=0.08). After adjusting for key covariables with face validity, POMS participants had a mean 0.086 shorter T/S ratio than controls (95% CI 0.015 to 0.157, p=0.018). Conclusions POMS participants demonstrated shorter telomeres than age-similar controls in a multivariable model adjusting for sociodemographic variables, suggesting that MS may contribute to accelerated biological ageing.

Abstract Background Hidradenitis suppurativa (HS) is a chronic, relapsing, debilitating skin disease characterized by deep‐seated nodules, abscesses and tunnels. Objectives To investigate the efficacy of bimekizumab using International Hidradenitis Suppurativa Severity Score System (IHS4) outcomes in patients with moderate to severe HS in the pooled BE HEARD I and II Phase 3 studies. Methods Patients received (initial/maintenance) bimekizumab 320 mg every 2 weeks (Q2W)/Q2W, bimekizumab Q2W/every 4 weeks (Q4W), bimekizumab Q4W/Q4W or placebo/bimekizumab Q2W. Change from baseline (CfB) in IHS4, IHS4 severity stages and the dichotomous IHS4‐55/75/90/100 (an improvement of at least 55%/75%/90%/100% in IHS4 from baseline) are reported to Week 48. Lesion count data by lesion type are reported to Week48. Results In total, 1014 patients were enrolled across BE HEARD I and II. At baseline, mean (standard deviation [SD]) IHS4 for bimekizumab‐treated patients ranged from 33.4 (25.4) for bimekizumab Q2W/Q2W to 36.0 (34.0) for bimekizumab Q2W/Q4W versus 30.6 (21.8) for placebo. At Week16, patients receiving bimekizumab demonstrated greater reductions in mean (SD) IHS4 from baseline, ranging from −17.2 (24.8) for bimekizumab Q4W/Q4W to −17.8 (21.1) for bimekizumab Q2W/Q2W versus −6.1 (16.3) for placebo. Proportions of patients with severe HS at baseline ranged from 83.7% (bimekizumab Q2W/Q2W) to 88.4% (bimekizumab Q2W/Q4W) and decreased by ~50% to Week48 across all treatment arms, ranging from 28.6% (placebo/bimekizumab Q2W) to 34.3% (bimekizumab Q2W/Q2W). Proportions of patients with IHS4 = 0 at Week48 ranged from 23.7% (bimekizumab Q2W/Q4W) to 26.7% (placebo/bimekizumab Q2W). At Week16, IHS4‐55, IHS4‐75, IHS4‐90 and IHS4‐100 thresholds were achieved by greater proportions of patients treated with bimekizumab versus placebo, while comparable improvements were seen across treatment arms from Week16 to Week48. At Week16, lesion counts were lower for patients treated with bimekizumab versus placebo, decreasing to comparable numbers across all groups at Week48. Conclusions Bimekizumab‐treated patients showed improvements across IHS4 outcome measures.

Abstract Intravital imaging studies have provided insights into the spatial and temporal variations of platelet activation and thrombin generation that occur during hemostasis; however, these studies are generally limited to small vessels due to the practical limitations of imaging in thicker tissues. Recent advances in cleared tissue fluorescence imaging as well as volume electron microscopy (vEM) coupled with machine learning–based image segmentation provide an opportunity for analysis of the 3-dimensional structure of complex tissues. We utilized these technologies to examine hemostatic plugs from murine jugular veins and carotid arteries to investigate the spatial distribution of platelet activation and biochemical responses in these disparate physiologic contexts. Both venous and arterial hemostatic plugs had a heterogeneous structure with regions of sparsely and densely packed platelets. Despite similar injury sizes, arterial hemostatic plugs were at least an order of magnitude larger than venous plugs. The difference in plug size was primarily due to a 19-fold increase in the population of densely packed platelets in the extravascular compartment. Venous plugs displayed significant platelet aggregation extending into the vessel lumen and developed distinctive fibrin and red blood cell–filled cavities. Complementary fluorescence microscopy revealed that platelet activation was spatially heterogeneous in both contexts, with α-granule secretion and phosphatidylserine exposure confined to specific microenvironments, highlighting tightly regulated thrombin activity. Overall, our findings reveal both conserved and distinct mechanisms of hemostatic thrombus formation in different physiologic contexts. They also demonstrate the power of vEM coupled with machine learning–based image segmentation for the quantitative analysis of large imaging data sets from complex tissues.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Abstract This publication represents the first part of an update to the clinical practice guideline on the diagnosis and management of group A streptococcal (GAS) pharyngitis, developed by the Infectious Diseases Society of America (IDSA). Diagnosis of GAS pharyngitis by clinician judgment alone is unreliable, and universal testing incurs cost and inconvenience for individuals at low risk of having GAS infection. Clinical scoring systems have been used to quantify the probability of a positive GAS throat culture based on standardized criteria such as the presence of fever, tonsillar enlargement or exudate, tender and enlarged anterior cervical lymph nodes, and the absence of cough. The goal of this manuscript is to review the evidence and provide a recommendation as to whether a scoring system should be used to decide which patients should have a GAS diagnostic test (ie, rapid antigen test [RADT], molecular method, and/or throat culture) performed. We performed a systematic review of randomized and nonrandomized studies that compared the use of a clinical scoring system to clinician judgment alone in predicting the result of a throat culture. Evidence from studies in children and adults suggests the diagnostic accuracy is comparable or slightly higher using a scoring system compared to clinician judgment alone. Although the studies are limited due to small size, lack of uniformity in outcome measures, and incomplete data, the consensus of the panel is that the balance of benefits and harms favors incorporation of a clinical scoring system as part of the evaluation of patients with sore throat and suspected GAS pharyngitis.

Abstract INTRODUCTION The Centiloid scale is the standard for amyloid (Aβ) PET quantification in research and clinical settings. However, variability between tracers and scanners remains a challenge. METHODS This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalizing implausible longitudinal trajectories during training. The model was trained using data from 2,129 participants (7,149 Aβ positron emission tomography [PET] scans) in the Australian Imaging, Biomarkers and Lifestyle Study of ageing (AIBL)/Alzheimer's Disease Neuroimaging Initiative (ADNI) and validated using 15,807 Aβ PET scans from 10,543 participants across 10 external datasets. RESULTS DeepSUVR increased correlation between tracers, and reduced variability in the Aß‐negatives. It showed significantly stronger association with cognition, visual reads, neuropathology, and increased longitudinal consistency between studies. DeepSUVR also increased the effect size for detecting small treatment related slowing of amyloid accumulation in the A4 study. DISCUSSION DeepSUVR substantially advances Aβ PET quantification, outperforming all standard approaches, which is particularly important for clinical decision making and to detect subtle or early changes in Aβ. Highlights Novel artificial intelligence (AI)‐method that penalizes biologically implausible longitudinal trajectories, enabling the model to learn standardized uptake value ratios (SUVR) correction factors without requiring longitudinal data at inference time. Improves Centiloid consistency across tracers and studies, significantly enhancing cross‐sectional and longitudinal amyloid positron emission tomography (PET) quantification. DeepSUVR‐derived Centiloids show stronger associations with cognition, visual reads, and neuropathology. Longitudinal variability is reduced three‐ to five‐fold, enabling more reliable tracking of amyloid accumulation and better detection of treatment effects. Novel reference and target masks derived from DeepSUVR replicate most of the model's performance, offering a practical alternative for integration into existing pipelines.

BACKGROUND AND OBJECTIVES: En bloc spondylectomies are essential for controlling malignant spinal tumors, but existing classification systems are often complex and impractical. This study introduces the Column, Line-of-Sight, Margins, Ring (CLiMR) framework, a novel system simplifying and standardizing en bloc spondylectomy planning and classification. METHODS: A retrospective review of patients who underwent single- or multistage en bloc spinal tumor resections was conducted at a single academic center (October 2019-December 2024). The CLiMR framework assigns scores to 4 components: Column (osteotomies/diskectomies for tumor release), Line-of-Sight (approach for circumferential access), Margin (adjacent structures sacrificed), and Ring (size of the vertebral ring window for safe delivery of neural tissue). Scores were applied using operative notes and imaging. RESULTS: Column scores ranged from 0.5 to 4.5. Of the patients included, 40.9% underwent sagittal split osteotomies, 22.7% radical diskectomies, 18.2% horizontal osteotomies, and the remaining 18.2% combinations of previous osteotomies . A posterior-only approach (Line-of-Sight score = 1) was used in 45.4% of cases, whereas 45.4% required a multistage approach (score = 2). Margin scores reflected increasing morbidity: 31.8% (n = 7) involving chest wall/pleura resection (grade 3), 40.9% (n = 9) requiring eloquent nerve sacrifice (grade 6), and 9.1% (n = 2) necessitating limb sacrifice (grade 7). The majority (86.4%, n = 19) of ring scores were grade 1, requiring laminectomies/facetectomies. The mean CLiMR score was 9.36 ± 2.43, with higher scores correlating with longer hospital stays (R = 0.64, P = .0012), longer case durations (R = 0.61, P = .0023), and increased blood loss (R = 0.40, P = .067). Patients with local recurrence, positive margins, or complications trended toward greater CLiMR scores. CONCLUSION: The CLiMR framework provides a novel, user-friendly method for planning and communicating en bloc spondylectomies. By addressing technical complexities and morbidity, CLiMR enables standardized assessment, facilitates surgical decision-making, and supports future research. This study demonstrates feasibility and lays the foundation for future validation studies.

Abstract The phase 1/2 Intergroup study E4412 investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) combined with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) in relapsed/refractory classic Hodgkin lymphoma. A total of 147 patients aged ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients were included in the primary efficacy analysis. The complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (1-sided P = .29). The median survival follow-up was 38.0 months (interquartile range, 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the 2 arms (hazard ratio [HR], 0.78, confidence interval [CI], 0.39-1.57; 1-sided P = .24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, were similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was a higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared with BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned before hoc comparison; 58 patients received SCT, and 36-month PFS (from SCT) was >90% for both arms. Sixty-six patients were progression free after the first scan and did not undergo SCT. The 36-month PFS was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared with 45.8% (26.3, 63.4) for BV/Nivo (HR, 0.45; CI, 0.19-1.08; 1-sided P = .03). The study did not meet its primary end point of superior CR rate for the triplet, but it supports the use of checkpoint antibody-drug conjugate induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT with the triplet of BV/Ipi/Nivo. This trial was registered at www.clinicaltrials.gov as NCT01896999.