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ABSTRACT Background Chronic obstructive pulmonary disease (COPD) is associated with musculoskeletal comorbidities, including cachexia. Weight loss (WL) is the major criterion for cachexia and increases risk for mortality in COPD. Risk factors for WL in COPD are incompletely understood. We performed this whole genome sequencing (WGS) analysis to identify genetic risk variants for WL in COPD. Methods We studied 16 972 participants from the Trans‐Omics for Precision Medicine (TOPMed) Initiative and All of Us Research Program. COPD was diagnosed using spirometry in TOPMed, while diagnosis codes were used in All of Us. WL was defined as WL ≥ 5% or a final body mass index (BMI) < 20 kg/m 2 . WGS data came from white blood cells in all cohorts. Single‐variant testing was conducted on both race‐ and study‐stratified cohorts and in a cosmopolitan, ancestry‐independent manner using GENESIS in TOPMed and SAIGE in All of Us. SAIGE‐GENE+ gene‐based analyses were performed on race‐stratified and cosmopolitan cohorts. Single variant meta‐analyses were conducted using METAL within (B/AA and NHW analyses of Black/African–American and non‐Hispanic white participants, respectively) and across racial groups (COSMO). Rare variant gene‐based results were combined using Fisher's method. Transcriptomic effects were predicted using MetaXcan. We used the GWAS Catalogue to analyse for colocalization with other related traits. Results Two single variants were associated with WL in COPD among All of Us participants: one intronic variant in HCN1 in Black/African–American participants (chr5:45271359:TACACAC:T, odds ratio with 95% confidence interval (OR (CI 95 )) = 2.43(1.78–3.31), p = 1.95 × 10 −8 ) and one intergenic variant between PPP4R2 and PDZRN3 in the cosmopolitan and NHW cohorts (chr3:73345901:A:G, OR (CI 95 ) = 0.21(0.12–0.35), p = 8.84 × 10 −9 in cosmopolitan and OR (CI 95 ) = 0.18(0.10–0.33), p = 9.44 × 10 −9 in NHW). Single‐variant meta‐analysis identified two loci associated with WL in COPD: five variants within DRAIC in the B/AA meta‐analysis (lead variant chr15:69571341:A:G, OR (CI 95 ) = 1.37(1.23–1.51), p = 1.29 × 10 −9 ) and two intronic variants within RFX3 in the cosmopolitan meta‐analysis (lead variant chr9:3390983:T:C, OR (CI 95 ) = 1.50(1.31–1.73), p = 1.06 × 10 −8 ). Rare variants within RNU6‐565P (NHW analysis in All of Us; p = 2.83 × 10 −7 ) and LOC339298 (B/AA analysis in All of Us, p = 1.85 × 10 −6 ) were associated with WL in COPD. The RNU‐565P signal remained significant after combination with TOPMed results (p combined = 1.23 × 10 −6 ). MetaXcan predicted differential expression of LNC00959 in visceral adipose tissue ( p = 1.16 × 10 −6 in COSMO analysis). Colocalization analyses identified genomic associations between BMI and variants in or near DRAIC , RFX3 , PDZRN3 , and LINC00959 . Conclusions In the first WGS analysis of WL in COPD, we have identified seven novel loci. Further characterization of these loci will validate our findings and improve our understanding of the molecular pathophysiology of this condition.

Purpose To project the future utilization of open and arthroscopic rotator cuff repair (RCR) in the Medicare population through 2050, incorporating post‐COVID recovery data to provide insight into evolving surgical preferences, economic pressures, and implications for health care delivery. Methods We analyzed 2003‐2024 data from the Centers for Medicare and Medicaid Services Medicare Part‐B National Summary, which captures all Medicare beneficiaries undergoing open or arthroscopic RCR as identified by Current Procedural Terminology codes. Projections were based on 2003‐2019 and 2023‐2024 data, reflecting post‐COVID‐19 recovery and avoiding distortions from 2020 to 2022 pandemic‐related disruptions. Statistical models evaluated included log‐linear, Poisson, negative binomial, and autoregressive integrated moving average. Autoregressive integrated moving average was selected based on the lowest normalized root mean square error, reflecting superior predictive accuracy and its ability to capture time‐dependent trends, and was used to forecast RCR volumes through 2050. Results In 2024, there were 23,154 open and 188,700 arthroscopic RCR procedures, which served as the baseline for modeling. Open RCR is projected to decline on average by 5.91% annually, while arthroscopic RCR is projected to grow by 2.88% annually. By 2050, arthroscopic RCR volume is expected to reach 394,434 procedures (95% forecast interval: 363,424‐425,321), whereas open RCR is expected to decline to 4748 procedures (95% forecast interval: 1243‐43,747). Conclusions Autoregressive integrated moving average modeling projects that by 2050 arthroscopic RCR utilization will increase by 2‐fold and open RCR will decline to one‐fifth compared with 2024 baseline volumes. Level of Evidence Level III, retrospective cohort study.

ABSTRACT Immediate early genes (IEGs) encode master transcription factors, including EGR1 , FOS , JUN , and MYC genes that drive robust transcription in the G1 phase of cell cycle. Our previous studies indicate that topoisomerase IIβ (TOP2B) critically regulates IEG transcription and that the activities of TOP2B are dynamically controlled through post-translational modifications by BRCA1-BARD1 and ERKs. Here, we show that two E2 enzymes, UBCH5b and UBC13/MMS2, differentiate the effects and functions of TOP2B ubiquitination by BRCA1-BARD1. Comprehensive transcriptomics, proteomics, and biochemical and molecular cellular analyses revealed a close relationship between BARD1 and key mitogen-activated protein kinase pathway genes and identified activated ERK2 as a novel kinase that phosphorylates BARD1 at S391, a previously reported mitotic phosphorylation site, whose genetic mutation has been linked to tumorigenesis. Mechanistically, the catalytic activity of ERK2 stimulates TOP2B ubiquitination mediated by BRCA1-BARD1 in complex with UBCH5b and UBC13/MMS2, which controls the binding and function of TOP2B and BARD1 for transcriptional activation at representative IEGs. Taken together, our data propose that there is a functional regulatory circuit involving TOP2B, BARD1, and ERK2, three key transcriptional activators for IEG transcription, in which the gene association and catalytic activity of TOP2B are regulated through E2-differentiated ubiquitination by BRCA1-BARD1 and the phosphorylation of BARD1 by ERK2 for productive transcription.

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.

Background: Previous studies suggest that internalized HIV stigma (IHS) results in HIV viral nonsuppression via directly increasing depression, which then reduces adherence leading to nonsuppression; however, the dynamics between IHS and mental health are likely more complex. We sought to better understand IHS-mental health dynamics using data from a longitudinal clinical cohort of people with HIV (PWH) receiving healthcare across 10 US primary care clinics. Methods: Among 8,506 PWH who had ≥2 timepoints in which IHS, depression, and anxiety were measured, we examined changes over time in both two-state (i.e., impact of IHS on depression or anxiety and vice versa) and four-state combinations of depression-IHS (i.e., no depression or IHS, depression/no IHS, no depression/IHS, both depression/IHS) and anxiety-IHS. Transition probabilities between states and factors influencing transitions were identified using multistate Markov models. Results: The impact of IHS on the transition rates of mental health measures (i.e., depression, anxiety) and vice versa were almost the same, suggesting that each influences the other. Over 50% of PWH remained in the same IHS-depression or IHS-anxiety state. PWH with IHS had almost twice the rate of transitioning from no depression/anxiety to having depression/anxiety compared to PWH without IHS; with similar results for the depression or anxiety with no IHS to reporting IHS transition. Conclusions: We demonstrate that IHS and mental health dynamics are more complex than previously suspected and that the associations are bidirectional, which has implications for both future analyses and optimal management of these conditions among PWH.

Abstract The hallmark of heparin-induced thrombocytopenia (HIT) is the presence of immunoglobulin G (IgG) antibodies against platelet factor 4/heparin (PF4/H) complexes, typically detected by PF4/H enzyme-linked immunosorbent assay (ELISA); thus, negative ELISA results are commonly used to exclude this diagnosis. Here, we report a prevalent yet previously unrecognized subset of antibodies that are undetectable by PF4/H ELISA (ELISA−) but activate platelets in the PF4-dependent P-selectin expression assay (PEA+). In 11 patients with clinically confirmed HIT who tested positive in both PF4/H ELISA and platelet activation assays, ELISA−PEA+ antibodies accounted for 65% ± 19% of total platelet-activating IgG activity and coexisted with ELISA+PEA+ antibodies. Consistent with this finding, single-cell cloning from 7 patients with HIT identified 23 PEA+ antibody-producing B-cell clones, of which 17 were ELISA−, outnumbering the ELISA+ clones. Functionally, ELISA−PEA+ antibodies closely resembled ELISA+PEA+ antibodies: platelet binding and activation required exogenous PF4 and were inhibited by FcγRIIA blockade, high-dose heparin, or Fab fragments made from ELISA+PEA+ antibodies. Importantly, these antibodies induced thrombocytopenia in a humanized mouse model of HIT. Despite lacking PF4/H reactivity in ELISAs, they recognize PF4 on platelets and showed no appreciable binding to neutrophil-activating peptide-2, interleukin-8, or PF4 alone. Structurally, these antibodies were heterogeneous, with a subset sharing heavy-chain features with ELISA+PEA+ antibodies. Collectively, our findings demonstrate that ELISA−PEA+ antibodies are a common, previously unrecognized feature of HIT, with functional relevance, supporting the possibility that they play an important, perhaps even central, role in HIT pathogenesis. Defining their prevalence, kinetics, and clinical impact deserves high priority for further investigation.

Enteroblastic, hepatoid, and clear cell carcinomas are rare subtypes of colorectal carcinoma (CRC) with histologic and immunohistochemical (IHC) overlap. We assessed 37 CRCs that possibly represent these subtypes. Provisional criteria for each subtype, along with case photomicrographs and IHC data, were circulated among the authors to provide diagnostic interpretations. Based on plurality consensus, the carcinomas were classified as enteroblastic (n=13), hepatoid (n=6), and clear cell (n=18). Unanimous agreement was reached in 18% (3 clear cell, 3 hepatoid). Interobserver analysis revealed a mean pairwise Cohen κ of 0.63 (range: 0.32 to 0.91), with the hepatoid subtype eliciting the greatest consensus. Clear cell areas were the most likely to intermix with areas of conventional CRC ( P <0.001). Seven patients (20%) had inflammatory bowel disease (mostly linked to enteroblastic CRC). Twenty-three of 34 patients (68%) had nodal metastasis, and 12 (32%) had distant metastasis (mostly to the liver) at presentation. Median recurrence-free survival was 17 months, with enteroblastic cases the most likely to recur (54%, P =0.015). Median follow-up length was 27 months, with 14 patients (40%) dying of disease (representing 7 enteroblastic, 4 hepatoid, and 3 clear cell CRC). Mutations were identified in TP53 (n=8) , APC (n=3) , FBXW7 (n=2), and KRAS (n=1). Inflammatory bowel disease significantly worsened recurrence-free survival on multivariate analysis, while distant metastasis significantly worsened both recurrence-free and overall survival on multivariate analysis. Enteroblastic, hepatoid, and clear cell CRC demonstrate morphologic and IHC overlap, leading to interobserver variability in diagnosis. Given potential differences in clinical correlations and outcomes, more refined criteria are likely necessary.