Citations

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.

Abstract Background Hyponatremia has long been recognized as a common electrolyte abnormality among skilled nursing facility (SNF) residents. In the literature, hyponatremia is associated with increases in falls, cognitive impairment, hospitalization, and increased mortality. Although many medical conditions and medications contribute to hyponatremia risk, the role of enteral feeding tubes in this population has not been well defined in clinical practice. This study examined the association between enteral feeding tube use and incident hyponatremia and evaluated selected chronic conditions and medication exposures in SNF patients. Methods We conducted a retrospective cohort study using secondary data from a suburban skilled nursing facility. Adults aged ≥ 18 years residing in the SNF with available laboratory data were included (n = 1,256). Exposures included presence of an enteral feeding tube at admission, selected chronic conditions, and high-risk medication exposures. The primary outcome was incident hyponatremia, defined as any corrected serum sodium value < 135 mEq/L occurring after admission. Relative risks were estimated using modified Poisson regression. Results Incident hyponatremia occurred in 34.6% of residents. In adjusted models, enteral feeding tubes (aRR 2.42; 95% CI 1.84–3.19), chronic kidney disease (aRR 1.87; 95% CI 1.43–2.44), and Liver Disease (aRR 1.58; 95% CI 1.20–2.07) remained the significant independent predictors. Congestive Heart Failure, ethnicity, sex, age, and high-risk medication exposure were not significantly associated with risk at the predetermined alpha = 0.01, and no significant interactions were observed between CKD, CHF, and liver disease and enteral feeding tubes on incident hyponatremia. Conclusions Hyponatremia remains a common electrolyte abnormality among SNF residents. Enteral feeding tube use was strongly associated with increased cumulative risk of incident hyponatremia. Both CKD and liver disease also pose risk of incident hyponatremia. SNF residents with enteral feeding tubes may benefit from targeted monitoring and risk stratification in long-term care settings. Clinicians should be aware of these risks while ordering water flushing of enteral tubes and assess these patients regularly for hyponatremia.

ABSTRACT Polyglucosan body myopathy type 2 (PGBM2; OMIM #616199) is an autosomal recessive myopathy caused by biallelic variants in GYG1 , which encodes glycogenin‐1. It is characterized by progressive muscle weakness and PAS‐positive, diastase‐resistant polyglucosan inclusions on muscle biopsy. We report a 64‐year‐old woman who developed progressive proximal weakness beginning in her early 50s, with polyglucosan bodies identified on muscle histopathology. Genome sequencing (GS) detected a single heterozygous pathogenic splice‐site variant, NM_004130.4( GYG1 ):c.143+3G>C. Given strong histopathologic evidence of PGBM2, GS data were reanalyzed, revealing an additional rare deep intronic variant, NM_004130.4( GYG1 ):c.7+992T>G, predicted to activate a cryptic exon. RNA sequencing (RNA‐seq) confirmed aberrant splicing from both variants, demonstrating exon 2 skipping associated with c.143+3G>C and cryptic exon inclusion caused by c.7+992T>G. Variant phasing posed a diagnostic challenge due to unavailable parental DNA, and long‐range PCR results were inconclusive. Long‐read GS definitively demonstrated that the two variants were in trans , establishing compound heterozygosity and confirming the molecular diagnosis. These findings enabled reclassification of the deep intronic variant as likely pathogenic. This case highlights the diagnostic limitations of conventional phasing approaches in adult‐onset recessive disorders and demonstrates the clinical utility of integrating genome reanalysis, RNA‐seq, and long‐read GS for resolving complex phasing challenges.

Background: The most critical exam components in patients seeking rhinoplasty have not been established. Objective: To identify concordance among experienced rhinoplasty surgeons regarding the most important exam features for various deformities. Methods: An online questionnaire was distributed to board-certified facial plastic and plastic surgeons experienced in rhinoplasty, with seven nasal deformity categories: dorsal hump, crooked nose, boxy tip, pinched tip, droopy tip, saddle nose, and nonallergic nasal obstruction. For each, respondents were asked to rank the three most important anatomic regions to examine from the following: nasal bones, midvault cartilage, skin, radix, facial profile, lip, tip, septum, internal nasal valve, nostrils, inferior and middle turbinates. For each ranked region, up to three important features were chosen. Normalized Attention Scores (NAS) were calculated to determine agreement amongst surgeons. Results: A total of 13 facial plastic and 8 plastic surgeons were invited to participate and completed the questionnaire. All cases had high agreement demonstrated by NAS, with the dorsal hump case exhibiting the greatest variability in responses. Conclusions: In this survey of 21 rhinoplasty surgeons, there was general agreement regarding the most relevant anatomical structures and features, which may provide a conceptual foundation for identifying key exam features for seven common complaints in patients seeking rhinoplasty.

Abstract The purpose of this study was to identify glioblastoma (GBM) proteins that contribute to the hijacking of the tumor microenvironment through extracellular vesicles (EVs). GBM is the most aggressive primary brain tumor in adults. It presents significant challenges due to its universal recurrence and limited survival rates, exacerbated when its located proximal to the lateral ventricles (LV). The cellular subpopulation of brain tumor-initiating cells (BTICs) plays a pivotal role in tumor initiation and invasiveness, interacting with the microenvironment, particularly the cellular components in the subventricular zone (SVZ) in the LV. We employed an integrated multi-omic strategy combining cell-specific proteomics of EV cargo and whole-cell transcriptomics of EV-treated neural progenitor cells (NPCs) to define mechanisms by which BTICs remodel the tumor microenvironment. Using the TurboID cell-specific protein labeling system, we identified a previously unrecognized repertoire of BTIC-derived proteins selectively packaged into EVs. Among these, DPYSL2 (CRMP2) emerged as a prominent EV cargo as it is implicated in cancer cell migration and invasion. Functionally, exposure of human NPCs to BTIC-derived EVs significantly increased NPC proliferation and migratory capacity in vitro, findings that were recapitulated in vivo following intracranial and intranasal delivery of GBM-derived EVs. To define the molecular basis of these phenotypic changes, we performed RNA sequencing of NPCs following EV treatment. Bioinformatic integration, including ontogenic and pathway enrichment analyses, revealed robust activation of oncogenic signaling pathways, notably JAK/STAT, mTOR, and WNT, accompanied by upregulation of downstream effector genes. Importantly, integrative proteomic-transcriptomic analyses identified DPYSL2 as a mechanistic link between EV cargo and NPC transcriptional reprogramming. Prior studies demonstrate that DPYSL2 can interact with JAK kinases, promoting STAT3 activation and transcription of genes such as Vimentin (VIM) and CALCA, consistent with the transcriptomic changes observed in EV-treated NPCs. Overall, we have identified DPYSL2 as a novel regulator of tumor microenvironment hijacking mediated by extracellular vesicles. This multi-omic approach is the first use of cell-specific proteomics to study extracellular vesicles and the first time pairing this method to identify upstream regulators of transcriptomic changes in neural progenitor cells. Collectively, these findings establish a direct molecular connection between BTIC-derived EV proteins and functional reprogramming of neural progenitor cells, providing mechanistic insight into how glioblastoma exploits developmental programs to promote tumor progression. Citation Format: Marissa Russo, Emily Norton, Weiwei Wang, Shreyartha Mukherjee, Daniel Wickland, TuKiet Lam, Hugo Guerrero-Cazares. DPYSL2 mediates extracellular vesicle-driven reprogramming of the glioblastoma tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB228.

In a large, multicenter cohort of HIV and non–HIV immunocompromised patients with Pneumocystis jirovecii pneumonia, chest CT most commonly demonstrated diffusely distributed ground-glass opacity, with no imaging features distinguishing between immunocompromise etiology.

Lung transplantation presents numerous intraoperative challenges, particularly related to pulmonary artery and vein anastomotic integrity and hemodynamic stability. We present 3 cases where intraoperative transesophageal echocardiography (TEE) provided real-time diagnostic insights that directly altered surgical decision-making. Case 1 highlights pulmonary vein flow acceleration initially concerning for ostial stenosis, ultimately diagnosed as external compression from a retractor. Case 2 demonstrates true right pulmonary vein stenosis requiring immediate revision. Case 3 illustrates severe right pulmonary artery narrowing, detected by TEE and corrected intraoperatively to prevent early graft dysfunction. These cases underscore the critical role of intraoperative TEE in detecting subtle anastomotic abnormalities, distinguishing functional from structural stenosis, and guiding timely surgical correction. Incorporating comprehensive 2D and 3D TEE evaluation into routine lung transplant protocols enhances diagnostic accuracy, reduces postoperative complications, and contributes to improved long-term allograft function. Intraoperative 3D TEE should be considered an essential imaging modality in cardiothoracic transplantation and an invaluable educational tool for perioperative teams.

Abstract Background and Aims Acute myocarditis (AM) is a T cell-mediated myocardial disease with clinical manifestations ranging from mild chest pain to cardiogenic shock. Reliable biomarkers to stratify patients and guide therapy are currently lacking. In particular, the extent of the dysregulation of inflammatory pathways, and the impact on myocardial dysfunction, remain elusive. Methods Serum analyses were performed in prospectively recruited AM patients (n = 103) from two independent cohorts. Multimodal data integration combining profiling of cytokine and chemokine dysregulation with clinical biomarkers was used to define clinical phenotypes with distinct inflammatory signatures. Machine-learning and regression models were applied to determine biomarkers that indicate clinical severity. Results Immuno-proteomic profiling revealed conserved inflammatory patterns across AM cohorts, dominated by T cell-related cytokines and chemokines. In addition, AM patients showed dysregulation of fibroblast-derived cytokines, including hepatocyte growth factor (HGF), bone morphogenic protein 4 (BMP4) and the BMP4 inhibitors Gremlin-1 (GREM1) and Gremlin-2 (GREM2). Data integration and unsupervised clustering revealed two immuno-clinical phenotypes, linking T cell activation and fibroblast dysregulation to disease severity. Machine learning-based analysis identified CXCL10, GREM2 and LVEF as critical parameters for stratifying disease severity. Conclusions These findings highlight a systemic T cell activation signature as diagnostic hallmark of AM. In addition, dysregulation of fibroblast-derived tissue cytokines serves as an indicator for distinct immuno-clinical phenotypes in myocardial inflammatory disease. Thus, the clinically relevant link between T cell-driven immune activation, myocardial inflammation and fibroblast-driven remodelling provides a versatile set of parameters to identify severe manifestations of AM. Graphical Abstract Key Question: Are serological immune signatures linked to clinical severity in acute myocarditis and do they enable patient stratification? Key Findings: T cell- and fibroblast associated proteomic signatures indicate disease severity in acute myocarditis. Novel immuno-clinical phenotypes stratify patients according to distinct immune responses and clinical manifestations. CXCL10, GREM2 and LVEF are the most important parameters to identify immuno-clinical phenotypes. Take Home Message: CXCL10, GREM2 and LVEF emerge as key determinants for a severe immuno-clinical phenotype in acute myocarditis, highlighting the role of T cell-fibroblast interaction in the disease process and linking T cell activation, fibroblastic tissue remodelling and impaired cardiac function.