Citations

Abstract Background Inflammatory bowel disease (IBD) can lead to a hypercoagulable state, particularly at initial diagnosis. Consequently, venous thromboembolism (VTE) represents a serious complication associated with IBD. For children, the risk of VTE near the time of IBD diagnosis has not yet been quantified, and guidance for VTE prophylaxis remains unclear. Methods This multisite matched case-control study examined pediatric patients with a new diagnosis of IBD from 2019-2024. Cases were those who developed VTE ≤30 days prior or ≤90 days post IBD diagnosis. Controls were newly diagnosed IBD patients without VTE. Each case was matched to 2-6 controls based on IBD subtype and age at IBD diagnosis. Demographics, laboratory values, prothrombotic risk factors and treatments were compared between matched cases and controls using conditional logistic regression stratified, by case sets. Results Study subjects included 15 cases and 52 controls, resulting in 70 matched pairs. Factors associated with early VTE included lower hemoglobin (P = .003), lower albumin (P = .002), corticosteroids use (P = .01), central line (P = .002), and any surgery ≤90 days post IBD diagnosis (P = .001). No association with VTE was detected for platelets, C-reactive protein, fecal calprotectin, family history of IBD or body mass index. Conclusions Albumin, hemoglobin, steroid use, central line, and any surgery ≤90 days post IBD diagnosis were associated with early VTE. These risk factors may be used in a future prediction model to stratify newly diagnosed pediatric IBD patients by their risk for early VTE development.

Abstract Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non‐amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large‐scale clinical trials, which typically focus on late‐onset, sporadic amnestic‐predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid‐targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early‐onset amnestic and non‐amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome‐specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

Abstract Rationale This Registry was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to arrest the rate of FEV1 decline (FEV1 decline) and prolong survival in lung allograft recipients with Bronchiolitis Obliterans refractory to standard of care therapy. Methods After IRB approval, 258 lung transplant recipients were enrolled from 20 US lung transplant centers. Subjects were assigned to ECP treatment (ECPRx) (i.e., 24 procedures over 6 months) at or a few months after enrollment based on spirometric criteria. Maintenance ECPRx (mECP) was at the discretion of managing clinicians. Rate of FEV1 decline in mL/month (FEV1 decline) was compared between 6 months prior to and 6 & 12 months after ECPRx initiation using linear mixed effects models. Time 0 for survival was set as the start of ECPRx for generation of Kaplan-Meier curves. Hazard Ratios (HR) with 95% confidence intervals (lower-upper) were generated using Cox Proportional Hazards Regression to characterize significant (p < 0.05) independent associations of mECP and/or any other covariates (i.e., demographic, operative, enrollment site, spirometric ) and survival. Results An 89% (78%-96%) decrease in the FEV1 decline was observed 12 months after ECPRx initiation in 191 participants assigned to ECPRx. FEV1 decline (-164 mL/month: 144-185) was greater (p < 0.001) in participants who expired within six months of Time 0 (n = 28) vs participants (-111 mL/month: 101-120) who died six months after Time 0 (n = 77). Of 159 participants who survived for at least six months after ECPRx initiation, 40 participants without mECP, who had up to 24 ECPRx (ECPRx: n = 19), had a lower survival HR: 2.43(1.75-3.4) (p < 0.001) relative to 119 participants who received mECP (ECPRx: n = 86)(see Figure). The response to ECPRx (% Change in FEV1 decline prior to and 6 months after 1st ECP) was similar between subcohorts (No mECP: -81 decrease vs mECP: -85%, p = 0.3). The association of mECP persisted after multivariate adjustment HR 1.8 (1.8-2.7)(p = 0.002) using significant covariates: FEV1 HR 0.37 (0.3-0.5), FEV1 decline HR 0.001 (0.001-0.04), Male Gender HR 2.4 (1.7-3.4); Reflux Disease HR 1.8 (1.2-2.8); Coronary Disease HR 1.8 (1.2-2.7). Conclusions This analysis indicates that mECP is independently associated with enhanced survival most likely due to attenuation of relapse six months after ECP initiation based on similar initial response to ECPRx. A risk-adjusted, control cohort is being pursued to facilitate submission of a scientifically rigorous petition to CMS to expand the ECP National Coverage Decision to include BOS predicated on CMS 2024 scientific guidelines. This abstract is funded by: Therakos Inc

Abstract INTRODUCTION Women are increasingly entering the dementia research workforce, but they frequently fail to attain senior leadership positions in academia. Discrepancies in academic research outputs were investigated to guide equity‐focused policy recommendations. METHODS Bibliometrics was conducted on 400,482 original research articles (2003–2022) followed by surveying the AD/ADRD research community, to quantitatively and qualitatively evaluate discrepancies in publication and authorship trends. In addition, an unsupervised learning algorithm was developed to analyze underlying relationships between author groups. RESULTS Male author gender was consistently predictive of better publication and citation metrics across all bibliometrics outcomes, with senior male authors outperforming all other subgroups and fewer senior female authors in most research areas. Female survey respondents reported more barriers, but comparable productivity and citation strategies as male authors. DISCUSSION Multi‐pronged approaches by stakeholders across institutions, funders, and journals are necessary to provide career support for early‐career scientists working to transition to senior research roles.

Apply It! By reading this article, you will: • Understand how commonly used cardiorespiratory fitness prediction equations can misclassify fitness in both high-performance and clinical populations. • Learn how common prediction equations were developed and why the population of prediction equation studies matters when interpreting estimated cardiorespiratory fitness and percent-predicted values. • Recognize how to critically assess the suitability of a given cardiorespiratory fitness equation based on your client’s or patient’s characteristics.

Abstract Large Language Models (LLMs) demonstrate strong capabilities in healthcare applications. However, recruiting human evaluators to assess usability and effectiveness becomes challenging in the large-scale LLM-generated outcomes. Existing metrics are often outdated for evaluating LLM-based healthcare technologies. This paper proposes a Research through Evaluation (RtE) approach that can refine metrics and improve assessments of LLM-generated outputs. We deploy RtE in a retrospective comparative study of prostate cancer patient inquiries, comparing responses from human clinical care teams with those generated by a GPT-4-based in-basket bot. Through three rounds of co-evaluations with clinical professionals and an LLM-as-graders study with four LLMs, the RtE method shows that starting with small, iterative evaluations helps human graders adjust metrics to suit their daily practices better. Additionally, in the LLM-as-graders study, LLMs exhibit similar behavior, preferring the in-basket bot's responses over the clinical care team. Our methodology and findings demonstrate that the RtE method can enhance the transparency and robustness of evaluation metrics for LLM-generated content, with the potential to generalize to evaluations in other clinical practices.

Introduction Uveal melanoma has a marked tropism for the liver where immune tolerance facilitates metastatic progression and resistance to immunotherapy. Impaired CD8 + T cell immunosurveillance is a central determinant of disease progression in uveal melanoma, yet the underlying mechanisms driving liver-mediated immune subpression and hepatic metastasis are not fully understood. Here, we investigate molecular pathways that regulated hepatic CD8 + T cell function and evaluate clinical outcomes associated with liver-directed therapy. Methods Expression of autotaxin (ATX), the expression responsible for generating lysophosphatidic acid (LPA), was evaluated in hepatic resident cell populations. ATX transcript levels were assessed in CD8 + T cells isolated from hepatic metastases and compared with matched peripheral blood and healthy donor control. Antigen-specific effector CD8 + T cells were used to characterize downstream signaling responses to LPA stimulation. Functional studies evaluating cytokine production during chronic antigen exposure were performed using CD8 + T cells from LPA receptor 5-deficient ( Lpar5 -/- ) mice. Results We identify the autotaxin-lysophosphatidic acid (ATX-LPA) axis as a prominent immunoregulatory pathway in the metastatic hepatic tumor microenvironment. ATX, the enzyme responsible for LPA production, is constitutively expressed by hepatic resident cells, is detectable on Kupffer cells and is associated with increased immunosubpressive markers. CD8 + T cells isolated from hepatic metastasis in a patient with uveal melanoma display markedly elevated ATX transcripts compared to matched peripheral blood (>5 log 2 fold change) and healthy controls. Using antigen-specific effector CD8 + T cells, we demonstrate LPA signaling induces low level, persistent ERK phosphorylation distinct from canonical antigen-induced TCR signaling. Genetic deletion of the LPA receptor 5 ( Lpar5 -/- ) on CD8 + T cells restores CD8 T cell percentages and cytokine function during persistent antigen stimulation in the presence of LPA. Discussion These findings define an ATX-LPA mechanisms of dysfunctional ERK signaling that may contribute to hepatic immune subpression in uveal melanoma. We highlight this pathway as a rational therapeutic target alongside liver-directed clinical interventions.

Abstract As an intrinsically mechanosensitive organ, the lung experiences a range of mechanical forces. Chronic obstructive pulmonary disease (COPD) involves abnormal macroscopic cellular and extracellular matrix (ECM) changes that impact mechanical properties of the lung. Mechanosensitive Piezo1/2 channels are expressed in the lung including on airway smooth muscle cells (ASM) that mediate cellular responses to stretch and ECM biomechanics. The expression and roles of Piezos in COPD lung ASM are not known. We hypothesized that Piezo expression and activation are altered in COPD lung ASM influencing ECM regulation. Distribution of Piezo proteins in ASM and epithelium of small airways of COPD stage II and IV vs. non-COPD controls was assessed using immunohistochemistry and ImageJ (n=10-17/group). Isolated ASM cells from control (n=6) vs. COPD stage II and IV patients (n=3 each stage) were exposed to stretch or the Piezo1 agonist Yoda1 followed by measurement of ECM gene and protein expression. Less Piezo2 staining was observed in COPD IV patients compared to controls, with lesser area and intensity of staining in the epithelial layer, and lower intensity of staining in ASM and small airways as a whole. Fura-2-based imaging of ASM Ca 2+ showed lower influx after Yoda1 exposure in COPD II compared to control and COPD IV. Gene expression of Piezo1 increased upon stretching in controls but not in COPD ASM, while Piezo2 protein expression decreased with stretching in all groups. Yoda1 treatment resulted in decreased collagen1 , fibulin1 and periostin gene and collagen 1 and periostin protein expression in ASM. Overall, these results support a role for Piezo activation in abnormal ECM-ASM cell crosstalk in COPD.

Importance Currently, there are no standardized outcome domains or measures in clinical trials for facial aging. Heterogeneity in outcome domains and measurement instruments across clinical trials creates difficulty in directly comparing interventions, determining superior therapies, and developing high-quality meta-analyses. Objective To develop a core outcome set (COS) of essential domains to be reported in clinical trials evaluating the efficacy of interventions for facial aging. Evidence Review PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, and CINAHL were searched from September 2005 to September 2015. An updated search of the same databases was performed from September 2015 to February 2026. Studies were included if (1) they were randomized clinical trial or controlled clinical trial in design, (2) they assessed the efficacy or safety of an intervention for facial aging, (3) they were published in English, and (4) they involved human participants. Complementary sources, including patient interviews, were used to capture further relevant outcomes. Two rounds of Delphi surveys, followed by consensus meetings, were used to identify outcome domains considered most important by both patient and physician stakeholders. Findings The final COS consists of 6 outcome domains: (1) overall convenience of treatment; (2) time to return to normal work and social activity; (3) overall assessment of focused area of treatment (at the point in time when treatment is expected to provide peak benefit); (4) duration of treatment effect; (5) severity of persistent local or systemic adverse events, including pigmentary change, skin texture change, delayed healing, scarring, and serious adverse events; and (6) patient satisfaction with treatment. Conclusions and Relevance The 6 outcome domains identified through a Delphi consensus are recommended for reporting in future facial aging trials to ensure that outcomes that matter most to patients and clinicians are measured and that results are comparable across interventions.