Publications by Year: 2026

AIMS OF THE STUDY: Anoxic brain injury following cardiac arrest is a leading cause of death in the United States. Withdrawal of life-sustaining therapy (WLST) is a common end-of-life decision in these patients, but its contributing factors and outcomes remain poorly understood. We developed machine learning models to enable large-scale, automated phenotyping to identify patients who died following WLST.

METHODS: We used structured and unstructured EHR (Electronic Health Record) data from two major hospitals to train models that identify (1) patients with cardiac arrest and coma, and (2) patients who died after WLST. Performance was evaluated using the area under the receiver operating characteristic (AUROC) and precision-recall (AUPRC) curves, as well as other precision metrics.

RESULTS: On holdout (internal) testing the models achieved AUROC/AUPRC values of 0.984/0.968 (cardiac arrest) and 0.992/0.991 (WLST). Cross-hospital evaluation showed strong performance for the cardiac arrest phenotype but variable generalizability for the WLST phenotype, with sensitivity depending on the training site. Population-level error rates were low (<0.5 %) for the cardiac arrest phenotype; estimates for WLST varied by hospital.

CONCLUSION: These models establish a reproducible framework for automated cohort identification. Nearly half of comatose post-arrest patients died following WLST, with 42 % of these deaths occurring within 72 h, highlighting the impact of early prognostication decisions. The models enable rapid cohort identification for research on neuroprognostication, including how WLST decisions may perpetuate self-fulfilling prophecies. Broader validation across health systems and larger cohorts will improve generalizability and inform evidence-based end-of-life decision-making. Institutional review board approval: Mass General Brigham IRB BIDMC: 2022P000481; MGB: 2013P001024. All procedures complied with institutional and national ethical standards; informed consent was waived for use of de-identified data.

Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.

BACKGROUND: Psychological distress (eg, depression) and social stressors (eg, HIV-related stigma) can affect HIV-related outcomes such as antiretroviral therapy adherence and health-related quality of life (HRQL). Limited research on adverse childhood experiences such as childhood household violence (CHV) has shown a similar impact on HIV-related outcomes, particularly virologic suppression, although little is known about mediating pathways with factors such as psychological distress and social stressors.

SETTING: Data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort were analyzed. This article examines the relationship between CHV and HIV-related outcomes, and potential differences between those with and without CHV by age (<50 vs. ≥50 years).

METHODS: Bivariate comparisons, linear regressions, and mediation analyses between CHV and other variables were used to assess association with outcome measures.

RESULTS: Among 7705 people with HIV, CHV was reported by 19% (n = 1498). CHV was associated with lower antiretroviral therapy adherence (P < 0.001), more HIV symptoms (P < 0.001), and lower HRQL (P < 0.001). In addition, CHV exposure was associated with worse depressive symptoms (P < 0.001), increased panic symptoms (P < 0.001), lower social support (P < 0.001), greater self-report of HIV stigma (P < 0.001), and more exposure to intimate partner violence (P < 0.001). Psychological distress and social stressors mediated the relationship between CHV and adherence, HIV symptoms, and HRQL, with depressive and panic symptoms accounting for the greatest proportion mediated.

CONCLUSIONS: CHV has an adverse impact on social and psychological factors in adulthood for people with HIV. Depressive symptoms and panic symptoms are potential targets for interventions.

BACKGROUND AND OBJECTIVE: Accurate prediction of recurrence and progression risk in non-muscle invasive bladder cancer (NMIBC) is essential for patient counseling and risk-adapted management. However, conventional models fail to account for the decrease in baseline risk over time. We therefore examined the conditional survival free of recurrence and progression in older adults with NMIBC to develop a dynamic risk prediction model.

METHODS: We identified patients 66 to 89 years with Ta/Tis/T1 cN0 cM0 urothelial bladder cancer treated with transurethral resection of bladder tumor (TURBT) between 2000 and 2017 in SEER-Medicare. Conditional recurrence-free (RFS) and progression-free (PFS) survival were estimated using the Kaplan-Meier method. The associations of baseline characteristics with RFS and PFS at prespecified landmark times were evaluated using Cox-proportional hazards models.

KEY FINDINGS AND LIMITATIONS: A total of 39,862 patients were included. Of these, 26,339 (66%) had Ta, 11,758 (29%) had T1, and 1,765 (4%) had Tis-disease. Median follow-up was 65 months. The 60-month RFS and PFS increased from 0.39 and 0.85 at baseline to 0.73 and 0.89 at 24-months event-free survival. Conditional RFS rapidly improved within the first 24 months before plateauing. Patients with T1-disease demonstrated the greatest improvement in conditional RFS. On multivariable analyses, T stage and tumor grade were less predictive of RFS with longer landmark times. Limitations include measurement error and risk heterogeneity within grade and stage subgroups.

CONCLUSIONS AND CLINICAL IMPLICATIONS: Among patients with NMIBC, recurrence and progression risks decrease with longer event-free intervals, particularly among patients at highest risk of each event as reflected by tumor stage and grade. A dynamic risk prediction model can improve patient counseling and support risk-adapted management during follow-up.

BACKGROUND: Dysregulation of mitochondrial dynamics, including fusion/fission, transport, mitophagy and biogenesis, plays a crucial role in neurodegenerative diseases. However, a systematic quantitative mapping of the knowledge structure (i.e., key research themes, foundational references, and citation/collaboration clusters) and evolving research trends (i.e., research hotspots over time) in this research field is lacking.

METHODS: Empirical and review article on mitochondrial dynamics in neurodegenerative diseases, which published in English from 2005 to 2025, were retrieved from the Web of Science Core Collection and Scopus. BibliometriX, VOSviewer, and CiteSpace were applied to perform the bibliometric analysis and science mapping. Scientific performance analyses, collaborative networks of authors/institutions/countries, reference co-citation networks, keyword bursts analysis were conducted.

RESULTS: A total of 834 documents were included, revealing a rapid growth in scientific productivity from 2005 to 2025. The United States, China, and Germany were the most productive countries, with institutions such as Case Western Reserve University and Texas Tech University serving as major hubs. Co-citation and keyword burst analyses reveal a distinct temporal shift: from foundational studies of fusion/fission machinery and oxidative stress toward an integrated Mitochondrial Quality Control paradigm encompassing mitophagy, dynamics, and biogenesis. Key emerging hotspots include mitochondrial biogenesis, mitochondrial transport, and quality control mechanisms. Translational frontiers prioritize enhancing PINK1/Parkin-mediated mitophagy, inhibiting Drp1-driven excessive fission, and activating PGC-1α-dependent biogenesis.

CONCLUSION: This bibliometric study maps the intellectual structure and evolutionary trajectory of mitochondrial dynamics research in neurodegenerative diseases. It documents a field-wide paradigm shift toward a translational agenda centered on the MQC framework. Furthermore, the findings highlight the necessity of integrating pharmacological interventions with lifestyle modifications and precision medicine approaches to overcome translational barriers and develop effective disease-modifying strategies.

Members of NASPAG provide reproductive health care to adolescent patients. This document aims to provide a comprehensive overview of the recommended counseling for any clinician caring for an adolescent patient with a positive pregnancy test, while addressing legal, ethical, and clinical considerations. The document will discuss strategies for guiding patients through the pregnancy testing process, as well as various issues to consider when ordering tests, disclosing results, and managing the situation if the test is positive. Due to variability between institutions and clinical scenarios, this review will not explicitly advise for or against universal pregnancy testing in medical settings.

Rho-associated coiled-coil kinases (ROCK1 and ROCK2) are important therapeutic targets in fibrosis. ROCK transduces profibrotic biomechanical (substrate stiffness) and biochemical (transforming growth factor-β, lysophosphatidic acid, connective tissue growth factor) stimuli from circulation and the extracellular matrix to cells. Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 strongly inhibited ROCK in biochemical and cellular assays and exhibited optimal drug-like pharmacokinetics and physicochemical properties. ROC-101 was well tolerated following oral administration and had desirable selectivity against non-ROCK kinases and other high liability targets. ROC-101 treatment disrupted profibrotic gene expression in fibroblasts and reduced markers of vascular leakage in vivo. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure-lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming in vivo target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These in vivo and functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis and pulmonary hypertension.