Philadelphia VA Medical Center

BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

Precise and synchronized multimodal data capture in neurosurgical environments is essential for further understanding brain function and will be crucial to advancing the development of brain-computer interface technology. We have developed an open-source software platform named Thalamus, for multimodal data capture integrated with existing sensors and hardware commonly utilized in the operating room and other clinical environments such as pulse oximeters, inertial sensors, electromyography and neural electrophysiology. Thalamus facilitates synchronous recording of neural and behavioral data, enabling real-time computation for closed-loop experiments and detailed analysis of complex motor functions and neural activity. Thalamus uses a modular, configurable node-based pipeline with a tiered Python and C + + architecture. These design elements allow Thalamus to support a wide range of high-resolution sensors for diverse behavioral data types and enable robust closed-loop synchronization of various data streams. Validation experiments demonstrate that Thalamus is capable of data integration and concurrent analysis with up to sub-millisecond precision, offering great potential for enhancing neurosurgical research and clinical applications. By leveraging conventional sensors and hardware already in use, Thalamus supports adoption into the clinical environment, paving the way for more comprehensive, data-driven approaches to neurological care and improving the personalization and rigor of treatment strategies.

Guidelines recommend i.v. albumin after large-volume paracentesis to prevent postparacentesis circulatory dysfunction and acute kidney injury (AKI). However, real-world effects of albumin on paracentesis outcomes in outpatient settings are understudied. We aimed to address this using national data from a well-established cirrhosis cohort. This was a retrospective cohort study of Veterans with cirrhosis undergoing outpatient paracentesis. Albumin administration and paracentesis volumes were extracted, in addition to hospitalization for AKI within 7 days of outpatient paracentesis. Mixed-effects logistic regression identified factors associated with albumin administration and the association between albumin and incident AKI hospitalization. Among 9467 patients who received 56,941 outpatient paracentesis procedures, i.v. albumin was used 17% of the time. The use was higher with Model for End-Stage Liver Disease-Sodium; (OR: 1.02, 95% CI: 1.02-1.03, p<0.001), lower estimated glomerular filtration rate (OR: 3.06 for <30 vs. ≥90mL/min/1.73m2, 95% CI: 2.64-3.54, p<0.001), and HE (OR: 1.22, 95% CI: 1.13-1.33, p<0.001). Albumin administration was associated with lower odds of AKI-related hospitalizations (OR: 0.66, 95% CI: 0.54-0.81, p<0.001), with a greater effect observed in patients with lower estimated glomerular filtration rate (interaction p value=0.03). In a subcohort of 48,401 procedures with available dosing information, higher-dose albumin (≥6-8g/L removed) was associated with lower odds of AKI hospitalization (OR:: 0.36, 95% CI:: 0.20-0.64, p=0.001) with similar associations noted irrespective of paracentesis volume. Albumin administration after outpatient paracentesis was associated with a reduced risk of hospitalization with AKI, with a greater effect at lower estimated glomerular filtration rates. Strategies that tailor albumin administration based on intravascular volume and hemodynamics should be prospectively tested.

Background: Geriatrics specialists are scarce but needed to provide comprehensive, individualized care to older rural Veterans with complex needs. Tele-geriatrics and geriatric mental health (tele-GGMH) services, where clinicians provide specialized consultation and/or time-limited care to residents of a wide geographic area via telehealth, can help meet these needs. Clinicians referring Veterans patients to tele-GGMH services were surveyed to understand their reasons for requesting consultations and satisfaction with services provided. Methods: Veterans Health Administration clinicians from seven regions referring to tele-GGMH services between October 2021 and September 2023 completed the survey. Qualitative and quantitative analyses summarized referring clinicians’ experience and satisfaction with tele-GGMH services. Differences between rural- and nonrural-serving clinicians and prescribing and nonprescribing clinicians were examined. Results: Sixty-nine clinicians responded. Most learned about the tele-GGMH services via word-of-mouth and believed the service increased access to geriatric mental health care. Follow-through with specialists’ recommendations was associated with satisfaction, however nonprescribers and nonrural clinicians had decreased follow-through linked to lower satisfaction. Qualitative data indicated that the top reasons clinicians asked for consultation was to request specific services including subcategories of diagnostic clarification or evaluations, medication management or recommendations and nonpharmalogical interventions. The most frequent barrier reported was postservice barriers implementing the recommendations. Most additional feedback was of general satisfaction and appreciation. Conclusions: Tele-GGMH services are appreciated by referring clinicians and facilitate access to geriatrics expertise. Ability to follow through with the specialist’s advice predicted satisfaction with the service. Receiving assistance with specific services was the most frequent reason for requesting services.

BackgroundDepressive symptoms and anxiety are highly prevalent among people with chronic obstructive pulmonary disease (COPD), strongly associated with poor outcomes, and rarely recognized or treated. Integrating families into interventions may amplify supportive care treatment effects and overcome common challenges, yet this strategy is understudied. The Supporting Evidence-based Responses to Emotional Needs in Emphysema (SERENE) trial’s main objective is to identify the mechanisms through which a family-partnered Coping Skills Training (CST) reduces depressive symptoms among patients with COPD, testing five putative mechanisms: family relationship quality, patient and caregiver self-efficacy, patient loneliness, and caregiver psychological distress.MethodsSERENE will enroll 375 patient-support person (i.e., family caregiver) dyads from two academic health systems. Eligible patients have documented COPD, elevated levels of depressive symptoms (i.e. PHQ-8 scores ≥ 8), and age ≥ 18 years old. Ineligible participants are those with new or changing behavioral health treatments or behavioral health emergencies. After enrollment by research staff, we randomize dyads in a 2:1 ratio to receive either a 12-week CST program or a 12-week COPD education program, respectively. Both are delivered to the dyads via phone or videoconferencing sessions and, therefore, arm assignment is not blinded to staff nor participants. We will test whether randomization to receipt of CST leads to improvements in patients’ depressive symptoms and test mechanisms of efficacy. The primary efficacy outcome is PHQ-9 scores 14 weeks following enrollment. Our five putative mechanisms, corresponding to those previously specified, are measured with the Family Emotional Involvement and Criticism Scale, the General Self-efficacy Scale, the UCLA Loneliness Scale, the PHQ-9, and the Generalized Anxiety Disorder-7. We will measure secondary outcomes through 12 months. Those performing data analyses will remain blinded to group assignments at the individual level until completion of the primary analyses. The study team identifies and reports serious adverse events (i.e., suicidal behaviors or psychiatric hospitalizations).DiscussionSERENE will determine how scalable supportive care interventions that strengthen existing social networks, including the crucial support of family caregivers, improve outcomes in COPD. The results will lay the foundation for paradigm-shifting approaches to managing COPD and similar illnesses through family-directed supportive care interventions.Trial registrationClinicalTrials.gov Identifier NCT06600126. Registered 6 September 2024, https://clinicaltrials.gov/study/NCT06600126. The first enrollment occurred on 30 September 2024.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-025-09210-0.

Epidemiological literature describes widespread psychiatric-physical comorbidity. However, the extent to which observed bivariate risk is transdiagnostic remains uncertain. We apply Genomic SEM and introduce Genomic E-SEM, an exploratory factor-analytic extension of Genomic SEM, here applied to 73 physical outcomes (~1.9 million cases) across eight medical domains. We then modeled latent physical illness factors alongside previously identified psychiatric factors. Thought/psychotic and compulsive factors exhibited few associations with physical illness factors. Conversely, internalizing, neurodevelopmental, and substance-use factors showed substantial genome-wide genetic correlations with all physical illness systems. Multivariate GWAS of a transdiagnostic physical illness factor, defined by 21 physical disorders, identified 27 genomic risk loci and exhibited substantial predictive validity in subsequent PheWAS. This transdiagnostic factor again exhibited substantial genome-wide genetic correlations with internalizing, neurodevelopmental, and substance-use factors. Our results reveal pervasive risk sharing between specific groups of psychiatric and physical conditions and suggest the need for additional nosological frameworks.

ObjectiveCognitive impairment is prevalent in Rheumatoid Arthritis (RA), yet risk factors are not well understood. We explored associations between clinical characteristics and cognitive impairment in an RA cohort.MethodsData were from a longitudinal RA cohort at Veterans Affairs Puget Sound Health Care System. Cognition was evaluated using the Saint Louis University Mental Status (SLUMS) exam. Demographics and health factors, objectively measured physical function, participant-reported symptoms, RA disease characteristics, and comorbidities were evaluated. Univariable linear regressions explored the association between clinical factors and SLUMS score. Those with p<0.1 in the univariable models were evaluated in separate multivariable linear regressions controlling for age, sex, and years of education.Results145 participants with RA were included, aged 64.5±11.6 years and were predominantly male (74%). Using the SLUMS, 42 (29%) participants had normal cognition, 83 (57%) had mild cognitive impairment, and 20 (14%) had dementia. Physical performance [aβ:0.35 (0.11 to 0.59)], self-reported exhaustion [aβ:−2.22 (−3.44 to −0.99)], pain [aβ:−0.25 (−0.50 to −0.00)], disability [aβ:−1.79 (−3.16 to −0.42)], and trouble falling asleep [aβ:−2.57 (−4.00 to −1.14)] were all independently associated with a lower SLUMS score (all p<0.05).ConclusionCognitive impairment was prevalent in our cohort of Veterans with RA and was associated with several modifiable clinical factors. Future longitudinal studies are needed to determine the directionality of these associations and evaluate interventions for modifiable risk factors that may mitigate cognitive dysfunction.

Intervertebral disc degeneration (IVDD) initiates a cascade of structural and biological changes that compromise mechanical function, often leading to chronic pain. While small animal models have provided insight into inflammatory and nociceptive mechanisms of IVDD, translational studies require large animal models that more closely replicate human spine anatomy and physiology. This study induced cervical disc degeneration via intradiscal chondroitinase ABC (ChABC) injection in a large animal model and evaluated the associated disc pathology and neuroinflammatory responses across IVDs and within spinal cord and dorsal root ganglia (DRG) tissues. Results confirmed structural degeneration at ChABC-injected levels and revealed additional evidence of adjacent segment degeneration. Neuroinflammatory analyses revealed innervation, via deposition of PGP9.5 and NFH, throughout both ChABC-injected and adjacent IVDs. Monocyte markers were significantly increased in ChABC-degenerated IVDs. Across experimental groups, the level of monocyte (Ly6C) and macrophage (CD68) markers correlated with worsened histological scores and with reduced mechanical integrity. Similarly, increased production of the neuropeptide, Substance P, in IVDs was significantly positively correlated with compromised IVD mechanical function. Finally, we observed elevated production of the microglia marker, Iba1, and Substance P production in the spinal cord, with similar trends in DRGs, in degenerative spines. By establishing quantitative relationships between disc pathology, immune responses, and neural activation, this work established possible disease-contributing neuroinflammatory activation and further validated a clinically relevant model for preclinical evaluation of regenerative and therapeutic strategies.

Treatment algorithms for hepatocellular carcinoma (HCC) account for tumor burden/stage and severity of liver disease. There are conflicting data on the differential benefit of curative versus non-curative treatments based on BCLC stage. Therefore, we sought to leverage a nationally representative sample of patients in the Veterans Health Administration (VHA) to address this question. We performed a retrospective cohort study of patients with cirrhosis and HCC in the VHA. We conducted a landmark analysis and fit survival models, censored at 3 years, to evaluate the association of treatment type based on the highest level (non-curative vs. curative vs. combination), stratified by BCLC stage, for patients with early-stage to intermediate-stage HCC. We evaluated 1191 patients with confirmed HCC (535 received only non-curative treatment, 227 only curative, and 429 received a combination of curative and non-curative). Among BCLC-0 patients, patients who received curative-intent therapy had significantly better survival at all time points compared with patients receiving non-curative treatment only (HR ranging from 0.53 at 6 months to 0.77 at 3 years). In contrast, for patients with BCLC-A stage disease, receiving either curative treatment alone or combination therapy was associated with significantly better survival compared with non-curative treatment (HR ranged from 0.41 to 0.76 over the study period). However, for BCLC-B stage disease, only combination therapy had significantly better survival (HR 0.44 at 6 months to 0.65 at 3 years). Our real-world data demonstrate that among patients with early-stage to intermediate-stage HCC, curative-intent treatment is associated with the best survival for patients with BCLC-0 and BCLC-A stage disease, while combination therapy yields the best outcomes in patients with BCLC-B stage disease.