Publications

Major depressive disorder (MDD) remains a highly heterogeneous condition, presenting significant challenges for effective diagnosis and treatment. Traditional diagnostic systems often fail to capture the diverse clinical and biological phenotypes of MDD, limiting the efficacy and predictability of therapeutic interventions. The advent of wearable technology has enabled the continuous collection of real-time, objective data. By leveraging advanced artificial intelligence (AI) methodologies, these data streams can be transformed into dynamic digital phenotypes that may correlate with the complex psychopathological manifestations of depression. This integration offers a novel, data-driven approach to augment traditional subjective assessments, paving the way for more precise classification and personalized treatment strategies. This review explores the potential of AI-enhanced digital phenotyping to revolutionize depression diagnosis and management, advocating for a paradigm shift toward a more personalized, precision-based approach in psychiatric practice.

Organ-on-a-chip (OoC) technology is a powerful tool for creating physiologically relevant microscale models applicable to biomedical studies. Despite the advances in OoC technology, its fabrication method still primarily relies on soft lithography, which has a long design-to-prototype cycle that creates a bottleneck in the acceleration of OoC innovation. To increase the agility of the OoC fabrication process, a system is developed to fabricate OoC using a digital photomask aligned with a microchamber. The approach uses a pre-defined microfluidic chamber customized by xurography and microfluidic channels photopatterned by a digital photomask. The versatility of the approach offered previously unattainable features in the fabrication of OoC, including non-reticular height profiles of the OoC architecture, and real-time modification of channel designs to trap suspension culture (e.g., spheroids). In summary, this work highlights a versatile system to fabricate OoC by direct photopatterning that can accommodate various OoC design requirements of microenvironments of specific organ tissues. It is anticipated that the system can facilitate the rapid fabrication of OoC, potentially supporting advancements in OoC design innovation, which can potentially increase the adoption of the OoC technology for therapeutic screening and elucidation of disease mechanisms in the scientific community.

OBJECTIVE: Frailty occurs prematurely in rheumatoid arthritis (RA) and is associated with poor health outcomes. We compared the performance of four frailty instruments, including a pragmatic alternative measure using chair sit-to-stand (STS), and evaluated their abilities to predict poor health outcomes.

METHODS: Frailty was measured at baseline using four instruments: the Fried Frailty Phenotype with STS (Fried-STS), the Fried Frailty Phenotype with hand grip strength (Fried-HGS), the Veterans Affairs Frailty Index (VA-FI), and the FRAIL Scale. Outcomes collected at the one-year follow-up included category of falls (none, one, more than one), category of days hospitalized (none, one to three, more than three), and a composite outcome of fall, hospitalization, or death. Ordinal logistic or logistic regression models, adjusted for age and sex, explored the association of frailty and each outcome.

RESULTS: A total of 143 participants were included (mean ± SD age 64.5 ± 11.7 years, 73% male, and 69% White). Categorization as frail differed by instrument: Fried-STS, 17%; Fried-HGS, 15%; VA-FI, 36%; and FRAIL Scale, 20%. There was poor agreement between frailty instruments (k = 0.07-0.31) except for the Fried-STS and Fried-HGS (k = 0.62). Frailty by the Fried-STS, Fried-HGS, and FRAIL Scale was associated with falls (adjusted odds ratios [aORs] 3.83-9.54, P < 0.05). Frailty by the VA-FI was associated with days hospitalized (aOR 5.21, P = 0.017). Frailty by the Fried-STS, VA-FI, and FRAIL Scale was associated with higher odds of the composite measure of incident fall, hospitalization, or death (aORs 2.93-7.25, P < 0.05).

CONCLUSION: Each frailty measure predicted adverse health outcomes, with phenotypic and patient-reported measures predicting falls and the deficit accumulation model predicting hospitalization days. Being frail by the Fried-HGS did not predict poor outcomes as well as the other frailty instruments, including the Fried-STS.

INTRODUCTION: Treatment-refractory obsessive-compulsive disorder (trOCD) is a complex network disorder that may require personalized treatment strategies due to disease heterogeneity. A multi-site, multi-stage, double-blinded, randomized crossover clinical trial is underway, using stereo-electroencephalography (sEEG) to guide selection of multi-nodal targets for deep brain stimulation (DBS) for trOCD.

OBJECTIVES: To describe the clinical trial design, emphasizing personalized surgical targeting strategies that ensure the feasibility and precision of sEEG electrode placement, and enable adequate sampling of relevant targets in trOCD for network evaluation and modulation.

METHODS: Adults with severe trOCD (Yale-Brown Obsessive Compulsive Scale ≥28) who meet eligibility criteria are enrolled in this three-stage clinical trial (NCT05623306). Stage 1 involves sEEG electrode implantation in trOCD implicated regions and inpatient evaluation. Individualized probabilistic tractography-guided target refinement is performed for surgical planning. Multimodal recordings are taken while participants stay in the psychiatric monitoring unit for 12 days. In stage 2, up to four permanent DBS electrodes are implanted followed by stimulation optimization. Stage 3 is the randomized, double-blinded crossover phase.

EXPECTED OUTCOMES: Safety, feasibility and preliminary efficacy will be assessed in this ongoing study. We anticipate that the use of sEEG to guide selection of multi-nodal targets for DBS will be safe, feasible and result in clinically meaningful improvements in symptom severity and functional impairment in trOCD.

DISCUSSION: We present the clinical protocol of sEEG-guided investigation of brain networks involved in trOCD and describe our tractography-guided surgical targeting strategy designed to optimize individualized network engagement and neuromodulation.

Remote ischemic conditioning (RIC) is a simple, noninvasive intervention hypothesized to reduce ischemia-reperfusion injury in acute ischemic stroke (AIS). Its role as an adjunct to intravenous thrombolysis (IVT) remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials assessing RIC in AIS patients treated exclusively with IVT. Major databases were searched through February 2025 (PROSPERO: CRD420251144277). The risk of bias was evaluated using the Cochrane tool, and evidence certainty was assessed with Grading of Recommendations Assessment, Development, and Evaluation. Trial sequential analysis was also performed. Six randomized controlled trials (n = 955; RIC = 502, control = 453) met eligibility. Safety outcomes were comparable between groups, with no significant differences in stroke recurrence [risk ratio (RR) = 0.97; 95% confidence interval (CI), 0.63-1.48], hemorrhagic transformation (RR = 1.24; 95% CI, 0.67-2.31), or 90-day mortality (RR = 1.19; 95% CI, 0.46-3.07). RIC did not significantly improve excellent functional outcome (modified Rankin Scale 0-1 at 90 days: RR = 1.07; 95% CI, 0.95-1.20) or functional independence (modified Rankin Scale 0-2: RR = 1.03; 95% CI, 0.89-1.03). Barthel Index scores showed a nonsignificant trend toward benefit (mean difference = 2.77; 95% CI, -1.51-7.06), and National Institutes of Health Stroke scores at 24 hours, 7 days, 30 days, and follow-up were unchanged. Trial sequential analysis showed the required information size was not reached, and the Grading of Recommendations Assessment, Development, and Evaluation certainty was low to very low. RIC is safe but has not yet been shown to significantly improve functional or neurological outcomes in AIS patients treated with IVT. Future trials should assess RIC in patients receiving different types of thrombolysis (alteplase vs tenecteplase).

BACKGROUND: Identifying genetic mechanisms of inborn errors of immunity (IEI) is important for diagnosis and treatment of patients, yet most patients with suspected IEI have negative genetic testing results. Genetic mosaicism is an emerging mechanism of IEI, but it is challenging to identify.

OBJECTIVE: We used a discovery-based approach to identify mosaic variants in genes relevant to immune dysregulation in patient and healthy cohorts.

METHODS: We developed custom panels for high-depth sequencing of genes known or hypothesized to cause dominant immune dysregulation. Samples from 452 patients with immune dysregulation (affected) and 154 currently healthy were sequenced using 71- or 101-gene targeted panels.

RESULTS: We identified mosaic variants in 9.5% of undiagnosed patients and 7.8% of healthy individuals. Using a strategy to predict pathogenicity of variants in IEI, 33% of variants identified in patients were predicted to be likely pathogenic or pathogenic, while no mosaic variants in healthy individuals were predicted to be pathogenic. Genes with mosaicism in >1 affected undiagnosed patients included FAS, STAT3, CARD11, CARD14, NRAS, TNFAIP3, NLRP3, and IKZF2. Four patients had variants in FAS with allele fractions <5% in blood but highly enriched in double-negative T cells, diagnostic for somatic FAS autoimmune lymphoproliferative syndrome.

CONCLUSION: These findings establish the utility of a high-depth sequencing panel to identify mosaic variants and demonstrate that mosaicism in immune-relevant genes is present in healthy individuals.

BACKGROUND & AIMS: Disruption of the intestinal barrier facilitates microbial translocation to the liver and contributes to chronic liver disease. We aimed to study the role of the fecal proteome for disease progression in patients with alcohol-associated hepatitis.

METHODS: We used fecal proteomics data from a multicenter cohort of patients with alcohol-associated hepatitis (n=80), alcohol use disorder (n=20), and controls (n=19) (InTeam), and a cathepsin B activity assay in an independent multicenter cohort of patients with alcohol-associated hepatitis (n=80), alcohol use disorder (n=20), and controls (n=18) (AlcHepNet). Mice lacking cathepsin B in myeloid cells and transgenic mice overexpressing occludin in intestinal epithelial cells, were subjected to the chronic-plus-binge ethanol feeding model (NIAAA).

RESULTS: Fecal proteomics and activity analysis revealed that the protease cathepsin B progressively increased with alcohol use disorder and alcohol-associated hepatitis compared to controls, and is associated with higher short-term mortality in patients with alcohol-associated hepatitis. Cathepsin B is predominantly expressed in intestinal macrophages and is upregulated by ethanol. Cathepsin B deficiency in myeloid cells or oral treatment with the gut-restricted cathepsin B inhibitor CA074 stabilized gut barrier by preserving the tight junction protein occludin, lowered serum LPS levels, and attenuated ethanol-induced steatohepatitis. Transgenic overexpression of occludin in intestinal epithelial cells sufficed to reduce steatohepatitis and blunted the effects of CA074 in ethanol-fed mice. Cathepsin B proteolytically cleaves occludin in enzymatic assays, and its inhibition prevented occludin degradation and barrier disruption in intestinal organoids and epithelial monolayers. Molecular modeling and peptide profiling reveal specific cathepsin B-induced cleavage sites in the extracellular region of occludin.

CONCLUSIONS: Intestinal cathepsin B is an essential mediator of gut barrier dysfunction and therapeutic target in alcohol-associated liver disease.

IMPACT AND IMPLICATIONS: Intestinal barrier disruption facilitates the microbial translocation to the liver, contributing to the progression of alcohol-associated hepatitis, however the molecular mechanisms driving barrier dysfunction remain incompletely understood. Our study identified the protease cathepsin B as a key contributor to the progression of alcohol-associated liver disease by degrading the extracellular region of tight junction protein occludin in the intestine, which in turn leads to barrier disruption. This work advances the field by addressing causality, uncovering the molecular target, and proposing cathepsin B as a promising therapeutic target in alcohol-associated hepatitis, a condition for which liver transplantation remains the only effective treatment in a limited subset of patients.

Patients often need to interrupt anticoagulation for invasive procedures or surgery. Periprocedural bleeding can contribute to substantial morbidity and mortality. Procedural bleed risk stratification informs whether anticoagulation needs to be interrupted, for how long, and when to restart anticoagulation after procedure. Guidance on procedure-specific bleeding risk varies and contributes to discordant perioperative anticoagulation management. To address this important knowledge gap, the Perioperative and Critical Care Thrombosis and Hemostasis Subcommittee of the International Society on Thrombosis and Haemostasis undertook a review of contemporary procedural bleeding risk stratification schemas and developed a practical bleeding risk stratification approach for use in anticoagulated adult patients having a planned elective surgery or procedures.

BACKGROUND: Spironolactone and oral minoxidil are effective female alopecia monotherapies. Combination therapy is commonly used, though safety and tolerability data are limited.

OBJECTIVE: To assess safety and tolerability by adverse effect incidence.

METHODS: Retrospective cohort study conducted in females aged ≥18 taking combination therapy for hair loss.

RESULTS: A total of 432 patients were included. Average spironolactone and low-dose oral minoxidil doses at time of adverse drug effects were 87.6 ± 51.4 mg and 1.8 ± 1.1 mg, respectively. Adverse effect incidence was 37.7% (n = 163). Hypertrichosis was most common (n = 53, 12.3%) followed by dizziness/lightheadedness/orthostasis (n = 52, 12.0%). Simultaneous initiation was observed to reduce hypertrichosis risk by 64.8% (odds ratio: 0.35; 95% confidence interval 0.13-0.94; P = .037). Concurrent use of ≥1 additional blood pressure-altering medications increased orthostatic effects risk (odds ratio: 3.29; 95% confidence interval: 1.65-6.58; P = .001). Dosage and treatment initiation pattern did not significantly increase risk of blood pressure effects. In 46.0% of cases, the therapeutic regimen was unmodified. When adjustments were made, they largely occurred in the outpatient setting (94.3%).

LIMITATIONS: Retrospective descriptive study lacking a control group.

CONCLUSION: Adverse effects from combination therapy are generally mild and managed outpatient. Concomitant use of ≥1 blood pressure-altering drugs increases risk of hypotension-related symptoms. Simultaneous initiation may reduce risk of hypertrichosis without increasing risk of hypotension-related effects.