Publications

Obstructive sleep apnea (OSA) and insomnia could accelerate biological aging through pathways including oxidative stress and systemic inflammation. This systematic review aimed to determine the association of sleep disorders with circulating markers of biological aging. We searched MEDLINE, Embase, CINAHL, Cochrane, PsycINFO from inception to October 2024. Eligibility criteria included full manuscript English studies on adult humans examining OSA or insomnia and circulating markers of aging. Of the 1839 deduplicated records screened, 49 full-text studies were eligible for inclusion. Included studies ranged from poor to good quality and assessed telomere length (TL), DNA methylation clocks (epigenetics), mitochondrial alterations, sirtuin levels and activity, autophagy protein levels, and klotho gene expression. Telomeres were the most extensively studied marker, with our findings showing a significant association between TL and OSA, based on both unadjusted and adjusted values (SMD = -0.451, 95% CI: 0.688 to -0.215, p = 0.0026 and SMD = -3.01, 95% CI: 4.98 to -1.04, p = 0.033, respectively). Most studies linked insomnia and poor sleep quality to shorter TL. Although evidence for other aging biomarkers was more limited, the published literature supports the role of OSA and insomnia in accelerating biological aging, especially for telomere length.

BACKGROUND: Borderline personality disorder (BPD) is often accompanied by interpersonal dysfunction. Psychotherapy can improve interpersonal functioning, but individual characteristics may moderate outcomes. This systematic review used individual participant data meta-analysis (IPD-MA) to examine such moderators.

METHOD: A literature search up to 26 November 2025 across 10 databases (including PubMed, Medline, Embase, PsychINFO, CINAHL, Web of Science, and Cochrane CENTRAL) identified randomised clinical trials (RCTs) investigating the effects of psychotherapy on interpersonal functioning in individuals with BPD compared to treatment as usual (TAU) or clinical management control interventions (CM). Authors of included trials were contacted to retrieve IPD. IPD-MAs employed a one-stage random-effects approach to estimate treatment effects on interpersonal functioning and potential moderators in bivariate linear mixed-effects models. The study was registered with PROSPERO (CRD42021210688).

RESULTS: Out of 23,735 identified records, 32 RCTs (2762 participants) met inclusion criteria. Individual participant data (IPD) were available for 17 trials (1431 participants). All trials were rated as having either high risk of bias or some concerns. Missing data were common, with 321 out of 1431 participants (23%) lost to follow-up. Meta-analyses of both aggregate data and IPD yielded comparable effect estimates, though statistical significance differed (IPD-MA: β = -0.21, CI: -0.45 to -0.02, SE = 0.12, p = 0.0778; 17 trials, 1071 participants). In unadjusted analyses, the presence of co-occurring anxiety disorder(s) (β = -0.40, 95% CI: -0.73 to -0.08) and a higher number of co-occurring disorders (β = -0.08, 95% CI: -0.15 to -0.01) were associated with larger treatment effects (not significant after alpha correction).

CONCLUSION: Psychotherapy appears to be effective for individuals with BPD. Although moderator effects did not remain statistically significant after alpha correction, unadjusted analyses suggested larger treatment effects in individuals with co-occurring anxiety and greater clinical complexity. Importantly, these findings indicate that such comorbidities may not be a contraindication for psychotherapy for BPD.

BACKGROUND: Branched-chain amino acids (BCAAs) are widely used in endurance sports, yet their impact on performance remains unclear. This review evaluated whether biochemical changes from BCAA or leucine supplementation translate into functional benefits.

METHODS: A systematic review was conducted in accordance with PRISMA 2020, the Cochrane Handbook for Systematic Reviews of Interventions, and the GRADE approach. Searches were performed in PubMed, Embase, and Web of Science up to 11 July 2024. Eligible studies included endurance runners or athletes, used BCAA or leucine supplementation, and reported outcomes related to performance, recovery, or adverse effects.

RESULTS: From 152 records, 15 studies met inclusion criteria. No consistent improvement was observed in performance, fatigue, or recovery. Only two studies reported significant differences. One trial found a 42% reduction in muscle soreness (p < 0.05), though with inadequate control for protein intake and confounders. Biochemical changes included: increase 140% valine (p < 0.01), low plasma glucose (p < 0.01), increase free fatty acids (p < 0.001), and raise 25% protein synthesis post-exercise (95% CI: 20-30%, p = 0.01). Mental performance improved after 12 km and 30 km runs (p < 0.05), but no functional performance gains were consistently observed.

CONCLUSION: BCAA and leucine supplementation do not result in meaningful improvements in endurance performance or muscle recovery. Despite biochemical alterations, current evidence - limited by low methodological quality, surrogate outcomes, and risk of bias - does not support the use of BCAA as an effective strategy for endurance athletes.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is characterized by chronic progressive stenosis of intracranial vessels and subsequent formation of abnormal collateral vessel networks. Indirect revascularization techniques, such as encephalo-duro-arterio-synangiosis (EDAS), promote angiogenesis to restore perfusion but have variable success rates. This study aimed to identify clinical and radiographic predictors of successful collateral vessel ingrowth after EDAS, emphasizing the role of contralateral interhemispheric collaterals.

MATERIALS AND METHODS: We conducted a single-center retrospective analysis of cerebral hemispheres from adult MMD patients who underwent EDAS. We assessed demographic characteristics, clinical presentation, procedural details, clinical and radiographic outcomes. Angiographic outcomes were assessed using the Orbital Grading System. Univariate analysis was performed to identify factors associated with favorable postoperative collateral development. Consequently, preoperative contralateral interhemispheric collateralization was quantitatively evaluated through pixel density analysis on digital subtraction angiography (DSA), comparing the moyamoya-affected hemisphere to the contralateral hemisphere.

RESULTS: 61 MMD hemispheres of 43 adult patients were included in the study. Median times to last clinical and angiographic follow up were 29.9 months and 13.6 months, respectively. Higher Suzuki-stages (V and VI; p=<0.01), occlusions of the anterior cerebral artery (ACA; p=0.03) and internal carotid artery (ICA; p=0.048) were associated with superior postoperative collateralization. The presence of robust contralateral collaterals on preoperative angiography significantly predicted poor postoperative neovascularization (p=0.01). Pixel density analysis showed that increased pixel density ratios of moyamoya-affected hemisphere to contralateral hemisphere significantly correlated with reduced postoperative collateral vessel formation (Orbital Grading System, OR=130.94, p=0.008; Matsushima grading system, OR=52.09, p=0.018).

CONCLUSION: Higher Suzuki-stages, ACA and ICA occlusion predict successful neovascularization after EDAS. The presence of robust preoperative contralateral interhemispheric collaterals is an important predictor of poor collateral vessel ingrowth following EDAS. This finding suggests that such collateralization might reduce the local ischemic stimulus required for effective indirect revascularization. These findings could refine surgical decision-making by identifying patients who may be less likely to benefit from EDAS.

A 'gut-brain axis' is an intricate bidirectional connection between the gut and the central nervous system, serving as a key pathway for signal exchange. However, current in vitro models do not fully capture these dynamic interactions, limiting mechanistic insight and therapeutic testing. Here, we show a 3D human gut-brain-vascular microphysiological platform that integrates lumenized villus-like intestinal barrier, blood vascular-astrocyte interactions, and brain tissue to model circulation-mediated crosstalk between the gut and brain. Using this system, we demonstrate gut-to-brain signaling by delivering bacterial-derived toxins to the gut compartment, which traverse the gut and neurovascular barriers and trigger neuroinflammatory responses and tau-associated pathology in the brain tissue. Conversely, we show that Alzheimer's- and Parkinson's-relevant stimuli applied to the brain compartment elicit neuroinflammation and disrupt both vascular and intestinal barrier integrity, indicating brain-to-gut feedback. Together, our platform provides a human-relevant tool to dissect mechanisms of bidirectional gut-brain communication and to evaluate therapeutic strategies for neurogastrointestinal disease.

Cerebral ischemia/reperfusion injury (CIRI) commonly occurs during the treatment of ischemic stroke and leads to severe consequences, including neuronal death and permanent loss of motor function. Accurate differentiation between the ischemic penumbra (IP) and the ischemic core area is crucial for timely intervention. Multimodal MRI plays a crucial role in the early diagnosis and treatment evaluation of acute ischemic stroke. PANoptosis is a recently discovered form of programmed cell death including apoptosis, necroptosis, and pyroptosis. It has been implicated in neuronal loss during CIRI, especially through absent in melanoma 2 (AIM2). Melatonin (Mel) exerts neuroprotective effects; however, whether PANoptosis is the main cause of neuronal death in CIRI and whether Mel exerts anti-PANoptotic effects to rescue CIRI remain unclear. This study aimed to examine the effects of Mel on PANoptosis in the IP of rats with CIRI and to systematically investigate the underlying mechanisms using multimodal MRI combined with histopathologic techniques. A rat CIRI model comprising 42 healthy male Sprague-Dawley rats, weighing 240-270 g, was established using the modified Zea-Longa wire bolus method. Multimodal MRI, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI)-MRI, and chemical exchange saturation transfer (CEST), was performed to evaluate the ischemic lesions and identify IP. T2WI, DWI-MRI, and tissue staining demonstrated that Mel significantly reduced infarct volume, improved neuron morphology, and decreased the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The IP was identified as the mismatch region between CEST and DWI-MRI, which was expanded by Mel treatment. In addition, Mel inhibited the expression of PANoptotic key proteins, as well as AIM2 expression, in IP neurons. In summary, multimodal MRI enables dynamic monitoring of IP after CIRI in vivo and effectively evaluates the neuroprotective effects of Mel on IP. Mel broadens the time window for CIRI rescue and exerts a neuroprotective effect by downregulating AIM2 expression in neurons, thereby suppressing PANoptotic neuronal death in the IP areas and alleviating brain injury in rats with CIRI.

BACKGROUND: The benefits and harms of using macrolides for asthma remain unclear.

OBJECTIVE: As part of upcoming Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters guidelines addressing severe asthma, we systematically reviewed the efficacy and safety of macrolides for asthma.

METHODS: We systematically searched MEDLINE, Embase, and CENTRAL to April 12, 2025, for randomized trials comparing macrolides with placebo or standard care for asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects analysis of covariance models addressed asthma control and asthma-related quality of life. Random effects meta-analyses addressed severe exacerbations and harms. We used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate certainty of evidence. Our study protocol is registered in PROSPERO (CRD42023408677).

RESULTS: Our meta-analysis comprised 19 trials enrolling 1825 participants. Compared with placebo, macrolides improve asthma control (6-item Asthma Control Questionnaire; score range 0-6, lower better; between-group mean difference: -0.23 [95% CI -0.32 to -0.13]; 40.6% vs 21.6% improving by minimally important difference of 0.5 point; high certainty), likely reduce severe exacerbations (incidence rate ratio: 0.75 [95% CI 0.57 to 0.98]; rate difference: 0.26 fewer events per patient-year [95% CI 0.45 to 0.02 fewer events]; moderate certainty), and likely modestly improve quality of life (Asthma Quality of Life Questionnaire; score range 1-7, higher better; mean difference: 0.11 [95% CI -0.06 to 0.29]; 47.6% vs 42.4% improving by minimally important difference of 0.5 points; moderate certainty) with little to no effect on serious adverse events and mortality (high certainty). Relative effects were similar among patients with type 2 high inflammation versus type 2 low inflammation asthma.

CONCLUSIONS: Macrolides likely reduce severe exacerbations and improve asthma control and quality of life with little to no difference in serious harms among patients with type 2 high inflammation or type 2 low inflammation asthma.

BACKGROUND: Inborn errors of immunity are classically identified in infants and young children with severe or recurrent infections. However, hypomorphic variants with a partial loss of function can remain unrecognized until later in life and may underlie clinically significant susceptibility to infections in previously healthy individuals.

OBJECTIVE: We sought to investigate how 3 novel heterozygous variants in dedicator of cytokinesis 2 (DOCK2) contribute to impaired antiviral immunity, extending the understanding of DOCK2 deficiency beyond an autosomal-recessive disease.

METHODS: After identifying the first DOCK2 variant, we screened 1109 exomes from 3 cohorts of patients with a history of at least 1 severe respiratory, blood-borne, or soft-tissue infection. We assessed the biologic impact of each variant via functional and transcriptional assays of the patients' primary PBMCs and in cell-based overexpression systems.

RESULTS: Six individuals from 3 unrelated families, aged 3 months to 50 years, carried 1 of 3 heterozygous variants in DOCK2 and experienced severe infections with human papilloma virus, respiratory syncytial virus, or severe acute respiratory syndrome coronavirus 2. All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling. Weekly IFN-α therapy led to complete resolution of refractory warts in 1 patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency.

CONCLUSIONS: These findings expand the spectrum of DOCK2-related disease by showing that heterozygous pathogenic variants disrupting DOCK2-ELMO1 interactions impair protein stability and antiviral immunity, revealing a previously unrecognized inborn error of immunity affecting otherwise healthy individuals.