Publications by Year: 2026

Alzheimer's disease (AD) risk is strongly influenced by genetic variants that converge on pathways regulating endosomal homeostasis. Among these, BIN1 and RIN3 have emerged as susceptibility genes, yet their functional relationship in AD remains largely unknown. Here, we investigated how BIN1 and RIN3 interaction regulates RAB5 activity and endosomal pathology. RIN3 has been shown to bind BIN1, and we previously reported that this interaction modulates amyloid-β (Aβ) precursor protein (APP) trafficking and Aβ generation in vitro. To extend these findings, we used Rin3 constitutive knockout (Rin3-CKO) mice and CRISPR-Cas9-edited human induced pluripotent stem cell-derived neurons carrying either BIN1 knockout or rare familial AD RIN3 missense mutations within the BIN1-binding domain. We found that disruption of BIN1-RIN3 binding, through either genetic deletion or pathogenic RIN3 variants, resulted in RIN3-mediated RAB5 hyperactivation and enlargement of neuronal endosomes, a hallmark of early AD pathology. Transcriptomic profiling further revealed dysregulated expression of AD-related genes. Together, these findings establish BIN1 as a critical regulator of RIN3-driven RAB5 activation and neuronal endosomal homeostasis.

BACKGROUND: Deep inferior epigastric perforator (DIEP) flaps are the gold standard in autologous breast reconstruction (ABR) despite being associated with significant abdominal donor-site morbidity. Some surgeons place mesh during abdominal closure to potentially mitigate the risk of postoperative hernias. Nonetheless, existing research on the efficacy of this practice has been limited by small cohort studies. This study aims to evaluate factors that influence mesh placement in DIEP ABR and to assess the short- and long-term effects of mesh placement on postoperative hernia development and donor-site morbidity using a large healthcare database.

METHODS: The TriNetX health database was queried to identify patients who underwent DIEP flap reconstruction with or without abdominal mesh using CPT and HCPCS codes. Cox regression analysis was performed to identify significant covariates influencing both mesh placement and postoperative hernia risk. Patients with BMI of ≥30 kg/m2 were stratified by mesh placement and propensity-score matched 1:1 by demographics and comorbidities. Risk ratios were calculated to determine 5-year hernia rates between the matched cohorts.

RESULTS: Among 12,593 patients who underwent DIEP ABR, 1100 patients (8.7%) had abdominal mesh placed at the time of surgery. Cox regression demonstrated that a BMI of ≥30 kg/m2 and advanced age were significant predictors of postoperative hernias (P < 0.0001). ABR patients were more likely to receive mesh if they had a BMI of ≥30 kg/m2 (P < 0.0001), prior hernia repairs (P < 0.05), tobacco use (P < 0.05), or advanced age (P < 0.01). After propensity-score matching, mesh placement did not significantly reduce 30-day donor-site morbidity or 5-year hernia rates in patients with a BMI of ≥30 kg/m2.

CONCLUSIONS: These findings suggest that surgeons preferentially place mesh in patients they perceive to be at high risk of postoperative complications, particularly those with obesity, history of hernia repairs, tobacco use, and advanced age. Nonetheless, mesh placement during DIEP reconstruction does not provide the anticipated protective effect against postoperative hernias or reduction in donor-site morbidity, even in higher risk patients with a BMI of ≥30 kg/m2. These findings challenge the routine use of mesh during abdominal closure in DIEP flap breast reconstruction and suggest that more targeted approaches to reducing donor-site complications are warranted.

BACKGROUND: Many popular botulinum neurotoxin treatments are off-label, yet no review has comprehensively captured their effects. This study provides a systematic review of neurotoxin's off-label aesthetic applications, focusing on muscle targets, aesthetic goals, outcomes, and patient satisfaction.

METHODS: A systematic review of PubMed, MEDLINE, and Web of Science was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eligible studies were published between 2014 and 2024, describing nonwrinkle aesthetic uses of botulinum toxin type A in adults. Data extracted included patient demographics, muscle targets, aesthetic goals, procedural approaches, outcome measures, and patient satisfaction. Proportion meta-analyses were performed using Stata software.

RESULTS: Of 531 search-identified studies, 38 met inclusion criteria, totaling 1903 patients aged 17 to 93 years. Patients were primarily female (94.3%, P < 0.0001), with a mean age of 43.7 years. Most interventions targeted the lower face (70.3%, P < 0.0001). Facial aesthetic goals included eyebrow lift, forehead fat graft retention, nasal flare reduction, nasal tip sculpting, facial slimming, and correction of gummy smile, downturned mouth, chin retrusion, mentalis strain, and lower-face descent. Nonfacial aesthetic goals included neck, arm, and calf contouring and scrotal relaxation. Interventions focused on reducing volume/bulk (n = 21, 61.8%) or reshaping (eg, lifts and smile correction) (n = 16, 47.1%). Overall satisfaction was high (94%; 95% confidence interval, 88%-98%). Studies with quantitative measurements during the first follow-up (n = 23) reported sustained results (75.0%, P < 0.0001), with minimal reported complications.

CONCLUSION: Beyond rhytid reduction, botulinum toxin type A demonstrates versatile aesthetic utility in facial and body contouring, with high patient satisfaction and minimal adverse effects. Standardized protocols and refined evaluation methods are needed to inform decision-making, expand clinical guidance, and optimize outcomes.

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

OBJECTIVE: Undiagnosed diabetes leads to delayed treatment and increased risk of complications, exacerbating global disease burdens. In this study, we estimated the prevalence and absolute numbers of individuals with undiagnosed diabetes globally and across regions and quantified gaps in national diabetes detection efforts.

RESEARCH DESIGN AND METHODS: We systematically compiled estimates of biomarker-based diabetes prevalence and self-reported diabetes diagnosis using 2003-2024 data from all eligible population-based studies and gray literature. We calculated proportions of individuals with undiagnosed diabetes and case numbers among adults aged 20-79 years. For countries without data, we extrapolated estimates using available data within the same geographic region and country income group. Country-level estimates were benchmarked against the World Health Organization 80% diagnosis target.

RESULTS: We identified 193 data sources on undiagnosed diabetes from 109 countries. Across all 215 countries/territories, 42.8% of individuals with diabetes were undiagnosed in 2024, equating to 251.7 million (95% uncertainty interval [UI] 250.4-253.0 million) adults. Proportions undiagnosed ranged from 16.2% in Colombia to 90.4% in Burkina Faso and 29.1% in North America and the Caribbean to 72.6% in Africa. A larger proportion of individuals were undiagnosed in low-income (58.7%) compared with high-income countries (28.9%). Middle-income countries accounted for 206.0 million (95% UI 202.3-209.7 million) adults with undiagnosed diabetes (81.8% of all individuals), including 127.1 million (95% UI 121.2-133.0 million [or 50.5%]) adults in China, India, and Indonesia alone. Less than 5% of all countries attained diabetes diagnosis levels ≥80%.

CONCLUSIONS: Substantial global variability in undiagnosed diabetes indicates opportunities to close existing care gaps, likely requiring context-specific solutions and investments.

BACKGROUND: Antihypertensive medications are essential for preventing cardiovascular events and have traditionally been taken in the morning. However, recent studies have suggested that taking the medication at bedtime may be more effective in reducing cardiovascular risk. This study aimed to examine the association between dosing time and cardiovascular outcomes.

METHODS: Randomized controlled trials were retrieved through a systematic literature review using PubMed and Embase. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of all-cause (or cardiovascular) death, myocardial infarction, stroke, and hospitalization for heart failure. Secondary outcomes included each component of the primary outcome. A random-effects model was applied to calculate the pooled hazard ratio (HR) for each outcome.

RESULTS: Five randomized controlled trials with 46,477 participants (bedtime, 23,178; morning, 23,299) were included. The median follow-up period ranged from 1.1 to 6.3 years, and the mean or median age ranged from 55.6 to 88 years. We found no evidence that bedtime antihypertensives administration was associated with the risk of MACE [HR = 0.71; 95% confidence interval (CI), 0.43-1.16], all-cause death (HR = 0.76; 95% CI, 0.49-1.17), stroke (HR = 0.70; 95% CI, 0.39-1.23), myocardial infarction (HR = 0.88; 95% CI, 0.56-1.38), or hospitalization for heart failure (HR = 0.58; 95% CI, 0.26-1.33), compared to morning administration.

CONCLUSIONS: Administration of antihypertensives at bedtime was not significantly associated with a lower incidence of cardiovascular outcomes in comparison with administration in the morning.

Deformable templates, or atlases, are images that represent a prototypical anatomy for a population, and are often enhanced with probabilistic anatomical label maps. They are commonly used in medical image analysis for population studies and computational anatomy tasks such as registration and segmentation. Because developing a template is a computationally expensive process, relatively few templates are available. As a result, analysis is often conducted with sub-optimal templates that are not truly representative of the study population, especially when there are large variations within this population. We propose a machine learning framework that uses convolutional registration neural networks to efficiently learn a function that outputs templates conditioned on subject-specific attributes, such as age and sex. We also leverage segmentations, when available, to produce anatomical segmentation maps for the resulting templates. The learned network can also be used to register subject images to the templates. We demonstrate our method on a compilation of 3D brain MRI datasets, and show that it can learn high-quality templates that are representative of populations. We find that annotated conditional templates enable better registration than their unlabeled unconditional counterparts, and outperform other templates construction methods.

Artificial intelligence (AI) is increasingly being integrated into everyday tasks and work environments. However, its adoption in medical image analysis has progressed more slowly due to high clinical stakes, limited availability of labeled data, and substantial variability in imaging protocols and population. These challenges are further pronounced in the field of fetal, infant, and toddler (FIT) neuroimaging, where datasets are especially scarce and subject to large amounts of anatomical variability. However, deep learning (DL), a specific method within machine learning, which is itself a subfield of AI, has emerged as a powerful framework to adapt to the challenges of medical image analysis. This review is written for the broad FIT research community, including clinicians, neuroscientists, and develop mental scientists who may not have formal training in AI. To make the material accessible, we provide a concise overview of DL concepts before reviewing a selected, and non-exhaustive, list of applications of DL in FIT neuroimaging, including structural image analysis, enhancement of data acquisition, modeling of cognitive and perceptual processes, and automated video tagging. In closing, we discuss best practices for data curation, ongoing challenges, and opportunities for future research.

BACKGROUND: Immediate administration of beta-blockers is recommended for acute myocardial infarction (AMI). However, the benefit of beta-blockers according to left ventricular ejection fraction (LVEF), especially for preserved LVEF, remains uncertain. This study aimed to examine the efficacy and safety of beta-blockers for patients with mildly reduced or preserved LVEF after AMI.

METHODS: We reviewed randomized controlled trials (RCTs) comparing standard therapy with versus without beta-blockers for patients with AMI with LVEF ≥40%. The primary outcome was a composite of all-cause death, myocardial infarction, and hospitalization for heart failure. The safety outcome was hospitalization for a composite of bradycardia, atrioventricular block, and pacemaker implantation. A pairwise meta-analysis was performed to evaluate hazard ratios (HRs) with 95% confidence intervals (CIs) using a random-effect model.

RESULTS: A total of 19,826 participants from four RCTs (9892 received beta-blocker therapy and 9934 received non-beta-blocker therapy) were included. The primary outcome (HR, 0.93; 95% CI, 0.82-1.04) and the safety outcome (HR, 1.06; 95% CI, 0.83-1.34) were comparable between the two groups. Beta-blockers were also not associated with significant different risks of other outcomes, including each component of the primary outcome and stroke.

CONCLUSIONS: In patients with AMI with preserved LVEF, beta-blocker therapy was not significantly associated with lower cardiovascular outcomes or higher bradyarrhythmic events compared to non-beta-blocker therapy. Further trials are warranted to clarify the role and necessity of beta-blockers.