Publications by Year: 2026

Fuchs endothelial corneal dystrophy (FECD) is an age-related disorder characterized by excessive extracellular matrix (ECM) deposition and loss of corneal endothelial cells (CEnCs), eventually leading to corneal blindness. Despite known environmental and genetic contributors, the roles of aging and hormonal influences, particularly in the predominantly female population, remain underexplored in FECD. This study investigates the impact of chronic exposure to combined ultra-violet (UV-A) light and the oxidized estrogen metabolite 4-hydroxyestradiol (4-OHE2) on healthy CEnCs, primarily focusing on the cellular senescence pathway implicated in FECD pathogenesis. Our results show that prolonged exposure triggers G0/G1 cell cycle arrest through the p16-pRB pathway, inducing a senescence-mediated pro-secretory phenotype. The senescent cells in G0/G1 phase concurrently upregulated the fibrotic and extracellular matrix (ECM) markers indicating a complex relationship between senescence with fibrosis and ECM deposition. Additionally, multiplex analysis to detect senescence-associated secretory phenotype (SASP) after chronic exposure revealed significant upregulation of pathogenic factors such as IL-8 and IL-17, which were attenuated by SB225002 (anti-CXCR2) and secukinumab (anti-IL-17A). Senolytic cocktail of Dasatinib and Quercetin treatment alleviated fibrosis by selectively eliminating senescent cells and improved the survival of healthy cells. This study introduces a novel in vitro model of FECD, revealing the crucial role of cell cycle modulation, senescence and interleukins in the disease advancement and pathogenesis. The findings suggest that targeting senescence and cytokine-driven inflammation could be a promising therapeutic strategy for mitigating FECD progression.

Nonsuicidal self-injury (NSSI) in youth is clinically heterogeneous. We aimed to identify distinct psychopathology-based profiles among children and adolescents reporting NSSI and their longitudinal correlates. Participants (N = 1 345) were drawn from the Brazilian High-Risk Cohort Study, which conducted extensive phenotypic assessments at baseline (ages 6-14 years) and across two follow-up waves (ages 9-18 and 13-23 years). First, we applied unsupervised machine-learning algorithms (Self-Organizing Maps and k-means clustering) to identify distinct psychopathology-based profiles among youth reporting NSSI at the second follow-up. We then employed three models to identify longitudinal predictors of these profiles: logistic regression, elastic net, and random forest. Analyses revealed two distinct profiles of youth reporting NSSI, characterized by high and low psychopathology. The high psychopathology profile (n = 117) was associated with factors identifiable earlier in life and characterized by persistent psychiatric symptoms and significant social adversity throughout development (e.g., family problems and bullying). The low psychopathology profile (n = 127) was marked by lower overall psychopathology and experienced mental health problems only later in development, with less severe challenges over time, such as school suspension and milder depressive symptoms. While the logistic regression did not provide overall significant performance, the elastic net (AUC = 0.72 95% CI 0.65-0.77) and random forest (AUC = 0.73 95% CI 0.67-0.78) did. The present study identified two distinct psychopathology-based profiles among youth reporting NSSI and their longitudinal correlates, using machine learning approaches. Early identification of youth in higher-risk profiles can inform early intervention strategies.

BACKGROUND: Emergency surgery (ES) is associated with a significantly higher risk of perioperative complications, including infectious, compared with elective surgery. This study aimed to identify the impact of time to surgical procedure and operative duration on infectious complications after ES.

PATIENTS AND METHODS: The 2013-2017 American College of Surgeons National Surgical Quality Improvement Program database was utilized to identify all ES patients ≥18 years using the variable "Emergency." Delayed surgical procedure was defined as >12 h and prolonged surgical procedure as >2 h. Multivariable logistic regression adjusting for age, comorbidities, and surgical approach was used to investigate the impact of delayed and prolonged surgical procedure on postoperative infection, defined as the presence of sepsis, septic shock, surgical site infection (i.e., superficial, deep incisional, and organ space), pneumonia, and urinary tract infection. Sensitivity analyses were performed to examine the same relationship in emergency general surgery (EGS), identified with Current Procedural Terminology codes, and three subsets of EGS patients: exploratory laparotomy, cholecystectomy, and appendectomy.

RESULTS: Out of 4,299,148 patients, 264,213 were included, of which 24,921 (9.4%) had postoperative infections. Patients with infectious complications were more likely to have comorbidities (e.g., obesity, diabetes), an open surgical approach, delayed surgical procedure (50.4% vs. 39.4%, p < 0.001), and prolonged surgical procedure (31.6% vs. 14.3%, p < 0.001). On multivariable analyses, delayed surgical procedure was significantly associated with a 14% higher risk of postoperative infection (adjusted odds ratios [aOR] 1.14; 95% confidence interval [CI] 1.1-1.18), and prolonged surgical procedure was significantly associated with twice the risk (aOR: 1.99; CI: 1.91-2.08). Similarly, delayed and prolonged surgical procedure were significantly associated with infectious complications in the subset of EGS patients (aOR: 1.16; CI: 1.11-1.22, aOR: 1.91; CI: 1.82-2.02, respectively). When examining the 3 sensitivity subsets of patients, prolonged surgical procedure was significantly associated with infectious complications in all cohorts (aOR: 1.45; CI: 1.28-1.64 in exploratory laparotomy, aOR: 1.93; CI: 1.52-2.46 in cholecystectomy, aOR: 2.06; CI: 1.69-2.53 in appendectomy), whereas delayed surgical procedure was significantly associated with infectious complications only in exploratory laparotomy (aOR: 1.23; CI: 1.13-1.33).

CONCLUSIONS: Delayed and prolonged surgical procedure are independently associated with increased risk of infectious complications in ES patients, including those undergoing EGS procedures. These findings highlight the importance of early and efficient surgical interventions in ES.

One of the key pillars of Ending the HIV Epidemic is ensuring adherence to oral HIV pre-exposure prophylaxis (PrEP). Men who have sex with men (MSM) who also have substance use disorders experience multiple challenges to maintaining PrEP adherence. We developed a digital pill system (DPS) linked to a personalized adherence intervention, PrEPSteps, to address barriers to PrEP adherence, and tested the feasibility and acceptability of this system, as well as its potential for an effect on PrEP adherence. We enrolled MSM with moderate to severe substance use disorder who were on oral PrEP in a two-arm pilot randomized controlled trial. Both arms received the DPS co-encapsulated with oral PrEP. Participants in the intervention arm also received "PrEPSteps" - a personalized cognitive-behavioral adherence intervention. Primary outcomes were feasibility and acceptability of DPS + PrEPSteps. To explore potential intervention effects, adherence changes from baseline to 3-month follow-up were compared across arms. At 6-month follow-up, adherence was assessed via self-report. Thirty-six participants were enrolled, 32, completed the run-in period, 28 were randomized, and 27 completed the 3-month intervention period. Of those, 26 completed six-month follow-up. Operation of the DPS and PrEPSteps was feasible, with consistent data recording throughout the 3-month intervention period. Qualitative interviews in the intervention arm at 3 months demonstrated PrEPSteps was acceptable. Intervention arm participants had 14% higher PrEP adherence (b = 13.67, 95%CI [.77-26.57], p = .039) at 3 month follow up. This effect persisted at six months, suggesting that PrEPSteps has the potential to improve PrEP adherence and help individuals sustain adherence benefits over time.Trial registration: www.ClinicalTrials.gov identifier: NCT03512418.

IMPORTANCE: Early and accurate identification of clinical warning signs in young infants may help avert sepsis morbidity and mortality in resource-limited settings.

OBJECTIVE: To systematically review evidence on the association and accuracy of clinical signs to diagnose sepsis or predict mortality in young infants aged 0 to 59 days to inform management in settings with limited laboratory diagnostics.

DATA SOURCES: MEDLINE, Embase, CINAHL, Global Index Medicus, and Cochrane CENTRAL Register were searched from inception through May 2023, with updated searches on September 5, 2024. An umbrella search of systematic reviews was conducted in January 2024.

STUDY SELECTION: Included studies reported data on 24 infant clinical signs informed by current World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) and hospital-based algorithms for the care of sick young infants reporting odds ratios (OR), risk ratios, or sensitivity and specificity.

DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by 2 reviewers. Quality assessment used the Newcastle-Ottawa, Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), and Quality Assessment of Prognostic Accuracy Studies (QUAPAS) scales. OR data were pooled using random-effects models. Data analysis was performed from July to September 2025.

MAIN OUTCOMES AND MEASURES: OR of all-cause mortality, culture-confirmed sepsis, or clinical sepsis (with access to laboratory investigations).

RESULTS: Of 7641 studies, 52 studies with 140 885 participants were included. A total of 16 clinical signs were significantly associated with mortality, 11 with culture-confirmed sepsis, and 13 with clinical sepsis. For mortality, the 5 strongest associations were weak, abnormal, or absent cry (OR, 20.48; 95% CI, 6.59-63.67); not able to feed at all (OR, 18.32; 95% CI, 6.00-55.97); not feeding well (OR, 13.39; 95% CI, 6.97-25.72); drowsiness or unconsciousness (OR, 12.46; 95% CI, 6.06-25.62); and prolonged capillary refill (OR, 12.06; 95% CI, 2.77-52.53). The top 5 signs associated with culture-confirmed sepsis were not feeding well (OR, 4.52; 95% CI, 1.10-18.59); prolonged capillary refill (OR, 3.59; 95% CI, 2.05-6.28); lethargy (OR, 3.44; 95% CI, 1.89-6.26); drowsiness or unconsciousness (OR, 3.07; 95% CI, 2.01-4.68); and feeding intolerance (OR, 2.95; 95% CI, 1.67-5.21).

CONCLUSIONS AND RELEVANCE: All current WHO IMCI clinical signs were significantly associated with mortality or culture-confirmed sepsis. Several signs not in IMCI were identified that may improve identification of life-threatening illness in young infants in resource-limited settings where clinical sign algorithms are the primary diagnostic tool.

Cardiovascular adverse effects of drugs have significant practical implications for patient management. While cardiovascular adverse effects have commonly been associated with oncologic therapeutics, a growing body of evidence suggests that non-oncologic medications can also be associated with significant cardiovascular harm. These adverse effects range from arrhythmias, conduction abnormalities, QT prolongation, heart failure, myocardial infarction, or structural cardiomyopathy. Non-oncologic drugs that have been implicated include antibiotics (e.g. macrolides, fluoroquinolones), antidiabetics (e.g. thiazolidinediones), non-steroidal anti-inflammatory drugs, drugs for gastrointestinal and urological conditions, and most importantly, cardiovascular drugs. In this narrative review, we focus on the most common non-oncologic drugs that cause cardiovascular adverse effects, their proposed underlying mechanisms with particular emphasis on their clinical manifestations and clinical implications for everyday cardiovascular practice.

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analyzed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing, and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer's disease metabolome. A PD acylcarnitine signature was further replicated in human postmortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.

BACKGROUND AND AIMS: Statins have been investigated for their potential to reduce liver-related complications in chronic liver diseases, but evidence in primary biliary cholangitis (PBC) remains limited. This study aimed to assess the association between statin use and the risk of hepatic decompensation using a target trial emulation (TTE) design.

APPROACH AND RESULTS: We performed a sequential TTE using 2 electronic health record databases: Mass General Brigham (MGB, Boston, USA) and Asan Medical Center (AMC, Seoul, Korea). Adults diagnosed with PBC between 2001 and 2024 were eligible. Statin use was defined as a cumulative duration of ≥90 days. In each monthly trial, statin initiators were matched 1:2 to non-users using propensity score matching. The primary outcome was hepatic decompensation; the secondary outcome was a composite major adverse liver outcome (MALO), including decompensation, hepatocellular carcinoma, and liver transplantation. Among 2889 eligible patients, 443 statin users were matched to 886 non-users. Over a median follow-up of 3.8 years, hepatic decompensation occurred in 24 statin users (5.4%) and in 67 non-users (7.6%) [hazard ratio (HR), 0.61; 95% confidence interval (CI): 0.38-0.97]. Statin use was also associated with a reduced risk of MALO (HR, 0.58; 95% CI: 0.38-0.89). Sensitivity analyses stratified by data source (MGB, HR 0.65; AMC, HR 0.60) and cirrhosis status (HR 0.70 for cirrhosis; HR 0.57 for without) showed similar directional trends.

CONCLUSIONS: Statin use was consistently associated with a lower risk of hepatic decompensation and major liver events in patients with PBC, supporting a potential protective effect.