Citations

Background Suicide is the second leading cause of death among children and adolescents, with rates of pediatric suicidal behavior rising substantially over the past two decades. The neurobiology of suicide has been extensively studied in adults, yet pediatric-specific evidence remains limited and the extent to which adult findings can be extrapolated to youth is unclear. This review synthesizes current evidence on the neurobiological correlates of suicidal ideation, suicide attempt, and death by suicide in pediatric and adolescent populations across neurological, genetic, epigenetic, inflammatory, metabolic, and endocrine domains. Methods A literature search was conducted in PubMed, Embase, PsycINFO, and Google Scholar for peer-reviewed, English-language human studies. Priority was given to pediatric and adolescent samples, with adult data included where pediatric evidence was lacking. Studies were grouped by biological domain and by suicidal phenotype. Results Suicidal ideation, suicide attempt, and death by suicide showed partially distinct biological signatures rather than lying on a single continuum of severity. Different markers, most notably cortisol regulation and stress-related DNA methylation, differed in direction between pediatric and adult cohorts, indicating that adult biomarker data cannot be directly extrapolated to youth. Findings converged on a developmental cascade in which genetic liability and early-life adversity influence the hypothalamic-pituitary-adrenal axis, with downstream effects on epigenetic regulation, neuroinflammation, neurochemistry, and frontolimbic circuitry. Conclusions Pediatric suicidal behavior reflects developmentally distinct biological processes that cannot be inferred from adult findings. Advancing the field will require longitudinal, multimodal pediatric studies that disaggregate suicidal phenotypes, span the pubertal transition, and apply age-stratified reference ranges, supporting biologically informed stratification and mechanism-targeted intervention.

ABSTRACT Aims To evaluate the real‐world associations between semaglutide 2.4 mg and cardiometabolic comorbidities, biomarkers and cardiovascular risk among adults with overweight or obesity. Methods This retrospective cohort study used US claims data and laboratory measurements from the Komodo Research Database (2016–2024). Adults with obesity or with overweight and ≥ 1 obesity‐related comorbidity were included. Patients on semaglutide 2.4 mg for ≥ 12 months were compared with non‐users (including users of other obesity medications) using propensity score weighting with residual imbalances adjusted in regression model. Outcomes included time to onset of cardiometabolic comorbidities, change in cardiometabolic biomarkers and changes in 10‐year ASCVD risk score at 12 months. Results 25 783 semaglutide 2.4 mg users and 8 948 913 non‐users were identified. Semaglutide 2.4 mg was associated with significantly lower risks for incident prediabetes or type 2 diabetes, type 2 diabetes only, hypertension, ASCVD, heart failure and CVD (HRs 0.45–0.75; all p < 0.05), as well as greater improvements in BMI (−4.1 kg/m 2 ), SBP (−6.2 mmHg), HbA1c (−0.4%), LDL cholesterol (−7.7 mg/dL), triglycerides (−28.6 mg/dL) and HDL cholesterol (+1.9 mg/dL; all p < 0.001). At 12 months, semaglutide 2.4 mg users ( N = 161) demonstrated a greater reduction in ASCVD risk score (−0.7% vs. +0.3%; between‐group difference −1.0%, p < 0.001), with a decrease in the proportion at intermediate‐high ASCVD risk (14.9%–9.3% vs. 17.7%–18.7%; OR 0.3 [95% CI: 0.1, 0.6], p < 0.001). Conclusions Semaglutide 2.4 mg was associated with lower risk of multiple cardiometabolic comorbidities, favourable changes in biomarkers, and lower estimated ASCVD risk in this population.

Abstract Background: Glioblastoma recurrence is inevitable despite aggressive surgical resection of contrast enhancing (CE) tumor. Unlike the deep molecular characterization of CE glioblastoma, unresected infiltrating tumor, representing minimal residual disease (MRD) has not been well profiled. Increasingly, clinical trials are being conducted in the MRD setting for glioblastoma patients, necessitating understanding of unresected infiltrating tumor for targeted therapeutic development. Methods: Visium HD spatial transcriptomics was used to profile a cohort of newly diagnosed, treatment-naïve glioblastoma patients that underwent supramaximal resection, with both core and infiltrating in situ components. Spatial profiles generated expression signatures of infiltrative and CE tumor. For in silico prediction of therapeutics targeting the MRD, expression signatures of infiltrative and CE tumor were compared with drug perturbation signatures from the NIH L1000 database using the sRGES method to predict reversal of disease expression patterns. IC50 data from human cell lines were aggregated from the Genomics of Drug Sensitivity in Cancer or individual study data while blood-brain barrier (BBB) penetrance was predicted using the CNS-MPO approach. Findings: Infiltrative tumor expression profiles were enriched for genes corresponding to neural and oligodendrocyte progenitor like cells. In contrast CE glioblastoma displayed mesenchymal and astrocytic programs, suggesting spatial concentration of glioblastoma states within MRD and CE tumor. For CE glioblastoma, proteasome inhibitors and glucocorticoid receptor agonists were predicted to have the highest antitumor activity. In contrast, histone deacetylase inhibitors (HDACi) were highly ranked for MRD while exhibiting low predicted efficacy in CE tumor. Synergy analysis of drug candidates provided multiple dual treatment options for both the CE and MRD contexts. Conclusions: Cumulatively, these data indicate that the resected tumor does not reflect the MRD state, providing clarity on why targeted therapeutics for glioblastoma have not been particularly successful. Spatial profiling of the MRD demonstrates vulnerability to unique drug targets, which if utilized in the correct setting could confer greater survival benefit. Citation Format: Harrshavasan Congivaram, Shashwat Tripathi, Mateo Gomez, Katy McCortney, Ching Man Wai, Ruochen Du, Thomas K. Sears, Jianzhong Zhang, Daniel J. Brat, Craig M. Horbinski, Mark W. Youngblood, Jared T. Ahrendsen, Adam M. Sonabend, Stephen T. Magill, Matthew C. Tate, Maciej S. Lesniak, Sean Sachdev, Timothy Sita, Priya Kumthekar, Karan Dixit, Robin Buerki, Ditte Primdahl, Mustafa Khasraw, John de Groot, David A. Reardon, Rimas V. Lukas, Roger Stupp, Amy B. Heimberger. In silico screening of therapeutics candidates targeting minimal residual disease in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2496.

Abstract Genome-wide association studies (GWAS) have linked more than a hundred non-coding genomic loci to Parkinson’s disease (PD) risk. Deciphering their functional impact on gene regulation requires cell type-aware modeling approaches to assess the effects of sequence variation on enhancer function and target gene expression. To address this challenge, we generated a comprehensive matched dataset from 190 human donors (115 controls and 75 PD), comprising long-read whole-genome sequencing alongside single nucleus multiome atlases (snATAC-seq and snRNA-seq for 3.1 and 1.1 million nuclei respectively) of the anterior cingulate cortex and substantia nigra. By integrating chromatin accessibility quantitative trait loci (caQTL), DNA methylation QTL (meQTL), and allele-specific chromatin accessibility (ASCA), we identified 53,841 high-confidence cis -acting genetic variants that modulate cell type-specific enhancer accessibility in one or both brain regions. We further demonstrate that sequence-to-function models can accurately predict the impact of these variants directly from the genomic sequence. Novel explainability approaches allowed stratifying these variants according to their regulatory function, with the majority disrupting specific transcription factor binding sites in a cell type specific manner. Integrating these “enhancer variants” (EV) with eQTL mapping and gene locus modeling linked a subset of EVs to their target genes. Finally, we applied these models to prioritize regulatory variants at known PD GWAS loci, bypassing statistical limitations in rare disease-relevant populations like dopaminergic neurons. All together, we establish a unique resource and new sequence modeling strategies to interpret functional non-coding variation in the human brain.

In this study, we propose two new mathematical models able to quantify glucagon secretion during a graded glucose infusion, in the presence and absence of amino acids. The models provide an index of α-cell responsivity, G 50 , i.e., the glucose increase required to suppress glucose secretion rate (GSR) by 50%. Results show that the presence of amino acids reduced α-cell responsivity to glucose.

Background/Objectives: Streptococcus intermedius, a member of the Streptococcus anginosus group, is characterized by a marked propensity for abscess formation but only rarely causes native-joint septic arthritis. Involvement of the acromioclavicular (AC) joint is particularly uncommon. We describe a case of native AC joint septic arthritis due to S. intermedius in a patient with multiple predisposing factors and highlight diagnostic and management considerations. Methods: We report the clinical course of a 72-year-old man with poorly controlled type 2 diabetes mellitus who presented with progressive right shoulder pain, erythema, and swelling following recurrent minor skin abrasions from a newly adopted dog. Initial management for presumed inflammatory shoulder pathology included brief systemic corticosteroids and an ultrasound-guided intra-articular ketorolac injection. Magnetic resonance imaging (MRI) was performed after symptom progression. The patient underwent operative irrigation and debridement with collection of synovial fluid and deep tissue cultures. Blood cultures and transthoracic echocardiography were obtained to evaluate for systemic involvement. Results: MRI demonstrated multiloculated periarticular abscesses and osteolysis centered on the AC joint. Operative cultures yielded high colony counts of S. intermedius from synovial fluid and deep tissues. Blood cultures and echocardiography were negative. The patient required multiple operative debridements with irrigation, adjunctive local antibiotic therapy, and prolonged targeted β-lactam treatment. Clinical and radiographic improvement was achieved following surgical source control and antimicrobial therapy. Conclusions: Native AC joint septic arthritis due to S. intermedius is rare. Older age, uncontrolled diabetes, recent intra-articular intervention, and possible zoonotic inoculation from canine wound licking may represent contributory risk factors. Early imaging, prompt surgical source control, and guideline-concordant antimicrobial therapy are essential when bone and soft tissue involvement is present.

Early allograft failure (EAF) after living donor liver transplantation (LDLT) remains a clinical challenge. Existing prediction models developed for deceased donor transplantation poorly apply to LDLT due to distinct surgical and physiological factors. This study identifies clinical determinants of EAF and develops an LDLT-specific prediction model. We conducted a multicenter retrospective cohort study from 17 high-volume LDLT centers (January 2016–December 2020) with external validation at a tertiary center in Saudi Arabia (January 2015–December 2022). The primary outcome was EAF (graft loss or patient death ≤90 d). Multivariable mixed-effects logistic regression identified preoperative/intraoperative risk factors. The EAGLE-LDLT model was constructed using postoperative laboratory values. Performance was compared against established models (EAD, MEAF, A2ALL) using ROC analysis and decision curve analysis. The development cohort included 2944 adult LDLT recipients (67.7% male; median age 55 y; median MELD 14) with a 5.5% EAF rate. External validation included 1020 recipients (median MELD 21, 6.7% EAF). Independent risk factors for EAF were MELD (OR 1.06, 95% CI 1.04–1.08), donor BMI (OR 1.05, 95% CI 1.00–1.10), portal vein thrombosis (OR 1.73, 95% CI 1.13–2.63), and hepaticojejunostomy (OR 1.58, 95% CI 1.06–2.36). The EAGLE-LDLT model incorporating peak ALT (>468 U/L), peak INR (>1.9), and bilirubin (>3.5 mg/dL) and INR (>1.3) at POD7, demonstrated superior discrimination (AUC=0.81) compared with MEAF (AUC=0.77, p =0.004), EAD (AUC=0.67, p <0.001), and A2ALL (AUC=0.65, p <0.001). EAGLE-LDLT achieved balanced sensitivity (75.0%) and specificity (73.7%), effectively stratifying patients into high-risk (15% of patients; 40.4% EAF incidence) and low-risk groups. Preoperative and intraoperative clinical factors predict EAF in LDLT. The EAGLE-LDLT model accurately identifies LDLT recipients at the highest risk for EAF postoperatively.

Abstract Background Leishmaniasis is a rare protozoan parasitic disease transmitted through the bite of infected Phlebotomus and Lutzomyia sandflies. Clinical presentation is variable due to numerous species and host immunity differences. We present our clinical experiences with CL to guide timely diagnosis and treatment in returning travelers. Methods We retrospectively analyzed a cohort of adult patients 18+ years old who were diagnosed with CL from 2005 and 2025. We describe the demographic, clinical, and diagnostic features of CL. Results Biopsy-confirmed CL was diagnosed in 20 returning travelers (Table 1) from various endemic regions, most commonly Costa Rica (Fig. 1). The median time from travel to symptom onset was 36.5 days (SD 102), with an additional 75.5 days (SD 87) prior to biopsy diagnosis. All patients were evaluated by dermatology and 70% were evaluated by infectious disease (n=14). On initial presentation, lesions were described as ulcerated (50%, n=10), nodular (30%, n=6), painful (20%, n=4), and necrotic (10%, n=2; Fig. 2). Most lesions were located on the upper extremity (55%, n=11), followed by the face (35%, n=7), lower extremity (30%, n=6), and trunk (15%, n=3). 15% of individuals (n=3) had constitutional symptoms. No patients had definitive mucosal involvement, however, 10% (n=2) endorsed lip edema. No patients had visceral involvement. Species level identification occurred in 14 cases (70%), of which the most common was L.V. panamensis (50%), L.L. mexicana (21%), L. V. guyanensis (14%), L. L. tropica (7%), and L. V. braziliensis (7%). Initial treatments included azoles, liposomal amphotericin B (AmBisome), and miltefosine (each 20%); cryotherapy and parenteral pentamidine (each 10%); with compounded topical paromomycin added in 15% of cases. 35% of individuals (n=7) failed initial treatment and required additional treatment courses due to persistent lesions (57%) or relapse following initial resolution (14%). 10% (n=2) required a third treatment course due to persistent/recurrent lesions. Conclusion While CL in travelers has a variety of clinical manifestations, travel history, knowledge of key clinical features, and lesion patterns can aid in early diagnosis and treatment. CL is associated with early treatment failure rate for uncertain reasons. Disclosures All Authors: No reported disclosures