Citations

Abstract Objective To evaluate 2-year cost to insured patients treated with Roux-en-Y gastric bypass (RYGB) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for type 2 diabetes (T2D) and obesity. Methods Using the 2017 to 2023 Merative™ claims database, we identified adult patients with severe obesity and T2D who were treated with a RYGB or GLP-1 RAs. Patients with RYGB had no treatment with GLP-1 RAs, and those who received GLP-1 RA therapy with tirzepatide or semaglutide for ≥ 2 years had no metabolic and bariatric surgery (MBS) procedures. The study cohorts were matched on demographics including obesity, associated medical problems, and baseline direct or out-of-pocket (OOP) costs to patients in the year prior to treatment initiation. Direct costs included those from outpatient services, inpatient admissions, and outpatient prescription filled that were paid directly by patients. We compared this cost up to two years after treatment initiation using paired t-tests. Results 1012 matched RYGB and GLP-1 RA patients were analyzed, including 35% male. At 1-year after treatment initiation, healthcare costs paid directly by patients were similar for the RYGB ($2,301) and GLP-1 RA ($2,179) (delta = $122, p = 0.15) cohorts. From one to two years after index treatment date, OOP costs were significantly lower in the RYGB treatment group ($1,277 vs. $2,104, p < 0.01). Two years after treatment initiation, RYGB patients spent $704 less in OOP costs than similar patients treated with GLP-1 RA medications (p < 0.01). Conclusions Direct OOP healthcare costs were lower for RYGB compared to GLP-1 RA use patients 2-years after treatment initiation.

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to drive aggressive growth remains elusive. Here, we infused 13C-labeled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumor vs. cortex. Through the first direct and comprehensive measurements of carbon and nitrogen labeling in both cortex and glioma tissues, we uncover profound metabolic transformations. In human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters GBM metabolism, slows tumor growth, and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumors exploit glucose to suppress normal physiological activity in favor of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

Background Admixture mapping can be leveraged to identify genomic loci associated with disease traits in admixed individuals such as Hispanic Americans. Methods and Results We characterized fine‐scale population structure of participants (n=105 108) in the multiethnic eMERGE‐III (electronic Medical Records and Genomics) cohort, using reference panels from the 1000 Genomes Project and a Native American cohort. We defined “genetically admixed Hispanic Americans” as those having ≥10% Native American genetic ancestry (n=5025), in addition to European (specifically, Iberian) and African genetic ancestry. This population descriptor was subsequently applied to 3 other cohorts: the MESA (Multi‐Ethnic Study of Atherosclerosis; n=1176), WHI (Women’s Health Initiative; n=2873), and the HCHS/SOL (Hispanic Community Health Study/Study of Latinos; n=7804). We inferred local ancestry along the genome in genetically admixed Hispanic Americans in each cohort using RFMix2 with phased haplotypes from SHAPEIT2. Local ancestry proportions were used for admixture mapping of lipid traits (low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, total cholesterol, and triglycerides) using extended linear mixed models that incorporated multiple or single ancestries. After accounting for fixed‐effect covariates and random effects, ancestry proportions at the following loci were associated with lipid traits in the HCHS/SOL cohort: 11q12.2 ( P =6.8×10 −7 ) with low‐density lipoprotein cholesterol, 2p23.3 ( P =5.2×10 −7 ) with total cholesterol, and 11q23.3 ( P =7.3×10 −12 ) with triglycerides. The LDL cholesterol and triglyceride loci replicated in at least one independent cohort, whereas the total cholesterol locus showed suggestive evidence for replication in the eMERGE cohort ( P =0.073). Native American (NAMR) ancestry appeared to drive the LDL‐C association, whereas both NAMR and Iberian population in Spain (IBS) ancestries contributed to the triglyceride signal. Conclusions Admixture mapping in genetically admixed Hispanic Americans identified genomic loci influencing lipid traits and the different ancestral origins driving these associations.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Nephrotic syndrome is a rare, heterogeneous kidney disorder characterized by proteinuria, hypoalbuminemia, and edema. To elucidate its genetic architecture, we conducted a large-scale, electronic health record (EHR)-linked, multi-ancestry genome-wide association study comprising 5,214 cases and 1,601,060 controls. We identified 37 distinct loci associated with disease risk, including novel associations at JAML and STPG2 , and confirmed prior signals at PLA2R1 , HMCN1 , and APOL1 . Fine-mapping of the major histocompatibility complex (MHC) revealed the strongest association at DRB103:01:01G in individuals of European ancestry (OR = 2.01, P = 1.4×10⁻²⁰), alongside nominal ancestry-specific associations in African ( DOA01:01:05 ) and Latino ( DPB1*14:01:01G ) populations. Transcriptome-wide association analysis (TWAS) identified 484 significant gene-tissue associations, including C4A in kidney cortex. Expression quantitative trait locus (eQTL) mapping revealed numerous cis-eQTLs in glomerular and tubular renal tissues, largely within the MHC region. We observed significant genetic correlation between adult and pediatric nephrotic syndrome (Rg = 0.63, P = 3.5x10 -11 ), suggesting shared genetic etiology. Pathway analyses implicated estrogen receptor signaling and histone modification. Mendelian randomization implicated APOM expression and apomorphine exposure with increased disease risk (OR = 4.93, P = 1.8x10 -19 ). These results expand the understanding of nephrotic syndrome pathogenesis and highlight ancestry-informed targets for therapeutic development.