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Importance Rapid whole-genome sequencing (WGS) has advanced inpatient genetic diagnosis, although most evidence comes from neonatal and pediatric intensive care unit (ICU) populations. Its utility for pediatric neurology inpatients across broader acute settings remains insufficiently established. Objective To assess the diagnostic yield, clinical impact, and factors associated with phenotype-concordant rapid WGS diagnoses. Design, Setting, and Participants This was a retrospective cohort study conducted from June 1, 2022, through January 17, 2026, at a tertiary medical center. Pediatric inpatients in the neonatal ICU, pediatric ICU, or general floor with an unexplained neurologic presentation were included. Those with established nongenetic etiology were excluded from analyses. Exposures Trio (77.8%), duo (9.1%), or singleton (13.1%) rapid WGS. Main Outcomes and Measures The primary outcome was the initial phenotype-concordant diagnostic yield at the point of care. Secondary outcomes were reanalysis yield (new diagnoses from reinterpreting nondiagnostic cases prompted by a new unexplained phenotype or family request), cumulative yield, and management change. Associations were assessed by logistic regression (odds ratios [ORs] and 95% CIs). Results Among 175 children (median [IQR] age, 4 months [1 day-4 years]; 93 male [53.1%]) who met inclusion criteria (82 neonates, 93 nonneonates), initial rapid WGS established a phenotype-concordant diagnosis in 79 (45.1%), higher in nonneonates (49 of 93 [52.7%]) than neonates (30 of 82 [36.6%]). Preliminary results returned at mean (SD) 4.0 (1.6) days and final reports at 10.4 (4.5) days. Positive nonconcordant findings occurred in 33 children (18.9%). Reanalysis of 14 nondiagnostic cases yielded 3 additional diagnoses, for a cumulative yield of 82 of 175 children (46.9%). Most diagnoses were monogenic (63 [76.8%]). Management changed in 54 of 82 phenotype-concordant cases (65.9%; 53 at the point of care, 1 after reanalysis) and 8 of 33 (24.2%) positive nonconcordant cases. Family history was most strongly associated with diagnosis (adjusted OR [aOR], 6.46; 95% CI, 3.23-12.93; P < .001), followed by multisystem involvement (aOR, 2.85; 95% CI, 1.24-6.54; P = .01) and congenital anomaly or dysmorphism (aOR, 2.47; 95% CI, 1.07-5.68; P = .03). Hypotonia was most strongly associated in neonates (OR, 20.63; 95% CI, 5.46-77.87; P < .001); ICU admission (OR, 10.25; 95% CI, 2.79-37.67; P < .001) predominated in nonneonates. Conclusions and Relevance Results of this cohort study suggest that rapid WGS diagnosed nearly half of pediatric neurology inpatients and changed management in two-thirds of diagnosed cases, supporting its potential use as early diagnostic testing. Associated features may guide patient selection, and reanalysis extends yield longitudinally.

Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.

OBJECTIVE Genetic variation in the glucagon-like peptide 1 receptor (GLP1R) has been implicated in type 2 diabetes (T2D) risk and treatment response. We investigated whether GLP1R R131Q, which was previously reported as a T2D-protective variant in genome-wide association studies, alters receptor signaling, β-cell function, and response to glucagon-like peptide 1 receptor agonists (GLP-1RAs). RESEARCH DESIGN AND METHODS Trajectory of β-cell function was evaluated in a 20-year community-based prospective cohort in Korea (n = 6,373), where participants underwent biennial 2-h 75-g oral glucose tolerance tests, and disposition index was used as surrogate marker. Pharmacogenetic response to GLP-1RAs was assessed in a hospital-based T2D cohort in Korea (n = 177). Hyperglycemic clamp studies (n = 17), human islet experiments (n = 21), and in vitro assays were conducted to characterize GLP1R R131Q effects on receptor signaling and islet function. RESULTS GLP1R R131Q was associated with slower decline in disposition index in individuals without T2D, with reductions from baseline of 30% in homozygous carriers, 35% in heterozygotes, and 37% in wild-type individuals. In people with T2D, each allele conferred an additional 0.53% or 5.8 mmol/mol reduction in HbA1c after 6 months of GLP-1RA treatment (P = 5.8 × 10−4). Hyperglycemic clamp and human islet experiments demonstrated allele-dependent enhancement of GLP-1RA–stimulated insulin secretion (P = 0.050 and P = 0.037, respectively). In vitro, GLP1R R131Q increased GLP-1RA–stimulated cAMP production with directional observations consistent with pathway bias. CONCLUSIONS GLP1R R131Q is a gain-of-function variant associated with preservation of β-cell function and enhanced glycemic response to GLP-1RA treatment, supporting further investigation as a candidate pharmacogenetic marker for precision diabetes care.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Background: Increased arterial stiffness, a marker of cardiovascular disease (CVD), is prevalent among African American (AA) adults and contributes to persistent CVD disparities. The Cardio-Ankle Vascular Index (CAVI) is a validated measure of arterial stiffness and predictor of adverse CVD outcomes. However, its relationship with the novel American Heart Association’s Life’s Essential 8 (LE8) cardiovascular health (CVH) construct has not been examined among AAs. Hypothesis: We hypothesized that increased arterial stiffness would be associated with lower CVH among AA adults. Methods: We analyzed baseline data from AA adults in the Techquity by FAITH! Trial, a 2-arm cluster randomized controlled trial conducted across 18 AA churches in Rochester and Minneapolis–St. Paul, Minnesota. Eligible participants (age ≥18 years with suboptimal diet or physical activity [PA]) completed validated electronic surveys (e.g., PA patterns) and clinical assessments (e.g., blood pressure [BP], lipids). CAVI was summarized as mean and categorized as normal (<8), borderline (8 to <9), or abnormal (≥9). CVH was assessed using the LE8 score (range 0-100 points) and categorized as low (<50), moderate (50-79), or high (≥80). Associations between CAVI and LE8 were assessed using multivariable linear regression adjusted for age, sex, and income (continuous) and Fisher’s exact test (categorical). LE8 components were compared across CAVI categories using Kruskal–Wallis tests. Results: Among 140 participants (mean age 53.0 years [SD 14.6]; 68% female), the mean LE8 score was 62.7 (SD 14.0). Nicotine exposure LE8 score was the highest (84.6 [SD 26.6]) and diet was the lowest (40.7 [SD 13.7]). Mean CAVI was 7.9 (SD 1.5), with 50% of participants classified as normal, 22% borderline, and 28% abnormal. No association between continuous CAVI and LE8 scores was observed after adjustment (unadjusted R 2 = 3.5%). All participants with high LE8 had normal CAVI, while abnormal CAVI was more prevalent among those with low (40%) and moderate (30%) LE8 scores (p<0.001). LE8 scores differed across CAVI categories for BP (median 50 in normal CAVI vs 30 in borderline/abnormal CAVI; p=0.003) and glucose LE8 scores (median 100 vs 60; p=0.014). Conclusions: Greater arterial stiffness was associated with lower CVH categories, with notable component-level differences in BP and glucose. Although not independently associated with overall LE8, integrating CAVI and LE8 categories may improve CVD risk stratification among AAs.

Abstract Clinical empathy is essential for patient care, but physicians need continually balance emotional warmth with factual precision under the cognitive and emotional constraints of clinical practice. This study investigates how large language models (LLMs) can function as empathy editors, refining physicians’ written responses to enhance empathetic tone while preserving underlying medical information. More importantly, we introduce novel quantitative metrics, an Empathy Ranking Score and a MedFactChecking Score to systematically assess both emotional and factual quality of the responses. Experimental results show that LLM-edited responses significantly increase perceived empathy while preserving factual accuracy compared with fully LLM-generated outputs. These findings suggest that using LLMs as editorial assistants, rather than autonomous generators , offers a safer, more effective pathway to empathetic and trustworthy AI-assisted healthcare communication.