Drug-induced liver injury accounts for approximately 10% of acute hepatitis and up to 50% of acute liver failure. Despite its clinical significance, treatment remains largely limited to cessation of the offending agent. SLIT/ROBO signaling, known for roles in organ development, angiogenesis, leukocyte migration, and cancer metastasis, has demonstrated protective effects against various organ damage. In mouse models of liver injury induced by acetaminophen (APAP), thioacetamide, bile duct ligation, and serum from patients with toxic liver disease, Slit2 expression significantly increases, while Slit1 and Slit3 remain unchanged. Liver-specific Slit2 knockdown exacerbates liver injury, whereas recombinant SLIT2 alleviates liver damage by reducing oxidative stress via CYP2E1 downregulation and suppressing inflammation through nuclear factor κB inhibition. Notably, among ROBO receptors, only ROBO4 was induced in hepatocytes after APAP exposure. ROBO4 knockdown eliminates the hepatoprotective effects of SLIT2, highlighting the importance of SLIT2/BOBO4 signaling in toxic liver injury. Furthermore, the novel Slit2-derived peptide 5 (SP5), designed from the ROBO4-binding LRR2 domain, significantly reduces liver damage and inflammation. Notably, both recombinant SLIT2 and SP5 confer hepatoprotection even when administered 24 h after APAP challenge. These findings suggest that SLIT2/ROBO4-targeted therapies may offer a promising approach for preventing fulminant hepatitis in the context of toxic liver injury.
Publications by Year: 2026
2026
When given a sample of 100 emergency department discharge instructions, Claude Sonnet, a large language model, produced accurate Spanish translations as evaluated by Spanish-speaking physicians and medical interpreters.
The recent rapid rise in the number of identified genetic disorders that are potentially treatable has far outpaced the development of treatments, resulting in a worsening bottleneck in the translational pipeline. New therapeutics that target an individual's specific genetic variant, or "personalized" therapeutics, are being developed and tested at several academic medical centers. Personalized therapeutics represent a potentially transformative platform technology that could unlock new treatment models for rare disorders. At the same time, the field remains investigational, and developing and testing novel drugs in single individuals, particularly children, poses substantial sensitivities and challenges. In this review, we outline some important considerations for academic medical centers in determining their role in reviewing and supporting the development of personalized therapeutics for rare disorders, including oversight and resource allocation. We describe an institutional infrastructure and process for navigating this landscape, involving transparent oversight and communication processes.
Many patients with severe aortic stenosis present with concomitant multivalvular heart disease. The management of this condition remains challenging and requires a multidisciplinary approach that integrates clinical, hemodynamic, and multimodality imaging data to define the most effective and durable treatment strategy. Although randomized evidence to guide treatment decisions in this setting is limited, percutaneous interventions to address additional valvular lesions are being increasingly adopted. This review provides an overview of the pathophysiology of valvular diseases commonly associated with severe aortic stenosis, highlighting their prognostic implications after surgical or transcatheter treatment and their impact on risk stratification and therapeutic management.
OBJECTIVE: Glucagon-like peptide-1 (GLP-1) plays an important modulatory role in sodium and water homeostasis. Recent studies demonstrated that long-term treatment with GLP-1 receptor agonists (RAs) reduces fluid intake and urine output. To the best of our knowledge, no direct effect of GLP-1 on vasopressin has been observed. This secondary analysis aimed to investigate changes in copeptin levels in euvolemic participants treated with the GLP-1 RA dulaglutide versus placebo.
DESIGN: Secondary analysis of two randomized, double-blind, placebo-controlled, cross-over trials in 34 patients with primary polydipsia and 20 healthy participants.
METHODS: Participants received a 3-week intervention with dulaglutide (Trulicity) 1.5 mg or placebo (.9% sodium chloride) subcutaneously once weekly. Blood for copeptin analysis was collected at 08:00 after each treatment phase. To estimate the treatment effect of dulaglutide, we derived the absolute within-subject differences of copeptin between dulaglutide and placebo and used the Wilcoxon rank test for statistical analysis.
RESULTS: All 54 participants of the two cross-over trials were included. Median age was 27 years [interquartile range (IQR), 24-37.5 years], and 63% were female. Median body mass index (BMI) was 23 kg/m2 (IQR, 20.8-24.8). After 3-week treatment, dulaglutide was associated with a significant suppression of copeptin with a median within-subject difference of -.7 pmol/L (p = .047), corresponding to a 12% reduction compared to placebo. Treatment-induced changes in copeptin were not significantly correlated with GLP-1-mediated reductions in blood pressure, BMI, or incidence of nausea.
CONCLUSIONS: Our analysis provides evidence that the GLP-1-RA dulaglutide inhibits the vasopressin system and proposes physiological mechanisms that may explain the role of GLP-1 in sodium and water balance.
Lactoferrin is an iron-binding glycoprotein in human milk (HM) that reduces the risk of neonatal sepsis. Data from low- and middle-income countries regarding the determinants of HM lactoferrin concentration is limited. Our objectives were to assess how HM lactoferrin concentrations change over time and identify factors associated with lactoferrin concentration. From a pregnancy cohort in Sylhet, Bangladesh, we enrolled 99 women to join the lactation sub-cohort and provide HM samples at a median of 50 (T1) and 146 (T2) days postpartum. We measured HM lactoferrin concentrations with meso-scale discovery and examined associations with predictors including indices of maternal nutritional status [body mass index (BMI), mid-upper arm circumference (MUAC), hemoglobin], depression scores, infant gestational age, and birthweight-for-gestational age z-score. HM lactoferrin concentration increased by 21% from T1 to T2. Higher gestational age at birth was associated with lower HM lactoferrin concentration at T1. Higher maternal MUAC was associated with higher HM lactoferrin concentration at T2. In rural Bangladeshi women, HM lactoferrin concentration increased during the postpartum period. Higher lactoferrin was associated with earlier gestational age at delivery and better maternal nutritional status. Interventions to improve maternal nutritional status might also increase HM lactoferrin concentration and ultimately, benefit child outcomes.
IMPORTANCE: Skilled nursing facilities (SNFs) are the primary provider of institutional postacute care. Following the COVID-19 pandemic, there have been reports of SNFs reducing their capacity, affecting access to care and disrupting hospital discharges, yet little empirical evidence exists.
OBJECTIVE: To describe changes in SNF capacity after 2020 and assess whether changes were associated with staffing shortages and hospital discharge outcomes.
DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, data from the 2018-2024 Centers for Medicare & Medicaid Services Payroll-Based Journal on patient censuses in US skilled nursing facilities were assessed. Descriptive analyses characterized trends in SNF capacity from 2018 to 2024.
MAIN OUTCOMES AND MEASURES: Main outcomes were SNF licensed bed count and estimated operating capacity. Secondary outcomes included SNF staffing shortages, mean hospital length of stay, percentage of hospital admissions lasting 28 days or more, and the median distance traveled to admitting SNFs. County-level regression analyses examined the association between changes in SNF capacity and the frequency of SNF staffing shortages. Hospital-level regressions examined the association between changes in nearby SNF capacity and discharge outcomes.
RESULTS: Among US skilled nursing facilities, the number of licensed SNF beds declined by 2.5% between 2019 and 2024, while operating capacity declined by 5.0% over the same time period. There was substantial geographic variation-1 in 4 counties experienced operating capacity declines of 15.1% or more, with the largest declines being more common among rural counties. SNF capacity declines were larger in counties with more frequent reports of SNF staffing shortages-a 1-percentage point decline in county SNF capacity was associated with a 0.20-percentage point (95% CI, 0.11-0.29) increase in the frequency of reported shortages. Additionally, hospitals that experienced larger declines in nearby SNF capacity experienced greater increases in mean length of stay, percentage of stays lasting 28 or more days, and median distance traveled to admitting SNFs.
CONCLUSIONS AND RELEVANCE: Results of this study suggest that SNF operating capacity declined following the pandemic and these declines were larger than the observed declines in licensed SNF bed counts, potentially because of staffing shortages. Greater loss of SNF capacity was associated with longer hospital stays and increased travel distances to SNFs, suggesting that declines in operating capacity may be impairing access to care.
IMPORTANCE: Increasing germline genetic testing rates may impact contralateral prophylactic mastectomy (CPM) rates in patients with newly diagnosed breast cancer.
OBJECTIVE: To quantify the impact of a personalized contralateral breast cancer (CBC) risk counseling tool that incorporates genetic testing results.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial recruited participants from a single tertiary referral center between June 8, 2020, and December 31, 2022. Patients aged 18 to 80 years with unilateral breast cancer who underwent genetic counseling and surgery were eligible. Exclusion criteria were prior or metastatic breast cancer or prior multigene panel testing. Follow-up was completed June 30, 2023.
INTERVENTION: Personalized age-specific CBC risks were estimated based on the presence or absence of pathogenic variants associated with breast cancer and were incorporated into a visual decision support tool. Patients were randomized 1:1 to quantitative counseling via the tool vs standard counseling without personalized CBC risk estimates.
MAIN OUTCOMES AND MEASURES: Co-primary end points included patients' personal CBC risk knowledge and propensity to undergo CPM, before and after counseling, by randomization arm. The secondary end point was CPM rate. Sample size calculations assumed postcounseling CBC risk self-assessments would be 5% different from baseline (SD, 20%). A total of 199 patients in each arm would achieve 80% power and 5% type I error (based on a 2-sample t test). Univariate and multivariate analyses were performed for each end point.
RESULTS: A total of 400 patients were randomized (mean [SD] age, 54 [11] years), and 54 were excluded after randomization, leaving 346 patients. Among 341 patients with data available, 21 (6.2%) were Asian or Pacific Islander, 18 (5.3%) were Black, 295 (86.5%) were White, and 7 (2.1%) were of other race; 33 of 330 patients with available data (10.0%) were of Ashkenazi Jewish ancestry. Seventy-five of 346 patients (21.7%) had a first-degree relative with breast cancer. Patients who received quantitative counseling more accurately reported their CBC risk estimates than those who received standard counseling by univariate (coefficient, -9.39; 95% CI, -14.86 to -3.93; P < .001) and multivariate (coefficient, -9.52; 95% CI, -16.50 to -2.51; P = .008) analyses. The type of counseling did not significantly impact perception of risk, self-reported propensity to undergo CPM, or CPM rates.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, patients more accurately described their calculated CBC risk after quantitative counseling. This improved knowledge did not impact decisions to undergo CPM. The CBC risk assessment tool is publicly available and can be used for preoperative discussions.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04245176.