Aims/hypothesisImmunotherapies such as Teplizumab can preserve residual beta cell function in individuals with newly diagnosed type 1 diabetes (T1D), but treatment response is variable. Currently, no biomarker exists to identify individuals most likely to benefit from immunotherapy. We believe that baseline serum metabolomic profiles can distinguish individuals who respond to treatment from nonresponders and predict therapeutic response.MethodsBaseline serum samples from 41 individuals newly diagnosed with T1D enrolled in the AbATE trial (NCT00129259) were analyzed to identify metabolic predictors of response to Teplizumab therapy in the AbATE trial. Responders to Teplizumab, as per study protocol, were defined as individuals who exhibited less than a 40% decline in baseline C-peptide levels at 2 years after start of treatment. We analyzed baseline serum samples using a semi-targeted metabolomics approach via liquid chromatography–high-resolution tandem mass spectrometry. Metabolites that were significantly different between responders and nonresponders were identified (P < 0.05), and the significant metabolites were used to train a supervised Random Forest model to predict treatment response. Model performance was evaluated using a 70/30 training/testing split, 5-fold cross-validation, bootstrap resampling (1,000 iterations), and permutation testing (1,000 permutations).ResultsWe identified 15 significantly different metabolites at baseline between responders and nonresponders (P < 0.05). These metabolites included amino acids and their derivatives, tricarboxylic acid (TCA) cycle intermediates, and microbially derived metabolites. At baseline, responders exhibited higher levels of TCA cycle metabolites, amino acid derivatives, and microbial metabolites, whereas nonresponders showed elevated levels of glutamate and acylcarnitines. The Random Forest classifier achieved an accuracy of 0.769 and an area under the receiver operating characteristic curve (AUC) of 0.881 in the test dataset. Cross-validation yielded a mean AUC of 0.856 (SD 0.156; 95% CI 0.719–0.992). Bootstrap analysis produced a test AUC 95% CI of 0.619–1.000, and permutation testing confirmed significance (p = 0.012).Conclusions/interpretationBaseline serum metabolomic signatures can predict responders to Teplizumab with high accuracy. This could potentially be applicable when considering other immunotherapies in preventative efforts in T1D.Trial registrationClinicalTrials.govNCT00129259.Research in ContextWhat is already known about this subject?Teplizumab can delay beta cell decline in individuals with newly diagnosed T1D, but treatment response varies.No validated biomarkers currently exist to predict which individuals will respond to immunotherapy.Metabolomic profiling has shown potential for identifying metabolic signatures associated with disease progression and immune activity in T1D.What is the key question?Can baseline serum metabolomic profiles predict which individuals with newly diagnosed T1D will respond to Teplizumab therapy?What are the new findings?Fifteen baseline metabolites differed significantly between responders and nonresponders, including amino acid derivatives, tricarboxylic acid cycle intermediates, and microbially derived metabolites.Responders exhibited metabolic signatures consistent with preserved beta cell function and enhanced mitochondrial and immune-regulatory activity.A Random Forest model developed using these metabolites accurately predicted treatment response (AUC 0.881), demonstrating strong predictive potential.How might this impact on clinical practice in the foreseeable future?Baseline metabolomic profiling could support personalized treatment strategies by identifying individuals most likely to benefit from treatment with Teplizumab or other immunotherapies.

Methamphetamine is a potent sympathomimetic agent primarily associated with cardiovascular and neuropsychiatric effects. However, its gastrointestinal complications, particularly ischemic bowel disease, are under-recognized in emergency medicine literature.A 34-year-old man with a history of chronic methamphetamine use presented to the emergency department (ED) seeking medical clearance for rehabilitation admission. He also reported mild, diffuse abdominal pain persisting for three days. Vital signs revealed tachycardia and hypotension. Physical examination showed mild subjective diffuse abdominal tenderness without peritoneal signs. Laboratory studies indicated leukocytosis, elevated lactate, and acute kidney injury. Non-contrast abdominal and pelvic computed tomography (CT) demonstrated pneumoperitoneum and extensive mesenteric stranding consistent with ischemia. The patient was managed with intravenous fluids, broad-spectrum antibiotics, and emergent surgical consultation. Exploratory laparotomy revealed hemoperitoneum, a large abscess cavity, necrosis of the cecum, and mesenteric ischemia. A resection of the cecum and terminal ileum was performed. Postoperatively, the patient required intensive care management for septic shock and renal failure but eventually recovered and was discharged after 15 days.This case underscores the importance of considering chronic methamphetamine use as a potential etiology for gastrointestinal ischemia and sepsis, even in patients presenting with subtle abdominal complaints. Early recognition and intervention are crucial for improving outcomes in this high-risk population.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by uncontrolled macrophage and T-cell activation leading to multiorgan failure. While primary HLH has a genetic basis, secondary HLH can arise from various triggers. Macrophage activation syndrome (MAS) is a subtype of HLH associated with autoimmune disorders, whereas malignancy-associated HLH (mHLH) is typically linked to cancers, particularly T-cell lymphomas. HLH is frequently underrecognized and may initially be mistaken for MAS due to overlapping clinical and laboratory findings, especially in the context of an occult malignancy. We present a 58-year-old male who presented with fever, cytopenias, and transaminitis and met six of the HLH-2004 diagnostic criteria. MAS was the initial working diagnosis; however, a bone marrow biopsy demonstrated hemophagocytosis and T-cell lymphoma, confirming mHLH. Despite targeted treatment, the patient experienced progressive multiorgan failure and was transitioned to hospice care. This case highlights the diagnostic complexity of HLH and the importance of distinguishing mHLH from MAS. Because therapeutic strategies differ based on the predominant trigger, autoimmune versus malignant, early recognition and accurate classification are essential to optimize outcomes and avoid delays in appropriate therapy.

Background/Objectives: Hepatocellular carcinoma (HCC) therapies are limited by poor response, rapid resistance, and recurrence of aggressive disease. Sorafenib, a multi-tyrosine kinase inhibitor, can trigger β-catenin stabilization and activation, contributing to resistance. Overexpression of the chemokine receptor CXCR6 and its ligand CXCL16 and hyperactivation are implicated in HCC progression and β-catenin stabilization. We hypothesized that SBI-457, a small-molecule CXCR6 antagonist we developed, could disrupt CXCR6/β-catenin crosstalk and enhance sorafenib sensitivity. Methods: We tested SBI-457 alone and in combination with sorafenib in SK-Hep-1 xenograft models and a panel of human HCC cell lines. Tumor burden, β-catenin activation, and CXCR6 expression were assessed by tumor volume measurements, immunohistochemistry, Western blotting, and immunofluorescence. Soluble CXCL16 levels were quantified by ELISA, and cell death responses were evaluated using MTT assays. Results: In vivo, SBI-457 combined with sorafenib reduced normalized tumor volume by 55% compared to vehicle controls, modestly exceeding monotherapy effects, and attenuated sorafenib-induced β-catenin upregulation. In vitro, SBI-457 blocked nuclear accumulation of β-catenin and reversed sorafenib-induced increases in β-catenin levels. Enhanced cell death was observed in specific "responder" HCC cell lines (Hep-3B, SNU-398, JHH-5), which correlated with high intracellular β-catenin, secretion of soluble CXCL16, and expression of a high molecular weight form of CXCR6. In contrast, "non-responder" cell lines with conventional CXCR6 expression and low CXCL16 secretion showed no enhanced cell death response. Conclusions: CXCR6 antagonism with SBI-457 can modulate β-catenin activation and may help overcome sorafenib resistance in selected HCC models. These findings support further development of CXCR6 antagonists as single agents or combination therapies to improve treatment outcomes in HCC.

BackgroundTo evaluate the association between Glucagon-like peptide-1 receptor agonists (GLP-1RA) use and the risk of acute diabetes complications among adults with type 1 diabetes (T1D) who were eligible for anti-obesity medication (AOM) treatment.MethodsWe employed a target trial emulation using EHR data from the OneFlorida+ network (2014–2024) to investigate the association between GLP-1RA initiation and acute diabetes complications among adults with T1D. Eligible participants were adults with a diagnosis of T1D and who met clinical criteria for AOM treatment. GLP-1RA initiators were 1:1 matched to non-initiators using time-conditional propensity scores. The primary outcome was the occurrence of diabetic ketoacidosis (DKA). Secondary outcomes included severe hypoglycemia, all-cause hospitalizations, and emergency department (ED) visits. Cox proportional hazards models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We applied a causal learning approach to explore heterogeneous treatment effects.FindingsThe matched cohort included 651 GLP-1RA users and 651 non-users. For GLP-1RA users and non-users, the incidence rates were 13.5 vs. 21.8 per 1,000 person-years for DKA. Compared to non-users, GLP-1RA use was not significantly associated with incidence of DKA (HR 0.62 [95%CI 0.33–1.17]) or severe hypoglycemia (HR 0.52 [95%CI 0.17–1.55]); notably, GLP-1RA use was significantly associated with fewer hospitalizations (HR 0.74 [95%CI 0.62–0.90]) and ED visits (HR 0.73 [95%CI 0.57–0.92]).InterpretationAmong adults with T1D and obesity, GLP-1RA use was not associated with an increased risk of DKA or severe hypoglycemia but was linked to fewer ED visits and hospitalizations.FundingThe study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) R01DK133465.