Citations

ABSTRACT Background and Aims Autoimmune hepatitis is an immune‐mediated liver disease characterized by chronic inflammation and progressive fibrosis. Tissue‐resident memory T cells mediate organ‐specific immunity, but their role in autoimmune hepatitis remains poorly understood. We characterized tissue‐residency‐associated T‐cell populations and their cytokine profiles, assessed associations with disease severity and determined whether these signatures were reflected in peripheral blood. Methods Paired blood and liver samples were obtained from 19 patients with autoimmune hepatitis. Comparator cohorts included 20 patients with metabolic dysfunction‐associated steatotic liver disease and 20 surgical patients providing non‐inflamed adjacent non‐tumorous liver tissue. Multiparameter flow cytometry assessed tissue‐residency markers, T‐cell differentiation and cytokine production after polyclonal stimulation. Immune phenotypes were correlated with histological and clinical parameters. Results Autoimmune hepatitis was associated with compartment‐specific remodelling of T‐cell differentiation states and intrahepatic enrichment of CD8 + T cells expressing CD69, CD103 and CXCR6 relative to paired blood and comparator liver tissues. Intrahepatic CD8 + T cells exhibited an interferon‐γ‐dominant cytokine profile, whereas CD4 + T cells showed broader interferon‐γ‐, interleukin‐17A‐ and interleukin‐4‐associated responses. Despite the enrichment of tissue‐residency‐associated CD8 + T cells, cytokine‐producing CD8 + T‐cell populations with and without a tissue‐resident memory phenotype contributed comparably to the hepatic T‐cell compartment. Tissue‐residency‐associated phenotypes correlated positively with Ishak fibrosis stage, whereas the frequency of interferon‐γ‐positive intrahepatic CD8 + T cells correlated inversely with fibrosis. Conclusions Autoimmune hepatitis was characterized by intrahepatic accumulation of phenotypically distinct and functionally active CD8 + tissue‐resident memory T cells associated with fibrosis. This immune profile was not reflected in paired blood, indicating compartmentalized hepatic immune remodelling.

Cholera toxin (CTx) is a potent enterotoxin and widely used mucosal adjuvant, yet the acute host response to CTx itself, in the absence of a co-administered antigen, remains vague. In this study, we integrated physiological and metabolic phenotyping with intestinal transcriptomics, epithelial imaging, immune profiling, hepatic gene-expression analysis, and paired microbiome profiling to characterize the response to a single oral CTx exposure in mice. Within 24 h, CTx remodeled immune-cell composition in both epithelial and lamina propria compartments, with responses shaped by sex and genetic background. Recurrent changes included increased epithelial group 3 innate lymphoid cells, reduced lamina propria RORγt+ regulatory T cells, and decreased epithelial ILC1/NK cells in males of both strains. CTx also increased villus DCLK1+ tuft cells and reduced MUC2 immunoreactivity. Jejunal transcriptomics revealed induction of inflammatory defense, glycolytic, autophagy, and lipid-utilization programs together with suppression of proliferative and mitochondrial programs, consistent with coordinated stress adaptation. These local changes were accompanied by rapid restructuring of the fecal microbial community and by systemic hypometabolism, despite markedly different hypothermic responses across strains. CTx also elicited a selective hepatic stress and metabolic program, including conserved suppression of Cyp7a1 across sexes and strains. Together, these findings show that CTx alone rapidly reorganizes the intestinal immune, epithelial, metabolic, and microbial environment while suppressing whole-body metabolism. This work provides an integrated framework for understanding the acute host response to CTx and for interpreting its widespread use as a mucosal adjuvant.

Nontuberculous mycobacterial (NTM) infections are a scourge that affect growing patient populations due to the rise of risk factors associated with these opportunistic pathogens. Cure rates are unacceptably low despite intensive multidrug and multi-year therapy. The issue of poor drug exposure relative to inferior potency of repurposed antibiotics against NTM pathogens is broadly recognized as a major factor underlying dismal success rates. Yet, a quantitative and systematic evaluation of probabilities of pharmacokinetic-pharmacodynamic (PK-PD) target attainment (PTA) is lacking. Here, we leveraged published population PK models and minimum inhibitory concentration distributions across large patient populations to generate PTAs for standard of care antibiotics used in the treatment of NTM infections. PTAs of tuberculosis drugs were included in our analysis as a baseline since tuberculosis cure rates are excellent compared to NTM diseases. We found that PK-PD target attainment for NTM was low overall and that PTAs were generally consistent with reported clinical outcomes. Specifically, drugs for which genetic resistance is associated with worse outcome showed favorable PTAs, consistent with their contribution to cure. These include macrolides for M. abscessus and the M. avium complex (MAC), and rifampicin for M. kansasii. Bedaquiline emerged as a promising option against M. abscessus and MAC, and clofazimine against the latter, consistent with recent clinical reports. Omadacycline PTAs predict improved efficacy compared to tigecycline for patients with M. abscessus and suggest clinical utility for MAC. As is common practice for antibacterials, PTA considerations could inform NTM treatment guidelines and help select drug combinations in future trials.

ABSTRACT Background Cytomegalovirus (CMV) infection is among the most common infections after solid organ transplantation and leads to high rates of morbidity and mortality. With the proliferation of large, claims‐based datasets, there is a need to assess the validity of ICD‐10‐CM codes in identifying CMV infection. Methods We conducted a retrospective cohort study of solid organ transplant recipients (SOTRs) from a regional health system who underwent first transplantation between January 1, 2016, and June 30, 2025, had at least 30 days of post‐transplant follow‐up, and had known donor/recipient CMV serostatus. We performed cross‐sectional and time‐to‐event analyses comparing the test performance of B25 ICD‐10‐CM codes in identifying CMV infection, clinically significant CMV infection (csCMVi), CMV disease, and CMV DNA reaching various thresholds. Results Of 8169 SOTRs, 3084 (37.8%) had B25 coded during follow‐up. In addition, 4287 (52.5%) developed CMV infection, 2356 (28.8%) csCMVi, 297 (3.6%) CMV disease, and 1669 (20.4%) CMV DNA ≥ 1000 IU/mL. B25 codes were most specific to any CMV infection (88.5%), most sensitive to CMV DNA ≥ 100 000 IU/mL (98.2%), and csCMVi had the highest Youden's Index (0.651; sensitivity 84.1%, specificity 81.0%). Multivariable Cox regression provided similar results but with variations in effect measure between ICD‐10‐CM codes and clinical CMV definitions. Conclusions ICD‐10‐CM codes showed modest performance in identifying CMV infection, most closely resembling csCMVi. ICD‐10‐CM codes poorly reflect CMV severity, however, and may overestimate CMV infection by some clinical definitions. These limitations should be considered when using CMV diagnosis codes for claims‐based studies of SOTRs.

Background/Objectives: A 12-week trial demonstrated that phenotype-tailored lifestyle intervention (PLI) was associated with greater weight loss than standard lifestyle intervention (SLI); however, differences in dietary patterns between groups were not examined. Methods: This secondary analysis evaluated caloric and macronutrient intake at 12 weeks in adults with obesity (BMI ≥ 30 kg/m2), classified into four energy-balance phenotypes (abnormal satiation, reduced postprandial satiety, low energy expenditure, emotional eating) (n = 77) who underwent PLI or SLI. Dietary intake was assessed by 24-h recalls and verified by a blinded registered dietitian. Results: Groups were compared at 12 weeks adjusting for baseline values. PLI was associated with lower total energy intake than SLI (1273 ± 182 vs. 1894 ± 176 kcal/day; p = 0.018), due to lower carbohydrate (464 ± 76 vs. 818 ± 73 kcal/day; p = 0.002) and fat intake (479 ± 76 vs. 697 ± 73 kcal/day; p = 0.036); absolute protein intake did not differ. However, protein comprised a greater proportion of energy intake in PLI (26.8 ± 1.6%) than SLI (19.8 ± 1.5%; p = 0.003), and dairy protein contributed more to total energy in PLI (6.8 ± 0.8% vs. 3.7 ± 0.7%; p = 0.004). Conclusions: PLI was associated with lower energy intake, mainly due to reduced carbohydrate and fat intake, and a higher relative contribution of protein, consistent with phenotype-based recommendations rather than macronutrient prescriptions. These findings suggest a potential role for personalized dietary approaches in obesity management. However, the non-randomized design does not allow causal inferences.

Background Cardiac rehabilitation (CR) improves peak oxygen uptake (VO 2 peak) and body composition in patients with cardiovascular disease. However, improvement in VO 2 peak is not observed in all patients following a CR program, and whether VO 2 peak non-responders also demonstrate limited changes in body composition remains unclear. This study aimed to examine the association between changes in VO 2 peak and body composition in patients undergoing a CR program. Methods Retrospective analysis of patients who completed CR between 2015 and 2022 at Mayo Clinic. The study included 143 patients who completed cardiopulmonary exercise testing and dual-energy X-ray absorptiometry pre- and post-CR. Patients were grouped by the change in relative VO 2 peak response to CR (responders= Δ>0 vs non-responders=Δ ≤0 mL/kg/min). Two-way repeated ANOVA was used to compare groups, and regression models were used to examine the associations between baseline body composition and changes in body composition with VO 2 peak change. Results Among the cohort, 26% were classified as non-responders based on relative VO 2 peak measurements. Both groups exhibited a significant improvement in most body composition variables including body fat mass, body fat percentage, body lean percentage, and fat mass index (all p<0.001), with no differences in the percentage of change in body composition variables between groups (p>0.05). Regression models demonstrated that neither baseline body composition nor changes in body composition were significantly associated with changes in VO 2 peak. Conclusion Our data suggest that baseline and change in body composition were not significantly associated with changes in VO 2 peak in patients undergoing the CR program.

Abstract Objective Low back pain (LBP) is a leading cause of pain and disability worldwide. Recent studies demonstrate a vertebrogenic model involving the basivertebral nerve (BVN) as a cause of chronic LBP. Vertebral endplates are highly innervated by the BVN, and literature shows type 1 and 2 Modic changes at vertebral endplates are a source of vertebrogenic low back pain (VBP). As a result, intraosseous radiofrequency ablation of the BVN is a minimally invasive outpatient procedure used to treat VBP. We conducted a retrospective review of 1,145 patients that have undergone BVN ablation to assess for safety and complication management. Methods Chart reviews were conducted to obtain demographic and pre-procedural information regarding patient gender, age at the time of BVN ablation, duration of LBP, and BMI. Post-procedure information derived from chart notes included vertebral levels ablated and post-BVN ablation complications, which were categorized as increased LBP > 7 days, increased radicular pain > 7 days, lower extremity weakness, infection, vertebral compression fracture, superficial bleeding, spinal or epidural hematoma, serious neurological injury, visit to the ER, and deep vein thrombosis/clot. Results 1,145 patient charts were reviewed showing an overall complication rate of 3.2% (37 complications). Increased radicular pain was the most common complication at 2.2% (25 complications) and resolved completely in all but one patient. The overall complication rate fell to 1.1% (13 complications) when the 24 cases of transient radicular pain were not counted as adverse events. Conclusions In this multicenter retrospective review, the overall rate of complications related to BVN ablation was low (3.2%). The most common complication was temporary radicular pain that resolved with conservative care. These findings suggest that BVN ablation is a safe treatment for VBP in real-world clinical settings.