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.

Introduction: Ureteral stones are a common cause of emergency presentations. Definitive stone removal at the index encounter can reduce delays and repeat interventions. It is unknown whether fellowship-trained endourologists are more likely to perform definitive management than general/other subspecialist urologists. This multicenter retrospective cohort study evaluated the influence of endourology subspecialty training on the choice between upfront definitive stone treatment and initial ureteral decompression at first presentation. Patients managed with medical expulsive therapy alone were not included. Methods: Adults (≥18 years) presenting at 2022 to seven North American academic centers with symptomatic, noninfected, computed tomography-confirmed ureteral stones were included. Patients with infection, sepsis, positive nitrites, or intraoperative pyelonephritis were excluded from the study. Variables included demographics, stone size and location, subspecialty of the on-call urologist, and management type (definitive [ureteroscopy or shockwave lithotripsy] vs deferred [(initial stent]). Multivariate logistic regression was used to identify the predictors of definitive treatment. Results: Among the 395 patients, 190 (48.0%) underwent definitive management and 205 (52.0%) underwent deferred treatment. Distal stones were treated definitively more often than proximal stones were (51.1% vs 36.6%). An endourologist was on call for 150 encounters (38.0%); 64.7% of these patients received definitive treatment, compared with 38.0% under general/other subspecialist urologists. On multivariate analysis, endourologist on-call remained independently associated with definitive management (odds ratio [OR] 3.46, 95% confidence interval [CI] 2.19–5.47, p < 0.0001), as did distal stone location (OR: 2.46, 95% CI: 1.21–5.00, p = 0.013). Severe complications are rare, and none of the patients developed sepsis. Conclusions: Endourologists were more than three times more likely to perform definitive interventions for symptomatic, noninfected ureteral stones at initial presentation. Subspecialty expertise and timely operative access enable safe, efficient, single-stage management.

Background Parkinson's disease (PD) typically presents after age 60; however, approximately 10% of individuals experience early-onset PD (EOPD), with symptoms beginning between ages 21 and 50. Beyond motor and non-motor symptoms, PD can impact personal relationships through stigma, social isolation, and emotional burden. This study aims to examine the influence of PD on relationship outcomes such as divorce or separation. Methods This exploratory study analyzed data from the Fox Insight cohort, an online longitudinal research initiative supported by The Michael J. Fox Foundation. We included 470 individuals with self-reported PD who had complete data on marital status (“married” or “divorced”) and age at PD onset. Participants were categorized as having EOPD (<50 years) or late-onset PD (≥50 years). Chi-square tests assessed the association between PD onset group and marital status. A binary logistic regression model further evaluated gender and onset age as predictors of marital status in a subset of 330 participants. Results A significant association was found between PD onset group and marital status, with a higher divorce rate among the EOPD group (17.5%; 7/40) compared to late-onset PD (6.1%; 26/430) (p = 0.017). Logistic regression revealed no statistically significant predictors, though trends suggested lower odds of divorce in men and those with late-onset PD. Conclusion This exploratory analysis identified a potential association between early PD onset and higher divorce rates; however, with only 7 events in 40 EOPD participants, this finding is inherently unstable and should be regarded as hypothesis-generating only. Confirmation in larger, longitudinal cohorts is required before any conclusions can be drawn.

Abstract Senescent cell accumulation and fibrosis play a fundamental role in kidney ageing. Our aim was to determine whether the angiotensin IV/insulin-regulated aminopeptidase (IRAP) axis of the renin-angiotensin system contributes to renal function decline, fibrosis, and senescent cell accumulation in aged mice. We studied the role of IRAP in kidney ageing using IRAP knockout (KO) mice, as well as in wild-type (WT) mice treated with an IRAP inhibitor. Complementary proximal tubule and collecting duct cell models were used to determine the mechanisms by which IRAP inhibition exerts protective effects. Glomerular filtration rate (GFR) declined by 25% in WT mice between 3 and 23 months of age, concomitant with marked increases in albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis, and accumulation of senescent cells in the proximal tubules of the kidney. IRAP KO mice were protected against age-related decline in GFR, renal fibrosis, and senescence burden compared with age-matched WT mice. IRAP inhibition for 4 weeks (HFI-419, 500 ng/kg/min) in 28-month-old WT mice similarly prevented age-related decline in GFR and attenuated expression of cellular senescence markers. Using an in vitro model of cultured proximal tubule cells, IRAP inhibition mitigated the pro-senescent effects of oxidative stress. This was associated with shifts in the metabolic phenotype of proximal tubular cells, indicating the senoprotective effects of IRAP inhibition may be mediated in part via mitochondrial function. These studies provide evidence that IRAP deficiency is protective against chronic renal cellular senescence, fibrosis, and functional decline. Therefore, IRAP inhibition has therapeutic potential to attenuate pathological cardiorenal ageing through senoprotective mechanisms.

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Abstract Objective To assess the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) stratified by age, number of previously attempted antiseizure medications (ASMs), and SCN1A pathogenic variant status. Methods In this post hoc analysis, data from three randomized controlled trials (RCTs) in patients with DS (2–18 years) were pooled and stratified by age (<4; ≥4 years), number of previous ASMs (1–3; 4–6; ≥7), and SCN1A pathogenic variant status ( SCN1A +; SCN1A −). Stratified groups were assessed and compared with the pooled placebo group (change in monthly convulsive seizure frequency [MCSF], longest convulsive seizure‐free interval, and Clinical Global Impression–Improvement [CGI–I] scale scores rated by parents/caregivers and investigators), and safety (treatment‐emergent adverse events [TEAEs]: frequency, days to onset, and proportion resolved). Results Among 348 patients included in the RCTs, 216 were randomized to fenfluramine (0.7 mg/kg/day, n = 88; 0.4 mg/kg/day [with stiripentol], n = 43; 0.2 mg/kg/day, n = 85) and 132 to placebo. Compared with placebo, fenfluramine treatment (all doses combined) resulted in greater MCSF reductions, greater increases in longest convulsive seizure‐free intervals, and a higher proportion of parents/caregivers and investigators reporting clinically meaningful improvement (“Much Improved”, “Very Much Improved”) on CGI–I scores across all stratified groups. CGI–I scores were consistent across fenfluramine doses in most stratified groups, but patients with the fewest number of previous ASMs had the greatest frequency of clinically meaningful improvement on investigator‐rated CGI–I scores. Safety outcomes were similar across all strata. Most TEAEs resolved by end‐of‐study. Significance Fenfluramine treatment was associated with improved seizure outcomes and global functioning compared with placebo regardless of age, number of previous ASMs, and SCN1A status in patients with DS. Fenfluramine was well‐tolerated; no new safety signals were identified. Further studies with larger sample sizes (including adults) and a priori inferential analyses of stratified groups are warranted. Plain Language Summary Patients with Dravet syndrome struggle with seizures and everyday life. In three studies, patients aged 2–18 years received fenfluramine or placebo (sugar pill). Fenfluramine lowered seizures without many side effects. Researchers combined results from these studies to see how fenfluramine worked in different patient groups based on age, number of previous medications, and a gene called SCN1A . They looked at seizure reduction and whether doctors felt patients had improved. In all groups, fenfluramine worked better than placebo, with similar side effects. Researchers believe fenfluramine helped these patients, but some groups were small, so these results need to be confirmed.

Chimeric antigen receptor (CAR) T-cell therapy is a transformative modality for refractory hematologic malignancies; however, its adoption in Latin America and the Caribbean (LAC) is severely constrained by prohibitive manufacturing costs, limited specialized infrastructure, and fragmented regulatory frameworks. To address this translational gap, we propose a pragmatic, cost-adapted model for establishing Good Manufacturing Practice (GMP) laboratories tailored to the socioeconomic realities of LAC. This model advocates for decentralized, modular cleanroom facilities that integrate fully closed automated manufacturing platforms with risk-based quality management systems. Furthermore, we emphasize the strategic implementation of artificial intelligence (AI) and digital health tools—such as electronic batch records and predictive analytics—to optimize resource utilization and ensure stringent regulatory compliance. Essential to this framework is the cultivation of a specialized local workforce and the promotion of regional regulatory harmonization through initiatives like PAHO’s Red PARF. Ultimately, this scalable approach provides a realistic roadmap to democratize CAR T-cell therapy in LAC, fostering regional biomanufacturing autonomy and promoting equitable patient access.

Abstract Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.

Abstract Objective Resective surgery achieves seizure freedom in approximately 60%–80% of patients with drug‐resistant temporal lobe epilepsy (TLE), yet the extent to which seizure cessation permits recovery of disrupted functional brain networks remains unclear. Increasing evidence suggests that recurrent seizures alter subcortical–cortical communication involved in arousal and cognition, contributing to chronic interictal deficits, such as in executive function. Prior work demonstrates that the nucleus basalis of Meynert (NBM), the primary source of cortical cholinergic input to the cortex, exhibits aberrant functional connectivity in patients with TLE. We examined NBM connectivity in patients with TLE before and after surgery using patient‐specific NBM segmentations. We sought to investigate whether seizure freedom is associated with recovery of NBM functional connectivity, consistent with previous observations of interictal network dysfunction reversal in other subcortical arousal structures. Methods Resting‐state functional magnetic resonance imaging was analyzed in 75 patients with TLE, including 34 patients postoperatively, and 106 controls. Patient‐specific NBM segmentations were used to compute functional connectivity between the NBM and frontoparietal association cortex (FPAC) and across the whole brain. Subcortical arousal network community structure was assessed using community detection. Postoperative network changes were evaluated relative to seizure outcome. Results Prior to surgery, patients exhibited reduced bilateral NBM connectivity to the FPAC and whole brain compared to controls, indicating widespread cholinergic network disruption beyond the ipsilateral hemisphere. Following surgery, NBM connectivity increased and no longer differed from controls. Seizure‐free patients demonstrated greater postoperative increases in ipsilateral NBM‐FPAC connectivity than non‐seizure‐free patients, which was not explained by time to postoperative scan or volumetric change. Subcortical arousal community structure remained altered postoperatively. Significance Successful TLE surgery is associated with partial restoration of cholinergic arousal network connectivity, supporting the idea that seizure cessation enables recovery of brain networks disrupted by recurrent seizures. These findings position the NBM as a potential biomarker of network recovery following epilepsy surgery.