Citations

Background & Aims: We examined treatment patterns and clinical outcomes in a contemporary cohort of children with newly diagnosed inflammatory bowel disease (IBD) in a large, commercially insured U.S. population. Methods: Using the OptumLabs® Data Warehouse, we created an inception cohort of physician-diagnosed IBD in children aged 6–17 years between 2007–23. We examined cumulative incidence of hospitalization, surgery, safety events, and medication use in patients with Crohn's disease (CD) and ulcerative colitis (UC), overall and stratified by diagnostic era, race and ethnicity, sex, and age at diagnosis. Results: Among 787 children with newly diagnosed CD (age at diagnosis, 13.4±2.9y; 57% male; 82% White, 5% Black, 7% Hispanic) followed over mean 4.6±3.0y, 5-year risk of IBD-related hospitalization and major surgery was 30% and 10%, respectively. In children diagnosed in 2019–23, 1-year cumulative use of corticosteroids and advanced therapy was 46% and 75%, respectively; advanced therapy use increased significantly over time (aHR, 3.43 [95% CI, 2.71–4.32] for 2019–23 vs. 2007–12), while corticosteroid use declined (0.67 [0.53–0.84]). Risk of IBD-related hospitalization was lower in children diagnosed between 2019–23 (0.65 [0.43–0.97]) compared with those diagnosed between 2007-12; surgical risk did not decline significantly, with confidence intervals compatible with a clinically meaningful reduction. Among 399 children with newly diagnosed UC (age at diagnosis, 14.0±3.0y; 53% male; 78% White, 5% Black, 7% Hispanic) followed over 4.5±3.0y, 5-year risk of IBD-related hospitalization and colectomy was 36% and 8%, respectively. Advanced therapy use increased significantly over time (4.46 [2.85–6.98] for 2019–23 vs. 2007–12), with no significant change in hospitalization or surgical risk across eras. No consistent racial and ethnic, age, or sex differences in advanced therapy use or clinical outcomes were identified in either CD or UC. Conclusions: In a contemporary cohort of commercially insured children with newly diagnosed IBD, early advanced therapy use has increased markedly over time. Surgical risk did not decline significantly in either disease; however, the study was not powered to exclude a clinically meaningful reduction, and these findings are hypothesis-generating rather than conclusive.

Abstract Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.

Abstract Introduction Quantitative interpretation of pediatric brain [ 18 F]-FDG PET is limited by the lack of age-matched normative reference databases, despite substantial developmental variation in cerebral glucose metabolism. This study aimed to construct a large-scale normative pediatric [ 18 F]-FDG PET database and develop an age-specific z-score mapping framework for quantitative evaluation of pediatric epilepsy. Method Pediatric brain PET data were retrospectively derived from clinically acquired whole-body or dedicated [ 18 F]-FDG PET examinations in participants 0–19 years of age without neurologic disease or visible brain abnormalities. A total of 417 PET scans from 341 participants were stratified into five developmental age groups: infancy, early childhood, middle childhood/school age, adolescence, and late adolescence. SUVR maps were generated using whole-brain atlas and brainstem reference regions. Voxel-wise t-test analyses were performed to characterize age- and sex-related metabolic differences. Age-specific voxel-wise mean and standard deviation maps were generated from the normative cohort and used to calculate age-matched hypometabolic z-score maps in 14 pediatric patients with epilepsy. The resulting abnormalities were qualitatively evaluated for concordance with epileptogenic findings identified on clinical MRI and/or PET by expert image review. Results Voxel-wise analyses demonstrated prominent age-dependent SUVR differences, particularly between infancy and older age groups. With whole-brain atlas normalization, older children showed progressively higher relative SUVR in cortical and cerebellar gray matter regions, whereas infancy showed relatively higher SUVR in the occipital cortex, white matter, thalamus, and brainstem. Brainstem normalization produced distinct developmental patterns, emphasizing higher white matter SUVR in infancy and broader gray matter differences in older groups. Sex-related differences were limited and regionally specific. Whole-brain atlas normalization showed lower variability than brainstem normalization and was selected for z-score mapping. In representative epilepsy cases, age-matched z-score maps identified focal or regional hypometabolism corresponding to malformations of cortical development, focal cortical dysplasia, mesial temporal sclerosis, nonlesional MRI cases, remote insult, tumor-related abnormalities, and Sturge-Weber syndrome. Discussion A large-scale normative pediatric [18F]-FDG PET database can support developmentally appropriate quantitative interpretation of pediatric brain PET. Age-matched z-score mapping may complement visual assessment by highlighting abnormal cerebral glucose metabolism in pediatric epilepsy, although findings should be interpreted with MRI, EEG, seizure semiology, and other presurgical data.

Background: Normothermic machine perfusion (NMP) may reduce preservation injury in donation-after-circulatory-death (DCD) liver transplantation, but its association with patient-centered recovery and longer-term graft survival remains uncertain. Study Design: We retrospectively analyzed 306 consecutive adult DCD liver transplant recipients at a single center from January 2019 through December 2022, comparing NMP (n=95) with static cold storage (SCS; n=211). The primary endpoint was days alive and out of hospital at 365 days (DAOH365). Quasi-Poisson regression evaluated factors associated with DAOH365, and Cox regression evaluated graft survival. Propensity-matched and calendar-year sensitivity analyses assessed measured confounding. Results: Median DAOH365 was 357.0 (352.0, 360.0) days with NMP versus 353.0 (336.0, 359.0) with SCS (p<0.001), but preservation strategy was not independently associated with DAOH365 (adjusted rate ratio 1.02; p=0.331). NMP recipients had less early allograft dysfunction (35.8% vs 59.7%; p<0.001), ischemic cholangiopathy (4.2% vs 23.7%; p<0.001), and retransplantation within 2 years (0.0% vs 6.6%; p=0.007). Two-year patient survival did not differ significantly. NMP was associated with improved twoF-year graft survival (HR 2.9, 95% CI 1.23–6.87; p=0.015), an association maintained in propensity-matched and calendar-year sensitivity analyses. Adjusted total 1-year costs did not differ (p=0.512). Conclusions: In this single-center DCD cohort, NMP was associated with superior 2-year graft survival but not independently with DAOH365. These hypothesis-generating findings support multicenter prospective evaluation of NMP using both graft survival and patient-centered recovery endpoints.

Purpose: The purpose of this study is to characterize the clinical features, management strategies, and outcomes of endophthalmitis cases following pars plana vitrectomy using data from the American Academy of Ophthalmology (Academy) IRIS ® Registry (Intelligent Research in Sight). Methods: This is a retrospective cohort study of eyes that developed endophthalmitis following pars plana vitrectomy between 2013 and 2022. Data was collected from the Academy IRIS Registry. This study analyzed differences in visual acuity, intraocular pressure, rates of evisceration and enucleation, and rates of rhegmatogenous retinal detachment following endophthalmitis diagnosis. Results: A total of 1,223,777 unique eyes underwent a PPV during the study period, with 1,275 eyes meeting the inclusion criteria. The median time from pars plana vitrectomy to endophthalmitis diagnosis was 10 days. The majority of eyes (80.9%) were managed with intravitreal antibiotics alone, without a repeat pars plana vitrectomy. Long-term visual acuity, intraocular pressure, cup-to-disc ratio, and rate of evisceration or enucleation did not differ significantly between treatment groups. However, eyes that underwent the initial pars plana vitrectomy for retinal detachment repair had poorer long-term vision and higher rates of retinal detachment following endophthalmitis. Overall, 16.1% of eyes required evisceration or enucleation in this cohort. Conclusions: Despite its rarity, post-pars plana vitrectomy endophthalmitis can cause significant morbidity and even globe loss. There were no significant differences observed between eyes that were treated with intravitreal tap and inject versus repeat pars plana vitrectomy.

Diffuse B-cell lymphomas are the most prevalent canine hematologic malignancies, and their clinical presentation resembles that of human B-cell non-Hodgkin lymphomas (NHLs). However, a lack of a clear subtyping framework perpetuates imprecise treatment approaches that fail to address mechanisms of therapy resistance. Here, we employed deep phenotyping via serial sampling and longitudinal transcriptomics to evaluate intratumoral composition and therapy response in a 6-year-old neutered male goldendoodle with stage 5A marginal zone lymphoma (MZL). Following sequential treatment consisting of a single IV dose of oncolytic vesicular stomatitis virotherapy (VSV) and standard CHOP chemotherapy 30 days later, we performed scRNAseq on seven serial lymph node biopsies and spatial sequencing on a resection taken 10 days post-VSV treatment. B cells (>90%) comprised three transcriptionally distinct and temporally stable subpopulations, with specific copy number profiles and robust spatial organization despite disrupted lymph node architecture. Analysis across subpopulations revealed downregulation of the quiescence program including KLF2, suggesting similarity to KLF2-deficient human MZL. While VSV successfully reached target B cells, downstream transcriptional responses were predominantly localized to the T-cell compartment. T cells (≤6%) showed increased proliferation and upregulation of cytotoxicity markers post-VSV administration, enriching for leukocyte-mediated cytotoxicity pathways consistent with an anti-viral immune response. Ultimately, these results provide an in vivo proof-of-concept for the treatment paradigm in canine lymphoma, while emphasizing the need for improved subtyping frameworks and multidimensional treatment strategies targeting intratumoral heterogeneity.

Background Studies have demonstrated neighborhood structural inequities are associated with cardiovascular outcomes among breast cancer survivors. We investigated the associations between bias in mortgage lending practices (contemporary redlining and racial lending bias) and cardiovascular outcomes in women with breast cancer. Methods Using the SEER (Surveillance, Epidemiology, and End Results)–Medicare database, we identified 51 007 Black and White women diagnosed with breast cancer between 2010 and 2014 with follow‐up through 2020. We used Home Mortgage Disclosure Act data to calculate census‐tract contemporary redlining index and racial lending bias index, and assessed indices continuously and categorically (low, moderate, or high). We used Cox proportional hazards regression to estimate multivariable‐adjusted, cause‐specific hazard ratios (HRs) for major adverse cardiovascular events, ischemic heart disease, heart failure, stroke, and cardiovascular death. Results In the overall population, a 10%‐unit increase in redlining was associated with increased risk of major adverse cardiovascular events (HR, 1.04 [95% CI, 1.02–1.06]). Among Black women, those in high redlining neighborhoods had an increased heart failure risk compared with those in low redlining neighborhoods (HR, 1.22 [95% CI, 1.05–1.41]). Similarly, White women in high redlining neighborhoods had an increased risk of ischemic heart disease (HR, 1.23 [95% CI, 1.15–1.30]) and stroke (HR, 1.09 [95% CI, 1.03–1.16]). Black women in high racial lending bias neighborhoods had reduced cardiovascular mortality risk compared with those in low racial lending bias neighborhoods (HR, 0.69 [95% CI, 0.54–0.90]). Conclusions We identified associations between contemporary redlining and cardiovascular outcomes among breast cancer survivors. High racial lending bias was associated with reduced cardiovascular mortality risk among Black women. Bias in mortgage lending practices may serve as a structural driver of cardiovascular disparities.

Background Studies suggest that hypoperfusion from heart failure (HF) may contribute to cognitive decline. However, the relationship between the HF subtypes and cognition remains poorly described in real‐world populations. Methods We conducted a cross‐sectional study of patients aged ≥18 years seen at the Mayo Clinic in 2022 who underwent echocardiogram and cognitive assessment within 1 year. HF was classified per the 2022 American Heart Association as no HF, HF with preserved ejection fraction (EF), HF with mildly reduced EF, and HF with reduced EF. Cognitive impairment was categorized using the Montreal Cognitive Assessment score as normal (≥26), mild (18–25), and moderate to severe (<18). Linear regression assessed EF–Montreal Cognitive Assessment correlation and logistic regression the association between HF subtypes and cognitive dysfunction, adjusting for age, sex, race, and vascular risk factors. Results A total of 1592 patients met inclusion criteria (mean age, 75.7±13.8 years; 48.5% women). Lower EF was associated with worse cognitive performance (postadjustment β=0.033, P =0.013). Patients with HF with reduced EF and patients with HF with preserved EF had significantly lower Montreal Cognitive Assessment scores than those without HF (17.6±6.2 and 18.9±5.8 versus 19.9±6.0, P <0.001). The prevalence of moderate to severe cognitive impairment was highest in HF with reduced EF (43.3%), followed by HF with preserved EF (34.4%), no heart failure (28.6%), and HF with mildly reduced EF (23.4%) (adjusted trend P =0.032). Conclusions HF, independent of ejection fraction alone, is associated with cognitive impairment. Further studies should confirm these findings and evaluate the impact of interventions targeting EF and HF subtypes on cognitive outcomes.

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.