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Abstract Introduction This study investigated if acute alcohol exposure produces sex differences in aged rats compared to adult and adolescent rats on ataxia and nonspatial cognition. Materials and Methods Sex- and age-related differences were assessed by using aged, young adult, and adolescent Sprague–Dawley rats. For acute alcohol exposure, animals were administered either 1 or 2 g/kg alcohol via intraperitoneal injection before testing. To examine the effects of acute alcohol exposure on balance and motor control and nonspatial learning, animals underwent behavioral testing in the aerial righting reflex (ARR) and Morris water maze (MWM) tests. Blood alcohol levels were determined 60 min following administration of either 1.0 or 2.0 g/kg alcohol. Results Sex differences were found in the ARR, as aged females were significantly less sensitive to the effect of acute alcohol exposure compared to aged males. Age was also found to significantly affect ARR performance, where aged animals performed worse than younger animals in response to acute alcohol. However, these sex- and age-related differences were not found in the nonspatial MWM test or in blood alcohol concentrations. Conclusions These results indicate that the sex- and age-dependent effects of acute alcohol exposure are task specific. In conclusion, these findings highlight the importance of studying the effects of acute alcohol on the aged population.

Background: Lymphaticovenous anastomosis (LVA) is an effective surgical treatment for extremity lymphedema. Indocyanine green (ICG) fluorescent lymphography, the traditional standard for imaging lymphatic vessels, has limitations, including difficulty depicting deeper or congested lymphatics and contraindication in iodine hypersensitivity. This study evaluated contrast-enhanced ultrasound (CEUS) with microbubbles for identifying lymphatic vessels for LVA and compared it with ICG lymphography. Methods: In this single-center retrospective review, intraoperative CEUS with intradermal injection of microbubble suspension (Lumason, Bracco Diagnostics, Inc.) was used in patients before LVA surgery between October 2019 and February 2023. Pre- or intraoperative ICG lymphography was also used to identify target lymphatic vessels. All patients diagnosed with primary or secondary extremity lymphedema who underwent LVA were included. Technical success rate was defined as lymphatic vessels identified by CEUS that led to successful LVAs. Descriptive statistics were used. Results: Thirty-two patients underwent LVA surgery, with a mean age of 58.5 ± 13.9 years. CEUS identified lymphatic vessels in all 32 patients, including 7 in whom ICG failed. Two patients with ICG allergy underwent CEUS only. CEUS identified more candidate lymphatics per patient (5.3 ± 4.2) compared with ICG (2.5 ± 2.7). Of the 182 anastomoses, 96 (52.8%) were identified by both CEUS and ICG, 75 (41.2%) by CEUS only, and 11 (6%) by ICG only. Conclusions: CEUS is a promising tool for identifying lymphatic vessels in patients with lymphedema undergoing LVA, particularly when ICG lymphography is inadequate or contraindicated.

Abstract Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (<6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.

Abstract Background and Aims The long-term efficacy and safety of upadacitinib in patients with moderate to severe Crohn’s disease (CD) were evaluated in the U-ENDURE Long-Term Extension (LTE) study. Here we report the results after 2 years of total maintenance treatment. Methods U-ENDURE is an ongoing 240-week LTE study conducted at 243 sites across 43 countries (first patient enrolled in LTE 21 March 2019). Patients who completed the 52-week maintenance study continued their previously assigned treatment, once-daily upadacitinib 15 mg or upadacitinib 30 mg. Efficacy was analyzed at week 48 of the LTE; safety was analyzed in the cumulative study population (combined 52 week maintenance and 48 week LTE) and the LTE study population only (cutoff date: 19 December 2023). Results From LTE week 0 to week 48, as-observed efficacy rates for clinical remission (per stool frequency/abdominal pain score, upadacitinib 15 mg: 78.3% to 82.9%; upadacitinib 30 mg: 84.7% to 76.6%; per CD Activity Index, upadacitinib 15 mg: 81.3% to 83.1%; upadacitinib 30 mg: 86.1% to 86.8%), endoscopic response (upadacitinib 15 mg: 59.6% to 67.1%; upadacitinib 30 mg: 71.2% to 69.6%), inflammatory biomarkers, and quality-of-life outcomes remained stable. The safety profile of the cumulative maintenance population observed through LTE week 48 was consistent with previous trials in the upadacitinib CD program. Treatment-emergent adverse event rates for the cumulative maintenance population were 283.1 and 273.4 events/100 patient-years for upadacitinib 15 mg and upadacitinib 30 mg, respectively. Event rates of serious treatment-­emergent adverse events were 16.0 events/100 patient-years for upadacitinib 15 mg and 14.6 events/100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest (≥ 5.0 events/100 patient-years) were hepatic disorder, lymphopenia, creatine phosphokinase elevation, herpes zoster, and anemia. There was 1 treatment-emergent adverse event of suicide leading to death. Conclusion Sustained clinical, endoscopic, quality-of-life, and biomarker outcomes were observed in patients who were initial responders to upadacitinib and completed 2 years of maintenance therapy, with no new safety signals identified. Clinical trial identifier U-ENDURE; ClinicalTrials.gov number, NCT03345823.

Background Eosinophilic oesophagitis (EoE) is a food allergen-induced inflammatory disorder characterised by interleukin (IL)-13-mediated oesophageal inflammation and epithelial basal cell hyperplasia (BCH). The role of mitochondria in EoE pathogenesis remains elusive. Design Prompted by single cell transcriptomics data, we interrogated the role of mitochondria in EoE pathobiology using patient biopsies, EoE-mouse models and oesophageal epithelial cells grown in monolayer and three-dimensional (3D) organoid cultures treated with EoE-relevant cytokines. 3D organoids and EoE-bearing mice were treated with omeprazole—a proton-pump inhibitor used as first-line EoE therapy. We performed CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference in mouse organoids to identify the key mitochondrial regulatory genes whose depletion may lead to BCH. We analysed mitochondrial membrane potential, mass and superoxide production by flow cytometry, cellular oxygen consumption by respirometry, mitochondrial structures and perturbation of cellular energy homeostasis by immunoblotting. Results Mitochondrial dysfunction appeared to be a hallmark of EoE-related BCH where mitochondrial structural damage was associated with impaired oxidative respiratory capacity, elevation of mitochondrial superoxide and decreased adenosine triphosphate (ATP) production, as corroborated by activation of the adenosine monophosphate (AMP) -activated protein kinase and suppression of mammalian target-of-rapamycin signalling. Depletion of PGC1A, the master regulator of mitochondria biogenesis, recapitulated EoE-related BCH, suggesting that mitochondrial dysfunction drives BCH. Further, omeprazole alleviated mitochondrial damage and dysfunction in EoE-related BCH modelled in mice and patient-derived organoids. Conclusion Mitochondrial dysfunction is tightly linked to perturbation of redox homeostasis in EoE-related BCH, which is promoted by IL-13 and reversible with omeprazole treatment.

Background: EUS-guided gastroenterostomy (EUS-GE) is an effective option for the management of gastric outlet obstruction (GOO). Due to the poor prognosis of patients undergoing it, data on its long-term adverse events (AE) is scarce. Herein, we describe a cohort of patients with gastro-entero-colic fistula (GECF) as a late AE of previously successful EUS-GE. Methods: Patients who developed a GECF after EUS-GE from 10 high-volume centers were analyzed. Information collected included demographic characteristics, indications, clinical and technical success rates, stent type and size, fistula characteristics, management, and outcomes. Results: Sixteen cases were identified. The mean interval from index EUS-GE to the diagnosis of GECF was 4 to 8 weeks. The most common cause of GOO was pancreatic adenocarcinoma (PDAC). The transverse colon was the most common site for the GECF (14 patients). A 20×10 mm lumen apposing metal stent (LAMS) was utilized in 10 patients. Endoscopic management with a variety of modalities was successful in 13 cases. Follow-up interval after endoscopic management of the fistula averaged 2 to 4 weeks. At the time of the manuscript elaboration, 10 patients had died, 5 were alive, and 1 was lost to follow-up. Conclusions: This is the first description of a cohort of patients with GECF after EUS-GE. The exact mechanisms leading to GECF in these cases are unknown. Possible explanations include inadvertent colon puncture during the index procedure and/or entrapment of mesocolon. More data is needed to further characterize this AE.

SummaryIn individuals with high‐count monoclonal B‐cell lymphocytosis (MBL), we investigated if lymphadenopathy or splenomegaly found by imaging was associated with shorter time to first chronic lymphocytic leukaemia (CLL) therapy (TTFT) and overall survival (OS). Individuals with MBL seen at Mayo Clinic (2002–2019) were retrospectively divided into three cohorts based on imaging studies within 1 year of diagnosis: no imaging studies (Cohort A); imaging with no evidence of lymphadenopathy/splenomegaly (Cohort B); imaging with evidence of lymphadenopathy/splenomegaly (Cohort C). We compared baseline characteristics, TTFT and OS across the MBL cohorts to a cohort of individuals with small lymphocytic lymphoma (SLL). A total of 1078 patients were included: 640 with MBL and 438 with SLL. Compared to Cohort B, individuals in Cohort C were more likely to have unmutated immunoglobulin heavy chain variable region (IGHV) (43% vs. 25% p = 0.016), high‐risk fluorescence in situ hybridization (FISH) (del17p and del11q in 15% vs. 4%, p = 0.038) and higher expression of CD38 (31% vs. 16%; p = 0.011). After adjusting for sex and CLL‐International Prognostic Index (IPI), lymphadenopathy/splenomegaly was associated with a shorter TTFT (hazard ratio [HR] = 2.04, 95% confidence interval [CI]: 1.02–4.04, p = 0.042) but not OS (HR = 1.09, 95% CI: 0.62–1.92, p = 0.775). Lymphadenopathy/splenomegaly on imaging in individuals with high‐count MBL is associated with a more unfavourable risk profile and shorter time to first CLL‐directed therapy.

INTRODUCTION: Chronic pancreatitis (CP) remains difficult to manage with few treatment options. Prior studies have implicated prostaglandin E 2 (PGE 2 ) in mediating chronic inflammation in the pancreas. Therefore, we aimed to evaluate whether indomethacin, a cyclooxygenase-2 enzyme inhibitor, would reduce PGE 2 levels in CP. METHODS: In this pilot multicenter randomized controlled trial, participants with CP received oral indomethacin (50 mg) or placebo twice daily for 28 days. Measurement of PGE 2 levels in pancreatic fluid collected endoscopically after secretin administration at baseline and posttreatment (day 28) was performed. Quality of life and pain were also assessed at baseline and posttreatment. RESULTS: A total of 27 participants were randomized (indomethacin = 13, placebo = 14). Although PGE 2 levels decreased after treatment in pancreas fluid, plasma, and saliva in the indomethacin group, there was no significant difference in mean change in pancreas fluid PGE 2 levels between the indomethacin and placebo groups (−457.7 pg/mL vs −840.4 pg/mL, P = 0.25). There was also no significant change in pain severity composite score (−1.3 indomethacin vs −0.5 placebo, P = 0.33), but the improvement in pain interference score (−2.9 indomethacin vs −0.4, P = 0.058) trended toward significance. There was no difference in adverse events between the 2 groups. DISCUSSION: In this phase 1/2 study, oral indomethacin was safe and well tolerated by patients with CP. Although there was no significant difference in change in PGE 2 levels, further studies are needed to determine the effect of indomethacin on the inflammatory pathway of CP and patient-centered outcomes.