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Nonalcoholic steatohepatitis (NASH) has become a growing public health problem worldwide, yet its pathophysiology remains unclear. Liver sinusoidal endothelial cells (LSEC) have unique morphology and function, and play a critical role in liver homeostasis. Emerging literature implicates LSEC in many pathological processes in the liver, including metabolic dysregulation, inflammation, angiogenesis, and carcinogenesis. In this review, we highlight the current knowledge of the role of LSEC in each of the progressive phases of NASH pathophysiology (steatosis, inflammation, fibrosis, and the development of hepatocellular carcinoma). We discuss processes that have important roles in NASH progression including the detrimental transformation of LSEC called “capillarization”, production of inflammatory and profibrogenic mediators by LSEC as well as LSEC-mediated angiogenesis. The current review has a special emphasis on LSEC adhesion molecules, and their key role in the inflammatory response in NASH. Moreover, we discuss the pathogenic role of extracellular vesicles and their bioactive cargos in liver intercellular communication, inflammation, and fibrosis. Finally, we highlight LSEC-adhesion molecules and derived bioactive product as potential therapeutic targets for human NASH.

AbstractThe JAK/STAT3 signaling pathway may be aberrantly activated and have various and conflicting roles in breast cancer. The current study explored prognostic implications of activated STAT3 in human epidermal growth factor receptor 2 (HER2)‐positive primary breast cancers in the context of a large prospective study (ALTTO). Activated STAT3 was determined by immunohistochemical analysis of STAT3 phosphorylation (Y705) performed on the primary tumors. This analysis evaluated whether patients with activated STAT3 had disease‐free survival (DFS) and overall survival (OS) different from patients without activated STAT3. A total of 5694 patients out of the 8381 patients enrolled in ALTTO were included in this analysis (67.9%), and 2634 of them (46%) had evidence of STAT3 activation (minimum tumor Allred score ≥2). The median follow‐up was 6.93 years (6.85‐6.97 years), at the end of which 1035 (18.18%) and 520 (9.13%) patients experienced DFS and OS events, respectively. Patients with STAT3 activation experienced improved DFS compared to those without it (multivariable hazard ratio [HR], 0.84; 95% confidence interval [CI] 0.74‐0.95; P = .006). There were no group differences in OS (multivariable HR, 0.92; 95% CI 0.78‐1.10; P = .37). This effect was limited to ER‐positive tumors. In conclusion, these findings support the role of STAT3 activation as a marker of favorable outcome in ER‐positive/HER2‐positive breast cancer patients.

Introduction: Cytokine release syndrome (CRS) is an expected and potentially life-threatening toxicity associated with CAR T cell therapy. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, demonstrated promising efficacy in triple-class exposed and highly refractory patients with multiple myeloma in the pivotal phase 2 KarMMa study, with an overall response rate (ORR), complete response (CR) rate, median duration of response, and median progression-free survival of 73%, 33%, 10.7 months, and 8.8 months, respectively, across the target dose levels of 150−450 × 106 CAR+ T cells, and 82%, 39%, 11.3 months, and 12.1 months at the highest target dose of 450 × 106 CAR+ T cells (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). Identifying the patterns of CRS evolution, associations with baseline patient and disease characteristics, and the impact of interventions are key to understanding this adverse event in the context of ide-cel. In addition, a better understanding of lower-grade CRS, including maximum grade 1 events, is important as these are easier to manage and represent a lower burden on the healthcare system. We report results of an examination of CRS events in the KarMMa study. Methods: Patients in the KarMMa trial (NCT03361748) were required to have ≥3 prior regimens (including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody) and were refractory to their last regimen per International Myeloma Working Group criteria. Patients received ide-cel target doses of 150, 300, or 450 × 106 CAR+ T cells 2 days after lymphodepletion with cyclophosphamide 300 mg/m2 plus fludarabine 30 mg/m2 daily for 3 days. The primary endpoint was ORR. The key secondary endpoint was CR rate; other secondary endpoints included safety. CRS was graded according to criteria in Lee et al. (Blood. 2014;124:188). Patient characteristics and CRS management were examined by CRS grade to identify variables associated with higher-grade CRS. Management of CRS included tocilizumab 8 mg/kg with the addition of corticosteroids and other agents as needed. Results: Of 128 patients treated with ide-cel, 107 (84%) experienced CRS; 61 patients (48%) had maximum grade 1 and 46 (36%) had maximum grade ≥2 CRS (grade 2, n=39; grade 3, n=5; grade 4, n=1; and grade 5, n=1). Baseline characteristics were generally balanced among patients with maximum grade 1 and grade ≥2 (Table). Thirty patients (65%) with maximum grade ≥2 CRS progressed from initial grade 1 events, whereas 16 (35%) had initial grade ≥2. Median time to onset of CRS was the same (1 day) regardless of initial or maximum grade (Table). Median duration was 5.0 days in patients with maximum grade 1, 5.5 days in patients with maximum grade 2, and 11.0 days in patients with maximum grade ≥3 CRS. Median duration was shorter in patients with maximum grade 1 CRS than in those with initial grade 1 events that progressed to grade ≥2 (5.0 days vs 7.0 days). Most patients (83%) with maximum grade ≥2 CRS received at least 1 dose of tocilizumab and approximately one-third (35%) received corticosteroids, compared with 48% and 5%, respectively, of patients with maximum grade 1 CRS. A higher percentage of patients with initial grade ≥2 vs initial grade 1 CRS received multiple doses of tocilizumab (50% vs 37%) or at least 1 dose of corticosteroids (50% vs 27%). Conclusions: Almost half of the patients treated with ide-cel experienced maximum grade 1 CRS. Baseline disease and patient characteristics were similar among patients experiencing grade 1 and higher-grade CRS events. CRS was effectively managed with tocilizumab and corticosteroids, and more frequent use of these interventions in patients with grade ≥2 CRS was not associated with prolonged CRS events. The time to onset of CRS was predictable and equivalent in patients with maximum grade 1 and higher-grade CRS events. Duration of CRS was similar in patients with maximum grade 1 and 2 but was longer in patients with maximum grade ≥3 CRS. These data demonstrate the feasible management of CRS and thus confirm the tolerability of ide-cel in patients with relapsed and refractory multiple myeloma. Table 1 Disclosures Kansagra: Karyopharm: Honoraria; Pharmacyclics: Honoraria; Alnylam: Honoraria; BMS: Honoraria; GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Lin:Novartis: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding. Berdeja:BMS: Consultancy, Research Funding; Cellularity: Research Funding; Lilly: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Poseida: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Prothena: Consultancy; Legend: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Karyopharm: Consultancy; Constellation: Research Funding; Novartis: Research Funding; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Glenmark: Research Funding; EMD Sorono: Research Funding; Vivolux: Research Funding; Genentech, Inc.: Research Funding; CURIS: Research Funding; Acetylon: Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Oriol:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. Yakoub-Agha:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria. Einsele:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rambaldi:BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.. Truppel-Hartmann:bluebird bio, Inc: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); F. Hoffmann La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Rowe:Bristol-Myers Squibb: Current Employment. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Agarwal:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Lonial:Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Novartis: Consultancy, Honoraria, Other: Personal fees; Millennium: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy.

Abstract Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

The COVID-19 pandemic has had a profound impact on provision of endoscopy services globally as staff and real estate were repurposed. As we begin to recover from the pandemic, a cohesive international approach is needed, and guidance on how to resume endoscopy services safely to avoid unintended harm from diagnostic delays. The aim of these guidelines is to provide consensus recommendations that clinicians can use to facilitate the swift and safe resumption of endoscopy services. An evidence-based literature review was carried out on the various strategies used globally to manage endoscopy during the COVID-19 pandemic and control infection. A modified Delphi process involving international endoscopy experts was used to agree on the consensus statements. A threshold of 80% agreement was used to establish consensus for each statement. 27 of 30 statements achieved consensus after two rounds of voting by 34 experts. The statements were categorised as pre-endoscopy, during endoscopy and postendoscopy addressing relevant areas of practice, such as screening, personal protective equipment, appropriate environments for endoscopy and infection control precautions, particularly in areas of high disease prevalence. Recommendations for testing of patients and for healthcare workers, appropriate locations of donning and doffing areas and social distancing measures before endoscopy are unique and not dealt with by any other guidelines. This international consensus using a modified Delphi method to produce a series of best practice recommendations to aid the safe resumption of endoscopy services globally in the era of COVID-19.

AbstractNonalcoholic hepatitis (NASH) is the progressive inflammatory form of nonalcoholic fatty liver disease. Although the mechanisms of hepatic inflammation in NASH remain incompletely understood, emerging literature implicates the proinflammatory environment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. Interestingly, numerous NASH-promoting kinases in hepatocytes, immune cells, and adipocytes are activated by the lipotoxic insult associated with obesity. In the current review, we discuss recent advances in NASH-promoting kinases as disease mediators and therapeutic targets. The focus of the review is mainly on the mitogen-activated protein kinases including mixed lineage kinase 3, apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 MAPK; the endoplasmic reticulum (ER) stress kinases protein kinase RNA-like ER kinase and inositol-requiring protein-1α; as well as the Rho-associated protein kinase 1. We also discuss various pharmacological agents targeting these stress kinases in NASH that are under different phases of development.

AbstractObjectiveWe describe the clinical characteristics and genetic etiology of several new cases within the ACO2‐related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear‐encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the ACO2 gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice‐site ACO2 variants in patients with a spectrum of clinical manifestations and disease severities.MethodsWe describe a cohort of five novel patients with biallelic pathogenic variants in ACO2. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated ACO2 variants and compare with those described previously in the literature.ResultsTwo siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months.InterpretationIn this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation.

Background and Aims Reliance on exception points to prioritize children for liver transplantation (LT) stems from concerns that the Pediatric End‐Stage Liver Disease (PELD) score underestimates mortality. Renal dysfunction and serum sodium disturbances are negative prognosticators in adult LT candidates and various pediatric populations, but are not accounted for in PELD. We retrospectively evaluated the effect of these parameters in predicting 90‐day wait‐list death/deterioration among pediatric patients (<12 years) listed for isolated LT in the United States between February 2002 and June 2018. Approach and Results Among 4,765 patients, 2,303 (49.3%) were transplanted, and 231 (4.8%) died or deteriorated beyond transplantability within 90 days of listing. Estimated glomerular filtration rate (eGFR) (hazard ratio [HR] 1.09 per 5‐unit decrease, 95% confidence interval [CI] 1.06‐1.10) and dialysis (HR 7.24, 95% CI 3.57‐14.66) were univariate predictors of 90‐day death/deterioration (P < 0.001). The long‐term benefit of LT persisted in patients with renal dysfunction, with LT as a time‐dependent covariate conferring a 2.4‐fold and 17‐fold improvement in late survival among those with mild and moderate‐to‐severe dysfunction, respectively. Adjusting for PELD, sodium was a significant nonlinear predictor of outcome, with 90‐day death/deterioration risk increased at both extremes of sodium (HR 1.20 per 1‐unit decrease below 137 mmol/L, 95% CI 1.16‐1.23; HR per 1‐unit increase above 137 mmol/L 1.13, 95% CI 1.10‐1.17, P < 0.001). A multivariable model incorporating PELD, eGFR, dialysis, and sodium demonstrated improved performance and superior calibration in predicting wait‐list outcomes relative to the PELD score. Conclusions Listing eGFR, dialysis, and serum sodium are potent, independent predictors of 90‐day death/deterioration in pediatric LT candidates, capturing risk not accounted for by PELD. Incorporation of these variables into organ allocation systems may highlight patient subsets with previously underappreciated risk, augment ability of PELD to prioritize patients for transplantation, and ultimately mitigate reliance on nonstandard exceptions.