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Aerodynamic canopy height (ha) is the effective height of vegetation canopy for its influence on atmospheric fluxes and is a key parameter of surface-atmosphere coupling. However, methods to estimate ha from data are limited. This synthesis evaluates the applicability and robustness of the calculation of ha from eddy covariance momentum-flux data. At 69 forest sites, annual ha robustly predicted site-to-site and year-to-year differences in canopy heights (R2 = 0.88, 111 site-years). At 23 cropland/grassland sites, weekly ha successfully captured the dynamics of vegetation canopies over growing seasons (R2 > 0.70 in 74 site-years). Our results demonstrate the potential of flux-derived ha determination for tracking the seasonal, interannual, and/or decadal dynamics of vegetation canopies including growth, harvest, land use change, and disturbance. The large-scale and time-varying ha derived from flux networks worldwide provides a new benchmark for regional and global Earth system models and satellite remote sensing of canopy structure.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Evidence suggests that access to urban green spaces (UGS) may encourage physical exercise and impact nutritional status and health. Nevertheless, the quality of UGS is an understudied area. Novel digital tools allow the analysis of urban environments. This study aims to explore the quality of UGS and its association with obesity in Córdoba, Argentina, using Google Street View (GSV) images., Study Design: Population-based cross-sectional study., Methods: Lifestyle and sociodemographic data were collected in Córdoba, Argentina (n = 1322 adults) during 2020-2022. Anthropometric measurements were obtained. Buffers of 500m were established around dwellings to identify the presence of large-area UGS (≥1ha). The quality of 226 UGS was evaluated across specific dimensions using a multi-dimensional assessment tool adapted for remote monitoring through GSV. Two-level logistic regression models for obesity outcome (yes/no) were fitted using a random intercept to account for spatial variability. Odds ratios (OR) and their 95 % confidence intervals (95 % CI) were estimated as measures of association., Results: Obesity was present in 25.9 % of participants. The UGS quality dimensions that showed an inverse association with obesity were safety (OR = 0.33; 95 % CI 0.32-0.82), potential usage (OR = 0.42; 95 % CI 0.21-0.81), surroundings (OR = 0.54; 95 % CI 0.31-0.93), access (OR = 0.55; 95 % CI 0.31-0.97), aesthetics (OR = 0.55; 95 % CI 0.34-0.87) and amenities (OR = 0.62; 95 % CI 0.42-0.91). Proximity to UGS was not significantly associated with obesity., Conclusions: Rather than their proximity, the quality of the UGS might play a key role as a determinant of obesity. In urban areas, digital tools such as GSV are useful to explore these topics., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

The Soil and Water Management Research Unit of the USDA-Agricultural Research Service is located in St. Paul, MN, and conducts long-term research at the University of Minnesota Research and Outreach Center located at Rosemount, MN. As part of USDA's Long-Term Agroecosystem Research (LTAR) network, the croplands common experiment (CCE) at this location is focused on integration of a kura clover (Trifolium ambiguum M. Bieb.) living mulch (KCLM) system into the prevailing 2-year rotation of corn (Zea mays L.) and soybean (Glycine max L.) that is typical of the midwestern Corn Belt. The LTAR-CCE conducted at Rosemount, MN, aims to compare the long-term environmental and agronomic performance of KCLM while identifying challenges and developing management strategies for this alternative practice. The use of a living mulch for this region is advantageous because, once established, it does not require additional time for fall field operations typically associated with winter cover crops. Results from LTAR-CCE studies at this site show that KCLM results in a substantial increase in soil field-saturated hydraulic conductivity and decreases in leaching of nitrate-nitrogen (NO 3 - -N). Disadvantages of the KCLM system include potential for increased emissions of nitrous oxide (N 2 O) and reduced crop yields, particularly during drought. Also, the optimal approach for crop row establishment in the spring remains uncertain. Ongoing LTAR-CCE research with KCLM aims to better understand and quantify both benefits and risks across conditions of interannual weather variability and changing climate to develop guidance for suitable adoption and management of this alternative practice., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Journal of Environmental Quality published by Wiley Periodicals LLC on behalf of American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America.)

Alternative agronomic practices are needed to address the various climatic, agronomic, edaphic, and water quality related challenges faced by the dairy farmers of the Driftless Area (DA) in the Upper Mississippi River Basin (UMRB). These practices should be innovative in nature, inclusive of regional stakeholders, and sustainable to meet the future food and climate related challenges of Wisconsin agriculture. Here, we outline our Integrated (grazing and cropland) Long-Term Agroecosystem Research Common Experiment at the University of Wisconsin-Platteville Pioneer Farm (UW-P PF) in the UMRB and describe our collaboration in this USDA network. In this field-scale experiment, we are comparing the conventional dairy production system common to this region (i.e., corn-on-corn [Zea mays L.] for 4 years, followed by alfalfa [Medicago sativa L.] for 3 years, with no cover crops) with two alternative dairy production systems-(1) soil health management with no-till, cover crops, and application of a novel manure-based nutrient-rich stable product, and (2) management intensive grazing-and rotational grazing on pastures established with diverse forage-legume mix. Meteorological, edaphic, hydrologic, and agronomic data are collected and analyzed at regular frequencies. Going forward, the experiment will continue as a form of stakeholder-driven adaptive research and receive evaluation on a regular basis to determine whether any changes are required to address the "real-world" challenges faced by the farmers in the Midwest., (© 2024 The Author(s). Journal of Environmental Quality © 2024 American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America.)

Intensive agricultural activities have significantly altered watershed hydrological and biogeochemical processes, resulting in water quality issues and loss of ecosystem functions and biodiversity. A major challenge in effectively mitigating nitrogen (N) loss from agricultural watersheds stems from the heterogeneity of N transformation and transport processes that complicates accurate quantification and modeling of N sources and sinks at the watershed scale. This study utilized stable isotopes of water and nitrate (NO 3 - ) in conjunction with spatial stream network modeling (SSNMs) to explore watershed hydrology, N transformation, and sources within a mesoscale river network in the U.S. Corn Belt (Cannon River Watershed, Minnesota) under contrasting hydrological conditions. The results show that the wet season had elevated riverine NO 3 - concentration (medium: 8.4 mg N L -1 ), driven by high watershed wetness conditions that mobilizes NO 3 - from the near-surface source zone. Furthermore, the strong hydrologic connectivity also reduced the denitrification potential by shortening water travel times. In comparison, the dry season showed lower NO 3 - concentrations (0.9 mg N L -1 ) and stronger denitrification NO 3 - isotope signals. During this period, the decrease in hydrologic connectivity shifted the predominant water source to deep groundwater, with longer water travel time promoting denitrification. After accounting for isotopic fractionations during nitrification and denitrification, we identified fertilizer N as the main NO 3 - source during the wet season (98.2±1.3%), whereas the dry season showed contributions from diverse sources (64.4±11.9% fertilizer, 26.0±15.8% soil N, and 9.5±6.0% manure and sewage). During the dry season, karst regions with high hydrologic connectivity display increased shallow groundwater inputs, carrying elevated NO 3 - levels from leaching of applied chemical fertilizers. These findings highlight the importance of integrating drainage water management and N accumulation in groundwater into nutrient management strategies to develop adaptive measures for controlling N pollution in agricultural watersheds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Abstract: There are no agreed upon terminology to define "refractory" pediatric immune thrombocytopenia (ITP). Guidelines are therefore limited to arbitrary and outdated definitions. The Pediatric ITP Consortium of North America held a meeting in 2023 to define this entity. With 100% agreement, the faculty established that pediatric ITP that is refractory to emergent therapy could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies. With 100% agreement, the working group established that pediatric patients with ITP that continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease-modifying therapies represent a challenging subset of ITP. These patients are at higher risk of ongoing disease burden and merit additional investigation as well as consideration for clinical trials or novel therapies. Future efforts to define disease burden and disease response will be completed in collaboration with the ITP International Working Group., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Patients with hypertensive disorders of pregnancy have a high rate of postpartum readmission., Objective: This study aimed to evaluate whether the type of antihypertensive medication prescribed at discharge was associated with postpartum readmission after a hypertensive disorder of pregnancy., Study Design: This was a retrospective cohort study of 57,254 pregnancies complicated by hypertensive disorders of pregnancy between 2012 and 2018 in the electronic obstetrical database of Kaiser Permanente Northern California. Postpartum readmissions occurred within 6 weeks after discharge from delivery hospitalization. Cox regression models were used to evaluate the association between the type of antihypertensive medication prescription at discharge (none, labetalol only, nifedipine only, or 2 or more antihypertensive medications) and postpartum readmission, adjusted for type of hypertensive disorder of pregnancy, final inpatient systolic and diastolic blood pressures, age, body mass index, mode of delivery, insurance status, race and ethnicity, delivery facility, comorbidity score, smoking, preterm delivery, parity, and Neighborhood Deprivation Index., Results: Among eligible patients with a hypertensive disorder of pregnancy, 1696 (3.0%) were readmitted within 6 weeks. Approximately 86% of patients were discharged without a prescription for antihypertensive medication; among those discharged with a prescription for antihypertensive medication, most were prescribed either labetalol only (54%) or nifedipine only (30%). The unadjusted readmission risk was the highest for patients discharged with a prescription for labetalol only (7.6%), lower for those discharged with a prescription for nifedipine only (3.6%) or 2 or more antihypertensive medications (3.2%), and the lowest for those discharged without a prescription for antihypertensive medication (2.5%). In the adjusted models, compared with discharge without a prescription for antihypertensive medication, discharge with a prescription for labetalol only was associated with a 63% (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) greater incidence of postpartum readmission, and discharge with a prescription for nifedipine only and discharge with a prescription for 2 or more antihypertensive medications were associated with 26% (hazard ratio, 0.74; 95% confidence interval, 0.59-0.93) and 47% (hazard ratio, 0.53; 95% confidence interval, 0.38-0.74) lower incidence of postpartum readmission, respectively. There was no strong evidence to suggest that the effect of the type of antihypertensive medication at discharge on the incidence of readmission varied by race and ethnicity (interaction P=.88). The results indicating an elevated risk associated with labetalol use were consistent in models that excluded patients with prepregnancy hypertension., Conclusion: Discharge with a prescription for nifedipine alone or multiple antihypertensive medications (vs no medication) was associated with a lower incidence of readmission, whereas discharge with a prescription for labetalol alone was associated with an elevated readmission incidence. A large-scale, prospective research to compare the effectiveness of commonly prescribed hypertension medications at discharge is warranted., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which has been suggested to cause CAR T cell fratricide and exhaustion. Whether CMT indeed causes CAR T cell dysfunction and the molecular mechanisms conferring CMT remain unknown. Using a selective degrader of trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen on the CAR T cell surface directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we found that the cysteine protease cathepsin B (CTSB) is essential for CMT and that inhibition of CTSB is sufficient to prevent CAR T cell fratricide and exhaustion. Our data demonstrate that it is feasible to separate CMT from cytotoxic activity and that CAR T cell persistence, a key factor associated with clinical CAR T cell efficacy, is directly linked to CTSB activity in CAR T cells.

Background: Early life exposure to organophosphate (OP) pesticides is linked with adverse neurodevelopment and brain function in children. However, we have limited knowledge of how these exposures affect functional connectivity, a measure of interaction between brain regions. To address this gap, we examined the association between early life OP pesticide exposure and functional connectivity in adolescents., Methods: We administered functional near-infrared spectroscopy (fNIRS) to 291 young adults with measured prenatal or childhood dialkylphosphates (DAPs) in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal study of women recruited during pregnancy and their offspring. We measured DAPs in urinary samples collected from mothers during pregnancy (13 and 26 weeks) and children in early life (ages 6 months, 1, 2, 3, and 5 years). Youth underwent fNIRS while they performed executive function and semantic language tasks during their 18-year-old visit. We used covariate-adjusted regression models to estimate the associations of prenatal and childhood DAPs with functional connectivity between the frontal, temporal, and parietal regions, and a mediation model to examine the role of functional connectivity in the relationship between DAPs and task performance., Results: We observed null associations of prenatal and childhood DAP concentrations and functional connectivity for the entire sample. However, when we looked for sex differences, we observed an association between childhood DAPs and functional connectivity for the right interior frontal and premotor cortex after correcting for the false discovery rate, among males, but not females. In addition, functional connectivity appeared to mediate an inverse association between DAPs and working memory accuracy among males., Conclusion: In CHAMACOS, a secondary analysis showed that adolescent males with elevated childhood OP pesticide exposure may have altered brain regional connectivity. This altered neurofunctional pattern in males may partially mediate working memory impairment associated with childhood DAP exposure., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Indirect nitrous oxide (N 2 O) emissions from streams and rivers are a poorly constrained term in the global N 2 O budget. Current models of riverine N 2 O emissions place a strong focus on denitrification in groundwater and riverine environments as a dominant source of riverine N 2 O, but do not explicitly consider direct N 2 O input from terrestrial ecosystems. Here, we combine N 2 O isotope measurements and spatial stream network modeling to show that terrestrial-aquatic interactions, driven by changing hydrologic connectivity, control the sources and dynamics of riverine N 2 O in a mesoscale river network within the U.S. Corn Belt. We find that N 2 O produced from nitrification constituted a substantial fraction (i.e., >30%) of riverine N 2 O across the entire river network. The delivery of soil-produced N 2 O to streams was identified as a key mechanism for the high nitrification contribution and potentially accounted for more than 40% of the total riverine emission. This revealed large terrestrial N 2 O input implies an important climate-N 2 O feedback mechanism that may enhance riverine N 2 O emissions under a wetter and warmer climate. Inadequate representation of hydrologic connectivity in observations and modeling of riverine N 2 O emissions may result in significant underestimations.

Background Aims: Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies have revolutionized the treatment of B-cell lymphomas. Unfortunately, relapses after CD19-targeted CAR-T are relatively common and, therefore, there is a critical need for assays able to assess the function and potency of CAR-T products pre-infusion, which will hopefully help to optimize CAR-T therapies. We developed a novel multicolor fluorescent spot assay (MFSA) for the functional assessment of CAR-T products on a single-cell level, combining the numerical assessment of CAR-T products with their functional characterization., Methods: We first used a standard single-cell interferon (IFN)-γ enzyme-linked immune absorbent spot assay to measure CD19-targeted CAR-T responses to CD19-coated beads. We then developed, optimized and validated an MFSA that simultaneously measures the secretion of combinations of different cytokines on a single CAR-T level., Results: We identified IFN-γ/tumor necrosis factor-α/granzyme B as the most relevant cytokine combination, and we used our novel MFSA to functionally and numerically characterize two clinical-grade CAR-T products., Conclusions: In conclusion, we have developed a novel assay for the quantitative and functional potency assessment of CAR-T products. Our optimized MFSA is cost-effective, easy to perform, reliable, can be performed overnight, allowing for a fast delivery of the product to the patient, and requires relatively minimal maintenance and training. The clinical value of our novel assay will be assessed in studies correlating the pre-infusion assessment of CAR-T products with the patients' outcome in a prospective fashion., Competing Interests: Declaration of Competing Interest SD serves on advisory boards for Bristol-Myers Squibb, Incyte and Atara Biotherapeutics. The remaining authors declare that they do not have any competing interests., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

During October 2021-June 2023, a total of 392 cases of acute hepatitis of unknown etiology in children in the United States were reported to Centers for Disease Control and Prevention as part of national surveillance. We describe demographic and clinical characteristics, including potential involvement of adenovirus in development of acute hepatitis, of 8 fatally ill children who met reporting criteria. The children had diverse courses of illness. Two children were immunocompromised when initially brought for care. Four children tested positive for adenovirus in multiple specimen types, including 2 for whom typing was completed. One adenovirus-positive child had no known underlying conditions, supporting a potential relationship between adenovirus and acute hepatitis in previously healthy children. Our findings emphasize the importance of continued investigation to determine the mechanism of liver injury and appropriate treatment. Testing for adenovirus in similar cases could elucidate the role of the virus.

Background: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported., Methods: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity., Results: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4 + central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells., Conclusions: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin α 4 (A4 ko ), an adhesion molecule essential for migration across the blood-brain barrier. A4 ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells., Competing Interests: CONFLICTS OF INTEREST EAM, DA, and TL are inventors on U.S. patent application 63/285843 describing the use of LINGO1 CAR T cells and knockout of integrin α4 for the treatment of ES. The other authors are not declaring any conflicts of interest.

Background: Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years., Methods: We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language., Results: There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (β per ten-fold increase in DAPs = 3.37; 95% CI: -0.02, 6.77 and β = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (β = -3.10; 95% CI: -6.43, 0.22 and β = -3.67; 95% CI: -7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task., Discussion: We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Asa Bradman reports a relationship with The Organic Center that includes: board membership., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The American Heart Association (AHA/ACC) sets as a goal for blood pressure (BP) control not to exceed values of 130/80 mmHg, both in individuals with and without a diagnosis of hypertension (HT), standards not evaluated so far in the Argentine population. The objective was to determine the prevalence of high BP (HBP) in individuals with and without a diagnosis of HT taking into account the AHA/ACC criteria and to evaluate its association with sociodemographic and lifestyle factors., Materials and Methods: Cross-sectional populationbased study in 911 persons >18 years of age in Córdoba, Argentina (period 2020-2022). Sociodemographic and lifestyle data, history of HT, diabetes and medication use, anthropometric measurements, BP and dietary intake were collected. HBP was defined for systolic and/or diastolic BP ≥130 / ≥80mmHg, respectively at the time of measurement. The presence of HT was assessed by self-report and/or consumption of antihypertensive medication. The association of HBP with lifestyle was assessed using multiple logistic regression models., Results: 84.8% and 55.6% of the patients with and without hypertension had HBP, respectively. HBP was positively associated with age and BMI, the latter only in persons without HT (OR:1.10; 95%CI:1.06-1.14), while hours of sleep showed an inverse association (OR:0.63; 95%CI:0.45-0.88)., Discussion: There is a high prevalence of HBP in the city of Córdoba, Argentina. It is of utmost importance and urgency to implement sanitary measures to control BP in order to avoid adverse health consequences.

Background: Adenovirus is a known cause of hepatitis in immunocompromised children, but not in immunocompetent children. In April, 2022, following multiple reports of hepatitis of unknown aetiology and adenovirus viraemia in immunocompetent children in the USA and UK, the US Centers for Disease Control and Prevention (CDC) and jurisdictional health departments initiated national surveillance of paediatric acute hepatitis of unknown aetiology. We aimed to describe the clinical and epidemiological characteristics of children identified with hepatitis of unknown aetiology between Oct 1, 2021, and Sept 30, 2022, in the USA and to compare characteristics of those who tested positive for adenovirus with those who tested negative., Methods: In this national surveillance investigation in the USA, children were identified for investigation if they were younger than 10 years with elevated liver transaminases (>500 U/L) who had an unknown cause for their hepatitis and onset on or after Oct 1, 2021. We reviewed medical chart abstractions, which included data on demographics, underlying health conditions, signs and symptoms of illness, laboratory results, vaccination history, radiological and liver pathology findings, diagnoses and treatment received, and outcomes. Caregiver interviews were done to obtain information on symptoms and health-care utilisation for the hepatitis illness, medical history, illness in close contacts or at school or daycare, diet, travel, and other potential exposures. Blood, stool, respiratory, and tissue specimens were evaluated according to clinician discretion and available specimens were submitted to CDC for additional laboratory testing or pathology evaluation., Findings: Surveillance identified 377 patients from 45 US jurisdictions with hepatitis of unknown aetiology with onset from Oct 1, 2021, to Sept 30, 2022. The median age of patients was 2·8 years (IQR 1·2-5·0) and 192 (51%) were male, 184 (49%) were female, and one patient had sex unknown. Only 22 (6%) patients had a notable predisposing underlying condition. 347 patients (92%) were admitted to hospital, 21 (6%) subsequently received a liver transplant, and nine (2%) died. Among the 318 patients without notable underlying conditions, 275 were tested for adenovirus. Of these 116 (42%) had at least one positive specimen, and species F type 41 was the most frequent type identified (19 [73%] of 26 typed specimens were HAdV-41). Proportions of patients who had acute liver failure, received a liver transplant, and died were similar between those who tested positive for adenovirus compared with those who tested negative. Adenovirus species F was detected by polymerase chain reaction in nine pathology liver evaluations, but not by immunohistochemistry in seven of the nine with adequate liver tissue available. Interviews with caregivers yielded no common exposures., Interpretation: Adenovirus, alone or in combination with other factors, might play a potential role in acute hepatitis among immunocompetent children identified in this investigation, but the pathophysiologic mechanism of liver injury is unclear. To inform both prevention and intervention measures, more research is warranted to determine if and how adenovirus might contribute to hepatitis risk and the potential roles of other pathogens and host factors., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.

Background: The complex nature of obesity increasingly requires a comprehensive approach that includes the role of environmental factors. For understanding contextual determinants, the resources provided by technological advances could become a key factor in obesogenic environment research. This study aims to identify different sources of non-traditional data and their applications, considering the domains of obesogenic environments: physical, sociocultural, political and economic., Methods: We conducted a systematic search in PubMed, Scopus and LILACS databases by two independent groups of reviewers, from September to December 2021. We included those studies oriented to adult obesity research using non-traditional data sources, published in the last 5 years in English, Spanish or Portuguese. The overall reporting followed the PRISMA guidelines., Results: The initial search yielded 1583 articles, 94 articles were kept for full-text screening, and 53 studies met the eligibility criteria and were included. We extracted information about countries of origin, study design, observation units, obesity-related outcomes, environment variables, and non-traditional data sources used. Our results revealed that most of the studies originated from high-income countries (86.54%) and used geospatial data within a GIS (76.67%), social networks (16.67%), and digital devices (11.66%) as data sources. Geospatial data were the most utilised data source and mainly contributed to the study of the physical domains of obesogenic environments, followed by social networks providing data to the analysis of the sociocultural domain. A gap in the literature exploring the political domain of environments was also evident., Conclusion: The disparities between countries are noticeable. Geospatial and social network data sources contributed to studying the physical and sociocultural environments, which could be a valuable complement to those traditionally used in obesity research. We propose the use of information available on the Internet, addressed by artificial intelligence-based tools, to increase the knowledge on political and economic dimensions of the obesogenic environment., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic activity against different types of cancer. However, the wider use of CAR T cells has been hindered by the potential for life-threatening toxicities due to on-target off-tumor killing of cells expressing low amounts of the target antigen. CD229, a signaling lymphocyte-activation molecule (SLAM) family member, has previously been identified as a target for CAR T cell-mediated treatment of multiple myeloma (MM) due to its high expression on the surfaces of MM cells. CD229 CAR T cells have shown effective clearance of MM cells in vitro and in vivo. However, healthy lymphocytes also express CD229, albeit at lower amounts than MM cells, causing their unintended targeting by CD229 CAR T cells. To increase the selectivity of CD229 CAR T cells for MM cells, we used a single amino acid substitution approach of the CAR binding domain to reduce CAR affinity. To identify CARs with increased selectivity, we screened variant binding domains using solid-phase binding assays and biolayer interferometry and determined the cytotoxic activity of variant CAR T cells against MM cells and healthy lymphocytes. We identified a CD229 CAR binding domain with micromolar affinity that, when combined with overexpression of c-Jun, confers antitumor activity comparable to parental CD229 CAR T cells but lacks the parental cells' cytotoxic activity toward healthy lymphocytes in vitro and in vivo. The results represent a promising strategy to improve the efficacy and safety of CAR T cell therapy that requires clinical validation.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA 1,2 . Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA 3-7 , although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Rationale: Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown. Objectives: To establish and interrogate the role of the gut microbiome in calibrating body temperature. Methods: We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal LPS in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals. Measurements and Main Results: Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that the composition of patients' gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures compared with control animals. The Lachnospiraceae family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice. Conclusions: The gut microbiome is a key modulator of body temperature variation in both health and critical illness and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.

Objective: The number of office-based procedure centers with the capability of performing a wide range of endovascular procedures has substantially increased over the past decade. This shift in practice settings has occurred faster in the private sector as compared to the academic environment. The purpose of our study was to evaluate the clinical outcomes of endovascular procedures performed at a dedicated academic outpatient procedural center., Methods: We reviewed the clinical data of 400 patients who underwent 499 endovascular procedures in a university-based, academic outpatient procedure center between November 2013 and December 2016. Outcomes analyzed included procedure-related complications, limb loss, mortality, and emergency department visits or hospital admissions that occurred within 30 days following the procedure., Results: The 400 patients had a mean age of 65 ± 13 years with slightly more females (51%; n = 203) as compared to males (49%; n = 197). Most patients (71%; 284) were Caucasian while 80 (20%) were African-Americans. Associated comorbidities included hypertension (86%), diabetes mellitus (51%), chronic kidney disease (42%), and obesity (mean body mass index of 29 ± 6). Based on anesthetic risk, most were ASA class 3 (81%), while ASA 1 and 2 comprised 17% and ASA 4 only 2%. Medicare beneficiaries accounted for 254 (64%) of our patients. Pre-operative studies included mainly duplex ultrasound (62%) and other noninvasive arterial studies (57%).The mean procedural time was 58 min (range, 7 to 200) with an overall technical success rate of 97%. There were no deaths. Complications developed in 10 patients following the 483 procedures (2.1%) being hospitalized with four of them transferred directly to the emergency room. The reasons for these hospitalizations included acute limb ischemia, arterial pseudoaneurysm, deep vein thrombosis, congestive heart failure, myocardial infarction, and lower extremity pain not vascular in origin. Financial reimbursement at the office-based center was higher than that seen with hospital-based procedures., Conclusions: Endovascular procedures performed in an academic office-based procedure center are safe and associated with good clinical outcomes. A small minority of patients have subsequent ER visits or hospital admissions. Academic institutions should consider adding an office-based procedure center based on today's competitive healthcare market.