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Objectives: Behavioral factors of pain catastrophizing and perceived injustice are associated with pain intensity in chronic pain. Diminished heart rate variability (HRV) is also strongly associated with chronic pain. These factors have been less explored earlier in the pain experience and it is unclear whether they play a role in the transition from acute to chronic pain. The aim of this study was to determine the relationship between pain catastrophizing, perceived injustice, pain intensity, and HRV in naturally occurring acute pain., Materials and Methods: Ninety-seven patients were recruited from local outpatient physical therapy clinics. Seated HRV was captured on 94 patients via Polar chest strap while patients were taking a survey via iPad. In addition to sociodemographic data, the survey included the Pain Catastrophizing Scale (PCS), Injustice Experience Questionnaire (IEQ), and Numeric Pain Rating Scale (NPRS). The natural log of high-frequency power (lnHFP) HRV was used in the statistical analysis., Results: Multiple linear regression modeling revealed that lower pain catastrophizing, higher perceived injustice, and lower pain intensity were associated with lower HRV, and accounted for 11.4% of the variance in HRV., Discussion: While greater chronic pain intensity is associated with lower HRV, the relationship is reversed in the setting of acute pain. These findings highlight the need to better understand the unique factors that contribute to lower HRV in the acute phase., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cachexia is a common complication of cancer and is associated with an increased risk of death. The level of growth differentiation factor 15 (GDF-15), a circulating cytokine, is elevated in cancer cachexia. In a small, open-label, phase 1b study involving patients with cancer cachexia, ponsegromab, a humanized monoclonal antibody inhibiting GDF-15, was associated with improved weight, appetite, and physical activity, along with suppressed serum GDF-15 levels., Methods: In this phase 2, randomized, double-blind, 12-week trial, we assigned patients with cancer cachexia and an elevated serum GDF-15 level (≥1500 pg per milliliter) in a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg or to receive placebo, administered subcutaneously every 4 weeks for three doses. The primary end point was the change from baseline in body weight at 12 weeks. Key secondary end points were appetite and cachexia symptoms, digital measures of physical activity, and safety., Results: A total of 187 patients underwent randomization. Of these patients, 40% had non-small-cell lung cancer, 32% had pancreatic cancer, and 29% had colorectal cancer. At 12 weeks, patients in the ponsegromab groups had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg (95% credible interval, 0.37 to 2.25) in the 100-mg group, 1.92 (95% credible interval, 0.92 to 2.97) in the 200-mg group, and 2.81 (95% credible interval, 1.55 to 4.08) in the 400-mg group. Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400-mg ponsegromab group relative to placebo. Adverse events of any cause were reported in 70% of the patients in the ponsegromab group and in 80% of those in the placebo group., Conclusions: Among patients with cancer cachexia and elevated GDF-15 levels, the inhibition of GDF-15 with ponsegromab resulted in increased weight gain and overall activity level and reduced cachexia symptoms, findings that confirmed the role of GDF-15 as a driver of cachexia. (Funded by Pfizer; ClinicalTrials.gov number, NCT05546476.)., (Copyright © 2024 Massachusetts Medical Society.)

Waxes comprise a diverse set of materials from lubricants and coatings to biological materials such as the intracuticular wax layers on plant leaves that restrict water loss to inhibit dehydration. Despite the often mixed hydrocarbon chain lengths and functional groups within waxes, they show a propensity for ordering into crystalline phases, albeit with a wealth of solid solution behavior and disorder modes that determine chemical transport and mechanical properties. Here, we reveal the microscopic structure and heterogeneity of replica leaf wax models based on the dominant wax types in the Schefflera elegantissima plant, namely C 31 H 64 and C 30 H 61 OH and their binary mixtures. We observe defined grain microstructure in C 31 H 64 crystals and nanoscale domains of chain-ordered lamellae within these grains. Moreover, nematic phases and dynamical disorder coexist with the domains of ordered lamellae. C 30 H 61 OH exhibits more disordered chain packing with no grain structure or lamellar domains. Binary mixtures from 0-50% C 30 H 61 OH exhibit a loss of grain structure with increasing alcohol content accompanied by increasingly nematic rather than lamellar chain packing, suggesting a partial but limited solid solution behavior. Together, these results unveil the previously unseen microstructural features governing flexibility and permeability in leaf waxes and outline an approach to microstructure analysis across agrochemicals, pharmaceuticals, and food., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Competing Interests: Competing interests statement:The authors declare no competing interest.

Background & Aims: The pathophysiology of irritable bowel syndrome (IBS) is multifactorial and includes epithelial barrier dysfunction, a key element at the interface between the gut lumen and the deeper intestinal layers. Beneath the epithelial barrier there is the vascular one representing the last barrier to avoid luminal antigen dissemination The aims of this study were to correlate morpho-functional aspects of epithelial and vascular barriers with symptom perception in IBS., Methods: Seventy-eight healthy subjects (controls) and 223 patients with IBS were enrolled in the study and phenotyped according to validated questionnaires. Sugar test was used to evaluate in vivo permeability. Immunohistochemistry, western blot, and electron microscopy were used to characterize the vascular barrier. Vascular permeability was evaluated by assessing the mucosal expression of plasmalemma vesicle-associated protein-1 and vascular endothelial cadherin. Caco-2 or human umbilical vein endothelial cell monolayers were incubated with soluble mediators released by mucosal biopsies to highlight the mechanisms involved in permeability alteration. Correlation analyses have been performed among experimental and clinical data., Results: The intestinal epithelial barrier was compromised in patients with IBS throughout the gastrointestinal tract. IBS-soluble mediators increased Caco-2 permeability via a downregulation of tight junction gene expression. Blood vessel density and vascular permeability were increased in the IBS colonic mucosa. IBS mucosal mediators increased permeability in human umbilical vein endothelial cell monolayers through the activation of protease-activated receptor-2 and histone deacetylase 11, resulting in vascular endothelial cadherin downregulation. Permeability changes correlated with intestinal and behavioral symptoms and health-related quality of life of patients with IBS., Conclusions: Epithelial and vascular barriers are compromised in patients with IBS and contribute to clinical manifestations., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Up to 25% of patients recovering from antibiotic-treated Clostridioides difficile infection (CDI) develop functional symptoms reminiscent of Post-Infectious Irritable Bowel Syndrome (PI-IBS). For patients with persistent symptoms following infection, a clinical dilemma arises as to whether to provide additional antibiotic treatment or to adopt a conservative symptom-based approach. Here, we review the literature on CDI-related PI-IBS and compare the findings with PI-IBS. We review proposed mechanisms, including the role of C. difficile toxins and the microbiota, and discuss implications for therapy. We suggest that gut dysfunction post-CDI may be initiated by toxin-induced damage to enteroglial cells and that a dysbiotic gut microbitota maintains the clinical phenotype over time, prompting consideration of microbiota-directed therapies. While Fecal Microbial Transplant (FMT) is currently reserved for recurrent CDI (rCDI), we propose that microbiota-directed therapies may have a role in primary CDI in order to avoid or mitigate futher antibiotic treatment that further disrupts the microbiota and thus prevent PI-IBS. We discuss novel microbial transfer therapies and as they emerge, we recommend clinical trials to determine whether microbial transfer therapy of the primary infection prevents both rCDI and CDI-related PI- IBS., Competing Interests: Conflict of interest The authors have no conflict of interest to declare., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Single-atom catalysts (SACs) are an emerging class of materials, leveraging maximum atom utilization and distinctive structural and electronic properties to bridge heterogeneous and homogeneous catalysis. Direct imaging methods, such as aberration-corrected high-angle annular dark-field scanning transmission electron microscopy, are commonly applied to confirm the atomic dispersion of active sites. However, interpretations of data from these techniques can be challenging due to simultaneous contributions to intensity from impurities introduced during synthesis processes, as well as any variation in position relative to the focal plane of the electron beam. To address this matter, this paper presents a comprehensive study on two representative SACs containing isolated nickel or copper atoms. Spectroscopic techniques, including X-ray absorption spectroscopy, were employed to prove the high metal dispersion of the catalytic atoms. Employing scanning transmission electron microscopy imaging combined with single-atom-sensitive electron energy loss spectroscopy, we scrutinized thin specimens of the catalysts to provide an unambiguous chemical identification of the observed single-atom species and thereby distinguish impurities from active sites at the single-atom level. Overall, the study underscores the complexity of SACs characterization and establishes the importance of the use of spectroscopy in tandem with imaging at atomic resolution to fully and reliably characterize single-atom catalysts., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Anthropometric prevalence indicators such as stunting, wasting, and underweight are widely-used population-level tools used to track trends in childhood nutrition. Threats to the validity of these data can lead to erroneous decision making and improper allocation of finite resources intended to support some of the world's most vulnerable populations. It has been demonstrated previously that aggregated prevalence rates for these indicators can be highly sensitive to biases in the presence of non-directional measurement errors, but the quantitative relationship between the contributing factors and the scale of this bias has not been fully described. In this work, a Monte Carlo simulation exercise was performed to generate high-statistics z-score distributions with a wide range of mean and standard deviation parameters relevant to the populations in low- and middle-income countries (LMIC). With the important assumption that the distribution's standard deviation should be close to 1.0 in the absence of non-directional measurement errors, the shift in prevalence rate due to this common challenge is calculated and explored. Assuming access to a given z-score distribution's mean and standard deviation values, this relationship can be used to evaluate the potential scale of prevalence bias for both historical and modern anthropometric indicator results. As a demonstration of the efficacy of this exercise, the bias scale for a set of 21 child anthropometry datasets collected in LMIC contexts is presented., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Grange et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Helicobacter pylori (H. pylori)-a gastric bacteria affecting almost 50% of the global population and leading to ulcers and cancer in severe cases-is a growing health concern among Indigenous populations who report a high burden of reported poor general health and gastrointestinal distress. We test hypothesized associations between H. pylori exposure patterns and environmental, social, and biological conditions among a sample of 212 Indigenous Awajún adults (112 males, 100 females, ages 18-65 years) living in the northern Peruvian Amazon., Materials and Methods: Dried blood spots were analyzed for H. pylori-specific IgG using a recently developed enzyme-linked immunosorbent assay. Resulting seropositivity rates and antibody concentrations, proxying past exposures to H. pylori were analyzed in relation to relevant environmental (toilet type, floor material, reported water quality), social (household size and education level), and biological (age, sex, BMI, blood pressure, immune and metabolic biomarkers) factors using multivariable regression analyses., Results: We found near ubiquitous seropositivity for H. pylori exposure in our sample (99.1% seropositive). In the regression analyses, elevations in H. pylori antibody concentrations were significantly higher among males compared to females (β = 0.36, p = 0.01). No associations were found with any other factors., Discussion: Anthropological research in the study communities suggests that the male bias in elevations of H. pylori antibody concentrations is related to cultural and biological factors. Future research is needed to further unravel these biocultural dynamics and determine whether elevations in H. pylori antibody concentrations have clinical relevance for gastrointestinal health outcomes in this population., (© 2024 The Authors. American Journal of Biological Anthropology published by Wiley Periodicals LLC.)

Competing Interests: Competing interests statement:The authors declare no existing or potential competing interest.

There is a longstanding debate about the role of nitrogen (N) vs phosphorus (P) in limiting primary production in lakes and whether co-nutrient limitation should be considered for managing eutrophication. We evaluated nutrient limitation and eutrophication at a subcontinental scale. Using U.S. Environmental Protection Agency National Lakes Assessment data, we assessed broad-scale patterns in nutrient limitation and compared samples of all surveyed lakes and lakes resurveyed in multiple surveys. We found that N correlated more strongly with productivity in the western U.S., while P correlated more strongly in the eastern U.S. The aggregated subcontinental effect suggests the importance of factors like N-deposition, terrestrial vegetation, underlying geology, and land use for understanding drivers of nutrient dynamics in lakes. Our study showed how patterns can aggregate across subcontinental scales yet still demonstrate considerable variation when more deeply examined on an individual lake level. Overall, we found that nutrient limitation is dynamic over space and time, with most lakes being co-limited. The prevalence of co-limitation also increased from 2007 to 2017. Trophic states within each limitation category varied substantially. Our findings underscore the need for combined N and P reductions to mitigate accelerated eutrophication.

Frontloading home care visits has been found to be effective in the nursing profession but has not been investigated in physical therapy (PT) practice. This study aimed to examine the impact of frontloading home PT visits on function in persons with heart failure (HF). This was a prospective multi-center randomized controlled trial with blinded raters. A total of 82 ambulatory patients with a primary diagnosis of HF discharged from an acute care facility to home care participated in the study. Subjects were randomly allocated to an experimental frontloaded group (FLG) or control group (CG) for 4 weeks. FLG visit frequencies were five sessions per week for 2 weeks, and three sessions per week for 2 weeks. The CG received two sessions per week for 4 weeks. Functional measures including the 2-minute step test (2MST), 2-minute walk test (2MWT), gait speed (GS), Timed Up and Go (TUG), and 30-second chair rise test (30-CRT) were collected at the onset of care, at the end of 2 weeks and 4 weeks. The groups were statistically similar at baseline for all measures. All subjects significantly improved scores in all functional measures over time, within-subject main effect (p < .01). Significant between-subject effects were noted for 30-CRT (p = .04). Interaction effects were noted for GS (p = .03) and TUG test (p = .02). This is the first study to report meaningful improvements in function in individuals with HF. Significant treatment effect differences between the FLG and CG were found for GS, TUG, and 30-CRT. Future studies should examine the use of a standardized intervention to validate the effectiveness of frontloading home visits on quality of life and readmission rates., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Artificial light at night (ALAN) is negatively impacting numerous species of nocturnally active birds. Nocturnal positive phototaxis, the movement towards ALAN, is exhibited by many marine birds and can result in stranding on land. Seabird species facing major population declines may be most at risk. Leach's Storm-Petrels (Hydrobates leucorhous) are small, threatened seabirds with an extensive breeding range in the North Atlantic and North Pacific Oceans. The Atlantic population, which represents approximately 40-48% of the global population, is declining sharply. Nocturnal positive phototaxis is considered to be a key contributing factor. The Leach's Storm-Petrel is the seabird species most often found stranded around ALAN in the North Atlantic, though there is little experimental evidence that reduction of ALAN decreases the occurrence of stranded storm-petrels. During a two-year study at a large, brightly illuminated seafood processing plant adjacent to the Leach's Storm-Petrel's largest colony, we compared the number of birds that stranded when the lights at the plant were on versus significantly reduced. We recorded survival, counted carcasses of adults and juveniles, and released any rescued individuals. Daily morning surveys revealed that reducing ALAN decreased strandings by 57.11% (95% CI: 39.29% - 83.01%) per night and night surveys revealed that reducing ALAN decreased stranding of adult birds by 11.94% (95% CI: 3.47% - 41.13%) per night. The peak stranding period occurred from 25 September to 28 October, and 94.9% of the birds found during this period were fledglings. These results provide evidence to support the implementation of widespread reduction and modification of coastal artificial light as a conservation strategy, especially during avian fledging and migration periods., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Burt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tryptophan is an essential amino acid transformed by host and gut microbial enzymes into metabolites that regulate mucosal homeostasis through aryl hydrocarbon receptor (AhR) activation. Alteration of tryptophan metabolism has been associated with chronic inflammation; however, whether tryptophan supplementation affects the metabolite repertoire and AhR activation under physiological conditions in humans is unknown. We performed a randomized, double blind, placebo-controlled, crossover study in 20 healthy volunteers. Subjects on a low tryptophan background diet were randomly assigned to a 3-wk l-tryptophan supplementation (3 g/day) or placebo, and after a 2-wk washout switched to opposite interventions. We assessed gastrointestinal and psychological symptoms by validated questionnaires, AhR activation by cell reporter assay, tryptophan metabolites by liquid chromatography and high-resolution mass spectrometry, cytokine production in isolated monocytes by ELISA, and microbiota profile by 16S rRNA Illumina technique. Oral tryptophan supplementation was well tolerated, with no changes in gastrointestinal or psychological scores. Compared with placebo, tryptophan increased AhR activation capacity by duodenal contents, but not by feces. This was paralleled by higher urinary and plasma kynurenine metabolites and indoles. Tryptophan had a modest impact on fecal microbiome profiles and no significant effect on cytokine production. At the doses used in this study, oral tryptophan supplementation in humans induces microbial indole and host kynurenine metabolic pathways in the small intestine, known to be immunomodulatory. The results should prompt tryptophan intervention strategies in inflammatory conditions of the small intestine where the AhR pathway is impaired. NEW & NOTEWORTHY We demonstrate that in healthy subjects, orally administered tryptophan activates microbial indole and host kynurenine pathways in the small intestine, the primary metabolic site for dietary components, and the richest source of immune cells along the gut. This study provides novel insights in how to optimally activate immunomodulatory AhR pathways and indole metabolism in the small intestine, serving as basis for future therapeutic trials using l-tryptophan supplementation in chronic inflammatory conditions affecting the small intestine.

Background: Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors., Methods: Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian E max model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities., Perspective: Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life., Trial Registration: ClinicalTrials.gov ID: NCT05546476., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Introduction: Water insecurity-the inability to access and benefit from affordable, reliable and safe water for basic needs-is a considerable global health threat. With the urgent need to target interventions to the most vulnerable, accurate and meaningful measurement is a priority. Households use diverse strategies to cope with water insecurity; however, these have not been systematically characterised nor measured. The Food Insecurity Coping Strategies Index has been insightful for targeting nutrition interventions to the most vulnerable. As a first step towards creating an analogous scale for water, this study characterises the largest empirical data set on water insecurity coping strategies and proposes guidance on measuring it using a novel toolkit., Methods: Open-ended responses on water insecurity coping (n=2301) were collected across 11 sites in 10 low- and middle-income countries in the Household Water InSecurity Experiences (HWISE) Scale validation study. Responses were characterised and compared with behaviours identified in the literature to construct an instrument to systematically assess coping., Results: We identified 19 distinct strategies that households used when experiencing water insecurity. These findings, paired with prior literature, were used to develop a Water Insecurity Coping Strategies Assessment Toolkit with guidance on its piloting to assess coping prevalence, frequency and severity., Conclusions: The widespread occurrence of water insecurity coping strategies underscores the importance of understanding their prevalence and severity. The Water Insecurity Coping Strategies Assessment Toolkit offers a comprehensive approach to evaluate these strategies and inform the design and monitoring of interventions targeting those most vulnerable to water insecurity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

The purpose of this study was to observe if core stabilization training plays a significant role in firefighter time-to-completion during a functional performance test. A within subjects study design was used in which subjects ( n = 13, 84.6% male, 33.7 ± 7.4 years of age, 91.06 ± 13.29 kg, 25.79 ± 6.55 percent body fat, 8.96 ± 7.51 years of firefighting experience) completed two performance tests (pre and post core training), comprised of 7 firefighter-specific exercises performed while wearing a 22.68 kg weight vest to mimic typical firefighter equipment. Between testing sessions, subjects were prescribed specific core stabilization exercises to perform at least three days a week for a total of 4 weeks. Time-to-completion was significantly quicker between the first (300.89 ± 42.11s) and second (256.92 ± 34.31s) performance testing, on average by 43.8 seconds ( p < 0.001). Body mass index ( p = 0.065) and rating of perceived exertion during testing ( p = 0.084) did not significantly decrease across the course of the study. Adequate fitness is essential to firefighters' job task performance. Data from this study suggests that regular core stabilization training may assist in optimizing the effectiveness, and potentially safety, of firefighters' performance in high intensity functional skills.

Mild traumatic brain injury (mTBI) is a leading cause of disability in the United States, with neuropsychiatric disturbances such as depression, anxiety, PTSD, and social disturbances being common comorbidities following injury. The molecular mechanisms driving neuropsychiatric complications following neurotrauma are not well understood and current FDA-approved pharmacotherapies employed to ameliorate these comorbidities lack desired efficacy. Concerted efforts to understand the molecular mechanisms of and identify novel drug candidates for treating neurotrauma-elicited neuropsychiatric sequelae are clearly needed. Serotonin (5-HT) is linked to the etiology of neuropsychiatric disorders, however our understanding of how various forms of TBI directly affect 5-HT neurotransmission is limited. 5-HT neurons originate in the raphe nucleus (RN) of the midbrain and project throughout the brain to regulate diverse behavioral phenotypes. We hypothesize that the characterization of the dynamics governing 5-HT neurotransmission after injury will drive the discovery of novel drug targets and lead to a greater understanding of the mechanisms associated with neuropsychiatric disturbances following mild TBI (mTBI). Herein, we provide evidence that closed-head mTBI alters total DRN 5-HT levels, with RNA sequencing of the DRN revealing injury-derived alterations in transcripts required for the development, identity, and functional stability of 5-HT neurons. Further, using gene ontology analyses combined with immunohistological analyses, we have identified a novel mechanism of transcriptomic control within 5-HT neurons that may directly influence 5-HT neuron identity/function post-injury. These studies provide molecular evidence of injury-elicited 5-HT neuron dysregulation, data which may expedite the identification of novel therapeutic targets to attenuate TBI-elicited neuropsychiatric sequelae., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/purpose: No studies have observed the effects of a collegiate lacrosse season on movement pattern quality, dynamic postural control, or the accuracy of athletes' perceived movement pattern quality. The purpose was to examine the effects of a nontraditional fall season on movement pattern quality, perceived movement pattern quality, and dynamic postural control in collegiate lacrosse athletes., Design: Cross-sectional laboratory study., Methods: Fifty men's (age=19.38±1.24 years, height=182.63±6.16 cm, mass=82.37±8.46 kg) and 22 women's (age=19.68±1.17 years, height=165.10±6.88 cm, mass=64.09±8.72 kg) lacrosse players were recruited. Outcome measures included individual Functional Movement Screen™ (FMS™) scores, self-reported perceived movement pattern quality scores, lower and upper extremity Y-Balance Test (YBT) measurements, and active dorsiflexion range of motion (ROM) before the start and again at the end of the fall lacrosse season. Pre- and post-season measurements were assessed using paired t-tests and chi-squared analyses., Results: FMS™ composite scores did not significantly change from preseason to postseason for males (p=0.74) or females (p=0.07). Male perceived movement pattern quality was significantly higher than measured for 10 of 12 movements (p<0.05). Female perceived movement pattern quality was significantly higher than measured for four of 12 movements (p<0.05). Asymmetry frequency significantly increased in males in the hurdle step from two individuals to nine ( χ 2 1 =25.52, p<0.01), inline lunge from 10 to 20 ( χ 2 1 =12.50, p<0.01), and shoulder mobility from 4 to 21 ( χ 2 1 =78.53, p<0.01). Asymmetries in male athletes significantly decreased in the active straight leg raise from 26 to 8 ( χ 2 1 =25.96, p<0.01). YBT composite scores increased in males for the right leg (p=0.001) and left leg (p<0.03). Right dorsiflexion ROM (p<0.001) and left dorsiflexion ROM (p<0.001) significantly decreased in males from preseason to postseason. YBT scores for the right leg significantly increased in females from preseason to postseason (p=0.01). YBT scores for females for the right arm significantly increased from preseason to postseason (p=0.045)., Conclusions: A 5-week season may not change overall movement pattern quality of men's or women's lacrosse players, but some individual movement scores diminished. Athletes may overestimate self-reported movement pattern quality and are therefore unlikely to individually address movement deficits. Male dynamic postural control may change throughout a season, resulting in a potential increased risk of injury later in the season due to compensatory patterns or changes in mobility, proprioception, or balance., Level of Evidence: 3b., Competing Interests: The authors report no conflicts of interest, (© The Author(s).)

Systematic control and design of solid-state chemical reactions are required for modifying materials properties and in novel synthesis. Understanding chemical dynamics at the nanoscale is therefore essential to revealing the key reactive pathways. Herein, we combine focused ion beam-scanning electron microscopy (FIB-SEM) and time-of-flight secondary ion mass spectrometry (TOF-SIMS) to track the migration of sodium from a borate coating to the oxide scale during in situ hot corrosion testing. We map the changing distribution of chemical elements and compounds from 50 to 850 °C to reveal how sodium diffusion induces corrosion. The results are validated by in situ X-ray diffraction and post-mortem TOF-SIMS. We additionally retrieve the through-solid sodium diffusion rate by fitting measurements to a Fickian diffusion model. This study presents a step change in analyzing microscopic diffusion mechanics with high chemical sensitivity and selectivity, a widespread analytical challenge that underpins the defining rates and mechanisms of solid-state reactions.

Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium associated with localized aggressive periodontitis as well as some systemic diseases. The strains of A. actinomycetemcomitans most closely associated with disease produce more of a secreted leukotoxin (LtxA) than isolates from healthy carriers, suggesting a key role for this toxin in disease progression. LtxA is released into the bacterial cytosol in a free form as well as in association with the surface of outer membrane vesicles (OMVs). We previously observed that the highly leukotoxic A. actinomycetemcomitans strain JP2 produces two populations of OMVs: a highly abundant population of small (<100 nm) OMVs and a less abundant population of large (>300 nm) OMVs. Here, we have developed a protocol to isolate the OMVs produced during each specific phase of growth and used this to demonstrate that small OMVs are produced throughout growth and lack LtxA, while large OMVs are produced only during the exponential phase and are enriched with LtxA. Our results indicate that surface-associated DNA drives the selective sorting of LtxA into large OMVs. This study provides valuable insights into the observed heterogeneity of A. actinomycetemcomitans vesicles and emphasizes the importance of understanding these variations in the context of bacterial pathogenesis.

Absolute gamma-ray emission intensities for 36 characteristic gamma rays from the decay of 224 Ra, 212 Pb, and their progeny were determined by measuring sources calibrated for activity by means of primary methods based on well-defined high-purity germanium (HPGe) detectors at both NIST and NPL. Results from the two laboratories agree with recent data evaluations, except for gamma rays with low emission intensities. The decay schemes have been re-balanced based on the new results. In addition, the half-life for 212 Pb was measured using several HPGe detectors, ionization chambers, and a well-type NaI(Tl) detector., 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., (Published by Elsevier Ltd.)

Purpose: Prebiotic foods can be used to increase production of short-chain fatty acids (SCFA) in the gut. Of the SCFA, propionate is credited with the strongest anorectic activity. In previous work, a 50/50 blend of inulin and arabinoxylan was produced (I + AX) that significantly increased propionate production in an in vitro gut model. This study sought to establish whether chronic consumption of a prebiotic blend of I + AX decreases appetite and energy intake and increases intestinal propionate production in human participants., Methods: MIXSAT (clinicaltrials.gov id: NCT02846454, August 2016) was a double-blind randomised acute-within-chronic crossover feeding trial in healthy adult men (n = 20). Treatments were 8 g per day I + AX for 21 days or weight-matched maltodextrin control. The primary outcome measure was perceived satiety and appetite during an acute study visit. Secondary outcomes were energy intake in an ad libitum meal, faecal SCFA concentration, and faecal microbiota composition., Results: Perceived satiety and appetite were not affected by the intervention. I + AX was associated with a reduction in energy intake in an ad libitum meal, increased faecal SCFA concentration, and an increase in cell counts of Bifidobacteria, Lactobacilli, and other microbial genera associated with health., Implications: Chronic consumption of this blend of prebiotics decreased energy intake in a single sitting. Further studies are needed to confirm mechanism of action and to determine whether this might be useful in weight control., (© 2023. Crown.)

Purpose: Cachexia is common in patients with advanced cancer and is associated with elevated serum growth differentiation factor 15 (GDF-15) concentrations. This first-in-patient (phase Ib), 24-week study assessed use of ponsegromab, a mAb against GDF-15, in adults with advanced cancer, cachexia, and elevated GDF-15 serum concentration., Patients and Methods: Participants (n = 10) received open-label ponsegromab subcutaneous 200 mg every 3 weeks for 12 weeks in addition to standard-of-care anticancer treatment. Ponsegromab safety, tolerability, and pharmacokinetics were assessed in addition to serum GDF-15 concentrations and exploratory measures of efficacy., Results: No treatment-related treatment-emergent adverse events, injection site reactions, or adverse trends in clinical laboratory tests, vital signs, or electrocardiogram parameters attributable to ponsegromab were identified. Median serum unbound GDF-15 concentration at baseline was 2.269 ng/mL. Following initiation of study treatment, median unbound GDF-15 concentrations were below the lower limit of quantification (0.0424 ng/mL) from day 1 (3 hours postdose) through week 15. Increases in body weight were observed at all time points during the treatment and follow-up periods. A least-squares mean (SE) increase of 4.63 (1.98) kg was observed at week 12, an increase of approximately 6.6% relative to baseline. Ponsegromab-mediated improvements in actigraphy-based assessments of physical activity and in quality of life, including appetite as assessed by Functional Assessment of Anorexia-Cachexia Therapy total and subscale scores, were also observed., Conclusions: Ponsegromab was well tolerated, suppressed serum GDF-15 concentrations, and demonstrated preliminary evidence of efficacy. These findings support the continued development of ponsegromab for the treatment of cachexia., (©2023 The Authors; Published by the American Association for Cancer Research.)

Simple, efficient and well-tolerated delivery of CRISPR genome editing systems into primary cells remains a major challenge. Here we describe an engineered Peptide-Assisted Genome Editing (PAGE) CRISPR-Cas system for rapid and robust editing of primary cells with minimal toxicity. The PAGE system requires only a 30-min incubation with a cell-penetrating Cas9 or Cas12a and a cell-penetrating endosomal escape peptide to achieve robust single and multiplex genome editing. Unlike electroporation-based methods, PAGE gene editing has low cellular toxicity and shows no significant transcriptional perturbation. We demonstrate rapid and efficient editing of primary cells, including human and mouse T cells, as well as human hematopoietic progenitor cells, with editing efficiencies upwards of 98%. PAGE provides a broadly generalizable platform for next-generation genome engineering in primary cells., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background & Aims: Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract., Methods: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88 -/- Trif -/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot., Results: Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects., Conclusions: Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Inconsistencies within the 68 Ga half-life dataset have been repeatedly identified in nuclear decay data evaluations performed over the past decade. In this paper, a half-life has been determined using ionisation chambers measurements and HPGe gamma-ray spectrometry (T 1/2  = 67.783(27) min). The current literature has been reviewed and possible causes of discrepancy have been identified, such as neglected contaminant effects, robustness of analysis, and underestimation of systematic effects. This could lead to a significant improvement of the half-life in future evaluations., 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 © 2023. Published by Elsevier Ltd.)

The health care industry has sought to reduce errors and patient harm by drawing upon human factors research developed largely in the aviation industry. However, literature that explicitly applies human factors concepts to physical therapist practice is scarce. Therefore, this clinical perspective highlights the key concepts in aviation safety and training that should be considered for application to physical therapist education and practice in the acute care setting, including the law of primacy, pilot in command, crew resource management, situational awareness, the instrument scan, currency versus proficiency, the advanced qualification program, and the use of checklists. The authors identify, discuss, and apply existing parallel concepts in physical therapist literature. The authors then challenge acute care physical therapists, academic faculty, and clinical instructors on ways to integrate these concepts in practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Many seabirds are attracted to anthropogenic light, and the risk is greater for recent fledglings. Moon phase predicts the probability of stranding (fewer birds strand on the full moon), but it remains uncertain whether moon phase is associated with when young seabirds fledge. Fledging behaviour of nocturnal, burrowing seabirds can be difficult to monitor using traditional methods but can provide insight into environmental factors that influence the risk of stranding. We used passive integrated transponder tags to monitor the fledging dates and times of Leach's storm-petrel ( Hydrobates leucorhous ) chicks across four breeding seasons (2017, 2018, 2021, 2022) at a major colony in Newfoundland and Labrador, Canada. We also assessed whether moon phase and incident illumination related to fledging date and time. The median fledge time was 1.6 h after sunset (0.6-11.7 h). The median fledge date was 10 October, and fledging dates ranged from 13 September to 13 November. Most importantly, moon phase was not associated with the time and date that Leach's storm-petrel chicks fledged. These results suggest that recently fledged storm-petrels are less attracted to anthropogenic light during high levels of natural illumination, which could indicate periods of higher stranding risk and help concentrate conservation efforts.

Terbium-152 is one of four terbium radioisotopes that together form a potential theranostic toolbox for the personalised treatment of tumours. As 152  Tb decay by positron emission it can be utilised for diagnostics by positron emission tomography. For use in radiopharmaceuticals and for activity measurements by an activity calibrator a high radionuclide purity of the material and an accurate and precise knowledge of the half-life is required. Mass-separation and radiochemical purification provide a production route of high purity 152 Tb. In the current work, two mass-separated samples from the CERN-ISOLDE facility have been assayed at the National Physical Laboratory to investigate the radionuclide purity. These samples have been used to perform four measurements of the half-life by three independent techniques: high-purity germanium gamma-ray spectrometry, ionisation chamber measurements and liquid scintillation counting. From the four measurement campaigns a half-life of 17.8784(95) h has been determined. The reported half-life shows a significant difference to the currently evaluated half-life (ζ-score = 3.77), with a relative difference of 2.2 % and an order of magnitude improvement in the precision. This work also shows that under controlled conditions the combination of mass-separation and radiochemical separation can provide high-purity 152 Tb., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lead mixed-halide perovskites offer tunable bandgaps for optoelectronic applications, but illumination-induced phase segregation can quickly lead to changes in their crystal structure, bandgaps, and optoelectronic properties, especially for the Br-I mixed system because CsPbI3 tends to form a non-perovskite phase under ambient conditions. These behaviors can impact their performance in practical applications. By embedding such mixed-halide perovskites in a glassy metal-organic framework, a family of stable nanocomposites with tunable emission is created. Combining cathodoluminescence with elemental mapping under a transmission electron microscope, this research identifies a direct relationship between the halide composition and emission energy at the nanoscale. The composite effectively inhibits halide ion migration, and consequently, phase segregation even under high-energy illumination. The detailed mechanism, studied using a combination of spectroscopic characterizations and theoretical modeling, shows that the interfacial binding, instead of the nanoconfinement effect, is the main contributor to the inhibition of phase segregation. These findings pave the way to suppress the phase segregation in mixed-halide perovskites toward stable and high-performance optoelectronics., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Introduction: Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using 133 Ba as a surrogate for 131 I imaging., Materials and Methods: Two sets of four traceable 133 Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68-107.4 mL). Corresponding hollow cylinders to be filled with liquid 131 I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of 133 Ba sources and liquid 131 I., Results: As anticipated, the 131 I pseudo-image calibration factors (cps/MBq) were higher than those for 133 Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12-1.5%. The site-specific cross-calibration method also showed agreement between 133 Ba and 131 I for all cylinder volumes, which highlights the potential use of 133 Ba sources to calculate recovery coefficients for partial volume correction., Conclusion: This comparison exercise demonstrated that traceable solid 133 Ba sources can be used as surrogate for liquid 131 I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with 131 I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals., (© 2023. The Author(s).)

The stellar optoelectronic properties of metal halide perovskites provide enormous promise for next-generation optical devices with excellent conversion efficiencies and lower manufacturing costs. However, there is a long-standing ambiguity as to whether the perovskite surface/interface (e.g. structure, charge transfer or source of off-target recombination) or bulk properties are the more determining factor in device performance. Here we fabricate an array of CsPbI 3 crystal and hybrid glass composites by sintering and globally visualise the property-performance landscape. Our findings reveal that the interface is the primary determinant of the crystal phases, optoelectronic quality, and stability of CsPbI 3 . In particular, the presence of a diffusion "alloying" layer is discovered to be critical for passivating surface traps, and beneficially altering the energy landscape of crystal phases. However, high-temperature sintering results in the promotion of a non-stoichiometric perovskite and excess traps at the interface, despite the short-range structure of halide is retained within the alloying layer. By shedding light on functional hetero-interfaces, our research offers the key factors for engineering high-performance perovskite devices., (© 2023. The Author(s).)

We present an approach to harnessing the tuneable catalytic properties of complex nanomaterials for continuous flow heterogeneous catalysis by combining them with the scalable and industrially implementable properties of carbon pelleted supports. This approach, in turn, will enable these catalytic materials, which largely currently exist in forms unsuitable for this application ( e.g. powders), to be fully integrated into large scale, chemical processes. A composite heterogeneous catalyst consisting of a metal-organic framework-based Lewis acid, MIL-100(Sc), immobilised onto polymer-based spherical activated carbon (PBSAC) support has been developed. The material was characterised by focused ion beam-scanning electron microscopy-energy dispersive X-ray analysis, powder X-ray diffraction, N 2 adsorption, thermogravimetric analysis, atomic absorption spectroscopy, light scattering and crush testing with the catalytic activity studied in continuous flow. The mechanically robust spherical geometry makes the composite material ideal for application in packed-bed reactors. The catalyst was observed to operate without any loss in activity at steady state for 9 hours when utilised as a Lewis acid catalyst for the intramolecular cyclisation of (±)-citronellal as a model reaction. This work paves the way for further development into the exploitation of MOF-based continuous flow heterogeneous catalysis.

Palladium nanoparticles stabilised by aniline modified polymer immobilised ionic liquid is a remarkably active catalyst for the hydrogenation of CO 2 to formate; the initial TOF of 500 h -1 is markedly higher than either unmodified catalyst or its benzylamine and N , N -dimethylaniline modified counterparts and is among the highest to be reported for a PdNP-based catalyst.

Species occurrence data are foundational for research, conservation, and science communication, but the limited availability and accessibility of reliable data represents a major obstacle, particularly for insects, which face mounting pressures. We present BeeBDC, a new R package, and a global bee occurrence dataset to address this issue. We combined >18.3 million bee occurrence records from multiple public repositories (GBIF, SCAN, iDigBio, USGS, ALA) and smaller datasets, then standardised, flagged, deduplicated, and cleaned the data using the reproducible BeeBDC R-workflow. Specifically, we harmonised species names (following established global taxonomy), country names, and collection dates and, we added record-level flags for a series of potential quality issues. These data are provided in two formats, "cleaned" and "flagged-but-uncleaned". The BeeBDC package with online documentation provides end users the ability to modify filtering parameters to address their research questions. By publishing reproducible R workflows and globally cleaned datasets, we can increase the accessibility and reliability of downstream analyses. This workflow can be implemented for other taxa to support research and conservation., (© 2023. The Author(s).)

Recently, increased attention has been focused on amorphous metal-organic frameworks (MOFs) and, more specifically, MOF glasses, the first new glass category discovered since the 1970s. In this work, we explore the fabrication of a compositional series of hybrid blends, the first example of blending a MOF and inorganic glass. We combine ZIF-62(Zn) glass and an inorganic glass, 30Na 2 O-70P 2 O 5 , to combine the chemical versatility of the MOF glass with the mechanical properties of the inorganic glass. We investigate the interfacial interactions between the two components using pair distribution function analysis and solid state NMR spectroscopy, and suggest potential interactions between the two phases. Thermal analysis of the blend samples indicated that they were less thermally stable than the starting materials and had a T g shifted relative to the pristine materials. Annular dark field scanning transmission electron microscopy tomography, X-ray energy dispersive spectroscopy (EDS), nanoindentation and 31 P NMR all indicated close mixing of the two phases, suggesting the formation of immiscible blends., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The monoamine neurotransmitter serotonin (5-HT) is important for the regulation of behavior, and aberrations in 5-HT signaling are linked to several neuropsychiatric and neurodevelopmental disorders. 5-HT signaling is dependent on and tightly regulated by the functional activity of the 5-HT transporter (SERT). Neurotrauma is known to structurally and functionally impact 5-HT neuronal tracts and 5-HT signaling; however, the extent to which various forms of neurotrauma alter homeostatic 5-HT signaling through the modulation of SERT expression and/or functional uptake capacity is currently not well characterized. We aimed to better characterize the protein expression and uptake activity of SERT following mild traumatic brain injury (mTBI). A murine model of blast-induced mTBI was utilized to characterize alterations in SERT expression and function following injury. mTBI was found to decrease (≈26%) the protein levels of SERT 3 days postinjury (DPI) in the dorsal raphe nucleus (DRN), the primary locale of 5-HT neuronal cell bodies within the central nervous system. Concomitant reductions in midbrain SERT-dependent radiolabeled 5-HT uptake were observed 3 DPI (≈24%). No alterations in SERT expression were observed 10 DPI in the DRN. Additionally, no alterations in SERT expression or function were observed in prefrontal cortex samples at any time point observed. This data reveals time- and location-dependent alterations in SERT expression and function following mTBI. These studies illustrate the critical importance of ongoing research efforts to characterize the molecular effects of various forms of neurotrauma on SERT protein expression and function, which may yield novel drug targets within 5-HT systems., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T cell therapy is used in treating human hematological malignancies, but its efficacy is limited by T cell exhaustion (T EX ). T EX arises at the expense of central memory T cells (T CM ), which exhibit robust antitumor efficacy. Reduction of the TET2 gene led to increased T CM differentiation in a patient with leukemia who experienced a complete remission. We show that loss of TET2 led to increased chromatin accessibility at exhaustion regulators TOX and TOX2, plus increased expression of TOX2. Knockdown of TOX increased the percentage of T CM . However, unexpectedly, knockdown of TOX2 decreased T CM percentage and reduced proliferation. Consistently, a T CM gene signature was reduced in the TOX2 knockdown, and TOX2 bound to promoters of numerous T CM genes. Our results thus suggest a role for human TOX2, in contrast to exhaustion regulator TOX, as a potentiator of central memory differentiation of CAR T cells, with plausible utility in CAR T cell cancer therapy via modulated TOX2 expression.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon-mediated inhibitory program but also independently expands early memory CAR T cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon-associated CAR T cell failure and shorter patient survival. These findings connect prolonged CAR T cell activation with deleterious immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biological system., Significance: To improve CAR T cell therapy outcomes, modulating molecular determinants of CAR T cell-intrinsic resistance is crucial. Editing the gene encoding the EGR2 transcriptional regulator renders CAR T cells impervious to type I interferon pathway-induced dysfunction and improves memory differentiation, thereby addressing major barriers to progress for this emerging class of cancer immunotherapies. This article is highlighted in the In This Issue feature, p. 1501., (©2023 American Association for Cancer Research.)