Maternal Microvascular Dysfunction During and After Preeclamptic Pregnancy.

Preeclampsia, a pregnancy disorder characterized by de novo hypertension and maternal multisystem organ dysfunction, is the leading cause of maternal mortality worldwide and is associated with a fourfold greater risk of cardiovascular disease throughout the lifespan. Current understanding of the etiology of preeclampsia remains unclear, due in part to the varying phenotypical presentations of the disease, which has hindered the development of effective and mechanism-specific treatment or prevention strategies both during and after the affected pregnancy. These maternal sequelae of preeclampsia are symptoms of systemic vascular dysfunction in the maternal nonreproductive microvascular beds that drives the development and progression of adverse cardiovascular outcomes during preeclampsia. Despite normalization of vascular disturbances after delivery, subclinical dysfunction persists in the nonreproductive microvascular beds, contributing to an increased lifetime risk of cardiovascular and metabolic diseases and all-cause mortality. Given that women with a history of preeclampsia demonstrate vascular dysfunction despite an absence of traditional CVD risk factors, an understanding of the underlying mechanisms of microvascular dysfunction during and after preeclampsia is essential to identify potential therapeutic avenues to mitigate or reverse the development of overt disease. This article aims to provide a summary of the existing literature on the pathophysiology of maternal microvascular dysfunction during preeclampsia, the mechanisms underlying the residual dysfunction that remains after delivery, and current and potential treatments both during and after the affected pregnancy that may reduce microvascular dysfunction in these high-risk women. © 2024 American Physiological Society. Compr Physiol 14:5703-5727, 2024.

Strategic insights from a Delphi study: enhancing employment for multiply marginalized people with disabilities.

Introduction: The employment landscape for multiply marginalized people with disabilities presents significant challenges, exacerbated by intersecting identities such as race/ethnicity, sexual orientation, gender identity, poverty, and geography. Recent studies highlight the compounded employment disparities faced by this group, including discriminatory hiring practices, inadequate accommodations, and uneven gains in employment during the COVID-19 public health emergency. Methods: Our study employed a three-round Delphi process with 20 diverse experts across 14 states across the United States (U.S.) to formulate recommendations for improving employment experiences for multiply marginalized people with disabilities. The panel's insights were gathered through surveys administered online, with each round designed to refine the collective recommendations. This iterative process aimed to build a consensus on the most effective policy and practice recommendations for improving employment outcomes within this population. Results: The Delphi study identified key areas for strategic focus, including emergency preparedness, education and training, transportation, assistive technology, workplace accommodations, and combating discrimination and stigma. Notable recommendations included improving emergency preparedness training, enhancing employment education, increasing funding for accessible transportation and assistive technology, and promoting inclusive hiring practices. The study also emphasized the need for policies supporting telework and simplifying disability-related benefits. Discussion: The findings highlight the critical role of tailored strategies to address employment challenges faced by people with disabilities from marginalized communities. Meaningfully and fully implementing these recommendations would create a more inclusive environment that improves employment outcomes for multiply marginalized people with disabilities.

Counting everyone: evidence for inclusive measures of disability in federal surveys.

The US Census Bureau has used the American Community Survey six-question set (ACS-6) to identify disabled people since 2008. In late 2023, the Census Bureau proposed changes to these questions that would have reduced disability prevalence estimates by 42%. Because these estimates inform funding and programs that support the health and independence of people with disabilities, many disability researchers and advocates feared this change in data collection would lead to reductions in funding and services. While the Census has paused-but not ruled out-the proposed changes, it is critical that alternate, more inclusive disability questions be identified and tested. We used data from the 2023/2024 National Survey on Health and Disability to explore alternative questions to identify disabled people in national surveys. A single broad question about conditions identified 11.2% more people with disabilities, and missed significantly fewer people with psychiatric disabilities compared to the current ACS-6 questions. A combination of a broad question and the existing ACS-6 questions may be necessary to more accurately and inclusively identify people with disabilities.

ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

Telemedicine-based serious illness conversations, healthcare utilization, and end of life care among patients with advanced lung cancer.

PURPOSE: Little is known about serious illness conversations (SIC) conducted during telemedicine visits and their impact on end-of-life (EOL) outcomes for patients with advanced cancer. PATIENTS AND METHODS: We conducted a retrospective analysis telemedicine visits for patients with metastatic lung cancer conducted during the first surge of the COVID-19 pandemic (October 3, 2020-October 6, 2020). We used natural language processing (NLP) to characterize documentation of SIC domains (ie, goals of care [GOC], limitation of life-sustaining treatment [LLST], prognostic awareness [PA], palliative care [PC], and hospice). We used unadjusted logistic regression to evaluate factors associated with SIC documentation and the relationship between SIC documentation and EOL outcomes. RESULTS: The study included 634 telemedicine visits across 360 patients. Documentation of at least one SIC domain was present in 188 (29.7%) visits with GOC and PA being the most discussed domains. Family presence (odds ratio [OR], 1.66; P = .004), progressive or newly diagnosed disease (OR, 5.42; P < .000), age ≥ 70 (OR, 1.80; P = .009), and male sex (OR, 2.23; P < .000) were associated with a greater likelihood of discussing ≥ 1 SIC domain. Of the 61 patients who died within 12 months of the study period, having ≥ 1 SIC domain discussed was associated with a lower likelihood of hospitalization in the last 30 days of life (OR, 0.27; P = .020). CONCLUSION: In this study of telehealth visits, we identified important factors associated with an increased likelihood of having documentation of an SIC and demonstrated that SIC documentation correlated with lower likelihood of hospitalization at EOL.

Long COVID Among People With Preexisting Disabilities.

Objectives. To document the prevalence of long COVID among a sample of survey respondents with long-term disabilities that existed before 2020 and to compare the prevalence among this group with that among the general population. Methods. We conducted a cross-sectional, descriptive study using data from the 2022 National Survey on Health and Disability (n = 2262) and comparative data for the general population from the federal Household Pulse Survey (HPS). Results. The prevalence of long COVID was higher among people with preexisting disabilities than in the general population (40.6% vs 18.9%). Conclusions. People with preexisting disabilities experienced and continue to experience increased exposure to COVID-19 and barriers to accessing health care, COVID-19 vaccines, and COVID-19 tests. These barriers, combined with long-standing health disparities in this population, may have contributed to the greater prevalence of long COVID among people with disabilities. Public Health Implications. The needs of people with disabilities must be centered in the response to the COVID-19 pandemic and future pandemics. (Am J Public Health. 2024;114(11):1261-1264. https://doi.org/10.2105/AJPH.2024.307794).

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

A Multi-Year Characterization of Confiscated Vaping Products from Virginia School Youth.

The United States (US) Food and Drug Administration's (FDA) regulatory oversight over electronic cigarettes (e-cigs) includes access restriction for persons <21 years of age and flavor restrictions for "cartridge-based" products. Despite the restrictions, consumption by US youth perseveres. Studies on youth e-cig use are limited by the reliability and accuracy of self-reports. As an alternative to self-reports, the current study examined nicotine, cannabinoid, and unlabeled e-cigs and other vaping products confiscated from Virginia public schools to characterize trends among students. Findings highlight a shift from JUUL and pod-based products to single use disposable e-cigs following the FDA flavor restrictions on cartridge-based e-cigs. Chemical analysis of e-liquids by gas chromatography-mass spectrometry identified a wide variety of flavorants and an increase in the prevalence of synthetic coolants. Most confiscated products were nicotine salt formulations, but the prevalence of cannabinoid-based vaping products increased. The popularity of flavored disposable e-cigs highlights the need for further restrictions to reduce youth consumption. The increasing use of synthetic coolants instead of menthol may suggest that manufacturers are employing tactics to bypass regulations. Continued youth access to e-cigs and the abundance of cannabinoid-based products is problematic from health and safety perspectives. Continued research incorporating confiscated product analysis can be used to understand youth access to vaping products and evolutions in manufacturing practices.

Integration of Germline Genetic Testing Into Routine Clinical Practice for Patients With Pancreatic Adenocarcinoma.

PURPOSE: Germline genetic testing (GT) is recommended for all patients with pancreatic ductal adenocarcinoma (PDAC), but the traditional clinical genetics infrastructure is limited in addressing the unique needs of this population. We describe the integration of point of care (POC) GT into routine clinical practice for all patients with PDAC at an academic medical center. METHODS: We developed a clinical POC workflow that leverages electronic health record (EHR) tools and behavioral nudges to enhance the sustainability and scalability of our previously described research-based POC model. For each of the research and clinical POC cohorts, we calculated the percentage of eligible patients who underwent GT. We used Wilcoxon rank-sum and Pearson's chi-squared tests to compare patients who did and did not undergo GT. We conducted surveys among oncology clinicians to evaluate the acceptability, appropriateness, and feasibility of the clinical POC model. RESULTS: The research POC cohort included 905 patients, of whom 694 (76.7%) underwent GT. The clinical POC cohort included 148 patients, of whom 126 (85.1%) underwent GT. Patients who underwent GT in the research POC cohort were significantly younger (median age, 67.0 v 70.9 years; P = .031) and more likely to be White (82.1% v 68.7%; P < .001) and commercially insured (41.8% v 28.0%; P < .001) compared with those who did not; there were no significant differences between GT groups in the clinical POC cohort. Oncology clinicians found the clinical POC model to be acceptable (mean 4.4/5), appropriate (4.6/5), feasible (4.0/5), and have a positive impact on their patients (4.9/5). CONCLUSION: A clinical POC model leveraging EHR tools and behavioral nudges is acceptable, appropriate, feasible, and associated with a >85% GT rate among patients with PDAC.

Electronic Medical Record-Based Nudge Intervention to Increase Comprehensive Molecular Genotyping in Patients With Metastatic Non-Small Cell Lung Cancer: Results From a Prospective Clinical Trial.

PURPOSE: Less than half of the patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) undergo comprehensive molecular testing. We designed an electronic medical record (EMR)-based "nudge intervention" to prompt plasma-based molecular testing at the time of initial medical oncology consultation. METHODS: A nonrandomized prospective trial was conducted at the University of Pennsylvania's academic practice and two affiliated community practices. Molecular genotyping was performed by tissue- and/or plasma-based next generation sequencing methods. Comprehensive testing was defined as testing for EGFR, ALK, BRAF, ROS1, MET, RET, KRAS, and NTRK. Guideline-concordant treatment was defined as the use of the appropriate first-line (1L) therapy as per the National Comprehensive Cancer Network (NCCN) guidelines. Proportion of patients with comprehensive molecular genotyping results available at any time, molecular results available before 1L therapy, and guideline-concordant 1L treatment were compared between the preintervention and postintervention cohorts using Fisher's exact test or Pearson's chi-squared test. RESULTS: Five hundred and thirty-three patients were included, 376 in the preintervention cohort and 157 in the postintervention cohort. After implementation of the EMR-based nudge, a higher proportion of patients underwent comprehensive molecular testing in the postintervention versus the preintervention cohort (100% v 88%, P = <.001), had results of comprehensive molecular testing available before initiating 1L treatment (97.3% v 91.6%, P = .026), and received NCCN guideline-concordant care (89.8% v 78.2%, P = .035). CONCLUSION: Across three practice sites in a large health system, implementation of a provider team-focused EMR-based nudge intervention was feasible, and led to a higher number of patients with NSCLC undergoing comprehensive molecular genotyping. These findings demonstrate that behavioral nudges can promote molecular testing and should be studied further as a tool to improve guideline-concordant care in both community and academic sites.

NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.

A diverse proteome is present and enzymatically active in metabolite extracts.

Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.

Association between oral targeted cancer drug net health benefit, uptake, and spending.

BACKGROUND: Targeted cancer drugs (TCDs) have revolutionized oncology but vary in clinical benefit and patient out-of-pocket (OOP) costs. The American Society of Clinical Oncology (ASCO) Value Framework uses survival, toxicity, and symptom palliation data to quantify the net health benefit (NHB) of cancer drugs. We evaluated associations between NHB, uptake, and spending on oral TCDs. METHODS: We conducted a retrospective cohort study of patients aged 18-64 years with an incident oral TCD pharmacy claim in 2012-2020 in a nationwide deidentified commercial claims dataset. TCDs were categorized as having high (>60), medium (40-60), and low (<40) NHB scores. We plotted the uptake of TCDs by NHB category and used standard descriptive statistics to evaluate patient OOP and total spending. Generalized linear models evaluated the relationship between spending and TCD NHB, adjusted for cancer indication. RESULTS: We included 8524 patients with incident claims for 8 oral TCDs with 9 first-line indications in advanced melanoma, breast, lung, and pancreatic cancer. Medium- and high-NHB TCDs accounted for most TCD prescriptions. Median OOP spending was $18.78 for the first 28-day TCD supply (interquartile range [IQR] = $0.00-$87.57); 45% of patients paid $0 OOP. Median total spending was $10 118.79 (IQR = $6365.95-$10 600.37) for an incident 28-day TCD supply. Total spending increased $1083.56 for each 10-point increase in NHB score (95% confidence interval = $1050.27 to $1116.84, P < .01 for null hypothesis H0 = $0). CONCLUSION: Low-NHB TCDs were prescribed less frequently than medium- and high-NHB TCDs. Total spending on oral TCDs was high and positively associated with NHB. Commercially insured patients were largely shielded from high OOP spending on oral TCDs.

Overall Volume of Upper Gastrointestinal Surgery Positively Impacts Gastric Cancer Outcomes at Centers with Low Gastrectomy Volume.

BACKGROUND: The relationship between hospital volume and surgical mortality is well documented. However, complete centralization of surgical care is not always feasible. The present study investigates how overall volume of upper gastrointestinal surgery at hospitals influences patient outcomes following resection for gastric adenocarcinoma. PATIENTS AND METHODS: National Cancer Database (2010-2019) patients with pathologic stage 1-3 gastric adenocarcinoma who underwent gastrectomy were identified. Three cohorts were created: low-volume hospitals (LVH) for both gastrectomy and overall upper gastrointestinal operations, mixed-volume hospital (MVH) for low-volume gastrectomy but high-volume overall upper gastrointestinal operations, and high-volume gastrectomy hospitals (HVH). Chi-squared tests were used to analyze sociodemographic factors and surgical outcomes and Kaplan-Meier method for survival analysis. RESULTS: In total, 26,398 patients were identified (LVH: 20,099; MVH: 539; HVH: 5,760). The 5-year survival was equivalent between MVH and HVH for all stages of disease (MVH: 56.0%, HVH 55.6%; p = 0.9866) and when stratified into early (MVH: 69.9%, HVH: 65.4%; p = 0.1998) and late stages (MVH: 24.7%, HVH: 32.0%; p = 0.1480), while LVH had worse survival. After matching patients, postoperative outcomes were worse for LVH, but there was no difference between MVH and HVH in terms of adequate lymphadenectomy, margin status, readmission rates, and 90-day mortality rates. CONCLUSIONS: Despite lower gastrectomy volume for cancer, postoperative gastrectomy outcomes at centers that perform a high number of upper gastrointestinal cancer surgeries were similar to hospitals with high gastrectomy volume. These hospitals offer a blueprint for providing equivalent outcomes to high volume centers while enhancing availability of quality cancer care.

The Volar Cortical Hinge: An Independent Risk Factor for Distal Radius Fracture Displacement.

Background Displaced distal radius fractures are prone to redisplacement after manipulation. This can result in the need for delayed surgery. Several criteria have been studied to predict the likelihood of redisplacement. We hypothesized that reduction in the volar cortex would be an additional predictive factor. Purpose The aim of this study was to assess whether the quality of the volar cortex reduction predicts the subsequent need for further intervention (surgery or remanipulation). As a secondary outcome, we assessed whether the quality of the reduction predicts the rate of malunion. Methods A retrospective review was performed of displaced adult distal radius fractures over a 2-year period that had undergone closed reduction at presentation. We identified 105 patients and a review of their electronic notes and radiographs was then performed. The volar cortex reduction was defined as "anatomical," "opposed," or "displaced." We assessed the radial height, radial inclination, radial/ulnar translation, volar/dorsal angulation, teardrop angle, presence of dorsal comminution, quality of the cast (molding, cast index), and volar cortex reduction. These measurements were taken at five time points (prereduction, postreduction, 1 week, 2 weeks, and 6 weeks). All patients that subsequently required surgical fixation or repeat reduction were identified as the primary outcome measure. The 6-week radiographs were assessed for radiographic malunion as our secondary outcome measure. A statistical analysis was then performed to assess the factors that influenced a loss of position and the need for delayed surgical intervention. Results Of the 105 patients, 22 patients required delayed surgery, 3 patients underwent a repeat manipulation, and 12 patients had a radiographic malunion at 6 weeks. During the study period, the proportion of patients requiring surgery or repeat manipulation in the displaced group was 10/21 (47.6%), in the opposed group it was 11/50 (23.4%), and in the anatomic group it was 4/36 (11.1%; p = 0.008). We then included the patients with a radiographic malunion and found the proportion of patients with an adverse outcome in the displaced group was 14/21 (66.7%), in the opposed group it was 17/47 (36.2%), and in the anatomic group it was 6/36 (16.7%; p = 0.001). At the 1-week time point, this association was equally significant, as the proportion in the displaced group was 17/33 (51.5%), in the opposed group it was 15/45 (33.3%) and in the anatomic group it was 1/22 (4.5%; p = 0.001). The patients' age, quality of cast, presence of dorsal comminution, and degree of initial displacement did not predict the subsequent need for surgery or remanipulation. Conclusion The most important factor in our study for significant redisplacement of an initially dorsally displaced distal radius fracture is the association of the volar cortex. This parameter maintains significance at the 1-week time point. This data shows that volar cortex reduction is a useful clinical measurement in assessing which distal radius fractures will undergo delayed displacement requiring intervention. Level of evidence Level 3-Retrospective comparative study.

Thoracic irrigation for prevention of secondary intervention after thoracostomy tube drainage for hemothorax: A Western Trauma Association multi-center study.

BACKGROUND: Retained hemothorax (rHTX) requiring intervention occurs in up to 20% of patients who undergo chest tube (TT) placement for a hemothorax (HTX). Thoracic irrigation at the time of TT placement decreases the need for secondary intervention in this patient group but those findings are limited because of the single center design. A multi-center study was conducted to evaluate the effectiveness of thoracic irrigation. METHODS: A multi-center, prospective, observational study was conducted between June 2018 and July 2023. Eleven sites contributed patients. Patients were included if they had a TT placed for a HTX and were excluded if: age < 18 years, TT for pneumothorax, thoracotomy or VATS performed within 6 hours of TT, TT >24 hours after injury, TT removed <24 hours, or death within 48 hours. Thoracic irrigation was performed at the discretion of the attending. Each hemithorax was considered separately if bilateral HTX. The primary outcome was secondary intervention for HTX-related complications (rHTX, effusion, or empyema). Secondary intervention was defined as: TT placement, instillation of thrombolytics, VATS, or thoracotomy. Irrigated and non-irrigated hemithoraces were compared using a propensity weighted analysis with age, sex, mechanism of injury, Abbreviated Injury Scale (AIS) chest and TT size as predictors. RESULTS: 493 patients with 462 treated hemothoraces were included, 123 (25%) had thoracic irrigation at TT placement. There were no significant demographic differences between the cohorts. Fifty-seven secondary interventions were performed, 10 (8%) and 47 (13%) in the irrigated and non-irrigated groups, respectively (p = 0.015). Propensity weighted analysis demonstrated a reduction in secondary interventions in the irrigated cohort (Odds Ratio 0.56 (0.34-0.85); p = 0.005). CONCLUSION: This Western Trauma Association multi-center study demonstrates a benefit of thoracic irrigation at the time of TT placement for a HTX. Thoracic irrigation reduces the odds of a secondary intervention for rHTX-related complications by 44%. LEVEL OF EVIDENCE: Therapeutic Study, Level II.

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

The latent structure of the Delis-Kaplan system for autism.

A core feature of autism is deficits in executive functioning (EF), including difficulty with planning, cognitive flexibility, and working memory. Despite a growing need for evidence-based assessments of EF for autism populations, statistical models of many commonly used measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), have not been investigated for a sample of autistic participants. The purpose of this study was to address a gap in the literature regarding the latent structure of the D-KEFS in a sample of autistic individuals. The D-KEFS is one of the most widely used clinical assessments of executive function, but its factor structure has not been examined in a sample of autistic participants. Reliability analyses were performed for sample subgroups based on participants' clinical and demographic characteristics, including IQ, autism severity, age, and race/ethnicity. Verbal Fluency (VF) was found to consistently decrease or not affect the overall reliability score. Additionally, one- and two-factor structure models were tested for the D-KEFS with a sample of autistic participants. The one-factor model was not found to be a good fit for the data. However, the two-factor model, with Cognitive Flexibility and Abstraction latent factors, was found to fit the data relatively well. This two-factor model was reexamined excluding the VF observed variable, resulting in a better overall model fit. Communication deficits are a common feature of autism, which explains why the VF task, that requires participants to produce novel words, may not be an adequate measure of executive function for autism populations.

Randomized Feasibility Pilot of an Executive Functioning Intervention Adapted for Children's Mental Health Settings.

The critical role of executive functioning in autism as well as the co-occurring mental health challenges common among autistic youth support to the immense value of interventions targeting executive functioning for enhancing mental health services for autistic children. The goal of the present study was to conduct a randomized feasibility trial of Unstuck and On Target, an executive functioning intervention, adapted for delivery in children's community mental health setting. Mental health therapists (n = 26) enrolled with participating autistic clients (n = 32) were randomized to receive training in and deliver the adapted Unstuck intervention or to deliver care as usual. We completed masked observational measures of Unstuck strategy use (fidelity) during recorded sessions of participating therapist-client dyads and collected measures of acceptability from participating clients and their caregivers. We also collected measures of pre-post changes in executive functioning and mental health symptoms. Therapists trained in Unstuck demonstrated significantly higher use of Unstuck strategies compared to usual care therapists. Caregivers and autistic clients perceive adapted Unstuck as highly acceptability and helpful. Autistic clients whose therapists were trained in adapted Unstuck demonstrated larger pre-post changes in executive functioning compared to usual care. Across all participating clients, changes in executive functioning were significantly related to changes in mental health symptoms. Finally, clients of therapists trained in adapted Unstuck demonstrated moderate improvements in overall mental health symptoms. The current study provides preliminary evidence of the feasibility and impact of Unstuck and On Target for children's community mental health settings.