Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.

Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

Urinary Silicon Excretion in Relation to Lactation and Bone Mineral Density - a Longitudinal Study Post-partum.

Silicon (Si) may be a mineral beneficial for bone health. Pregnancy and lactation have major impacts on maternal bone metabolism as bone minerals, including calcium (Ca), are required for growth of the foetus and for milk production. Like urinary Ca excretion, Si excretion has been reported to be high in pregnant women, but there are no data post-partum and during lactation. The aim of the present study was to investigate the urinary excretion of Si (U-Si), from the third trimester of pregnancy until 18 months post-partum, and in relation to the length of lactation, to determine if changes in U-Si are associated with changes in areal bone mineral density (aBMD). This longitudinal study included 81 pregnant women, of whom 56 completed the study. Spot urine samples were collected at the third trimester and at 0.5, 4, 12, and 18 months post-partum and were analysed for Si and Ca by ICP-OES. The aBMD was measured post-partum at lumbar spine and femoral neck by dual-energy x-ray absorptiometry. Women lactating for 4-8.9 and ≥ 9 months had significantly higher U-Si at 4 months post-partum, compared with the third trimester. No significant longitudinal differences in U-Si were found after correcting for creatinine. Changes in U-Si and in aBMD were not correlated, except at the lumbar spine from 0.5 to 12 months post-partum in the women lactating for 4-8.9 months. Taken together, our results suggest that there is a possibility that U-Si increases post-partum in women lactating for 4 months or longer, although it is not related to changes in aBMD.

Adoptive transfer of CD49a+ Tissue resident memory cells reverses pulmonary fibrosis in mice.

Pulmonary fibrosis is a devastating disease with no effective treatments to cure, stop or reverse the unremitting, fatal fibrosis. A critical barrier to treating this disease is the lack of understanding of the pathways leading to fibrosis as well as those regulating the resolution of fibrosis. Fibrosis is the pathologic side of normal tissue repair that results when the normal wound healing programs go awry. Successful resolution of tissue injury requires several highly coordinated pathways, and this research focuses on the interplay between these overlapping pathways: immune effectors, inflammatory mediators and fibroproliferation in the resolution of fibrosis. Previously we have successfully prevented, mitigated, and even reversed established fibrosis using vaccinia vaccination immunotherapy in two models of murine lung fibrosis. The mechanism by which vaccinia reverses fibrosis is by vaccine induced lung specific Th1 skewed tissue resident memory (TRMs) in the lung. In this study, we isolated a population of vaccine induced TRMs - CD49a+ CD4+ T cells - that are both necessary and sufficient to reverse established pulmonary fibrosis. Using adoptive cellular therapy, we demonstrate that intratracheal administration of CD49a+ CD4+ TRMs into established fibrosis, reverses the fibrosis histologically, by promoting a decrease in collagen, and functionally, by improving lung function, without the need for vaccination. Furthermore, co-culture of in vitro derived CD49+ CD4+ human TRMs with human fibroblasts from individuals with idiopathic pulmonary fibrosis (IPF) results in the down regulation of IPF fibroblast collagen production. Lastly, we demonstrate in human IPF lung histologic samples that CD49a+ CD4+ TRMs, which can down regulate human IPF fibroblast function, fail to increase in the IPF lungs, thus potentially failing to promote resolution. Thus, we define a novel unappreciated role for tissue resident memory T cells in regulating established lung fibrosis to promote resolution of fibrosis and re-establish lung homeostasis. We demonstrate that immunotherapy, in the form of adoptive transfer of CD49a+ CD4+ TRMs into the lungs of mice with established fibrosis, not only stops progression of the fibrosis but more importantly reverses the fibrosis. These studies provide the insight and preclinical rationale for a novel paradigm shifting approach of using cellular immunotherapy to treat lung fibrosis.

Safety and immunogenicity of a single dose of Tdap compared to Td in pregnant women in Mali and 3 its effect on infant immune responses: a single-centre, randomised, double-blind, active-controlled phase 2 study.

Background: While maternal pertussis vaccination is a strategy to reduce infant morbidity, safety and immunogenicity data are limited in sub-Saharan Africa. We aimed to evaluate the safety of a single dose of tetanus, diphtheria and acellular pertussis vaccine (Tdap) vaccine compared to tetanus and diphtheria vaccine (Td) vaccine in pregnant women in Bamako, Mali and to assess the pertussis toxin (PT) antibody response at birth. Methods: In this phase 2, single-centre, randomised, double-blind, active-controlled study, from 23 January 2019 to 10 July 2019, healthy 18-39 year old women in the second trimester of a singleton pregnancy were randomised 2:1 to receive Tdap or Td. Blood was tested for serum immunoglobulin G (IgG) against PT and other vaccine antigens using a qualified Meso Scale Discovery multiplex immunoassay. The co-primary objectives evaluated safety and birth anti-PT levels. Infant immune responses to whole-cell pertussis vaccine (DTwP) were assessed. Statistical analysis was descriptive. This trial is registered with clinicaltrials.gov, NCT03589768. Findings: 133 women received Tdap and 67 received Td, with 126 and 66 livebirths, respectively. In the Tdap group, 22 serious adverse events (SAEs) including one maternal death occurred in 20 participants (15·0%), with 10 SAEs in 10 participants (14·9%) in the Td group. Among infants, 18 events occurred among 13 participants (10.3%) and 8 SAEs in 6 participants (9.1%), including three and two infant deaths, occurred in Tdap and Td groups, respectively. None were related to study vaccines. Anti-PT geometric mean concentration (GMC) at birth in the Tdap group was higher than in the Td group (55.4 [46.2-66.6] IU/ml vs 7.9 [5.4-11.5] IU/ml). One month after the third dose of DTwP, the GMC in infants born to mothers in the Tdap group were lower compared to the Td group (20.2 [13.7-29.9] IU/ml vs 77.2 [32.2-184.8] IU/ml). By 6 months of age, the anti- PT GMCs were 17.3 [12.8-23.4] IU/ml and 67.1 [35.5-126.7] IU/ml in Tdap and Td groups, respectively. At birth, anti-tetanus toxin (TT) GMCs were higher in infants in the Td vs Tdap group (5.9 [5.0-7.0] IU/ml vs 4.1 [3.5-4.8] IU/ml). Anti-diphtheria toxin GMCs were similar in both groups. Interpretation: Tdap administered to pregnant women in Mali is safe and well-tolerated. Infants of mothers who received Tdap were born with high PT and protective anti-TT antibody levels. By six months of age, after primary vaccination, the PT levels were lower in the Tdap group compared to the Td group. The blunted immune responses to primary DTwP vaccination in the Tdap infant group warrant further study. Funding: This project was funded by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under contract numbers 75N93021C00012 (The Emmes Company), and HHSN27220130000221 (University of Maryland, Baltimore). Dr. Susana Portillo was supported by NIH award no. T32AI007524. NIAID, NIH provided Tdap vaccine (BOOSTRIX).

Statewide implementation of the cardiac arrest registry to enhance survival in Ohio.

Objective: Public health surveillance is essential for improving community health. The Cardiac Arrest Registry to Enhance Survival (CARES) is a surveillance system for out-of-hospital cardiac arrest (OHCA). We describe results of the organized statewide implementation of Ohio CARES. Methods: We performed a retrospective analysis of CARES enactment in Ohio. Key elements included: establishment of statewide leadership, appointment of a dedicated coordinator, conversion to a statewide subscription, statewide dissemination of information, fundraising from internal and external stakeholders, and conduct of resuscitation academies. We identified all adult (≥18 years) OHCA reported in the registry during 2013-2020. We evaluated OHCA characteristics before (2013-2015) and after (2016-2019) statewide implementation using chi-square test. We evaluated trends in OHCA outcomes using the Cochran-Armitage test of trend. Results: Statewide CARES promotion increased participation from 2 (urban) to 136 (129 urban, 7 rural) EMS agencies. Covered population increased from 1.2 M (10% of state) to 4.8 M (41% of state). After statewide implementation, OHCA populations increased male (58.1% vs 60.8%, p < 0.01), white (50.1% vs 63.7%, p < 0.01), bystander witnessed (26.9% vs 32.9%, p < 0.01) OHCAs. Bystander CPR (34.7% vs 33.2%, p = 0.22), bystander AED (13.5% vs 12.3%, p = 0.55) and initial rhythm (shockable 18.0% vs 18.3%, p = 0.32) did not change. From 2013 to 2019 there were temporal increases in ROSC (29.7% to 31.9%, p-trend = 0.028), survival (7.4% to 12.3%, p-trend < 0.001) and survival with good neurologic outcome (5.6% to 8.6%, p-trend = 0.047). Conclusion: The organized statewide implementation of CARES in Ohio was associated with marked increases in community uptake and concurrent observed improvements in patient outcomes. These results highlight key lessons for community-wide fostering of OHCA surveillance.

Association between EMS Workforce Density and Population Health Outcomes in the U.S.

BACKGROUND: The prehospital care provided by emergency medical services (EMS) personnel is a critical component of the public health, public safety, and health care systems in the U.S.; however, the population-level value of EMS care is often overlooked. No studies have examined how the density of EMS personnel relates to population-level health outcomes. Our objectives were to examine the geographic distribution and density of EMS personnel in the U.S.; and quantify the association between EMS personnel density and population-level health outcomes. METHODS: We conducted a cross-sectional evaluation of county-level EMS personnel density using estimates from the National Registry of Emergency Medical Technicians in nine states that require continuous national certification (Alabama, Louisiana, Massachusetts, Minnesota, New Hampshire, North Dakota, South Carolina, Vermont, and Washington, D.C.). Outcomes of interest included life expectancy, all-cause mortality, and cardiac arrest mortality. We used quantile regression models to examine the association between a 10-person increase in EMS personnel density and each outcome at the 10th, 50th (median), and 90th percentiles, controlling for population characteristics and area health resources. RESULTS: There were 356 counties included, with a mean EMS density of 223 EMS personnel per 100,000 population. Density was higher in rural compared to urban counties (247 versus 186 per 100,000 population; p = 0.001). In unadjusted models, there was a significant association between increase in EMS personnel density and an increase in life expectancy at each examined percentile (e.g., 50th percentile, increase of 52.9 days; 95% CI 40.2, 65.5; p < 0.001), decrease in all-cause mortality at each examined percentile, and decrease in cardiac arrest mortality at the 50th and 90th percentiles. These associations were not statistically significant in the adjusted models. CONCLUSIONS: EMS personnel density differs between urban and rural areas, with higher density per population in rural areas. There were no statistically significant associations between EMS density and population-level health outcomes after controlling for population characteristics and other health resources. The best approach to quantifying the community-level value that EMS care may or may not provide remains unclear.

Measuring the Implementation Preferences of Emergency Medical Services Clinicians Using Discrete Choice Experiments.

INTRODUCTION: Prehospital research and evidence-based guidelines (EBGs) have grown in recent decades, yet there is still a paucity of prehospital implementation research. While recent studies have revealed EMS agency leadership perspectives on implementation, the important perspectives and opinions of frontline EMS clinicians regarding implementation have yet to be explored in a systematic approach. The objective of this study was to measure the preferences of EMS clinicians for the process of EBG implementation and whether current agency practices align with those preferences. METHODS: This study was a cross-sectional survey of National Registry of Emergency Medical Technicians registrants. Eligible participants were certified paramedics who were actively practicing EMS clinicians. The survey contained discrete choice experiments (DCEs) for three EBG implementation scenarios and questions about rank order preferences for various aspects of the implementation process. For the DCEs, we used multinomial logistic regression to analyze the implementation preference choices of EMS clinicians, and latent class analysis to classify respondents into groups by their preferences. RESULTS: A total of 183 respondents completed the survey. Respondents had a median age of 39 years, were 74.9% male, 89.6% White, and 93.4% of non-Hispanic ethnicity. For all three DCE scenarios, respondents were significantly more likely to choose options with hospital feedback and individual-level feedback from EMS agencies. Respondents were significantly less likely to choose options with email/online only education, no feedback from hospitals, and no EMS agency feedback to clinicians. In general, respondents' preferences favored classroom-based training over in-person simulation. For all DCE questions, most respondents (66.2%-77.1%) preferred their survey DCE choice to their agency's current implementation practices. In the rank order preferences, most participants selected "knowledge of the underlying evidence behind the change" as the most important component of the process of implementation. CONCLUSIONS: In this study of EMS clinicians' implementation preferences using DCEs, respondents preferred in-person education, feedback on hospital outcomes, and feedback on their individual performance. However, current practice at EMS agencies rarely matched those expressed EMS clinician preferences. Collectively, these results present opportunities for improving EMS implementation from the EMS clinician perspective.

Comparison of the Scope of Practice of the Army Combat Medic Specialist and Civilian National EMS Certification Levels.

INTRODUCTION: The transition of Army Combat Medic Specialists (Military Occupational Specialty Code: 68W) from military to civilian emergency medical services (EMS) is challenging, and the pathway is not clearly defined. Our objective was to evaluate the current military requirements for 68W and how they compare to the 2019 EMS National Scope of Practice Model (SoPM) for the civilian emergency medical technician (EMT) and advanced emergency medical technician (AEMT). METHODS: This was a cross-sectional evaluation of the 68W skill floor as defined by the Soldier's Manual and Trainer's Guide Healthcare Specialist and Medical Education and Demonstration of Individual Competence in comparison to the 2019 SoPM, which categorizes EMS tasks into seven skill categories. Military training documents were reviewed and extracted for specific information on military scope of practice and task-specific training requirements. Descriptive statistics were calculated. RESULTS: Army 68Ws were noted to perform all (59/59) tasks that coincide with the EMT SoPM. Further, Army 68W practiced above scope in the following skill categories: airway/ventilation (3 tasks); medication administration route (7 tasks); medical director approved medication (6 tasks); intravenous initiation maintenance fluids (4 tasks); and miscellaneous (1 task). Army 68W perform 96% (74/77) of tasks aligned with the AEMT SoPM, excluding tracheobronchial suctioning of an intubated patient, end-tidal CO2 monitoring or waveform capnography, and inhaled nitrous oxide monitoring. Additionally, the 68W scope included six tasks that were above the SoPM for AEMT; airway/ventilation (2 tasks); medication administration route (2 tasks); and medical director approved medication (2 tasks). CONCLUSIONS: The scope of practice of U.S. Army 68W Combat Medics aligns well with the civilian 2019 Scope of Practice Model for EMTs and AEMTs. Based on the comparative scope of practice analysis, transitioning from Army 68W Combat Medic to civilian AEMT would require minimal additional training. This represents a promising potential workforce to assist with EMS workforce challenges. Although aligning the scope of practice is a promising first step, future research is needed to assess the relationship of Army 68Ws training with state licensure and certification equivalency to facilitate this transition.

Mobile Integrated Health Care Roles of US EMS Clinicians: A Descriptive Cross-Sectional Study.

OBJECTIVE: Mobile integrated health care (MIH) leverages emergency medical services (EMS) clinicians to perform local health care functions. Little is known about the individual EMS clinicians working in this role. We sought to describe the prevalence, demographics, and training of EMS clinicians providing MIH in the United States (US). METHODS: This is a cross-sectional study of US-based, nationally certified civilian EMS clinicians who completed the National Registry of Emergency Medical Technicians (NREMT) recertification application during the 2021-2022 cycle and completed the voluntary workforce survey. Workforce survey respondents self-identified their job roles within EMS, including MIH. If an MIH role was selected, additional questions clarified the primary role in EMS, type of MIH provided, and hours of MIH training received. We merged the workforce survey responses with the individual's NREMT recertification demographic profile. The prevalence of EMS clinicians with MIH roles and data on demographics, clinical care provided, and MIH training were calculated using descriptive statistics, including proportions with associated binomial 95% confidence intervals (CI). RESULTS: Of 38,960 survey responses, 33,335 met inclusion criteria and 490 (1.5%; 95%CI 1.3-1.6%) EMS clinicians indicated MIH roles. Of these, 62.0% (95%CI 57.7-66.3%) provided MIH as their primary EMS role. EMS clinicians with MIH roles were present in all 50 states and certification levels included emergency medical technician (EMT) (42.8%; 95%CI 38.5-47.2%), advanced emergency medical technician (AEMT) (3.5%; 95%CI 1.9-5.1%), and paramedic (53.7%; 95%CI 49.3-58.1%). Over one-third (38.6%; 95%CI 34.3-42.9%) of EMS clinicians with MIH roles received bachelor's degrees or above, and 48.4% (95%CI 43.9%-52.8%) had been in their MIH roles for less than 3 years. Nearly half (45.6%; 95%CI 39.8-51.6%) of all EMS clinicians with primary MIH roles received less than 50 hours (h) of MIH training; only one-third (30.0%; 95%CI 24.7-35.6%) received more than 100 h of training. CONCLUSION: Few nationally certified US EMS clinicians perform MIH roles. Only half of MIH roles were performed by paramedics; EMT and AEMT clinicians performed a substantial proportion of MIH roles. The observed variability in certification and training suggest heterogeneity in preparation and performance of MIH roles among US EMS clinicians.

Medical Directors, Facilities, and Finances: Resource Deficiencies in Accredited Paramedic Programs.

BACKGROUND: Initial paramedic education must have sufficient rigor and appropriate resources to prepare graduates to provide lifesaving prehospital care. Despite required national paramedic accreditation, there is substantial variability in paramedic pass rates that may be related to program infrastructure and clinical support. Our objective was to evaluate US paramedic program resources and identify common deficiencies that may affect program completion. METHODS: We conducted a cross-sectional mixed methods analysis of the 2018 Committee on Accreditation of Educational Programs for the Emergency Medical Services Professions annual report, focusing on program Resource Assessment Matrices (RAM). The RAM is a 360-degree evaluation completed by program personnel, advisory committee members, and currently enrolled students to identify program resource deficiencies affecting educational delivery. The analysis included all paramedic programs that reported graduating students in 2018. Resource deficiencies were categorized into ten categories: faculty, medical director, support personnel, curriculum, financial resources, facilities, clinical resources, field resources, learning resources, and physician interaction. Descriptive statistics of resource deficiency categories were conducted, followed by a thematic analysis of deficiencies to identify commonalities. Themes were generated from evaluating individual deficiencies, paired with program-reported analysis and action plans for each entry. RESULTS: Data from 626 programs were included (response rate = 100%), with 143 programs reporting at least one resource deficiency (23%). A total of 406 deficiencies were identified in the ten categories. The largest categories (n = 406) were medical director (14%), facilities (13%), financial resources (13%), support personnel (11%), and physician interaction (11%). The thematic analysis demonstrated that a lack of medical director engagement in educational activities, inadequate facility resources, and a lack of available financial resources affected the educational environment. Additionally, programs reported poor data collection due to program director turnover. CONCLUSION: Resource deficiencies were frequent for programs graduating paramedic students in 2018. Common themes identified were a need for medical director engagement, facility problems, and financial resources. Considering the pivotal role of EMS physicians in prehospital care, a consistent theme throughout the analysis involved challenges with medical director and physician interactions. Future work is needed to determine best practices for paramedic programs to ensure adequate resource availability for initial paramedic education.

Ensuring Intervention Fidelity of an Attention Control Arm in a Multisite Randomized Controlled Trial.

BACKGROUND: Intervention fidelity is a critical element of randomized controlled trials, yet reporting of intervention fidelity among attention control arms is limited. Lack of fidelity to attention control procedures can affect study outcomes by either overestimating or underestimating the efficacy of the intervention under examination. OBJECTIVES: This brief report describes the approach researchers took to promote fidelity to the attention control arm of a pediatric palliative care randomized controlled trial funded by the National Institutes of Health. METHODS: The Informational Meetings for Planning and Coordinating Treatment trial aims to determine the efficacy of a communication intervention that uses care team dyads (i.e., physicians partnered with nurses or advanced practice providers) to engage parents of children with cancer who have a poor prognosis in structured conversations about prognostic information, goals of care, and care planning. The intervention is compared with an attention control arm, which provides parents with structured conversations on common pediatric cancer education topics, such as talking to their child about their cancer, clinical trials, cancer treatment, side effects, and so forth. National Institutes of Health guidelines for assessing and implementing strategies to promote intervention fidelity were used to design (a) the attention control arm of a randomized controlled trial, (b) related attention control arm training, and (c) quality assurance monitoring. RESULTS: Attention control study procedures were designed to mirror that of the intervention arm (i.e., same number, frequency, and time spent in study visits). Cluster randomization was used to allocate care team dyads to one arm of the randomized controlled trial. Care team dyads assigned to the attention control arm participated in online training sessions to learn attention control procedures, the different roles of research team members, and quality assurance methods. Fidelity to attention control procedures is assessed by both the interveners themselves and a quality assurance team. DISCUSSION: Study design, training, and delivery are all critical to attention control fidelity. Baseline training often needs to be supplemented with booster training when time gaps occur between study start-up and implementation. Quality assurance procedures are essential to determine whether interveners consistently deliver attention control procedures correctly.

Hematopoietic Bone Marrow Transplant to Treat Systemic EBV-positive T-cell Lymphoma of Childhood.

Systemic Epstein-Barr virus-positive T-cell lymphoma of childhood (S-EBV-TCL) is a rare disease for which there is no standard of care. S-EBV-TCL is often associated with hemophagocytic lymphohistiocytosis and is generally thought of on the spectrum of EBV-related disease. For the few reported cases of cure in the literature, hematopoietic stem cell transplant has been required because it is the only treatment that has induced complete remission in patients suffering from EBV-associated T-cell or natural killer cell lymphoproliferative diseases, except hemophagocytic lymphohistiocytosis. Here, we present the case of one patient who was successfully cured with a modified regimen of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), followed by hematopoietic stem cell transplant using a reduced-intensity conditioning regimen.

Successful Crizotinib-targeted Therapy of Pediatric Unresectable ERC1::ALK Fusion Sarcoma.

Anaplastic lymphoma kinase ( ALK )-fusion sarcomas are rare part of the emerging theoretically targetable tyrosine kinase RAS::MAPK pathway fusion myopericytic-ovoid sarcomas. We report our clinicopathologic and treatment experience with an ALK fusion sarcoma. A novel ELKS/RAB6-interacting/CAST family member 1 - unaligned ALK fusion infiltrative nonmetastatic low-grade sarcoma of the right hand of a 15-month-old male was treated with crizotinib, an ALK tyrosine kinase inhibitor as oral monotherapy, inducing complete radiographic and clinical resolution by 10 months and sustained response now over 12 months after elective discontinuation. Crizotinib can successfully be used to treat unresectable novel ALK fusion sarcomas.

Evidence-Based Guidelines for Prehospital Airway Management: Methods and Resources Document.

INTRODUCTION: Emergency airway management is a common and critical task EMS clinicians perform in the prehospital setting. A new set of evidence-based guidelines (EBG) was developed to assist in prehospital airway management decision-making. We aim to describe the methods used to develop these EBGs. METHODS: The EBG development process leveraged the four key questions from a prior systematic review conducted by the Agency for Healthcare Research and Quality (AHRQ) to develop 22 different population, intervention, comparison, and outcome (PICO) questions. Evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework and tabulated into the summary of findings tables. The technical expert panel then used a rigorous systematic method to generate evidence to decision tables, including leveraging the PanelVoice function of GRADEpro. This process involved a review of the summary of findings tables, asynchronous member judging, and online facilitated panel discussions to generate final consensus-based recommendations. RESULTS: The panel completed the described work product from September 2022 to April 2023. A total of 17 summary of findings tables and 16 evidence to decision tables were generated through this process. For these recommendations, the overall certainty in evidence was "very low" or "low," data for decisions on cost-effectiveness and equity were lacking, and feasibility was rated well across all categories. Based on the evidence, 16 "conditional recommendations" were made, with six PICO questions lacking sufficient evidence to generate recommendations. CONCLUSION: The EBGs for prehospital airway management were developed by leveraging validated techniques, including the GRADE methodology and a rigorous systematic approach to consensus building to identify treatment recommendations. This process allowed the mitigation of many virtual and electronic communication confounders while managing several PICO questions to be evaluated consistently. Recognizing the increased need for rigorous evidence evaluation and recommendation development, this approach allows for transparency in the development processes and may inform future guideline development.

Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

Identifying beliefs driving COVID-19 vaccination: Lessons for effective messaging.

Increasing vaccination acceptance has been essential during the COVID-19 pandemic and in preparation for future public health emergencies. This study aimed to identify messaging strategies to encourage vaccine uptake by measuring the drivers of COVID-19 vaccination among the general public. A survey to assess COVID-19 vaccination acceptance and hesitancy was advertised on Facebook in February-April 2022. The survey included items asking about COVID-19 vaccination status and participant demographics, and three scales assessing medical mistrust, perceived COVID-19 risk, and COVID-19 vaccine confidence (adapted from the Oxford COVID-19 vaccine confidence and complacency scale). The main outcome was vaccination, predicted by patient demographics and survey scale scores. Of 1,915 survey responses, 1,450 (75.7%) were included, with 1,048 (72.3%) respondents reporting they had been vaccinated. In a multivariable regression model, the COVID-19 vaccine confidence scale was the strongest predictor of vaccination, along with education level and perceived COVID-19 risk. Among the items on this scale, not all were equally important in predicting COVID-19 vaccination. The items that best predicted vaccination, at a given score on the COVID-19 vaccine confidence scale, included confidence that vaccine side effects are minimal, that the vaccine will work, that the vaccine will help the community, and that the vaccine provides freedom to move on with life. This study improved our understanding of perceptions most strongly associated with vaccine acceptance, allowing us to consider how to develop messages that may be particularly effective in encouraging vaccination among the general public for both the COVID-19 pandemic and future public health emergencies.

SIKs Regulate HDAC7 Stabilization and Cytokine Recall in Late-Stage T Cell Effector Differentiation.

Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. In this study, we report the identification of a previously unappreciated regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate that liver kinase B1 (LKB1)-mediated activation of salt-inducible kinases epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed that salt-inducible kinase-mediated phosphorylation-dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels, which correlated with total and cytokine loci-specific reductions in the activating transcription mark histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine genes upon restimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a previously unrecognized target for enhancing effector T cell functionality.

EMS Responses for Pediatric Behavioral Health Emergencies in the United States: A 4-Year Descriptive Evaluation.

BACKGROUND: The occurrence of behavioral health emergencies (BHEs) in children is increasing in the United States, with patient presentations to Emergency Medical Services (EMS) behaving similarly. However, detailed evaluations of EMS encounters for pediatric BHEs at the national level have not been reported. METHODS: This was a secondary analysis of a national convenience sample of EMS electronic patient care records (ePCRs) collected from January 1, 2018 through December 31, 2021. Inclusion criteria were all EMS activations documented as 9-1-1 responses involving patients < 18 years of age with a primary or secondary provider impression of a BHE. Patient demographics, incident characteristics, and clinical variables including administration of sedation medications, use of physical restraint, and transport status were examined overall and by calendar year. RESULTS: A total of 1,079,406 pediatric EMS encounters were present in the dataset, of which 102,014 (9.5%) had behavioral health provider impressions. Just over one-half of BHEs occurred in females (56.2%), and 68.1% occurred in patients aged 14-17 years. Telecommunicators managing the 9-1-1 calls for these events reported non-BHE patient complaints in 34.7%. Patients were transported by EMS 68.9% of the time, while treatment and/or transport by EMS was refused in 12.5%. Prehospital clinicians administered sedation medications in 1.9% of encounters and applied physical restraints in 1.7%. Naloxone was administered for overdose rescue in 1.5% of encounters. CONCLUSION: Approximately one in ten pediatric EMS encounters occurring in the United States involve a BHE, and the majority of pediatric BHEs attended by EMS result in transport of the child. Use of sedation medications and physical restraints by prehospital clinicians in these events is rare. National EMS data from a variety of sources should continue to be examined to monitor trends in EMS encounters for BHEs in children.