Regulation of immune responses by mTOR.

mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism. In this review, we discuss the ability of mTOR to direct the adaptive immune response. Specifically, we focus on the role of mTOR in promoting differentiation, activation, and function in T cells, B cells, and antigen-presenting cells.

Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR.

Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.

Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation.

The asymmetric partitioning of fate-determining proteins has been shown to contribute to the generation of CD8(+) effector and memory T cell precursors. Here we demonstrate the asymmetric partitioning of mTORC1 activity after the activation of naive CD8(+) T cells. This results in the generation of two daughter T cells, one of which shows increased mTORC1 activity, increased glycolytic activity and increased expression of effector molecules. The other daughter T cell has relatively low mTORC1 activity and increased lipid metabolism, expresses increased amounts of anti-apoptotic molecules and subsequently displays enhanced long-term survival. Mechanistically, we demonstrate a link between T cell antigen receptor (TCR)-induced asymmetric expression of amino acid transporters and RagC-mediated translocation of mTOR to the lysosomes. Overall, our data provide important insight into how mTORC1-mediated metabolic reprogramming affects the fate decisions of T cells.

An engineered IL-2 partial agonist promotes CD8+ T cell stemness.

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.

The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex.

SGK1 is an AGC kinase that regulates the expression of membrane sodium channels in renal tubular cells in a manner dependent on the metabolic checkpoint kinase complex mTORC2. We hypothesized that SGK1 might represent an additional mTORC2-dependent regulator of the differentiation and function of T cells. Here we found that after activation by mTORC2, SGK1 promoted T helper type 2 (TH2) differentiation by negatively regulating degradation of the transcription factor JunB mediated by the E3 ligase Nedd4-2. Simultaneously, SGK1 repressed the production of interferon-γ (IFN-γ) by controlling expression of the long isoform of the transcription factor TCF-1. Consistent with those findings, mice with selective deletion of SGK1 in T cells were resistant to experimentally induced asthma, generated substantial IFN-γ in response to viral infection and more readily rejected tumors.

Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways.

Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1-ARNT-HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.

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.

PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress.

The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy1. Its hyperactivation contributes to disease in numerous organs, including the heart1,2, although broad inhibition of mTORC1 risks interference with its homeostatic roles. Tuberin (TSC2) is a GTPase-activating protein and prominent intrinsic regulator of mTORC1 that acts through modulation of RHEB (Ras homologue enriched in brain). TSC2 constitutively inhibits mTORC1; however, this activity is modified by phosphorylation from multiple signalling kinases that in turn inhibits (AMPK and GSK-3ß) or stimulates (AKT, ERK and RSK-1) mTORC1 activity3-9. Each kinase requires engagement of multiple serines, impeding analysis of their role in vivo. Here we show that phosphorylation or gain- or loss-of-function mutations at either of two adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) can bidirectionally control mTORC1 activity stimulated by growth factors or haemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remains unchanged. In the heart, or in isolated cardiomyocytes or fibroblasts, protein kinase G1 (PKG1) phosphorylates these TSC2 sites. PKG1 is a primary effector of nitric oxide and natriuretic peptide signalling, and protects against heart disease10-13. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knock-in mice that express a phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that cannot be rescued by PKG1 stimulation. However, cardiac disease is reduced and survival of heterozygote Tsc2S1365A knock-in mice subjected to the same stress is improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (TSC2(S1365E)). Resting mTORC1 activity is not altered in either knock-in model. Therefore, TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. The serine residues identified here provide a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.

Signatures of GVHD and relapse after posttransplant cyclophosphamide revealed by immune profiling and machine learning.

The key immunologic signatures associated with clinical outcomes after posttransplant cyclophosphamide (PTCy)-based HLA-haploidentical (haplo) and HLA-matched bone marrow transplantation (BMT) are largely unknown. To address this gap in knowledge, we used machine learning to decipher clinically relevant signatures from immunophenotypic, proteomic, and clinical data and then examined transcriptome changes in the lymphocyte subsets that predicted major posttransplant outcomes. Kinetics of immune subset reconstitution after day 28 were similar for 70 patients undergoing haplo and 75 patients undergoing HLA-matched BMT. Machine learning based on 35 candidate factors (10 clinical, 18 cellular, and 7 proteomic) revealed that combined elevations in effector CD4+ conventional T cells (Tconv) and CXCL9 at day 28 predicted acute graft-versus-host disease (aGVHD). Furthermore, higher NK cell counts predicted improved overall survival (OS) due to a reduction in both nonrelapse mortality and relapse. Transcriptional and flow-cytometric analyses of recovering lymphocytes in patients with aGVHD identified preserved hallmarks of functional CD4+ regulatory T cells (Tregs) while highlighting a Tconv-driven inflammatory and metabolic axis distinct from that seen with conventional GVHD prophylaxis. Patients developing early relapse displayed a loss of inflammatory gene signatures in NK cells and a transcriptional exhaustion phenotype in CD8+ T cells. Using a multimodality approach, we highlight the utility of systems biology in BMT biomarker discovery and offer a novel understanding of how PTCy influences alloimmune responses. Our work charts future directions for novel therapeutic interventions after these increasingly used GVHD prophylaxis platforms. Specimens collected on NCT0079656226 and NCT0080927627 https://clinicaltrials.gov/.

Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.

The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.

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.

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.

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.

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.

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.

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.

State-Based Evaluation of the Workforce Pipeline from Paramedic Program Enrollment to Agency Affiliation.

OBJECTIVES: The strength and stability of the paramedic workforce is dependent on the continual flow of EMS clinicians into the field. Workforce entry requires three distinct steps: program completion, certification attainment, and affiliation with an EMS agency. At each of these steps, future EMS clinicians may be lost to the workforce but the contribution of each is unknown. Our objective was to evaluate these inflection points using a state-based registry of EMS clinicians from their point of entry into the EMS education system to eventual EMS agency affiliation.METHODS: This is a retrospective cohort evaluation of paramedic students in the Commonwealth of Virginia. We included any student who enrolled in a paramedic program in 2017 or 2018. Data were provided by the Virginia Office of Emergency Medical Services, who tracks the development of EMS clinicians from the point of entry into an educational program through their affiliation with an EMS agency upon employment. Our primary outcomes include proportions of enrolled students who complete a program, graduating students who attain national/state certification, and nationally certified EMS clinicians who affiliate with an EMS agency. Proportions were calculated at each step and compared to the overall population of students enrolled.RESULTS: In 2017 and 2018, 775 and 603 students were enrolled in paramedic programs, respectively. Approximately a quarter of students did not complete their paramedic program (2017: 25% [192/775]; 2018: 28% [170/603]). Of those who graduated, the proportion of students not gaining certification was lower (2017: 11% [62/583]; 2018: 17% [75/433]). Of those who certified, those not affiliating was similarly low (2017: 15% [77/521]; 2018: 13% [46/358]). Evaluating the effect of each of these steps on the total entry into the workforce, nearly half of those who originally enrolled did not join the workforce through agency affiliation (2017: 43% [331/775]; 2018: 48% [291/603]).CONCLUSIONS: There are multiple areas to enhance retention of potential EMS trainees from program enrollment to EMS agency affiliation. This analysis suggests that educational attrition has a larger impact on the availability of new paramedics than certification examinations or agency affiliation decisions, though is limited to a singular state evaluation.

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.