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.

Evidence-Based Guideline for Prehospital Airway Management.

Airway management is a cornerstone of emergency medical care. This project aimed to create evidence-based guidelines based on the systematic review recently conducted by the Agency for Healthcare Research and Quality (AHRQ). A technical expert panel was assembled to review the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The panel made specific recommendations on the different PICO (population, intervention, comparison, outcome) questions reviewed in the AHRQ review and created good practice statements that summarize and operationalize these recommendations. The recommendations address the use of ventilation with bag-valve mask ventilation alone vs. supraglottic airways vs. endotracheal intubation for adults and children with cardiac arrest, medical emergencies, and trauma. Additional recommendations address the use of video laryngoscopy and drug-assisted airway management. These recommendations, and the associated good practice statements, offer EMS agencies and clinicians an opportunity to review the available evidence and incorporate it into their airway management strategies.

Body composition and mortality in men receiving prostate radiotherapy: A pooled analysis of NRG/RTOG 9406 and NRG/RTOG 0126.

PURPOSE: To validate the association between body composition and mortality in men treated with radiation for localized prostate cancer (PCa). Secondarily, to integrate body composition as a factor to classify patients by risk of all-cause mortality. MATERIALS AND METHODS: Participants of NRG/Radiation Therapy Oncology Group (RTOG) 9406 and NRG/RTOG 0126 with archived computed tomography were included. Muscle mass and muscle density were estimated by measuring the area and attenuation of the psoas muscles on a single slice at L4-L5. Bone density was estimated by measuring the attenuation of the vertebral body at mid-L5. Survival analyses, including Cox proportional hazards models, assessed the relationship between body composition and mortality. Recursive partitioning analysis (RPA) was used to create a classification tree to classify participants by risk of death. RESULTS: Data from 2066 men were included in this study. In the final multivariable model, psoas area, comorbidity score, baseline prostate serum antigen, and age were significantly associated with survival. The RPA yielded a classification tree with four prognostic groups determined by age, comorbidity, and psoas area. Notably, the classification among older (≥70 years) men into prognostic groups was determined by psoas area. CONCLUSIONS: This study strongly supports that body composition is related to mortality in men with localized PCa. The inclusion of psoas area in the RPA classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. More research is needed to determine the clinical impact of body composition on prognostic models in men with PCa.

A phase I/II study of preoperative letrozole, everolimus, and carotuximab in stage 2 and 3 hormone receptor-positive and Her2-negative breast cancer.

PURPOSE: In nonmetastatic hormone receptor-positive and Her2-negative breast cancer, preoperative endocrine therapies can yield outcomes similar with chemotherapy. We evaluated the tolerability and preliminary antitumor activity of preoperative letrozole, everolimus, and carotuximab, a monoclonal antibody targeting endoglin, in nonmetastatic breast cancer. METHODS: Eligible patients had newly diagnosed, stage 2 or 3, hormone receptor-positive and Her2/neu-negative breast cancer. Patients received escalating doses of everolimus; the dose of letrozole and carotuximab were fixed at 2.5 mg PO daily and 15 mg/kg intravenously every 2 weeks, respectively. The primary objective was to determine the safety and tolerability of the combination. Secondary objectives included pharmacokinetic and pharmacodynamic studies and assessments of antitumor activity. RESULTS: Fifteen patients enrolled. The recommended phase 2 dose of everolimus in combination with letrozole and carotuximab was 10 mg PO daily. The most frequent adverse events were headache (67%), fatigue (47%), facial flushing and swelling (47%), gingival hemorrhage (40%), epistaxis (33%), nausea and vomiting (27%). Headache constituted a dose-limiting toxicity. At least two signs of mucocutaneous telangiectasia developed in 92% of patients. Carotuximab accumulated in the extravascular space and accelerated the biodistribution and clearance of everolimus. All patients had residual disease. Gene expression analyses were consistent with downregulation of genes involved in proliferation and DNA repair. Among 6 patients with luminal B breast cancer, 5 converted to luminal A after one cycle of therapy. CONCLUSION: Letrozole, everolimus, and carotuximab were tolerated in combination at their single-agent doses. Pharmacokinetic studies revealed an interaction between everolimus and carotuximab. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (Identifier: NCT02520063), first posted on August 11, 2015, and is active, not recruiting.

Evidence-Based Guidelines for Prehospital Pain Management: Literature and Methods.

INTRODUCTION: Emergency Medical Services (EMS) clinicians commonly encounter patients with acute pain. A new set of evidence-based guidelines (EBG) was developed to assist in the prehospital management of pain. Our objective was to describe the methods used to develop these evidence-based guidelines for prehospital pain management. METHODS: The EBG development process was supported by a previous systematic review conducted by the Agency for Healthcare Research and Quality (AHRQ) covering nine different population, intervention, comparison, and outcome (PICO) questions. A technical expert panel (TEP) was formed and added an additional pediatric-specific PICO question. Identified evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework and tabulated into Summary of Findings tables. The TEP then utilized a rigorous systematic method, including the PanelVoice function, for recommendation development which was applied to generate Evidence to Decision Tables (EtD). This process involved review of the Summary of Findings tables, asynchronous member judging, and facilitated panel discussion to generate final consensus-based recommendations. RESULTS: The work product described above was completed by the TEP panel from September 2020 to April 2021. For these recommendations, the overall certainty of 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, one strong and seven conditional recommendations were made, with two PICO questions lacking sufficient evidence to generate a recommendation. CONCLUSION: We describe a protocol that leveraged established EBG development techniques, the GRADE framework in conjunction with a previous AHRQ systematic review to develop treatment recommendations for prehospital pain management. This process allowed for mitigation of many confounders due to the use of virtual and electronic communication. Our approach may inform future guideline development and increase transparency in the prehospital recommendations development processes.

Evidence-Based Guidelines for Prehospital Pain Management: Recommendations.

This project sought to develop evidence-based guidelines for the administration of analgesics for moderate to severe pain by Emergency Medical Services (EMS) clinicians based on a separate, previously published, systematic review of the comparative effectiveness of analgesics in the prehospital setting prepared by the University of Connecticut Evidence-Based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). A technical expert panel (TEP) was assembled consisting of subject matter experts in prehospital and emergency care, and the development of evidence-based guidelines and patient care guidelines. A series of nine "patient/population-intervention-comparison-outcome" (PICO) questions were developed based on the Key Questions identified in the AHRQ systematic review, and an additional PICO question was developed to specifically address analgesia in pediatric patients. The panel made a strong recommendation for the use of intranasal fentanyl over intravenous (IV) opioids for pediatric patients without intravenous access given the supporting evidence, its effectiveness, ease of administration, and acceptance by patients and providers. The panel made a conditional recommendation for the use of IV non-steroidal anti-inflammatory drugs (NSAIDs) over IV acetaminophen (APAP). The panel made conditional recommendations for the use of either IV ketamine or IV opioids; for either IV NSAIDs or IV opioids; for either IV fentanyl or IV morphine; and for either IV ketamine or IV NSAIDs. A conditional recommendation was made for IV APAP over IV opioids. The panel made a conditional recommendation against the use of weight-based IV ketamine in combination with weight-based IV opioids versus weight-based IV opioids alone. The panel considered the use of oral analgesics and a conditional recommendation was made for either oral APAP or oral NSAIDs when the oral route of administration was preferred. Given the lack of a supporting evidence base, the panel was unable to make recommendations for the use of nitrous oxide versus IV opioids, or for IV ketamine in combination with IV opioids versus IV ketamine alone. Taken together, the recommendations emphasize that EMS medical directors and EMS clinicians have a variety of effective options for the management of moderate to severe pain in addition to opioids when designing patient care guidelines and caring for patients suffering from acute pain.

Acute outreach service to nursing homes: A systematic review with GRADE and triple aim approach.

BACKGROUND: People living in nursing homes face the risk of visiting the emergency department (ED). Outreach services are developing to prevent unnecessary transfers to ED. AIMS: We aim to assess the performance of acute care services provided to people living in nursing homes or long-term homecare, focusing on ED transfer prevention, safety, cost-effectiveness and experiences. MATERIALS & METHODS: This review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Studies were eligible for inclusion if they were peer-reviewed and examined acute outreach services dedicated to delivering care to people in nursing homes or long-term homecare. The service models could also have preventive components. The databases searched were Scopus and CINAHL. In addition, Robins-I and SIGN checklists were used. The primary outcomes of prevented ED transfers or hospitalisations and the composite outcome of adverse events (mortality/Emergency Medical Service or ED visit after outreach service contact related to the same clinical condition) were graded with GRADE. RESULTS: Fifteen relevant original studies were found-all were observational and focused on nursing homes. The certainty of evidence for acute outreach services with preventive components to prevent ED transfers or hospitalisations was low. Stakeholders were satisfied with these services. The certainty of evidence for solely acute outreach services to prevent ED transfers or hospitalisations was very low and inconclusive. Reporting of adverse events was inconsistent, certainty of evidence for adverse events was low. CONCLUSION: Published data might support adopting acute outreach services with preventive components for people living in nursing homes to reduce ED transfers, hospitalisations and possibly costs. If an outreach service is started, it is recommended that a cluster-randomised or quasi-experimental research design be incorporated to assess the effectiveness and safety of the service. More evidence is also needed on cost-effectiveness and stakeholders' satisfaction. Systematic review registration number: PROSPERO CRD42020211048, date of registration: 25.09.2020.

An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer.

BACKGROUND: Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. METHODS: A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. RESULTS: Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. CONCLUSIONS: Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014.

Lipid microsphere bound oxycodone for pain management in patients receiving radiotherapy for head and neck cancer.

BACKGROUND: Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be utilized for extended release analgesia in patients undergoing radiation (RT) for head-and-neck cancer (HNC) and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. METHODS AND MATERIALS: We performed a prospective trial that enrolled participants > 18 years with histologically confirmed HNC who were scheduled to receive RT. Analgesia was prescribed in accordance with the WHO pain ladder. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30 mg of morphine sulfate equivalent and was titrated weekly during RT. Pain level and effect on quality of life were assessed using the Brief Pain Inventory. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3 months of RT for reasons other than pain resolution. RESULTS: Twenty-six eligible patients were enrolled. Microsphere oxycodone was initiated in 16 (61.5%) patients. Six (23.1%) patients utilized a gastrostomy tube to administer microsphere oxycodone during all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy. No patients were discontinued due to toxicity or difficulty with administration. Ratings for average pain was 3.1 (± 3.4) at enrollment, 4.0 (± 2.4) at week 6 of RT, and 1.8 (± 2.2) at 3-month follow-up. CONCLUSIONS: These results support the feasibility and safety of microsphere oxycodone for extended release analgesia among patients with HNC undergoing RT.

Role of orbitofrontal cortex in incubation of oxycodone craving in male rats.

One of the main challenges in treating opioid-use disorders is relapse during abstinence, triggered by re-exposure to drug-associated cues. Previous studies have demonstrated that drug-seeking in rats progressively increases over time during withdrawal (incubation of drug craving). Here, we used male rats and examined neural mechanisms underlying incubation of craving to oxycodone, a commonly abused prescription opioid, and we focused on orbitofrontal cortex (OFC), a brain region previously implicated in incubation of heroin craving. We first used neuronal activity marker Fos and measured neuronal activation in OFC (ventral and lateral OFC) associated with day-1 and day-15 relapse tests. Next, we determined the effect of pharmacological reversible inactivation of OFC on incubated oxycodone seeking on withdrawal day 15. Finally, we determined the effect of reversible inactivation of OFC on nonincubated oxycodone seeking on withdrawal day 1. We found that lever presses during relapse tests were higher on withdrawal day 15 than on withdrawal day 1 (incubation of oxycodone craving). Incubation of oxycodone craving is accompanied with a time-dependent increase of Fos protein expression in both ventral and lateral OFC. Lastly, OFC inactivation decreased oxycodone seeking on withdrawal day 15 but had no effect on withdrawal day 1. Together with the previous heroin study, results here show that OFC plays a critical role in incubation of opioid craving.

Systematic Review of Evidence-Based Guidelines for Prehospital Care.

Introduction: Multiple national organizations have identified a need to incorporate more evidence-based medicine in emergency medical services (EMS) through the creation of evidence-based guidelines (EBGs). Tools like the Appraisal of Guidelines for Research and Evaluation (AGREE) II and criteria outlined by the National Academy of Medicine (NAM) have established concrete recommendations for the development of high-quality guidelines. While many guidelines have been created that address topics within EMS medicine, neither the quantity nor quality of prehospital EBGs have been previously reported. Objectives: To perform a systematic review to identify existing EBGs related to prehospital care and evaluate the quality of these guidelines using the AGREE II tool and criteria for clinical guidelines described by the NAM. Methods: We performed a systematic search of the literature in MEDLINE, EMBASE, PubMED, Trip, and guidelines.gov, through September 2018. Guideline topics were categorized based on the 2019 Core Content of EMS Medicine. Two independent reviewers screened titles for relevance and then abstracts for essential guideline features. Included guidelines were appraised with the AGREE II tool across 6 domains by 3 independent reviewers and scores averaged. Two additional reviewers determined if each guideline reported the key elements of clinical practice guidelines recommended by the NAM via consensus. Results: We identified 71 guidelines, of which 89% addressed clinical aspects of EMS medicine. Only 9 guidelines scored >75% across AGREE II domains and most (63%) scored between 50 and 75%. Domain 4 (Clarity of Presentation) had the highest (79.7%) and domain 5 (Applicability) had the lowest average score across EMS guidelines. Only 38% of EMS guidelines included a reporting of all criteria identified by the NAM for clinical practice guidelines, with elements of a systematic review of the literature most commonly missing. Conclusions: EBGs exist addressing a variety of topics in EMS medicine. This systematic review and appraisal of EMS guidelines identified a wide range in the quality of these guidelines and variable reporting of key elements of clinical guidelines. Future guideline developers should consider established methodological and reporting recommendations to improve the quality of EMS guidelines.

Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity.

The discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody-based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination and instead would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin (Ig) knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain superphysiologic numbers of bNAb precursor-expressing B cells, and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti-HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center (GC) B cell recruitment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the GC when there are as few as 10 such cells per mouse. However, at low precursor frequencies, the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to GCs is variable and dependent on recirculation.

Peanut allergy diagnosis: A 2020 practice parameter update, systematic review, and GRADE analysis.

Given the burden of disease and the consequences of a diagnosis of peanut allergy, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. However, a test that indicates there is peanut sensitization present (eg, a "positive" test) is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions, and based on the systematic reviews and meta-analyses, makes recommendations for the clinician who is evaluating a patient for peanut allergy. These questions relate to when diagnostic tests should be completed, which diagnostic tests to utilize, and the utility (or lack thereof) of diagnostic testing to predict the severity of a future allergic reaction to peanut.

Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.

Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1ß, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.

Making the GRADE in anaphylaxis management: Toward recommendations integrating values, preferences, context, and shared decision making.

OBJECTIVE: To review GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methods and discuss the clinical application of conditional recommendations in clinical guidelines, specifically in the context of anaphylaxis. DATA SOURCES: Articles that described GRADE, evidence synthesis, evidence to recommendation frameworks, and shared decision making were used to discuss conditional recommendations of the 2020 Anaphylaxis GRADE guideline. STUDY SELECTIONS: A narrative review detailing concepts of GRADE and approaches to translate conditional recommendations to individualized and contextualized patient care. RESULTS: GRADE methods encourage a nuanced relationship between certainty of evidence and strength of recommendations. Strength of recommendation must incorporate key factors, including the balance between benefits and harms, patient values and preferences, and resource allocation (costs), with equity, feasibility, and acceptability also often included as considerations. GRADE guidelines provide recommendations that are characterized by directionality (for or against) and strength (strong or conditional). A conditional recommendation is tailored to context and primarily applied through a lens of patient preferences related to the likelihood of outcomes of importance and a shared decision-making approach. Although the 2020 Anaphylaxis GRADE guideline better informs the practice of anaphylaxis prevention through (1) identification and mitigation of risk factors for biphasic anaphylaxis and (2) evaluation of the use of glucocorticoid and/or antihistamine pretreatment, all GRADE recommendations, although directional, are conditional and as such should not be universally applied to every circumstance. CONCLUSION: Clinical guidelines provide an important opportunity to critically appraise evidence and translate evidence to practice. Patients, practitioners, and policy makers should appreciate the strength of recommendation and certainty of evidence and understand how this affects guideline applicability and implementation.

Transition in Care from EMS Providers to Emergency Department Nurses: A Systematic Review.

Background: Transitions in care between emergency medical services (EMS) providers and emergency department (ED) nurses are critical to patient care and safety. However, interactions between EMS providers and ED nurses can be problematic with communication gaps and have not been extensively studied. The aim of this review was to examine (1) factors that influence transitions in care from EMS providers to ED nurses and (2) the effectiveness of interventional strategies to improve these transitions. Methods: We conducted a mixed-methods systematic review that included searches of electronic databases (DARE, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, Joanna Briggs Institute EBP), gray literature databases, organization websites, querying experts in emergency medicine, and the reference lists cited in included studies. All English-language studies of any design were eligible for inclusion. Two reviewers independently screened titles/abstracts and full-texts for inclusion and methodological quality, as well as extracted data from included studies. We used narrative and thematic synthesis to integrate and explore relationships within the data. Results: In total, 8,348 studies were screened and 130 selected for full text review. The final synthesis included 20 studies. Across 15 studies of moderate-to-high methodological quality, 6 factors influenced transitions: different professional lenses, operational constraints, professional relationships, information shared between the professions, components of the transition process, and patient presentation and involvement. Three interventions were identified in 6 methodologically weak studies: (1) transition guideline (DeMIST, Identification, Mechanism/Medical complaint, Injuries/Information related to the complaint, Signs, Treatment and Trends - Allergies, Medication, Background history, Other information [IMIST-AMBO]) with training, (2) mobile web-based technology (EMS smartphone and geographic information system location data), and (3) a new clinical role (ED ambulance off-load nurse dedicated to triaging and assessing EMS patients). There were mixed findings for the effectiveness of transition guidelines and the new clinical role. Mobile technology was seen positively by both EMS providers and ED nurses as helpful for better describing the pre-hospital context and for planning flow in the ED. Conclusion: While multimedia applications may potentially improve the handoff process, future intervention studies need to be rigorously designed. We recommend interdisciplinary training of EMS and ED staff in the use of flexible structured protocols, especially given review findings that interdisciplinary communication and relationships can be challenging.

Patient classification based on volume and case-mix in the emergency department and their association with performance.

Predicting daily patient volume is necessary for emergency department (ED) strategic and operational decisions, such as resource planning and workforce scheduling. For these purposes, forecast accuracy requires understanding the heterogeneity among patients with respect to their characteristics and reasons for visits. To capture the heterogeneity among ED patients (case-mix), we present a patient coding and classification scheme (PCCS) based on patient demographics and diagnostic information. The proposed PCCS allows us to mathematically formalize the arrival patterns of the patient population as well as each class of patients. We can then examine the volume and case-mix of patients presenting to an ED and investigate their relationship to the ED's quality and time-based performance metrics. We use data from five hospitals in February, July and November for the years of 2007, 2012, and 2017 in the city of Calgary, Alberta, Canada. We find meaningful arrival time patterns of the patient population as well as classes of patients in EDs. The regression results suggest that patient volume is the main predictor of time-based ED performance measures. Case-mix is, however, the key predictor of quality of care in EDs. We conclude that considering both patient volume and the mix of patients are necessary for more accurate strategic and operational planning in EDs.

Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 µM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.

Distinct Influence of Hypercaloric Diets Predominant with Fat or Fat and Sucrose on Adipose Tissue and Liver Inflammation in Mice.

Overfeeding of a hypercaloric diet leads to obesity, diabetes, chronic inflammation, and fatty liver disease. Although limiting fat or carbohydrate intake is the cornerstone for obesity management, whether lowering fat or reducing carbohydrate intake is more effective for health management remains controversial. This study used murine models to determine how dietary fat and carbohydrates may influence metabolic disease manifestation. Age-matched C57BL/6J mice were fed 2 hypercaloric diets with similar caloric content, one with very high fat and low carbohydrate content (VHF) and the other with moderately high fat levels with high sucrose content (HFHS) for 12 weeks. Both groups gained more weight and displayed hypercholesterolemia, hyperglycemia, hyperinsulinemia, and liver steatosis compared to mice fed a normal low-fat (LF) diet. Interestingly, the VHF-fed mice showed a more robust adipose tissue inflammation compared to HFHS-fed mice, whereas HFHS-fed mice showed liver fibrosis and inflammation that was not observed in VHF-fed mice. Taken together, these results indicate macronutrient-specific tissue inflammation with excess dietary fat provoking adipose tissue inflammation, whereas moderately high dietary fat with extra sucrose is necessary and sufficient for hepatosteatosis advancement to steatohepatitis. Hence, liver and adipose tissues respond to dietary fat and sucrose in opposite manners, yet both macronutrients are contributing factors to metabolic diseases.