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Background: Cabozantinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated efficacy in metastatic renal cell carcinoma (mRCC). The association between toxicity and therapeutic effectiveness has been established with other TKIs. We investigated whether cabozantinib dose reductions, a surrogate for toxicity and adequate drug exposure, were associated with improved clinical outcomes in mRCC., Methods: Employing the CKCis database, we analyzed patients treated with cabozantinib in the second line or later between 2011 to 2021. The cohort was stratified into those needing dose reductions (DR) during treatment and those not (no-DR). Outcomes, including objective response rate (ORR), time to treatment failure (TTF), and overall survival (OS), were compared based on dose reduction status. The influence of the initial dose on outcomes was also explored., Results: Among 319 cabozantinib-treated patients, 48.3% underwent dose reductions. Response rates exhibited no significant difference between the DR and no-DR groups (15.1% vs. 18.2%, P = .55). Patients with DR had superior median OS (26.15 vs. 15.47 months, P = .019) and TTF (12.74 vs. 6.44 months, P = .022) compared to no-DR patients. These differences retained significance following adjustment for IMDC risk group (OS HR = 0.67, P = .032; TTF HR = 0.65, P = .008). There was no association between the initial dose and ORR, OS, or TTF., Conclusion: This study highlights the link between cabozantinib dose reductions due to toxicity and improved survival and time to treatment failure in mRCC patients. These findings underscore the potential of using on-treatment toxicity as an indicator of adequate drug exposure to individualize dosing and optimize treatment effectiveness. Larger studies are warranted to validate these results and develop individualized strategies for cabozantinib when given alone or in combination with immunotherapy., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objective: Metastatic renal cell carcinoma (mRCC) patients have been reported to have better outcomes when treated with immunotherapies (IO) compared to targeted therapies (TT). This study aims to evaluate the impact of first-line systemic therapies on survival of mRCC patients with or without sarcomatoid features using real-world data., Methods: Metastatic RCC patients of International mRCC Database Consortium (IMDC) intermediate or high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system. Patients were classified by initial treatment: (1) targeted therapy (TT) used alone or (2) immunotherapy (IO)-based systemic therapies used in combination of either IO-IO or IO-TT. The inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazard models were used to assess the impact of initial treatment received on overall survival (OS)., Key Findings and Limitations: Of the 1202 eligible patients, 791 were treated with TT and 411 with IO combinations. Of the patients, 76% were male, and the majority (91%) had a nephrectomy before systemic therapy. In nonsarcomatoid patients (639 TT and 320 IO patients), treatment with IO was associated with improved OS compared with patients treated with TT (median of 72 vs 48 mo, hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50-0.80, objective response rate [ORR] of 38.5% for IO and 23.5% for TT). In sarcomatoid patients (152 TT and 91 IO patients), treatment with IO was associated with improved OS (median of 48 vs 18 mo, HR 0.41, 95% CI 0.26-0.64, ORR of 49.5% for IO and 13.8% for TT). Similar results were observed in patients with synchronous metastatic disease only., Conclusions and Clinical Implications: IO treatment was associated with improved survival in mRCC patients. The magnitude of benefit is increased in patients with sarcomatoid mRCC, consequently, identifying the sarcomatoid status early on could help healthcare providers make a better treatment decision., Patient Summary: Metastatic renal cell carcinoma (mRCC) patients of International mRCC Database Consortium intermediate and high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). In this study, treatment with immunotherapy was associated to an improved survival and response rates for mRCC patients with and without sarcomatoid features. The magnitude of benefit is increased in patients with sarcomatoid mRCC., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Clinical supervisors hesitate to report learner weaknesses, a widely documented phenomenon referred to as "failure to fail." They also struggle to discuss weaknesses with learners themselves. Their reluctance to report and discuss learner weaknesses threatens the validity of assessment-of-learning decisions and the effectiveness of assessment for learning. Personal and interpersonal factors have been found to act as barriers to reporting learners' difficulties, but the precise role of the resident-supervisor relationship remains underexplored, specifically in the emergency setting. This study aims to better understand if and how factors related to the resident-supervisor relationship are involved in assessment of and for learning in the emergency setting., Methods: We conducted a qualitative study, using semistructured interviews of 15 clinical supervisors in emergency medicine departments affiliated with our institution. Transcripts were independently coded by three members of the team using an iterative mixed deductive-inductive thematic analysis approach. The team then synthesized the coding and discussed analysis following guidelines for thematic analysis., Results: Participating emergency medicine supervisors valued resident-supervisor relationships built on collaboration and trust and believed that such relationships support learning. They described how these relationships influenced assessment of and for learning and how in turn assessment influenced the relationship. Almost all profiles of resident-supervisor relationships in our study could hinder the disclosing of resident weaknesses, through a variety of mechanisms. To protect residents and themselves from the discomfort of disclosing weaknesses and to avoid deteriorating the resident-supervisor relationship, many downplayed or even masked residents' difficulties. Supervisors who described themselves as able to provide negative assessment of and for learning often adopted a more distant or professional stance., Conclusions: This study contributes to a growing literature on failure to fail by confirming the critical impact that the resident-supervisor relationship has on the willingness and ability of emergency medicine supervisors to play their part as assessors., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. AEM Education and Training published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Importance: The KEYNOTE-826 randomized clinical trial showed statistically significant and clinically meaningful survival benefits with the addition of pembrolizumab to chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Treatment effects in patient subgroups of the study population are unknown., Objective: To assess efficacy outcomes in patient subgroups of KEYNOTE-826., Design, Setting, and Participants: Exploratory subgroup analyses were conducted in a global, phase 3, randomized, double-blind, placebo-controlled clinical trial. Participants included women with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. This subanalysis was conducted from November 20, 2018, to May 3, 2021., Interventions: Pembrolizumab, 200 mg, every 3 weeks or placebo for up to 35 cycles plus chemotherapy (paclitaxel, 175 mg/m2, plus cisplatin, 50 mg/m2, or carboplatin AUC 5 [area under the free carboplatin plasma concentration vs time curve]) with or without bevacizumab, 15 mg/kg., Main Outcomes and Measures: Overall survival (OS) and progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior chemoradiotherapy (CRT) exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with programmed cell death ligand 1-positive tumors (defined as a combined positive score [CPS] ≥1) and in the intention-to-treat population., Results: A total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior CRT only (HR, 0.56; 95% CI, 0.39-0.81) and without prior CRT only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type. In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior CRT only (HR, 0.64; 95% CI, 0.45-0.91) and without prior CRT only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type. Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations., Conclusions and Relevance: The findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT03635567.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The phase III, double-blind KEYNOTE-826 trial of pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with or without bevacizumab, showed statistically significant survival benefits with the addition of pembrolizumab for patients with persistent, recurrent, or metastatic cervical cancer (primary data cutoff: May 3, 2021). This article reports the protocol-specified final overall survival (OS) results tested in the PD-L1 combined positive score (CPS) ≥1, all-comer, and CPS ≥10 populations. At the final data cutoff (October 3, 2022), the median study follow-up duration was 39.1 months (range, 32.1-46.5 months). In the PD-L1 CPS ≥1 (N = 548), all-comer (N = 617), and CPS ≥10 (N = 317) populations, median OS with pembrolizumab-chemotherapy versus placebo-chemotherapy was 28.6 months versus 16.5 months (hazard ratio [HR] for death, 0.60 [95% CI, 0.49 to 0.74]), 26.4 months versus 16.8 months (HR, 0.63 [95% CI, 0.52 to 0.77]), and 29.6 months versus 17.4 months (HR, 0.58 [95% CI, 0.44 to 0.78]), respectively. The incidence of grade ≥3 adverse events was 82.4% with pembrolizumab-chemotherapy and 75.4% with placebo-chemotherapy. These results show that pembrolizumab plus chemotherapy, with or without bevacizumab, continued to provide clinically meaningful improvements in OS for patients with persistent, recurrent, or metastatic cervical cancer.

Purpose: Standard-of-care therapies for metastatic renal cell carcinoma (mRCC) have greatly evolved. However, the availability of emerging options in global health care systems can vary. We sought to describe the integration and usage of systemic therapies for mRCC in Canada since 2011., Methods: We included patients with mRCC enrolled in the Canadian Kidney Cancer Information System, a prospective cohort of patients from 14 Canadian academic centers, who received systemic therapy from January 1, 2011, to December 31, 2021. Patients were stratified by treatment era (cohort 1: 2011-2015, cohort 2: 2016-2021). Stacked bar charts were used to present treatment proportions; Sankey diagrams were used to show the evolution of treatment sequencing between the two cohorts., Results: Four thousand one hundred seven patients were diagnosed with mRCC, of whom 2,752 (67%) received systemic therapy. Among these patients, mean age was 64 years, 74% were male, 75% had clear cell histology, and International Metastatic RCC Database Consortium risk classification was favorable, intermediate, and poor in 16%, 56%, and 28%, respectively. Utilization of immune checkpoint inhibition (ICI)-based treatments has increased in Canada and reflects global and local patterns of approval and adoption. The use of therapies after doublet ICI has mostly shifted toward vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) that were previously used in first line with subsequent treatments reflecting approved and available agents after previous VEGF-TKI. Clinical trial participation among patients who received systemic therapy was 18% in first, 21% in second, and 24% in third line., Conclusion: In Canada's publicly funded health care system, availability of standard mRCC therapies broadly reflects access from government-funded clinical trials and compassionate access program sources. In an evolving therapeutic landscape, ongoing advocacy is required to continue to facilitate patient access to efficacious therapies.

Introduction: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context., Methods: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement., Results: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data., Conclusions: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

Background: In the KEYNOTE-826 study, the addition of the anti-PD-1 monoclonal antibody pembrolizumab to chemotherapy with or without bevacizumab improved overall survival and progression-free survival (primary endpoints) versus placebo plus chemotherapy with or without bevacizumab, with manageable toxicity, in patients with persistent, recurrent, or metastatic cervical cancer. In this Article, we report patient-reported outcomes (PROs) from KEYNOTE-826., Methods: KEYNOTE-826 is a multicentre, randomised, phase 3 trial in 151 cancer treatment centres in 19 countries. Eligible patients were aged 18 years or older with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy (previous radiosensitising chemotherapy was allowed) and not amenable to curative treatment and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) centrally by means of an interactive voice response system in a double-blind manner to receive either pembrolizumab 200 mg or placebo every 3 weeks intravenously for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m 2 plus cisplatin 50 mg/m 2 or carboplatin area under the curve 5 mg/mL per min, intravenously) with or without bevacizumab 15 mg/kg every 3 weeks intravenously. Randomisation (block size of 4) was stratified by metastatic disease at diagnosis, planned bevacizumab use, and PD-L1 combined positive score. Patients, investigators, and other study personnel involved in study treatment administration or clinical evaluation of patients were unaware of treatment group assignments. PRO instruments were the EORTC Quality-of-Life-Core 30 (QLQ-C30), the EORTC cervical cancer module (QLQ-CX24), and the EuroQol-5 dimension-5 level (EQ-5D-5L) visual analogue scale, each collected before treatment at cycles 1-14 and every other cycle thereafter. Primary endpoints were overall survival and progression-free survival per RECIST version 1.1 by investigator review. Change from baseline in QLQ-C30 global health status (GHS)-quality of life (QoL) was a prespecified secondary endpoint and was assessed in the PRO full analysis population (all patients who received at least one dose of study treatment and completed at least one post-baseline PRO assessment). Other PRO analyses were protocol-specified exploratory endpoints. The study is registered with ClinicalTrials.gov, NCT03635567, and is ongoing., Findings: Between Nov 20, 2018, and Jan 31, 2020, of 883 patients screened, 617 were randomly assigned (pembrolizumab group, n=308; placebo group, n=309). 587 (95%) of 617 patients received at least one dose of study treatment and completed at least one post-baseline PRO assessment and were therefore included in the PRO analyses (pembrolizumab group, n=290; placebo group, n=297). Median follow-up was 22·0 months (IQR 19·1-24·4). At week 30, QLQ-C30 completion was 199 (69%) of 290 patients in the pembrolizumab group and 168 (57%) of 297 patients in the placebo group; compliance was 199 (94%) of 211 and 168 (90%) of 186, respectively. The least squares mean change in QLQ-C30 GHS-QoL score from baseline to week 30 was -0·3 points (95% CI -3·1 to 2·6) in the pembrolizumab group and -1·3 points (-4·2 to 1·7) in the placebo group, with a between-group difference in least squares mean change of 1·0 point (95% CI -2·7 to 4·7). Median time to true deterioration in GHS-QoL was not reached (NR; 95% CI 13·4 months-NR) in the pembrolizumab group and 12·9 months (6·6-NR) in the placebo group (hazard ratio 0·84 [95% CI 0·65-1·09]). 122 (42%) of 290 patients in the pembrolizumab group versus 85 (29%) of 297 in the placebo group had improved GHS-QoL at any time during the study (p=0·0003)., Interpretation: Addition of pembrolizumab to chemotherapy with or without bevacizumab did not negatively affect health-related quality of life. Along with the efficacy and safety results already reported from KEYNOTE-826, these data support the benefit of pembrolizumab and the value of immunotherapy in patients with recurrent, persistent, or metastatic cervical cancer., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests All authors' institutions received research funding from Merck Sharp & Dohme, a subsidiary of Merck (Rahway, NJ, USA), for the conduct of this study. BJM was a consultant to or received honoraria from AbbVie, Agenus, Akeso Biopharma, Aravive, AstraZeneca, Clovis Oncology, Eisai, Elevar Therapeutics, EMD Serono, Genentech, Genmab–Seattle Genetics, GlaxoSmithKline, GOG Foundation, Gradalis, ImmunoGen, Incyte Corporation, Iovance Biotherapeutics, Janssen Biotech, Karyopharm Therapeutics, Merck, Mersana Therapeutics, Myriad Genetic Laboratories, Novocure, Pfizer, Pfizer International, Puma Biotechnology, Regeneron Pharmaceuticals, Sorrento Therapeutics, Takeda Development Center Americas, US Oncology, and VBL Therapeutics. KST received research grant to institution, and consultant–speaker's bureau fees from Merck. CD was on an endpoint review committee for Merck. KH was a scientific advisory board member and received honoraria, contracted research and study funding to their institution from Merck Sharp & Dohme. RS-F received speaker honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Roche, Medison, and Neopharm; a research grant to their institution from Merck Sharp & Dohme, and was an advisory board member for Merck Sharp and Dohme, VBL Therapeutics, and Clovis Oncology. PS received research support from Merck and participated in advisory boards for BMS, AstraZeneca, Janssen, and Novartis. MG received speaker's bureau–advisory board fees from Amgen, and received advisory board fees (institutional) from from AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Merck, Novartis, Pfizer, and Takeda Oncology, and travel fees from F Hoffmann-La Roche. VS was a consultant or advisory board member for GlaxoSmithKline and Merck. VC received a grant to institution from AstraZeneca, Bayer, Bayer Healthcare, Bristol Myers Squibb, Merck, Seagen; consultant–advisory board fees from Bristol Myers Squibb, Ipsen Biopharmaceuticals, Merck, Pfizer Canada, and Seagen; and consultant fees from AstraZeneca Canada and Pfizer Canada. CT, KL, AMN, and MJM are employees of Merck Sharp & Dohme and own stock in Merck. NC reports fees for advisory board membership from AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, Immunogen, Mersana, Merck Sharp & Dohme–Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris, Roche; fees as an invited speaker for AstraZeneca, Novartis, Clovis Oncology, GlaxoSmithKline, and Merck–Merck Sharp & Dohme; institutional research grants from AstraZeneca, PharmaMar, and Roche; and non-remunerated activities as member of the ESMO Guidelines Steering Committee and chairs for of the Scientific Committee of Alleanza contro il tumore ovarico. DL was a consultant for Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Gynecological Cancer InterGroup, Merck Sharp and Dohme, Pharma Mar; received a research grant to institution from AstraZeneca, Clovis Oncology, F Hoffmann-La Roche, Genmab, GlaxoSmithKline, ImmunoGen, Incyte Corporation, Merck, Merck Sharp and Dohme, PharmaMar; and was a data and safety monitoring board member for Novartis. MVC, EY, MOHdM, and AA declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aims: The time-dependent prognostic role of bystander cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) patients has not been described with great precision, especially for neurologic outcomes. Our objective was to assess the association between bystander CPR, emergency medical service (EMS) response time, and OHCA patients' outcomes., Methods: This cohort study used the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registries. Bystander-witnessed adult OHCA treated by EMS were included. The primary outcome was survival to hospital discharge and secondary outcome was survival with a good neurologic outcome (modified Rankin scale 0-2). Multivariable logistic regression models were used to assess the associations and interactions between bystander CPR, EMS response time and clinical outcomes., Results: Out of 229,637 patients, 41,012 were included (18,867 [46.0%] without bystander CPR and 22,145 [54.0%] with bystander CPR). Bystander CPR was independently associated with higher survival (adjusted odds ratio [AOR] = 1.70 [95%CI 1.61-1.80]) and survival with a good neurologic outcome (AOR = 1.87 [95%CI 1.70-2.06]), while longer EMS response times were independently associated with lower survival to hospital discharge (each additional minute of EMS response time: AOR = 0.92 [95%CI 0.91-0.93], p < 0.001) and lower survival with a good neurologic outcome (AOR = 0.88 [95%CI 0.86-0.89], p < 0.001). There was no interaction between bystander CPR and EMS response time's association with survival (p = 0.12) and neurologic outcomes (p = 0.65)., Conclusions: Although bystander CPR is associated with an immediate increase in odds of survival and of good neurologic outcome for OHCA patients, it does not influence the negative association between longer EMS response time and survival and good neurologic outcome., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: This pilot study aimed to test the feasibility of conducting a randomized controlled trial to examine how simulation environments (in situ versus laboratory) influence teamwork skills development and cognitive load among novice healthcare trauma professionals in the emergency department., Method: Twenty-four novice trauma professionals (nurses, medical residents, respiratory therapists) were assigned to in situ or laboratory simulations. They participated in two 15-minute simulations separated by a 45-minute debriefing on teamwork. After each simulation, they completed validated teamwork and cognitive load questionnaires. All simulations were video recorded to assess teamwork performance by trained external observers. Feasibility measures (e.g., recruitment rate, randomization procedure and intervention implementation) were recorded. Mixed ANOVAs were used to calculate effect sizes., Results: Regarding feasibility, several difficulties were encountered, such as a low recruitment rate and the inability to perform randomization. Outcome results suggest that the simulation environment does not affect novice trauma professionals' teamwork performance and cognitive load (small effect sizes), but a large effect size was observed for perceived learning., Conclusion: This study highlights several barriers to conducting a randomized study in the context of interprofessional simulation-based education in the emergency department. Suggestions are made to guide future research in the field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Studies evaluating the prognostic value of the pulseless electrical activity (PEA) heart rate in out-of-hospital cardiac arrest (OHCA) patients have reported conflicting results. The objective of this study was to evaluate the association between the initial PEA heart rate and favorable clinical outcomes for OHCA patients., Methods: The present post-hoc cohort study used the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry Version 3, which included OHCA patients in seven US and three Canadian sites from April 2011 to June 2015. The primary outcome was survival to hospital discharge and the secondary outcome was survival with a good functional outcome. For the primary analysis, the patients were separated into eight groups according to their first rhythms and PEA heart rates: (1) initial PEA heart rate of 1-20 beats per minute (bpm); (2) 21-40 bpm; (3) 41-60 bpm; (4) 61-80 bpm; (5) 81-100 bpm; (6) 101-120 bpm; (7) over 120 bpm; (8) initial shockable rhythm (reference category). Multivariable logistic regression models were used to assess the associations of interest., Results: We identified 17,675 patients (PEA: 7,089 [40.1%]; initial shockable rhythm: 10,797 [59.9%]). Patients with initial PEA electrical frequencies ≤100 bpm were less likely to survive to hospital discharge than patients with initial shockable rhythms (1-20 bpm: adjusted odds ratio [AOR] = 0.15 [95%CI 0.11-0.21]; 21-40 bpm: AOR = 0.21 [0.18-0.25]; 41-60 bpm: AOR = 0.30 [0.25-0.36]; 61-80 bpm: AOR = 0.37 [0.28-0.49]; 81-100 bpm: AOR = 0.55 [0.41-0.65]). However, there were no statistical outcome differences between PEA patients with initial electrical frequencies of >100 bpm and patients with initial shockable rhythms (101-120 bpm: AOR = 0.65 [95%CI 0.42-1.01]; >120 bpm: AOR = 0.72 [95%CI 0.37-1.39]). Similar results were observed for survival with good functional outcomes (101-120 bpm: AOR = 0.60 [95%CI 0.31-1.15]; >120 bpm: AOR = 1.08 [95%CI 0.50-2.28])., Conclusions: We observed a good association between higher initial PEA electrical frequency and favorable clinical outcomes for OHCA patients. As there is no significant difference in outcomes between patients with initial PEA heart rates of more than 100 bpm and those with initial shockable rhythms, we can hypothesize that these patients could be considered in the same prognostic category.

Background: The role and sequencing of combination immuno-oncology (IO) therapy following progression on or after first-line IO therapy has not been well-established. The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) program is an open-label, phase 2 platform trial designed to evaluate multiple IO combinations in patients with advanced renal cell carcinoma (aRCC) who progressed during or after prior IO therapy. Here, we describe the results for patients treated with nivolumab plus ipilimumab. For enrollment in track 2 (reported here), patients with histologically confirmed clear cell aRCC, Karnofsky performance status ≥70%, and life expectancy ≥3 months who had previously progressed after IO (anti-programmed death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)) therapy were eligible. Previous treatment with anti-CTLA-4 therapy plus anti-PD-1/PD-L1 therapy precluded eligibility for enrollment in the nivolumab plus ipilimumab arm. Patients were treated with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for up to 2 years or until progression, toxicity, or protocol-specified discontinuation. The primary outcome measures were objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Secondary outcomes were safety and tolerability up to 2 years. Overall survival (OS) was a tertiary/exploratory endpoint. Overall, 46 patients were included with a median follow-up of 33.8 months. The ORR was 17.4% (95% CI, 7.8 to 31.4) with eight (17.4%) patients achieving partial response. Stable disease was achieved in 19 (41.3%) patients, while 14 (30.4%) had progressive disease. Median DOR (range) was 16.4 (2.1+ to 27.0+) months. The PFS rate at 24 weeks was 43.2%, and median OS was 23.8 (95% CI, 13.2 to not reached) months. Grade 3-4 immune-mediated adverse events were reported in seven (15.2%) patients. No treatment-related deaths were reported. Patients with aRCC treated with nivolumab plus ipilimumab may derive durable clinical benefit after progression on previous IO therapies, including heavily pretreated patients, with a manageable safety profile that was consistent with previously published safety outcomes. These outcomes contribute to the knowledge of optimal sequencing of IO therapies for patients with aRCC with high unmet needs., Trial Registration Number: NCT02996110., Competing Interests: Competing interests: TKC reports consulting or advisory board fees, honoraria, and research grants from AstraZeneca, Aravive, AVEO Pharmaceuticals, Bayer, Bristol Myers Squibb (BMS), Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH and others), outside the submitted work. Institutional patents filed on molecular mutations and immunotherapy response/toxicity, and circulating tumor DNA. Equity holdings: Tempest, Pionyr, Osel, and Precede Bio. Committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan. Medical writing and editorial assistance support may have been funded by communications companies in part. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. Dr Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, and Loker Pinard Funds for Kidney Cancer Research at DFCI. CV provided upon request for scope of clinical practice and research. HK reports institutional research grant funding from Apexigen, BMS, and Merck; personal fees from Array Biopharma, BMS, Calithera Biosciences, Celldex, ChemoCentryx, Clinigen, Elevate Bio, GI reviewers, GigaGen, Immunocore, Instil Bio, Iovance, Merck, Shionogi, and Signatera. SG reports consulting or advisory role from BMS, Bayer, Pfizer, Exelixis, Corvus Pharmaceuticals, Sanofi/Genzyme, EMD Serono, Seattle Genetics/Astellas, Eisai, Merck, AVEO Pharmaceuticals, and QED Therapeutics; and research funding (institutional) from Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Calithera Biosciences, Immunomedics, Corvus Pharmaceuticals, and Surface Oncology. SST reports consulting or advisory board fees from Merck, Intellisphere LLC, Natera, BMS, and Exelixis; patent pending (Fred Hutchinson Cancer Center); and research funding (institutional) from Genentech, BMS, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, and Clinigen Group. TMK has nothing to disclose. RP reports consulting fees from Karyopharm Therapeutics and BiolineRx. SN has nothing to disclose. GP reports advisory board fees from AstraZeneca, BMS, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, and Pfizer. MAC reports consulting or advisory fees from Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, and Foundation Medicine; and research funding (institutional) from BMS, AstraZeneca, Pfizer, and Gilead Science. VC reports consulting or speakers’ bureau fees from Ipsen, Eisai, Merck, AstraZeneca, Pfizer, Novartis, BMS, Astellas and Janssen. EF has nothing to disclose. C-HL reports research funding (institutional) from BMS, Calithera Biosciences, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; consulting fees from Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono; and honoraria from AiCME, Intellisphere, and Research to Practice. SJH reports compensation for advisory boards and speakers’ bureaus from Astellas, AstraZeneca, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem; institutional research or grant funding from Astellas, AstraZeneca, Ayala, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem. WHM reports consulting or advisory board fees from BMS, Merck, Roche, Novartis, GlaxoSmithKline, and Amgen; honoraria from BMS, Roche, Novartis, and GlaxoSmithKline; and research funding (institutional) from Merck, BMS, Novartis, GlaxoSmithKline, Roche, AstraZeneca, MethylGene, and MedIm. SSS, C-WL, HD, and PB are employed by and has stock ownership in BMS. RJM reports advisory board fees from AstraZeneca, AVEO Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and research funding (institutional) from BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. BE reports research funding (institutional) from BMS; consulting fees from Pfizer, BMS, Ipsen, AVEO Pharmaceuticals, Oncorena, and Eisai; honoraria from Pfizer, BMS, Ipsen, Oncorena, and Eisai; and travel accommodations and expenses from BMS, Ipsen, and Merck Sharp & Dohme., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Self-reported approaches that assess opioid usage can be subject to social desirability and recall biases that may underestimate actual pill consumption. Our objective was to determine the accuracy of patient self-reported opioid consumption using a 14-day daily paper or electronic diary., Design: Prospective cohort study., Setting: Multicentre study conducted in four Québec (Canada) emergency departments (ED): three university-affiliated centres, two of them Level I trauma centres and one urban community hospital., Participants: ED patients aged ≥18 years with acute pain (≤2 weeks) who were discharged with an opioid prescription. Patients completed a 14-day daily diary (paper or electronic) assessing the quantity of opioids consumed. On diary completion, a random sample from the main cohort was selected for a follow-up visit to the hospital or a virtual video visit where they had to show and count the remaining pills. Patients were blinded to the main objective of the follow-up visit., Outcomes: Quantity of opioid pills consumed during the 2-week follow-up period self-reported in the 14-day diary (paper or electronic) and calculated from remaining pills counted during the follow-up visit. Intraclass correlation coefficient (ICC) and Bland-Altman plots were used to assess accuracy., Results: A total of 166 participants completed the 14-day diary as well as the in-person or virtual visit; 49.4% were women and median age was 47 years (IQR=21). The self-reported consumed quantity of opioid in the 14-day diary and the one calculated from counting remaining opioid pills during the follow-up visit were very similar (ICC=0.992; 95% CI: 0.989 to 0.994). The mean difference between both measures from Bland-Altman analysis was almost zero (0.048 pills; 95% CI: -3.77 to 3.87)., Conclusion: Self-reported prescription opioid use in a 14-day diary is an accurate assessment of the quantity of opioids consumed in ED discharged patients., Trial Registration Number: NCT03953534., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The no-flow time (NFT) can help establish prognosis in out-of-hospital cardiac arrest (OHCA) patients. It is often used as a selection criterion for extracorporeal resuscitation. In patients with an unwitnessed OHCA for whom the NFT is unknown, the initial rhythm has been proposed to identify those more likely to have had a short NFT. Our objective was to determine the predictive accuracy of an initial shockable rhythm for an NFT of 5 minutes or less (NFT ≤ 5)., Design: Retrospective analysis of prospectively collected data., Setting: Prehospital OHCA in eight U.S. and three Canadian sites., Patients: A total of 28,139 adult patients with a witnessed nontraumatic OHCA were included, of whom 11,228 (39.9%) experienced an emergency medical service-witnessed OHCA (NFT = 0), 695 (2.7%) had a bystander-witnessed OHCA, and an NFT less than or equal to 5, and 16,216 (57.6%) with a bystander-witnessed OHCA and an NFT greater than 5., Interventions: Sensitivity, specificity, and likelihood ratios of an initial shockable rhythm to identify patients with an NFT less than or equal to 5 minutes., Measurements and Main Results: The sensitivity of an initial shockable rhythm to identify patients with an NFT less than or equal to 5 was poor (25% [95% CI, 25-26]), but specificity was moderate (70% [95% CI, 69-71]). The positive and likelihood ratios were inverted (negative accuracy) (positive likelihood ratio, 0.76 [95% CI, 0.74-0.79]; negative likelihood ratio, 1.12 [95% CI, 1.10-1.12]). Including only patients with a bystander-witnessed OHCA improved the sensitivity to 48% (95% CI, 45-52), the positive likelihood ratio to 1.45 (95% CI, 1.33-1.58), and the negative likelihood ratio to 0.77 (95% CI, 0.72-0.83), while slightly lowering the specificity to 67% (95% CI, 66-67)., Conclusions: Our analysis demonstrated that the presence of a shockable rhythm at the time of initial assessment was poorly sensitive and only moderately specific for OHCA patients with a short NFT. The initial rhythm, therefore, should not be used as a surrogate for NFT in clinical decision-making., Competing Interests: Drs. Cournoyer, Morris, and Daoust received support for article research from Fonds des Urgentistes de l’Hôpital du Sacré-Cœur de Montréal; and Département de médecine familiale et de médecine d’urgence de l’Université de Montréal. Dr. Morris’ institution received funding from Milestones Pharmaceuticals. Dr. Daoust’s institution received funding from Fonds des Urgentistes de l’Hôpital du Sacré-Cœur de Montréal’ and ‘Département de médecine familiale et de médecine d’urgence de l’Université de Montréal. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: This study's objective was to examine emergency department (ED) workers' perspectives during the Canadian COVID-19 first wave., Methods: This qualitative study included workers from nine Canadian EDs who participated in 3 monthly video focus groups between April and July 2020 to explore (1) personal/professional experiences, (2) patient care and ED work, (3) relationships with teams, institutions and governing bodies. Framework analysis informed data collection and analysis., Results: Thirty-six focus groups and 15 interviews were conducted with 53 participants (including 24 physicians, 16 nurses). Median age was 37.5 years, 51% were female, 79% had more than 5 years' experience. Three main themes emerged. (1) Early in this pandemic, participants felt a responsibility to provide care to patients and solidarity toward their ED colleagues and team, while balancing many risks with their personal protection. (2) ED teams wanted to be engaged in decision-making, based on the best available scientific knowledge. Institutional decisions and clinical guidelines needed to be adapted to the specificity of each ED environment. (3) Working during the pandemic created new sources of moral distress and fatigue, including difficult clinical practices, distance with patients and families, frequent changes in information and added sources of fatigue. Although participants quickly adapted to a "new normal", they were concerned about long-term burnout. Participants who experienced high numbers of patient deaths felt especially unprepared., Interpretation: ED workers believe they have a responsibility to provide care through a pandemic. Trust in leadership is supported by managers who are present and responsive, transparent in their communication, and involve ED staff in the development and practice of policies and procedures. Such practices will help protect from burnout and ensure the workforce's long-term sustainability., (© 2022. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Introduction: Ipilimumab plus nivolumab was associated with a survival benefit in a phase III clinical trial of first-line treatment for metastatic renal cell carcinoma (mRCC). In this study, mRCC patients from the Canadian Kidney Cancer Information System (CKCis) database who received first-line ipilimumab plus nivolumab were analyzed to determine the safety and outcomes in a real-world setting., Patients and Methods: Patients who received ipilimumab plus nivolumab as first-line therapy for mRCC in CKCis, were identified, and the amount of treatment received, discontinuation rates, and reasons for discontinuing treatment were determined. Toxicity data, including type and grade, were collected. Efficacy outcomes of interest included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR)., Results: The cohort included 195 patients, the majority with clear cell histology (74%). All 4 cycles of ipilimumab plus nivolumab were administered in 124 patients (64%). Progressive disease (n = 87; 45%) and toxicity (n = 36; 18%) were the most common causes for discontinuing treatment. Several patients (n = 18) did not receive all 4 doses of ipilimumab but received single agent nivolumab. The estimated median OS was 54.5 months (95% CI, 17.7 - NE) and 12-month OS was 72.2% (95% CI, 65.0 - 79.3). Median PFS was 7.4 months (95% CI 5.3 - 10.2) and ORR was 42.5%. Patients who received all 4 cycles of ipilimumab plus nivolumab had better ORR (50% vs. 28%) and a longer PFS and OS than those who received less than 4 cycles (P < .0001). Ninety-five AEs were documented in 72 patients who required dose reduction/change, with colitis being the most frequent., Conclusion: In this real-world cohort of treatment-naïve mRCC patients, outcomes, and safety were comparable to previously reported clinical trial data., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: With the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone., Methods and Materials: Data were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories., Results: In total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P  = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P  = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P  = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P  = .63)., Conclusions: In this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need., (© 2022 The Author(s).)

Background: Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)-positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab., Methods: In a double-blind, phase 3 trial, we randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1-staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis., Results: In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P = 0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively)., Conclusions: Progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab. (Funded by Merck Sharp and Dohme; KEYNOTE-826 ClinicalTrials.gov number, NCT03635567.)., (Copyright © 2021 Massachusetts Medical Society.)

Aims: For out-of-hospital cardiac arrest (OHCA) patients, the influence of the delay before the initiation of resuscitation, termed the no-flow time (NFT), and duration of bystander-only resuscitation low-flow time (BLFT) on the type of electrical rhythm observed has not been well described. The objective of this study is to determine the relationship between NFT, BLFT and the likelihood of a shockable rhythm over time., Methods: Using a North American prospective registry (2005-2015; mostly urban settings), we selected adult (18 years and over) patients who experienced a witnessed OHCA from a suspected cardiac etiology. Patients with an emergency medical services witnessed OHCA were only included in sensitivity analyses. The association between the NFT, BLFT and the presence of a shockable rhythm was evaluated using a multivariable logistic regression adjusting for the registry version, age, sex, and public location., Results: A total of 229,632 patients were logged in the registry, 50,957 of whom were included. Of these, 17,704 (34.7%) had an initial shockable rhythm. After the first minute, a significant decrease over time in the occurrence of shockable rhythm is observed but is slower when bystander cardiopulmonary resuscitation (CPR) is provided (each supplemental minute of BLFT: adjusted odds ratio = 0.95, 95 %CI = 0.94-0.95; each supplemental minute of NFT: adjusted odds ratio = 0.91, 95 %CI = 0.90-0.91])., Conclusions: In this large observational study, we were able to demonstrate that longer NFT were associated with lower odds of shockable presenting rhythms. Bystander CPR significantly mitigates the degradation of shockable rhythms over time, strengthening the need to improve bystander CPR rates around the world., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The prevalence of multiple myeloma is increasing and there is a need to evaluate escalating therapy costs (Canadian Cancer Statistics A, 2020). The MYX.1 phase II trial showed that high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone (wKCD) is efficacious in relapsed and refractory disease. We conducted a descriptive cost analysis, from the perspective of the Canadian public healthcare system, using trial data., Methods: The primary outcome was the mean total cost per patient. Resource utilization data were collected from all 75 trial patients over a trial time horizon. Costs are presented in Canadian dollars (2020)., Results: The cost of treatment was calculated from the time of patient (pt) enrollment until the second data lock. The mean total cost was $203 336.08/pt (range $17 891.27-$505 583.55) Canadian dollars (CAD, where 1 CAD = 0.67 Euro (EUR)) and $14 081.45/pt per cycle. The median number of cycles was 15. The predominant cost driver was the cost of chemotherapy accounting for an average of $179 332.78/pt or $12 419.17/pt per cycle. Carfilzomib acquisition accounted for the majority of chemotherapy costs - $162 471.65/pt or $11 251.50/pt per cycle. Fifty-six percent (56%) of patients had at least one hospitalization during the trial period with an average cost of $12 657.86 per hospitalization. Three patients developed thrombotic microangiopathy (TMA) with an average cost of $18 863.32/pt including the cost of hospitalizations and therapeutic plasma exchange., Conclusions: High-dose wKCD is an active triplet regimen for relapsed and refractory multiple myeloma (RRMM) associated with reduced total cost compared with twice-weekly carfilzomib-based regimens., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Treatment of acute pain after emergency department (ED) discharge remains a challenge in the opioid crisis context. Our objective was to determine the proportion of patients using opioid vs non-opioid pain medication following discharge from the ED with acute pain, and the association of type of pain medication with average pain intensity before pain medication intake and report of pain relief., Methods: This was a prospective cohort study of ED patients aged ≥ 18 years with an acute pain (≤ 2 weeks) who were discharged with an opioid prescription. Patients completed a 14-day diary assessing daily pain intensity level before each pain medication intake (0-10 numeric rating scale), type of pain medication use (opioid vs non-opioid), and if pain was relieved by the medication used that day. Multilevel analyses were used to compare the effect of type of analgesic used on pain intensity and relief., Results: A total of 381 participants completed the 14-day diary; 50% were women and median age was 54 years (IQR = 43-66). Average daily pain intensity before pain medication intake was significantly higher for patients who used opioids (5.9; 95% CI 5.7-6.2) as compared to non-opioid analgesics (4.2; 95% CI 4.0-4.5) or no pain medication (2.2; 95% CI 1.9-2.5). Controlling for pain intensity, patients using opioids were more likely to report a pain relief (OR = 1.3; 95% CI 1.1-1.8) as compared to those who used non-opioid analgesics., Conclusion: Overall, opioids appear to be effective and used as intended by the prescribing physician.

Study Objective: To synthesize the evidence regarding the infection risk associated with different modalities of oxygen therapy used in treating patients with severe acute respiratory infection. Health care workers face significant risk of infection when treating patients with a viral severe acute respiratory infection. To ensure health care worker safety and limit nosocomial transmission of such infection, it is crucial to synthesize the evidence regarding the infection risk associated with different modalities of oxygen therapy used in treating patients with severe acute respiratory infection., Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2000, to April 1, 2020, for studies describing the risk of infection associated with the modalities of oxygen therapy used for patients with severe acute respiratory infection. The study selection, data extraction, and quality assessment were performed by independent reviewers. The primary outcome measure was the infection of health care workers with a severe acute respiratory infection. Random-effect models were used to synthesize the extracted data., Results: Of 22,123 citations, 50 studies were eligible for qualitative synthesis and 16 for meta-analysis. Globally, the quality of the included studies provided a very low certainty of evidence. Being exposed or performing an intubation (odds ratio 6.48; 95% confidence interval 2.90 to 14.44), bag-valve-mask ventilation (odds ratio 2.70; 95% confidence interval 1.31 to 5.36), and noninvasive ventilation (odds ratio 3.96; 95% confidence interval 2.12 to 7.40) were associated with an increased risk of infection. All modalities of oxygen therapy generate air dispersion., Conclusion: Most modalities of oxygen therapy are associated with an increased risk of infection and none have been demonstrated as safe. The lowest flow of oxygen should be used to maintain an adequate oxygen saturation for patients with severe acute respiratory infection, and manipulation of oxygen delivery equipment should be minimized., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: Opioid side effects are common when treating chronic pain. However, the frequency of opioid side effects has rarely been examined in acute pain conditions, particularly in a post emergency department (ED) setting. The objective of this study was to evaluate the short-term incidence of opioid-induced side effects (constipation, nausea/vomiting, dizziness, drowsiness, sweating, and weakness) in patients discharged from the ED with an opioid prescription., Methods: This is a prospective cohort study of patients aged ≥18 years who visited the ED for an acute pain condition (≤2 weeks) and were discharged with an opioid prescription. Patients completed a 14-day diary assessing daily pain medication use and side effects., Results: We recruited 386 patients with a median age of 54 years (IQR:43-66); 50% were women. During the 2-week follow-up, 80% of patients consumed opioids. Among the patients who used opioids, 79% (95%CI:75-83) reported side effects compared to 38% (95%CI:27-49) for non-users. Adjusting for age, sex, and pain condition, patients who used opioids were more likely to report constipation (OR:7.5; 95%CI:3.1-17.9), nausea/vomiting (OR:4.1; 95%CI:1.8-9.5), dizziness (OR:5.4; 95%CI: 2.2-13.2), drowsiness (OR:4.6; 95%CI:2.5-8.7), and weakness (OR:4.2; 95%CI:1.6-11.0) compared to non-users. A dose-response trend was observed for constipation but not for the other side effects. Nausea/vomiting (OR:2.0; 95%CI:1.1-3.6) and dizziness (OR:1.9; 95%CI:1.1-3.4) were more often associated with oxycodone than with morphine., Conclusion: As observed for chronic pain treatment, side effects are highly prevalent during short-term opioid treatment for acute pain. Physicians should inform patients about those side effects and should consider prescribing laxatives., Competing Interests: Declaration of Competing Interest There is no financial benefit or conflict of interests to report from any of the authors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: There is a growing interest in developing interprofessional education (IPE) in the community of healthcare educators. Tabletop exercises (TTX) have been proposed as a mean to cultivate collaborative practice. A TTX simulates an emergent situation in an informal environment. Healthcare professionals need to take charge of this situation as a team through a discussion-based approach. As TTX are gaining in popularity, performing a review about their uses could guide educators and researchers. The aim of this scoping review is to map the uses of TTX in healthcare., Methods and Analysis: A search of the literature will be conducted using medical subject heading terms and keywords in PubMed, Medline, EBM Reviews (Evidence-Based Medicine Reviews), CINAHL (Cumulative Index of Nursing and Allied Health Literature), Embase and ERIC (Education Resources Information Center), along with a search of the grey literature. The search will be performed after the publication of this protocol (estimated to be January 1st 2020) and will be repeated 1 month prior to the submission for publication of the final review (estimated to be June 1st 2020). Studies reporting on TTX in healthcare and published in English or French will be included. Two reviewers will screen the articles and extract the data. The quality of the included articles will be assessed by two reviewers. To better map their uses, the varying TTX activities will be classified as performed in the context of disaster health or not, for IPE or not and using a board game or not. Moreover, following the same mapping objective, outcomes of TTX will be reported according to the Kirkpatrick model of outcomes of educational programs., Ethics and Dissemination: No institutional review board approval is required for this review. Results will be submitted for publication in a peer-reviewed journal. The findings of this review will inform future efforts to TTX into the training of healthcare professionals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objective: Multisource feedback is a process through which different members of the care team assess and provide feedback on residents' competencies, usually those that are less often addressed by traditional assessment methods (ie, communication, collaboration, and professionalism). Feasibility and reliability of multisource feedback have been addressed in previous research. The present study explores emergency residents' perceptions of multisource feedback provided by teaching physicians, nurses, and patients they have worked with during a rotation in an emergency department (ED)., Methods: A multisource feedback intervention was proposed to residents during 9 months in the ED of a tertiary care university hospital. Residents distributed feedback questionnaires to physicians, nurses, and patients that focused on competencies (collaboration, communication, and professionalism) from the CanMEDS framework. Responses were compiled and reported to participating residents. To assess residents' perceptions of multisource feedback, semistructured group and individual interviews were held 3 months after the intervention. Transcripts were analyzed qualitatively, following Miles and Huberman's method for intrasite case analysis., Results: According to residents (n=10), each source (physicians, nurses, and patients) provided relevant comments that differed significantly in their content. Physicians focused primarily on medical expertise; nurses addressed competencies related to leadership, collaboration, and communication; and patients commented on the competencies of professionalism and communication. Residents concluded that obtaining feedback from nurses and patients was acceptable and useful. They reported modifying certain behaviors after receiving the multisource feedback., Conclusion: Residents perceived the multisource feedback to be acceptable and useful for the assessment of medical competencies such as communication, collaboration, professionalism, and leadership., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Studies evaluating long-term prescription opioid use are retrospective and based on filled opioid prescriptions from governmental databases. These studies cannot evaluate if opioids were really consumed and are unable to differentiate if they were used for a new pain or chronic pain or were misused. The aim of this study was to assess opioid use rate and reasons for consuming 3 months after being discharged from the emergency department (ED) with an opioid prescription., Methods: This is a prospective cohort study conducted in the ED of a tertiary care urban center with a convenience sample of discharged patients ≥ 18 years who consulted for an acute pain condition (≤2 weeks). Three months post-ED visit, participants were interviewed by phone on their past 2-week opioid consumption and their reasons for consuming: a) for pain related to the initial ED visit, b) for a new unrelated pain, or c) for another reason., Results: Of the 524 participants questioned at 3 months (mean ± SD age = 51 ± 16 years, 47% women), 47 patients (9%, 95% confidence interval [CI] = 7%-12%) reported consuming opioids in the previous 2 weeks. Among those, 34 (72%) reported using opioids for their initial pain, nine (19%) for a new unrelated pain and four (9%) for another reason (0.8%, 95% CI = 0.3%-2.0%, of the whole cohort). Patients who used opioids during the 2 weeks after the ED visit were 3.8 (95% CI = 1.2-12.7) times more likely to consume opioids at 3 months., Conclusion: Opioid use at the 3-month follow-up in ED patients discharged with an opioid prescription for an acute pain condition is not necessarily associated with opioid misuse; 91% of those patients consumed opioids to treat pain. Of the whole cohort, less than 1% reported using opioids for reasons other than pain. The rate of long-term opioid use reported by prescription-filling database studies should not be viewed as a proxy for incidence of opioid misuse., (© 2019 by the Society for Academic Emergency Medicine.)

Study Objective: The objective of the study is to evaluate the acute pain intensity evolution in emergency department (ED) discharged patients, using group-based trajectory modeling. This method identifies patient groups with similar profiles of change over time without assuming the existence of a particular pattern or number of groups., Methods: This was a prospective cohort study of ED patients aged 18 years or older, with an acute pain condition (≤2 weeks), and discharged with an opioid prescription. Patients completed a 14-day diary assessing daily pain intensity level (numeric rating scale of 0 to 10) and pain medication use., Results: Among the 372 included patients, 6 distinct post-ED pain intensity trajectories were identified. Two started with severe levels of pain; one remained with severe pain intensity (12.6% of the sample) and the other ended with a moderate pain intensity level (26.3%). Two other trajectories had severe initial pain; one decreased to mild pain (21.7%) and the other to no pain (13.8%). Another trajectory had moderate initial pain that decreased to a mild level (15.9%) and the last one started with mild pain intensity and had no pain at the end of the 14-day period (9.7%). The pain trajectory patterns were significantly associated with age, type of painful conditions, pain intensity at ED discharge, and opioid consumption., Conclusion: Acute pain resolution after an ED visit seems to progress through 6 different trajectory patterns that are more informative than simple linear models and could be useful to adapt acute pain management in future research., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

An in-person multidisciplinary continuing medical education (CME) program was designed to address previously identified knowledge gaps regarding quality indicators of care in kidney cancer. The objective of this study was to develop a CME program and determine if the program was effective for improving participant knowledge. CME programs for clinicians were delivered by local experts (uro-oncologist and medical oncologist) in four Canadian cities. Participants completed knowledge assessment tests pre-CME, immediately post-CME, and 3-month post-CME. Test questions were related to topics covered in the CME program including prognostic factors for advanced disease, surgery for advanced disease, indications for hereditary screening, systemic therapy, and management of small renal masses. Fifty-two participants attended the CME program and completed the pre- and immediate post-CME tests. Participants attended in Ottawa (14; 27%), Toronto (13; 25%), Québec City (18; 35%), and Montréal (7; 13%) and were staff urologists (21; 40%), staff medical oncologists (9; 17%), fellows (5; 10%), residents (16; 31%), and oncology nurses (1; 2%). The mean pre-CME test score was 61% and the mean post-CME test score was 70% (p = 0.003). Twenty-one participants (40%) completed the 3-month post-CME test. Of those that completed the post-test, scores remained 10% higher than the pre-test (p value 0.01). Variability in test scores was observed across sites and between French and English test versions. Urologists had the largest specialty-specific increase in knowledge at 13.8% (SD 24.2, p value 0.02). The kidney cancer CME program was moderately effective in improving provider knowledge regarding quality indicators of kidney cancer care. These findings support continued use of this CME program at other sites.