Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study.

BACKGROUND: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy. This study aims to describe the efficacy and safety of encorafenib/cetuximab +/- binimetinib in patients with BRAF V600E-mutated mCRC in a real-world setting. PATIENTS AND METHODS: This retrospective study included patients with BRAF V600E-mutated mCRC who received this combination from January 2020 to June 2022 in 30 centers. RESULTS: A total of 201 patients were included, with 55% of women, a median age of 62 years, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) >1 in 20% of cases. The main tumor characteristics were 60% of right-sided primary tumor, 11% of microsatellite instability/mismatch repair deficient phenotype, and liver and peritoneum being the two main metastatic sites (57% and 51%). Encorafenib/cetuximab +/- binimetinib was prescribed in the first, second, third, and beyond third line in 4%, 56%, 29%, and 11%, respectively, of cases, with the encorafenib/cetuximab/binimetinib combination for 21 patients (10%). With encorafenib/cetuximab treatment, 21% of patients experienced grade ≥3 adverse events (AEs), with each type of grade ≥3 AE observed in <5% of patients. The objective response rate was 32.2% and the disease control rate (DCR) was 71.2%. The median progression-free survival (PFS) was 4.5 months [95% confidence interval (CI) 3.9-5.4 months] and the median overall survival (OS) was 9.2 months (95% CI 7.8-10.8 months). In multivariable analysis, factors associated with a shorter PFS were synchronous metastases [hazard ratio (HR) 1.66, P = 0.04] and ECOG-PS >1 (HR 1.88, P = 0.007), and those associated with a shorter OS were the same factors (HR 1.71, P = 0.03 and HR 2.36, P < 0.001, respectively) in addition to treatment beyond the second line (HR 1.74, P = 0.003) and high carcinoembryonic antigen level (HR 1.72, P = 0.003). CONCLUSION: This real-world study showed that in patients with BRAF V600E-mutated mCRC treated with encorafenib/cetuximab +/- binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS >1.

Effectiveness of ultraportable automated external defibrillators: A scoping review.

Background: Ultraportable automated external defibrillators (AEDs) are a new generation of defibrillators that are small, lightweight, easy to carry on one's person, and affordable for personal and home use. They offer the opportunity to increase AED availability in case of out-of-hospital cardiac arrest (OHCA) and therefore improve outcomes.We aimed to review evidence supporting the potential effect on outcomes and the performance of these ultraportable AEDs. Methods: We searched Ovid Medline, Embase and Cochrane databases from 2012 to July 4th, 2024 to identify any studies related to ultraportable AED. The population was adult and children with OHCA who were treated with an ultra-portable AED. All outcomes were accepted. We limited study designs to randomized controlled trials and non-randomized studies. Data charting was done by the primary author using standardized data abstraction forms. Results: The search strategy identified 54 studies (Pubmed = 26, Embase = 28, with 19 duplicates). We included three articles in the final review. One study was a medico-economic simulation study including 600,000 simulated patients, one is the study protocol of cluster randomized trial of providing ultraportable AEDs to first responders and one is an abstract with preliminary results of this trial reporting 1805 community responders recruited, 903 allocated to ultraportable AED. No studies to date have reported patient outcomes. Conclusion: This review found no evidence of ultraportable AED device performance, clinical or safety outcomes. There is an urgent need for further research to determine the safety and effectiveness of ultraportable AEDs.

The accuracy of prehospital triage decisions in English trauma networks - a case-cohort study.

BACKGROUND: Care for injured patients in England is provided by inclusive regional trauma networks. Ambulance services use triage tools to identify patients with major trauma who would benefit from expedited Major Trauma Centre (MTC) care. However, there has been no investigation of triage performance, despite its role in ensuring effective and efficient MTC care. This study aimed to investigate the accuracy of prehospital major trauma triage in representative English trauma networks. METHODS: A diagnostic case-cohort study was performed between November 2019 and February 2020 in 4 English regional trauma networks as part of the Major Trauma Triage Study (MATTS). Consecutive patients with acute injury presenting to participating ambulance services were included, together with all reference standard positive cases, and matched to data from the English national major trauma database. The index test was prehospital provider triage decision making, with a positive result defined as patient transport with a pre-alert call to the MTC. The primary reference standard was a consensus definition of serious injury that would benefit from expedited major trauma centre care. Secondary analyses explored different reference standards and compared theoretical triage tool accuracy to real-life triage decisions. RESULTS: The complete-case case-cohort sample consisted of 2,757 patients, including 959 primary reference standard positive patients. The prevalence of major trauma meeting the primary reference standard definition was 3.1% (n=54/1,722, 95% CI 2.3 - 4.0). Observed prehospital provider triage decisions demonstrated overall sensitivity of 46.7% (n=446/959, 95% CI 43.5-49.9) and specificity of 94.5% (n=1,703/1,798, 95% CI 93.4-95.6) for the primary reference standard. There was a clear trend of decreasing sensitivity and increasing specificity from younger to older age groups. Prehospital provider triage decisions commonly differed from the theoretical triage tool result, with ambulance service clinician judgement resulting in higher specificity. CONCLUSIONS: Prehospital decision making for injured patients in English trauma networks demonstrated high specificity and low sensitivity, consistent with the targets for cost-effective triage defined in previous economic evaluations. Actual triage decisions differed from theoretical triage tool results, with a decreasing sensitivity and increasing specificity from younger to older ages.

Randomised controlled trial of analgesia for the management of acute severe pain from traumatic injury: study protocol for the paramedic analgesia comparing ketamine and morphine in trauma (PACKMaN).

BACKGROUND: Prehospital analgesia is often required after traumatic injury, currently morphine is the strongest parenteral analgesia routinely available for use by paramedics in the United Kingdom (UK) when treating patients with severe pain. This protocol describes a multi-centre, randomised, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury. METHODS: A two arm pragmatic, phase III trial working with two large NHS ambulance services, with an internal pilot. Participants will be randomised in equal numbers to either (1) morphine or (2) ketamine by IV/IO injection. We aim to recruit 446 participants over the age of 16 years old, with a self-reported pain score of 7 or above out of 10. Randomised participants will receive a maximum of 20 mg of morphine, or a maximum of 30 mg of ketamine, to manage their pain. The primary outcome will be the sum of pain intensity difference. Secondary outcomes measure the effectiveness of pain relief and overall patient experience from randomisation to arrival at hospital as well as monitoring the adverse events, resource use and cost-effectiveness outcomes. DISCUSSION: The PACKMAN study is the first UK clinical trial addressing the clinical and cost-effectiveness of ketamine and morphine in treating acute severe pain from traumatic injury treated by NHS paramedics. The findings will inform future clinical practice and provide insights into the effectiveness of ketamine as a prehospital analgesia. TRIAL REGISTRATION: ISRCTN, ISRCTN14124474. Registered 22 October 2020, https://www.isrctn.com/ISRCTN14124474.

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study.

BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.

The nationwide impact of COVID-19 on life support courses. A retrospective evaluation by Resuscitation Council UK.

Aim: To determine the impact of the COVID-19 pandemic on Resuscitation Council UK Advanced Life Support (ALS) and Immediate Life Support (ILS) course numbers and outcomes. Methods: We conducted a before-after study using course data from the Resuscitation Council UK Learning Management System between January 2018 and December 2021, using 23 March 2020 as the cut-off between pre- and post-pandemic periods. Demographics and outcomes were analysed using chi-squared tests and regression models. Results: There were 90,265 ALS participants (51,464 pre-; 38,801 post-) and 368,140 ILS participants (225,628 pre-; 142,512 post-). There was a sharp decline in participants on ALS/ILS courses due to COVID-19. ALS participant numbers rebounded to exceed pre-pandemic levels, whereas ILS numbers recovered to a lesser degree with increased uptake of e-learning versions. Mean ALS course participants reduced from 20.0 to 14.8 post-pandemic (P < 0.001).Post-pandemic there were small but statistically significant decreases in ALS Cardiac Arrest Simulation Test pass rates (from 82.1 % to 80.1 % (OR = 0.90, 95 % CI = 0.86-0.94, P < 0.001)), ALS MCQ score (from 86.6 % to 86.0 % (mean difference = -0.35, 95 % CI -0.44 to -0.26, P < 0.001)), and overall ALS course results (from 95.2 %to 94.7 %, OR = 0.92, CI = 0.85-0.99, P = 0.023). ILS course outcomes were similar post-pandemic (from 99.4 % to 99.4 %, P = 0.037). Conclusion: COVID-19 caused a sharp decline in the number of participants on ALS/ILS courses and an accelerated uptake of e-learning versions, with the average ALS course size reducing significantly. The small reduction in performance on ALS courses requires further research to clarify the contributing factors.

Sugar or salt ("SOS"): A protocol for a UK multicentre randomised trial of mannitol and hypertonic saline in severe traumatic brain injury and intracranial hypertension.

Hyperosmolar solutions are widely used to treat raised intracranial pressure following severe traumatic brain injury. Although mannitol has historically been the most frequently administered, hypertonic saline solutions are increasingly being used. However, definitive evidence regarding their comparative effectiveness is lacking. The Sugar or Salt Trial is a UK randomised, allocation concealed open label multicentre pragmatic trial designed to determine the clinical and cost-effectiveness of hypertonic saline compared with mannitol in the management of patients with severe traumatic brain injury. Patients requiring intensive care unit admission and intracranial pressure monitoring post-traumatic brain injury will be allocated at random to receive equi-osmolar boluses of either mannitol or hypertonic saline following failure of routine first-line measures to control intracranial pressure. The primary outcome for the study will be the Extended Glasgow Outcome Scale assessed at six months after randomisation. Results will inform current clinical practice in the routine use of hyperosmolar therapy as well as assess the impact of potential side effects. Pre-planned longer term clinical and cost effectiveness analyses will further inform the use of these treatments.

Resuscitation highlights in 2021.

BACKGROUND: This review is the latest in a series of regular annual reviews undertaken by the editors and aims to highlight some of the key papers published in Resuscitation during 2021. METHODS: Hand-searching by the editors of all papers published in Resuscitation during 2021. Papers were selected based on then general interest and novelty and were categorised into themes. RESULTS: 98 papers were selected for brief mention. CONCLUSIONS: Resuscitation science continues to evolve and incorporates all links in the chain of survival.

Bystander cardiopulmonary resuscitation for paediatric out-of-hospital cardiac arrest in England: An observational registry cohort study.

INTRODUCTION: Bystander cardiopulmonary resuscitation (BCPR) is strongly advocated by resuscitation councils for paediatric out-of-hospital cardiac arrests (OHCAs). However, there are limited reports on rates of BCPR in children and its relationship with return of spontaneous circulation (ROSC) or survival outcomes. OBJECTIVE: We describe the rate of BCPR and its association with any ROSC and survival- to- hospital-discharge. METHODS: We conducted retrospective analysis of prospectively collected paediatric (<18 years of age) OHCA cases in England; we included specialist registry patients treated by emergency medical services (EMS) with known BCPR status and outcome between January 2014 and November 2018. Data included patient demographics, aetiology, witness status, initial rhythm, EMS, season, time of day and bystander status. Associations between BCPR, and any ROSC and survival-to-hospital-discharge outcomes were explored using multivariable logistic regression. RESULTS: There were 2363 paediatric OHCAs treated across 11 EMS regions. BCPR was performed in 69.6% (1646/2363) of the cases overall (range 57.7% (206/367) to 83.7% (139/166) across EMS regions). Only 34.9% (550/1572) of BCPR cases were witnessed. Overall, any ROSC was achieved in 22.8% (523/2289) and survival to hospital discharge in 10.8% (225/2066). Adjusted odds ratio (aOR) for any ROSC was significantly improved following BCPR compared to no BCPR (aOR 1.37, 95% CI 1.03-1.81), but adjusted odds ratio for survival-to-hospital-discharge were similar (aOR 1.01, 95% CI 0.66-1.55). CONCLUSIONS: BCPR was associated with improved rates of any ROSC but not survival-to-hospital-discharge. Variations in EMS BCPR rates may indicate opportunities for regional targeted increase in public BCPR education.

Outcomes and interventions in patients transported to hospital with ongoing CPR after out-of-hospital cardiac arrest - An observational study.

INTRODUCTION: The main objective was to present characteristics and outcome of patients without sustained field return of spontaneous circulation (ROSC) transported to hospital with ongoing cardiopulmonary resuscitation (CPR). Our secondary objectives were to investigate hospital-based interventions and the performance of the universal Termination of Resuscitation-rule (uTOR). METHODS: In this retrospective observational cohort study, out-of-hospital cardiac arrest (OHCA) patients arriving to the emergency department of a university hospital in Sweden during a six-year period (2010-2015) were identified using a prospectively recorded hospital-based registry. Additional data were retrieved from medical records and from the Swedish cardiopulmonary resuscitation registry. RESULTS: Among 409 patients transported with ongoing CPR, 7 survived to hospital discharge (1.7%). Hospital-based interventions against a suspected cause of arrest were attempted during ongoing resuscitation in 34 patients (8.3%), of whom 3 survived to hospital discharge. The remaining 4 survivors had spontaneous in-hospital ROSC. Survivors presented with either a shockable rhythm (n = 4) or pulseless electrical activity (n = 3). The uTOR identified non-survivors with a positive predictive value (PPV) of 98.4% and a specificity of 71.4% for termination. CONCLUSION: Survival after OHCA where sustained prehospital ROSC is not achieved is rare and available in-hospital interventions are rarely utilised. No patient with asystole as the first recorded rhythm survived. The uTOR identified non-survivors with a PPV of 98.4% but showed poor specificity.

Characteristics of Restart a Heart 2019 event locations in the UK.

INTRODUCTION: Restart a Heart (RSAH) is an annual CPR mass training initiative delivered predominantly by ambulance services in the UK. The aim of this study was to identify to what extent voluntary participation in the 2019 initiative delivered training to the population with the highest need. METHODS: A cross-sectional observational study of location characteristics for RSAH training events conducted by UK ambulance services. Descriptive statistics were used to analyse event and area characteristics. National cardiac arrest registry data were used to establish proportions of training coverage in "hot spot" areas with above national median incidence of cardiac arrest and below median bystander CPR rates. The significance of observed differences were tested using chi-square for proportions and t-test for means. RESULTS: Twelve of 14 UK ambulance services participated, training 236,318 people. Most of the events (82%) were held in schools, and schoolchildren comprised most participants (81%). RSAH events were held in areas that were less densely populated (p < 0.001), were more common in affluent areas (p < 0.001), and had a significantly lower proportion of black residents (p < 0.05) and higher proportion of white residents (p < 0.05). Events were held in 28% of known "hot spot" areas in England. CONCLUSION: With mandatory CPR training for school children in England, Scotland and Wales there is an opportunity to re-focus RSAH resources to deliver training for all age groups in OHCA "hot spots", communities with higher proportions of black residents, and areas of deprivation. In Northern Ireland, we recommend targeting schools in areas with similar characteristics.

Changes in temperature management and outcome after out-of-hospital cardiac arrest in United Kingdom intensive care units following publication of the targeted temperature management trial.

AIM: To investigate how the publication of the targeted temperature management (TTM) trial in December 2013 affected the trends in temperature management and outcome following admission to UK intensive care units (ICUs) after out-of-hospital cardiac arrest (OHCA). METHODS: We used a national ICU database of 1,181,405 consecutive admissions to 235 adult ICUs. OHCA admissions mechanically ventilated in the first 24 h in the ICU were divided into a pre-TTM trial cohort of patients admitted before publication of the TTM trial (January 2010-December 2013) and post-TTM cohort of patients admitted after TTM trial publication (January 2014-December 2017). The primary outcome variables were lowest temperature in the first 24 h in ICU and survival to hospital discharge. RESULTS: The lowest temperature recorded in the first-24 h of admission was significantly higher in the post-TTM cohort (n = 18,106) than in the pre-TTM cohort (n = 12,162) (mean 34.7 (±1.6) versus 33.6 °C (±1.8); absolute difference 1.12 °C (95% CI 1.08-1.16). The post-TTM cohort had a greater prevalence of fever (>38.0 °C) (24.8% vs 14.7%; (odds ratio (OR) 1.91 (95% CI 1.80-2.03); p < 0.001)) and higher unadjusted in-hospital mortality (63.7% vs 61.6%). In a multilevel model, accounting for time trend and including site as a random effect, neither the step change in acute hospital mortality following publication of the TTM trial result (OR 1.04, 95% CI 0.95-1.15; p = 0.37), nor the change in slope (from OR 1.00 per year, 95% CI 0.97-1.04, to 1.04 per year, 95% CI 1.02-1.07; p = 0.059), was statistically significant. Adjusted analyses were limited by the models' dependence on temperature and temperature-related variables. CONCLUSIONS: The lowest temperature recorded in the first-24 h of admission in OHCA patients was higher in the post-TTM cohort compared with the pre-TTM cohort. There has been an increase in the proportion of patients with fever (>38 °C) in the first 24 h. Although crude mortality was slightly higher in the post-TTM cohort, an analysis accounting for time trend and variation between critical care units, found no significant change associated with the TTM publication.

Gut-derived acetate promotes B10 cells with antiinflammatory effects.

Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes antiinflammatory Tregs and protects mice from type 1 diabetes, colitis, and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10-producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-coenzyme A, which fueled the TCA cycle and promoted posttranslational lysine acetylation. Acetate also promoted B10 cells from human blood cells through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood-derived B10 cells. Direct delivery of acetate or indirect delivery via diets or bacteria that produce acetate might be a promising approach to restore B10 cells in noncommunicable diseases.

Resuscitation highlights in 2020.

BACKGROUND: This review is the latest in a series of regular annual reviews undertaken by the editors and aims to highlight some of the key papers published in Resuscitation during 2020. The number of papers submitted to the Journal in 2020 increased by 25% on the previous year.MethodsHand-searching by the editors of all papers published in Resuscitation during 2020. Papers were selected based on then general interest and novelty and were categorised into general themes.ResultsA total of 103 papers were selected for brief mention in this review.ConclusionsResuscitation science continues to evolve rapidly and incorporate all links in the chain of survival.

Resuscitation and emergency care in drowning: A scoping review.

BACKGROUND: The ILCOR Basic Life Support Task Force and the international drowning research community considered it timely to undertake a scoping review of the literature to identify evidence relating to the initial resuscitation, hospital-based interventions and criteria for safe discharge related to drowning. METHODS: Medline, PreMedline, Embase, Cochrane Reviews and Cochrane CENTRAL were searched from 2000 to June 2020 to identify relevant literature. Titles and abstracts and if necessary full text were reviewed in duplicate. Studies were eligible for inclusion if they reported on the population (adults and children who are submerged in water), interventions (resuscitation in water/boats, airway management, oxygen administration, AED use, bystander CPR, ventilation strategies, ECMO, protocols for hospital discharge (I), comparator (standard care) and outcomes (O) survival, survival with a favourable neurological outcome, CPR quality, physiological end-points). RESULTS: The database search yielded 3242 references (Medline 1104, Pre-Medline 202, Embase 1722, Cochrane reviews 12, Cochrane CENTRAL 202). After removal of duplicates 2377 papers were left for screening titles and abstracts. In total 65 unique papers were included. The evidence identified was from predominantly high-income countries and lacked consistency in the populations, interventions and outcomes reported. Clinical studies were exclusively observational in nature. CONCLUSION: This scoping review found that there is very limited evidence from observational studies to inform evidence based clinical practice guidelines for drowning. The review highlights an urgent need for high quality research in drowning.

Feedback in advanced life support: A quality improvement initiative.

AIM: To identify participant, course characteristics and centre factors associated with participant satisfaction and ALS outcomes. METHODS: 17,690 participants enrolled on ALS courses between 1st December 2017 and 30th November 2018. Participant, course and centre characteristics were explored in relation to course learning outcomes and participant experience. Learning outcomes were assessed through a post-course MCQ score and technical and non-technical skills through a cardiac arrest simulation test (CAS-Test). Successful completion of knowledge and skill-based assessments led to overall course success. Participant feedback was collected on a post-course questionnaire. Multivariable analyses identified variables associated with course outcomes and feedback. Adjusted funnel plots compared inter-course centre outcomes. RESULTS: Mean post-course MCQ score was 86.7% (SD = 6.7). First attempt CAS-Test pass rate was 82.6% and overall course pass rate 94.4%. Participant characteristics explained the majority of variation between course centres. Characteristics associated with knowledge, skill and course outcomes were age, prior experience, pre-course MCQ score, course type, ethnicity, place of work, profession and seniority. Feedback scores were predicted by course type, pre-course MCQ, ethnicity, profession and seniority. CONCLUSION: This is the first study to identify variables associated with both ALS feedback scores and assessment outcomes. It has demonstrated that both course outcomes and participant experience are similar across a large number of course centres. Identifying the demographic traits of participants who may struggle with ALS, may enable bespoke support from an earlier stage. Analysis of feedback scores and outcomes enables ongoing appraisal and targeted improvement of the Resuscitation Council UK ALS course.