Dietary palmitic acid promotes a prometastatic memory via Schwann cells.

Fatty acid uptake and altered metabolism constitute hallmarks of metastasis1,2, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood3,4. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.

Targeted prophylactic anticoagulation based on the TRiP(cast) score in patients with lower limb immobilisation: a multicentre, stepped wedge, randomised implementation trial.

BACKGROUND: Prophylactic anticoagulation in emergency department patients with lower limb trauma requiring immobilisation is controversial. The Thrombosis Risk Prediction for Patients with Cast Immobilisation-TRiP(cast)-score could identify a large subgroup of patients at low risk of venous thromboembolism for whom prophylactic anticoagulation can be safely withheld. We aimed to prospectively assess the safety of withholding anticoagulation for patients with lower limb trauma at low risk of venous thromboembolism, defined by a TRiP(cast) score of less than 7. METHODS: CASTING was a stepped-wedge, multicentre, cluster-randomised trial with blinded outcome assessment. 15 emergency departments in France and Belgium were selected and randomly assigned staggered start dates for switching from the control phase (ie, anticoagulation prescription according to the physician's usual practice) to the intervention phase (ie, targeted anticoagulation according to TRiP(cast) score: no prescription if score <7 and anticoagulation if score was ≥7). Patients were included if they presented to a participating emergency department with lower limb trauma requiring immobilisation for at least 7 days and were aged 18 years or older. The primary outcome was the 3-month cumulative rate of symptomatic venous thromboembolism during the intervention phase in patients with a TRiP(cast) score of less than 7. The targeted strategy was considered safe if this rate was less than 1% with an upper 95% CI of less than 2%. The primary analysis was performed in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT04064489). FINDINGS: Between June 16, 2020, and Sept 15, 2021, 15 clusters and 2120 patients were included. Of the 1505 patients analysed in the intervention phase, 1159 (77·0%) had a TRiP(cast) score of less than 7 and did not receive anticoagulant treatment. The symptomatic venous thromboembolism rate was 0·7% (95% CI 0·3-1·4, n=8/1159). There was no difference between the control and the intervention phases in the cumulative rate of symptomatic venous thromboembolism or in bleeding rates. INTERPRETATION: Patients with a TRiP(cast) score of less than 7 who are not receiving anticoagulation have a very low risk of venous thromboembolism. A large proportion of patients with lower limb trauma and immobilisation could safely avoid thromboprophylaxis. FUNDING: French Ministry of Health.

A synthetic lethality screen reveals ING5 as a genetic dependency of catalytically dead Set1A/COMPASS in mouse embryonic stem cells.

Embryonic stem cells (ESCs) are defined by their ability to self-renew and the potential to differentiate into all tissues of the developing organism. We previously demonstrated that deleting the catalytic SET domain of the Set1A/complex of proteins associated with SET1 histone methyltransferase (Set1A/COMPASS) in mouse ESCs does not impair their viability or ability to self-renew; however, it leads to defects in differentiation. The precise mechanisms by which Set1A executes these functions remain to be elucidated. In this study, we demonstrate that mice lacking the SET domain of Set1A are embryonic lethal at a stage that is unique from null alleles. To gain insight into Set1A function in regulating pluripotency, we conducted a CRISPR/Cas9-mediated dropout screen and identified the MOZ/MORF (monocytic leukaemia zinc finger protein/monocytic leukaemia zinc finger protein-related factor) and HBO1 (HAT bound to ORC1) acetyltransferase complex member ING5 as a synthetic perturbation to Set1A. The loss of Ing5 in Set1AΔSET mouse ESCs decreases the fitness of these cells, and the simultaneous loss of ING5 and in Set1AΔSET leads to up-regulation of differentiation-associated genes. Taken together, our results point toward Set1A/COMPASS and ING5 as potential coregulators of the self-renewal and differentiation status of ESCs.

Temporal Trends in the Use of Computed Tomographic Pulmonary Angiography for Suspected Pulmonary Embolism in the Emergency Department : A Retrospective Analysis.

BACKGROUND: Recently, validated clinical decision rules have been developed that avoid unnecessary use of computed tomographic pulmonary angiography (CTPA) in patients with suspected pulmonary embolism (PE) in the emergency department (ED). OBJECTIVE: To measure any resulting change in CTPA use for suspected PE. DESIGN: Retrospective analysis. SETTING: 26 European EDs in 6 countries. PATIENTS: Patients with CTPA performed for suspected PE in the ED during the first 7 days of each odd month between January 2015 and December 2019. MEASUREMENTS: The primary end points were the CTPAs done for suspected PE in the ED and the number of PEs diagnosed in the ED each year adjusted to an annual census of 100 000 ED visits. Temporal trends were estimated using generalized linear mixed regression models. RESULTS: 8970 CTPAs were included (median age, 63 years; 56% female). Statistically significant temporal trends for more frequent use of CTPA (836 per 100 000 ED visits in 2015 vs. 1112 in 2019; P < 0.001), more diagnosed PEs (138 per 100 000 in 2015 vs. 164 in 2019; P = 0.028), a higher proportion of low-risk PEs (annual percent change [APC], 13.8% [95% CI, 2.6% to 30.1%]) with more ambulatory management (APC, 19.3% [CI, 4.1% to 45.1%]), and a lower proportion of intensive care unit admissions (APC, -8.9% [CI, -17.1% to -0.3%]) were observed. LIMITATION: Data were limited to 7 days every 2 months. CONCLUSION: Despite the recent validation of clinical decision rules to limit the use of CTPA, an increase in the CTPA rate along with more diagnosed PEs and especially low-risk PEs were instead observed. PRIMARY FUNDING SOURCE: None specific for this study.

Derivation and validation of a risk-stratification model for patients with probable or proven COVID-19 in EDs: the revised HOME-CoV score.

BACKGROUND: The HOME-CoV (Hospitalisation or Outpatient ManagEment of patients with SARS-CoV-2 infection) score is a validated list of uniquely clinical criteria indicating which patients with probable or proven COVID-19 can be treated at home. The aim of this study was to optimise the score to improve its ability to discriminate between patients who do and do not need admission. METHODS: A revised HOME-CoV score was derived using data from a previous prospective multicentre study which evaluated the original Home-CoV score. Patients with proven or probable COVID-19 attending 34 EDs in France, Monaco and Belgium between April and May 2020 were included. The population was split into a derivation and validation sample corresponding to the observational and interventional phases of the original study. The main outcome was non-invasive or invasive ventilation or all-cause death within 7 days following inclusion. Two threshold values were defined using a sensitivity of >0.9 and a specificity of >0.9 to identify low-risk and high-risk patients, respectively. The revised HOME-CoV score was then validated by retrospectively applying it to patients in the same EDs with proven or probable COVID-19 during the interventional phase. The revised HOME-CoV score was also tested against original HOME-CoV, qCSI, qSOFA, CRB65 and SMART-COP in this validation cohort. RESULTS: There were 1696 patients in the derivation cohort, of whom 65 (3.8%) required non-invasive ventilation or mechanical ventilation or died within 7 days and 1304 patients in the validation cohort, of whom 22 (1.7%) had a progression of illness. The revised score included seven clinical criteria. The area under the curve (AUC) was 87.6 (95% CI 84.7 to 90.6). The cut-offs to define low-risk and high-risk patients were <2 and >3, respectively. In the validation cohort, the AUC was 85.8 (95% CI 80.6 to 91.0). A score of <2 qualified 73% of patients as low risk with a sensitivity of 0.77 (0.55-0.92) and a negative predictive value of 0.99 (0.99-1.00). CONCLUSION: The revised HOME-CoV score, which does not require laboratory testing, may allow accurate risk stratification and safely qualify a significant proportion of patients with probable or proven COVID-19 for home treatment.

Comparison of chest compression quality between the overlapping hands and interlocking hands techniques: A randomised cross-over trial.

BACKGROUND: Performing quality chest compressions is fundamental to the management of cardiopulmonary arrest. The aim of this study was to compare the efficacy of two hand positions: overlapping versus interlocking for performing chest compressions during cardiopulmonary arrest. METHODS: The HP2C (for Hands Position and Chest Compression) was a prospective, randomised, open-label, cross-over, single-centre study. Participants were recruited from the Emergency Medical Service (EMS) teams and the prehospital firefighter teams. They were randomised to start chest compressions either with overlapping or interlocking hands and then performed the other technique after a washout period. The judgement criteria were the overall chest compressions success score generated by software in accordance with ILCOR recommendations, the quality of compression, release, rate and subjective intensity measured with the Borg scale. RESULTS: A total of 100 participants were included in the study. The mean age of the caregivers was 38 ± 9.3 years. The median CPR score was 79.5% IQR [48.5-94.0] in the overlapping hands group and 71% IQR [38.0-92.8] in the interlocking hands group (p-value = 0.37). There was no significant difference for the other criteria, especially no difference in term of intensity of effort. However, there was a trend towards better results with overlapping hands. CONCLUSIONS: This study failed to demonstrate a difference in effectiveness between overlapping and interlocking hand chest compressions during cardiopulmonary resuscitation.

Prognostic accuracy of using lactate in addition to the quick Sequential Organ Failure Assessment score and the National Early Warning Score for emergency department patients with suspected infection.

BACKGROUND: The aim of this study was to determine whether: (1) the quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) and National Early Warning Score (NEWS) clinical prediction tools alone, (2) modified versions of these prediction tools that integrate lactate into their scores, or (3) use of the two tools in tandem with lactate better predicts in-hospital 28-day mortality among adult EDpatients with suspected infection. METHODS: From 1 January through 31 December 2018, this retrospective cohort study enrolled consecutive adult patients with suspected infection evaluated at two EDs in France. Patients were included if blood cultures were obtained and non-prophylactic antibiotics were administered in the ED. qSOFA, NEWS criteria and lactate measurements were recorded when patients were clinically suspected of having an infection. Two composite scores (lactate qSOFA (LqSOFA) and lactate NEWS (LNEWS)) integrating lactate were created. Diagnostic test performances for predicting in-hospital mortality within 28days were assessed for qSOFA≥2, LqSOFA≥2, qSOFA≥2 or lactate≥2 mmol/L, and for NEWS≥7, LNEWS≥7, and NEWS≥7 or lactate≥2 mmol/L. RESULTS: 1003 patients were included, 130 (13%) of whom had died by day 28. Sensitivities for 28-day mortality were 50% (95%CI41% to 59%) for qSOFA≥2,69% (95% CI60% to 77%) for LqSOFA≥2,77% (95% CI69% to 84%) for qSOFA or lactate≥2 mmol/L; and 69% (95% CI60% to 77%) for NEWS≥7, 80% (95% CI72% to 86%) for LNEWS≥7, 87% (95% CI80% to 92%) for NEWS≥7 or lactate≥2 mmol/L. CONCLUSION: Lactate used in tandem with qSOFA or NEWS yielded higher sensitivities in predicting in-hospital 28-day mortality, as compared with integration of lactate into these prediction tools or usage of the tools independently.

A clinical decision rule to rule out bloodstream infection in the emergency department: retrospective multicentric observational cohort study.

BACKGROUND: We aimed to identify patients at low risk of bloodstream infection (BSI) in the ED. METHODS: We derived and validated a prediction model to rule out BSI in the ED without the need for laboratory testing by determining variables associated with a positive blood culture (BC) and assigned points according to regression coefficients. This retrospective study included adult patients suspected of having BSI (defined by at least one BC collection) from two European ED between 1 January 2017 and 31 December 2019. The primary end point was the BSI rate in the validation cohort for patients with a negative Bacteremia Rule Out Criteria (BAROC) score. The effect of adding laboratory variables to the model was evaluated as a second step in a two-step diagnostic strategy. RESULTS: We analysed 2580 patients with a mean age of 64 years±21, of whom 46.1% were women. The derived BAROC score comprises 12 categorical clinical variables. In the validation cohort, it safely ruled out BSI without BCs in 9% (58/648) of patients with a sensitivity of 100% (95% CI 95% to 100%), a specificity of 10% (95% CI 8% to 13%) and a negative predictive value of 100% (95% CI 94% to 100%). Adding laboratory variables (creatinine ≥177 µmol/L (2.0 mg/dL), platelet count ≤150 000/mm3 and neutrophil count ≥12 000/mm3) to the model, ruled out BSI in 10.2% (58/570) of remaining patients who had been positive on the BAROC score. The BAROC score with laboratory results had a sensitivity of 100% (95% CI 94% to 100%), specificity of 11% (95% CI 9% to 14%) and negative predictive value of 100% (95% CI 94 to 100%). In the validation cohort, there was no evidence of a difference in discrimination between the area under the receiver operating characteristic for BAROC score with versus without laboratory testing (p=0.6). CONCLUSION: The BAROC score safely identified patients at low risk of BSI and may reduce BC collection in the ED without the need for laboratory testing.

Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: the HOME-PE randomized trial.

AIMS: The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment. METHODS AND RESULTS: Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm. CONCLUSIONS: For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.

Suspected Acute Pulmonary Embolism: Gestalt, Scoring Systems, and Artificial Intelligence.

Pulmonary embolism (PE) remains a diagnostic challenge in 2021. As the pathology is potentially fatal and signs and symptoms are nonspecific, further investigations are classically required. Based on the Bayesian approach, clinical probability became the keystone of the diagnostic strategy to rule out PE in the case of a negative testing. Several clinical probability assessment methods are validated: gestalt, the Wells score, or the revised Geneva score. While the debate persists as to the best way to assess clinical probability, its assessment allows for the good interpretation of the investigation results and therefore directs the correct diagnostic strategy. The wide availability of computed tomography pulmonary angiography (CTPA) resulted in a major increase in investigations with a moderate increase in diagnosis, without any notable improvement in patient outcomes. This leads to a new challenge for PE diagnosis which is the limitation of the number of testing for suspected PE. We review different strategies recently developed to achieve this goal. The last challenge concerns the implementation in clinical practice. Two approaches are developed: simplification of the strategies versus the use of digital support tools allowing more sophisticated strategies. Artificial intelligence with machine-learning algorithms will probably be a future tool to guide the physician in this complex approach concerning acute PE suspicion.

Adaptation of ED design layout during the COVID-19 pandemic: a national cross-sectional survey.

BACKGROUND: The aim was to describe the organisational changes in French EDs in response to the COVID-19 pandemic with regard to architectural constraints and compare with the recommendations of the various bodies concerning the structural adjustments to be made in this context. METHODS: As part of this cross-sectional study, all heads of emergency services or their deputies were contacted to complete an electronic survey. This was a standardised online questionnaire consisting of four parts: characteristics of the responding centre, creation of the COVID-19 zone and activation of the hospital's emergency operations plan, flow and circulation of patients and, finally, staff management. Each centre was classified according to its workload related to COVID-19 and its size (university hospital centre, high-capacity hospital centre and low-capacity hospital centre). The main endpoint was the frequency of implementation of international guidelines for ED organisation. RESULTS: Between 11 May and 20 June 2020, 57 French EDs completed the online questionnaire and were included in the analysis. Twenty-eight EDs were able to separate patient flows into two zones: high and low viral density (n=28/57, 49.1%). Of the centres included, 52.6% set up a specific triage area for patients with suspected COVID-19 (n=30/57). Whereas, in 15 of the EDs (26.3%), the architecture made it impossible to increase the surface area of the ED. CONCLUSION: All EDs have adapted, but many of the changes recommended for the organisation of ED could not be implemented. ED architecture constrains adaptive capacities in the context of COVID-19.

Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR.

5-Aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside (AICAR, or acadesine) is a precursor of the monophosphate derivative 5-amino-4-imidazole carboxamide ribonucleoside 5'-phosphate (ZMP), an intermediate in de novo purine biosynthesis. AICAR proved to have promising anti-proliferative properties, although the molecular basis of its toxicity is poorly understood. To exert cytotoxicity, AICAR needs to be metabolized, but the AICAR-derived toxic metabolite was not identified. Here, we show that ZMP is the major toxic derivative of AICAR in yeast and establish that its metabolization to succinyl-ZMP, ZDP, or ZTP (di- and triphosphate derivatives of AICAR) strongly reduced its toxicity. Affinity chromatography identified 74 ZMP-binding proteins, including 41 that were found neither as AMP nor as AICAR or succinyl-ZMP binders. Overexpression of karyopherin-ß Kap123, one of the ZMP-specific binders, partially rescued AICAR toxicity. Quantitative proteomic analyses revealed 57 proteins significantly less abundant on nuclei-enriched fractions from AICAR-fed cells, this effect being compensated by overexpression of KAP123 for 15 of them. These results reveal nuclear protein trafficking as a function affected by AICAR.

Overcrowding in the Dispatching Centre During the COVID-19 Crisis: Are Medical Students a Resource?

INTRODUCTION: In February, the emergence of COronaVIrus Disease 2019 (COVID - 19) in France made it necessary to rapidly adapt emergency and SAMU services in order to take care of many infected patients. To respond to the increase in the number of calls in the dispatch centers, reinforcements were necessary on the fronts of the Medical Regulation Assistants (ARM). The aim of this study was to assess the relevance of medical students' responses to first calls exclusively concerning COVID-19. METHODS: This prospective, observational cohort study was carried out at the University Hospital Centre (CHU) in Angers. Twenty medical students mostly in the 5th year were voluntarily enrolled in the first line COVID-19 call taker team. Calls on the 1st, 3rd, and 5th starting day for each medical student, and randomly selected calls from the experienced first-line call taker were listened to by a medical expert to assess the adequate level of prioritization and orientation (emergency physician or general practitioner). The percentage of agreement between the expert, students, and experienced first-line call handlers were assessed. All participants gave their free consent to participate. The study was approved by the Ethics Committee of Angers (N° 2020-48). RESULTS: From March 18 to April 23, 2020, 302 calls from medical students (n = 20 students) and 40 calls from experienced first-line call handlers were analyzed. The average prioritization agreement rate between the expert and students was 76.16% (95% Confidence Interval: 71.04 to 80.62%) (n = 230/302) compared to 87.50% (95% CI: 73.9 to 94.5%) (n = 45/50) for the experienced first-line call handlers (P = 0.15). Medical students took more time per call with an absolute difference of 2 minutes 16 seconds (P < 0.001). CONCLUSION: The lessons to be observed from this COVID-19 crisis are that in the early days of increasing calls heralding a strain on the healthcare system, support by medical students must be considered.

Nurses' moral judgements during emergency department triage - A prospective mixed multicenter study.

INTRODUCTION: In EDs, triage ensures that patients whose condition requires immediate care are prioritized while reducing overcrowding. Previous studies have described the manifestation of caregivers' moral judgements of patients in EDs. The equal treatment of patients in clinical practice presents a major issue. Studying the impact of prejudice on clinical practice in the ED setting provides an opportunity to rethink clinical tools, organizations and future training needs. Our study sought to describe the moral judgements expressed by triage nurses during admission interviews in emergency departments and to assess their impact on patient management. METHODS: An exploratory sequential mixed-method study was performed. The study was conducted between January 1, 2018, and February 18, 2018, in the EDs of three French hospitals. Five hundred and three patients and 79 triage nurses participated in the study. Audio recordings, observations and written handover reports made by nurses during admission triage interviews were analyzed with a view to discerning whether moral judgements were expressed in them. We studied the impact of moral judgements on patient management in the emergency department. RESULTS: Abstract Moral judgements were made in 70% of the triage situations studied (n=351/503). They could be classified in seven categories. Patients were more likely to be subjected to moral judgements if they were over 75 years old, visibly disabled or if they had visible signs of alcohol intoxication. Being subjected to moral judgement was associated with differential treatment, including assignment of a triage score that differed from the theoretical triage score. CONCLUSION: More than two thirds of patients admitted to EDs were triaged using moral criteria. Patients who were morally judged at the admission interview were more likely to be treated differently.

Efficacy and safety of antibiotics targeting Gram-negative bacteria in nosocomial pneumonia: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Multiple randomized controlled studies have compared numerous antibiotic regimens, including new, recently commercialized antibiotics in the treatment of nosocomial pneumonia (NP). The objective of this Bayesian network meta-analysis (NMA) was to compare the efficacy and the safety of different antibiotic treatments for NP. METHODS: We conducted a systematic search of PubMed, Medline, Web of Science, EMBASE and the Cochrane Library databases from 2000 through 2021. The study selection included studies comparing antibiotics targeting Gram-negative bacilli in the setting of NP. The primary endpoint was 28 day mortality. Secondary outcomes were clinical cure, microbiological cure and adverse events. RESULTS: Sixteen studies encompassing 4993 patients were included in this analysis comparing 13 antibiotic regimens. The level of evidence for mortality comparisons ranged from very low to moderate. No significant difference in 28 day mortality was found among all beta-lactam regimens. Only the combination of meropenem plus aerosolized colistin was associated with a significant decrease of mortality compared to using intravenous colistin alone (OR = 0.43; 95% credible interval [0.17-0.94]), based on the results of the smallest trial included. The clinical failure rate of ceftazidime was higher than meropenem with (OR = 1.97; 95% CrI [1.19-3.45]) or without aerosolized colistin (OR = 1.40; 95% CrI [1.00-2.01]), imipemen/cilastatin/relebactam (OR = 1.74; 95% CrI [1.03-2.90]) and ceftazidime/avibactam (OR = 1.48; 95% CrI [1.02-2.20]). For microbiological cure, no substantial difference between regimens was found, but ceftolozane/tazobactam had the highest probability of being superior to comparators. In safety analyses, there was no significant difference between treatments for the occurrence of adverse events, but acute kidney failure was more common in patients receiving intravenous colistin. CONCLUSIONS: This network meta-analysis suggests that most antibiotic regimens, including new combinations and cefiderocol, have similar efficacy and safety in treating susceptible Gram-negative bacilli in NP. Further studies are necessary for NP caused by multidrug-resistant bacteria. Registration PROSPERO CRD42021226603.

Effect of the 1-h bundle on mortality in patients with suspected sepsis in the emergency department: a stepped wedge cluster randomized clinical trial.

PURPOSE: The efficacy of the 1-h bundle for emergency department (ED) patients with suspected sepsis, which includes lactate measurement, blood culture, broad-spectrum antibiotics administration, administration of 30 mL/kg crystalloid fluid for hypotension or lactate ≥ 4 mmol/L, remains controversial. METHODS: We carried out a pragmatic stepped-wedge cluster-randomized trial in 23 EDs in France and Spain. Adult patients with Sepsis-3 criteria or a quick sequential organ failure assessment (SOFA) score ≥ 2 or a lactate > 2 mmol/L were eligible. The intervention was the implementation of the 1-h sepsis bundle. The primary outcome was in-hospital mortality truncated at 28 days. Secondary outcomes included volume of fluid resuscitation at 24 h, acute heart failure at 24 h, SOFA score at 72 h, intensive care unit (ICU) length of stay, number of days on mechanical ventilation or renal replacement therapy, vasopressor free days, unnecessary antibiotic administration, and mortality at 28 days. 1148 patients were planned to be analysed; the study period ended after 873 patients were included. RESULTS: 872 patients (mean age 66, 42% female) were analyzed: 387 (44.4%) in the intervention group and 485 (55.6%) in the control group. Median SOFA score was 3 [1-5]. Median time to antibiotic administration was 40 min in the intervention group vs 113 min in the control group (difference - 73 [95% confidence interval (CI) - 93 to - 53]). There was a significantly higher rate, volume, and shorter time to fluid resuscitation within 3 h in the intervention group. There were 47 (12.1%) in-hospital deaths in the intervention group compared to 61 (12.6%) in the control group (difference in percentage - 0.4 [95% CI - 5.1 to 4.2], adjusted relative risk (aRR) 0.81 [95% CI 0.48 to 1.39]). There were no differences between groups for other secondary endpoints. CONCLUSIONS: Among patients with suspected sepsis in the ED, the implementation of the 1-h sepsis bundle was not associated with significant difference in in-hospital mortality. However, this study may be underpowered to report a statistically significant difference between groups.

Pulmonary Embolism and Respiratory Deterioration in Chronic Cardiopulmonary Disease: A Narrative Review.

Patients with chronic cardiopulmonary pathologies have an increased risk of developing venous thromboembolic events. The worsening of dyspnoea is a frequent occurrence and often leads patients to consult the emergency department. Pulmonary embolism can then be an exacerbation factor, a differential diagnosis or even a secondary diagnosis. The prevalence of pulmonary embolism in these patients is unknown, especially in cases of chronic heart failure. The challenge lies in needing to carry out a systematic or targeted diagnostic strategy for pulmonary embolism. The occurrence of a pulmonary embolism in patients with chronic cardiopulmonary disease clearly worsens their prognosis. In this narrative review, we study pulmonary embolism and chronic obstructive pulmonary disease, after which we turn to pulmonary embolism and chronic heart failure.