The evolutionary conserved proteins CEP90, FOPNL, and OFD1 recruit centriolar distal appendage proteins to initiate their assembly.

In metazoa, cilia assembly is a cellular process that starts with centriole to basal body maturation, migration to the cell surface, and docking to the plasma membrane. Basal body docking involves the interaction of both the distal end of the basal body and the transition fibers/distal appendages, with the plasma membrane. Mutations in numerous genes involved in basal body docking and transition zone assembly are associated with the most severe ciliopathies, highlighting the importance of these events in cilium biogenesis. In this context, the ciliate Paramecium has been widely used as a model system to study basal body and cilia assembly. However, despite the evolutionary conservation of cilia assembly events across phyla, whether the same molecular players are functionally conserved, is not fully known. Here, we demonstrated that CEP90, FOPNL, and OFD1 are evolutionary conserved proteins crucial for ciliogenesis. Using ultrastructure expansion microscopy, we unveiled that these proteins localize at the distal end of both centrioles/basal bodies in Paramecium and mammalian cells. Moreover, we found that these proteins are recruited early during centriole duplication on the external surface of the procentriole. Functional analysis performed both in Paramecium and mammalian cells demonstrate the requirement of these proteins for distal appendage assembly and basal body docking. Finally, we show that mammalian centrioles require another component, Moonraker (MNR), to recruit OFD1, FOPNL, and CEP90, which will then recruit the distal appendage proteins CEP83, CEP89, and CEP164. Altogether, we propose that this OFD1, FOPNL, and CEP90 functional module is required to determine in mammalian cells the future position of distal appendage proteins.

MKS-NPHP module proteins control ciliary shedding at the transition zone.

Ciliary shedding occurs from unicellular organisms to metazoans. Although required during the cell cycle and during neurogenesis, the process remains poorly understood. In all cellular models, this phenomenon occurs distal to the transition zone (TZ), suggesting conserved molecular mechanisms. The TZ module proteins (Meckel Gruber syndrome [MKS]/Nephronophtysis [NPHP]/Centrosomal protein of 290 kDa [CEP290]/Retinitis pigmentosa GTPase regulator-Interacting Protein 1-Like Protein [RPGRIP1L]) are known to cooperate to establish TZ formation and function. To determine whether they control deciliation, we studied the function of 5 of them (Transmembrane protein 107 [TMEM107], Transmembrane protein 216 [TMEM216], CEP290, RPGRIP1L, and NPHP4) in Paramecium. All proteins are recruited to the TZ of growing cilia and localize with 9-fold symmetry at the level of the most distal part of the TZ. We demonstrate that depletion of the MKS2/TMEM216 and TMEM107 proteins induces constant deciliation of some cilia, while depletion of either NPHP4, CEP290, or RPGRIP1L prevents Ca2+/EtOH deciliation. Our results constitute the first evidence for a role of conserved TZ proteins in deciliation and open new directions for understanding motile cilia physiology.

Effect of Noninvasive Airway Management of Comatose Patients With Acute Poisoning: A Randomized Clinical Trial.

Importance: Tracheal intubation is recommended for coma patients and those with severe brain injury, but its use in patients with decreased levels of consciousness from acute poisoning is uncertain. Objective: To determine the effect of intubation withholding vs routine practice on clinical outcomes of comatose patients with acute poisoning and a Glasgow Coma Scale score less than 9. Design, Setting, and Participants: This was a multicenter, randomized trial conducted in 20 emergency departments and 1 intensive care unit (ICU) that included comatose patients with suspected acute poisoning and a Glasgow Coma Scale score less than 9 in France between May 16, 2021, and April 12, 2023, and followed up until May 12, 2023. Intervention: Patients were randomized to undergo conservative airway strategy of intubation withholding vs routine practice. Main Outcomes and Measures: The primary outcome was a hierarchical composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Key secondary outcomes included adverse events resulting from intubation as well as pneumonia within 48 hours. Results: Among the 225 included patients (mean age, 33 years; 38% female), 116 were in the intervention group and 109 in the control group, with respective proportions of intubations of 16% and 58%. No patients died during the in-hospital stay. There was a significant clinical benefit for the primary end point in the intervention group, with a win ratio of 1.85 (95% CI, 1.33 to 2.58). In the intervention group, there was a lower proportion with any adverse event (6% vs 14.7%; absolute risk difference, 8.6% [95% CI, -16.6% to -0.7%]) compared with the control group, and pneumonia occurred in 8 (6.9%) and 16 (14.7%) patients, respectively (absolute risk difference, -7.8% [95% CI, -15.9% to 0.3%]). Conclusions and Relevance: Among comatose patients with suspected acute poisoning, a conservative strategy of withholding intubation was associated with a greater clinical benefit for the composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Trial Registration: ClinicalTrials.gov Identifier: NCT04653597.

Lymphocyte-to-C-Reactive Protein (LCR) Ratio Is Not Accurate to Predict Severity and Mortality in Patients with COVID-19 Admitted to the ED.

Health care systems worldwide have been battling the ongoing COVID-19 pandemic. Since the beginning of the COVID-19 pandemic, Lymphocytes and CRP have been reported as markers of interest. We chose to investigate the prognostic value of the LCR ratio as a marker of severity and mortality in COVID-19 infection. Between 1 March and 30 April 2020, we conducted a multicenter, retrospective cohort study of patients with moderate and severe coronavirus disease 19 (COVID-19), all of whom were hospitalized after being admitted to the Emergency Department (ED). We conducted our study in six major hospitals of northeast France, one of the outbreak's epicenters in Europe. A total of 1035 patients with COVID-19 were included in our study. Around three-quarters of them (76.2%) presented a moderate form of the disease, while the remaining quarter (23.8%) presented a severe form requiring admission to the ICU. At ED admission, the median LCR was significantly lower in the group presenting severe disease compared to that with moderate disease (versus 6.24 (3.24-12) versus 12.63 ((6.05-31.67)), p < 0.001). However, LCR was neither associated with disease severity (OR: 0.99, CI 95% (0.99-1)), p = 0.476) nor mortality (OR: 0.99, CI 95% (0.99-1)). In the ED, LCR, although modest, with a threshold of 12.63, was a predictive marker for severe forms of COVID-19.

A Real-World Cost-Effectiveness Study Evaluating Imaging Strategies for the Diagnostic Workup of Renal Colic in the Emergency Department.

Introduction Both non-contrast Computed Tomography (CT) and ultrasound (US) are used for the diagnosis of renal colic in the emergency department (ED). Although US reduces radiation exposure, its diagnostic accuracy is inferior to that of CT. In this context, data regarding the cost and organizational impact of these strategies represent essential elements in the choice of imaging; however, they remain poorly documented. Aim of the study The aim of this study was to compare the costs and effectiveness of diagnostic workup by US and CT for patients consulting with renal colic in the ED. Methods We conducted a monocentric real-life retrospective study of patients consulting for a renal colic in an ED between 1 July 2018 and 31 December 2018. We estimated length of stay (LOS), total hospital costs at 60 days including ED, and initial and repeat admissions. Patients with initial US in the ED were compared to patients with initial CT using inverse probability weighting of the propensity score calculated from demographic variables, vital parameters, and clinical presentation. We calculated the incremental cost effectiveness ratio as the difference in costs by the difference in LOS. The variability of the results was assessed using non-parametric bootstrapping. Results In this study, of the 273 patients included, 67 were patients assessed with US and 206 with CT. The average costs were €1159 (SD 1987) and €956 (SD 1462) for US and CT, respectively, and the ED LOS was 8.9 [CI 95% 8.1; 9.4] and 8.7 [CI 95% 7.9; 9.9] hours for US and CT, respectively. CT was associated with a decreased LOS by 0.139 [CI 95% -1.1; 1.5] hours and was cost-saving, with a €199 [CI 95% -745; 285] reduction per patient. Conclusion When imaging is required in the ED for suspected renal colic as recommended, there is real-life evidence that CT is a cost-effective strategy compared to US, reducing costs and LOS in the ED.

Organizational Benefits of Ultra-Low-Dose Chest CT Compared to Chest Radiography in the Emergency Department for the Diagnostic Workup of Community-Acquired Pneumonia: A Real-Life Retrospective Analysis.

Background and Objectives: Chest radiography remains the most frequently used examination in emergency departments (ED) for the diagnosis of community-acquired pneumonia (CAP), despite its poor diagnostic accuracy compared with ultra-low-dose (ULD) chest computed tomography (CT). However, although ULD CT appears to be an attractive alternative to radiography, its organizational impact in ED remains unknown. Our objective was to compare the relevant timepoints in ED management of CT and chest radiography. Materials and Methods: We conducted a retrospective study in two ED of a University Hospital including consecutive patients consulting for a CAP between 1 March 2019 and 29 February 2020 to assess the organizational benefits of ULD chest CT and chest radiography (length of stay (LOS) in the ED, time of clinical decision after imaging). Overlap weights (OW) were used to reduce covariate imbalance between groups. Results: Chest radiography was performed for 1476 patients (mean age: 76 years [63; 86]; 55% men) and ULD chest CT for 133 patients (mean age: 71 [57; 83]; 53% men). In the weighted population with OW, ULD chest CT did not significantly alter the ED LOS compared with chest radiography (11.7 to 12.2; MR 0.96 [0.85; 1.09]), although it did significantly reduce clinical decision time (6.9 and 9.5 h; MR 0.73 [0.59; 0.89]). Conclusion: There is real-life evidence that a strategy with ULD chest CT can be considered to be a relevant approach to replace chest radiography as part of the diagnostic workup for CAP in the ED without increasing ED LOS.

MRI dedicated to the emergency department for diplopia or dizziness: a cost-effectiveness analysis.

OBJECTIVES: The purpose of this study was to compare the costs and organizational benefits of diagnostic workup without and with MRI dedicated to the ED. METHODS: We conducted a prospective observational uncontrolled before-after study in one ED of a university hospital in France from July 1, 2018, and January 3, 2020. We included all consecutive patients presenting with dizziness or diplopia. The main outcomes were the clinical decision time of ED physicians and the total costs for each strategy. Outcomes were compared using propensity score with inverse probability weighting in the 2 arms and an incremental cost-effectiveness ratio (ICER) was calculated. RESULTS: Among the 199 patients during the "before" period (average age: 60.4 years ± 17.6): 112 men (57%), and 181 during the "after" period (average age, 54.8 years ± 18.5): 107 men (59%), the average costs were €2701 (95% CI 1918; 3704) and €2389 (95% CI: €1627; 3280) per patient, respectively. The average time to clinical decision was 9.8 h (95% CI: 8.9 10.7) in the group "before" and 7.7 h (95% CI: 7.1; 8.4) in the group "after" (ICER: €151 saved for a reduction of 1 h in clinical decision time). The probabilistic sensitivity analysis estimated a 71% chance that the MRI dedicated to ED was dominant (less costly and more effective). CONCLUSION: Easy access to MRI in the ED for posterior circulation stroke-like symptoms must be considered a relevant approach to help physicians for an appropriate and rapid diagnostic with reduction of costs. TRIAL REGISTRATION: NCT03660852 KEY POINTS: • A dedicated MRI in the ED for diplopia or dizziness may be considered an efficient strategy improving diagnostic performance, reducing physicians' decision time, and decreasing hospital costs. • This strategy supports clinical decision-making with early treatment and management of patients with posterior circulation-like symptoms in the ED. • There is 71% chance that the MRI dedicated to ED was dominant (less costly and more effective) compared with a strategy without dedicated MRI.

[Anaphylaxis and pathophysiology]. / Physiopathologie de l'anaphylaxie.

Anaphylaxis is the most severe of the allergic hypersensitivity reactions. It is caused by the release of mediators from blood components such as mast cells and basophils into the bloodstream. Anaphylaxis is a common disease, its diagnosis is clinical and, given its pathophysiology, the treatment of choice is adrenaline.

C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disorder characterized by destructive respiratory disease and laterality abnormalities due to randomized left-right body asymmetry. PCD is mostly caused by mutations affecting the core axoneme structure of motile cilia that is essential for movement. Genes that cause PCD when mutated include a group that encode proteins essential for the assembly of the ciliary dynein motors and the active transport process that delivers them from their cytoplasmic assembly site into the axoneme. We screened a cohort of affected individuals for disease-causing mutations using a targeted next generation sequencing panel and identified two unrelated families (three affected children) with mutations in the uncharacterized C11orf70 gene (official gene name CFAP300). The affected children share a consistent PCD phenotype from early life with laterality defects and immotile respiratory cilia displaying combined loss of inner and outer dynein arms (IDA+ODA). Phylogenetic analysis shows C11orf70 is highly conserved, distributed across species similarly to proteins involved in the intraflagellar transport (IFT)-dependant assembly of axonemal dyneins. Paramecium C11orf70 RNAi knockdown led to combined loss of ciliary IDA+ODA with reduced cilia beating and swim velocity. Tagged C11orf70 in Paramecium and Chlamydomonas localizes mainly in the cytoplasm with a small amount in the ciliary component. IFT139/TTC21B (IFT-A protein) and FLA10 (IFT kinesin) depletion experiments show that its transport within cilia is IFT dependent. During ciliogenesis, C11orf70 accumulates at the ciliary tips in a similar distribution to the IFT-B protein IFT46. In summary, C11orf70 is essential for assembly of dynein arms and C11orf70 mutations cause defective cilia motility and PCD.

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus.

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

Effect of a Diagnostic Strategy Using an Elevated and Age-Adjusted D-Dimer Threshold on Thromboembolic Events in Emergency Department Patients With Suspected Pulmonary Embolism: A Randomized Clinical Trial.

Importance: Uncontrolled studies suggest that pulmonary embolism (PE) can be safely ruled out using the YEARS rule, a diagnostic strategy that uses varying D-dimer thresholds. Objective: To prospectively validate the safety of a strategy that combines the YEARS rule with the pulmonary embolism rule-out criteria (PERC) rule and an age-adjusted D-dimer threshold. Design, Settings, and Participants: A cluster-randomized, crossover, noninferiority trial in 18 emergency departments (EDs) in France and Spain. Patients (N = 1414) who had a low clinical risk of PE not excluded by the PERC rule or a subjective clinical intermediate risk of PE were included from October 2019 to June 2020, and followed up until October 2020. Interventions: Each center was randomized for the sequence of intervention periods. In the intervention period (726 patients), PE was excluded without chest imaging in patients with no YEARS criteria and a D-dimer level less than 1000 ng/mL and in patients with 1 or more YEARS criteria and a D-dimer level less than the age-adjusted threshold (500 ng/mL if age <50 years or age in years × 10 in patients ≥50 years). In the control period (688 patients), PE was excluded without chest imaging if the D-dimer level was less than the age-adjusted threshold. Main Outcomes and Measures: The primary end point was venous thromboembolism (VTE) at 3 months. The noninferiority margin was set at 1.35%. There were 8 secondary end points, including chest imaging, ED length of stay, hospital admission, nonindicated anticoagulation treatment, all-cause death, and all-cause readmission at 3 months. Results: Of the 1414 included patients (mean age, 55 years; 58% female), 1217 (86%) were analyzed in the per-protocol analysis. PE was diagnosed in the ED in 100 patients (7.1%). At 3 months, VTE was diagnosed in 1 patient in the intervention group (0.15% [95% CI, 0.0% to 0.86%]) vs 5 patients in the control group (0.80% [95% CI, 0.26% to 1.86%]) (adjusted difference, -0.64% [1-sided 97.5% CI, -∞ to 0.21%], within the noninferiority margin). Of the 6 analyzed secondary end points, only 2 showed a statistically significant difference in the intervention group compared with the control group: chest imaging (30.4% vs 40.0%; adjusted difference, -8.7% [95% CI, -13.8% to -3.5%]) and ED median length of stay (6 hours [IQR, 4 to 8 hours] vs 6 hours [IQR, 5 to 9 hours]; adjusted difference, -1.6 hours [95% CI, -2.3 to -0.9]). Conclusions and Relevance: Among ED patients with suspected PE, the use of the YEARS rule combined with the age-adjusted D-dimer threshold in PERC-positive patients, compared with a conventional diagnostic strategy, did not result in an inferior rate of thromboembolic events. Trial Registration: ClinicalTrials.gov Identifier: NCT04032769.

White blood cell count and eosinopenia as valuable tools for the diagnosis of bacterial infections in the ED.

Identifying an infection may be difficult in the ED. Neutrophilic leukocytosis is often used in the diagnosis of infection despite its lack of specificity in situations of stress. Our objective was to study the value of each parameter of the WBC count, in particular eosinopenia, to diagnose bacterial infections in the ED. We conducted a retrospective and observational study over a period of 6 months. All patients with one of the following diagnoses were eligible: pneumonia (9.9%), pyelonephritis (26.2%), prostatitis (8.4%), appendicitis (26.2%), cholecystitis (8.4%), and diverticular sigmoiditis (5%). A total of 466 infected patients were included for statistical analysis, and a control group of 466 uninfected patients was randomly selected in the same period of time. All leukocyte count parameters were significantly modified (p < 0.001) in the infected group compared with the control group. Neutrophils and total leukocytes remain the two most suitable parameters for the diagnosis of infections in the ED. Eosinopenia represented the most efficient parameter of the WBC count for the diagnosis of urinary and biliary tract infections. Deep eosinopenia presented a specificity of 94% for the diagnosis of infection. Any modification of the WBC count associated with an elevation of CRP (> 40 mg/L) or fever (> 38.5 °C) showed a high specificity for the diagnosis of infection. A careful analysis of the WBC count remains a valuable tool for the diagnosis of infection in the ED.

[An underestimated cause of seizure in Europe]. / Une cause sous-estimée de convulsion en Europe.

Seizures are very common in the Emergency Department (ED). We present here a case of a young woman with neurocysticercosis ; a worldwide and nearly endemic cause of seizure in the southern hemisphere. Clinical manifestations are very different between patients from asymptomatic to life-threatening hydrocephalus. Diagnosis is based on a combination of clinical presentation, neuroimaging (CT and MRI) findings, history of exposure, and serologic testing.

Les convulsions sont un motif fréquent de consultation aux urgences. Nous présentons ici le cas d'une jeune patiente qui illustre une cause rare de convulsions en Europe : la neurocysticercose. La présentation initiale de cette maladie souvent hétérogène rend son diagnostic difficile pour le clinicien. Celui-ci repose sur un ensemble d'arguments clinico-immunologiques associé à un séjour en zone d'endémie de cysticercose. La neuro-imagerie (scanner et IRM) joue un rôle prépondérant dans le diagnostic et le suivi des différentes phases de la maladie.

Training approaches and devices utilization during endotracheal intubation in French Emergency Departments: a nationwide survey.

BACKGROUND AND IMPORTANCE: Endotracheal intubation is a lifesaving procedure that is reportedly associated to a significant risk of adverse events. Recent trials have reported that the use of videolaryngoscope and of a stylet might limit this risk during emergency intubation. OBJECTIVES: The objective of this study was to provide a national description of intubation practices in French Emergency Departments (EDs). SETTINGS AND PARTICIPANTS: We conducted an online nationwide survey by sending an anonymous 37-item questionnaire via e-mail to 629 physicians in French EDs between 2020 and 2022. INTERVENTION: A single questionnaire was sent to a sole referent physician in each ED. OUTCOME MEASURES AND ANALYSIS: The primary endpoint was to assess the proportion of French EDs in which videolaryngoscopy was available for emergency intubation and its use in routine practice. Secondary endpoints included the presence of local protocol or standard of procedure for intubation, availability of capnography, and routine use of a stylet. MAIN RESULTS: Of the surveyed EDs, 342 (54.4%) returned the completed questionnaire. A videolaryngoscope was available in 193 (56%) EDs, and direct laryngoscopy without a stylet was majorly used as the primary approach in 280 (82%) EDs. Among the participating EDs, 74% had an established protocol for intubation and 92% provided a capnography device for routine verification of tube position. In cases of difficult intubation, the use of a bougie was recommended in 227 (81%) EDs, and a switch to a videolaryngoscope in 16 (6%) EDs. The most frequently used videolaryngoscope models were McGrath Mac Airtraq (51%), followed by Airtraq (41%), and Glidescope (14%). CONCLUSION: In this large French survey, the majority of EDs recommended direct laryngoscopy without stylet, with seldom use of videolaryngoscopy.

Testing the validity of three acute care assessment tools for assessing residents' performance during in situ simulation: the ACAT-SimSit study.

BACKGROUND: The assessment of technical and nontechnical skills in emergency medicine requires reliable and usable tools. Three Acute Care Assessment Tools (ACATs) have been developed to assess medical learners in their management of cardiac arrest (ACAT-CA), coma (ACAT-coma) and acute respiratory failure (ACAT-ARF). OBJECTIVE: This study aims to analyze the reliability and usability of the three ACATs when used for in situ (bedside) simulation. METHODS: This prospective multicenter validation study tested ACATs using interprofessional in situ simulations in seven emergency departments and invited training residents to participate in them. Each session was rated by two independent raters using ACAT. Intraclass correlation coefficients (ICC) were used to assess interrater reliability, and Cronbach's alpha coefficient was used to assess internal consistency for each ACAT. The correlation between ACATs' scores and the learners' level of performance was also assessed. Finally, a questionnaire and two focus groups were used to assess the usability of the ACATs. RESULTS: A total of 104 in situ simulation sessions, including 85 residents, were evaluated by 37 raters. The ICC for ACAT-CA, ACAT-coma and ACAT-ARF were 0.95 [95% confidence interval (CI), 0.93-0.98], 0.89 (95% CI, 0.77-0.95) and 0.92 (95%CI 0.83-0.96), respectively. The Cronbach's alphas were 0.79, 0.80 and 0.73, respectively. The ACAT-CA and ARF showed good construct validity, as third-year residents obtained significantly higher scores than first-year residents ( P  < 0.001; P  < 0.019). The raters supported the usability of the tools, even though they expressed concerns regarding the use of simulations in a summative way. CONCLUSION: This study reported that the three ACATs showed good external validity and usability.

TLRs1-10 Protein Expression in Circulating Human White Blood Cells during Bacterial and COVID-19 Infections.

INTRODUCTION: Toll-like receptors play crucial roles in the sepsis-induced systemic inflammatory response. Septic shock mortality correlates with overexpression of neutrophilic TLR2 and TLR9, while the role of TLR4 overexpression remains a debate. In addition, TLRs are involved in the pathogenesis of viral infections such as COVID-19, where the single-stranded RNA of SARS-CoV-2 is recognized by TLR7 and TLR8, and the spike protein activates TLR4. METHODS: In this study, we conducted a comprehensive analysis of TLRs 1-10 expressions in white blood cells from 71 patients with bacterial and viral infections. Patients were divided into 4 groups based on disease type and severity (sepsis, septic shock, moderate, and severe COVID-19) and compared to 7 healthy volunteers. RESULTS: We observed a significant reduction in the expression of TLR4 and its co-receptor CD14 in septic shock neutrophils compared to the control group (p < 0.001). Severe COVID-19 patients exhibited a significant increase in TLR3 and TLR7 levels in neutrophils compared to controls (p < 0.05). Septic shock patients also showed a similar increase in TLR7 in neutrophils along with elevated intermediate monocytes (CD14+CD16+) compared to the control group (p < 0.005 and p < 0.001, respectively). However, TLR expression remained unchanged in lymphocytes. CONCLUSION: This study provides further insights into the mechanisms of TLR activation in various infectious conditions. Additional analysis is needed to assess their correlation with patient outcome and to evaluate the impact of TLR-pathway modulation during septic shock and severe COVID-19.

Variability of treatment of locally advanced cervical cancer: How French multidisciplinary teams follow European guidelines?

INTRODUCTION: Cervical cancer is a global public health concern. Despite ESGO recommendations and FIGO classification changes, management of locally advanced cervical cancer (LACC) remains debated in France. Our study aimed to review LACC treatment practices and assess adherence to ESGO recommendations among different practitioners. METHODS: From February 2021 to August 2022, we conducted a survey among gynecologic oncology surgeons, radiation oncologists, and medical oncologists practicing in France and managing LACC (FIGO stages IB3-IVA) according to the 2018 FIGO classification. We analyzed responses against the 2018 ESGO recommendations as a "gold standard." RESULTS: Among 115 respondents (56% radiation oncologists, 30% surgeons, 13% medical oncologists), 48.6% of gynecologic surgeons didn't perform para-aortic lymphadenectomy (PAL) with significant radiologic pelvic involvement. PAL, when indicated by PET-CT, was more common in university hospitals (66.7% of surgeons). Surgeons in university hospitals also followed ESGO recommendations more closely. Overall, compliance with all ESGO recommendations was low: 5.7% of surgeons, 21.5% of radiation oncologists, and 60% of medical oncologists. Prophylactic para-aortic irradiation, per ESGO, was more frequent in comprehensive cancer centers (52% of radiation oncologists). CONCLUSION: Adherence to ESGO recommendations for LACC treatment appears low in France, particularly in surgery, with limited PAL in cases of lymph node negativity on PET-CT. However, these recommendations are more often followed by surgeons in university hospitals and radiation oncologists in cancer centers. Adherence to these recommendations may impact patient survival and warrants evaluation of care quality, justifying the organization of LACC management in expert centers.

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.

Micro-costing analysis of suspected lower respiratory tract infection care in a French emergency department.

Introduction: In the context of budgetary constraints faced by healthcare systems, the medical-economic evaluation of care strategies becomes essential. In particular, valuing consumed resources in the overcrowded emergency departments (EDs) has become a priority to adopt more efficient approaches in treating the growing number of patients. However, precisely measuring the cost of care is challenging. While bottom-up micro-costing is considered the gold standard, its practical application remains limited. Objective: The objective was to accurately estimate the ED care cost for patients consulting in a French ED for suspected lower respiratory tract infection. Methods: The authors conducted a cost analysis using a bottom-up micro-costing method. Patients were prospectively included between January 1, and March 31, 2023. The primary endpoint was the mean cost of ED care. Resources consumed were collected using direct observation method and cost data were obtained from information available at Strasbourg University Hospital. Results: The mean cost of ED care was €411.68 (SD = 174.49). The cost elements that made the greatest contribution to the total cost were laboratory tests, labor, latency time, imaging and consumables. Considering this cost and the current epidemiological data on respiratory infections in France, the absence of valuation for outpatient care represents an annual loss of over 17 million euros for healthcare facilities. Conclusion: Micro-costing is a key element in valuing healthcare costs. The importance of accurately measuring costs, along with measuring the health outcomes of a defined care pathway, is to enhance the relevance of health economic evaluations and thus ensure efficient care.