Importance:The effect of wrist-strap physical restraints on outcomes in patients receiving mechanical ventilation in the intensive care unit (ICU) remains uncertain. Objective:To investigate the effect of a low-use wrist-strap physical restraint strategy in critically ill patients receiving invasive mechanical ventilation. Design, Setting, and Participants:Open-label randomized clinical trial conducted across 10 ICUs in France. Between January 5, 2021, and January 2, 2024, 405 adult patients who had initiated invasive mechanical ventilation within the previous 6 hours and were expected to require ventilation for at least 48 hours were enrolled. Follow-up was completed on May 17, 2024. Statistical analysis was conducted from June 1, 2025, to December 15, 2025. Interventions:Patients were randomized to undergo either a restrictive, low-use physical restraint strategy (wrist straps avoided unless necessary because of severe agitation, defined as a Richmond Agitation-Sedation Scale score of ≥3 [on a scale from -5 (unresponsive) to 4 (combative)]; n = 201) or a liberal, high-use strategy (wrist straps applied systematically and reassessed daily; n = 204). Discontinuation of restraints was allowed in patients who were awake or extubated without delirium (measured via the Confusion Assessment Method for the ICU). Main Outcomes and Measures:The primary outcome was the number of days alive without coma or delirium during the first 14 days after randomization. Secondary outcomes included incidence of self-extubation and day-90 mortality. Results:Among 396 patients with available primary outcome data, the median (IQR) age was 65 (56-73) years, 245 (62%) were male, and the median (IQR) Sequential Organ Failure Assessment score was 7 (4-10). The mean days alive without coma or delirium were 6.67 days (95% CI, 5.69-7.65) in the low-use strategy group and 6.30 days (95% CI, 5.35-7.24) in the high-use strategy group (adjusted mean difference, 0.37 days [95% CI, -0.71 to 1.46]; P = .51). Self-extubation occurred in 18 patients (9.2%) in the low-use strategy group and 17 (8.5%) in the high-use strategy group, and day-90 mortality was 37.2% and 41.0%, respectively. Conclusions and Relevance:In this randomized clinical trial, among adult patients receiving mechanical ventilation in the ICU, a low-use wrist-strap physical restraint strategy compared with a high-use strategy did not reduce days free of delirium or coma at 14 days. Trial Registration:ClinicalTrials.gov Identifier: NCT04273360.

OBJECTIVES:To evaluate the suitability of three major open-access ICU databases (Medical Information Mart for Intensive Care IV [MIMIC-IV], eICU Collaborative Research Database [eICU-CRD], and Amsterdam University Medical Center Database [AmsterdamUMCdb]) for artificial intelligence (AI)-based sepsis research, with a focus on data completeness, internal consistency, terminological standardization, and structural redundancy affecting clinical interpretability and reproducibility. DESIGN:A descriptive comparative design was employed to evaluate data completeness, terminological consistency, structural integrity, and clinical usability, with emphasis on sepsis-related variables such as antimicrobial administration, hemodynamic support, and mortality indicators. SETTING:Open-access ICU electronic health record databases including MIMIC-IV (2008-2019), eICU-CRD (2014-2015), and AmsterdamUMCdb (2003-2016), accessed under credentialed use agreements. Documentation, schema, and metadata were reviewed in parallel to primary datasets. INTERVENTIONS:Structured queries and descriptive analyses were performed to quantify missing values, distinct diagnosis strings, medication administration completeness, and redundancy of mortality markers. Manual semantic inspection of terminology, units, and coding (International Classification of Diseases, 9th revision/10th revision) was applied to evaluate inconsistency and typographical variability. Comparisons were made across key clinical dimensions including diagnosis, mortality, microbiology, and antibiotic administration. MEASUREMENTS AND MAIN RESULTS:Marked heterogeneity and data quality limitations were identified. MIMIC-IV demonstrated extensive missingness in medication route (49%) and dose (58%), 99.9% missing fields in microbiology quantity, and diagnosis redundancy with 17,557 unique strings and 174 near-duplicate variants. eICU-CRD exhibited 1.9% admissions lacking diagnosis and discordance between ICU and hospital mortality in 7,319 stays. AmsterdamUMCdb showed fewer structural inconsistencies but limited demographics and the highest proportion of admissions without diagnosis (61.4%), complicated by mixed English-Dutch terminology. All three databases lacked reliable sepsis diagnosis timestamps, constraining analysis of early intervention. CONCLUSIONS:Although widely used and valuable for sepsis research, open-access ICU databases exhibit substantial missingness, redundancy, semantic variability, and demographic imbalance. These limitations require rigorous preprocessing and highlight the need for standardized data collection to improve the validity and generalizability of AI-driven sepsis studies.

OBJECTIVES:This study assessed the clinical significance of negative BioFire® FilmArray® Pneumonia Panel (FA-PP) results in ICU patients with suspected hospital-acquired (HAP) or ventilator-associated pneumonia (VAP), evaluating its impact on diagnosis, antimicrobial management, and outcomes, and identifying factors associated with false-negative results. METHODS:A retrospective single-center study (April 2021 to July 2023) included 190 critically ill patients with negative FA-PP results on deep respiratory samples. Patients with microbiologically confirmed HAP/VAP were compared to those without. RESULTS:Among 190 patients, 69 (36%) had culture-confirmed HAP/VAP. Gram-negative bacilli (GNB) on Gram stain independently predicted true infection (OR = 3.08, 95% CI [1.47-6.45], P = 0.003). The false-negative rate for FA-PP-detectable bacteria was 12% (31/251), mainly Klebsiella pneumoniae and Pseudomonas aeruginosa. Nontargeted GNBs accounted for 27% (19/69) of confirmed cases. Recent broad-spectrum antibiotic exposure (≤3 months) reduced confirmed infection likelihood (OR = 0.28, 95% CI [0.13-0.6], P < 0.001). No inappropriate antibiotic de-escalation occurred, but 6% (7/121) of noninfected patients had antibiotics withdrawn based solely on FA-PP negativity. CONCLUSIONS:Negative FA-PP results do not exclude HAP/VAP, especially with nontargeted GNBs or recent antibiotic exposure. Gram stain remains a valuable complementary tool. Integrated diagnostic approaches are essential for optimal antimicrobial stewardship in ICU settings.

ABSTRACT Background Japanese encephalitis virus (JEV) is a mosquito-borne pathogen responsible for Japanese encephalitis (JE) clinical cases in Asia and the Western Pacific. Non-JE-vaccinated patients can develop potentially life-threatening neurologic forms. Case Summary Here, we present two severe, non-fatal JEV cases in returning travelers from Cambodia (Case 1) and Cambodia and Vietnam (Case 2), imported to France in 2023–2024. Neither patient was vaccinated, and both presented neurologic symptoms requiring hospitalization. Cases were confirmed by RT-qPCR, IgM, and IgG rise and seroneutralization. Interestingly, this is the second report to describe the detection of the JEV genome in urine by RT-qPCR. Conclusion This study highlights the critical importance of JE vaccination and the implementation of other personal protective measures to avoid mosquito bites when traveling to a JEV-endemic region.

Background: Currently, diagnosis of bacterial infections is based on culture, possibly followed by the amplification and sequencing (Sanger method) of the 16S rDNA- encoding gene when cultures are negative. Clinical metagenomics (CMg), i.e. the sequencing of a sample's entire nucleic acids, may allow for the identification of bacteria not detected by conventional methods. Here, we tested the performance of CMg compared to 16S rDNA sequencing (Sanger) in 50 patients with suspected bacterial infection but negative cultures. Methods: This is a prospective cohort study. Fifty patients (73 samples) with negative culture and a 16S rDNA sequencing demand (Sanger) were recruited from two sites. On the same samples, CMg (Illumina NextSeq) was also performed and compared to 16S rDNA Sanger sequencing. Bacteria were identified using MetaPhlAn4. Results: Among the 73 samples, 20 (27 %, 17 patients) had a clinically relevant 16S rDNA Sanger sequencing result (used for patient management) while 11 (15 %, 9 patients) were considered contaminants. At the patient level, the sensitivity of CMg was 70 % (12/17) compared to 16S rDNA. In samples negative for 16S rDNA Sanger sequencing (n = 53), CMg identified clinically-relevant bacteria in 10 samples (19 %, 10 patients) with 14 additional bacteria. Conclusions: CMg was not 100 % sensitive when compared to 16S, supporting that it may not be a suitable replacement. However, CMg did find additional bacteria in samples negative for 16S rDNA Sanger. CMg could therefore be positioned as a complementary to 16S rDNA Sanger sequencing.

BACKGROUND:Isavuconazole is approved for first-line treatment of aspergillosis, including COVID-19-associated pulmonary aspergillosis, and as an alternative for mucormycosis. However, its use in intensive care units (ICU) is not well characterized. RESEARCH DESIGN AND METHODS:We developed a population pharmacokinetic (popPK) model using 134 isavuconazole plasma concentrations retrospectively collected from 22 ICU patients over four years. Monte Carlo simulations were performed to optimize dosing strategies for rapid and maximal isavuconazole exposure. RESULTS:Diagnoses included suspected or probable aspergillosis (n = 17) and mucormycosis (n = 3). During the first 10 days of treatment, one-third of observed trough concentrations were below the target of 1 mg/L. A two-compartment model best estimated pharmacokinetic parameters, with no significant covariates identified to explain high variability. Simulations indicated that the standard dosing regimen (200 mg q8h for 2 days, then 200 mg qd) would not achieve the targeted area under the concentration-time curve during a 24-hour period to the minimal inhibitory concentration ratio of 33.34 mg/L in 45% of patients during the first ten days. Conversely, a loading dose of 400 mg q8h followed by a maintenance dose of 400 mg qd achieved the target in over 80% of patients. CONCLUSIONS:Isavuconazole exposure in the ICU was suboptimal with high pharmacokinetic variability. Pending external validation, isavuconazole concentrations should be monitored, and higher dosing regimens considered at treatment initiation.

Accurate microbiological documentation seems central for managing severe pneumonia. While the FilmArray® Pneumonia + panel (FA-PP) offers rapid pathogen identification, its effectiveness during antibiotic treatment and in predicting clinical outcomes remains unclear. We conducted a prospective observational study across four ICUs from April 2022 to June 2024, including patients with ventilator-associated pneumonia (VAP) or ventilated hospital-acquired pneumonia (vHAP). Bacterial loads were monitored on days 0, 1, 3, 7 and 10 and 3 days after stopping antibiotics, using endotracheal aspirates (ETAs) analyzed by FA-PP and standard cultures. The main objective was to assess the correlation between quantitative changes in FA-PP results and clinical success. Quantitative changes over time were analyzed using mixed ordinal logistic regression. Of the 93 patients enrolled, 60.2

Background:Morbidity associated with central nervous system tuberculosis (CNS TB) remains high due to persistent inflammation despite standard-of-care (SOC) treatment, including antituberculosis therapy and corticosteroids. Tumor necrosis factor alpha (TNF-α) is a key cytokine driving this inflammatory response, and a limited number of case reports suggest that TNF-α inhibitors may improve outcomes. We report the 1-year outcome of a cohort of consecutive patients treated with infliximab for severe CNS TB. Methods:Following the guidance provided by the French Tuberculosis Consilium, a standardized regimen of intravenous infliximab at 5 mg/kg per dose was used to treat CNS TB unresponsive to SOC. We retrospectively included consecutive patients who received at least 1 infliximab injection for CNS TB from 2017 to September 2021. Results:Eighteen patients with CNS TB, 94% with tuberculous meningitis, were included. Most had severe disease: 82% were classified as British Medical Research Council grade II or III, and 44% required intensive care unit admission. All demonstrated clinical and radiological worsening despite SOC; in 89% due to paradoxical reaction. At infliximab initiation, symptoms remained disabling, with a median modified Rankin scale (mRS) score of 3.5 (interquartile range, 3-4). One month after the first infusion, 38% showed improved mRS scores, increasing to 78% at 1 year. One-year survival was 94%; 1 death occurred 12 months after a single infliximab dose and was unrelated to TB treatment. Conclusions:Infliximab may represent a promising adjunctive treatment for CNS TB unresponsive to SOC, including paradoxical reaction. Prospective studies are needed to confirm these findings.

Real-time PCR (rt-PCR) using cycle threshold (Ct) is a semi-quantitative way to assess DNA amounts, which has become broadly used to diagnose Pneumocystis jirovecii pneumonia (PJP) in non-HIV immunocompromised patients. We aimed to describe the non-HIV immunocompromised patients hospitalized in intensive care unit (ICU) for acute respiratory failure (ARF) and to evaluate the relevance of PJP rt-PCR Ct value in diagnosing PJP. Moreover, the added value of serum 1.3 ß-D-glucan (BDG) assay in this population was also assessed. All non-HIV immunocompromised ICU patients with ARF with at least one rt-PCR performed in broncho-alveolar lavage (BAL) from 2013 to 2023 were retrospectively included. Patients with a positive RT-PCR were classified by reviewers aware of the PCR result, but blinded to Ct values, into confirmed, uncertain, or ruled-out PJP groups based on clinical presentation, imaging findings, organism identification, laboratory results, presence of alternative diagnoses, and the resolution of acute respiratory failure with or without appropriate PJP treatment. PJ rt-PCR Ct and BDG assays of each group were compared. Uncertain diagnoses were excluded from the primary analysis and successively considered as confirmed PJP or ruled-out PJP in a secondary analysis. Using the area under the curve (AUC) of the receiver operating characteristics curves, the best threshold of Ct value was defined. Out of the 481 non-HIV immunocompromised patients who underwent a PJ rt-PCR in BAL, 59 (12

BACKGROUND:Hyperparasitemia (HP), defined as a parasitemia > 4%, is the most frequent severity criterion considered in adults with imported malaria. Isolated hyperparasitemia (iHP), accounting for 10-40% of cases, has a controversial prognostic significance. METHODS:Multicenter retrospective study including all adult patients with imported Plasmodium falciparum malaria and HP admitted to 16 hospitals in the Greater Paris area between 2018 and 2022 and reported to the National Reference Center. Amongst HP patients, iHP at hospital admission was identified by retrospective analysis of medical records to minimize classification bias. The primary endpoint was a composite outcome using the Desirability of Outcome Ranking (DOOR) method with three levels of decreasing desirability: hospital survival, absence of organ support requirement, shortest length of stay. Association between HP, iHP and outcomes was evaluated by negative binomial regression models. RESULTS:Of 355 patients enrolled with HP, 135 (38%) had iHP. iHP patients were predominantly male (55.6%), aged 41 (32-52.3) years and born in an endemic country (86.4%). Compared with patients with HP and additional severity criteria, iHP was independently associated with a lower risk of worse DOOR [RR 0.56, 95%CI (0.48-0.65)]. No deaths were recorded in the iHP population, and 2/135 (1.5%) patients required organ support. In the iHP population, immunosuppression [RR 1.65, 95%CI (1.16-2.37)] and parasitemia>10% [RR 1.57, 95%CI (1.01-2.24)] were independently associated with worse DOOR. Only 47 (34.8%) iHP patients were admitted to an ICU at diagnosis, and 40 (29.6%) were treated with oral therapy alone. CONCLUSION:In imported malaria in France, iHP was associated with a low risk of serious adverse outcomes overall. In patients with iHP, immunosuppression and parasitemia >10% were associated with an increased risk of adverse outcome, highlighting the importance of a close hospital monitoring.

We aimed to develop a population pharmacokinetic model of cefazolin in children undergoing maintenance hemodialysis for kidney failure and simulate dosing regimens to optimize patients' exposure. Cefazolin plasma concentrations were quantified using high-performance liquid chromatography. A non-linear mixed-effect modeling approach was used to investigate cefazolin pharmacokinetics. Optimal dosing regimens were determined using Monte Carlo simulations targeting 100% of the time a free plasma concentration four times above the minimum inhibitory concentration (MIC) and total plasma concentration less than 80 mg/L (100% fT > 4 × MIC and C < 80 mg/L). Eighty-three samples were analyzed from six patients aged 1.3-14.6 years and weighing 11.4-51 kg. A one-compartment model with first-order elimination best fitted the data, with a significant between-subject variability (BSV). Body weight (BW), using the allometric rule, was a significant predictor of residual elimination clearance (CL) and volume of distribution (Vd), while dialysis membrane surface area (DMSA) explained almost all the BSV on dialysis clearance (CLdial). The parameter relationships were Vdi(L) = 14.6 × (BWi/70), CLi(L/h) = 0.186 × (BWi/70)0.75, CLdiali(L/h)=1.98 × (DMSAi/1)1.26, CLtoti = CLi + CLdialDMSAi, where the subscript i denotes the ith patient's covariate value. Dosing regimens were simulated for six CL ranges, targeting two concentration intervals: 40-80 mg/L and 20-80 mg/L for MIC of 2 and 1 mg/L, respectively. In children on maintenance hemodialysis for kidney failure, due to the persistence of a large unexplained BSV on CL that substantially affects them, optimal dosing regimen would not be accurately determined a priori and should be individually determined using therapeutic drug monitoring, taking BW, DMSA, and CL into account.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02539407.

Abstract Background Sepsis-associated encephalopathy (SAE) may be worsened by early systemic insults. We aimed to investigate the association of early systemic insults with outcomes of critically ill patients with severe SAE. Methods We performed a retrospective analysis using data from the French OUTCOMEREA prospective multicenter database. We included patients hospitalized in intensive care unit (ICU) for at least 48 h with severe SAE (defined by a score on the Glasgow Coma Scale (GCS) ≤ 13 and severe sepsis or septic shock (SEPSIS 2.0 criteria)) requiring invasive ventilation and who had no primary brain injury. We analyzed early systemic insults (abnormal glycemia (< 3 mmol/L or ≥ 11 mmol/L), hypotension (diastolic blood pressure ≤ 50 mmHg), temperature abnormalities (< 36 °C or ≥ 38.3 °C), anemia (hematocrit < 21%), dysnatremia (< 135 mmol/L or ≥ 145 mmol/L), oxygenation abnormalities (PaO2 < 60 or > 200 mmHg), carbon dioxide abnormalities (< 35 mmHg or ≥ 45 mmHg), and the impact of their correction at day 3 on day-28 mortality and awakening, defined as a recovery of GCS > 13. Results We included 995 patients with severe SAE, of whom 883 (89%) exhibited at least one early systemic insult that persisted through day 3. Compared to non-survivors, survivors had significantly less early systemic insults (hypoglycemia, hypotension, hypothermia, and anemia) within the first 48 h of ICU admission. The absence of correction of the following systemic insults at day 3 was independently associated with mortality: blood pressure (adjusted hazard ratio (aHR) = 1.77, 95% confidence interval (CI) 1.34–2.34), oxygenation (aHR = 1.78, 95% CI 1.20–2.63), temperature (aHR = 1.46, 95% CI 1.12–1.91) and glycemia (aHR = 1.41, 95% CI 1.10–1.80). Persistent abnormal blood pressure, temperature and glycemia at day 3 were associated with decreased chances of awakening. Conclusions In patients with severe SAE, the persistence of systemic insults within the first three days of ICU admission is associated with increased mortality and decreased chances of awakening.

IMPORTANCE:Long-term functional outcomes and health-related quality of life (HRQoL) in survivors of cardiogenic shock treated with venoarterial extracorporeal membrane oxygenation (ECMO) remain poorly understood. OBJECTIVES:This study aimed to evaluate these outcomes in a cohort of venoarterial ECMO survivors. DESIGN, SETTING, AND PARTICIPANTS:This single-center observational study was conducted in the ICU of a French academic hospital and included consecutive adult patients treated with venoarterial ECMO who were discharged alive between February 2016 and December 2021. MAIN OUTCOMES AND MEASURES:The primary endpoint was a favorable functional outcome at least one year after ICU discharge, defined as a score on the modified Rankin Scale of 0 or 1, indicating no functional limitations affecting usual activities. Secondary endpoints included HRQoL, assessed using the EuroQol 5D five levels (EQ-5D-5L) and 36-item short-form health survey (SF-36) questionnaires. Of 79 hospital survivors, 65 patients were evaluated after a median follow-up of 2.8 years (1.2-4.2 yr). A favorable functional outcome was observed in 35 of 65 patients (54%). No association was found between ICU admission characteristics, serum neurobiomarkers (neuron-specific enolase, S100B), electroencephalogram findings during venoarterial ECMO, and functional outcome. Male sex was the only parameter associated with higher odds of favorable functional outcome (adjusted odds ratio, 4.19; 95% CI, 1.35-14.5). HRQoL assessments showed moderate-to-severe issues in 15% of patients, mainly affecting mobility, pain/discomfort, and mental health. Patients with favorable outcomes reported better scores across all domains of the EQ-5D-5L and higher scores on both the physical and mental components of the SF-36. CONCLUSIONS AND RELEVANCE:Approximately half of venoarterial ECMO survivors achieved excellent long-term functional outcomes. Nonetheless, a subset experienced ongoing limitations, particularly related to physical function and mental health, underscoring the need for targeted long-term follow-up and support.