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Background Tick-borne lymphadenopathy (TIBOLA) is a tick-borne disease transmitted by Dermacentor ticks and is usually caused by Rickettsia . In 2021, clinicians in northeastern France reported an increase in TIBOLA cases. Methods This entomo-clinical, multicenter, retrospective, and observational study aimed to describe the evolution of the number of TIBOLA cases between 2016 and 2021 in northeastern France as well as the evolution of the Dermacentor tick population. Results A total of 35 cases of TIBOLA were identified, 16 of which occurred in 2021, with clear predominance in April and May. A longitudinal study performed in the Alsace region (endemic for ticks and tick-borne diseases) revealed a peak in tick activity in 2021. A trend toward an increase in TIBOLA cases in 2021 in the northeastern region of France was observed, as was an increase in the Dermacentor tick population in some biotopes. Conclusions TIBOLA appears to be an emerging disease that should be monitored, as should the Dermacentor population. Graphical Abstract

Background Posterior reversible encephalopathy syndrome is a rare disorder encompassing multiple neurological symptoms usually corroborated by specific neuro magnetic resonance imaging features. Posterior reversible encephalopathy syndrome may be triggered by multiple clinical situations such as blood pressure fluctuations, ischemic stroke, inflammatory and autoimmune disorders, renal failure, pre-eclampsia and eclampsia, hematopoietic stem cell transplantation, cytotoxic drugs, calcineurin inhibitors (cyclosporine A), and other immunosuppressants, as well as a wide range of surgical procedures (mainly cranial and solid organ transplantation). Although rare after cardiac transplantation, posterior reversible encephalopathy syndrome remains a major adverse event among feared complications promoted by use of immunosuppressive drugs. Clinical symptomatology, imaging features, and evolution of posterior reversible encephalopathy syndrome as well therapeutic strategy and identification of contributing factors will be discussed on the basis of our experience and data from literature review. Case presentation We report the case of a 59-year-old white male patient who was diagnosed with posterior reversible encephalopathy syndrome 3 months after cardiac transplantation. Neurologic complications gradually worsened within weeks after transplantation from an immediate postoperative paraparesis to seizures and coma requiring specific management in the intensive care unit. Initial brain computed tomography and magnetic resonance imaging were not contributive. Ultimately, magnetic resonance imaging characteristics of posterior reversible encephalopathy syndrome gradually appeared 10 weeks after transplantation and were concomitant with epileptic seizures, coma, and occurrence of Shiga toxin-producing Escherichia coli -hemolytic–uremic syndrome in a context of blood pressure variations and administration of cyclosporine A. Conclusion This case highlighted the necessity for clinicians to be familiar with posterior reversible encephalopathy syndrome to prevent misdiagnosis and optimize neurological outcomes. In addition, it emphasized the underlying non-dose-dependent neurotoxicity of cyclosporine A.

Although the respiratory tract is the main target of SARS-CoV-2, other tissues and organs are permissive to the infection. In this report, we investigated this wide-spectrum tropism by studying the SARS-CoV-2 genetic intra-host variability in multiple tissues. The virological and histological investigation of multiple specimens from a post-mortem COVID-19 patient was performed. SARS-CoV-2 genome was detected in several tissues, including the lower respiratory system, cardio-vascular biopsies, stomach, pancreas, adrenal gland, mediastinal ganglion and testicles. Subgenomic RNA transcripts were also detected, in favor of an active viral replication, especially in testicles. Ultra-deep sequencing allowed us to highlight several SARS-CoV-2 mutations according to tissue distribution. More specifically, mutations of the spike protein, i.e., V341A (18.3%), E654 (44%) and H655R (30.8%), were detected in the inferior vena cava. SARS-CoV-2 variability can contribute to heterogeneous distributions of viral quasispecies, which may affect the COVID-19 pathogeny.

Using a large dataset, we evaluated prevalence and severity of alterations in liver enzymes in COVID-19 and association with patient-centred outcomes. We included hospitalized patients with confirmed or suspected SARS-CoV-2 infection from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) database. Key exposure was baseline liver enzymes (AST, ALT, bilirubin). Patients were assigned Liver Injury Classification score based on 3 components of enzymes at admission: Normal; Stage I) Liver injury: any component between 1-3x upper limit of normal (ULN); Stage II) Severe liver injury: any component ≥3x ULN. Outcomes were hospital mortality, utilization of selected resources, complications, and durations of hospital and ICU stay. Analyses used logistic regression with associations expressed as adjusted odds ratios (OR) with 95% confidence intervals (CI). Of 17,531 included patients, 46.2% (8099) and 8.2% (1430) of patients had stage 1 and 2 liver injury respectively. Compared to normal, stages 1 and 2 were associated with higher odds of mortality (OR 1.53 [1.37-1.71]; OR 2.50 [2.10-2.96]), ICU admission (OR 1.63 [1.48-1.79]; OR 1.90 [1.62-2.23]), and invasive mechanical ventilation (OR 1.43 [1.27-1.70]; OR 1.95 (1.55-2.45). Stages 1 and 2 were also associated with higher odds of developing sepsis (OR 1.38 [1.27-1.50]; OR 1.46 [1.25-1.70]), acute kidney injury (OR 1.13 [1.00-1.27]; OR 1.59 [1.32-1.91]), and acute respiratory distress syndrome (OR 1.38 [1.22-1.55]; OR 1.80 [1.49-2.17]). Liver enzyme abnormalities are common among COVID-19 patients and associated with worse outcomes.

Background: Cefiderocol (CFD) is a novel siderophore cephalosporin developed for the treatment of infections involving multidrug-resistant (MDR) Gram-negative bacilli (GNB) infections (1–3). For bone and joint infections (BJIs), the use of CFD is currently neither part of its market authorization nor recommended, and has not yet been assessed by large-scale studies. Objectives: To fill the scarcity of data regarding the use of CFD in BJIs, we aimed to describe patients’ and infection characteristics along with the outcomes of the infection. Methods: We conducted a retrospective observational multicenter study in 22 French centers from January 2019 to December 2023. Results: From January 2019 to December 2023, 45 patients were included. Patients were mainly males (73%) with a median age of 62 years (interquartile range [IQR] 29), and a median Charlson comorbidity index of 3. Implant-related infections (20) were the most prominent, accounting for 44% of the cases. Carbapenemase-producing GNB were involved in 74% of the cases (n = 17/23), among which Pseudomonas aeruginosa accounted for 38% of these cases. Most patients received 6 g of CFD per day. CFD was used in combination with an antibiotic in 40 out of 45 cases (89%). The median duration of CFD treatment was 34 days. Seven patients (16%) experienced side effects, mainly gastro-intestinal disorders, including three (7%) who induced treatment cessation. Infection control included surgery in 37 (82%) patients. Failures and deaths occurred, respectively, in 22 (49%) and 10 (22%) cases. Conclusions: Our results suggest that CFD may be an alternative in MDR-GNB infections with limited therapeutic options.

Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate ( e.g .: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. Intervention and comparator The four experimental treatments planned in protocol version 1.2 (April 8 th , 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. Main outcome The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. Randomisation Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan ( i.e .: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs . nursing home). Blinding (masking) This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. Numbers to be randomised (sample size) A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. Trial Status This describes the Version 1.2 (April 8 th , 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15 th , 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15 th , 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms < 3 days replaced by time since first symptoms < 5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. Trial registration The trial was registered on Clinical Trials.gov on April 22 nd , 2020 (Identifier: NCT04356495): and on EudraCT on April 10 th , 2020 (Identifier: 2020-001435-27). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Lethality of (Sa) infective endocarditis (IE) is high and might be due to yet unidentified prognostic factors. The aim of this study was to search for new potential prognostic factors and assess their prognostic value in SaIE. We used a two-step exploratory approach. First, using a qualitative approach derived from mortality and morbidity conferences, we conducted a review of the medical records of 30 patients with SaIE (15 deceased and 15 survivors), randomly extracted from an IE cohort database (NCT03295045), to detect new factors of possible prognostic interest. Second, we collected quantitative data for these factors in the entire set of SaIE patients and used multivariate Cox models to estimate their prognostic value. A total of 134 patients with modified Duke definite SaIE were included, 64 of whom died during follow-up. Of the 56 candidate prognostic factors identified at the first step, 3 had a significant prognostic value in multivariate analysis: the prior use of non-steroidal anti-inflammatory drugs [aHR 3.60, 95% CI (1.59-8.15), = 0.002]; the non-performance of valve surgery when indicated [aHR 1.85, 95% CI (1.01-3.39), = 0.046]; and the decrease of vegetation size on antibiotic treatment [aHR 0.34, 95% CI (0.12-0.97), = 0.044]. We identified three potential SaIE prognostic factors. These results, if externally validated, might eventually help improve the management of patients with SaIE.

BackgroundThe immuno-receptor Triggering Expressed on Myeloid cells-1 (TREM-1) is activated during bacterial infectious diseases, where it amplifies the inflammatory response. Small studies suggest that TREM-1 could be involved in viral infections, including COVID-19. We here aim to decipher whether plasma concentration of the soluble form of TREM-1 (sTREM-1) could predict the outcome of hospitalized COVID-19 patients.MethodsWe conducted a multicentre prospective observational study in 3 university hospitals in France. Consecutive hospitalized patients with confirmed infection with SARS-CoV-2 were enrolled. Plasma concentration of sTREM-1 was measured on admission and then at days 4, 6, 8, 14, 21, and 28 in patients admitted into an ICU (ICU cohort: ICUC) or 3 times a week for patients hospitalized in a medical ward (Conventional Cohort: ConvC). Clinical and biological data were prospectively recorded and patients were followed-up for 90 days. For medical ward patients, the outcome was deemed complicated in case of requirement of increased oxygen supply > 5 L/min, transfer to an ICU, or death. For Intensive Care Unit (ICU) patients, complicated outcome was defined by death in the ICU.ResultsPlasma concentration of sTREM-1 at inclusion was higher in ICU patients (n = 269) than in medical ward patients (n = 562) (224 pg/mL (IQR 144–320) vs 147 pg/mL (76–249), p < 0.0001), and higher in patients with a complicated outcome in both cohorts: 178 (94–300) vs 135 pg/mL (70–220), p < 0.0001 in the ward patients, and 342 (288–532) vs 206 pg/mL (134–291), p < 0.0001 in the ICU patients. Elevated sTREM-1 baseline concentration was an independent predictor of complicated outcomes (Hazard Ratio (HR) = 1.5 (1.1–2.1), p = 0.02 in ward patients; HR = 3.8 (1.8–8.0), p = 0.0003 in ICU patients). An sTREM-1 plasma concentration of 224 pg/mL had a sensitivity of 42%, and a specificity of 76% in the ConvC for complicated outcome. In the ICUC, a 287 pg/mL cutoff had a sensitivity of 78%, and a specificity of 74% for death. The sTREM-1 concentrations increased over time in the ConvC patients with a complicated outcome (p = 0.017), but not in the ICUC patients.ConclusionsIn COVID-19 patients, plasma concentration of sTREM-1 is an independent predictor of the outcome, although its positive and negative likelihood ratio are not good enough to guide clinical decision as a standalone marker.

PurposeFew data have been published on the efficacy of linezolid in enterococcal urinary tract infection (e-UTI). The aims of this study were to describe the characteristics of patients with enterococci UTI treated with linezolid, and to evaluate the efficacy and the tolerance of linezolid treatment.MethodsAn observational multicentre retrospective study was conducted in 5 hospitals in France. Patients were included if they met the following criteria: ≥18 years, clinical and microbiological criteria for enterococcal UTI and linezolid treatment > 48 h. Primary outcome was clinical failure.ResultsEighty-one patients were included between January 2015 and December 2021. The median age was 73.0 [64; 83] years and 47 (58%) were men. The median Charlson comorbidity index was 3.00 [2; 6]. E. faecium was reported in 65 (80%) cases and E. faecalis in 26 cases (32%). Polymicrobial infections occurred in 41 (51%) cases. No enterococci was resistant to vancomycin. Before linezolid prescription an empiric antimicrobial treatment was started in 48 (59%) cases and was effective against enterococci in 19/48 (39.5%) patients for a median of 3.5 days [2.0; 4.0]. The median duration of linezolid antibiotic treatment was 13 days [10; 14]. Three adverse events were reported, none were serious but one led to discontinuation of treatment. Treatment failure was reported in 2 cases (2.5%).ConclusionThis study provides evidence for efficacy and safety of linezolid in enterococcal UTI.

The alarmin IL-33 has been described to be upregulated in human and murine viral hepatitis. However, the role of endogenous IL-33 in viral hepatitis remains obscure. We aimed to decipher its function by infecting IL-33-deficient mice (IL-33 KO) and their wild-type (WT) littermates with pathogenic mouse hepatitis virus (L2-MHV3). The IL-33 KO mice were more sensitive to L2-MHV3 infection exhibiting higher levels of AST/ALT, higher tissue damage, significant weight loss, and earlier death. An increased depletion of B and T lymphocytes, NKT cells, dendritic cells, and macrophages was observed 48 h postinfection (PI) in IL-33 KO mice than that in WT mice. In contrast, a massive influx of neutrophils was observed in IL-33 KO mice at 48 h PI. A transcriptomic study of inflammatory and cell-signaling genes revealed the overexpression of IL-6, TNFα, and several chemokines involved in recruitment/activation of neutrophils (CXCL2, CXCL5, CCL2, and CCL6) at 72 h PI in IL-33 KO mice. However, the IFNγ was strongly induced in WT mice with less profound expression in IL-33 KO mice demonstrating that endogenous IL-33 regulated IFNγ expression during L2-MHV3 hepatitis. In conclusion, we demonstrated that endogenous IL-33 had multifaceted immunoregulatory effect during viral hepatitis via induction of IFNγ, survival effect on immune cells, and infiltration of neutrophils in the liver.