Approximately 50% of glioblastomas (GBMs) are characterized by overexpression of the epidermal growth factor receptor (EGFR) and EGFR gene amplification. In approximately 25% of instances, ...constitutively activated EGFR mutants are present. These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM.
In a randomized, controlled, phase II trial, 110 patients with progressive GBM after prior radiotherapy were randomly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine (BCNU). The primary end point was 6-month progression-free survival (PFS). Tumor specimens obtained at first surgery were investigated for EGFR expression; EGFRvIII mutants; EGFR amplification; EGFR mutations in exons 18, 19, and 21; and pAkt. These results were correlated with outcome. Pharmacokinetic analysis was part of the study. RESULTS; Treatment was well tolerated in general; skin toxicity was the most frequent adverse effect of erlotinib. The 6-month PFS rate in the erlotinib arm was 11.4% (95% CI, 4.6% to 21.5%), and it was 24% in the control arm. Of all explored biomarkers, only low pAkt expression appeared to be of borderline significance to an improved outcome. None of the eight patients who had tumors with EGFRvIII mutant presence and PTEN expression had 6-month PFS. The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance, but pharmacokinetic findings were not related to outcome.
Erlotinib has insufficient single-agent activity in unselected GBM. No clear biomarker associated with improved outcome to erlotinib was identified.
IntroductionFluid overload is associated with a poor prognosis in the critically ill patients, especially at the time of weaning from mechanical ventilation as it may promote weaning failure from ...cardiac origin. Some data suggest that early administration of diuretics would shorten the duration of mechanical ventilation. However, this strategy may expose patients to a higher risk of haemodynamic and metabolic complications. Currently, there is no recommendation for the use of diuretics during weaning and there is an equipoise on the timing of their initiation in this context.Methods and analysisThis study is a multicentre randomised controlled trial comparing two strategies of fluid removal during weaning in 13 French intensive care units (ICU). The preventive strategy is initiated systematically when the fluid balance or weight change is positive and the patients have criteria for clinical stability; the curative strategy is initiated only in case of weaning failure documented as of cardiac origin. Four hundred and ten patients will be randomised with a 1:1 ratio. The primary outcome is the duration of weaning from mechanical ventilation, defined as the number of days between randomisation and successful extubation (alive without reintubation nor tracheostomy within the 7 days after extubation) at day 28. Secondary outcomes include daily and cumulated fluid balance, metabolic and haemodynamic complications, ventilator-associated pneumonia, weaning complications, number of ventilator-free days, total duration of mechanical ventilation, the length of stay in ICU and mortality in ICU, in hospital and, at day 28. A subgroup analysis for the primary outcome is planned in patients with kidney injury (Kidney Disease: Improving Global Outcomes class 2 or more) at the time of randomisation.Ethics and disseminationThe study has been approved by the ethics committee (Comité de Protection des Personnes Paris 1) and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04050007.Protocol versionV.1; 12 March 2019.
(1) Background: In the quest to accurately model the radiolysis of water in its supercritical state, a detailed understanding of water’s molecular structure, particularly how water molecules are ...arranged in this unique state, is essential. (2) Methods: We conducted molecular dynamics simulations using the SPC/E water model to investigate the molecular structures of supercritical water (SCW) over a wide temperature range, extending up to 800 °C. (3) Results: Our results show that at a constant pressure of 25 MPa, the average intermolecular distance around a reference water molecule remains remarkably stable at ~2.9 Å. This uniformity persists across a substantial temperature range, demonstrating the unique heterogeneous nature of SCW under these extreme conditions. Notably, the simulations also reveal intricate patterns within SCW, indicating the simultaneous presence of regions with high and low density. As temperatures increase, we observe a rise in the formation of molecular clusters, which are accompanied by a reduction in their average size. (4) Conclusions: These findings highlight the necessity of incorporating the molecular complexity of SCW into traditional track-structure chemistry models to improve predictions of SCW behavior under ionizing radiation. The study establishes a foundational reference for further exploration of the properties of supercritical water, particularly for its application in advanced nuclear technologies, including the next generation of water-cooled reactors and their small modular reactor variants that utilize SCW as a coolant.
Background
Necrotizing skin and soft tissue infections (NSTIs) are rare but serious and rapidly progressive infections characterized by necrosis of subcutaneous tissue, fascia and even muscle. The ...care pathway of patients with NSTIs is poorly understood. A better characterization of the care trajectory of these patients and a better identification of patients at risk of a complicated evolution, requiring prolonged hospitalization, multiple surgical re-interventions, or readmission to the intensive care unit (ICU), is an essential prerequisite to improve their care. The main objective of this study is to obtain large-scale data on the care pathway of these patients. We performed a retrospective multicenter observational cohort study in 13 Great Paris area hospitals, including patients hospitalized between January 1, 2015 and December 31, 2019 in the ICU for surgically confirmed NSTIs.
Results
170 patients were included. The median duration of stay in ICU and hospital was 8 (3–17) and 37 (14–71) days, respectively. The median time from admission to first surgical debridement was 1 (0–2) day but 69.9% of patients were re-operated with a median of 1 (0–3) additional debridement. Inter-hospital transfer was necessary in 52.4% of patients. 80.2% of patients developed organ failures during the course of ICU stay with 51.8% of patients requiring invasive mechanical ventilation, 77.2% needing vasopressor support and 27.7% renal replacement therapy. In-ICU and in-hospital mortality rates were 21.8% and 28.8%, respectively. There was no significant difference between patients with abdomino-perineal NSTIs (
n
= 33) and others (
n
= 137) in terms of in-hospital or ICU mortality. Yet, immunocompromised patients (
n
= 43) showed significantly higher ICU and in-hospital mortality rates than non-immunocompromised patients (
n
= 127) (37.2% vs. 16.5%,
p
= 0.009, and 53.5% vs. 20.5%,
p
< 0.001). Factors associated with a complicated course were the presence of a polymicrobial infection (adjusted odds ratio aOR = 3.18 (1.37–7.35);
p
= 0.007, of a bacteremia aOR = 3.29 (1.14–9.52);
p
= 0.028 and a higher SAPS II score aOR = 1.05 (1.02–1.07);
p
< 0.0001. 62.3% of patients were re-hospitalized within 6 months.
Conclusion
In this retrospective multicenter study, we showed that patients with NSTI required complex management and are major consumers of care. Two-thirds of them underwent a complicated hospital course, associated with a higher SAPS II score, a polymicrobial NSTI and a bacteremia.
Interest is growing in the radiation science of supercritical water (SCW), yet how radiation energy is deposited still remains a question not well understood. To unveil the molecular structures of ...SCW, we carried out molecular dynamics simulations at 400 °C and different densities (0.17, 0.31, and 0.55 g cm
−3
). The results clearly show the heterogeneous character of these structures with coexisting high- and low-density regions. This water "clustering" behavior is consistent with observations in previous studies. It also supports the proposed role played by pre-existing polymeric clusters in the localization and hydration mechanisms of excess electrons in SCW. This underlying molecularity of SCW should be taken into account in track-structure chemistry models of SCW radiolysis.
Molecular dynamics simulations are used to examine the molecular microstructures and the "clustering" behavior of supercritical water at 400 °C and different densities.
The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in ...patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support.
DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948.
Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 15% of 414 in the remdesivir group vs 73 17% of 418 in the control group); (2) not hospitalised, limitation on activities (129 31% vs 132 32%); (3) hospitalised, not requiring supplemental oxygen (50 12% vs 29 7%); (4) hospitalised, requiring supplemental oxygen (76 18% vs 67 16%); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 4% vs 14 3%); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 15% vs 79 19%); (7) death (21 5% vs 24 6%). The difference between treatment groups was not significant (odds ratio 0·98 95% CI 0·77–1·25; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 33% of 406 vs control, 130 31% of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome).
No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support.
European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation.
For the French translation of the abstract see Supplementary Materials section.
Buschke-Löwenstein tumor is a giant condyloma acuminata infection that is characterized by degeneration, invasion, and recurrence. It is associated with human papilloma virus infection. It develops ...around the genital and perineal area, sometimes causing a large budding ulcerated lesion. Although human immunodeficiency virus infection is frequent in Africa, there are few descriptions of Buschke-Löwenstein tumor diagnosis and its management. Screening for other sexually transmitted infections must be systematic among these patients.
We report herein the case of a 21-year-old African origin male patient who developed a perineal swelling. Physical examination showed evidence of a huge exophytic tumor made up of budding pinkish vegetations, with serrated crests, a ''butterfly wing'' structure, and a cauliflower-like appearance crowned with centrifugal circinate lesions. Multiple condylomatous lesions of the anal margin were also present. The patient tested positive for human immunodeficiency virus (cluster of differentiation 4 count of 119 cells/mm
) and hepatitis B infections. Real-time polymerase chain reaction revealed human papilloma virus-16 and other high-risk human papilloma virus deoxyribonucleic acid. The diagnosis of Buschke-Löwenstein tumor was made on mass biopsy, and the patient underwent multidisciplinary intervention (surgery, podophyllin application, and antiretroviral therapy). Medium-term evolution was, however, fatal due to opportunistic infection.
Buschke-Löwenstein tumor is a rare tumor associated with human immunodeficiency virus infection. It is more frequent in male human immunodeficiency virus-positive patients. There is a need to screen for other sexually transmitted infections. In most cases, the treatment is surgical, in association with local therapies. However, recurrences are common.
Type 1 hepatorenal syndrome (HRS) is a severe complication of cirrhosis associated with a short median survival time (<2 weeks). Although the administration of terlipressin improves renal function, ...its effect on survival is unknown. This study investigated predictive factors of survival in patients with type 1 HRS treated with terlipressin.
Ninety-nine patients with type 1 HRS treated with terlipressin in 24 centers were retrospectively studied. Terlipressin-induced improved renal function was defined as a decrease in serum creatinine value to <130 μmol/L or a decrease of at least 20% at the end of treatment.
At inclusion, the Child-Pugh score was 11.8 ± 1.6 (mean ± SD). Terlipressin (3.2 ± 1.3 mg/day) was administered for 11 ± 12 days. Renal function improved in 58% of patients (serum creatinine decreased by 46% ± 17% from 272 ± 114 μmol/L). Median survival time was 21 days. Survival rate was 40% at 1 month. Multivariate analysis showed that improved renal function and Child-Pugh score <11 at inclusion were independent predictive factors of survival (P < 0.0001 and 0.02, respectively). Thirteen patients underwent liver transplantation (92 ± 95 days after HRS onset), 10 of whom had received terlipressin and had had improved renal function.
This retrospective uncontrolled study shows that in patients with type 1 HRS, terlipressin-induced improved renal function is associated with an increase in survival. Thus, a randomized trial investigating the effect of terlipressin on survival in patients with type 1 HRS should be performed.
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