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Abstract The bacterial Makes caterpillars floppy 1 (Mcf1) toxin promotes apoptosis in insects, leading to loss of body turgor and death. The molecular mechanism underlying Mcf1 intoxication is poorly understood. Here, we present the cryo-EM structure of Mcf1 from Photorhabdus luminescens, revealing a seahorse-like shape with a head and tail. While the three head domains contain two effectors, as well as an activator-binding domain (ABD) and an autoprotease, the tail consists of two putative translocation and three putative receptor-binding domains. Rearrangement of the tail moves the C-terminus away from the ABD and allows binding of the host cell ADP-ribosylation factor 3, inducing conformational changes that position the cleavage site closer to the protease. This distinct activation mechanism that is based on a hook-loop interaction results in three autocleavage reactions and the release of two toxic effectors. Unexpectedly, the BH3-like domain containing ABD is not an active effector. Our findings allow us to understand key steps of Mcf1 intoxication at the molecular level.

Introduction Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome.Methods and analysis Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial.Ethics and dissemination The trial was approved by the responsible ethics committee and by Germany’s Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany’s Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers.Trial registration number NCT06134492.

Introduction Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host–pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose–response trial is necessary to assess the potential harm of this drug in this new indication.Methods and analysis Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive.Ethics and dissemination The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals.Trial registration number NCT05033808.

Introduction Improving sustainable transportation options will help cities tackle growing challenges related to population health, congestion, climate change and inequity. Interventions supporting active transportation face many practical and political hurdles. Implementation science aims to understand how interventions or policies arise, how they can be translated to new contexts or scales and who benefits. Sustainable transportation interventions are complex, and existing implementation science frameworks may not be suitable. To apply and adapt implementation science for healthy cities, we have launched our mixed-methods research programme, CapaCITY/É. We aim to understand how, why and for whom sustainable transportation interventions are successful and when they are not.Methods and analysis Across nine Canadian municipalities and the State of Victoria (Australia), our research will focus on two types of sustainable transportation interventions: all ages and abilities bicycle networks and motor vehicle speed management interventions. We will (1) document the implementation process and outcomes of both types of sustainable transportation interventions; (2) examine equity, health and mobility impacts of these interventions; (3) advance implementation science by developing a novel sustainable transportation implementation science framework and (4) develop tools for scaling up and scaling out sustainable transportation interventions. Training activities will develop interdisciplinary scholars and practitioners able to work at the nexus of academia and sustainable cities.Ethics and dissemination This study received approval from the Simon Fraser University Office of Ethics Research (H22-03469). A Knowledge Mobilization Hub will coordinate dissemination of findings via a website; presentations to academic, community organisations and practitioner audiences; and through peer-reviewed articles.

Background Infective endocarditis represents a life‐threatening disease with high mortality rates. A fraction of patients receives exclusively conservative antibiotic treatment due to their comorbidities and high operative risk, despite fulfilling criteria for surgical therapy. The aim of the present study is to compare outcomes in patients with infective endocarditis and indication for surgical therapy in those who underwent or did not undergo valve surgery. Methods and Results Three databases were systematically assessed. A pooled analysis of Kaplan–Meier–derived reconstructed time‐to‐event data from studies with longer follow‐up comparing conservative and surgical treatment was performed. A landmark analysis to further elucidate the effect of surgical intervention on mortality was carried out. Four studies with 3003 patients and median follow‐up time of 7.6 months were included. Overall, patients with an indication for surgery who were surgically treated had a significantly lower risk of mortality compared with patients who received conservative treatment (hazard ratio [HR], 0.27 [95% CI, 0.24–0.31], P

Purpose Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models. Methods A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision. Results The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|.sub.median_all_models 45.1/67.5%; MAPE.sub.median_all_models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models. Conclusion The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM., Author(s): Sebastian Greppmair [sup.1], Alexander Brinkmann [sup.2], Anka Roehr [sup.3], Otto Frey [sup.3], Stefan Hagel [sup.4], Christoph Dorn [sup.5], Amélie Marsot [sup.6], Ibrahim El-Haffaf [sup.6], Michael Zoller [sup.1], Thomas Saller [...]

Traumatic brain injury (TBI), which is characterized by damage to the brain resulting from a sudden traumatic event, is a major cause of death and disability worldwide. It has short- and long-term effects, including neuroinflammation, cognitive deficits, and depression. TBI consists of multiple steps that may sometimes have opposing effects or mechanisms, making it challenging to investigate and translate new knowledge into effective therapies. In order to better understand and address the underlying mechanisms of TBI, we have developed an in vitro platform that allows dynamic simulation of TBI conditions by applying external magnetic forces to induce acceleration and deceleration injury, which is often observed in human TBI. Endothelial and neuron-like cells were successfully grown on magnetic gels and applied to the platform. Both cell types showed an instant response to the TBI model, but the endothelial cells were able to recover quickly?in contrast to the neuron-like cells. In conclusion, the presented in vitro model mimics the mechanical processes of acceleration/deceleration injury involved in TBI and will be a valuable resource for further research on brain injury.

Abstract Background Concerns regarding health equity (HE) and the built environment (BE) are well established in the Canadian urban context. Transport and injury prevention professionals across sectors, such as transportation and public health, are involved in designing and implementing BE interventions that enhance the safety of vulnerable road users (VRUs). Results from a larger study examining barriers and facilitators to BE change are used to illustrate how transport and injury prevention professionals perceive HE concerns in their work in five Canadian municipalities. Broadening our understanding of how HE influences the professional BE change context is crucial when advocating for modifications that enhance the safety of equity-deserving VRUs and groups who experience marginalization. Methods Interview and focus group data were gathered from transport and injury prevention professionals working in policy/decision-making, transport, police services, public health, non-profit organizations, schools/school boards, community associations, and private sectors across five Canadian urban municipalities: Vancouver, Calgary, Peel Region, Toronto, and Montréal. Data were analyzed using thematic analysis (TA) to illustrate how equity considerations were perceived and applied in participants’ BE change work. Results The results of this study illustrate transport and injury prevention professionals’ awareness of the varying needs of VRUs, as well as the inadequacies of current BEs in the Canadian urban context and consultation processes utilized to guide change. Participants emphasized the importance of equitable community consultation strategies, as well as specific BE changes that would support the health and safety of VRUs. Overall, the results highlight how HE concerns inform transport and injury prevention professionals’ BE change work in the Canadian urban context. Conclusion For professionals working in urban Canadian transport and injury prevention sectors HE concerns influenced their perspectives of the BE and BE change. These results illustrate a growing need for HE to guide BE change work and consultation processes. Further, these results contribute to ongoing efforts in the Canadian urban context to ensure that HE is at the forefront of BE policy change and decision-making, while promoting existing strategies to ensure that the BE, and related decision-making processes, are accessible and informed by a HE lens.

BackgroundFeasible estimations of perioperative changes in oxygen consumption (VO2) could enable larger studies of its role in postoperative outcomes. Current methods, either by reverse Fick calculations using pulmonary artery catheterisation or metabolic by breathing gas analysis, are often deemed too invasive or technically requiring. In addition, reverse Fick calculations report generally lower values of oxygen consumption.MethodsWe investigated the relationship between perioperative estimations of VO2 (EVO2), from LiDCO™plus-derived (LiDCO Ltd, Cambridge, UK) cardiac output and arterial-central venous oxygen content difference (Ca-cvO2), with indirect calorimetry (GVO2) by QuarkRMR (COSMED srl. Italy), using data collected 2017-2018 during a prospective observational study on perioperative oxygen transport in 20 patients >65 years during epidural and general anaesthesia for open pancreatic or liver resection surgery. Eighty-five simultaneous intra- and postoperative measurements at different perioperative stages were analysed for prediction, parallelity and by traditional agreement assessment.ResultsUnadjusted bias between GVO2 and EVO2 indexed for body surface area was 26 (95% CI 20 to 32) with limits of agreement (1.96SD) of -32 to 85 ml min-1m-2. Correlation adjusted for the bias was moderate, intraclass coefficient(A,1) 0.51(95% CI 0.34 to 0.65) [F (84,84) = 3.07, PConclusionBased on this data, estimations from LiDCO™plus-derived cardiac output and Ca-cvO2 are not reliable as a surrogate for perioperative VO2. Results were in line with previous studies comparing Fick-based and metabolic measurements but limited by variability of data and possible underpowering. The parallelity at different perioperative stages and the prediction model can provide useful guidance and methodological tools for future studies on similar methods in larger samples.

BackgroundPost-traumatic stress disorder (PTSD) and chronic pain are highly prevalent comorbid conditions. Veterans dually burdened by PTSD and chronic pain experience more severe outcomes compared to either disorder alone. Few studies have enrolled enough women Veterans to test gender differences in pain outcomes [catastrophizing, intensity, interference] by the severity of PTSD symptoms.AimExamine gender differences in the association between PTSD symptoms and pain outcomes among Veterans enrolled in a chronic pain clinical trial.MethodsParticipants were 421 men and 386 women Veterans with chronic pain who provided complete data on PTSD symptoms and pain outcomes. We used hierarchical linear regression models to examine gender differences in pain outcomes by PTSD symptoms.ResultsAdjusted multivariable models indicated that PTSD symptoms were associated with higher levels of pain catastrophizing (0.57, 95% CI [0.51, 0.63]), pain intensity (0.30, 95% CI [0.24, 0.37]), and pain interference (0.46, 95% CI [0.39, 0.52]). No evidence suggesting gender differences in this association were found in either the crude or adjusted models (all interaction p-valuesConclusionThese findings may reflect the underlying mutual maintenance of these conditions whereby the sensation of pain could trigger PTSD symptoms, particularly if the trauma and pain are associated with the same event. Clinical implications and opportunities testing relevant treatments that may benefit both chronic pain and PTSD are discussed.

In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.

This article analyzes how to create a city based on Smartseille, a real estate operation that is not attached to existing buildings and the first stone in the extension of Euroméditerranée in Marseille, in a context of large wastelands, in an impoverished neighborhood that is under-equipped. Labelled as an industrial demonstrator for the sustainable city, it is based on a requirement for innovation which the actors have seized as an opportunity for experimentation and the right to make mistakes. This project has become an "already there" in terms of new construction, and has notably contributed to the reference framework currently being developed by Euroméditerranée. Far from the initial idea of a model, its reproducibility moves away from copying and pasting and is built as much on the success of certain innovations as on what did not work. Smartseille is the result of an opportunity urbanism that combines the intentions of a promoter and a developer with the availability of land, and is slow to become part of the city. Behind the concepts, tools and constraints with which the actors deal, the analysis of this operation on which the rest of the project will be based questions the limits of the modes of production and what makes it possible to make a city.