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ImportanceBefore surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines.ObjectiveTo evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery.Design, setting, and participantsRandomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France.InterventionPatients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115).Main outcomes and measuresThe primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery.ResultsOf the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes.Conclusions and relevanceAmong patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy.Trial registrationClinicalTrials.gov Identifier: NCT03374449.

Julie Brault,1,2 Guillaume Vaganay,3 Aline Le Roy,4–6 Jean-Luc Lenormand,1 Sandra Cortes,3 Marie José Stasia1,2 1UMR CNRS 5525, University of Grenoble Alpes, Grenoble, France; 2CGD Diagnosis and Research Centre, University Hospital Centre of Grenoble Alpes, Grenoble, France; 3Synthelis SAS, La Tronche, France; 4IBS, University of Grenoble Alpes, Grenoble, France; 5CNRS, IBS, University Grenoble Alpes, Grenoble, France; 6CEA, IBS, University of Grenoble Alpes, Grenoble, France Abstract: Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency due to dysfunction of the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex leading to severe and recurrent infections in early childhood. The main genetic form is the X-linked CGD leading to the absence of cytochrome b558 composed of NOX2 and p22phox, the membrane partners of the NADPH oxidase complex. The first cause of death of CGD patients is pulmonary infections. Recombinant proteoliposome-based therapy is an emerging and innovative approach for membrane protein delivery, which could be an alternative local, targeted treatment to fight lung infections in CGD patients. We developed an enzyme therapy using recombinant NOX2/p22phox liposomes to supply the NADPH oxidase activity in X0-linked CGD (X0-CGD) macrophages. Using an optimized prokaryotic cell-free protein synthesis system, a recombinant cytochrome b558 containing functional hemes was produced and directly inserted into the lipid bilayer of specific liposomes. The size of the NOX2/p22phox liposomes was estimated to be around 700 nm. These proteoliposomes were able to generate reactive oxygen species (ROS) in an activated reconstituted cell-free NADPH oxidase activation assay in the presence of recombinant p47phox, p67phox and Rac, the cytosolic components of the NADPH oxidase complex. Furthermore, using flow cytometry and fluorescence microscopy, we demonstrated that cytochrome b558 was successfully delivered to the plasma membrane of X0-CGD-induced pluripotent stem cell (iPSC)-derived macrophages. In addition, NADPH oxidase activity was restored in X0-CGD iPSC-derived macrophages treated with NOX2/p22phox liposomes for 8 h without any toxicity. In conclusion, we confirmed that proteoliposomes provide a new promising technology for the delivery of functional proteins to the membrane of targeted cells. This efficient liposomal enzyme replacement therapy will be useful for future treatment of pulmonary infections in CGD patients refractory to conventional anti-infectious treatments. Keywords: protein therapy, proteoliposomes, chronic granulomatous disease, NADPH oxidase, induced pluripotent stem cells, macrophages

Abstract Preclinical mouse models are critical for understanding the pathophysiological response to infections and developing treatment strategies for sepsis. In keeping with ethical values, researchers follow guidelines to minimize the suffering of the mice. Weight loss is a criteria used as a humane end point, but there is no official recommendation for a maximum weight loss leading to euthanasia. To evaluate whether the thresholds used in daily practice are optimal, we performed a comprehensive retrospective analysis of data generated over 10 years with > 2300 mice used in models of infection with Listeria monocytogenes, Streptococcus pneumoniae, Candida albicans and H1N1 influenza virus. Weight loss segregated mice that survived from those that did not. Statistical analyses revealed that lowering the weight loss thresholds used (none, 30% or 20%) would have increased mortality rates due to the sacrifice of mice that survived infections (p

Since the beginning of the industrial revolution, atmospheric carbon dioxide (CO2) concentrations have risen steadily and have induced a decrease of the averaged surface ocean pH by 0.1 units, corresponding to an increase in ocean acidity of about 30 %. In addition to ocean warming, ocean acidification poses a tremendous challenge to some marine organisms, especially calcifiers. The need for long-term oceanic observations of pH and temperature is a key element to assess the vulnerability of marine communities and ecosystems to these pressures. Nearshore productive environments, where a large majority of shellfish farming activities are conducted, are known to present pH levels as well as amplitudes of daily and seasonal variations that are much larger than those observed in the open ocean. Yet, to date, there are very few coastal observation sites where these parameters are measured simultaneously and at high frequency. To bridge this gap, an observation network was initiated in 2021 in the framework of the CocoriCO2 project. Six sites were selected along the French Atlantic and Mediterranean coastlines based on their importance in terms of shellfish production and the presence of high- and low-frequency monitoring activities. At each site, autonomous pH sensors were deployed, both inside and outside shellfish production areas, next to high-frequency CTD (conductivity–temperature–depth) probes operated through two operating monitoring networks. pH sensors were set to an acquisition rate of 15 min, and discrete seawater samples were collected biweekly in order to control the quality of pH data (laboratory spectrophotometric measurements) as well as to measure total alkalinity and dissolved inorganic carbon concentrations for full characterization of the carbonate system. While this network has been up and running for more than 2 years, the acquired dataset has already revealed important differences in terms of pH variations between monitored sites related to the influence of diverse processes (freshwater inputs, tides, temperature, biological processes). Data are available at https://doi.org/10.17882/96982 (Petton et al., 2023a).

Summary: Background: In industrialized countries, the incidence of inflammatory bowel disease (IBD) appears stabilized. This study examined the incidence and phenotype of IBD in Northern France over a 30-year period. Methods: Including all IBD patients recorded in the EPIMAD population-based registry from 1988 to 2017 in Northern France, we described the incidence and clinical presentation of IBD according to age, sex and time. Findings: A total of 22,879 incident IBD cases were documented (59% (n = 13,445) of Crohn’s disease (CD), 38% (n = 8803) of ulcerative colitis (UC), 3% (n = 631) of IBD unclassified (IBDU)). Over the study period, incidence of IBD, CD and UC was 12.7, 7.2 and 5.1 per 105 person-years, respectively. The incidence of CD increased from 5.1/105 in 1988–1990 to 7.9/105 in 2015–2017 (annual percent change (APC): +1.9%, p

The intestinal microbiota is increasingly recognized as a crucial player in the development and maintenance of various chronic conditions, including obesity and associated metabolic diseases. While most research focuses on the fecal microbiota due to its easier accessibility, the small intestine, as a major site for nutrient sensing and absorption, warrants further investigation to determine its microbiota composition and functions. Here, we conducted a clinical research project in 30 age- and sex-matched participants with (n = 15) and without (n = 15) obesity. Duodenojejunal fluid was obtained by aspiration during endoscopy. Phenotyping included clinical variables related to metabolic status, lifestyle, and psychosocial factors using validated questionnaires. We performed metagenomic analyses of the oral, duodenojejunal, and fecal microbiome, alongside metabolomic data from duodenojejunal fluid and feces, integrating these data with clinical and lifestyle information. Our results highlight significant associations between duodenojejunal microbiota composition and usual dietary intake, as well as clinical phenotypes, with larger effect sizes than the associations between these variables and fecal microbiota. Notably, we found that the duodenojejunal microbiota of patients with obesity exhibited higher diversity and showed distinct differences in the abundance of several duodenojejunal microbiota species compared with individuals without obesity. Our findings support the relevance of studying the role of the small intestinal microbiota in the pathogenesis of nutrition-related diseases.

Magnetic polymer composites are very versatile candidates to fabricate soft robots and actuators thanks to their unique properties such as flexibility and shape memory effect. Thus, the possibility to reproduce natural shapes provides new tools for bioengineering applications. The wide panel of deformations of magnetic polymer composites can be implemented to mimic the movements and curvatures of living tissue. Herein, magnetic polymer membranes are developed to explore cell growth under curved, reversible, and controlled deformations. NdFeB/polydimethylsiloxane composite membranes (86 μm and 46 μm thick) are obtained by soft lithography and magnetized in rolled position under 3 T. Once actuated by a low magnetic field (5–86 mT), the membranes are deformed in wavy shapes with a deformation height of maximum 1.4 and 1.7 mm and a curvature radius of minimum 1.8 and 0.6 mm (86 μm and 46 μm thick membranes, respectively), for a maximum magnetic field of 86 mT. Then, Caco‐2 cell viability is studied on deformed substrates under a static (106 mT) and varying (8–78 mT) magnetic field. No increase in cell death is observed, validating a well‐characterized and promising approach for a new generation of dynamic and curved substrates for cell culture.

Abstract In flying animals, wing morphology is typically assumed to influence flight behaviours. Whether seasonal polymorphism in butterfly morphology is linked to adaptive flight behaviour remains unresolved. Here, we compare the flight behaviours and wing morphologies of the spring and summer forms of two closely related butterfly species, Pieris napi and P. rapae. We first quantify three‐dimensional flight behaviour by reconstructing individual flight trajectories using stereoscopic high‐speed videography in an experimental outdoor cage. We then measure wing size and shape, which are characteristics assumed to influence flight behaviours in butterflies. We show that seasonal, but not interspecific, differences in flight behaviour might be associated with divergent forewing shapes. During spring, Pieris individuals are small and have elongated forewings, and generally fly at low speed and acceleration, while having a high flight curvature. On the contrary, summer individuals are larger and exhibit rounded forewings. They fly at high speed and acceleration, while having high turning acceleration and advance ratio. Our study provides one of the first quantitative pieces of evidence of different flight behaviours between seasonal forms of two Pieris butterfly species. We discuss the possibility that this co‐divergence in flight behaviour and morphology is an adaptation to distinct seasonal environments. Properly identifying the mechanisms underpinning such divergence, nonetheless, requires further investigations to disentangle the interacting effects of microhabitats, predator community, parasitoid pressure and behavioural differences between sexes.

BackgroundWhen faced with a surge of physically injured individuals, especially following a traumatic event like an attack, frontline practitioners prioritize early triage. Detecting potential psychological injuries soon after such events remains challenging. Some individuals might develop post-traumatic stress disorder (PTSD) according to DSM-V criteria. Others may exhibit PTSD symptoms without meeting full diagnostic criteria, termed partial or sub-syndromal PTSD, a less-explored area in literature. This study aims to identify predictive factors for both full and partial PTSD.MethodIn a cohort of victims of the 2015 Paris attacks, multinomial logistic regressions explored predictive factors for partial or full PTSD status 8 to 18 months post-attacks. Analyses considered pre, peri, and posttraumatic factors chosen from literature review and univariate analysis within each group.ResultsWithin the cohort, 50 individuals showed no signs of PTSD, 35 experienced partial PTSD, and 30 presented with full PTSD. After logistic regression, risk factors associated with full PTSD included a history of trauma (OR = 1.30, CI [1.02-1.66], p < 0.05), the intensity of peri-traumatic physical reactions (OR = 1.22, CI [1.09-1.36], p < 0.001), the difficulties in suppressing intrusive thoughts (OR = 1.11, CI [1.02-1.21], p < 0.013). Only the intensity of peri-traumatic physical reactions emerged as a risk factor for partial PTSD (OR = 1.13, [CI 1.02-1.24], p < 0.001).DiscussionThis study revealed that a history of trauma, the intensity of peri-traumatic physical reactions (e.g., tachycardia, trembling, flushes, numbness.), and the difficulties in suppressing intrusive thoughts constitute risk factors for the development of full PTSD. Moreover, the study identified that only the intensity of peri-traumatic physical reactions emerged as a risk factor for partial PTSD. These findings seem to underscore the significance of peri-traumatic experiences in influencing the development of post-traumatic stress symptoms.ConclusionThis study emphasizes the significance of examining peri-traumatic reactions in PTSD development, suggesting its potential as a straightforward screening tool for post-traumatic stress disorder. It also underscores the influence of prior traumatic experiences, before de novo traumatization, in shaping vulnerability to PTSD and illuminates the crucial role of compromised control of intrusive thoughts that could perpetuate PTSD.

Abstract Patients with spinal cord injury (SCI) suffer from major bowel dysfunction, whose exact pathophysiology, particularly the involvement of the enteric nervous system or epithelial dysfunction is poorly understood. Herein, we aimed to characterize the mucosal biopsies of the right and left colon in SCI patients vs controls (CT): (1) remodeling of key enteric neurotransmitters, (2) remodeling of enteroendocrine cells, and (3) mucosal inflammation compared to those in controls. In SCI, mucosal ACh concentration was lower in the right colon as compared to CT, but no change was observed in the left colon, and AChE expression was lower in both the right and left colons than in CT. While the VIP concentration was similar in the right and left colons, VIP mRNA expression was increased in the right colon and decreased in the left colon, in SCI patients as compared to CT. Interestingly, 5-HT concentration was reduced in the left colon but not in the right colon in SCI patients. Moreover, in SCI patients, as compared to CT, SERT mRNA expression was selectively increased in the left colon while TPH1 mRNA expression was increased in the right and left colons. Although mucosal TNFα and IL-1β mRNA expression did not significantly differ between SCI and CT groups, we identified a significant positive correlation between TNFα and IL-1β mRNA expression and left colon transit time in the SCI group. In conclusion, region-specific changes occur in the enteric neurotransmitter, serotonergic, and inflammatory pathways in the colon of SCI patients. The significant correlations between these pathways and clinical parameters in the left colon further set a scientific basis for designing therapeutic targets to improve colonic motor dysfunction in patients. Biobank information: Spinal cord injury patients: PHRC ConstiCAPE—clinical trial NCT02566746. Controls: Anosain—clinical trial NCT03054415 and biobank of the “Institut des Maladies de l’Appareil Digestif (IMAD)” registered under number DC-2008-402.

(1) Background: 18F-FDG PET/CT diagnostic accuracy for liver metastasis (LM) could be influenced by technical parameters, lesion size, and the patient’s covariates. This retrospective study aimed to evaluate these covariates’ impact on PET/CT sensitivity. (2) Methods: Consecutive patients with suspected LMs who underwent 18F-FDG PET/CT scans were included. PET/CT scans were interpreted visually. The reference standard integrated histopathological and imaging follow-up. Logistic regression modeling and average marginal predictions were used to calculate per-lesion diagnostic performance measures with cluster robust 95% confidence intervals and to assess the covariates’ impact on PET/CT sensitivity. (3) Results: We included 192 patients with 330 lesions. 18F-FDG PET/CT exhibited a per-lesion sensitivity, specificity, positive predictive value, and negative predictive value of 86%, 79%, 91%, and 69%, respectively. In multivariate analysis, TOF PET/CT exhibited a higher sensitivity than non-TOF PET/CT (91% vs. 78%, p = 0.02). Sensitivity was reduced for lesions < 10 mm compared to larger lesions (56% vs. 93%, p < 0.001). A 5 kg/m2 increase in BMI led to an average 5% sensitivity reduction (p < 0.001). Age, sex, blood glucose level below 11 mmol/L, and liver density did not significantly impact sensitivity (p > 0.05). (4) Conclusions: 18F-FDG PET/CT sensitivity might be reduced with non-TOF PET, lesions < 10 mm, and higher BMI.

Locomotor and balance disorders are major limitations for subjects with hemiparesis. The Timed Up and Go (TUG) test is a complex navigational task involving oriented walking and obstacle circumvention. We hypothesized that subjects with hemiparesis adopt a cautious gait during complex locomotor tasks. The primary aim was to compare spatio-temporal gait parameters, indicators of cautious gait, between the locomotor subtasks of the TUG (Go, Turn, Return) and a Straight-line walk in people with hemiparesis. Our secondary aim was to analyze the relationships between TUG performance and balance measures, compare spatio-temporal gait parameters between fallers and non-fallers, and identify the biomechanical determinants of TUG performance. Biomechanical parameters during the TUG and Straight-line walk were analyzed using a motion capture system. A repeated measures ANOVA and two stepwise ascending multiple regressions (with performance variables and biomechanical variables) were conducted. Gait speed, step length, and % single support phase (SSP) of the 29 participants were reduced during Turn compared to Go and Return and the Straight-line walk, and step width and % double support phase were increased. TUG performance was related to several balance measures. Turn performance (R2 = 63%) and Turn trajectory deviation followed by % SSP on the paretic side and the vertical center of mass velocity during Go (R2 = 71%) determined TUG performance time. People with hemiparesis adopt a cautious gait during complex navigation at the expense of performance.