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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.

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

Carbapenemase-producing Enterobacterales (CPEs) pose a considerable threat to public health because of antimicrobial resistance. In France, the most prevalent carbapenemases are OXA-48-like type. More than 55 variants of OXA-48-like enzymes [...]

The Enterobacter cloacae complex (ECC) is highly diverse; its many species and subspecies can be distinguished by using phenotypic methods or matrix-assisted laser desorption/ionization time-offlight mass spectrometry. Whole-genome sequencing enables [...]

Abstract Commensal Neisseria (Nc) mainly occupy the oropharynx of humans and animals. These organisms do not typically cause disease; however, they can act as a reservoir for antimicrobial resistance genes that can be acquired by pathogenic Neisseria species. This study characterised the carriage and antimicrobial susceptibility profiles of Nc from the oropharynx of 50 participants. Carriage prevalence of Nc species was 86% with 66% of participants colonised with more than one isolate. Isolates were identified by MALDI-ToF and the most common species was N. subflava (61.4%). Minimum inhibitory concentrations (MICs) to penicillin, ceftriaxone, ciprofloxacin, azithromycin, tetracycline, and gentamicin were determined by agar dilution and E-test was used for cefixime. Using Ng CLSI/EUCAST guidelines, Nc resistance rates were above the WHO threshold of 5% resistance in circulating strains for changing the first line treatment empirical antimicrobial: 5% (CLSI) and 13 (EUCAST) for ceftriaxone and 29.3% for azithromycin. Whole genome sequencing of 30 Nc isolates was performed, which identified AMR genes to macrolides and tetracycline. Core gene MLST clustered Nc into three main groups. Gonococcal DNA uptake sequences were identified in two Nc clusters. This suggests that Nc have the potential AMR gene pool and transfer sequences that can result in resistance transfer to pathogenic Neisseria within the nasopharyngeal niche.

We examined the emergence and characteristics of oxacillinase-484–producing Enterobacterales in France during 2012–2023. Genomic analysis identified 2 predominant sequence types in Escherichia coli: ST410 and ST1722. Plasmid analysis revealed that blaOXA-484 genes were carried mostly on an IncX3-type plasmid associated with genetic elements including insertion sequences IS3000 and ISKpn19.

Background: Rooms illuminated by “black light” (

Abstract The auditory ossicles amplify and transmit sound from the environment to the inner ear. The distribution of bone mineral density is crucial for the proper functioning of sound transmission as the ossicles are suspended in an air-filled chamber. However, little is known about the distribution of bone mineral density along the human ossicular chain and within individual ossicles. To investigate this, we analyzed fresh-frozen human specimens using synchrotron-based phase-contrast microtomography. In addition, we analyzed the volume and porosity of the ossicles. The porosity for the auditory ossicles lies, on average, between 1.92% and 9.85%. The average volume for the mallei is 13.85 ± 2.15 mm3, for the incudes 17.62 ± 4.05 mm3 and 1.24 ± 0.29 mm3 for the stapedes. The bone density distribution showed a similar pattern through all samples. In particular, we found high bone mineralization spots on the anterior crus of the stapes, its footplate, and along areas that are crucial for the transmission of sound. We could also see a correlation between low bone mineral density and holey areas where the bone is only very thin or missing. Our study identified a similar pattern of bone density distribution within all samples: regions exposed to lower forces generally show higher bone density. Further, we observed that the stapes shows high bone mineral density along the anterior crus and its footplate, which may indicate its importance in transmitting sound waves to the inner ear.

Abstract Documenting the organization of the retinal capillaries is of importance to understand the visual consequences of vascular diseases which may differentially affect the microvascular layers. Here we detailed the spatial organization of the macular capillaries in ten healthy human subjects using a prototypic adaptive optics-enhanced optical coherence tomography angiography (AO-OCTA) system. Within the central 6° × 6°, the radial peripapillary capillaries and the superficial, intermediate and deep vascular plexuses (SVP, IVP and DVP, respectively) were consistently resolved. In 8 out of the 10 eyes, the capillary segments composing the perifoveal arcade (PFA) were perfused only by the SVP, while drainage of the PFA showed more variability, comprising a case in which the PFA was drained by the DVP. Around the center, a distinct central avascular zone could be documented for each layer in 7 of the 10 cases; in three eyes, the IVP and SVP merged tangentially around the center. In all eyes, the foveal avascular zone was larger in the DVP than in the SVP and IVP. In one eye with incomplete separation of the inner foveal layers, there was continuity of both the SVP and the IVP; a central avascular zone was only present in the DVP. The diversity of perfusion and drainage patterns supported a connectivity scheme combining parallel and serial organizations, the latter being the most commonly observed in perifoveal vessels. Our results thus help to further characterize the diversity of organization patterns of the macular capillaries and to robustly analyze the IVP, which will help to characterize early stages of microvascular diseases.

Abstract This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices.

Poplar plantations cover 31.4 million ha around the world and supply timber for paper, sawn wood and other wood-based products. In each region where poplars are planted, it is possible to identify “model clones” which are massively adopted by foresters. Improving the rationale of clone selection in breeding programs requires a comprehensive understanding of the physiological traits that explain the differences in genotypes growth. Moreover, given that growth is related to the use of resources (water, light and nutrients) we also need to determine which morphological and physiological traits explain the model condition of most widespread clones. A controlled-condition study was carried out to evaluate eight Populus deltoides and two Populus × canadensis clones, including the model Populus deltoides €˜Australiano 129/60’. For each clone, physiological and morphological traits related to biomass partitioning (roots, stem and leaf dry mass), growth (height, diameter), light use (leaf area duration, leaf size, net photosynthetic rate), water use (stem hydraulic conductivity, water consumption) and nutrient use (nitrogen and phosphorus concentrations) were measured. High variability in the physiology and morphology was observed among clones, and similar and contrasting clones in relation to the model clone were identified. Similarities among clones varied depending on the characteristic being evaluated at the time-water use, light use or nutrient use. The results showed that variability not only relates to visible phenotype, but also to functionality. This information is significant since the breeding programs can evaluate non-traditional traits and select genotypes which are similar or complementary to the model clone. The characterization of model clones is key for breeding programs which seek new candidates taking into account the use of water, nutrients and light. It is also important because it helps explain why foresters prefer one clone over others. Knowledge about functional variability within clones of the same species enables foresters to conduct more intelligent and site-specific silviculture and to optimize the genotype selection in breeding programs.

We characterized a collection of IMI-like–producing Enterobacter spp. isolates (n = 112) in France. The main clone corresponded to IMI-1–producing sequence type 820 E. cloacae subspecies cloacae that was involved in an outbreak. Clinicians should be aware of potential antimicrobial resistance among these bacteria.

IntroductionCitrus is an important fruit crop for human health. The sensitivity of citrus trees to a wide range of abiotic stresses is a major challenge for their overall growth and productivity. Among these abiotic stresses, salinity results in a significant loss of global citrus yield. In order to find straightforward and sustainable solutions for the future and to ensure citrus productivity, it is of paramount importance to decipher the mechanisms responsible for salinity stress tolerance. Thisstudy aimed to investigate how ploidy levels influence salt stress tolerance in citrus by comparing the transcriptomic responses of diploid and tetraploid genotypes. In a previous article we investigated the physiological and biochemical response of four genotypes with different ploidy levels: diploid trifoliate orange (Poncirus trifoliata [L.] Raf.) (PO2x) and Cleopatra mandarin (Citrus reshni Hort. Ex Tan.) (CL2x) and their respective tetraploids (PO4x, CL4x).MethodsIn this study, we useda multifactorial gene selection and gene clustering approach to finely dissect the influence of ploidy level on the salt stress response of each genotype. Following transcriptome sequencing, differentially expressed genes (DEGs) were identified in response to salt stress in leaves and roots of the different citrus genotypes.Result and discussionGene expression profiles and functional characterization of genes involved in the response to salt stress, as a function of ploidy level and the interaction between stress response and ploidy level, have enabled us to highlight the mechanisms involved in the varieties tested. Saltstress induced overexpression of carbohydrate biosynthesis and cell wall remodelling- related genes specifically in CL4x Ploidy level enhanced oxidative stress response in PO and ion management capacity in both genotypes. Results further highlighted that under stress conditions, only the CL4x genotype up- regulated genes involved in sugar biosynthesis, transport management, cell wall remodelling, hormone signalling, enzyme regulation and antioxidant metabolism. These findings provide crucial insights that could inform breeding strategies for developing salt-tolerant citrus varieties.

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AimsThe once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period.MethodsA total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24 h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5.ResultsA two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit–blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60 years and younger.ConclusionThe 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60 years or younger would be highest, while CYP3A5*/1 non-carriers older than 60 years would require the lowest doses.