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Increasing numbers of pyelonephritis-associated uropathogenic Escherichia coli (UPEC) are exhibiting high resistance to antibiotic therapy. They include a particular clonal group, the CTX-M-15-producing O25b:H4-ST131 clone, which has been shown to have a high dissemination potential. Here we show that a representative isolate of this E. coli clone, referred to as TN03, has enhanced metabolic capacities, acts as a potent intestine- colonizing strain, and displays the typical features of UPEC strains. In a modified streptomycin-treated mouse model of intestinal colonization where streptomycin was stopped 5 days before inoculation, we show that TN03 outcompetes the commensal E. coli strains K-12 MG1655, IAI1, and ED1a at days 1 and 7. Using an experimental model of ascending UTI in C3H/HeN mice, we then show that TN03 colonized the urinary tract. One week after the transurethral inoculation of the TN03 isolates, the bacterial loads in the bladder and kidneys were significantly greater than those of two other UPEC strains (CFT073 and HT7) belonging to the same B2 phylogenetic group. The differences in bacterial loads did not seem to be directly linked to differences in the inflammatory response, since the intrarenal expression of chemokines and cytokines and the number of polymorphonuclear neutrophils attracted to the site of inflammation was the same in kidneys colonized by TN03, CFT073, or HT7. Lastly, we show that in vitro TN03 has a high maximum growth rate in both complex (Luria-Bertani and human urine) and minimum media. In conclusion, our findings indicate that TN03 is a potent UPEC strain that colonizes the intestinal tract and may persist in the kidneys of infected hosts.

Background Rapid diagnostic tests detecting microbial resistance are needed for limiting the duration of inappropriateness of empirical antimicrobial therapy (EAT) in intensive care unit patients, besides reducing the use of broad-spectrum antibiotics. We hypothesized that the betaLACTA® test (BLT) could lead to early increase in the adequacy of antimicrobial therapy. Methods This was a case-control study. Sixty-one patients with BLT-guided adaptation of EAT were prospectively included, and then matched with 61 “controls” having similar infection characteristics (community or hospital-acquired, and source of infection), in whom EAT was conventionally adapted to antibiogram results. Endpoints were to compare the proportion of appropriate (primary endpoint) and optimal (secondary endpoint) antimicrobial therapies with each of the two strategies, once microbiological sample culture results were available. Results Characteristics of patients, infections and EAT at inclusion were similar between groups. Nine early escalations of EAT occurred in the BLT-guided adaptation group, reaching 98% appropriateness vs. 77% in the conventional adaptation group ( p  < 0.01). The BLT reduced the time until escalation of an inappropriate EAT from 50.5 (48–73) to 27 (24–28) hours ( p  < 0.01). Seventeen early de-escalations occurred in the BLT-guided adaptation group, compared to one in the conventional adaptation group, reducing patients’ exposure to broad-spectrum beta-lactam such as carbapenems. In multivariate analysis, use of the BLT was strongly associated with early appropriate (OR = 18 (3.4–333.8), p  = 0.006) and optimal (OR = 35.5 (9.6–231.9), p  < 0.001) antimicrobial therapies. Safety parameters were similar between groups. Conclusions Our study suggests that a BLT-guided adaptation strategy may allow early beta-lactam adaptation from the first 24 hours following the beginning of sepsis management.

Background There is an unresolved debate on the best screening method for hematuria as a symptom of glomerulonephritis or urological malignancies. The urinary dipstick is generally considered as an imperfect surrogate for urine microscopy analysis. Results We designed a study to compare urine microscopy analysis, urinary dipstick and flow cytometry, using controlled dilutions of blood in urine samples from volunteers collected in two different physiologically-relevant conditions (basal state and hyperhydration). We found that although all techniques were 100 % effective in detecting hematuria at basal state, these results were variably reproduced when testing the same final amount of hematuria in urine collected after hyperhydration. Our data shows a variable sensitivity for the detection of hematuria by urine microscopy analysis or flow cytometry, but not by urinary dipstick. Conclusions Urinary dipstick qualifies as a better screening test for hematuria than urine microscopy analysis or flow cytometry, as it is sensitive and performs better in unstandardized conditions. It is universally available and also faster and cheaper than cytometric techniques.

Summary Uropathogenic Escherichia coli (UPEC) colonizing kidneys is the main cause of acute pyelonephritis. TLR5 that senses flagellin was shown to be highly expressed in the bladder and to participate in host defence against flagellated UPEC, although its role in kidneys still remains elusive. Here we show that TLR5 is expressed in renal medullary collecting duct (MCD) cells, which represent a preferential site of UPEC adhesion. Flagellin, like lipopolysaccharide, stimulated the production of the chemoattractant chemokines CXCL1 and CXCL2, and subsequent migration capacity of neutrophils in cultured wild‐type (WT) and Tlr4−/− MCDs, but not in Tlr5−/− MCDs. UPEC can translocate across intact MCD layers without altering tight junctions. Strikingly, the invasion capacity and transcellular translocation of the UPEC strain HT7 were significantly lower in Tlr5−/− than in WT MCDs. The non‐motile HT7ΔfliC mutant lacking flagellin also exhibited much lower translocation capacities than the HT7 isolates. Finally, Tlr5−/− kidneys exhibited less infiltrating neutrophils than WT kidneys one day after the transurethral inoculation of HT7, and greater delayed renal bacterial loads in the day 4 post‐infected Tlr5−/− kidneys. Overall, these findings indicate that the epithelial TLR5 participates to renal antibacterial defence, but paradoxically favours the translocation of UPEC across intact MCD cell layers.

IntroductionThe dramatic increase of the incidence of infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has led to an increase of 50% of carbapenem consumption all around Europe in only 5 years. This favours the spread of carbapenem-resistant Gram-negative bacilli (GNB), causing life-threatening infections. In order to limit use of carbapenems for infections actually due to ESBL-PE, health authorities promote the use of rapid diagnostic tests of bacterial resistance. The objective of this work conducted in the intensive care unit (ICU) is to determine whether an early de-escalation of empirical carbapenems guided by the result of the βLACTA test is not inferior to the reference strategy of de-escalating carbapenems after the antibiogram result has been rendered.Methods and analysisThis multicentre randomised controlled open-label non-inferiority clinical trial will include patients suffering from respiratory and/or urinary and/or bloodstream infections documented with GNB on direct examination and empirically treated with carbapenems. Empirical carbapenems will be adapted before the second dose depending on the results of the βLACTA test performed directly on the microbiological sample (intervention group) or after 48–72 hours depending on the definite antibiogram (control group). The primary outcome will combine 90-day mortality and percentage of infection recurrence during the ICU stay. The secondary outcomes will include the number of carbapenems defined daily doses and carbapenem-free days after inclusion, the proportion of new infections during ICU stay, new colonisation of patients’ digestive tractus with multidrug-resistant GNB, ICU and hospital length of stay and cost-effectiveness ratio.Ethics and disseminationThis protocol has been approved by the ethics committee of Paris-Ile-de-France IV, and will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals.Trial registration number NCT03147807.

This study focuses on the relationship in global climate models between three features: the Saharan Heat Low (SHL), Sahel precipitation, and the Atlantic Intertropical Convergence Zone (ITCZ). Previous work showed that both coupled (CMIP) and uncoupled (AMIP) ocean/atmosphere models that place the SHL farther to the north are associated with increased precipitation across the Sahel. Further, the northward SHL placement is also associated with a northward shift in the Atlantic ITCZ in coupled CMIP models, but an eastward shift in uncoupled AMIP models. We perform three experiments with the Community Earth System Model to better understand relationships between these features. We find that when a northward-shifted Atlantic ITCZ is locally forced, there is no coherent response in the SHL and Sahel precipitation. However, when a northward-shifted Atlantic ITCZ is forced by altering the cross equatorial energy transport, the SHL shifts northward and Sahel precipitation increases, consistent with model biases. Finally, when the SHL strength is forced directly, there is a weak but robust increase in Sahel precipitation and a northward shift in the Atlantic ITCZ. The results of these experiments emphasize the important role of global scale energy biases on the simulation of West African climate, and show a possible feedback from West African climate onto the Atlantic ITCZ.

Representing the West African monsoon (WAM) is a major challenge in climate modeling because of the complex interaction between local and large-scale mechanisms. This study focuses on the representation of a key aspect of West African climate, namely the Saharan heat low (SHL), in 22 global climate models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) multimodel dataset. Comparison of the CMIP5 simulations with reanalyses shows large biases in the strength and location of the mean SHL. CMIP5 models tend to develop weaker climatological heat lows than the reanalyses and place them too far southwest. Models that place the climatological heat low farther to the north produce more mean precipitation across the Sahel, while models that place the heat low farther to the east produce stronger African easterly wave (AEW) activity. These mean-state biases are seen in model ensembles with both coupled and fixed sea surface temperatures (SSTs). The importance of SSTs on West African climate variability is well documented, but this research suggests SSTs are secondary to atmospheric biases for understanding the climatological SHL bias. SHL biases are correlated across the models to local radiative terms, large-scale tropical precipitation, and large-scale pressure and wind across the Atlantic, suggesting that local mechanisms that control the SHL may be connected to climate model biases at a much larger scale.

In situ carbonyl sulfide (OCS) measurements from the Stratospheric Aerosol processes, Budget and Radiative Effects (SABRE) 2023 airborne campaign are used to evaluate the sulfate budget in the Arctic stratosphere during boreal winter. The strong correspondence between these measurements and remote retrievals from the Atmospheric Chemistry Experiment–Fourier Transform Spectrometer provide robust validation of the satellite's capability to monitor stratospheric OCS globally. We demonstrate how trends in the tropical tropopause layer and National Oceanic and Atmospheric Administration OCS surface data reveal a post‐2016 ∼8% global decline in OCS abundance, which is absent from many global climate models. New simulations with a revised planetary boundary layer OCS abundance show improved agreement with remote retrievals and in situ data across multiple stratospheric layers, but remaining model biases highlight the need for additional in situ OCS observations. The revised representation reduces the stratospheric sulfate burden, resulting in an increased shortwave solar flux at the tropical tropopause by as much as 0.3 Wm−2 locally, with implications for stratospheric circulation, radiative forcing, and climate feedbacks.

Objective Prognostic models in patients living with diabetes allow physicians to estimate individual risk based on medical records and biological results. Clinical risk factors are not always all available to evaluate these models so that they may be complemented with models from claims databases. The objective of this study was to develop, validate and compare models predicting the annual risk of severe complications and mortality in patients living with type 2 diabetes (T2D) from a national claims data. Research design and methods Adult patients with T2D were identified in a national medical claims database through their history of treatments or hospitalizations. Prognostic models were developed using logistic regression (LR), random forest (RF) and neural network (NN) to predict annual risk of outcome: severe cardiovascular (CV) complications, other severe T2D-related complications, and all-cause mortality. Risk factors included demographics, comorbidities, the adjusted Diabetes Severity and Comorbidity Index (aDSCI) and diabetes medications. Model performance was assessed using discrimination (C-statistics), balanced accuracy, sensibility and specificity. Results A total of 22,708 patients with T2D were identified, with mean age of 68 years and average duration of T2D of 9.7 years. Age, aDSCI, disease duration, diabetes medications and chronic cardiovascular disease were the most important predictors for all outcomes. Discrimination with C-statistic ranged from 0.715 to 0.786 for severe CV complications, from 0.670 to 0.847 for other severe complications and from 0.814 to 0.860 for all-cause mortality, with RF having consistently the highest discrimination. Conclusion The proposed models reliably predict severe complications and mortality in patients with T2D, without requiring medical records or biological measures. These predictions could be used by payers to alert primary care providers and high-risk patients living with T2D.