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Abstract Wind turbines used to combat climate change pose a green-green dilemma when endangered and protected wildlife species are killed by collisions with rotating blades. Here, we investigated the geographic origin of bats killed by wind turbines along an east-west transect in France to determine the spatial extent of this conflict in Western Europe. We analysed stable hydrogen isotopes in the fur keratin of 60 common noctule bats ( Nyctalus noctula ) killed by wind turbines during summer migration in four regions of France to predict their geographic origin using models based on precipitation isoscapes. We first separated migratory from regional individuals based on fur isotope ratios of local bats. Across all regions, 71.7% of common noctules killed by turbines were of regional and 28.3% of distant origin, the latter being predominantly females from northeastern Europe. We observed a higher proportion of migratory individuals from western sites compared to eastern sites. Our study suggests that wind-turbine-related losses of common noctule bats may impact distant breeding populations across whole Europe, confirming that migratory bats are highly vulnerable to wind turbines and that effective conservation measures, such as temporary curtailment of turbine operation, should be mandatory to protect them from colliding with the rotating blades of wind turbines.

Introduction: Broad-spectrum beta-lactams are commonly prescribed for empirical or selective treatment of bacterial infections in children with malignancies. In the immunocompromised, appropriate concentration exposure is crucial to ensure antimicrobial efficacy. Augmented renal clearance (ARC) is increasingly recognized in this population, and raises concern for unmet concentration targets. We conducted a retrospective evaluation of meropenem and piperacillin exposure in our hospital's pediatric hematology-oncology patients.Materials and Methods: We compared trough levels of meropenem and piperacillin in a cohort of unselected pediatric hematology-oncology patients stratified based on their estimated renal function as decreased, normal or with ARC, and on their neutrophil count.Results: Thirty-two children provided a total of 51 meropenem and 76 piperacillin samples. On standard intermittent intravenous regimen, 67% of all trough plasma concentrations were below targeted concentrations. In neutropenic children with bacterial infection, all meropenem and 60% of piperacillin levels were below target. Nearly two-thirds of total samples came from children with ARC. In these patients, antimicrobial exposure was insufficient in 85% of cases (compared to 36% in the decreased or normal renal function groups), despite a dosage sometimes exceeding the maximum recommended daily dose. Under continuous infusion of piperacillin, only 8% of plasma levels were insufficient.Discussion: Intermittent administration of meropenem and piperacillin often fails to ensure sufficient concentration exposure in children treated for malignancies, even at maximal recommended daily dosage. This can in part be attributed to ARC. We recommend thorough assessment of renal function, resolute dosage adjustment, continuous infusion whenever possible and systematic therapeutic drug monitoring.

Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic–pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils’ time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies.

Abstract Background Monitoring the impact of case management strategies at large scale is essential to evaluate the public health benefit they confer. The use of methodologies relying on objective and standardized endpoints, such as drug levels in the blood, should be encouraged. Population drug use, diagnosis and treatment appropriateness in case of fever according to patient history and anti-malarials blood concentration was evaluated. Methods A cross-sectional survey took place between May and August 2015 in three regions of Tanzania with different levels of malaria endemicity. Interviews were conducted and blood samples were collected by dried blood spots through household surveys for further anti-malarial measurements. Appropriate testing when individuals attended care was defined as a patient with history of fever being tested for malaria and appropriate treatment as (i) having anti-malarial in the blood if the test result was positive (ii) having anti-malarial in the blood if the person was not tested, and (iii) no anti-malarial in the blood when the test result was negative. Results Amongst 6391 participants included in the anti-malarial analysis, 20.8% (1330/6391) had anti-malarial drug detected in the blood. Only 28.0% (372/1330) of the individuals with anti-malarials in their blood reported the use of anti-malarials within the previous month. Amongst all participants, 16.0% (1021/6391) reported having had a fever in the previous 2 weeks and 37.5% of them (383/1021) had detectable levels of anti-malarials in the blood. Of the individuals who sought care in health facilities, 69.4% (172/248) were tested and 52.0% (129/248) appropriately treated. When other providers were sought, 6% (23/382) of the persons were appropriately tested and 44.2% (169/382) appropriately treated. Overall, the proportion of individuals treated was larger than that being tested [47.3% (298/630) treated, 31.0% (195/630) tested]. Conclusion This study showed high prevalence of circulating anti-malarial drug in the sampled population. Efforts should be made to increase rapid diagnostic tests use at all levels of health care and improve compliance to test result in order to target febrile patients that are sick with malaria and reduce drug pressure. Objective drug measurements collected at community level represent a reliable tool to evaluate overall impact of case management strategies on population drug pressure.

Bats are a reservoir for a diverse range of viruses, including coronaviruses (CoVs). To determine the presence of CoVs in French bats, fecal samples were collected between July and August of 2014 from four bat species in seven different locations around the city of Bourges in France. We present for the first time the presence of alpha-CoVs in French Pipistrellus pipistrellus bat species with an estimated prevalence of 4.2%. Based on the analysis of a fragment of the RNA-dependent RNA polymerase (RdRp) gene, phylogenetic analyses show that alpha-CoVs sequences detected in French bats are closely related to other European bat alpha-CoVs. Phylogeographic analyses of RdRp sequences show that several CoVs strains circulate in European bats: (i) old strains detected that have probably diverged a long time ago and are detected in different bat subspecies; (ii) strains detected in Myotis and Pipistrellus bat species that have more recently diverged. Our findings support previous observations describing the complexity of the detected CoVs in bats worldwide.

BACKGROUND:Understanding pattern of antimalarials use at large scale helps ensuring appropriate use of treatments and preventing the spread of resistant parasites. We estimated the proportion of individuals in community surveys with residual antimalarials in their blood and identified the factors associated with the presence of the most commonly detected drugs, lumefantrine and/or desbutyl-lumefantrine (LF/DLF) or sulfadoxine-pyrimethamine (SP). METHODS:A cross-sectional survey was conducted in 2015 in three regions of Tanzania with different levels of malaria endemicity. Interviews were conducted and blood samples collected through household surveys for further antimalarial measurements using liquid chromatography coupled to tandem mass spectrometry. In addition, diagnosis and treatment availability was investigated through outlet surveys. Multilevel mixed effects logistic regression models were used to estimate odds ratios for having LF/DLF or SP in the blood. RESULTS:Amongst 6391 participants, 12.4% (792/6391) had LF/DLF and 8.0% (510/6391) SP in the blood. Factors associated with higher odds of detecting LF/DLF in the blood included fever in the previous two weeks (OR = 2.6, p

Since bat rabies surveillance was first implemented in France in 1989, 48 autochthonous rabies cases without human contamination have been reported using routine diagnosis methods. In this retrospective study, data on bats submitted for rabies testing were analysed in order to better understand the epidemiology of EBLV-1 in bats in France and to investigate some epidemiological trends. Of the 3176 bats submitted for rabies diagnosis from 1989 to 2013, 1.96% (48/2447 analysed) were diagnosed positive. Among the twelve recognised virus species within the Lyssavirus genus, two species were isolated in France. 47 positive bats were morphologically identified as Eptesicus serotinus and were shown to be infected by both the EBLV-1a and the EBLV-1b lineages. Isolation of BBLV in Myotis nattereri was reported once in the north-east of France in 2012. The phylogenetic characterisation of all 47 French EBLV-1 isolates sampled between 1989 and 2013 and the French BBLV sample against 21 referenced partial nucleoprotein sequences confirmed the low genetic diversity of EBLV-1 despite its extensive geographical range. Statistical analysis performed on the serotine bat data collected from 1989 to 2013 showed seasonal variation of rabies occurrence with a significantly higher proportion of positive samples detected during the autumn compared to the spring and the summer period (34% of positive bats detected in autumn, 15% in summer, 13% in spring and 12% in winter). In this study, we have provided the details of the geographical distribution of EBLV-1a in the south-west of France and the north-south division of EBLV-1b with its subdivisions into three phylogenetic groups: group B1 in the north-west, group B2 in the centre and group B3 in the north-east of France.

BACKGROUND:Repeated antimalarial treatment for febrile episodes and self-treatment are common in malaria-endemic areas. The intake of antimalarials prior to participating in an in vivo study may alter treatment outcome and affect the interpretation of both efficacy and safety outcomes. We report the findings from baseline plasma sampling of malaria patients prior to inclusion into an in vivo study in Tanzania and discuss the implications of residual concentrations of antimalarials in this setting. METHODS AND FINDINGS:In an in vivo study conducted in a rural area of Tanzania in 2008, baseline plasma samples from patients reporting no antimalarial intake within the last 28 days were screened for the presence of 14 antimalarials (parent drugs or metabolites) using liquid chromatography-tandem mass spectrometry. Among the 148 patients enrolled, 110 (74.3%) had at least one antimalarial in their plasma: 80 (54.1%) had lumefantrine above the lower limit of calibration (LLC = 4 ng/mL), 7 (4.7%) desbutyl-lumefantrine (4 ng/mL), 77 (52.0%) sulfadoxine (0.5 ng/mL), 15 (10.1%) pyrimethamine (0.5 ng/mL), 16 (10.8%) quinine (2.5 ng/mL) and none chloroquine (2.5 ng/mL). CONCLUSIONS:The proportion of patients with detectable antimalarial drug levels prior to enrollment into the study is worrying. Indeed artemether-lumefantrine was supposed to be available only at government health facilities. Although sulfadoxine-pyrimethamine is only recommended for intermittent preventive treatment in pregnancy (IPTp), it was still widely used in public and private health facilities and sold in drug shops. Self-reporting of previous drug intake is unreliable and thus screening for the presence of antimalarial drug levels should be considered in future in vivo studies to allow for accurate assessment of treatment outcome. Furthermore, persisting sub-therapeutic drug levels of antimalarials in a population could promote the spread of drug resistance. The knowledge on drug pressure in a given population is important to monitor standard treatment policy implementation.

Background Invasive fungal infections (IFIs) are severe and difficult-to-treat infections affecting immunocompromised patients. Antifungal drug penetration at the site of infection is critical for outcome and may be difficult to achieve. Data about antifungal drug distribution in infected human tissues under real circumstances of IFI are scarce. Methods Multiple samples were obtained from soft tissue abscesses of a lung transplant patient with Candida albicans invasive candidiasis who underwent recurrent procedures of drainage, while receiving different consecutive courses of antifungal therapy [itraconazole (ITC), fluconazole, caspofungin]. Antifungal drug concentrations were measured simultaneously at the site of infection (surrounding inflammatory tissue and fluid content of the abscess) and in plasma for calculation of the tissue/plasma ratio (R). The concentration within the infected tissue was interpreted as appropriate if it was equal or superior to the MIC of the causal pathogen. Results A total of 30 tissue samples were collected for measurements of ITC (n  = 12), fluconazole (n  = 17) and caspofungin (n  = 1). Variable concentrations were observed in the surrounding tissue of the lesions with median R of 2.79 (range 0.51–15.9) for ITC and 0.94 (0.21–1.37) for fluconazole. Concentrations ranges within the fluid content of the abscesses were 0.39–1.83 for ITC, 0.66–1.02 for fluconazole and 0.23 (single value) for caspofungin. The pharmacodynamic target (tissue concentration ≥ MIC) was achieved in all samples for all three antifungal drugs. Conclusions This unique dataset of antifungal drug penetration in infected human soft tissue abscesses suggests that ITC, fluconazole and caspofungin could achieve appropriate concentrations in soft tissue abscesses. [ABSTRACT FROM AUTHOR]

To fill the need for environmentally sensitive fluorescent unnatural amino acids able to operate in the red region of the spectrum, we have designed and synthesized Alared, a red solvatochromic and fluorogenic amino acid derived from the Nile Red chromophore. The new unnatural amino acid can be easily integrated into bioactive peptides using classical solid‐phase peptide synthesis. The fluorescence quantum yield and the emission maximum of Alared‐labeled peptides vary in a broad range depending on the peptide's environment, making Alared a powerful reporter of biomolecular interactions. Due to its red‐shifted absorption and emission spectra, Alared‐labeled peptides could be followed in living cells with minimal interference from cellular autofluorescence. Using ratiometric fluorescence microscopy, we were able to track the fate of the Alared‐labeled peptide agonists of the apelin G protein‐coupled receptor upon receptor activation and internalization. Due to its color‐shifting environmentally sensitive emission, Alared allowed for distinguishing the fractions of peptides that are specifically bound to the receptor or unspecifically bound to different cellular membranes. [ABSTRACT FROM AUTHOR]

Little information on the efficacy and pharmacokinetics of letermovir among immunocompromised children is currently available. We describe here the use of letermovir in a 2-year-old immunocompromised child with ganciclovir-resistant cytomegalovirus disease who required extracorporeal membrane oxygenation. Detailed information on therapeutic-drug-monitoring measures and dosage adjustments for letermovir is provided. [ABSTRACT FROM AUTHOR]