Biometry and Evolutionary Biology Laboratory

In our institution, therapeutic drug monitoring of daptomycin is performed routinely and cases of high trough concentrations have been observed in patients without known risk factors. The aim of this study was to identify risk factors of daptomycin overexposure. We performed a case-control study of daptomycin overexposure in patients who received daptomycin between 2013 and 2021. Cases and controls were defined as patients with trough concentration (Cmin) ≥60 mg/L and Cmin <60 mg/L, respectively. Univariate and multivariate analyses were performed with logistic regression models. Retained variables were further analyzed by subgroup analysis and comparison of the pharmacokinetic parameters of daptomycin. We analyzed data from 78 and 26 patients in the control and case groups, respectively. The male-to-female ratio was 1.5. The median (interquartile range) of age, body weight, and creatinine clearance was 66.5 (55-77) years, 77 (65-96) kg, and 98.5 (53-124) mL/min, respectively. Increasing body mass index (BMI) and co-administration of irbesartan were identified as risk factors of daptomycin overexposure with odds ratio (OR) (95% confidence interval [CI]) of 2.9 [1.4-6.2], and 6.1 [1.1-40.8], respectively, whereas increasing creatinine clearance was associated with decreasing risk, with OR of 0.16 [0.05-0.35]. The influence of BMI was attributed to the non-linear relationship between body weight and daptomycin PK parameters and the use of weight-based dosing in patients with high BMI. In addition to renal impairment, high BMI and irbesartan co-administration may be associated with an augmented risk of daptomycin overexposure. Dosing based on actual body weight should be avoided in obese patients.

ObjectivesTo identify risk factors for recurrence of giardiasis in naturally infected symptomatic dogs after specific treatment.Materials and MethodsMedical records were retrospectively reviewed (2006 to 2016) for dogs diagnosed with symptomatic Giardia duodenalis infection. Signalment, housing conditions, clinical signs, concurrent diseases, treatments and outcome were recorded. Data were compared between dogs with and without symptomatic recurrence within 6 months of specific treatment using univariate analysis and multivariable logistic regression.ResultsEighty‐two dogs were included. Fifty‐five were cured after treatment, and 27 had recurrent giardiasis. Factors significantly associated with recurrence on univariate analysis were age <6 months at first diagnosis, being a Retriever, living in a non‐household environment or with other dogs, having concurrent chronic inflammatory enteropathy and having received a specific treatment other than fenbendazole or adjuvant probiotics. On multivariate analysis, retriever breed (odds ratio, 7.75; 95% confidence interval, 2.03 to 34.90), concurrent food‐responsive enteropathy (odds ratio, 15.06; 95% confidence interval, 3.41 to 90.26) and adjuvant probiotics (odds ratio, 13.28; 95% confidence interval, 2.41 to 93.10) were independent risk factors for recurrence, while age >6 months at first diagnosis was a protective factor (odds ratio, 0.24; 95% confidence interval, 0.05 to 0.95).Clinical SignificanceNot only are puppies and dogs living in communities at risk of G. duodenalis infection but they are also at higher risk of recurrence. Concurrent chronic inflammatory enteropathy should also be investigated in cases of symptomatic recurrence. These findings may provide indicators for the prevention and management of recurrent giardiasis in dogs.

BackgroundhPG80 (circulating progastrin), initially recognized for its oncogenic properties due to its direct link to the Wnt signaling pathway, is secreted by cancer cells and detectable in the blood of cancer patients. The ONCOPRO centralized case-control study (NCT03787056) was designed to prospectively evaluate the diagnostic utility of hPG80 in patients with 16 different types of cancer.MethodshPG80 levels were measured in 421 patients with 16 newly diagnosed cancers (median age 65.6 years old) using the DxPG80.Lab kit (Biodena Care). The diagnostic performance of hPG80 (the primary endpoint) was assessed by comparing baseline hPG80 levels in cancer patients with those of 330 asymptomatic aged-matched healthy subjects from the general population.ResultsBetween 2018 and 2022, a total of 506 cancer patients were enrolled in the study, with 421 assessable across 16 distinct cancer cohorts. hPG80 concentrations were significantly higher in cancer patients compared to the healthy population (median 3.8 [IQR: 1.0-11.1] vs. 1.9 [IQR: 0.6–4.2] pM, P < 0.0001). hPG80 levels were not impacted by renal failure, liver dysfunction, or cancer-associated inflammation. The diagnostic accuracy in cancer patients was ROC AUC 0.63, 95% CI = [0.59–0.67]. The highest diagnostic accuracy was seen in patients with lung cancer (AUC 0.75, 95% CI [0.68–0.82]; specificity = 88% for hPG80 > 7.73 pM in patients aged > 58 years old) and hepatocellular carcinoma HCC (ROC AUC 0.75, 95% CI [0.66-083]; specificity = 88% for hPG80 > 7.73 pM in patients aged > 58 years old).ConclusionsThis large prospective study confirms that cancer patients have significantly higher hPG80 blood concentration compared to the healthy population. Incorporating this straightforward ELISA assay into screening programs is warranted.Trial registrationNCT03787056.

Purpose (1) To examine the structural validity of the French version of the Child and Adolescent Scale of Participation (CASP-Fr) in children with neuromuscular diseases (NMD). (2) To determine the influence of demographic and clinical factors on the participation of children with NMD. Materials and methods We conducted an observational, cross-sectional, multicentre study in 3 centres in France. The CASP-Fr was completed by parents of children with NMD (age 3–18 years). Exploratory Factor Analysis (EFA) was performed to evaluate the structural validity. Total CASP-Fr score was used to evaluate participation and the effect of relevant clinical factors on participation was determined using multivariate analysis. Results We included 138 children. Median (Q1–Q3) age: 10.6 (8.0–13.1 years); median CASP-Fr total score: 88.5 (81.3–94.1). CASP-Fr evaluated the self-care, communication, mobility and advanced activities constructs of participation. Only motor function was significantly associated with participation in the multivariate analysis. Conclusions The CASP-Fr evaluates slightly different constructs in children with NMD than the original CASP. The participation of children with NMD was relatively high. The association with motor function suggests a major influence of the environment that should be further explored to improve the involvement in life situations of children with NMD.

Simulating multiple sequence alignments (MSAs) using probabilistic models of sequence evolution plays an important role in the evaluation of phylogenetic inference tools and is crucial to the development of novel learning-based approaches for phylogenetic reconstruction, for instance, neural networks. These models and the resulting simulated data need to be as realistic as possible to be indicative of the performance of the developed tools on empirical data and to ensure that neural networks trained on simulations perform well on empirical data. Over the years, numerous models of evolution have been published with the goal to represent as faithfully as possible the sequence evolution process and thus simulate empirical-like data. In this study, we simulated DNA and protein MSAs under increasingly complex models of evolution with and without insertion/deletion (indel) events using a state-of-the-art sequence simulator. We assessed their realism by quantifying how accurately supervised learning methods are able to predict whether a given MSA is simulated or empirical. Our results show that we can distinguish between empirical and simulated MSAs with high accuracy using two distinct and independently developed classification approaches across all tested models of sequence evolution. Our findings suggest that the current state-of-the-art models fail to accurately replicate several aspects of empirical MSAs, including site-wise rates as well as amino acid and nucleotide composition.

The objective of this study was to compare three different approaches for estimating 30-day survival in ICU studies, considering the issue of informative censoring that occurs when patients are lost to follow-up after discharge. A comparative analysis was conducted to evaluate the effect of different approaches on the estimation of 30-day survival. Three methods were compared: the classical approach using the Kaplan-Meier (KM) estimator and Cox regression modeling, the competing risk approach using the Fine and gray model, considering censoring as a competing event, and the logistic regression approach. The study was conducted in a university ICU and data from patients admitted between 2010 and 2020 were included. Patient characteristics were collected from electronic records. A total of 10,581 patients were included in the study. The true date of death for each patient, obtained from a national registry, allowed for an absence of censoring. All patients were censored at the time of discharge from the ICU, and the three different approaches were applied to estimate the mortality rate and the effects of covariates on mortality. Regression analyses were performed using five variables known to be associated with ICU mortality. The 30-day survival rate for the included patients was found to be 80.5% (95% CI, 79.7-81.2%). The KM estimator severely underestimated the 30-day survival (50.6%; 95% CI, 48.0-53.4%), while the competing risk and logistic regression approaches provided similar results, only slightly overestimating the survival rate (84.5%; 95% CI, 83.8-85.2%). Regression analyses showed that the estimates were not systematically biased, with the Cox and logistic regression models exhibiting greater bias compared with the competing risk regression method. The competing risk approach provides more accurate estimates of 30-day survival and is less biased compared with the other methods evaluated.

BackgroundThe influence of microbiota in ecological interactions, and in particular competition, is poorly known. We studied competition between two insect species, the invasive pest Drosophila suzukii and the model Drosophila melanogaster, whose larval ecological niches overlap in ripe, but not rotten, fruit.ResultsWe discovered D. suzukii females prevent costly interspecific larval competition by avoiding oviposition on substrates previously visited by D. melanogaster. More precisely, D. melanogaster association with gut bacteria of the genus Lactobacillus triggered D. suzukii avoidance. However, D. suzukii avoidance behavior is condition-dependent, and D. suzukii females that themselves carry D. melanogaster bacteria stop avoiding sites visited by D. melanogaster. The adaptive significance of avoiding cues from the competitor’s microbiota was revealed by experimentally reproducing in-fruit larval competition: reduced survival of D. suzukii larvae only occurred if the competitor had its normal microbiota.ConclusionsThis study establishes microbiotas as potent mediators of interspecific competition and reveals a central role for context-dependent behaviors under bacterial influence.8rnTpNHTJmc8sxfvPzrBu3Video