Hepatic metabolism of chlorinated derivatives of bisphenol A (ClxBPA) and interspecies differences between rats and humans.

During chlorination treatments of drinking water, aqueous bisphenol A (BPA) can react with chlorine to form chlorinated derivatives of BPA (mono, di, tri and tetra-chlorinated derivatives) or ClxBPA. These emerging substances are endocrine disruptors associated with obesity, type II diabetes (TD2M) and myocardial infarction. ClxBPA are present in different human biological matrices but their toxicokinetics remain unknown. The aim of this study was to measure and compare the metabolic kinetics in the liver of four ClxBPA (ClBPA, Cl2BPA, Cl3BPA and Cl4BPA) between compounds and between species (Sprague-Dawley rats vs humans). To estimate their metabolic constants (Vmax, Km, Intrinsic clearance), metabolic assays were performed in hepatocyte suspensions. Assays revealed that metabolic constants of ClxBPA can greatly vary depending on substances and species. While ClBPA and Cl2BPA show similar unbound intrinsic clearances (ClintU) in rat incubation media, values for Cl3BPA and Cl4BPA are very different (3.109 and 0.684 mL/min/106 hepatocytes, respectively). Unlike in rats, human results are quite different as Cl3BPA and Cl4BPA have similar unbound intrinsic clearances, while ClBPA and Cl2BPA diverge (0.350 and 1.363 mL/min/106 hepatocytes, respectively). In both species, Cl2BPA and Cl3BPA have relatively similar clearances, and ClBPA is very different from Cl4BPA. Although we quantified the proportion of sulfo- and glucurono-metabolites, other metabolites may have been formed (e.g., glutathione, disulfate, or oxidative metabolites). This study showed that chlorination had an impact on hepatic intrinsic clearance of ClxBPA in rats and humans and measured values will be valuable for the development of PBPK models for use in exposure assessment.

Reservoir hosts experiencing food stress alter transmission dynamics for a zoonotic pathogen.

Food limitation is a universal stressor for wildlife populations and is increasingly exacerbated by human activities. Anthropogenic environmental change can significantly alter the availability and quality of food resources for reservoir hosts and impact host-pathogen interactions in the wild. The state of the host's nutritional reserves at the time of infection is a key factor influencing infection outcomes by altering host resistance. Combining experimental and model-based approaches, we investigate how an environmental stressor affects host resistance to West Nile virus (WNV). Using American robins (Turdus migratorius), a species considered a superspreader of WNV, we tested the effect of acute food deprivation immediately prior to infection on host viraemia. Here, we show that robins food deprived for 48 h prior to infection, developed higher virus titres and were infectious longer than robins fed normally. To gain an understanding about the epidemiological significance of food-stressed hosts, we developed an agent-based model that simulates transmission dynamics of WNV between an avian host and the mosquito vector. When simulating a nutritionally stressed host population, the mosquito infection rate rose significantly, reaching levels that represent an epidemiological risk. An understanding of the infection disease dynamics in wild populations is critical to predict and mitigate zoonotic disease outbreaks.

[Neonates exposure to parabens through medicines administered to inpatients]. / Exposition des nouveau-nés aux parabènes via les médicaments administrés durant leur hospitalisation.

OBJECTIVES: The objective of this study was to quantify parabens intake due to drug administration in neonates during hospitalization following their birth. METHOD: A monocentric prospective study was performed into a neonatalogy unit to collect all drug prescriptions. An exhaustive list of parabens containing medicines commercialized in France was completed from Theriaque® database. This list was combined with drug prescription to establish an exposure profile to parabens. For each paraben containing medicines, a HPLC-UV assay was performed to determine the average daily intake of paraben received by hospitalized neonates. RESULTS: More than 300 medicines commercialized in France contain at least one paraben. A combination of methylparaben and propylparaben was found in most cases. All hospitalized neonates (n=22) were exposed at least once to methylparaben and propylparaben through medicines while 50 % were exposed to ethylparaben. The average daily intake was higher in term newborns (572,0±249,0 versus 414,6±294,1µg/kg/j for methylparaben) but frequency was higher in prematures (65,0 versus 78,6% for methylparaben) as well as cumutives doses (1421,5±758,8 versus 8618,7±7922,3). These doses are lower than toxicological reference values but these latter do not take into account endocrine disrupting effects of these compounds. CONCLUSIONS: These results highlight medicines as a high source of exposure to parabens in hospitalized neonates. It should encourage pharmaceutical companies and health professionnal to prioritize therapeutic cares without parabens.

Demonstration of the herd effect in adults after the implementation of pneumococcal vaccination with PCV13 in children.

The purpose of this investigation was to describe the evolution of serotypes and antibiotic susceptibility of Streptococcus pneumoniae strains isolated from both adults and children from the same population area with invasive pneumococcal disease (IPD) or acute otitis media (AOM), 5 years after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). From 2009 to 2015, 839 strains of S. pneumoniae strains were collected (481 from adults and 358 from children). Serotyping by latex antisera and molecular methods was performed. Antimicrobial susceptibility was tested. Compared to 2009, the total number of strains isolated in 2015 decreased in children (263 vs. 53, respectively) and in adults (220 vs. 131, respectively). Serotype coverage of PCV13 for IPD decreased significantly in adults from 67.7% (149/220) to 25.2% (33/131) and in children from 75.1% (61/81) to 18.5% (5/27). Especially, serotypes 1, 7F and 19A decreased significantly in children, while serotypes 7F and 19A decreased significantly in adults. PCV13 serotypes involved in AOM decreased significantly over the 5-year period, from 85.7% (156/182) to 38.5% (10/26), and were more susceptible to penicillin, amoxicillin and cefotaxime, p < 0.05. Serotypes 8, 9N and 10A seemed to emerge in adults, whereas any serotype prevalence was observed in children. Between 2009 and 2015, the introduction of PCV13 has resulted in a significant decrease of the number of S. pneumoniae strains isolated from IPD in children as in adults. It highlights a strong herd effect of vaccination in adults.

Multicenter Comparison of the Etest and EUCAST Methods for Antifungal Susceptibility Testing of Candida Isolates to Micafungin.

In vitro susceptibility of 933 Candida isolates, from 16 French hospitals, to micafungin was determined using the Etest in each center. All isolates were then sent to a single center for determination of MICs by the EUCAST reference method. Overall essential agreement between the two tests was 98.5% at ±2 log2 dilutions and 90.2% at ±1 log2 dilutions. Categorical agreement was 98.2%. The Etest is a valuable alternative to EUCAST for the routine determination of micafungin MICs in medical mycology laboratories.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: introduction, methodology and recommendation overview.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The objective was to develop the first Canadian clinical practice guidelines for the management of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The guidelines were developed in accordance with the Appraisal of Guidelines for Research and Evaluation II tool. A Steering Committee and Working Group reviewed the relevant evidence on neuropathic pain management (encompassing screening and diagnosis, treatment and models of care) after SCI. The quality of evidence was scored using Grading of Recommendations Assessment, Development and Evaluation (GRADE). A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: The Working Group developed 12 recommendations for screening and diagnosis, 12 recommendations for treatment and 5 recommendations for models of care. Important clinical considerations accompany each recommendation. CONCLUSIONS: The Working Group recommendations for the management of neuropathic pain after SCI should be used to inform practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: Recommendations for treatment.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for treatment of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed the evidence for different treatment options and achieved consensus. The Working Group then developed clinical considerations for each recommendation. Recommendations for research are also included. RESULTS: Twelve recommendations were developed for the management of neuropathic pain after SCI. The recommendations address both pharmacologic and nonpharmacologic treatment modalities. CONCLUSIONS: An expert Working Group developed recommendations for the treatment of neuropathic pain after SCI that should be used to inform practice.

The CanPain SCI Clinical Practice Guideline for Rehabilitation Management of Neuropathic Pain after Spinal Cord: recommendations for model systems of care.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The project objectives were to develop the first Canadian recommendations on a model of care for the management of at- and below-level neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: On the basis of a review of the Accreditation Canada standards, the Steering Committee developed questions to guide the CanPainSCI Working Group when developing the recommendations. The Working Group agreed on recommendations through a consensus process. RESULTS: The Working Group developed five recommendations for the organization of neuropathic pain rehabilitation care in people with SCI. CONCLUSIONS: The Working Group recommendations for a model of care for at- and below-level neuropathic pain after SCI should be used to inform clinical practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: screening and diagnosis recommendations.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for screening and diagnosis of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed evidence to address clinical questions regarding screening and diagnosis of neuropathic pain after SCI. A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: Twelve recommendations, based on expert consensus, were developed for the screening and diagnosis of neuropathic pain after SCI. The recommendations address methods for assessment, documentation tools, team member accountability, frequency of screening and considerations for diagnostic investigation. Important clinical considerations accompany each recommendation. CONCLUSIONS: The expert Working Group developed recommendations for the screening and diagnosis of neuropathic pain after SCI that should be used to inform practice.

A critically prolonged avalanche burial with recorded cardiac electrical activity and complete recovery - a case report.

The probability of survival in avalanche accidents is time-dependent. Critically buried victims who undergo a long burial duration (over 60 min) face a possible mortality rate of over 80%. Understanding the physiological response during critical avalanche burial is crucial for improving rescue strategies and outcomes. We present the case of a 55-year-old male skier buried under an avalanche for 4 h and 51 min in the Italian Alps. Continuous heart rate monitoring revealed distinct phases of cardiac activity during burial. Despite severe hypothermia, the victim survived without extracorporeal rewarming. This case highlights the importance of continuous monitoring and appropriate on-site management in avalanche accidents. Factors such as the presence of an air pocket may positively influence survival. This case underscores the importance of comprehensive resuscitative measures and guidelines for managing avalanche victims with prolonged burial durations.

Drinking-water exposure to a mixture of nitrate and low-dose atrazine metabolites and small-for-gestational age (SGA) babies: a historic cohort study.

BACKGROUND: Groundwater, surface water and drinking water are contaminated by nitrates and atrazine, an herbicide. They are present as a mixture in drinking water and with their endocrine-disrupting activity, they may alter fetal growth. OBJECTIVES: To study an association between drinking-water atrazine metabolites/nitrate mixture exposure and small-for-gestational-age(SGA). METHODS: A historic cohort study based on birth records and drinking-water nitrate and pesticide measurements in Deux-Sèvres (France) between 2005 and 2009 was carried out. Exposure to drinking-water atrazine metabolites/nitrate mixture was divided into 6 classes according to the presence or absence of atrazine metabolites and to terciles of nitrate concentrations in each trimester of pregnancy. Regression analysis of SGA by mixture exposure at second trimester was subsequently conducted. RESULTS: We included 11,446 woman-neonate couples of whom 37.0% were exposed to pesticides, while 99.9% of the women were exposed to nitrates. Average nitrate concentration was from 0 to 63.30 mg/L. In the second trimester of pregnancy, the risk of SGA was different with mixture exposure when drinking-water atrazine metabolites, mainly 2 hydroxyatrazine and desethylatrazine, were present and nitrate dose exposure increased: compared to single first tercile of nitrate concentration exposure, single second tercile exposure OR was 1.74 CI 95% [1.10; 2.75] and atrazine metabolites presence in the third tercile of nitrate concentration exposure OR was 0.87 CI 95% [0.45;1.67]. CONCLUSIONS: It is possible that the association found at the second trimester of exposure with regard to birth weight may likewise be observed before birth, with regard to the estimated fetal weight, and that it might change in the event that the atrazine metabolites dose were higher or the nitrate dose lower. It would appear necessary to further explore the variability of effects.

[Share experiment: hospital mobile pharmaceutical teams, a proven concept!]. / Partage d'expérience : les équipes pharmaceutiques mobiles à l'hôpital, un concept qui fait ses preuves !

A few months ago, the pharmacy department of the University Hospital of Poitiers was located in the basement of the hospital; communicating with care units by fax, phone or messenger. Today, drugs and medical devices, are stored in a 3400m(2) logistic platform and most of the delivery activity is robotized. Control and validation of prescriptions and dispensing activities are done by the pharmaceutical teams directly in the care units. Quality indicators allow us to improve our services regularly. A great success and interesting prospects for clinical pharmacy.

An overview of the literature on emerging pollutants: Chlorinated derivatives of Bisphenol A (ClxBPA).

CONTEXT: Bisphenol A (BPA) is a ubiquitous contaminant with endocrine-disrupting effects in mammals. During chlorination treatment of drinking water, aqueous BPA can react with chlorine to form chlorinated derivatives of BPA (mono, di, tri and tetra-chlorinated derivatives) or ClxBPA. OBJECTIVE: The aim of this study is to summarize and present the state of knowledge on human toxicological risk assessment of ClxBPA. MATERIALS AND METHODS: A search on ClxBPA in the PubMed database was performed based on studies published between 2002 and 2021. Forty-nine studies on chlorinated derivatives of BPA were found. Available information on their sources and levels of exposure, their effects, their possible mechanisms of action and their toxicokinetics data was extracted and presented. RESULTS: ClxBPA have been essentially detected in environmental aqueous media. There is evidence in toxicological and epidemiological studies that ClxBPA also have endocrine-disrupting capabilities. These emerging pollutants have been found in human urine, serum, breast milk, adipose and placental tissue and can constitute a risk to human health. However, in vitro and in vivo toxicokinetic data on ClxBPA are scarce and do not allow characterization of the disposition kinetics of these compounds. CONCLUSION: More research to assess their health risks, specifically in vulnerable populations, is needed. Some water chlorination processes are particularly hazardous, and it is important to evaluate their chlorination by-products from a public health perspective.

Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia.

To study the effect of early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation (HSCT) on outcome in pediatric ALL, we reviewed 136 consecutive pediatric patients with ALL who received allogeneic HSCT between 1994 and 2005 at the Hospital for Sick Children, Toronto, Canada. Patients with an absolute lymphocyte count (ALC) <0.3 x 10(9) per liter at day 21 (n=104) had more than five times risk of relapse compared to those with ALC >0.3 x 10(9) per liter (n=32) (hazard ratio (HR) 5.3; P=0.002) and had inferior 3-year event-free survival, (EFS), 0.42 (95% confidence interval (CI) 0.32, 0.51) compared to 0.66 (95% CI 0.48, 0.82; P=0.02). Similarly, patients with an ALC <0.3 x 10(9) per liter (n=48) at day 30 were more than twice as likely to relapse compared to those with an ALC >0.3 x 10(9) per liter (n=88) (HR 2.2; P=0.01) and had an inferior 3-year EFS, 0.30 (95% CI 0.18, 0.45) compared to 0.57 (95% CI 0.46, 0.68; P=0.0001). Interestingly, increasing ALC at days 21 and 30 was not associated with increased incidence of acute or chronic GVHD or transplant-related mortality (TRM). Early lymphocyte recovery post-HSCT is associated with a significant GVL without increase in GVHD.

A comparison of the outcomes of children with acute myelogenous leukemia in either first or second complete remission (CR1 vs CR2) following allogeneic hematopoietic stem cell transplantation at a single transplant center.

We reviewed 70 consecutive children with AML who received hematopoietic stem cell transplantation (HSCT) in our institution between 1994 and 2005. Forty-seven children were transplanted in CR1 and 23 were transplanted in CR2. BU/CY was the most common pretransplant conditioning regimen for CR1 patients and a TBI-based conditioning regimen was the most common regimen for CR2 patients. Most patients transplanted in CR1 (81%) received related donor HSCT, whereas most of the CR2 patients (74%) received unrelated donor HSCT. Expectedly, there was a significant increase in acute GVHD incidence in CR2 patients (40 vs 25% for grades I-II and 30 vs 10% for grades III-IV; P=0.02) and a significant increase in transplant-related mortality (38 vs 11%; P=0.01). Although the difference between 3-year EFS for CR1 and CR2 was not statistically significant, there was a significantly superior 3-year overall survival for CR1 patients (74 vs 51%; P=0.05). Children with relapsed AML who achieve and maintain remission until HSCT, have a reasonable survival, but the outcome of children receiving HSCT in CR1 remains superior.

Coupling lattice Boltzmann and molecular dynamics models for dense fluids.

We propose a hybrid model, coupling lattice Boltzmann (LB) and molecular dynamics (MD) models, for the simulation of dense fluids. Time and length scales are decoupled by using an iterative Schwarz domain decomposition algorithm. The MD and LB formulations communicate via the exchange of velocities and velocity gradients at the interface. We validate the present LB-MD model in simulations of two- and three-dimensional flows of liquid argon past and through a carbon nanotube. Comparisons with existing hybrid algorithms and with reference MD solutions demonstrate the validity of the present approach.

[Imogam rage prescription assessment in the rabies prophylaxis center of Poitiers]. / Evaluation de la pertinence de la prescription d'Imogam rage au centre antirabique de Poitiers.

OBJECTIVES: Imogam rage (IgR) prescriptions were assessed in the rabies prophylaxis centre of Poitiers (France). MATERIAL AND METHODS: All medical records closed between January 1 and June 1, 2005 were retrospectively analyzed. An infectious disease specialist examined the pertinence of IgR prescription according to WHO references adapted to the epidemiological situation by the Pasteur Institute French rabies center. The indicator used was the proportion of patients treated by IgR among all patients treated by vaccination or vaccination with IgR. RESULTS: During the study period, 69 medical records have bewereen analyzed: 48 (70%) patients were treated including 22 (46%) with IgR. Imogam rage indication was not appropriate for 21 (95%) patients (one contact with a rodent, 8 low gravity contact, 12 contacts with a French animal) that is to say 86 IgR vials. The direct cost was 8,032 euros. CONCLUSION: This assessment permitted to underline an overprescription of IgR, to adapt guidelines to the local situation, and to improve care quality by adaptating medical record files, improving the prescription decisional tree and the local guidelines, and improving the training of interns.

Developing a Model of Care for Healing Pressure Ulcers With Electrical Stimulation Therapy for Persons With Spinal Cord Injury.

Background: Electrical stimulation therapy (EST) has been shown to be an effective therapy for managing pressure ulcers in individuals with spinal cord injury (SCI). However, there is a lack of uptake of this therapy, and it is often not considered as a first-line treatment, particularly in the community. Objective: To develop a pressure ulcer model of care that is adapted to the local context by understanding the perceived barriers and facilitators to implementing EST, and to describe key initial phases of the implementation process. Method: Guided by the Knowledge-to-Action (KTA) and National Implementation Research Network (NIRN) frameworks, a community-based participatory research (CBPR) approach was used to complete key initial implementation processes including (a) defining the practice, (b) identifying the barriers and facilitators to EST implementation and organizing them into implementation drivers, and (c) developing a model of care that is adapted to the local environment. Results: A model of care for healing pressure ulcers with EST was developed for the local environment while taking into account key implementation barriers including lack of interdisciplinary collaboration and communication amongst providers between and across settings, inadequate training and education, and lack of resources, such as funding, time, and staff. Conclusions: Using established implementation science frameworks with structured planning and engaging local stakeholders are important exploratory steps to achieve a successful sustainable best practice implementation project.

Genetic evidence for the existence of two quinone related inhibitor binding sites in NADH-CoQ reductase.

Using the NADH-CoQ reductase of Rhodobacter capsulatus as a model for the mitochondrial Complex I, we have for the first time isolated bacterial mutants resistant to piericidin-A, a classical inhibitor of the mitochondrial enzyme. Their sensitivity to other inhibitors directed towards the quinone binding domain of complex I gives direct genetic evidence for the existence of two inhibitor binding sites.

Evidence for a quinone binding site close to the interface between NUOD and NUOB subunits of Complex I.

Piericidin, rotenone and pyridaben are specific inhibitors of the NADH-ubiquinone oxidoreductase (Complex I) that bind to its ubiquinone binding site(s). Using site directed mutagenesis, we demonstrate that residues G409, D412, R413 and V407 of the C-terminus of Complex I NUOD subunit are directly involved in the binding of these inhibitors. We propose that the corresponding inhibitor/quinone binding site would be located close to NUOD-NUOB interface.