Pharmacokinetic drug-drug interaction of calcium channel blockers with cyclosporine in hematopoietic stem cell transplant children.

BACKGROUND: Cyclosporine (CsA) is frequently responsible for hypertension in bone marrow transplant children. Calcium channel blockers (CCBs) are considered to be the best treatment for CsA-induced hypertension, but they may alter the exposure and the effect of CsA by inhibiting the CYP3A4 pathway of CsA metabolism or P-gp. However, the inhibitory effect on CYP3A4 may vary among CCBs. METHODS: This study aimed to quantify the pharmacokinetic drug-drug interaction between CsA and nicardipine, amlodipine, and lacidipine. In all, 51 children who received CsA and CCB concomitantly were included. RESULTS: Dose-normalized CsA trough blood concentrations significantly increased in patients treated with nicardipine and amlodipine, whereas they remained stable in patients treated with lacidipine. CONCLUSIONS: Because lacidipine appears to have no effect on CsA exposure, it may be the best option among CCBs for treating high blood pressure caused by CsA in children.

Interconception care in Australian general practice: a qualitative study.

BACKGROUND: GPs provide care for women across the lifespan. This care currently includes preconception and postpartum phases of a woman's life. Interconception care (ICC) addresses women's health issues between pregnancies that then have impact on maternal and infant outcomes, such as lifestyle and biomedical risks, interpregnancy intervals, and contraception provision. However, ICC in general practice is not well established. AIM: To explore GP perspectives about ICC. DESIGN AND SETTING: Qualitative interviews were undertaken with GPs between May and July 2018. METHOD: Eighteen GPs were purposively recruited from South-Eastern Australia. Audiorecorded semi- structured interviews were transcribed verbatim and analysed thematically using the Framework Method. RESULTS: Most participants were unfamiliar with the concept of ICC. Delivery was mainly opportunistic, depending on the woman's presenting need. Rather than a distinct and required intervention, participants conceptualised components of ICC as forming part of routine practice. GPs described many challenges including lack of clarity about recommended ICC content and timing, lack of engagement and perceived value from mothers, and time constraints during consultations. Facilitators included care continuity and the availability of patient education material. CONCLUSION: Findings indicate that ICC is not a familiar concept for GPs, who feel that they have limited capacity to deliver such care. Further research to evaluate patient perspectives and potential models of care is required before ICC improvements can be developed, trialled, and evaluated. These models could include the colocation of multidisciplinary services and services in combination with well-child visits.

Rapid and Accurate Diagnosis of Dermatophyte Infections Using the DendrisCHIP® Technology.

Dermatophytosis is a superficial fungal infection with an ever-increasing number of patients. Culture-based mycology remains the most commonly used diagnosis, but it takes around four weeks to identify the causative agent. Therefore, routine clinical laboratories need rapid, high throughput, and accurate species-specific analytical methods for diagnosis and therapeutic management. Based on these requirements, we investigated the feasibility of DendrisCHIP® technology as an innovative molecular diagnostic method for the identification of a subset of 13 pathogens potentially responsible for dermatophytosis infections in clinical samples. This technology is based on DNA microarray, which potentially enables the detection and discrimination of several germs in a single sample. A major originality of DendrisCHIP® technology is the use of a decision algorithm for probability presence or absence of pathogens based on machine learning methods. In this study, the diagnosis of dermatophyte infection was carried out on more than 284 isolates by conventional microbial culture and DendrisCHIP®DP, which correspond to the DendrisCHIP® carrying oligoprobes of the targeted pathogens implicated in dermatophytosis. While convergence ranging from 75 to 86% depending on the sampling procedure was obtained with both methods, the DendrisCHIP®DP proved to identify more isolates with pathogens that escaped the culture method. These results were confirmed at 86% by a third method, which was either a specific RT-PCR or genome sequencing. In addition, diagnostic results with DendrisCHIP®DP can be obtained within a day. This faster and more accurate identification of fungal pathogens with DendrisCHIP®DP enables the clinician to quickly and successfully implement appropriate antifungal treatment to prevent the spread and elimination of dermatophyte infection. Taken together, these results demonstrate that this technology is a very promising method for routine diagnosis of dermatophytosis.

Therapeutic Fasting: Are Patients Aged 65 and Over Ready?

While being the main potential beneficiaries of therapeutic fasting's health benefits, the elderly are frequently thought of as being too fragile to fast. The main objective of our survey was to review the knowledge, practices, and acceptability of therapeutic fasting in subjects aged 65 years and over. From September 2020 to March 2021, an online questionnaire was sent to subjects aged 65 and over, using the mailing list of local organizations working in the field of aging. The mean age of the 290 respondents was 73.8 ± 6.5 years, 75.2% were women and 54.1% had higher education. Among the respondents, 51.7% had already fasted and 80.7% deemed therapeutic fasting interesting, 83.1% would be willing to fast if it was proven beneficial for their health, and 77.2% if it was proven to decrease the burden of chronic diseases. Subjects aged 65 to 74 years considered themselves as having the greatest physical and motivational abilities to perform therapeutic fasting. People aged 65 years, or more, are interested in therapeutic fasting and a large majority would be ready to fast if such practice was proven beneficial. These results pave the way for future clinical trials evaluating therapeutic fasting in elderly subjects.

The DendrisCHIP® Technology as a New, Rapid and Reliable Molecular Method for the Diagnosis of Osteoarticular Infections.

Osteoarticular infections are major disabling diseases that can occur after orthopedic implant surgery in patients. The management of these infections is very complex and painful, requiring surgical intervention in combination with long-term antibiotic treatment. Therefore, early and accurate diagnosis of the causal pathogens is essential before formulating chemotherapeutic regimens. Although culture-based microbiology remains the most common diagnosis of osteoarticular infections, its regular failure to identify the causative pathogen as well as its long-term modus operandi motivates the development of rapid, accurate, and sufficiently comprehensive bacterial species-specific diagnostics that must be easy to use by routine clinical laboratories. Based on these criteria, we reported on the feasibility of our DendrisCHIP® technology using DendrisCHIP®OA as an innovative molecular diagnostic method to diagnose pathogen bacteria implicated in osteoarticular infections. This technology is based on the principle of microarrays in which the hybridization signals between oligoprobes and complementary labeled DNA fragments from isolates queries a database of hybridization signatures corresponding to a list of pre-established bacteria implicated in osteoarticular infections by a decision algorithm based on machine learning methods. In this way, this technology combines the advantages of a PCR-based method and next-generation sequencing (NGS) while reducing the limitations and constraints of the two latter technologies. On the one hand, DendrisCHIP®OA is more comprehensive than multiplex PCR tests as it is able to detect many more germs on a single sample. On the other hand, this method is not affected by the large number of nonclinically relevant bacteria or false positives that characterize NGS, as our DendrisCHIP®OA has been designed to date to target only a subset of 20 bacteria potentially responsible for osteoarticular infections. DendrisCHIP®OA has been compared with microbial culture on more than 300 isolates and a 40% discrepancy between the two methods was found, which could be due in part but not solely to the absence or poor identification of germs detected by microbial culture. We also demonstrated the reliability of our technology in correctly identifying bacteria in isolates by showing a convergence (i.e., same bacteria identified) with NGS superior to 55% while this convergence was only 32% between NGS and microbial culture data. Finally, we showed that our technology can provide a diagnostic result in less than one day (technically, 5 h), which is comparatively faster and less labor intensive than microbial cultures and NGS.

Influence of exposure conditions on helium transport and bubble growth in tungsten.

Helium diffusion, clustering and bubble nucleation and growth is modelled using the finite element method. The existing model from Faney et al. (Model Simul Mater Sci Eng 22:065010, 2018; Nucl Fusion 55:013014, 2015) is implemented with FEniCS and simplified in order to greatly reduce the number of equations. A parametric study is performed to investigate the influence of exposure conditions on helium inventory, bubbles density and size. Temperature is varied from 120 K to 1200 K and the implanted flux of 100 eV He is varied from [Formula: see text] to [Formula: see text]. Bubble mean size increases as a power law of time whereas the bubble density reaches a maximum. The maximum He content in bubbles was approximately [Formula: see text] He at [Formula: see text]. After 1 h of exposure, the helium inventory varies from [Formula: see text] at low flux and high temperature to [Formula: see text] at high flux and low temperature. The bubbles inventory varies from [Formula: see text] bubbles m[Formula: see text] to [Formula: see text] bubbles m[Formula: see text]. Comparison with experimental measurements is performed. The bubble density simulated by the model is in quantitative agreement with experiments.

Toxicological Assessment of ITER-Like Tungsten Nanoparticles Using an In Vitro 3D Human Airway Epithelium Model.

The International Thermonuclear Experimental Reactor (ITER) is an international project aimed at the production of carbon-free energy through the use of thermonuclear fusion. During ITER operation, in case of a loss-of-vacuum-accident, tungsten nanoparticles (W-NPs) could potentially be released into the environment and induce occupational exposure via inhalation. W-NPs toxicity was evaluated on MucilAir™, a 3D in vitro cell model of the human airway epithelium. MucilAir™ was exposed for 24 h to metallic ITER-like milled W-NPs, tungstate (WO42-) and tungsten carbide cobalt particles alloy (WC-Co). Cytotoxicity and its reversibility were assessed using a kinetic mode up to 28 days after exposure. Epithelial tightness, metabolic activity and interleukin-8 release were also evaluated. Electron microscopy was performed to determine any morphological modification, while mass spectrometry allowed the quantification of W-NPs internalization and of W transfer through the MucilAir™. Our results underlined a decrease in barrier integrity, no effect on metabolic activity or cell viability and a transient increase in IL-8 secretion after exposure to ITER-like milled W-NPs. These effects were associated with W-transfer through the epithelium, but not with intracellular accumulation. We have shown that, under our experimental conditions, ITER-like milled W-NPs have a minor impact on the MucilAir™ in vitro model.

In Vitro Analysis of the Effects of ITER-Like Tungsten Nanoparticles: Cytotoxicity and Epigenotoxicity in BEAS-2B Cells.

Tungsten was chosen as a wall component to interact with the plasma generated by the International Thermonuclear Experimental fusion Reactor (ITER). Nevertheless, during plasma operation tritiated tungsten nanoparticles (W-NPs) will be formed and potentially released into the environment following a Loss-Of-Vacuum-Accident, causing occupational or accidental exposure. We therefore investigated, in the bronchial human-derived BEAS-2B cell line, the cytotoxic and epigenotoxic effects of two types of ITER-like W-NPs (plasma sputtering or laser ablation), in their pristine, hydrogenated, and tritiated forms. Long exposures (24 h) induced significant cytotoxicity, especially for the hydrogenated ones. Plasma W-NPs impaired cytostasis more severely than the laser ones and both types and forms of W-NPs induced significant micronuclei formation, as shown by cytokinesis-block micronucleus assay. Single DNA strand breaks, potentially triggered by oxidative stress, occurred upon exposure to W-NPs and independently of their form, as observed by alkaline comet assay. After 24 h it was shown that more than 50% of W was dissolved via oxidative dissolution. Overall, our results indicate that W-NPs can affect the in vitro viability of BEAS-2B cells and induce epigenotoxic alterations. We could not observe significant differences between plasma and laser W-NPs so their toxicity might not be triggered by the synthesis method.

Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

Innovative DendrisChips® Technology for a Syndromic Approach of In Vitro Diagnosis: Application to the Respiratory Infectious Diseases.

Clinical microbiology is experiencing the emergence of the syndromic approach of diagnosis. This paradigm shift will require innovative technologies to detect rapidly, and in a single sample, multiple pathogens associated with an infectious disease. Here, we report on a multiplex technology based on DNA-microarray that allows detecting and discriminating 11 bacteria implicated in respiratory tract infection. The process requires a PCR amplification of bacterial 16S rDNA, a 30 min hybridization step on species-specific oligoprobes covalently linked on dendrimers coated glass slides (DendriChips®) and a reading of the slides by a dedicated laser scanner. A diagnostic result is delivered in about 4 h as a predictive value of presence/absence of pathogens using a decision algorithm based on machine-learning method, which was constructed from hybridization profiles of known bacterial and clinical isolated samples and which can be regularly enriched with hybridization profiles from clinical samples. We demonstrated that our technology converged in more than 95% of cases with the microbiological culture for bacteria detection and identification.

[Bariatric surgery, stomas and other digestive tract reductions: Insufficient data and recommendations to adapt medicines regimens in therapeutic practice]. / Chirurgie bariatrique, stomies et autres réductions du tube digestif : trop peu de données et de recommandations pour l'adaptation des thérapeutiques médicamenteuses.

Surgery modifying digestive tract may alter drugs pharmacokinetics. To maintain concentrations of active substance in their therapeutic ranges, a dosage adjustment or change of drug may be necessary. This is particularly important when no pharmacological or pharmacodynamic parameter reflecting the medication effectiveness is easily measurable. Our objective was to gather the information and documentary tools that can guide prescription in these patients with rearranged digestive tract. We searched information on the documentary portals of French agencies, on gray literature, on MEDLINE and in the summaries product characteristics. No information was found on the website of French agencies, sparse data were identified in gray literature. Some document are discordant, most are imprecise. One hundred and ten studies or case reports referenced on MEDLINE describe 79 medications pharmacokinetics after gastrointestinal surgery. Four are not available in France. Six literature reviews were found. Four summaries of product characteristics provided information related to drug absorption. No documentary tool adapted to clinical routine exists. This unsatisfactory situation is a barrier to optimal patients care. Information is available. It is however necessary to gather under an ergonomic shape adapted to clinical routine, bringing the surgery type, pharmacokinetic changes induced and what to do about the dose adjustment.