Publication bias in pharmacogenetics of adverse reaction to antiseizure drugs: An umbrella review and a meta-epidemiological study.

Publication bias may lead to a misestimation in the association between pharmacogenetic biomarkers (PGx) and antiseizure drug's adverse effects (AEs). We aimed to assess its prevalence in this field. We searched for systematic reviews assessing PGx of antiseizure drug's AEs. For each unique association between a PGx, a drug and its AE, we used the available odds ratio (ORs) to generate corresponding funnel plots. We estimated the prevalence of publication bias using visual inspections and asymmetry tests. We explored the impact of publication bias using ORs adjusted for potential publication bias. Twenty-two associations were available. Our visual analysis suggested a publication bias in five out twenty-two funnel plots (23% [95%CI: 8; 45]). The Egger's test showed a significant publication bias in one (HLA-B*15:02 and phenytoin-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, p = 0.03) out of nine (11% [95%CI: 0; 48]) and the Begg's test in one (HLA-B*15:02 and carbamazepine-induced serious cutaneous reactions, p = 0.02) out of ten (10% [95%CI: 0; 45]) assessable funnel plots. Adjusting for publication bias may reduce by half the ORs of the pharmacogenetics associations. Publication bias in the pharmacogenetic of antiseizure drug's AEs is not uncommon and may affect the estimation of the effect of such biomarkers. When conducting pharmacogenetic studies, it is critical to publish also the negative one.

Molecular hydrogen in minerals as a clue to interpret ∂D variations in the mantle.

Trace amounts of water dissolved in minerals affect density, viscosity and melting behaviour of the Earth's mantle and play an important role in global tectonics, magmatism and volatile cycle. Water concentrations and the ratios of hydrogen isotopes in the mantle give insight into these processes, as well as into the origin of terrestrial water. Here we show the presence of molecular H2 in minerals (omphacites) from eclogites from the Kaapvaal and Siberian cratons. These omphacites contain both high amounts of H2 (70 to 460 wt. ppm) and OH. Furthermore, their ∂D values increase with dehydration, suggesting a positive H isotope fractionation factor between minerals and H2-bearing fluid, contrary to what is expected in case of isotopic exchange between minerals and H2O-fluids. The possibility of incorporation of large quantities of H as H2 in nominally anhydrous minerals implies that the storage capacity of H in the mantle may have been underestimated, and sheds new light on H isotope variations in mantle magmas and minerals.

Clomiphene citrate and neural tube defects: a meta-analysis of controlled observational studies.

BACKGROUND: At the end of the 1980s, several studies suggested a potential increased risk of neural tube defects (NTDs) with ovulation induction/fertility drugs, especially with clomiphene citrate (CC). A previous meta-analysis of observational studies evaluating the risk of NTDs associated with the use of CC performed in 1995 found a risk ratio of 1.08 (95% CI 0.76-1.51). Since then, additional studies have been published and the risk of NTDs associated with periconceptional CC exposure may have changed. OBJECTIVE: To perform an updated quantitative meta-analysis of the risk of NTDs associated with periconceptional CC exposure. SEARCH STRATEGY: MEDLINE, Web of Science, and Scopus were searched (October 2018). SELECTION CRITERIA: Comparative cohort and case-control studies investigating the risk of NTDs after periconceptional CC exposure. DATA COLLECTION AND ANALYSIS: Pooled effect sizes with corresponding 95% CIs were calculated using random effects models, comparing the risk of NTDs between pregnancies exposed and not exposed to CC. MAIN RESULTS: Thirteen studies met the inclusion criteria, totalling 218 819 pregnancies. Periconceptional exposure to CC was not significantly associated with an increased risk of NTDs (pooled odds ratio 1.21, 95% CI 0.88-1.66). No heterogeneity between studies was observed (I2  = 26%). A funnel plot and asymmetry test were not suggestive of publication bias. CONCLUSION: Our meta-analysis confirms that exposure to CC before or in early pregnancy was associated with a 21% increased risk of NTD in relation to CC exposure; however, this increased risk is not statistically significant. TWEETABLE ABSTRACT: A new meta-analysis finds that clomiphene citrate exposure before or in early pregnancy is not associated with an increased risk of NTDs.

Neuromuscular blocking agents induced anaphylaxis: Results and trends of a French pharmacovigilance survey from 2000 to 2012.

BACKGROUND: Perioperative anaphylaxis mainly involves neuromuscular blocking agents (NMBAs) with an IgE-mediated mechanism. In France, this life-threatening condition is reported by anesthetists and allergologists, and two safety alerts concerning suxamethonium were raised in 2011 and 2012. This led to start a national survey over the 2000-2012 period which objectives were to provide a descriptive analysis, to estimate incidence rates, and to analyze the trends over this period. METHODS: The French pharmacovigilance database was retrospectively queried for all the available NMBAs. Anaphylaxis cases with elevated tryptase and positive skin tests were qualified as "confirmed cases." Subgroup analysis compared atracurium and cisatracurium vs suxamethonium and rocuronium. RESULTS: A total of 680 confirmed cases and 944 nonconfirmed cases were identified. Suxamethonium was the most implied NMBA (64%). Incidence rates (according to sales data) of suxamethonium and rocuronium were, respectively, 10- and 13-folds higher than those of the others NMBAs, regardless the confirmed/nonconfirmed status. Cisatracurium incidence rates remained stable over the period, while suxamethonium and atracurium increased and rocuronium first decreased but re-increased after 2006. Male patients were more frequent in the subgroup "atracurium-cisatracurium" (P = .019), whereas obesity and emergency setting were more frequent in the subgroup "rocuronium-suxamethonium." Shared characteristics were the poorly documented previous exposure to NMBA(s) and an insufficient adherence of patients to perform skin tests, showing the need to improve this procedure. CONCLUSION: Suxamethonium and rocuronium are markedly more involved in perioperative anaphylaxis than the other available NMBAs. Patients should be more informed about their perioperative anaphylaxis and its consequences.

[Drug-induced pancreatitis. A review of French spontaneous reports]. / Pancréatites d'origine médicamenteuse. Revue des notifications spontanées en France.

PURPOSE: Identify the main pharmacological classes inducing pancreatitis using spontaneous reports recorded in the French pharmacovigilance database (FPVD). METHODS: Cases of pancreatitis recorded in FPVD between January 1st 1985 and December 31st 2013 were selected using the 2001 consensus conference criteria of the French High Health Authority. RESULTS: During this period, 2975 observations were selected with 1151 fulfilling criteria of drug-induced pancreatitis (i.e. 0.22% of total notifications in the FPVD). According to ATC classification, the pharmacological classes most frequently found were antiretroviral, analgesic, lipid-lowering, immunosuppressive and insulin secreting drugs. For some drugs (metformin, omeprazole, etc.) pancreatitis was "unlabelled" in the summary of product characteristics. CONCLUSION: This review allows to identify the main drug classes currently involved in spontaneous reporting of pancreatitis in France.

Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis.

BACKGROUND: Anaphylactic reactions to neuromuscular blocking agents (NMBAs) can be severe and even fatal. Our aim was to evaluate mortality rate in France from anaphylactic reactions to NMBAs, to identify risk factors for a fatal outcome, and to describe management of the cases that proved fatal. METHODS: The French National Pharmacovigilance Database was queried for reports of NMBA anaphylaxis that occurred between January 2000 and December 2011. A questionnaire was sent to regional pharmacovigilance centers to obtain further information on the management of cases with a fatal outcome. RESULTS: Two thousand and twenty-two cases of NMBA hypersensitivity were retrieved, of which 84 were fatal (4.1%). Among the 1247 cases of severe NMBA anaphylaxis (grades 3 and 4), independent risk factors associated with a fatal outcome in a multivariate analysis were male gender (female gender: OR = 0.4; 95% CI 0.2-0.7; P = 0.0004), an emergency setting (OR = 2.6; 95% CI 1.5-4.6; P = 0.0007), a history of hypertension (OR = 2.5; 95% CI 1.5-4.4; P = 0.0010) or of other cardiovascular disease (OR = 4.4; 95% CI 2.4-8.1; P < 0.0001), obesity (OR = 2.4; 95% CI 1.1-5.3; P = 0.0376), and ongoing beta-blocker treatment (OR = 4.2; 95% CI 1.8-9.8; P = 0.0011). All 31 patients with a fatal outcome received epinephrine in a titrated manner according to international guidelines. CONCLUSION: Obese males with a history of cardiovascular disease receiving ongoing beta-blocker treatment and undergoing surgery in an emergency setting were at high risk of a fatal outcome after NMBA-induced anaphylaxis. Some epinephrine-resistant cases may play a role in our high mortality rate. New therapeutic approaches need to be developed to treat these cases.

[Detection of Mycobacterium ulcerans DNA in water bugs collected outside the aquatic environment in Benin]. / Détection des signatures moléculaires de Mycobacterium ulcerans chez des punaises aquatiques capturées au Bénin en dehors de leur environnement aquatique.

Hosting of Mycobacterium ulcerans by water bugs is now well established and their vectoring role has been demonstrated experimentally. These findings were recently corroborated by detection of viable bacilli in the saliva of wild water bugs. However, the extent of water bug involvement in M. ulcerans ecology remains unclear and difficult to evaluate due to lack of understanding about water bug biology. The purpose of this study is to describe the first detection of M. ulcerans DNA in the tissue of water bugs captured outside the aquatic environment. This finding supports the hypothesis that water bug migratory behavior contributes not only to the spread of M. ulcerans but also to transmission outside the aquatic environment.

Assessment of the usefulness of performing bacterial identification and antimicrobial susceptibility testing 24 h a day in a clinical microbiology laboratory.

The impact of inoculating agar media with positive blood cultures and of performing bacterial identification and antimicrobial susceptibility testing (AST) for positive urine cultures, blood cultures and certain fluid cultures after day hours (night service (NS)) was evaluated in a clinical microbiology laboratory. The impact of the NS was assessed in terms of decreases in the delays from the time of sampling to the time at which results became available and of the consequences for patient management and antimicrobial treatment. Two major benefits were obtained: initiation of earlier appropriate treatment, and change to a reduced-spectrum but still efficient regimen. The hours of laboratory testing and the availability and transmission of results to the clinical staff were recorded. Concurrently, these hours were estimated as though laboratory tests had been performed in the absence of NS. Reductions in delay were defined as the differences between the hours actually spent and the estimated hours. Economic concerns were also considered. Overall, 430 samples for which an identification and/or AST were performed during the NS were included in the study. The NS led to the implementation of earlier appropriate therapy in 97 cases (22.6%), and to the change to reduced-spectrum but still efficient regimens in 23 additional cases (5.3%). In conclusion, there appeared to be benefits from a system providing bacterial identification and AST overnight, but a study of the cost-effectiveness of the NS would be useful to back up this observation.

[Pays de la Loire Pneumococcus Observatory: antimicrobial resistance of Streptococcus pneumoniae in 2007]. / Observatoire régional du pneumocoque en région Pays de la Loire: résistance de Streptococcus pneumoniae aux antibiotiques en 2007.

OBJECTIVES: Between 1st January and 31st December 2007, 331 Streptococcus pneumoniae strains were collected from 20 participating laboratories in the Pneumococcus Network Pays de la Loire county to assess their susceptibility to antibiotics and to evaluate serogroups of strains. METHOD: The coordinating centre performed MICs of penicillin G, amoxicillin and cefotaxime by the reference agar dilution method. Results were interpreted according to CA-SFM breakpoints. Sensitivity to other antibiotics were studied and serotyping of each strain performed. RESULTS: Three hundred and thirty one strains were isolated in 2007. They were collected from 30 cerebrospinal fluids, 239 blood samples, 53 middle ear fluids and nine pleural fluids. The percentage of pneumococci with decreased susceptibility to penicillin G (PDSP) was 39% and was higher in children (51%) than in adults (35%). The PDSP were often multidrug resistants especially with a high percentage of resistance to erythromycin (87.6% versus 8.4% for pneumococci sensitive to penicillin G). Finally, the most prevalent serogroup was the serogroup 19 (29.6% of isolates). CONCLUSION: A decrease of PDSP was observed since 2001 and high-level resistant strains to beta-lactams remain low. The rate of PDSP in Pays de la Loire is in the national average.

[Assessing the usefulness of a permanently opened clinical microbiology laboratory]. / Evaluation des services rendus par le système de fonctionnement en continu d'un laboratoire de bactériologie.

UNLABELLED: Since 2005, the clinical microbiology laboratory of the Angers teaching hospital has implemented after hours service requiring the overnight presence of a technician specialized in bacteriology. During that time, bacterial identifications and antibiotic susceptibility testing to antimicrobial agents can be performed for critical samples. OBJECTIVES: The authors wanted to evaluate the impact of the after-hours service on the decrease of delay from sampling to results, and from sampling to the implementation of an appropriate antimicrobial therapy. A therapy could be initiated, changed for more efficient agents, or changed to narrower-spectrum agents (major benefits). METHODS: A 4-month prospective study was made. All samples for which identification and/or susceptibility testing were performed during after-hours service (continued analyses) were included in the study. Delays observed were compared with theoretical delays estimated in the absence of the after-hours service. RESULTS: A minimum 24 hour-decrease of the delay for results was observed for 97 % of the 430 samples included. Overall, a major benefit was obtained for more than 25 % of the analyses, representing a cumulated 111-day benefit in days of efficient treatments and a cumulated 27-day benefit in days of prescription of narrower-spectrum agents. DISCUSSION: This organization, unique in French hospitals, is directly related to the improvement of antimicrobial treatments, like antibiotic practice guidelines or infection disease specialists. It was evaluated as a relevant strategy, potentially cost saving, with a significant impact on both the efficiency of treatments and microbial ecology.

Assessment of new chemical disinfectants for HBV virucidal activity in a cell culture model.

Several new chemical disinfectants were processed for Hepatitis B virus (HBV) virucidal activity in a cell culture model. A pooled HBV infected human plasma with 10(10.4) HBV DNA copies/mL was treated with the tested disinfectant. It was then subjected, for three days at several dilutions, to cell culture using the human hepatoma cell line, HepG2, with 4% polyethyleneglycol and 3 mM sodium butyrate. Thirty-seven assays were performed on 12 products, with up to 3 concentrations and 3 time exposures for each product tested. The mean viral titre without disinfectant was 10(5.18) infectious units per mL. Our results showed that products all four hand rubs examined, two of the three surface disinfectants and two of the three instrument disinfectants were highly active whatever concentrations and time exposures, reducing viral times by factors of 10(3)-10(4). However, other products such as one of the surface disinfectants was only active at concentrations above 0.5% for 15 min. Similarly the skin disinfectant, one of the instrument disinfectants and the hand wash agent (diluted to 50%) were less or not active (of <10(3) fold reduction). This is the first study using a cell culture model to assess virucidal activity against HBV of new disinfectants. It showed that most 9/12 products were active by either HBs antigen alteration (8/9) or probable envelope disruption (1/9). Further studies are in progress using this model to assess the activity of other chemical disinfectants such as peracetic acid against HBV.

Transcript profiling in Candida albicans reveals new cellular functions for the transcriptional repressors CaTup1, CaMig1 and CaNrg1.

The pathogenic fungus, Candida albicans contains homologues of the transcriptional repressors ScTup1, ScMig1 and ScNrg1 found in budding yeast. In Saccharomyces cerevisiae, ScMig1 targets the ScTup1/ScSsn6 complex to the promoters of glucose repressed genes to repress their transcription. ScNrg1 is thought to act in a similar manner at other promoters. We have examined the roles of their homologues in C. albicans by transcript profiling with an array containing 2002 genes, representing about one quarter of the predicted number of open reading frames (ORFs) in C. albicans. The data revealed that CaNrg1 and CaTup1 regulate a different set of C. albicans genes from CaMig1 and CaTup1. This is consistent with the idea that CaMig1 and CaNrg1 target the CaTup1 repressor to specific subsets of C. albicans genes. However, CaMig1 and CaNrg1 repress other C. albicans genes in a CaTup1-independent fashion. The targets of CaMig1 and CaNrg1 repression, and phenotypic analyses of nrg1/nrg1 and mig1/mig1 mutants, indicate that these factors play differential roles in the regulation of metabolism, cellular morphogenesis and stress responses. Hence, the data provide important information both about the modes of action of these transcriptional regulators and their cellular roles. The transcript profiling data are available at http://www.pasteur.fr/recherche/unites/RIF/transcriptdata/.

PLGA microsphere bioburden evaluation for radiosterilization dose selection.

The aim of this study was to determine the bioburden of PLGA microspheres produced by the solvent emulsion/extraction process as a means of determining an appropriate gamma-irradiation dose for sterilization. Bioburden was evaluated on the basis of ISO specifications. The analysis of initial microbial contamination was performed on blank microspheres, prepared by a non-aseptic laboratory scale process. A mean bioburden of 36.04 CFU (colony forming units)/110 mg microspheres was determined. Most of the detected germs originated from human commensal flora. According to the ISO dose-selection method, a gamma-irradiation dose of 19.6 kGy was found sufficient to ensure a sterility level of 10(-6). The effect of the selected irradiation dose on both the molecular weight of the polymer and the kinetics of 5-fluorouracil drug release from the microspheres was compared to the European Pharmacopeia recommended irradiation dose (25 kGy). This 20% reduced dose showed a lower extent of molecular weight reduction of PLGA and a better control of 5-FU release from microparticles. This can be related to reduce polymer radiation damage.

[Cat scratch disease. Clinical study of 26 patients. Role and importance of PCR]. / Maladie des griffes du chat. Etude clinique de 26 patients. Intérêt et place de la PCR.

PURPOSE: Cat scratch disease is a mild pathology but diagnosis often remain difficult. METHODS: A retrospective study has been conducted by the department of infectious diseases at the University hospital in Angers. Between January 1994 and October 1998, 26 observations were recorded providing the presence of three criteria out of four among the following: contact with a cat, clinical presentation and its favorable course, absence of any other cause noticed, and the presence of either a positive serology or a positive PCR, or the examination of a suggestive pathology. RESULTS: Fourteen men and 12 women were concerned. From a clinical point of view, the inoculation lesion was observed six times, all patients showed at least one adenopathy during their illness, 12 patients showed only an adenopathy without clinical signs. A surgical biopsy was carried out on nine patients and a diagnosis established. Bartonella henselae serology was done in all patients. Six presented a significant rate of IgG antibodies as early as the first dosage. A seroconversion was observed in four cases belatedly 1 to 2 months after the beginning of the symptomatology. The method's sensitivity was approximately 38%. A PCR search was accomplished in the pus obtained from a ganglionic puncture on 12 patients. It was positive seven times, which corresponds to a sensitivity of about 58%. In associating these two diagnostic criteria a sensitivity rate of nearly 92% was reached, the diagnosis not having been confirmed only in one case. The outcome proved to be favorable in all cases, with or without an antibiotic treatment. CONCLUSION: The association of serology and PCR in the pus permits a certain diagnosis in the majority of the cases and avoids the more aggressive biopsy.

Inactivation of hepatitis B virus in plasma by hospital in-use chemical disinfectants assessed by a modified HepG2 cell culture.

Because of the difficulties of the chimpanzee model and the genetic differences using the duck model, we developed a cell culture method to measure human hepatitis B virus (HBV) inactivation in vitro. Pooled HBV-infected human plasma that had been exposed to a disinfectant was left in contact for three days with a cell culture of the human hepatoma cell line, HepG2, with 4% polyethyleneglycol and 3 mM sodium butyrate. The mean log10 of the viral titre of unexposed plasma was 4.87 infectious units per mL. Our results showed that 1% glutaraldehyde, sodium hypochlorite at 4700 ppm free chlorine and an iodophor-detergent disinfectant containing 3.6% povidone-iodine reduced viral titres by factors exceeding 10(3)-10(4). However, sodium hypochlorite at 1000 ppm free chlorine had minimal activity and povidone-iodine at 9, 5 and 3.6% had no measurable activity (less than 10-fold reduction). This is the first study using a cell culture model to assess disinfectant activity against HBV. It demonstrates more rapidly than the chimpanzee model that glutaraldehyde and sodium hypochlorite, using standard concentrations and exposure times compatible with clinical practice, were highly active against HBV. However, unexpectedly for an enveloped virus, we found no antiviral activity for iodine in the absence of detergent.

[Pneumococcal antibiotic resistance. Data from 6 regional registries for 1999]. / Résistance du pneumocoque aux antibiotiques. Données de 6 observatoires régionaux pour l'année 1999.

RESISTANCE BY REGION: Resistance varied greatly by region, ranging from 34.2% resistant strains in Alsace to 63.1% in Brittany. The incidence of resistant strains was always higher in children (especially in children aged 1 to 5 years) and in ENT samples. The time course of resistance has varied between regions, as has that of serotypes. CRUCIAL FINDING: In these 6 regions, and despite a high incidence (that varied from one region to another) of reduced susceptibility strains for penicillin G, amoxicillin (19-32%) and cefotaxime (6.5-18.5%), amoxicillin-cefotaxime resistant strains remained very rare (0.2-3.5%).

Adherence of platelets to Candida species in vivo.

The in vivo interactions of platelets with Candida species yeast cells were investigated in a murine model. Mice were injected intravenously via the lateral caudal vein, and blood drawn by periorbital puncture was collected in phosphate-buffered saline-formaldehyde to avoid in vitro platelet activation. The study of the clearance of blastoconidia of Candida albicans and Candida glabrata showed that these cells disappeared quickly from the bloodstream. Microscopic observation of blood samples, stained by Calcofluor white or May Grunwald Giemsa, demonstrated the rapid attachment of platelets to fungal elements of all the Candida spp. tested. The attachment of murine platelets to C. albicans cells, observed by scanning electron microscopy, revealed morphological changes. The platelets lost their discoid shape, generated pseudopodia, and flattened against the yeast cells. The reversibility of platelet binding to C. albicans by chelating agents suggests a cation-dependent link. In contrast, the fixation of C. glabrata and Candida tropicalis was not modified by chelating agents. The mechanisms involved in the in vivo adherence of platelets to Candida cells may therefore differ according to the species of Candida.

[Clinical and respiratory function follow-up of 39 infants treated with neonatal respiratory extracorporeal assistance]. / Suivi clinique et fonctionnel respiratoire de 39 nourrissons traités par assistance respiratoire extracorporelle néonatale.

UNLABELLED: The aim of this prospective study was to evaluate the consequences of neonatal treatment with a venovenous extracorporeal respiratory assistance. POPULATION AND METHODS: Thirty nine neonates (28 boys) with acute respiratory failure were included. Extracorporeal respiratory assistance consisted of an apnoeic oxygenation with low frequency positive pressure ventilation and extracorporeal membrane CO2 removal through a venous single canula perfusion circuit. The causes of respiratory distress were: 15 meconium aspiration syndrome, 12 respiratory distress syndrome, six hyaline membrane disease, three sepsis, two diaphragmatic hernia, and one post-surgery Mendelson syndrome. The mean duration of mechanical ventilation was 18 days, including 5 days of extracorporeal respiratory assistance. The prospective follow-up included physical examination, chest radiographs, scintigraphy and pulmonary function tests. These tests studied the following parameters: functional residual capacity by helium dilution technique, lung resistance and dynamic lung compliance by the esophageal balloon technique and blood gases with arterialized blood samples. RESULTS: The mean duration of the follow-up was 21.3 months (6 months to 5 years). Results showed in the first year 33% of children with chronic obstructive pulmonary disease and chest (X-ray abnormalities, such as bronchopulmonary dysplasia in 23% of children. Data of pulmonary function test at the end of the first year: lung resistance and functional residual capacity were within limits of predicted values for height, and dynamic lung compliance was slightly decreased; according to the analysis of the functional profile: 31% without abnormality, 41% of obstructive syndrome and 26% with restrictive pattern. Blood gases were normal in 37 children. At the end of the second year, we noticed normal functional residual capacity, an increase of lung resistance while lung compliance was normalized; functional profile was quite different: with a decrease of the number of patients without abnormality (22%) and increase of those with obstructive syndrome (56%). CONCLUSION: The percentage of abnormalities is high but these are moderate in most cases, especially if we compare with the initial seriousness of the pulmonary pathology. We suggest a regular follow-up to study the respective incidence of pulmonary disease and/or extracorporeal respiratory assistance over these abnormalities.