Risk of Pseudotumor Cerebri Syndrome (PTCS) with hormonal contraceptive use

Background: Hormonal contraceptives (HC), one of the most prescribed classes of medication in women, have been linked with pseudotumor cerebri syndrome (PTCS). To date, no large epidemiologic study has examined this association.Methods: A case-control study using the IMS LifeLink Pharmetrics Plus database was conducted. Cases had an ICD-9-CM code for benign intracranial hypertension as well as a procedural code for a CT or MRI and a code for lumbar puncture procedure within 15 days of the PTCS code. Controls were selected from the cohort using density-based sampling.Results: From a cohort of 9,053,240 subjects, there were 288 cases of PTCS corresponding to 2,880 controls. The adjusted RRs for two or more prescriptions of oral combined contraceptive was 0.62 (95% confidence interval 0.39-0.99). RRs for overall HC use was 0.91 (95% CI 0.39-2.12) for one prescription of HCs and 0.69 (95% CI 0.45-1.05) for two or more prescriptions. The RRs for one and two or more prescriptions of progestin only HCs were 0.75 (95% CI 0.08-7.46) and 1.06 (95% CI 0.42-2.69), respectively.Conclusions: Overall HC use does not have a significant effect on incidence of PTCS, however harm associated with progestin-only contraceptives cannot be excluded

An in silico framework for integrating epidemiologic and genetic evidence with health care applications: ventilation-related pneumothorax as a case illustration

OBJECTIVE: To illustrate an in silico integration of epidemiologic and genetic evidence that is being developed at the Center for Devices and Radiological Health/US Food and Drug Administration as part of regulatory research on postmarket device performance. In addition to using conventional epidemiologic evidence from registries, this innovative approach explores the vast potential of open-access omics databases for identifying genetic evidence pertaining to devices. MATERIAL AND METHODS: A retrospective analysis of Agency for Healthcare Research and Quality (AHRQ)/Healthcare Cost and Utilization Project (HCUPNet) data (2002-2011) was focused on the ventilation-related iatrogenic pneumothorax (Vent-IP) outcome in discharges with mechanical ventilation (MV) and continuous positive airway pressure (CPAP). The derived epidemiologic evidence was analyzed in conjunction with pre-existing genomic data from Gene Expression Omnibus/National Center for Biotechnology Information and other databases. RESULTS: AHRQ/HCUPNet epidemiologic evidence showed that annual occurrence of Vent-IP did not decrease over a decade. While the Vent-IP risk associated with noninvasive CPAP comprised about 0.5%, the Vent-IP risk due to longer-term MV reached 2%. Along with MV posing an independent risk for Vent-IP, female sex and white race were found to be effect modifiers, resulting in the highest Vent-IP risk among mechanically ventilated white females. The Vent-IP risk was also potentiated by comorbidities associated with spontaneous pneumothorax (SP) and fibrosis. Consistent with the epidemiologic evidence, expression profiling in a number of animal models showed that the expression of several collagens and other SP/fibrosis-related genes was modified by ventilation settings. CONCLUSION: Integration of complementary genetic evidence into epidemiologic analysis can lead to a cost- and time-efficient discovery of the risk predictors and markers and thus can facilitate more efficient marker-based evaluation of medical product performance

Genetic Variations and Cisplatin Nephrotoxicity: A Systematic Review

Background: Nephrotoxicity is a notable adverse effect in cisplatin treated patients characterized by tubular injury and/or increased serum creatinine (SCr) with incidence varying from 20 to 70%. Pharmacogenomics has been shown to identify strongly predictive genetic markers to help determine which patients are more likely to experience, for example, a serious adverse drug reaction or receive optimal benefit through enhanced efficacy. Genetic variations have been reported to influence the risk of cisplatin nephrotoxicity; however, a comprehensive overview is lacking.Methods: A systematic review was performed using Pubmed, Embase and Web of Science on clinical studies that used cisplatin-based chemotherapy as treatment, had available genotyping data, and evaluated nephrotoxicity as an outcome. The quality of reporting was assessed using the STrengthening the REporting of Genetic Association Studies (STREGA) checklist.Results: Twenty-eight eligible studies were included; all were candidate gene studies. Over 300 SNPs across 135 genes were studied; 29 SNPs in 14 genes were significantly associated with cisplatin-induced nephrotoxicity. A variation in SLC22A2 rs316019, a gene involved in platinum uptake by the kidney, was associated with different measures of nephrotoxicity in four independent studies. Further, variants of ERCC1 (rs11615 and rs3212986) and ERCC2 (rs13181), two genes involved in DNA repair, were found to be positively associated with increased risks of nephrotoxicity in two independent studies.Conclusion: Three genes consistently associated with cisplatin-induced nephrotoxicity. Further research is needed to assess the biological mechanism and the clinical value of modifying treatment based on SLCC22A2 and ERCC1/2 genotypes

DRESS induced by amoxicillin-clavulanate in two pediatric patients confirmed by lymphocyte toxicity assay

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but serious delayed hypersensitivity reaction that can be caused by antibiotic exposure. The reaction typically develops in 2 to 6 weeks. The pathophysiology is thought to involve toxic drug metabolites acting as a hapten, triggering a systemic response. The diagnosis is made clinically but can be confirmed using assays such as the lymphocyte toxicity assay (LTA), which correlates cell death upon exposure to drug metabolites with susceptibility to hypersensitivity reactions. Case presentations: Case 1 involves a previously healthy 11-month-old male with first exposure to amoxicillin-clavulanate, prescribed for seven days to treat a respiratory infection. The patient developed DRESS fourteen days after starting the drug and was successfully treated with corticosteroids. LTA testing confirmed patient susceptibility to hypersensitivity reactions with amoxicillin-clavulanate. Parental samples were also tested, showing both maternal and paternal susceptibility. Neither parent reported prior hypersensitivity reactions. Lifelong penicillin avoidance for the patient was advised along with the notation in medical records of penicillin allergy. The parents were advised to avoid penicillin class antibiotics and be monitored closely for DRESS if they are exposed. Case 2 involves an 11-year-old female with atopic dermatitis with first exposure to amoxicillin-clavulanate, prescribed for ten days to treat a secondary bacterial skin infection. She developed DRESS eleven days after starting antibiotics and was successfully treated with corticosteroids. LTA testing confirmed patient susceptibility to hypersensitivity reactions with amoxicillin-clavulanate. Maternal samples were also tested and showed sensitivity. The mother reported no prior hypersensitivity reactions. Lifelong penicillin avoidance for the patient was advised along with the notation in medical records of penicillin allergy. Conclusions: Amoxicillin-clavulanate is a commonly used antibiotic and the cases we have described suggest that it should be recognized as a potential cause of DRESS in pediatric patients. Furthermore, these cases contribute to current literature supporting that there may be a shorter latent period in DRESS induced by antibiotics. We have also shown that the LTA can be a helpful tool to confirm DRESS reactions, and that testing may have potential implications for family members

Hair cortisol as a novel biomarker of HPA suppression by inhaled corticosteroids in children

Background: Asthma is the most common chronic condition in childhood, and the recommended pharmacotherapy for long-term control includes the use of inhaled corticosteroids (ICS). ICS were designed to act at the site of inflammation in the lung, thus decreasing systemic absorption and reducing the risk of adverse effects associated with corticosteroid use (e.g., HPA suppression and its consequent effects). Available data show that measurement of hair cortisol successfully reflects endogenous cortisol levels. We sought to examine whether hair cortisol measurements can be used to identify HPA suppression surrounding ICS therapy in children with asthma.Methods:Hair samples were collected from the vertex posterior region of the head of 18 asthmatic children. We compared their hair cortisol concentration during ICS use with the concentration prior to ICS use.Results:During ICS therapy, median hair cortisol levels were twofold lower compared with the period of no ICS use (median 89.8 ng/g vs. 198.2 ng/g, P = 0.0015).Conclusion:Hair cortisol is an effective biomarker of the HPA suppression associated with ICS therapy and can be a sensitive tool for determining systemic effects of ICS use and monitoring adherence. Future research is needed to characterize the effect of untreated asthma on hair cortisol concentrations, if any

Pharmacogenomic testing in paediatrics: Clinical implementation strategies

Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well-recognised barriers to obtaining high-quality PGx evidence, particularly when patient numbers may be small, and off-label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost-effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy

Guidelines for Physical Activity During Pregnancy: Comparisons From Around the World

Introduction. Women attain numerous benefits from physical activity during pregnancy. However, because of physical changes that occur during pregnancy, special precautions are also needed. This review summarizes current guidelines for physical activity among pregnant women worldwide. Methods. We searched PubMed (MedLINE) for country-specific governmental and clinical guidelines on physical activity during pregnancy through the year 2012. We cross-referenced with articles referring to guidelines, with only the most recent included. An abstraction form was used to extract key details and summarize. Results. In total, 11 guidelines were identified from 9 countries (Australia, Canada, Denmark, France, Japan, Norway, Spain, United Kingdom, United States). Most guidelines supported moderate-intensity physical activity during pregnancy (10/11) and indicated specific frequency (9/11) and duration/time (9/11) recommendations. Most guidelines provided advice on initiating an exercise program during pregnancy (10/11). Six guidelines included absolute and relative contraindications to exercise. All guidelines generally ruled-out sports with risks of falls, trauma, or collisions. Six guidelines included indications for stopping exercise during pregnancy. Conclusion. This review contrasted pregnancy-related physical activity guidelines from around the world, and can help inform new guidelines as they are created or updated and facilitate the development of a worldwide guideline. © 2013 The Author(s)