Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Practical guide to chemotherapy and hormonal therapy administration for physicians and nurses

Chemotherapy and endocrine therapy have been the milestones of cancer treatment for the past 3 decades. Various combinations are used, and ways of administering the drugs and the number of potentially active new drugs are continually increasing, adding to the complexity of the treatments.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Knowledge of pharmacists and parents towards antibiotic use in pediatrics: a cross-sectional study in Lebanon

Objectives: to assess the knowledge of both parents and community pharmacists regarding antibiotics use and resistance in pediatrics in Lebanon. Methods: A cross-sectional study was conducted between June and August 2017 in community pharmacies. A pre-established questionnaire targeting knowledge of parents and pharmacists regarding antibiotics use/misuse was carried out. An index of knowledge was computed to assess factors associated with good knowledge on antibiotics use/misuse. Results: The study showed that 28.7% of pharmacists did not know which factors may contribute to antimicrobial resistance. Concerning the misuse of antibiotics, pharmacists blamed at first parents (90.1%), at second level physicians (72.8%), and third themselves (59.4%). Furthermore, pharmacists believed that the socioeconomic problems of the country (86.1%), the level of resistance to the molecule of choice (80.8%), the lack of consultation time (71.2%) and the lack of national guidelines/recommendations (66.3%) might be additional factors contributing to antimicrobial resistance. In case of acute otitis media, the majority of pharmacists chose the correct treatment, dose and duration according to international guidelines; this was in contrast to the results obtained in case of pharyngitis. Female pharmacists had a significantly higher knowledge score compared to their male counterparts (ORa=2.51). Half of parents (42.6%) declared that antibiotics act against both viruses and bacteria, 55.9% still believe that the presence of fever requires the administration of antibiotics, 50% didn’t know the consequences of antibiotics misuse, 58.4% said that it is okay to give their child antibiotics without a physician's advice and/or based on a pharmacist’s recommendation, and 66.7% trusted the pharmacist in the antibiotic prescription. Parents with a university level of education or a master’s degree had significantly better knowledge compared to illiterate ones (ORa=9.04 and ORa=16.46, respectively). Conclusions: Based on the results obtained, it would be necessary to implement educational campaigns in order to increase awareness on antibiotics misuse and resistance in pediatrics

Analyses of the Rationale and Implementation of Research Biopsies in Oncology Clinical Trials at a Tertiary Cancer Center

Background: Biomarkers in clinical trials have led to massive incorporation of research biopsies, with potentially risks and no direct benefit for patients. In 2018, the American Society of Clinical Oncology (ASCO) released an ethical framework to provide guidance on incorporating research biopsies in cancer clinical trials. Materials and Methods: We collected biopsy requirements of cancer clinical trials conducted at Institut Jules Bordet (IJB) between 2015 and 2019 to examine adherence with the ASCO Ethical Framework. We used logistic regression models to test the association between the request for biopsy, the request for tissue, and the adherence to the ASCO framework as well as some trial characteristics. Results: Between January 2015 and December 2019, 178 oncological studies were conducted at IJB. Of these, 138 (78%) were sponsored by industry, 132 (74%) were phase II and III studies, and 141 (79%) concerned metastatic disease. Tissue was required for inclusion for 119 (67%) studies, among which 59 required at least one new biopsy. Adherence to ASCO's Ethical Framework was 67% for studies requiring tissue and went down to 39% for studies requiring at least one new biopsy. In multivariate analysis, requests for tissue or new biopsies increased in early-phase studies (p <.001, p <.001, respectively) and in studies investigating innovative treatments (immunotherapy or targeted therapies; p <.01, p =.02). Compliance to the ASCO framework significantly decreased with time (p <.001) and in early-phase studies (p <.001). Conclusion: Numerous studies required tissue or new biopsies for exploratory objectives of unknown clinical utility. Requests for tissue increased over the years, whereas compliance to ASCO's Ethical Framework decreased. Implications for Practice: In 2019, the American Society of Clinical Oncology (ASCO) developed an ethical framework to provide guidance on incorporating research biopsies in clinical trials. This study underlines the growing request for tissue in clinical trials with potentially no impact on drug development and no benefit to actual or future patients. Adherence to ASCO's Ethical Framework decreases through time. These results highlight the importance of improving the ethics of research biopsies. ASCO's Ethical Framework offers an opportunity to improve quality of care in clinical research by maximizing scientific utility and allowing for clinically meaningful correlative science and safe access to innovative treatments for a maximum number of patients.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Phase I clinical and pharmacology study of the epothilone analog BMS-247550 given weekly in patients (pts) with advanced solid tumors

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Docetaxel in combination with Amifostine (A) in metastatic breast cancer (MBC): A feasability and pharmacokinetic study of the EORTC-investigational drug branch for breast cancer (IDBBC)

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Docetaxel in combination with Amifostine (A) in metastatic breast cancer (MBC): A feasability and pharmacokinetic study of the EORTC-investigational drug branch for breast cancer (IDBBC)

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