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Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial (vol 21, pg 417, 2022)

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LANCET neurology 2022年第7期21卷 E7-E7页

作者： Knight, Pestana E. M. Amin, S. Bahi-Buisson, N. Epilepsy Center Cleveland Neurological Institute Cleveland Clinic Cleveland OH USA. Electronic address: pestane@***. Pediatric Neurology University Hospitals Bristol and Weston Bristol UK. Pediatric Neurology Necker Enfants Malades University Hospital Paris France. Department of Pediatrics and Neurology University of Colorado School of Medicine Children's Hospital Colorado Aurora CO USA. UCL NIHR BRC Great Ormond Street Institute of Child Health London UK. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program Department of Neurology Boston Children's Hospital and Harvard Medical School Boston MA USA. Rare and Complex Epilepsy Unit Department of Neuroscience Bambino Gesù Children's Hospital IRCCS Rome Italy. Department of Biostatistics University of Washington Seattle WA USA. Marinus Pharmaceuticals Radnor PA USA. New York University Langone Comprehensive Epilepsy Center New York NY USA.

BACKGROUND: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose

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GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

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Nature genetics 2023年第9期55卷 1471-1482页

作者： Remi Stevelink Dorothee Kasteleijn-Nolst Trenite Bobby P. C. Koeleman Dick Lindhout Anja C. M. Sonsma Ciarán Campbell Gianpiero L. Cavalleri Norman Delanty Hany El-Naggar Austin Lacey Peter Widdess-Walsh Colin P. Doherty Siwei Chen Claire Churchhouse Mark J. Daly Yen-Chen A. Feng Daniel P. Howrigan Mitja I. Kurki Benjamin M. Neale Aarno Palotie Wei Zhou Namrata Gupta Henrike O. Heyne Bassel Abou-Khalil Kevin F. Haas R. S. Taneja Oluyomi M. Adesoji Michael Nothnagel Peter Nürnberg Thomas Sander Zaid Afawi Ilan Blatt Amos D. Korczyn Elisabetta Amadori Ganna Balagura Antonella Riva Marcello Scala Paolo Scudieri Pasquale Striano Federico Zara Michele Iacomino Francesca Madia Alison Anderson Patrick Kwan Terence J. O’Brien Slavé Petrovski K. Meng Tan Marian Todaro Joseph Anderson Danielle M. Andrade Quratulain Zulfiqar Ali Grazia Annesi Pauls Auce Andreja Avbersek Simona Balestrini Vera Braatz Claudia B. Catarino Krishna Chinthapalli Jennifer Jamnadas-Khoda Dalia Kasperavičiūte Costin Leu Josemir W. Sander Sanjay M. Sisodiya Sara Zagaglia Melanie Bahlo Karen L. Oliver Mark D. Baker Beata Fonferko-Shadrach William O. Pickrell Carmen Barba Claudia Bianchini Viola Doccini Renzo Guerrini Davide Mei Martino Montomoli Elena Parrini Annalisa Vetro Karen Barboza Fabrice Bartolomei Thomas Bast Bernhard J. Steinhoff Larry Baum Stacey S. Cherny Pak Sham Tobias Baumgartner Christian E. Elger Kerstin Hallmann Wolfram S. Kunz Rainer Surges Randi von Wrede Gábor Zsurka Betül Baykan Nerses Bebek Yeşim Kesim Albert J. Becker Susanne Schoch Felicitas Becker Caitlin A. Bennett Samuel F. Berkovic Stephanie L. Leech Brigid M. Regan Ingrid E. Scheffer Bianca Berghuis Ahmad Beydoun Wassim Nasreddine Francesca Bisulli Lidia Di Vito Lorenzo Ferri Tania Giangregorio Laura Licchetta Raffaella Minardi Barbara Mostacci Carlotta Stipa Paolo Tinuper Lorenzo Muccioli Federica Pondrelli Dheeraj R. Bobbili Emadeldin Hassanin Roland Krause Zied Landoulsi Patrick May Ingo Borggraefe Christian Bosselmann Christian Hengsbach Josua Kegele Stephen Lauxmann Department of Genetics University Medical Center Utrecht Utrecht The Netherlands Stichting Epilepsie Instellingen Nederland (SEIN) Heemstede The Netherlands School of Pharmacy and Biomolecular Sciences The Royal College of Surgeons in Ireland Dublin Ireland The FutureNeuro Research Centre Dublin Ireland Department of Neurology Beaumont Hospital Dublin Ireland Department of Neurology St. James’s Hospital Dublin Ireland Analytic and Translational Genetics Unit Department of Medicine Massachusetts General Hospital and Harvard Medical School Boston MA USA Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA Stanley Center for Psychiatric Research Broad Institute of Harvard and M.I.T Cambridge MA USA Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland Psychiatric & Neurodevelopmental Genetics Unit Department of Psychiatry Massachusetts General Hospital and Harvard Medical School Boston MA USA Division of Biostatistics Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan Hasso Plattner Institute Digital Health Center University of Potsdam Potsdam Germany Hasso Plattner Institute Mount Sinai School of Medicine New York City NY USA Department of Neurology Vanderbilt University Medical Center Nashville TN USA Cologne Center for Genomics (CCG) University of Cologne Faculty of Medicine and University Hospital Cologne Cologne Germany University Hospital Cologne Cologne Germany Department of Neurology Charité Universitaetsmedizin Berlin Campus Virchow-Clinic Berlin Germany Tel-Aviv University Sackler Faculty of Medicine Ramat Aviv Israel Department of Neurology Sheba Medical Center Ramat Gan Israel Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genova Genova Italy IRCCS Istituto Giannina Gaslini Genova Italy Department of Medicine University of Melbour

epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

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CRISIS AFAR: an international collaborative study of the impact of the COVID-19 pandemic on mental health and service access in youth with autism and neurodevelopmental conditions

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Molecular autism 2023年第1期14卷 7页

作者： Bethany Vibert Patricia Segura Louise Gallagher Stelios Georgiades Panagiota Pervanidou Audrey Thurm Lindsay Alexander Evdokia Anagnostou Yuta Aoki Catherine S Birken Somer L Bishop Jessica Boi Carmela Bravaccio Helena Brentani Paola Canevini Alessandra Carta Alice Charach Antonella Costantino Katherine T Cost Elaine A Cravo Jennifer Crosbie Chiara Davico Federica Donno Junya Fujino Alessandra Gabellone Cristiane T Geyer Tomoya Hirota Stephen Kanne Makiko Kawashima Elizabeth Kelley Hosanna Kim Young Shin Kim So Hyun Kim Daphne J Korczak Meng-Chuan Lai Lucia Margari Lucia Marzulli Gabriele Masi Luigi Mazzone Jane McGrath Suneeta Monga Paola Morosini Shinichiro Nakajima Antonio Narzisi Rob Nicolson Aki Nikolaidis Yoshihiro Noda Kerri Nowell Miriam Polizzi Joana Portolese Maria Pia Riccio Manabu Saito Ida Schwartz Anish K Simhal Martina Siracusano Stefano Sotgiu Jacob Stroud Fernando Sumiya Yoshiyuki Tachibana Nicole Takahashi Riina Takahashi Hiroki Tamon Raffaella Tancredi Benedetto Vitiello Alessandro Zuddas Bennett Leventhal Kathleen Merikangas Michael P Milham Adriana Di Martino Autism Center Child Mind Institute 101 E 56Th Street Third Floor New York NY USA. Department of Psychiatry School of Medicine Trinity College Dublin Dublin Ireland. Department of Psychiatry and Behavioural Neurosciences McMaster University Hamilton ON Canada. Unit of Developmental and Behavioral Pediatrics First Department of Pediatrics School of Medicine National & Kapodistrian University of Athens "Aghia Sophia" Children's Hospital Athens Greece. Neurodevelopmental and Behavioral Phenotyping Service National Institute of Mental Health Bethesda MD USA. Center for the Developing Brain Child Mind Institute New York NY USA. Autism Research Centre Bloorview Research Institute Holland Bloorview Kids Rehabilitation Hospital Toronto ON Canada. Department of Paediatrics University of Toronto Toronto ON Canada. Medical Institute of Developmental Disabilities Research Showa University Tokyo Japan. Department of Pediatrics School of Medicine University of Toronto Toronto ON Canada. Division of Paediatric Medicine Hospital for Sick Children Toronto ON Canada. Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences University of California San Francisco CA USA. Department of Biomedical Sciences Section of Neuroscience & Clinical Pharmacology University of Cagliari Cagliari Italy. UOSD di Neuropsichiatria Infantile - Dipartimento di Scienze Mediche Traslazionali Università Federico II di Napoli Naples Italy. Department of Psychiatry Hospital das Clinicas HCFMUSP Faculty of Medicine University of São Paulo (USP) São Paulo Brazil. Department of Health Sciences Università Degli Studi Di Milano Milan Italy. Epilepsy Center - Sleep Medicine Center Childhood and Adolescence Neuropsychiatry Unit ASST SS. Paolo E Carlo San Paolo Hospital Milan Italy. Department of Medical Surgical and Pharmacy Unit of Child Neuropsychiatry University Hospital of Sassari Sassari Italy. Department of Psychiatry Hospital for Sick Children Peter

BACKGROUND:Heterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services. METHODS:Using a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups. RESULTS:Clustering revealed four subgroups. One subgroup-broad symptom worsening only (20%)-included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup. LIMITATIONS:Notable limitations of the study are its cross-sectional nature and focus on the first six mont

关键词： Autism spectrum disorder Behavioral problems COVID-19 pandemic Mental health outcomes Neurodevelopmental conditions Prediction Public health Risk and resilience factors Sleep

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Modulated High Frequency Oscillations Can Identify Regions of Interest in Human iEEG Using Hidden Markov Models

Modulated High Frequency Oscillations Can Identify Regions o...

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International IEEE/EMBS Conference on Neural Engineering

作者： Mirna Guirgis Yotin Chinvarun Martin del Campo Peter L. Carlen Berj L. Bardakjian Institute of Biomaterials and Biomedical Engineering (IBBME) University of Toronto Toronto Canada Comprehensive Epilepsy Program and Neurology Unit Phramongkutklao Hospital Bangkok Thailand Division of Neurology University Health Network Toronto Canada Dept. of Physiol. University Health Network Toronto Canada Department of Electrical and Computer Engineering University of Toronto Toronto Canada

This study investigated the seizure and non-seizure state transitions in the intracranial electroencephalogram (iEEG) recordings of extratemporal lobe epilepsy patients. Cross-frequency coupling between low and high frequency oscillations in conjunction with an unsupervised learning algorithm - namely, hidden Markov models - was used to objectively identify seizure and non-seizure states as well as transition states. Channels consistently capturing two and/or three distinct states in a 32-channel iEEG array were able to identify regions of interest located in resected tissue of patients who experienced improved post-surgical outcomes.

关键词： Hidden Markov models Frequency modulation Training Oscillators Computational modeling Electrodes

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Identification of Brain Regions of Interest for epilepsy Surgery Planning Using Support Vector Machines

Identification of Brain Regions of Interest for Epilepsy Sur...

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Annual International Conference of the IEEE Engineering in Medicine and Biology Society

作者： Joshua A. Dian Sinisa Colic Yotin Chinvarun Peter L. Carlen Berj L. Bardakjian Department of Electrical and Computer Engineering University of Toronto Toronto M5S 3G4 Canada Comprehensive Epilepsy Program and Neurology Unit Pramongkutk-lao Hospital Bangkok 10400 Thailand Institute of Biomaterial and Biomedical Engineering University of Toronto Toronto M5S 3G9 Canada

ISBN: (纸本)9781424492695

In patients with intractable epilepsy, surgical resection is a promising treatment;however, post surgical seizure freedom is contingent upon accurate identification of the seizure onset zone (SOZ). Identification of the SOZ in extratemporal epilepsy requires invasive intracranial EEG (iEEG) recordings as well as resource intensive and subjective analysis by epileptologists. Expert inspection yields inconsistent localization of the SOZ which leads to comparatively poor post surgical outcomes for patients. This study employs recordings from 6 patients undergoing resection surgery in order to develop an automated and scalable system for identifying regions of interest (ROIs). Leveraging machine learning techniques and features used for seizure detection, a classification system was trained and tested on patients with Engel class I to class IV outcomes, demonstrating superior performance in the class I patients. Further, classification using features based upon both high frequency and low frequency oscillations was best able to identify channels suited for resection. This study demonstrates a novel approach to ROI identification and provides a path for developing tools to improve outcomes in epilepsy surgery.

关键词： EEG SOZ iEEG

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Genetic locus heterogeneity in Lafora's progressive myoclonus epilepsy

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Annals of neurology 2001年第2期45卷

作者： Berge A. Minassian MD Jesus Sainz PhD Jose M. Serratosa MD, PhD Manyee Gee PhD Lise M. Sakamoto Saeed Bohlega MD Guy Geoffroy MD Cathy Barr PhD Steve W. Scherer PhD Uwamie Tomiyasu MD Stirling Carpenter MD Karen Wigg A. V. Sanghvi Antonio V. Delgado-Escueta MD Comprehensive Epilepsy Program Department of Neurology University of California Los Angeles School of Medicine Los Angeles CA Neurology and Research West Los Angeles DVA Medical Center Los Angeles CA Division of Neurology Department of Pediatrics Bloorview Epilepsy Program The Toronto Hospital University of Toronto Toronto Ontario Canada Department of Genetics Hospital for Sick Children University of Toronto Toronto Ontario Canada Epilepsy Unit Jimenez Diaz Foundation Madrid Spain Department of Medicine King Faisal Specialist Hospital Riyadh Saudi Arabia Department of Neurology Ste-Justine Hospital University of Montreal Montreal Canada Department of Psychiatry The Toronto Hospital University of Toronto Toronto Ontario Canada Pathology Services West Los Angeles DVA Medical Center Los Angeles CA Department of Pathology The Toronto Hospital University of Toronto Toronto Ontario Canada Brain Research Institute University of California Los Angeles School of Medicine Los Angeles CA

In 1995, we mapped a gene for Lafora's progressive myoclonus epilepsy in chromosome 6q23-25. In 1997 and 1998, we reduced the size of the locus to 300 kb, and an international collaboration identified mutations in the protein tyrosine phosphatase gene. Here, we examine for heterogeneity through the admixture test in 22 families and estimate the proportion of linked families to be 75 to 85%. Extremely low posterior probabilities of linkage (Wi), exclusionary LOD scores, and haplotypes identify 4 families unlikely to be linked to chromosome 6q24. Ann Neurol 1999;45:262–265

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