190 results on '"John Dean"'
Search Results
2. Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability
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Jill Clayton-Smith, Rebecca Bromley, John Dean, Hubert Journel, Sylvie Odent, Amanda Wood, Janet Williams, Verna Cuthbert, Latha Hackett, Neelo Aslam, Heli Malm, Gregory James, Lena Westbom, Ruth Day, Edmund Ladusans, Adam Jackson, Iain Bruce, Robert Walker, Sangeet Sidhu, Catrina Dyer, Jane Ashworth, Daniel Hindley, Gemma Arca Diaz, Myfanwy Rawson, and Peter Turnpenny
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Fetal valproate syndrome ,Expert consensus ,Management ,Guideline ,Teratogen ,Antiepileptic drug ,Medicine - Abstract
Abstract Background A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. Methods An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. Results Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. Conclusion The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.
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- 2019
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3. Systems approach to health service design, delivery and improvement: a systematic review and meta-analysis
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Yuanyuan Liu, Terry Dickerson, James Ward, Isla Kuhn, Tom Bashford, John Dean, P John Clarkson, Katharina Kohler, Alexander Komashie, Gulsum Kubra Kaya, Aslι Günay, Nicholas Boddy, Eugenia O'Kelly, Joseph Masters, and Catherine Meads
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Medicine - Abstract
Objectives To systematically review the evidence base for a systems approach to healthcare design, delivery or improvement.Design Systematic review with meta-analyses.Methods Included were studies in any patients, in any healthcare setting where a systems approach was compared with usual care which reported quantitative results for any outcomes for both groups. We searched Medline, Embase, HMIC, Health Business Elite, Web of Science, Scopus, PsycINFO and CINAHL from inception to 28 May 2019 for relevant studies. These were screened, and data extracted independently and in duplicate. Study outcomes were stratified by study design and whether they reported patient and/or service outcomes. Meta-analysis was conducted with Revman software V.5.3 using ORs—heterogeneity was assessed using I2 statistics.Results Of 11 405 records 35 studies were included, of which 28 (80%) were before-and-after design only, five were both before-and-after and concurrent design, and two were randomised controlled trials (RCTs). There was heterogeneity of interventions and wide variation in reported outcome types. Almost all results showed health improvement where systems approaches were used. Study quality varied widely. Exploratory meta-analysis of these suggested favourable effects on both patient outcomes (n=14, OR=0.52 (95% CI 0.38 to 0.71) I2=91%), and service outcomes (n=18, OR=0.40 (95% CI 0.31 to 0.52) I2=97%).Conclusions This study suggests that a systems approaches to healthcare design and delivery results in a statistically significant improvement to both patient and service outcomes. However, better quality studies, particularly RCTs are needed.PROSPERO registration numberCRD42017065920.
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- 2021
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4. A Novel Boot Camp Program to Help Guide Personalized Exercise in People with Parkinson Disease
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Josefa Domingos, John Dean, Travis M. Cruickshank, Katarzyna Śmiłowska, Júlio Belo Fernandes, and Catarina Godinho
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Parkinson disease ,personalized medicine ,clinical exercise ,exercise prescription ,boot camp ,physiotherapy ,Medicine - Abstract
Given the variety of exercise programs available for people with Parkinson’s disease (PD), such individuals may struggle to make decisions about what exercise to perform. The objective of this study was to assess the usefulness, satisfaction, and preferences regarding participation in a PD-personalized educational and exercise boot camp program. Attendees participated in a four-day program consisting of exercise sessions, workshops, and social activities. We collected demographic and clinical information. We assessed satisfaction and preferences immediately after. At one-month follow-up, participants assessed usefulness and changes in exercise habits. Eight individuals diagnosed with PD, with a mean age of 59.5 ± 6.8 years, participated. All participants felt “very satisfied” and likely to attend future events. The two favorite sessions were: cognitive stepping and dance-based movements. At one-month follow-up, participants considered the program “very useful” and reported changes in their exercise routine. Our results suggest that the boot camp program was considered useful and capable of influencing participants’ exercise habits.
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- 2021
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5. Survey of the Literature for September 2015 Issue of Sexual Medicine Journal
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Alexander W. Pastuszak, MD, PhD, Fabio Castiglione, MD, David Jacques Cohen, MD, Joana Carvalho, PhD, Christopher Fisher, PhD, and John Dean, MBBS, FRCGP, FECSM
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Medicine - Published
- 2015
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6. Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1: A multicentre cohort follow-up study.
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Mark J Hamilton, Yvonne Robb, Sarah Cumming, Helen Gregory, Alexis Duncan, Monika Rahman, Anne McKeown, Catherine McWilliam, John Dean, Alison Wilcox, Maria E Farrugia, Anneli Cooper, Josephine McGhie, Berit Adam, Richard Petty, Scottish Myotonic Dystrophy Consortium, Cheryl Longman, Iain Findlay, Alan Japp, Darren G Monckton, and Martin A Denvir
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Medicine ,Science - Abstract
ObjectiveHigh sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1).Methods117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months.ResultsFifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level < 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score.ConclusionsPlasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting.
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- 2017
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7. Correction: Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1: A multicentre cohort follow-up study.
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Mark J Hamilton, Yvonne Robb, Sarah Cumming, Helen Gregory, Alexis Duncan, Monika Rahman, Anne McKeown, Catherine McWilliam, John Dean, Alison Wilcox, Maria E Farrugia, Anneli Cooper, Josephine McGhie, Berit Adam, Richard Petty, Scottish Myotonic Dystrophy Consortium, Cheryl Longman, Iain Findlay, Alan Japp, Darren G Monckton, and Martin A Denvir
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0174166.].
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- 2017
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8. An Evidence-Based Unified Definition of Lifelong and Acquired Premature Ejaculation: Report of the Second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation
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Ege Can Serefoglu, MD, Chris G. McMahon, MD, Marcel D. Waldinger, MD, PhD, Stanley E. Althof, PhD, Alan Shindel, MD, Ganesh Adaikan, PhD, Edgardo F. Becher, MD, John Dean, MD, Francois Giuliano, MD, PhD, Wayne J.G. Hellstrom, MD, Annamaria Giraldi, MD, PhD, Sidney Glina, MD, PhD, Luca Incrocci, MD, PhD, Emmanuele Jannini, MD, Marita McCabe, PhD, Sharon Parish, MD, David Rowland, PhD, R. Taylor Segraves, MD, PhD, Ira Sharlip, MD, and Luiz Otavio Torres, MD
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Premature Ejaculation ,Definition ,Lifelong Premature Ejaculation ,Acquired Premature Ejaculation ,Intravaginal Ejaculatory Latency Time ,Ejaculatory Control ,Sexual Satisfaction ,Personal Distress ,Interpersonal Distress ,Negative Personal Psychological Consequences ,Medicine - Abstract
Introduction: The International Society for Sexual Medicine (ISSM) Ad Hoc Committee for the Definition of Premature Ejaculation developed the first evidence-based definition for lifelong premature ejaculation (PE) in 2007 and concluded that there were insufficient published objective data at that time to develop a definition for acquired PE. Aim: The aim of this article is to review and critique the current literature and develop a contemporary, evidence-based definition for acquired PE and/or a unified definition for both lifelong and acquired PE. Methods: In April 2013, the ISSM convened a second Ad Hoc Committee for the Definition of Premature Ejaculation in Bangalore, India. The same evidence-based systematic approach to literature search, retrieval, and evaluation used by the original committee was adopted. Results: The committee unanimously agreed that men with lifelong and acquired PE appear to share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. Men with acquired PE are older, have higher incidences of erectile dysfunction, comorbid disease, and cardiovascular risk factors, and have a longer intravaginal ejaculation latency time (IELT) as compared with men with lifelong PE. A self-estimated or stopwatch IELT of 3 minutes was identified as a valid IELT cut-off for diagnosing acquired PE. On this basis, the committee agreed on a unified definition of both acquired and lifelong PE as a male sexual dysfunction characterized by (i) ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy. Conclusion: The ISSM unified definition of lifelong and acquired PE represents the first evidence-based definition for these conditions. This definition will enable researchers to design methodologically rigorous studies to improve our understanding of acquired PE. Serefoglu EC, McMahon CG, Waldinger MD, Althof SE, Shindel A, Adaikan G, Becher EF, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An evidence-based unified definition of lifelong and acquired premature ejaculation: Report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. Sex Med 2014;2:41–59.
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- 2014
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9. An Update of the International Society of Sexual Medicine's Guidelines for the Diagnosis and Treatment of Premature Ejaculation (PE)
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Stanley E. Althof, PhD, Chris G. McMahon, MD, Marcel D. Waldinger, MD, PhD, Ege Can Serefoglu, MD, Alan W. Shindel, MD, P. Ganesan Adaikan, PhD, DSc, Edgardo Becher, MD, PhD, John Dean, MD, Francois Giuliano, MD, PhD, Wayne J.G. Hellstrom, MD, Annamaria Giraldi, MD, PhD, Sidney Glina, MD, PhD, Luca Incrocci, MD, PhD, Emmanuele Jannini, MD, Marita McCabe, PhD, Sharon Parish, MD, David Rowland, PhD, R. Taylor Segraves, MD, PhD, Ira Sharlip, MD, and Luiz Otavio Torres, MD
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Premature Ejaculation ,Definition of PE ,Diagnosis of PE ,Etiology of PE ,Pharmacotherapy of PE ,Prevalence of PE ,Psychotherapy of PE ,Medicine - Abstract
Introduction: In 2009, the International Society for Sexual Medicine (ISSM) convened a select panel of experts to develop an evidence-based set of guidelines for patients suffering from lifelong premature ejaculation (PE). That document reviewed definitions, etiology, impact on the patient and partner, assessment, and pharmacological, psychological, and combined treatments. It concluded by recognizing the continually evolving nature of clinical research and recommended a subsequent guideline review and revision every fourth year. Consistent with that recommendation, the ISSM organized a second multidisciplinary panel of experts in April 2013, which met for 2 days in Bangalore, India. This manuscript updates the previous guidelines and reports on the recommendations of the panel of experts. Aim: The aim of this study was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. Method: A comprehensive literature review was performed. Results: This article contains the report of the second ISSM PE Guidelines Committee. It offers a new unified definition of PE and updates the previous treatment recommendations. Brief assessment procedures are delineated, and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients. Conclusion: Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. We again recommend that these guidelines be reevaluated and updated by the ISSM in 4 years. Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG, Becher E, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An update of the International Society of Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation (PE). Sex Med 2014;2:60–90.
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- 2014
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10. Expanding the phenotype of <scp> ASXL3 </scp> ‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in <scp> ASXL3 </scp>
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Katherine Bergstrom, Nichola Foulds, Yue Si, Anne Slavotinek, John Dean, Evan Reid, Ruth Armstrong, Charlotte W. Ockeloen, Richard Fisher, Maria J. Guillen Sacoto, Dayna Morel, Fowzan S. Alkuraya, Costa Cinzia, Thomas D. Challman, Samantha A. Schrier Vergano, Francisca Milan Zamora, Naomi Meeks, John Pappas, Katheryn Grand, Abhijit Dixit, Julie S. Cohen, Ddd Study, Marjolein H. Willemsen, Serwet Demirdas, Rachel Harrison, Usha Kini, Bertrand Isidor, Patricia Blanchet, Emily Palen, Arjan Bouman, Jagdeep S. Walia, Ruth Newbury-Ecob, Rachel Rabin, Shadi Albaba, Diana Johnson, Paolo Prontera, Paula Girotto, Ange-Line Bruel, Meena Balasubramanian, Nicola K. Ragge, Schaida Schirwani, Deborah L. Renaud, Christopher Cunniff, John M. Graham, Natalie Dykzeul, Swati Naik, Valerie Slegesky, Hessa F Albassam, Maria Giovanna Tedesco, Sally Ann Lynch, Julie Vogt, Natalie Hauser, Dong Li, Deanna Alexis Carere, and Benjamin Cogné
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Genetics ,Biology ,medicine.disease ,Phenotype ,Hypotonia ,Natural history ,Neurodevelopmental disorder ,Intellectual disability ,medicine ,Missense mutation ,Hypertelorism ,medicine.symptom ,Genetics (clinical) ,Sequence (medicine) - Abstract
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
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- 2021
11. Fistulae involving the appendix: a systematic review of the literature
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Nicholas John Dean, Peter Stewart, Stephen J. McDonald, Felix Lee, and Lloyd J Ridley
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Male ,medicine.medical_specialty ,Fistula ,Umbilicus (mollusc) ,Appendix ,03 medical and health sciences ,0302 clinical medicine ,Intestinal Fistula ,medicine ,Appendectomy ,Humans ,In patient ,business.industry ,General surgery ,General Medicine ,Appendicitis ,Appendiceal Adenocarcinoma ,medicine.disease ,medicine.anatomical_structure ,Appendiceal Neoplasms ,030220 oncology & carcinogenesis ,Etiology ,Female ,030211 gastroenterology & hepatology ,Surgery ,Surgical history ,business - Abstract
Background The appendix has a unique place in surgical history. Although the first ever appendicectomy involved a fistula to the skin, fistulae involving the appendix remain uncommon and can lead to unique surgical considerations. Methods A systematic review of the literature was performed for case reports of appendiceal fistulae. We excluded cases in which the patient had a history of appendicectomy. Cases were categorized by site and aetiology, with information regarding relative frequency and demographics obtained. Results A total of 301 case reports of fistula involving the appendix were found. The most common sites of these fistulae were to the bladder (148 cases), skin (40 cases), vasculature (19 cases), umbilicus (16 cases) and to the gastrointestinal tract. The most common aetiology in sub-analysis was appendicitis alone (150 cases), with less common causes including appendiceal adenocarcinoma (32 cases) and congenital abnormalities (18 cases). There were significantly more appendiceal fistulae in males than in females, with a ratio of 1.7:1. In patients with appendiceal adenocarcinoma as a cause for fistula, there were significantly more females than males with a ratio of 2.3:1. Conclusion In conducting a systematic review of case reports of fistulae involving the appendix, we identified 301 unique case reports, with a range of different sites and aetiologies.
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- 2020
12. Guidance for the prevention and emergency management of adult patients with adrenal insufficiency
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Helen Simpson, Wiebke Arlt, John Dean, John A.H. Wass, and Jeremy W. Tomlinson
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Adult ,medicine.medical_specialty ,Acute medicine ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Adrenal insufficiency ,Humans ,Endocrine system ,In patient ,030212 general & internal medicine ,Letters to the Editor ,Emergency management ,Adult patients ,business.industry ,Adrenal crisis ,General Medicine ,Emergency department ,medicine.disease ,Acute Disease ,Emergency medicine ,Steroids ,Emergencies ,medicine.symptom ,Emergency Service, Hospital ,business ,Adrenal Insufficiency - Abstract
Adrenal insufficiency (AI) is an often-unrecognised endocrine disorder, which can lead to adrenal crisis and death if not identified and treated. Omission of steroids in patients with AI, particularly during physiological stress such as an intercurrent illness or surgery, can also lead to an adrenal crisis. The National Reporting and Learning System (NRLS) identified 78 incidents including two deaths and six incidents of severe harm to patients in a recent 4-year period. This guidance will go through causes of adrenal insufficiency, groups at risk of an adrenal crisis, emergency management and management for surgical procedures. A new NHS Steroid Emergency Card has been developed to be carried by patients at risk of adrenal crisis. We hope the new emergency card and this guidance will increase awareness of the need to start steroids promptly in patients at risk of an adrenal crisis, particularly those presenting in the emergency department or to acute medicine teams and those undergoing surgery or invasive procedures.
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- 2020
13. VIKING II, a Worldwide Observational Cohort of Volunteers with Northern Isles Ancestry
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James F. Wilson, David Buchanan, Zosia Miedzybrodzka, Rachel L. Edwards, Shona M. Kerr, and John Dean
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Shetland ,medicine.medical_specialty ,Research ethics ,Geography ,Genetic drift ,Epidemiology ,Cohort ,medicine ,Observational study ,Disease ,Computer-assisted web interviewing ,Demography - Abstract
IntroductionThe purpose of VIKING II is to create an observational cohort of volunteers with ancestry from the Northern Isles of Scotland, primarily for identifying genetic variants influencing disease. The new online protocol is separate to, but follows on from, earlier genetic epidemiological clinic-based studies in the isolated populations of Orkney and Shetland. These populations are favourable for the study of rarer genetic variants due to genetic drift, the large number of relatives, and availability of pedigree information.Methods and AnalysisOnline methods are being used to recruit ∼4,000 people who have Northern Isles ancestry, living anywhere in the world. The option for participants to have actionable genetic results returned is offered. Broad consent will be taken electronically. Data will be collected at baseline through an online questionnaire and longitudinally through linkage to NHS data in the electronic health record. The questionnaire collects a variety of phenotypes including personal and family health. DNA will be extracted from saliva samples then genome-wide genotyped and exome sequenced. VIKING II aims to capitalise on the special features of the Northern Isles populations to create a research cohort that will facilitate the analysis of genetic variants associated with a broad range of traits and disease endpoints.Ethics and DisseminationThe South East Scotland Research Ethics Committee gave the study a favourable opinion. VIKING II is sponsored by the University of Edinburgh and NHS Lothian. Summary research findings will be disseminated to participants and funding bodies, presented at conferences and reported in peer-reviewed publications.Article SummaryStrengths and limitations of this studyDetailed data and biological sample collection of research volunteers with unique ancestry.Consent for access to routinely collected clinical EHR data and for future re-contact, providing a longitudinal component.Optional consent for return of actionable genetic results.4,000 participants is a relatively small number for certain types of genetic analyses, so the cohort is underpowered on its own, in some study designs.Resources to maintain the cohort, and to store data and DNA samples, are significant, with sustainability dependent on infrastructure support and continued funding.
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- 2021
14. Implementation of a Community-Based Exercise Program for Parkinson Patients: Using Boxing as an Example
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Nienke M. de Vries, Sara Riggare, Joaquim J. Ferreira, Josefa Domingos, Catarina Godinho, John Dean, Bastiaan R. Bloem, Mariella Graziano, and Danique L.M. Radder
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Research Report ,0301 basic medicine ,medicine.medical_specialty ,Physical disability ,education ,Disease ,Community exercise ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Exercise program ,Patient Education as Topic ,medicine ,Humans ,Adverse effect ,Muscle aches ,Physiotherapy ,Qualitative Research ,physiotherapy ,Community based ,business.industry ,Process Assessment, Health Care ,Neurological Rehabilitation ,Parkinson Disease ,community exercise ,Boxing ,Patient Acceptance of Health Care ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Exercise Therapy ,030104 developmental biology ,Patient Satisfaction ,Educational resources ,Parkinson’s disease ,Physical therapy ,Boxing training ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Contains fulltext : 209024.pdf (Publisher’s version ) (Open Access) BACKGROUND: Persons with Parkinson's disease (PD) benefit from continuous exercise through participation in community-based exercise programs. However, community programs often lack PD-specific knowledge needed to provide safe and adequately dosed exercise. OBJECTIVE: To evaluate the acceptability and safety of a PD-specific boxing program in the community. METHODS: We developed specific educational resources to facilitate the boxing instructors. We also organized an educational and practical workshop for patients (n = 26) and instructors (n = 10), and assessed: (a) participants' satisfaction; (b) instructors' appreciation of the educational resources; and (c) numbers of patients interested in participating in the boxing program. After 18 months, patients and instructors completed a questionnaire evaluating: (a) participants' satisfaction; (b) adverse events; (c) facilitators and barriers; and (d) proportion of participants at follow-up. RESULTS: Twenty-six persons with PD (62% men) and 10 boxing instructors participated in the workshop. 81% of patients and 80% of instructors were very satisfied. Instructors found the educational materials "very helpful" (60%) or "helpful" (40%). Patients expressed a clear interest (54%) or possible interest (46%) in the program. We initiated classes with 10 participants. At 18-months follow-up, the program consisted of four boxing sessions/week, led by three instructors, with 40 participants. Seventeen patients responded to the questionnaire at follow-up. Participants were "very satisfied" (53%), "satisfied" (35%) and neither satisfied nor unsatisfied (12%) with the program. Adverse effects were mild (e.g., muscle aches). Transportation and physical disability were the main barriers for participation. CONCLUSIONS: The boxing program was well-received, with increasing numbers of participants at 18 months. The educational resources can support boxing instructors participating in current and future boxing classes being delivered in the community.
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- 2019
15. Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability
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Janet Williams, Amanda G. Wood, Adam Jackson, Robert W.M. Walker, Neelo Aslam, John Dean, Myfanwy Rawson, Latha Hackett, Iain A. Bruce, Peter D. Turnpenny, Rebecca Bromley, Ruth Day, Verna Cuthbert, Lena Westbom, Hubert Journel, Jill Clayton-Smith, Gregory James, Sylvie Odent, Edmund J. Ladusans, Jane Ashworth, Gemma Arca Diaz, Sangeet Sidhu, Heli Malm, Daniel Hindley, Catrina Dyer, Manchester University NHS Foundation Trust (MFT), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Helsinki, CHAFEA [HP-ERN-SGA-2017 - 769045], HUS Emergency Medicine and Services, Department of Diagnostics and Therapeutics, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki
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0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Expert consensus ,lcsh:Medicine ,CHILDREN ,FOLIC-ACID ,030105 genetics & heredity ,Guideline ,0302 clinical medicine ,Fetal Valproate Spectrum Disorder ,Pregnancy ,Intellectual disability ,Pharmacology (medical) ,Spectrum disorder ,Prospective Studies ,Position Statement ,Genetics (clinical) ,EPILEPSY ,ComputingMilieux_MISCELLANEOUS ,Neuropsychology ,1184 Genetics, developmental biology, physiology ,Cognition ,General Medicine ,3. Good health ,Management ,Teratogens ,PREGNANCY ,Anticonvulsants ,Female ,Antiepileptic drug ,COGNITIVE OUTCOMES ,medicine.medical_specialty ,Consensus ,ANTIEPILEPTIC DRUG EXPOSURE ,Fetal valproate syndrome ,SPINA-BIFIDA ,03 medical and health sciences ,Intellectual Disability ,medicine ,Humans ,MAJOR MALFORMATIONS ,Psychiatry ,business.industry ,Valproic Acid ,Uterus ,lcsh:R ,SODIUM VALPROATE ,Evidence-based medicine ,medicine.disease ,Teratogen ,Teratology ,Pregnancy Complications ,IN-UTERO EXPOSURE ,business ,030217 neurology & neurosurgery ,Medical literature - Abstract
Background A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. Methods An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. Results Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. Conclusion The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals. Electronic supplementary material The online version of this article (10.1186/s13023-019-1064-y) contains supplementary material, which is available to authorized users.
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- 2019
16. Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies
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Leah Slattery, Emma L. Baple, Hilde Van Esch, Eyby Leon, Farida Abid, Margaret P. Adam, Bo Yuan, Cecilie F. Rustad, Amy M. Breman, Juanita Neira, Weimin Bi, Weihong Jin, Olivia Wenger, Yaping Yang, Jill A. Rosenfeld, John Dean, Laura Jenkins, Jennifer E. Posey, Chin-To Fong, Christian P. Schaaf, Asbjørg Stray-Pedersen, Lettie E. Rawlins, Teresa Santiago-Sim, Marguerite Pietryga, Linda A. Ramsdell, Sau Wai Cheung, Jullianne Diaz, Davut Pehlivan, Laura Martin, Andrew H. Crosby, Chad A. Shaw, Christine M. Eng, Louanne Hudgins, Pengfei Liu, Dorothy K. Grange, Suneeta Madan-Khetarpal, James R. Lupski, LaDonna Immken, Alison A. Bertuch, Marianne McGuire, Kristian Tveten, Xiaofei Song, Scott E. Hickey, Rui Xiao, Vipulkumar Patel, and Janice L. Smith
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Male ,0301 basic medicine ,Cornelia de Lange Syndrome ,Adolescent ,Chromosomal Proteins, Non-Histone ,STAG2 ,STAG1 ,Cell Cycle Proteins ,030105 genetics & heredity ,Biology ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,Genetic Heterogeneity ,03 medical and health sciences ,Gene Frequency ,INDEL Mutation ,Locus heterogeneity ,De Lange Syndrome ,Proto-Oncogene Proteins ,Exome Sequencing ,medicine ,Humans ,Exome ,clinical exome sequencing (CES) ,Allele ,Child ,Alleles ,Genetics (clinical) ,Exome sequencing ,Retrospective Studies ,Genetics ,Genetic heterogeneity ,Nuclear Proteins ,Antigens, Nuclear ,Atypical cohesinopathies ,NIPBL ,medicine.disease ,Human genetics ,3. Good health ,Phenotype ,cohesin pathway ,030104 developmental biology ,Biological Variation, Population ,Child, Preschool ,Mutation ,Female ,Carrier Proteins - Abstract
Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange Syndrome (CdLS). We aim to delineate mutations in known and candidate cohesinopathy genes from a clinical exome perspective. Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N=10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. Results: Pathogenic or likely pathogenic single nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N=5), SMC1A (N=14), SMC3 (N=4), RAD21 (N=2) and HDAC8 (N=8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared to phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N=3), STAG2 (N=5), PDS5A (N=1) and WAPL (N=1), and one inherited SNV in PDS5A. We also identified copy number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. Conclusion: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.
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- 2019
17. Effects of Physical Exercise on Gait and Balance in Patients with Parkinson's Disease
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Hussain Mansour Tairan, Vivek Patel, and John Dean Chiong
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medicine.medical_specialty ,Parkinson's disease ,Gait (human) ,Physical medicine and rehabilitation ,business.industry ,Rehabilitation ,Medicine ,Physical Therapy, Sports Therapy and Rehabilitation ,Physical exercise ,In patient ,business ,medicine.disease ,Balance (ability) - Published
- 2019
18. Systems approach to health service design, delivery and improvement: a systematic review and meta-analysis
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T. Dickerson, Joseph Masters, Catherine Meads, Alexander Komashie, Katharina Kohler, Nicholas Boddy, Tom Bashford, John Dean, Isla Kuhn, Yuanyuan Liu, P. John Clarkson, Gulsum Kubra Kaya, James Ward, Eugenia O'Kelly, Aslι Günay, Komashie, Alexander [0000-0002-0715-4729], Bashford, Tom [0000-0003-0228-9779], Kaya, Gulsum Kubra [0000-0003-0663-3995], Liu, Yuanyuan [0000-0003-2331-2392], Günay, Aslι [0000-0002-5261-5889], Kohler, Katharina [0000-0003-1919-0193], O'Kelly, Eugenia [0000-0002-4748-3957], Meads, Catherine [0000-0002-2368-0665], Clarkson, P John [0000-0001-8018-7706], and Apollo - University of Cambridge Repository
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medicine.medical_specialty ,Systems Analysis ,MEDLINE ,Psychological intervention ,lcsh:Medicine ,CINAHL ,PsycINFO ,organisation of health services ,quality in health care ,03 medical and health sciences ,0302 clinical medicine ,Health care ,Medicine ,Health services research ,Humans ,030212 general & internal medicine ,Health policy ,Qualitative Research ,business.industry ,030503 health policy & services ,lcsh:R ,health policy ,General Medicine ,Health Services ,Meta-analysis ,Family medicine ,0305 other medical science ,business ,Delivery of Health Care - Abstract
ObjectivesTo systematically review the evidence base for a systems approach to healthcare design, delivery or improvement.DesignSystematic review with meta-analyses.MethodsIncluded were studies in any patients, in any healthcare setting where a systems approach was compared with usual care which reported quantitative results for any outcomes for both groups. We searched Medline, Embase, HMIC, Health Business Elite, Web of Science, Scopus, PsycINFO and CINAHL from inception to 28 May 2019 for relevant studies. These were screened, and data extracted independently and in duplicate. Study outcomes were stratified by study design and whether they reported patient and/or service outcomes. Meta-analysis was conducted with Revman software V.5.3 using ORs—heterogeneity was assessed using I2statistics.ResultsOf 11 405 records 35 studies were included, of which 28 (80%) were before-and-after design only, five were both before-and-after and concurrent design, and two were randomised controlled trials (RCTs). There was heterogeneity of interventions and wide variation in reported outcome types. Almost all results showed health improvement where systems approaches were used. Study quality varied widely. Exploratory meta-analysis of these suggested favourable effects on both patient outcomes (n=14, OR=0.52 (95% CI 0.38 to 0.71) I2=91%), and service outcomes (n=18, OR=0.40 (95% CI 0.31 to 0.52) I2=97%).ConclusionsThis study suggests that a systems approaches to healthcare design and delivery results in a statistically significant improvement to both patient and service outcomes. However, better quality studies, particularly RCTs are needed.PROSPERO registration numberCRD42017065920.
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- 2021
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19. Deletion of Exon 1 in AMER1 in Osteopathia Striata with Cranial Sclerosis
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Stephen P. Robertson, Benjamin J. Halliday, David Markie, Emma M. Wade, Padmini Parthasarathy, Timothy R. Morgan, Małgorzata J.M. Nowaczyk, John Dean, and Jingyi Mi
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0301 basic medicine ,lcsh:QH426-470 ,Case Report ,030105 genetics & heredity ,Biology ,DNA sequencing ,Osteopathia striata ,Frameshift mutation ,03 medical and health sciences ,Exon ,WTX ,Genetics ,medicine ,osteopathia striata with cranial sclerosis ,Multiplex ligation-dependent probe amplification ,Genetics (clinical) ,Exome sequencing ,Macrocephaly ,AMER1 ,medicine.disease ,Phenotype ,lcsh:Genetics ,030104 developmental biology ,medicine.symptom - Abstract
Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of AMER1, or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in AMER1. Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of AMER1 in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content.
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- 2020
20. SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect
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Emma Bedoukian, Chiara Fallerini, Francesca Mari, Ruth Newbury-Ecob, Diego Lopergolo, Luke Mansard, Alessandra Renieri, John Dean, Anne-Françoise Roux, Helen Cox, Marjolaine Willems, Alisdair McNeill, Tommaso Pippucci, David Baux, Ajith Kumar, Eric Delpire, Christel Vaché, Catherine Blanchet, David Goudie, and Emanuela Iovino
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Member 2 ,0301 basic medicine ,Adult ,Male ,Brain ,Corticogenesis ,De novo mutation ,Exome ,Neurodevelopmental disorder ,Adolescent ,Bilateral Vestibulopathy ,Child ,Child, Preschool ,Female ,Hearing Loss, Sensorineural ,Humans ,Infant ,Mutation ,Neurodevelopmental Disorders ,Solute Carrier Family 12, Member 2 ,Young Adult ,Solute Carrier Family 12 ,Sensorineural ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Preschool ,Hearing Loss ,Exome sequencing ,Genetics ,Neurogenesis ,medicine.disease ,030104 developmental biology ,Sensorineural hearing loss ,Neurology (clinical) ,Neural development ,030217 neurology & neurosurgery ,Reports - Abstract
The SLC12 gene family consists of SLC12A1–SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16–18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16–18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.
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- 2020
21. A coordinated approach to patient safety for people with adrenal insufficiency
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John Dean
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Concise Guidance ,medicine.medical_specialty ,Adult patients ,Emergency management ,Hydrocortisone ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,MEDLINE ,General Medicine ,030204 cardiovascular system & hematology ,Emergency treatment ,medicine.disease ,03 medical and health sciences ,Patient safety ,0302 clinical medicine ,Emergency medicine ,Adrenal insufficiency ,medicine ,Humans ,In patient ,030212 general & internal medicine ,Patient Safety ,business ,Glucocorticoids ,Adrenal Insufficiency - Abstract
The publication of ‘Guidance for the prevention and emergency management of adult patients with adrenal insufficiency’ and how it links to coordinated actions marks a potential landmark in patient safety in the UK. The challenge of reliable emergency treatment for people with known or potential
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- 2020
22. VTE prophylaxis for medical patients when they leave hospital: a wider approach to future research and evidence is required
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John Dean
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medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Nice ,Anticoagulants ,General Medicine ,Venous Thromboembolism ,030204 cardiovascular system & hematology ,Vte prophylaxis ,Hospitals ,Hospitalization ,03 medical and health sciences ,0302 clinical medicine ,Excellence ,Risk Factors ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,business ,Letters to the Editor ,Venous thromboembolism ,computer ,computer.programming_language ,media_common - Abstract
Editor – Clinical Medicine has published a summary of the National Institute for Health and Care Excellence (NICE) NG89 recommendations on venous thromboembolism (VTE) prophylaxis.[1,2][1] Subsequently the guidance for pharmacological prophylaxis for a minimum of 7 days for medical inpatients who
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- 2020
23. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients
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Thomas Besnard, Kristian Tveten, Hilary F Kitson, Jennifer A. Lee, Brieana Fregeau, Rachel Schot, Khadija Wilson, Katrin Õunap, Juliane Winkelmann, Anna Lehman, Nicola Longo, Servi J. C. Stevens, Megan T. Cho, Christina G.S. Palmer, Causes Study, Giovanni Battista Ferrero, Joy Dean, Lone W. Laulund, Grazia M.S. Mancini, Matias Wagner, Martin G. Martin, Sabine Lüttgen, Elizabeth J. Bhoj, Amanda J. Yoon, Thomas Klopstock, Janet S. Sinsheimer, Eric Vilain, Sébastien Küry, Francesca Clementina Radio, Jiddeke M. van de Kamp, Cameron Mrokse, Hakon Hakonarson, Samuel G. Cox, Jeanette C. Papp, Margot I. Van Allen, Raymond J. Louie, Constance T. R. M. Stumpel, Evan F. Joiner, Juanita Neira, Arve Vøllo, Amy Pizzino, Kelly Radtke, Celeste Simon, Michelle L. Thompson, Allison Zheng, Omar Sherbini, Marcia C. Willing, Tim M. Strom, Benjamin Garcia, Sara S. Cathey, Theresa A. Grebe, Dong Li, Marjan M. Weiss, Marco Tartaglia, Laura M Bryant, Sandra Mercier, Katherine L. Helbig, Martin Jakob Larsen, Ddd Study, Alexandrea Wadley, Alexander P.A. Stegmann, Sabina Barresi, A. Micheil Innes, Elaine H. Zackai, Gregory Costain, Davor Lessel, Molly Snyder, Heather P. Crawford, Richard Redon, Pearl Lee, Melissa Byler, Holly Dubbs, J. Gage Crump, K. E. Stuurman, Boris Keren, Stéphane Bézieau, Stan F. Nelson, Kristin G. Monaghan, Michael J. Lyons, Jeffrey W. Innis, Anna C.E. Hurst, Elizabeth A. Sellars, Samantha A. Schrier Vergano, Saadet Mercimek-Andrews, Monica H. Wojcik, Alison Ross, Heiko Reutter, Zuo-Fei Yuan, Dylan M. Marchione, Renee Bend, Diana Carli, Zöe Powis, Neil H. Parker, Jennifer Muncy Thomas, Luis A. Umaña, Adeline Vanderver, Julia Hoefele, Linda Manwaring, Christina Fagerberg, Elly Brokamp, M. Stephen Meyn, Pilvi Ilves, Xavier de la Cruz, Nina Powell-Hamilton, Caroline Nava, Garrett Gotway, Karit Reinson, Kristin D. Kernohan, Jennifer Norman, Alexandra Afenjar, Benjamin Cogné, Delphine Héron, Roman Günthner, Alfredo Brusco, John Dean, Kevin A. Janssen, Robert Roger Lebel, Divya Nair, Jijun Wan, Julian A. Martinez-Agosto, Elliott H. Sherr, Kyle Retterer, Claudia B. Catarino, Michael E. March, Natalia Padilla, Elise Brimble, Sylvie Odent, Jane L. Schuette, David Chitayat, Klaas J. Wierenga, Kirsty McWalter, Trine Prescott, Jonas Denecke, Wendy K. Chung, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), and Clinical Genetics
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metabolism [Zebrafish Proteins] ,RESIDUE ,metabolism [Histones] ,GENES ,Somatic cell ,CODE ,cancer mutation ,histone ,Biology ,VARIANTS ,medicine.disease_cause ,progressive neurologic dysfunction ,Histones ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Germline mutation ,SDG 3 - Good Health and Well-being ,histone, neurodevelopmental disorder, progressive neurologic dysfunction, congenital anomalies, cancer mutation ,medicine ,Animals ,Humans ,H3-3A protein, human ,metabolism [Zebrafish] ,TRANSCRIPTION ,PHOSPHORYLATION ,Gene ,Zebrafish ,Germ-Line Mutation ,030304 developmental biology ,Genetics ,genetics [Zebrafish] ,0303 health sciences ,Multidisciplinary ,foxd3 protein, zebrafish ,congenital anomalies ,Forkhead Transcription Factors ,Zebrafish Proteins ,biology.organism_classification ,genetics [Histones] ,neurodevelopmental disorder ,H3F3B ,Histone ,genetics [Forkhead Transcription Factors] ,genetics [Neurodegenerative Diseases] ,biology.protein ,ddc:500 ,Carcinogenesis ,030217 neurology & neurosurgery - Abstract
Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome. Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation
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- 2020
24. Irbesartan in Marfan syndrome (AIMS):a double-blind, placebo-controlled randomised trial
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Michael Mullen, Xu Yu Jin, Anne Child, A Graham Stuart, Matthew Dodd, José Antonio Aragon-Martin, David Gaze, Anatoli Kiotsekoglou, Li Yuan, Jiangting Hu, Claire Foley, Laura Van Dyck, Rosemary Knight, Tim Clayton, Lorna Swan, John D R Thomson, Guliz Erdem, David Crossman, Marcus Flather, John Dean, Bartosz Was, Heather Gow, Jane Murray, Mariella D'Allessandro, Michael Christie, Patricia Cooper, Philip Booth, Sharon Burns, Yvonne Paterson, Ashish Chikermane, Anthony Assing, Catherine Cotter, Gillian Atkins, Helen Williamson, Justin Barclay, Alan Jennison, Alex Henderson, Anna McSkeane, Helen Fairlamb, Julie Kelly, Nicola Kelsall, Scott Prentice, John O'Sullivan, Alison Head-Baister, Angela Phillipson, Anna Johnson, D Crossland, Jack Oliver, Jade Davison, Jill Wake, Louise Quinn, Maureen Foreman, Vera Wealleans, Niki Walker, Alexis Duncan, Evelyn Tibbs, Ruth Kelly, Sachin Khambadkone, Bridget Zotti, Cassie Brady, Elena Cervi, Ella Field, Eszter Szepezvary, Florence Mantey, Gillian Riley, Heather Titmus, Ilaria Bo, Juan Pablo Kaski, Loren Green, Nigel Jones, Rebecca Banks, Christopher Kiesewetter, Sujeev Mathur, Alessandra Frigiola, Alex Savis, Holly Belfield, Josephine Guzman, Julia Harris, Karen Wilson, Kelly Peacock, Kirsty Gibson, Paul Wellman, John Simpson, Saleha Kabir, Sitali Mushemi, Michael Stewart, Bev Atkinson, Cath Richardson, Elaine Leng, Paul Brennan, Annabel Nixon, Collette Spencer, James Oliver, Jan Forster, Louise Turner, Samantha Bainbridge, Anna Maria Choy, Adelle Dawson, Gwen Kiddie, Heather Kerr, Ify Mordi, Jackie Duff, Jacqueline Dunlop, Jonathan Berg, Pauline Armory, Leisa Freeman, Amir Anwar, Charles Graham, Clare London, Gail Healey, Ian Gallagher, Mary Ilsley, Rizwan Ahmed, Sheila Wood, Nigel Wheeldon, Cecilia Mason, Farook Nassim, Janet Middle, Justin Adams, Karen Angelini, Kay Housley, Kim Ryalls, Michael Agyemang, Rachel Walker, Robina Batigan, Tina Bennett, Paul Clift, Amor Mia Alvior, Annette Nilsson, Carole Green, Charlotte Crook, Connie Becani Palmer, Elizabeth Dwenger, Phillipa Doherty, Rebecca Igbokwe, Saba Sharif, Sonia MacDonald, Cathy West, Kevin Kirby, Nitha Naqvi, Sophie Welch, Suad Warsama, Wei Li, Zohreh Farzad, Ben Smith, Victoria Murday, Eamonn Murtagh, Emma Adams, Lesley Armour, Stuart Lilley, Bejal Pandya, Amy Richards, Mervyn Andiapen, Rebecca Macrae, Maite Tome, Carmel Hutchinson, Kameka Angulo, Rooba Kauppayamootoo, Sabiha Gati, Elizabeth Cruddas, William G Newman, Catherine Breen, Dhavendra Kumar, Dirk G Wilson, Adele Farrugia, Alan Fraser, Jayne Sumers, Jessie Powell, Julie Edwards, Terese Hale, Zoe Boult, Aisling Carroll, Gruschen Veldtman, Andrew Ho, David Black, Lisa Fletcher, Sue Mapstone, Tara Bharucha, Gary Marsh, Joanne Jones, Karen Sheehan, Kathleen Selway, Kirsty Stevenson, Martin Nelson, Rebecca Fairweather, Stephanie Curtis, Sue Simpson, Martin Denvir, Audrey White, Jill Steven, Joanna Munro, Wayne Lam, William Toff, Mario Petrou, Paul Silcocks, Raymond MacAllister, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Office of the Principal, and Acibadem University Dspace
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Marfan syndrome ,Adult ,Male ,medicine.medical_specialty ,Angiotensins ,Adolescent ,E-DAS ,030204 cardiovascular system & hematology ,Placebo ,Drug Administration Schedule ,Article ,law.invention ,Marfan Syndrome ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Irbesartan ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,Clinical endpoint ,Medicine ,Humans ,030212 general & internal medicine ,Young adult ,Adverse effect ,Child ,Aorta ,R2C ,Receptors, Angiotensin ,business.industry ,Incidence (epidemiology) ,~DC~ ,General Medicine ,medicine.disease ,United Kingdom ,Treatment Outcome ,Echocardiography ,Cardiology ,RC Internal medicine ,Female ,business ,BDC ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug ,RC - Abstract
Background Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. Methods We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6–40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. Findings Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12–28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of −0·22 mm per year (−0·41 to −0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means −0·10 per year, 95% CI −0·19 to −0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. Interpretation Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. Funding British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.
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- 2019
25. The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients
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Silvia Maitz, Elisa Rahikkala, Wayne Lam, Pedro A. Sanchez-Lara, Katherine Lachlan, Melissa Lees, Katherine L. Nathanson, Chey Loveday, Lionel Van Maldergem, Shane McKee, Dragana Josifova, Sally Ann Lynch, Katrina Tatton-Brown, Michael Parker, Ana Beleza-Meireles, Andrew G. L. Douglas, Sarina G. Kant, Philip J. Ostrowski, Tyler Mark Pierson, Yvonne Hilhorst-Hofstee, Sofia Douzgou, Kay Metcalfe, Marta Bertoli, Charlotte W. Ockeloen, Usha Kini, Diana Johnson, John Dean, Alice Spano, Trevor Cole, Alison Foster, Jennifer Hague, John M. Graham, Ian O. Ellis, Anna Zachariou, and Mariëtte J.V. Hoffer
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Scoliosis ,macrocephaly ,Young Adult ,CHD8 ,Intellectual disability ,Genetics ,medicine ,Humans ,Child ,overgrowth ,Genetics (clinical) ,Growth Disorders ,business.industry ,Macrocephaly ,Infant ,Syndrome ,medicine.disease ,Cadherins ,Umbilical hernia ,Neonatal hypotonia ,Phenotype ,intellectual disability ,Overgrowth syndrome ,Child, Preschool ,Autism ,Female ,Differential diagnosis ,medicine.symptom ,business ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Item does not contain fulltext CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference >/=2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (
- Published
- 2019
26. Premature Ejaculation (lifelong and acquired)
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John Dean, Luiz Otavio Torres, Alan W. Shindel, Robert Taylor Segraves, Emmanuele A. Jannini, Edgardo F. Becher, Ege Can Serefoglu, Chris McMahon, David L. Rowland, Stanley E. Althof, Ira D. Sharlip, Sidney Glina, Wayne J. G. Hellstrom, Luca Incrocci, Marcel D. Waldinger, Ganesh Adaikan, Annamaria Giraldi, F. Giuliano, Marita P. McCabe, and Sharon J. Parish
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medicine.medical_specialty ,Obstetrics ,business.industry ,Premature ejaculation ,medicine ,Personal distress ,medicine.symptom ,business - Published
- 2019
27. Parents’ views of genetic testing and treatment of familial hypercholesterolemia in children: a qualitative study
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Lorna McKee, William G. Simpson, Zosia Miedzybrodzka, Karen Forrest Keenan, Robert Finnie, and John Dean
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Parents ,0301 basic medicine ,medicine.medical_specialty ,Epidemiology ,Population ,Psychological intervention ,Context (language use) ,Disease ,030105 genetics & heredity ,03 medical and health sciences ,Familial hypercholesterolemia (FH) ,Qualitative interviews ,medicine ,Early childhood ,education ,Children ,Genetics (clinical) ,Genetic testing ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Public health ,Public Health, Environmental and Occupational Health ,Treatment ,030104 developmental biology ,Family medicine ,Original Article ,Thematic analysis ,business - Abstract
Familial hypercholesterolemia (FH) is a serious inherited disorder, which greatly increases individuals' risk of cardiovascular disease (CVD) in adult life. However, medical treatment and lifestyle adjustments can fully restore life expectancy. Whilst European guidance advises that where there is a known family mutation genetic testing is undertaken in early childhood, the majority of the at-risk population remain untested and undiagnosed. To date, only a small number of studies have explored parents' and children's experiences of testing and treatment for FH, and little is known about interactions between health professionals, parents, and children in clinic settings. In this study, in-depth interviews were undertaken with parents who had attended a genetics and/or lipid clinic for FH with their children (n = 17). A thematic analysis revealed four main themes: undertaking early prevention, postponing treatment, parental concerns, and the importance of the wider family context. The majority of parents supported genetic testing for FH in childhood. However, although some were very supportive of following early treatment recommendations, others expressed reluctance. Importantly, some parents were concerned that inappropriate information had been shared with their children and wished that more time had been given to discuss how, when, and what to tell in advance. Future research is needed to explore the long-term outcomes for children who undertake genetic testing and early treatment for FH and to trial interventions to improve the engagement, follow-up, and support of children who are at risk, or diagnosed, with this disorder.
- Published
- 2018
28. The frailest of the frail? Addressing the palliative care needs of frail older patients
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John Dean, Marie O'Neill, Mustafa Abu-Rabia, Joanne K. Taylor, Raymond Hyatt, and Nikesh Patel
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Advance care planning ,medicine.medical_specialty ,Focus on End-of-Life Care ,Palliative care ,Quality management ,business.industry ,media_common.quotation_subject ,030204 cardiovascular system & hematology ,medicine.disease ,Pro forma ,03 medical and health sciences ,0302 clinical medicine ,Family medicine ,Structured interview ,medicine ,Dementia ,Conversation ,Residence ,030212 general & internal medicine ,business ,media_common - Abstract
Managing patients with frailty is an increasing element of acute hospital care, constituting around 40% of acute hospital inpatients. Up to half of these patients may be approaching the end of their life, and many also have repeated hospital admissions. We therefore undertook a quality improvement project to help us identify the prevalence of frail older inpatients approaching end of life and to better identify these patients in advance. We also developed and evaluated a pro forma to assist in initiating an advance care planning conversation with the patient and/or family. Fifty percent of our frail older inpatients were assessed as approaching end of life. Factors identifying older inpatients as more likely to die during the hospital admission included residence in a care home, two or more hospital admissions over the preceding 12 months, and a diagnosis of some form of dementia for more than 3 years. A novel goals and priorities of care (GPOC) document was found to support and guide palliative care conversations. Acute hospital care could be organised more effectively to recognise the potential need for palliative care in frail older patients. Identifying those at higher risk and using structured interviews and documentation is helpful, ultimately resulting in more appropriate care. Well-developed communication skills are needed for these complex care planning conversations.
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- 2018
29. Extending the phenotype associated with the CSNK2A1‐ related Okur–Chung syndrome—A clinical study of 11 individuals
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Ceris I, Owen, Ramsay, Bowden, Michael J, Parker, Jo, Patterson, Joan, Patterson, Sue, Price, Ajoy, Sarkar, Bruce, Castle, Charulatha, Deshpande, Miranda, Splitt, Neeti, Ghali, John, Dean, Andrew J, Green, Charlene, Crosby, and Katrina, Tatton-Brown
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Heart malformation ,Amino Acid Motifs ,Clinical study ,03 medical and health sciences ,Swallowing ,Protein kinase CK2 ,Intellectual disability ,Genetics ,medicine ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Casein Kinase II ,Child ,Alleles ,Genetics (clinical) ,Exome sequencing ,business.industry ,Facies ,Exons ,medicine.disease ,Phenotype ,Hypotonia ,3. Good health ,030104 developmental biology ,Amino Acid Substitution ,Neurodevelopmental Disorders ,Mutation ,Female ,medicine.symptom ,business ,Protein Binding - Abstract
Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.
- Published
- 2018
30. 188 Development of WU-NK-101, a feeder cell-free expanded allogeneic memory NK cell product with potent anti-tumor activity
- Author
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Ayman Kabakibi, Niraj Shrestha, Alex Vessoni, Todd A. Fehniger, Michelle Becker-Hapak, Corey Johnson, Ethan McClain, Ken Chrobak, Mark P. Foster, Michael J. Dee, Malik Darwech, Ryan J. Sullivan, Alexander S. Hamil, Jennifer Govero, John Dean, You Zhou, Tom Leedom, Brunda Tumala, Carly Neal, Andrew Martens, Hing C. Wong, Melissa Berrien-Elliot, Mary Mathyer, and Matthew L. Cooper
- Subjects
Pharmacology ,Cancer Research ,medicine.medical_treatment ,T cell ,Immunology ,Cell ,Biology ,Cytokine ,medicine.anatomical_structure ,Oncology ,Cancer immunotherapy ,Cell culture ,medicine ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,Cytokine secretion ,IL-2 receptor ,K562 cells - Abstract
BackgroundAllogeneic Natural Killer (NK) cells are emerging as a safe and effective modality for the treatment of cancer, overcoming several limitations associated with adoptive T cell therapies. Cytokine induced memory-NK cells offer several advantages over conventional NK cells, including enhanced functional persistence, efficacy, and metabolic fitness. Additionally, unlike iPSC and cord blood derived NK cells, they do not require engineering to enable functionality. Here we describe the use of WU-PRIME, a GMP-grade fusion protein complex to generate memory NK cells, and WU-EXPAND, a feeder cell free expansion system to expand memory-NK cells and create WU-NK-101. Further cryopreservation enables the large-scale, off-the-shelf manufacture of memory NK for cancer immunotherapy, with high anti-tumor activity.MethodsNK cells derived from healthy donor leukopheresate were either activated with WU-PRIME and then expanded with WU-EXPAND to form WU-NK-101 or immediately expanded with WU- EXPAND as controls and then cryopreserved. We compared NK cell expansion as well as post- thaw NK cell functionality as assessed by cytokine secretion and short-term and long-term anti- tumor functionality, long-term persistence in NSG mice, as well as anti-tumor activity in vivo.ResultsNK cells activated with WU-PRIME followed by WU-EXPAND (WU-NK-101), expand robustly in large-scale reactions, over 250-fold in 14 days. The cells maintain durable expression of CD25 after expansion, as well as several other hallmarks of the memory-NK phenotype as assessed by mass cytometry. As compared to cells expanded with WU-EXPAND only, WU-NK-101 cells have improved in vitro activity against K562 cells, as well as AML cell lines (TF-1, THP-1, and HL-60). Notably, this functionality is maintained long-term upon repeated challenge. In vivo, WU-NK-101 cells, compared to expanded NK cells have improved in vivo persistence (figure 1; 50,290 v. 9,623, pAbstract 188 Figure 1NK cell persistence in tumor-bearing mice. 10e6 cryopreserved NK cells were injected into K562 tumor-bearing mice, and supported with 50,000IU human IL-2 every other day. After 9 days, blood was harvested by cheek bleed and assessed for NK cells (hCD45+, CD56+, CD3) in the blood by flow cytometry.ConclusionsThe data demonstrate that WU-NK-101 generated using a feeder cell-free expansion system has a memory phenotype and improved in vitro and in vivo anti-tumor activity compared to conventional NK cells. This activation and expansion platform will enable the development and clinical translation of multiple allogeneic NK cell therapies.
- Published
- 2021
31. Phenotypic spectrum associated with de novo mutations in QRICH1 gene
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John Dean, Ddd Study, A Ververi, Miranda Splitt, and Angela F. Brady
- Subjects
0301 basic medicine ,Genetics ,biology ,Inflammation ,medicine.disease ,Phenotype ,QRICH1 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Speech delay ,medicine ,biology.protein ,Autism ,Creatine kinase ,medicine.symptom ,Gene ,030217 neurology & neurosurgery ,Genetics (clinical) ,Exome sequencing - Abstract
Rare de novo mutations represent a significant cause of idiopathic developmental delay (DD). The use of next-generation sequencing (NGS) has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present 3 unrelated children with de novo loss-of-function (LoF) mutations in QRICH1, diagnosed through trio-based exome sequencing. QRICH1 encodes the glutamine-rich protein 1, which contains 1 caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. All 3 children had speech delay, learning difficulties, a prominent nose and a thin upper lip. In addition, 2 of them had mildly raised creatine kinase (CK) and 1 of them had autism. Despite their small number, the patients had a relatively consistent pattern of clinical features suggesting the presence of a QRICH1-associated phenotype. LoF mutations in QRICH1 are suggested as a novel cause of DD.
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- 2017
32. Existing and Future Educational Needs in Graduate and Postgraduate Education
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Sue W. Goldstein, John Dean, Ian Eardley, Yacov Reisman, Andrew C. Kramer, and Eli Coleman
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Urology ,Endocrinology, Diabetes and Metabolism ,education ,030232 urology & nephrology ,Specialty ,Human sexuality ,Sex Education ,Certification ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Sexual medicine ,Curriculum development ,Humans ,Medicine ,Sexual Dysfunctions, Psychological ,030212 general & internal medicine ,Curriculum ,Societies, Medical ,Reproductive health ,Medical education ,Education, Medical ,business.industry ,Sexual Dysfunction, Physiological ,Psychiatry and Mental health ,Reproductive Medicine ,Education, Medical, Graduate ,Education, Medical, Continuing ,Sexology ,Faculty development ,business - Abstract
Introduction This review was designed to make recommendations on future educational needs, principles of curricular development, and how the International Society for Sexual Medicine (ISSM) should address the need to enhance and promote human sexuality education around the world. Aim To explore the ways in which graduate and postgraduate medical education in human sexuality has evolved and is currently delivered. Methods We reviewed existing literature concerning sexuality education, curriculum development, learning strategies, educational formats, evaluation of programs, evaluation of students, and faculty development. We reviewed literature relating to four main areas: (i) the current status of the international regulation of training in sexual medicine; (ii) the current delivery of education and training in sexual medicine; (iii) resident and postgraduate education in sexual medicine surgery; and (iv) education and training for allied health professionals. Results The main findings in these four areas are as follows. Sexual medicine has grown considerably as a specialty during the past 20 years, with many drivers being identified. However, the regulatory aspects of training, assessment, and certification are currently in the early stages of development and are in many ways lagging behind the scientific and clinical knowledge in the field. However, there are examples of the development of curricula with accompanying assessments that have attempted to set standards of education and training that might underlie the delivery of high-quality care to patients in sexual medicine. The development of competence assessment has been applied to surgical training in sexual medicine, and there is increasing interest in simulation as a means of enhancing technical skills training. Although the focus of curriculum development has largely been the medical profession, there is early interest in the development of standards for training and education of allied health professionals. Conclusion Organizations of professionals in sexual health, such as the ISSM, have an opportunity, and indeed a responsibility, to provide and disseminate learning opportunities, curricula, and standards of training for doctors and allied health professionals in sexual medicine.
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- 2017
33. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy
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Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
- Subjects
0301 basic medicine ,Male ,Microcephaly ,[SDV]Life Sciences [q-bio] ,Haploinsufficiency ,autism ,epilepsy ,epileptic encephalopathy ,global developmental delay ,H3K4 methylation ,intellectual disability ,KMT2E ,neurodevelopmental disorder ,Adolescent ,Adult ,Child ,Child, Preschool ,DNA-Binding Proteins ,Epilepsy ,Female ,Humans ,Infant ,Neurodevelopmental Disorders ,Pedigree ,Phenotype ,Young Adult ,Genetic Variation ,Heterozygote ,0302 clinical medicine ,Neurodevelopmental disorder ,Intellectual disability ,Global developmental delay ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,Genetics ,0303 health sciences ,Hypotonia ,030220 oncology & carcinogenesis ,medicine.symptom ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,03 medical and health sciences ,Report ,medicine ,Journal Article ,Expressivity (genetics) ,Preschool ,030304 developmental biology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,business.industry ,Macrocephaly ,medicine.disease ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Autism ,business ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
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- 2019
34. MP40-13 UNDERSTANDING THE SEXUAL HABITS OF MEN TAKING MEDICATION FOR ERECTILE DYSFUNCTION: SURVEY RESULTS FROM AUSTRALIA, EGYPT, MEXICO AND UNITED KINGDOM
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John Dean, Ahmed I. El-Sakka, Shaantanu Donde, Tarek A. Hassan, and Chad D. Harshman-Smith
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medicine.medical_specialty ,Erectile dysfunction ,Sexual behavior ,business.industry ,Urology ,Family medicine ,medicine ,Effective management ,Survey result ,Context (language use) ,business ,medicine.disease ,Taking medication - Abstract
INTRODUCTION AND OBJECTIVES:Effective management of erectile dysfunction (ED) requires an understanding of people’s planning of intercourse, yet studies exploring sexual behavior in the context of ...
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- 2019
35. Correction: Are viral-infections associated with Ménière's Disease? A systematic review and meta-analysis of molecular-markers of viral-infection in case-controlled observational studies of MD
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Nicholas John Dean, Christopher Pastras, Daniel Brown, and Aaron Camp
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Multidisciplinary ,Databases, Factual ,Science ,Correction ,Cytomegalovirus ,Antibodies, Viral ,Observational Studies as Topic ,Virus Diseases ,DNA, Viral ,Odds Ratio ,Humans ,Medicine ,Meniere Disease - Abstract
Despite considerable research, it remains controversial as to whether viral-infections are associated with Meniere's Disease (MD), a clinically heterogeneous set of chronic inner-ear disorders strongly associated with endolymphatic hydrops. Here, we investigated whether viral-infections are associated with MD through a systematic review and meta-analysis of observational clinical studies using molecular-diagnostics. Eligible for inclusion were case-controlled studies which ascertained molecular-determinants of past or present viral-infection through either viral nucleic acids or host serological marker in MD cases and non-MD controls. Across online databases and grey literature, we identified 210 potentially relevant articles in the English language, from which a total of 14 articles fully satisfied our eligibility criteria such that meta-groups of 611 MD-cases and 373 controls resulted. The aggregate quality of the modest-sized (14 studies) body of evidence was limited and varied considerably with regards to participant selection, matching, and ascertainment(s) and determinant(s) of viral-infection. Most data identified concerned the human cytomegalovirus (CMV), and meta-analysis of eligible studies revealed that evidence of CMV-infection was associated approximately three-fold with MD compared to controls, however the timing of the infections was indeterminate as the pooled analyses combined antiviral serological markers with viral nucleic acid markers. No association was found for any of HSV-1, -2, VZV, or EBV. Associative analyses of any viral species not aforementioned were precluded by limited data, and thus potential associations between other viral species and MD, especially other than Herpesviridae, are yet to be characterised. Overall, we have found a small association between CMV-infection and MD, however it is to be determined for what sub-groups of MD this finding may be relevant, and ideally the reported association remains would be reproduced by a greater volume of higher quality evidence.
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- 2019
36. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia
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Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
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0301 basic medicine ,Male ,Adolescent ,Loss of Heterozygosity ,Context (language use) ,Postnatal microcephaly ,Neurotransmission ,medicine.disease_cause ,Bioinformatics ,Synaptic Transmission ,Loss of heterozygosity ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Calcium Channels, N-Type ,Report ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,Mutation ,Dyskinesias ,business.industry ,Infant ,medicine.disease ,Hypotonia ,Pedigree ,030104 developmental biology ,Dyskinesia ,Child, Preschool ,Calcium ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
© 2019 American Society of Human Genetics 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.
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- 2018
37. Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes
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Rebecca Bromley, Susan E. Holder, Jill Clayton-Smith, Charu Deshpande, Deciphering Developmental Disorders Study, Adam Jackson, Nora Shannon, Heather Ward, Pradeep Vasudevan, Diana Baralle, Ingrid Scurr, John Dean, and Jonathan Berg
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Male ,Developmental Disabilities ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,030225 pediatrics ,Exome Sequencing ,medicine ,Humans ,Copy-number variation ,Child ,Exome sequencing ,Retrospective Studies ,Epilepsy ,Microarray analysis techniques ,business.industry ,Valproic Acid ,Chromosome ,Abnormalities, Drug-Induced ,Carbamazepine ,medicine.disease ,Phenotype ,Developmental disorder ,Pregnancy Complications ,In utero ,Child, Preschool ,Prenatal Exposure Delayed Effects ,Pediatrics, Perinatology and Child Health ,Anticonvulsants ,Female ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.MethodsWe reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.ResultsSeven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).ConclusionsThis study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.
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- 2018
38. De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism
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Susan E. Holder, Claudio Graziano, Véronique Lefebvre, Joshua D. Smith, Ash Zawerton, Lisa Wischmann, Susanne J. Kühl, John Dean, Tommaso Pippucci, J. Paige Yeager, Deciphering Developmental Disorders Study, Daniela T. Pilz, Baojin Yao, Abdul Haseeb, and Alisdair McNeill
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0301 basic medicine ,Male ,Transcriptional Activation ,Heterozygote ,In silico ,Xenopus ,Mutation, Missense ,Biology ,Xenopus Proteins ,Article ,SOXC Transcription Factors ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,medicine ,Genetics ,Coffin-Lowry Syndrome ,Missense mutation ,Animals ,Humans ,Abnormalities, Multiple ,Amino Acid Sequence ,Child ,Transcription factor ,Exome sequencing ,Genetics (clinical) ,Conserved Sequence ,SOX Transcription Factors ,Reporter gene ,Neurogenesis ,Correction ,DNA ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,Neurodevelopmental Disorders ,Child, Preschool ,HMG-Box Domains ,Female ,030217 neurology & neurosurgery - Abstract
SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.
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- 2018
39. Phenotype-driven molecular autopsy for sudden cardiac death
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Dawn O'Sullivan, H. Hailey, John Dean, Michael Corbett, Stephen Tennant, Paul Broadhurst, Fiona Cann, James Hk Grieve, and Rosslyn Rankin
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0301 basic medicine ,medicine.medical_specialty ,DSC2 ,business.industry ,Cardiomyopathy ,Hypertrophic cardiomyopathy ,030204 cardiovascular system & hematology ,030105 genetics & heredity ,medicine.disease ,Sudden death ,Right ventricular cardiomyopathy ,Sudden cardiac death ,Arrhythmogenic right ventricular dysplasia ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Cardiology ,MYH7 ,business ,Genetics (clinical) - Abstract
A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.
- Published
- 2016
40. Structural and electrical cardiac abnormalities are prevalent in asymptomatic adults with myotonic dystrophy
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John Dean, Graham S. Hillis, David S. Celermajer, Preeti Choudhary, Paul Broadhurst, Heather Greig, Ramasami Nandakumar, and Rajesh Puranik
- Subjects
Male ,Ventricular Dysfunction, Right ,Action Potentials ,030204 cardiovascular system & hematology ,Doppler echocardiography ,Ventricular Function, Left ,0302 clinical medicine ,Heart Rate ,Risk Factors ,Natriuretic Peptide, Brain ,Prevalence ,Myotonic Dystrophy ,Ventricular Remodeling ,medicine.diagnostic_test ,Middle Aged ,Prognosis ,Magnetic Resonance Imaging ,Echocardiography, Doppler ,cardiovascular system ,Cardiology ,Female ,Electrical conduction system of the heart ,medicine.symptom ,Cardiomyopathies ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,Myotonic dystrophy ,Asymptomatic ,03 medical and health sciences ,Heart Conduction System ,Internal medicine ,medicine ,Humans ,Genetic testing ,Asymptomatic Diseases ,business.industry ,Myocardium ,Case-control study ,Arrhythmias, Cardiac ,Stroke Volume ,medicine.disease ,Fibrosis ,Scotland ,Case-Control Studies ,Electrocardiography, Ambulatory ,Ventricular Function, Right ,business ,Electrocardiography ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Cardiac disease accounts for a large burden of premature mortality and morbidity in patients with type 1 myotonic dystrophy (MD). However, little is known about structural cardiac abnormalities particularly in asymptomatic patients with MD. We sought to describe the prevalence and extent of structural cardiac abnormalities in patients with MD and to assess their association with functional, electrical, biochemical and genetic disturbances.In this case-control study, 40 adults with MD who had no contraindications to cardiac MRI (CMR) were identified from the Grampian region genetic database. Forty-one age-and-gender-matched healthy volunteers were also recruited. All subjects underwent detailed assessment including CMR, echocardiography, electrocardiography, signal-averaged electrocardiography, Holter monitoring and quantification of serum B-type natriuretic peptide (BNP). Genetic testing of patients with MD was performed with quantification of CTG trinucleotide repeat sequences. Results of clinical, electrical, genetic and biochemical investigations were correlated with cardiac structural and functional abnormalities detected on CMR.Electrical disturbances including prolongation of PR (187±29 vs 156±23 ms, p0.001) and QRS intervals (99±11 vs 89±9 ms, p0.001) were the most prevalent abnormality. Patients with MD had a significantly lower left ventricular (LV) mass (142±44 vs 172±73 g, p=0.03) and lower right ventricular (RV) ejection fraction (46±9 vs 50±7%, p=0.02) compared with controls, although LV ejection fraction was similar between the groups (58±8 vs 59±6%, p=0.34). LV non-compaction was also significantly more prevalent in the MD cohort (35% vs 12%, p=0.019). Late gadolinium enhancement was present in 13% of patients with MD. Muscular disability scores correlated with electrical changes (r=0.529, p0.001); however, the number of CTG repeat sequences did not correlate with either electrical or structural abnormalities.Patients with MD have a high prevalence of both electrical and structural abnormalities. These include reduced LV mass, impaired RV contractility, a high prevalence of LV non-compaction and myocardial fibrosis. These findings illustrate the potential utility of CMR detecting subclinical disease in otherwise asymptomatic patients with MD.
- Published
- 2016
41. Survey of the Literature December 2015
- Author
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Johanna L. Hannan, Lesley Marson, Rose Hartzell-Cushanick, John Dean, Theodore R. Saitz, Sophie Bergeron, and Michael Krychman
- Subjects
Information retrieval ,business.industry ,Urology ,Endocrinology, Diabetes and Metabolism ,lcsh:R ,lcsh:Medicine ,Dermatology ,lcsh:Other systems of medicine ,Survey of Literature ,lcsh:RZ201-999 ,Data science ,Behavioral Neuroscience ,Psychiatry and Mental health ,Endocrinology ,Text mining ,Reproductive Medicine ,Medicine ,business - Published
- 2015
42. A New, Atypical Case of Cobalamin F Disorder Diagnosed by Whole Exome Sequencing
- Author
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Shalaka Samant, Panayiotis Constantinou, John Dean, Paul Lochhead, Mariella D'Alessandro, W. Michael Bisset, and Catherine Hauptfleisch
- Subjects
Pediatrics ,medicine.medical_specialty ,Unilateral renal agenesis ,Pathology ,business.industry ,Prominent metopic suture ,Compound heterozygosity ,Cobalamin ,LMBRD1 mutation ,3. Good health ,chemistry.chemical_compound ,chemistry ,Novel Insights from Clinical Practice ,Failure to thrive ,Cobalamin F disorder ,Genetics ,medicine ,medicine.symptom ,LMBRD1 gene ,business ,Genetics (clinical) ,Exome sequencing - Abstract
Cobalamin F (cblF) disorder, caused by homozygous or compound heterozygous mutations in the LMBRD1 gene, is a recognised cause of developmental delay, pancytopaenia and failure to thrive which may present in the neonatal period. A handful of cases have been reported in the medical literature. We report a new case, diagnosed at the age of 6 years through whole exome sequencing, with atypical features including prominent metopic suture, cleft palate, unilateral renal agenesis and liver abnormalities, which broaden the phenotypic spectrum.
- Published
- 2015
43. Safety of referred doctors: All doctors are human and therefore vulnerable
- Author
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John Dean
- Subjects
medicine.medical_specialty ,media_common.quotation_subject ,Humiliation ,General Medicine ,030204 cardiovascular system & hematology ,Livelihood ,Sadness ,03 medical and health sciences ,0302 clinical medicine ,medicine ,030212 general & internal medicine ,Psychiatry ,Psychology ,media_common - Abstract
This Week, 7 March I read this news story1 with great sadness. A systemic failure has led to the suicide of a doctor fearing the loss of his livelihood, public disgrace, and humiliation based …
- Published
- 2020
44. Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection
- Author
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Basil Paul, Yong Xu, Guo-Lian Ding, Yan Kong, Ddd study, Qi Wu, Xinguo Hou, Wenjun Zhou, Atteeq U. Rehman, Sungguan Hong, Yanlin He, John Dean, Wenxian Zhou, Zhandong Liu, Pengfei Liu, Chuhan Wang, Zheng Sun, Emmanuel Scalais, Hari Krishna Yalamanchili, Ying-Wooi Wan, Mary O'Driscoll, Hao Liu, Jenny Morton, Yingyun Gong, and Qingchun Tong
- Subjects
0301 basic medicine ,Lateral hypothalamus ,Databases, Factual ,Hypothalamus ,Mice, Transgenic ,Hippocampal formation ,Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Memory ,Intellectual Disability ,Neural Pathways ,medicine ,Animals ,Nuclear Receptor Co-Repressor 1 ,Nuclear Receptor Co-Repressor 2 ,GABAergic Neurons ,Nuclear receptor co-repressor 1 ,Memory Disorders ,Neuronal Plasticity ,GABAA receptor ,General Neuroscience ,Excitatory Postsynaptic Potentials ,Long-term potentiation ,Receptors, GABA-A ,CA3 Region, Hippocampal ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Synaptic plasticity ,GABAergic ,Neuron ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.
- Published
- 2018
45. Marfan Syndrome and Related Disorders
- Author
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John Dean and Bart Loeys
- Subjects
Nosology ,Marfan syndrome ,Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Loeys–Dietz syndrome ,Craniosynostosis ,Pharmacotherapy ,Medicine ,Hypertelorism ,medicine.symptom ,business ,Ectopia lentis ,Genetic testing - Abstract
Marfan syndrome is the best known of the hereditary aortopathies, but its clinical variability and multisystem involvement often make diagnosis and management challenging. The skeletal and ocular findings overlap with other conditions, but FBN1 genetic testing and clinical assessment using the Ghent nosology is recommended. Loeys Dietz Syndrome is a related aortopathy, associated with changes in other genes in the same pathway (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 and SMAD2). Features such as cleft palate, bifid uvula, hypertelorism, craniosynostosis and osteoarthritis and the absence of ectopia lentis suggest Loeys Dietz. Trial evidence suggests that beta-blockers and angiotensin 2 receptor blockers delay dilatation of the Marfan aorta. Regular imaging is required to determine the timing of prophylactic aortic root surgery. Management of Loeys Dietz Syndrome follows similar principles, except that drug therapy has not been proven in trials, and more widespread imaging of the arterial tree and earlier surgery is recommended.
- Published
- 2018
46. Diagnosing secondary hypogonadism: important consequences for fertility and reversibility
- Author
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Edward D. Kim, Frederick C. W. Wu, Mario Maggi, Wayne J.G. Hellstrom, John Dean, Andrew McCullough, Bert-Jan de Boer, Mohit Khera, and Michael Zitzmann
- Subjects
Adult ,Male ,medicine.medical_specialty ,Urology ,media_common.quotation_subject ,030232 urology & nephrology ,Fertility ,Male infertility ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Testosterone ,Infertility, Male ,Aged ,media_common ,Gynecology ,030219 obstetrics & reproductive medicine ,business.industry ,Hypogonadism ,Testosterone (patch) ,Luteinizing Hormone ,Middle Aged ,medicine.disease ,Luteinizing hormone ,business - Published
- 2015
47. A mutation in theLMOD1actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections
- Author
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Yui Bong Alexander Wan, Yukiko Isekame, Jose Antonio Aragon-Martin, Daniel P. S. Osborn, Louise Benarroch, Maria Teresa Tome Esteban, Jaipreet Bharj, Guilleame Jondeau, Marjan Jahangiri, Anand Saggar, James Sneddon, Dongchuan Guo, Catherine Boileau, Elizabeth M. C. Fisher, Ellen S. Regalado, Alberto Smith, John Dean, Anne H. Child, Michael A. Simpson, Elijah R. Behr, and Dianna M. Milewicz
- Subjects
Proband ,Genetics ,medicine.anatomical_structure ,Mutation (genetic algorithm) ,Myosin ,medicine ,Missense mutation ,Smooth muscle contraction ,Biology ,Allele ,Aortic arches ,Exome - Abstract
We describe a mutation inLMOD1, which predisposes individuals to thoracic aortic aneurysms and dissections in a large multi-generation British family. Exome variant profiles for the proband and two distantly related affected relatives were generated and a rare protein-altering, heterozygous variant was identified, present in all the exome-sequenced affected individuals. The allele c.1784T>C, p.(V595A) inLMOD1is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family.LMOD1was further assessed in a consecutive series of 98 UK TAAD patients and one further mutation was found, yielding an incidence of ∼2% in our study group. Assessment ofLMOD1in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic.Validation ofLMOD1was undertaken using a zebrafish animal model. Knock-down of bothlmod1aandlmod1bparalogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the humanLMOD1c.1784T>C, p.(V595A) mutation demonstrated a likely dominant negative effect and illustrated a loss of function cause.Mutations found in the WH2 actin-binding domain ofLMOD1may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway.
- Published
- 2017
48. Psychotropic Medication and Substance Use during Pregnancy by Women with Severe Mental Illness
- Author
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Kate Brameld, John Dean, Vera A. Morgan, Assen Jablensky, and Jennifer Griffith
- Subjects
medicine.medical_specialty ,medical record linkage ,Poison control ,Suicide prevention ,Occupational safety and health ,03 medical and health sciences ,psychotropic medication ,0302 clinical medicine ,5. Gender equality ,Injury prevention ,medicine ,Psychiatric hospital ,030212 general & internal medicine ,Psychiatry ,Original Research ,Pregnancy ,business.industry ,demographic factors ,medicine.disease ,Mental illness ,mental illness ,030227 psychiatry ,3. Good health ,Psychiatry and Mental health ,pregnancy ,business ,hospitalization ,Diagnosis of schizophrenia - Abstract
Background Sociodemographic factors, alcohol and drug intake, and maternal health are known to be associated with adverse outcomes in pregnancy for women with severe mental illness in addition to their use of psychotropic medication. In this study, we describe the demographic characteristics of women hospitalized for severe mental illness along with their use of medication and other drugs during the pregnancy period. Methods A clinical case note review of women with psychosis who were hospitalized at the State Psychiatric Hospital in Western Australia during 1966–1996, gave birth between 1980 and 1992, and received psychiatric treatment during the pregnancy period. The mother’s clinical information was available from the case notes and the midwives record. The demographic characteristics of the mothers were described together with their hospitalization pattern and their medication and substance use during the pregnancy period. Results A total of 428 mothers with a history of severe mental illness were identified who gave birth during 1980–1992. Of these, 164 mothers received psychiatric care during the pregnancy period. One hundred thirty-two had taken psychotropic medication during this period. Mothers who were married, of aboriginal status or living in regional and remote areas appeared less likely to be hospitalized during the pregnancy period, while older mothers and those with a diagnosis of schizophrenia were more likely to be hospitalized. The number of mothers taking psychotropic medication in the first trimester of pregnancy was reduced compared to the previous 6 months. The decline in the number taking substances over the same period was not significant. In all, 16% of the women attempted suicide during the pregnancy period and 10% non-suicidal self-injury. Conclusion The women demonstrate a pattern of decreased use of psychotropic medication use from the period before pregnancy to the first trimester of pregnancy. Our data highlight the importance of women with severe mental illness receiving regular ongoing monitoring and support from their psychiatrist during pregnancy regarding the level of medication required as well as counseling with regard to substance use, non-suicidal self-injury, and attempted suicide.
- Published
- 2017
49. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations inSMARCB1,SMARCA4,SMARCE1, andARID1A
- Author
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Francesca Mari, Albertien M. Van Eerde, Bernd Wollnik, Krystyna Chrzanowska, Bregje Van Bon, Yoshinori Tsurusaki, Dagmar Wieczorek, and John Dean
- Subjects
Hypertrichosis ,Mutation ,medicine.medical_specialty ,Pathology ,Biology ,medicine.disease ,medicine.disease_cause ,Dermatology ,Intellectual disability ,Micrognathism ,Genetics ,medicine ,SMARCB1 ,Craniofacial ,Congenital Malformation Syndrome ,Coffin–Siris syndrome ,Genetics (clinical) - Abstract
Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.
- Published
- 2014
50. Proliferation of community exercise programs with limited evidence and expertise: Safety implications
- Author
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John Dean, Filipe Melo, Josefa Domingos, and Catarina Godinho
- Subjects
medicine.medical_specialty ,Parkinson's disease ,business.industry ,030229 sport sciences ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Neurology ,medicine ,Neurology (clinical) ,Limited evidence ,Intensive care medicine ,business ,030217 neurology & neurosurgery - Published
- 2018
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