146 results on '"Segurado R"'
Search Results
2. Genetic Classification of Populations using Supervised Learning
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Bridges, M., Heron, E. A., O'Dushlaine, C., Segurado, R., Consortium, The International Schizophrenia, Morris, D., Corvin, A., Gill, M., and Pinto, C.
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Quantitative Biology - Quantitative Methods - Abstract
There are many instances in genetics in which we wish to determine whether two candidate populations are distinguishable on the basis of their genetic structure. Examples include populations which are geographically separated, case--control studies and quality control (when participants in a study have been genotyped at different laboratories). This latter application is of particular importance in the era of large scale genome wide association studies, when collections of individuals genotyped at different locations are being merged to provide increased power. The traditional method for detecting structure within a population is some form of exploratory technique such as principal components analysis. Such methods, which do not utilise our prior knowledge of the membership of the candidate populations. are termed \emph{unsupervised}. Supervised methods, on the other hand are able to utilise this prior knowledge when it is available. In this paper we demonstrate that in such cases modern supervised approaches are a more appropriate tool for detecting genetic differences between populations. We apply two such methods, (neural networks and support vector machines) to the classification of three populations (two from Scotland and one from Bulgaria). The sensitivity exhibited by both these methods is considerably higher than that attained by principal components analysis and in fact comfortably exceeds a recently conjectured theoretical limit on the sensitivity of unsupervised methods. In particular, our methods can distinguish between the two Scottish populations, where principal components analysis cannot. We suggest, on the basis of our results that a supervised learning approach should be the method of choice when classifying individuals into pre-defined populations, particularly in quality control for large scale genome wide association studies., Comment: Accepted PLOS One
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- 2010
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3. The effect of combined Action Observation Therapy with eccentric exercises in the treatment of mid-portion Achilles-tendinopathy: a feasibility pilot randomised controlled trial
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Ryan, D, O’Donoghue, G, Rio, Ebonie, Segurado, R, and O’Sullivan, C
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Rehabilitation ,Physical Therapy, Sports Therapy and Rehabilitation ,Orthopedics and Sports Medicine ,Uncategorized - Abstract
Background Mid-portion Achilles Tendinopathy (AT) is a common musculoskeletal condition with varying rehabilitation success rates. Despite the prevalence of this condition, a considerable proportion of individuals experience persisting pain and functional deficits. Current treatment approaches bias the biomedical model which emphasises physically treating and loading the tendon. Overall, there is a lack of consideration for the central nervous system that is commonly implicated in chronic injuries. The aim of this pilot study was to explore the feasibility of combining Action Observation Therapy (AOT), a treatment technique which targets central changes and influences motor learning, with eccentric exercises in the treatment of mid-portion AT. AOT involves the observation of movements and is commonly followed by the physical performance of these same movements. Methodology This was a double-blinded randomised controlled pilot feasibility study. All participants underwent the 12-week Alfredson eccentric training protocol. The intervention group watched videos of the exercises prior to performing these exercises, whilst the control group watched nature videos before performing the same exercises. Study feasibility was the primary outcome measure, with the Victorian Institute of Sports Assessment- Achilles (VISA-A) selected as the primary clinical outcome measure. Results Thirty participants were recruited, reflecting a 75% eligibility rate and 100% of eligible participants enrolled in the study. The retention rate at week 12 was 80%. At week six the mean VISA-A score improved by 18.1 (95% CI 10.2–26.0) in the intervention group and 7.7 (95% CI 0.3–14.9) in the control group, and 75% and 33% of participants in the intervention and control group respectively exceeded the minimal clinically important difference (MCID). At week 12 the mean VISA-A score from baseline improved by 22.25 (95% CI 12.52–31.98) in the intervention group and 16.5-(95% CI 8.47–24.53) in the control group, equating to 75% and 58% in each group respectively exceeding the MCID. Conclusion The positive feasibility outcomes and exploratory data from the clinical outcome measures suggest that a larger scaled RCT is warranted to further investigate the impact of AOT in the rehabilitation of mid-portion AT. Trial registration ISRCTN58161116, first registered on the 23/12/2020.
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- 2023
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4. Challenges faced by parents of screen-detected children with Cystic Fibrosis: The ICOS study
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Bhatnagar, R, primary, Linnane, B, additional, Herzig, M, additional, Ni Chroinin, M, additional, Cox, D, additional, Elnazir, B, additional, Segurado, R, additional, Kirwan, L, additional, Southern, KW, additional, and Fitzpatrick, P, additional
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- 2022
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5. Parental age, birth order and neurodevelopmental disorders
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Merikangas, A K, Segurado, R, Kelleher, E, Hogan, D, Delaney, C, Gill, M, Gallagher, L, Corvin, A P, and Heron, E A
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- 2016
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6. Impact of COVID-19 on hospital care, employment and mental health of people with Cystic Fibrosis
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Bhatnagar, R, primary, Tecklenborg, S, additional, Segurado, R, additional, and Fitzpatrick, P, additional
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- 2021
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7. The phenotypic manifestations of rare genic CNVs in autism spectrum disorder
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Merikangas, A K, Segurado, R, Heron, E A, Anney, R JL, Paterson, A D, Cook, E H, Pinto, D, Scherer, S W, Szatmari, P, Gill, M, Corvin, A P, and Gallagher, L
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- 2015
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8. Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms
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Badner, J A, Koller, D, Foroud, T, Edenberg, H, Nurnberger, Jr, J I, Zandi, P P, Willour, V L, McMahon, F J, Potash, J B, Hamshere, M, Grozeva, D, Green, E, Kirov, G, Jones, I, Jones, L, Craddock, N, Morris, D, Segurado, R, Gill, M, Sadovnick, D, Remick, R, Keck, P, Kelsoe, J, Ayub, M, MacLean, A, Blackwood, D, Liu, C-Y, Gershon, E S, McMahon, W, Lyon, G J, Robinson, R, Ross, J, and Byerley, W
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- 2012
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9. P087 Impact of COVID-19 on mental health of children with cystic fibrosis and their parents
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Bhatnagar, R., primary, Tecklenborg, S., additional, Segurado, R., additional, and Fitzpatrick, P., additional
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- 2021
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10. P088 Impact of COVID-19 and cocooning on employment of people with cystic fibrosis
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Bhatnagar, R., primary, Tecklenborg, S., additional, Segurado, R., additional, and Fitzpatrick, P., additional
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- 2021
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11. P085 Impact of COVID-19 on hospital services and specialist care of adults with cystic fibrosis
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Bhatnagar, R., primary, Tecklenborg, S., additional, Segurado, R., additional, and Fitzpatrick, P., additional
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- 2021
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12. Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: data from NILVAD
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Dyer, A. H., Murphy, C., Lawlor, B., Kennelly, S. P., Segurado, R., Olde Rikkert, M. G. M., Howard, R., Pasquier, F., Börjesson-Hanson, A., Tsolaki, M., Lucca, U., Molloy, D. William, Coen, R., Riepe, M. W., Kálmán, J., Kenny, R. A., Cregg, F., O'Dwyer, S., Walsh, C., Adams, J., Banzi, R., Breuilh, L., Daly, L., Hendrix, S., Aisen, P., Gaynor, S., Sheikhi, A., Taekema, D. G., Verhey, F. R., Nemni, R., Nobili, F., Franceschi, M., Frisoni, G., Zanetti, O., Konsta, A., Anastasios, O., Nenopoulou, S., Tsolaki-Tagaraki, F., Pakaski, M., Dereeper, O., Sayette, V. D. L., Sénéchal, O., Lavenu, I., Devendeville, A., Calais, G., Crawford, F., Mullan, M., Aalten, P., Berglund, M. A., Claassen, J. A., De Heus, R. A., De Jong, D. L. K., Godefroy, O., Hutchinson, S., Ioannou, A., Jonsson, M., Kent, A., Kern, J., Nemtsas, P., Panidou, M.-K., Abdullah, L., Paris, D., Santoso, A. M., van Spijker, G. J., Spiliotou, M., Thomoglou, G., Wallin, A., and NILVAD Study Group
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medicine.medical_specialty ,Alzheimer disease ,Cognition ,Dementia ,Falls ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,medicine.medical_treatment ,Falls in older adults ,lcsh:Geriatrics ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Humans ,Cognitive Dysfunction ,030212 general & internal medicine ,Gait ,Aged ,Rehabilitation ,business.industry ,medicine.disease ,Gait speed ,Walking Speed ,lcsh:RC952-954.6 ,Cross-Sectional Studies ,Cohort ,Accidental Falls ,Geriatrics and Gerontology ,Alzheimer's disease ,business ,human activities ,030217 neurology & neurosurgery ,Research Article - Abstract
Background Previous evidence suggests that slower gait speed is longitudinally associated with cognitive impairment, dementia and falls in older adults. Despite this, the longitudinal relationship between gait speed, cognition and falls in those with a diagnosis of dementia remains poorly explored. We sought to assess this longitudinal relationship in a cohort of older adults with mild to-moderate Alzheimer Disease (AD). Methods Analysis of data from NILVAD, an 18-month randomised-controlled trial of Nilvadipine in mild to moderate AD. We examined: (i) the cross-sectional (baseline) association between slow gait speed and cognitive function, (ii) the relationship between baseline slow gait speed and cognitive function at 18 months (Alzheimer Disease Assessment Scale, Cognitive Subsection: ADAS-Cog), (iii) the relationship between baseline cognitive function and incident slow gait speed at 18 months and finally (iv) the relationship of baseline slow gait speed and incident falls over the study period. Results Overall, one-tenth (10.03%, N = 37/369) of participants with mild-to-moderate AD met criteria for slow gait speed at baseline and a further 14.09% (N = 52/369) developed incident slow gait speed at 18 months. At baseline, there was a significant association between poorer cognition and slow gait speed (OR 1.05, 95% CI 1.01–1.09, p = 0.025). Whilst there was no association between baseline slow gait speed and change in ADAS-Cog score at 18 months, a greater cognitive severity at baseline predicted incident slow gait speed over 18 months (OR 1.04, 1.01–1.08, p = 0.011). Further, slow gait speed at baseline was associated with a significant risk of incident falls over the study period, which persisted after covariate adjustment (IRR 3.48, 2.05–5.92, p Conclusions Poorer baseline cognition was associated with both baseline and incident slow gait speed. Slow gait speed was associated with a significantly increased risk of falls over the study period. Our study adds further evidence to the complex relationship between gait and cognition in this vulnerable group and highlights increased falls risk in older adults with AD and slow gait speed. Trial registration Secondary analysis of the NILVAD trial (Clincaltrials.gov NCT02017340; EudraCT number 2012–002764-27). First registered: 20/12/2013.
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- 2020
13. Erratum: Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22
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Lambert, D, Middle, F, Hamshere, M L, Segurado, R, Raybould, R, Corvin, A, Green, E, O'Mahony, E, Nikolov, I, Mulcahy, T, Haque, S, Bort, S, Bennett, P, Norton, N, Owen, M J, Kirov, G, Lendon, C, Jones, L, Jones, I, Holmans, P, Gill, M, and Craddock, N
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- 2006
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14. S02. TUMOUR RISKS AND GENOTYPE-PHENOTYPE ANALYSIS IN AN IRISH COHORT OF PATIENTS WITH GERMLINE MUTATIONS IN THE SUCCINATE DEHYDROGENASE SUBUNIT GENES SDHB, SDHC AND SDHD
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Hynds, P, Coghlan, D, Purcell, C, Green, A, Ward, A, Lynch, SA, Hough, O, Duff, M, Cody, N, Carroll, C, Bradley, L, Green, Andrew, Lynch, Sally-Ann, Crushell, E, Byrne, N, Gorman, K, King, M, Irvine, A, Monavari, A, Knerr, I, Cotter, M, McConnell, V, Browne, F, Lambert, D, Turner, J, Casey, J, Doyle, S, Nesbitt, IM, Fitzgibbon, M, Pastores, G, Kirk, R, Treacy, EP, Benson, KA, Kennedy, C, Yachnin, K, Cavalleri, G L, Conlon, P, McVeigh, Úna M, McVeigh, Terri P, Miller, Nicola, Morris, Derek W, Kerin, Michael J, Irwin, R., Caffrey, A., McLaughlin, M., McNulty, H., Cassidy, T., Pentieva, K., Walsh, C., Minguzzi, S, MacCooey, A, Brosnan, J, Brosnan, M, Henry, M, Meleady, P, Parle-McDermott, A, Gilbert, EH, O’Reilly, S, Merrigan, M, McGettigan, D, Molloy, AM, Brody, LC, Bodmer, W, Hutnik, K, Ennis, S, Lawson, DJ, Wilson, JF, Cavalleri, GL, Flynn, M, Whitton, L, Gill, M, Corvin, A, Donohoe, G, Morrison, C, Morris, D, Stapleton, CP., Birdwell, KA., Mark, PB., Sanders, ML., Phelan, PJ., Maxwell, AP., McKnight, AJ., Kennedy, C., Jardine, A., Traynor, J.P, Chapman, F., Keating, B., Conlon, PJ., Cavalleri, GL., Gunne, EA, Lambert, DM, Martin, R, Donnelly, DE, Callaghan, MB, Morrison, PJ, McConville, DO, Archbold, GP, Lewis, A, Morrison, P J, Das, S., Kelly, D., Moran, B., Harold, E., Han, K., Mulligan, N., Barrett, C., Buckley, P.G., Mc Mahon, P., McCaffrey, J, Van Essen, H. F., Connor, K., Ylstra, B., Lambrechts, D., Gallagher, W.M., O’Connor, D.P., Kelly, C.M., O’Neill, T, Power, C, de Franco, E, Ellard, S, Antao, B, O’Connell, SM, Dabir, T, Heggarty, S, Dockery, A, Carrigan, M, Wynne, N, Keegan, D, Stevenson, K, Silvestri, G, McCourt, J, Humphries, P, Kenna, PF., Farrar, GJ, Agbahovbe, R, Cohen, ASA, Gibson, WT, Cole, AM, Bohlender, R., Hu, H, Heinrich, E, Ramirez, C, Yu, Y, Powell, F, Gaio, E, Villafuerte, F., Taylor, C, Huff, C, Simonson, T., Cavalleri, G., Scullion, C, Irwin, R, Thakur, A, Walsh, C, Shortall, C, Palfi, A, Chadderton, N, Kenna, PF, Boomkamp, S, Shen, S, Hardcastle, AJ, Maloney, DM, Millington-Ward, S, Mackin, S-J, Irwin, R E., O’Neill, KM., Pollin, G, Apostolova, G, Dechant, G, Mackin, SJ, O’Neill, K, Walsh, CP, Sohedein, MNA, Morris, DW, Chaudhry, M, Segurado, R, Shields, D, Wilson, AG, Watkin, R.L., Piskareva, O., Madden, S., Stallings, R., Kerrigan, S.W., O’Neill, K M., Thursby, SJ, Bertens, C, Masala, L, Loughery, J, McArt, D, Amenyah, S. D., McMahon, A., Deane, J., Ward, M., Strain, J.J., Horigan, G., Purvis, J., Lees-Murdock, D., Lynch, SM., Ward, M, McNulty, H, Horigan, G, Purvis, J, Tackett, M, McKenna, DJ., Angel, Z, and Walsh, CP.
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Abstracts ,Poster Presentations ,Oral Presentations ,Article - Abstract
Neurofibromatosis (NF1) affects 1/2500 people throughout the world. Children with NF1 require a multidisciplinary service ideally, delivered on a single site. NF1 is a very variable condition with children requiring the expertise of genetics, paediatricians, ophthalmologists, dermatologists, neurologists and other specialities as required. Building such a service concentrates expertise, facilitates coordination of care and fosters ideal opportunities for research. Aims: 1) To develop a service ensuring children had access to a multidisciplinary clinic on an annual basis. 2) Hold monthly clinics offering ophthalmology, medical, developmental and dermatology follow up. 3) To create a registry of patients which captures the incidence and prevalence of NF1 in Ireland. To offer best possible care for the children attending the service by following international consensus guidelines. 4) To liaise with NF1 Association, families and research authorities. Methods: 1) Appointment of a CNS/CNM2 in Neurofibromatosis as funded by the NCH Foundation. 2) Visit to the complex NF1 Clinic in Manchester’s Children’s Hospital and learn from their service, MDT and guidelines. 3) Establish links with genetics, oncology, radiology and orthopaedic depts. in OLCHC. 4) Create a referral pathway for HCPs to ensure children with NF1 are referred to most appropriate service in a timely fashion. 5) To register the service on Orphanet and gain entry into an ERN as a multi-site service in conjunction with OLCHC. Results/Conclusion: To date, the service has been running for 9 months. The CNM2 provides telephone service and coordinates clinics. The Clinic has been registered in Orphanet and the process has begun to create a patient registry and enter the service in the ERN., Germline mutations in the succinate dehydrogenase subunit genes SDHB, SDHC and SDHD are the most frequent causes of inherited phaeochromocytomas and paragangliomas. Patients presenting with these tumours are usually offered genetic testing for these and other genes as part of standard clinical investigations. However, the information regarding penetrance and phenotype genotype correlations associated with SDHB/C/D mutations is variable, making it difficult to determine an optimum management strategy for this group. In order to address this issue we undertook a retrospective cohort study of patients who underwent genetic testing for SDHB, SDHC or SDHD. 195 patients were identified through the Irish Genetics laboratory electronic database as having had a genetic test for SDHB, SDHC or SDHD and referral source, referral reason and genetic test outcome were analysed. Analysis of penetrance and phenotype presentation was determined through a Clinical Genetics chart review of 147 patients from 40 separate families. Analysis of age-related tumour risks according to relevant gene and mutation type (for SDHB and SDHD) provided estimates of penetrance and genotype-phenotype correlations. Increased knowledge of the molecular basis of phenotypic variability commonly observed in individuals with germline SDHB/C/D mutations will facilitate the development of age-appropriate management protocols based on gene specific tumour risks., Irish Travellers are an endogamous, ethnically Irish population of ~40,000. Consanguinity is common. Knowledge of Traveller disorders exists but mainly in specialised Irish centres. Most Traveller disorders are published but ethnicity is not explicit, hampering diagnoses, particularly if the patient is overseas where knowledge about this population is poor. Aims: To catalogue inherited Irish Traveller disorders through identifying the disorders, detailing mutations, use of coding, (OMIM, Orphacodes & ICD10), publications, and help develop a database to facilitate diagnoses. Methods: A literature review was undertaken. Key national and international Clinician/scientists were contacted to identify relevant disorders and publications. Laboratory and clinical databases were searched to retrieve disorders & mutations. Annotations were updated. An Excel database was established listing each disorder, its appropriate code, associated mutation and relevant publication. Results: 86 distinct rare genetic disorders resulting in 75 phenotypes were identified; 78/86 were autosomal recessive; 4 of these were dominant disorders presenting only in the recessive state. Seven dominant disorders with no recessive phenotype were included as > one affected individual existed. One common 17q12 duplication was included, presenting in two unrelated families. Homozygous mutations were found in all recessive disorders bar one. The genetic basis of 78/86 was established. A further 2/76 have common haplotypes; the genetic basis of six disorders remains unclear. Linkage disequilibrium was observed in 4 families with co-existing McArdles disease and microcephaly & 11 individuals have co-existing Friedreich’s ataxia & galactosemia. Conclusion: Our work is the first step towards cataloguing inherited Irish Traveller disorders. Future challenges include development of an online mutation database., Primary Trimethylaminuria (TMA)(OMIM 136132), is an autosomal recessive rare disorder which results in diminished capacity to oxidise the dietary derived amine trimethylaminuria to its odourless metabolite Trimethylamine-n-oxide (TMA-n-Oxide). Severe primary TMA has been defined as the percentage of unmetabolised free TMA in urine being >40% and mild/moderate TMA range is 10-39%. More than 30 variants of the Flavin monooxygenase 3 (FMO3) have been reported to cause primary TMA. Diagnosis of primary TMA has implications for management of the patient in relation to treatment and genetic counselling. We sequenced the entire FMO3 gene coding region in 10 patients who had a biochemical diagnosis of TMA made in the past 5 years. Three of the patients had severe TMAU (% TMA range 39.4 to 45), (Group A) and 7 had mild to moderate TMAU (%TMA range 10-30), (Group B). We identified causative (loss of function) in 5/10 individuals. Homozygosity for loss of function mutations was detected for 2/3 cases with severe TMAuria (Group A). 3/7 of the patients with mild to moderate TMAuria biochemically had a genetic diagnosis. Two were homozygous for Glu158Lys/ Glu308Gly and the other was compound heterozygous for P153L and A232T. Primary TMAU is rare in Ireland and mutational analysis should not replace biochemical diagnosis.The rate of detection of pathogenic mutations was low using the recommended biochemical cut-offs. The E305X mutation the first FMO3 mutation described in OMIM (136132.0001) in an Irish Australian family may be an Irish Mutation. Two new apparent FMO3 mutations are described in this Irish population. A cut- off of free TMA levels higher than that suggested on the Gene Utility card may be more beneficial in directing genotyping., Background: As part of the Irish Kidney Gene project, 2000 people with renal disease were surveyed and >30% of participants reported a family history for their condition. This strongly suggests an underlying genetic component for the development of kidney disease. Blood and urine tests as well as kidney biopsies are frequently used to inform on aetiology of the disease. However, in around 10% of cases, aetiology is simply unknown, making it difficult for physicians to provide a clear diagnosis or prognosis to these patients. Aim: This project aims to utilise genomic sequencing to stratify patients with hereditary renal disease (HRD). In doing so we seek to aid clinical diagnosis, provide insight into pathogenesis and in some cases point to specific therapies. Methods: We developed a custom, targeted NGS panel for inherited kidney diseases which we have applied to 48 HRD patients. The panel includes 11 genes which are established causes of polycystic kidney disease, von Hippel Lindau syndrome, renal cysts and diabetes syndrome and Alport syndrome. The NimbleGen Heat-Seq kit was used for library preparation and samples were sequenced using an Illumina MiSeq platform at Beaumont Hospital. Data was analysed using a custom bioinformatics pipeline and variants were classified according to the ACMG guidelines. Results/Conclusions: To date, this panel has identified candidate pathogenic variation in a third of samples studied. Future work in this project will include the development of a larger targeted panel including >100 known renal disease genes., Breast cancer is the most common female malignancy worldwide. Up to 10% of cases are the result of an inherited monogenic mutation, while a further 25% appear in familial clusters. Only 30% of hereditary breast cancers are attributed to mutations in BRCA1 and BRCA2, identified as high-risk genes through linkage analysis. While BRCA mutational status is highly informative, and allows clinicians to modify surveillance, prevention and therapeutic strategies, the risk conferred by mutations in other genes is more difficult to define in light of variable penetrance. Next-generation sequencing has been rapidly evolving to advance testing sensitivity and throughput in a cost-effective manner. This progression has made multi-gene testing a practical option when looking to identify inherited mutation(s) in a clinical setting. However, current clinically available multi-gene panels generate many variants of unknown significance in genes that are presently not considered clinically useful. The aim of our study was to design a multi-gene panel to enable the detection of rare, probably pathogenic variants contributing to the susceptibility of breast cancer in an Irish population. An extensive literature review was conducted in order to generate a list of 282 genes with potential association to breast cancer. Targeted DNA enrichment and multiplexed next-generation sequencing was performed on a cohort of 167 samples from the west of Ireland. 90 breast cancer patients and 77 geographically-matched controls were included in this study. Bioinformatic analysis was performed following GATK best practices workflow. Variant data for our 282 selected genes will be presented and discussed., Increasingly accurate surveys of human health throughout the life course has led experts to propose that stresses on the developing child whilst in the mother’s womb can affect the individual’s health later in life. Such long-term effects on health are thought to be mediated by a semi-permanent trace on the genes called an epigenetic mark, mediated by processes such as DNA methylation. DNA methylation patterns may be altered by the mother’s diet, particularly folate – a key component in the DNA methylation cycle. Currently, mothers are recommended to supplement their diet with 400μg folic acid/day as a preventative measure against neural tube defects prior to/during the first trimester. However, there remains no clinical recommendation as to whether mothers should continue supplementation during the latter two trimesters and the potentially heritable effects. Thus, we analysed cord blood samples (n=93) from the Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) randomised control trial for genome-wide DNA methylation. Offspring exposed to folic acid in later pregnancy had fewer highly methylated genomic regions and more intermediately methylated sites. Upon further interrogation, gene ontology analysis revealed these sites are enriched for genes associated with cognition and neurological system processes, and tissue analysis revealed enrichment of affected genes associated with the brain. Cognitive and psychosocial testing of the children at age 7 years, using standardised tests (WPPSI, TEIQue-CSF, RASP), showed that the children supplemented during pregnancy scored significantly higher for emotional intelligence, resilience and verbal IQ. Thus, this study offers a potential biological mechanism linking maternal folate levels with childhood cognition., Introduction: We previously identified the mitochondrial 10-formyltetrahydrofolate synthase enzyme, MTHFD1L, as a risk factor for human Neural Tube Defects (NTD). This association was further supported by a mouse model of mutant mthfd1l, that exhibited an NTD and was rescued with maternal formate supplementation. The abundance of MTHFD1L is also increased in a range of cancers. MTHFD1L performs the last step in mitochondrial one carbon metabolism to produce formate for transport into the cytoplasm. Aim: Given the pivotal role of MTHFD1L in human disease, we sought to decipher the cellular response to the expression level of MTHFD1L in HEK293 cells. Methods: Human MTHFD1L was overexpressed in a stably transfected line using a pcDNA3.2 vector and knocked down using two inducible shRNA constructs that were clonally selected. Cells were grown and sampled over a five-day period. Expression level was confirmed by RT-qPCR. Intracellular and media formate levels were measured using GC-MS. Proteomics analysis was performed on whole cell lysates using LC-MS/MS on an Ultimate 3000 nano LC system coupled to a LTQ Orbitrap XL. Results: Intracellular and media formate levels directly correlated with expression level of MTHFD1L compared to controls within an approximately 1.5 to 3 fold range. Our proteomics analysis showed that MTHFD1L expression level had an effect on proteins involved in DNA synthesis, replication and repair. Discussion: We have demonstrated that MTHFD1L expression level has a direct impact on both intra- and extra-cellular levels of formate and may act as a signal for uncontrolled cell proliferation., Ireland has remained relatively isolated from mainland Europe, notwithstanding historical migrations including the Norse-Vikings, Anglo-Normans, and the British Plantations. Although previous studies have shown the Irish to have elevated levels of homozygosity compared to mainland Europe, the extent of genetic structure within Ireland, and the genomic impact of historical migrations, is largely unknown. Here we illustrate fine-scale genetic structure across Ireland that follows sociological boundaries and present evidence of admixture events into Ireland. Utilising the ‘Irish DNA Atlas’, a DNA cohort (n = 194) of genealogically described Irish individuals with four generations of ancestry linked to specific regions in Ireland, we analysed in combination with 2,039 individuals of regional British ancestry (the PoBI dataset) and show that the Irish population subdivides into 10 distinct geographically-stratified genetic clusters; three of shared British/Irish ancestry, and seven of predominantly ‘Gaelic’ Irish ancestry. This structure is remarkably homogenous, and is associated with very little gene flow barriers within Ireland. Additionally, using a reference of 6,760 European individuals and two ancient Irish genomes, we quantified the ancestry of these Irish clusters within the context of Europe as well as ancient Ireland. We show high levels of north-west French-like and Norwegian-like ancestry within Ireland, and homogenous levels of ancient Irish ancestry in our ‘Gaelic’ Irish clusters. Finally we detect admixture events into Ireland, coinciding with the Plantations of Ulster, as well as Norse-Viking activity within Ireland. Our work informs both on Irish history, as well as the study of Mendelian and complex disease genetics involving populations of Irish ancestry., Schizophrenia affects 1% of adults and is a major global health problem. I am interested in the potential role of the centrosome in schizophrenia. The centrosome, an organelle within cells, plays a crucial role in brain development where it directs cell shape, polarity and motility. The centrosome also seeds the growth of antenna-like signalling structures called primary cilia. Rare mutations in centrosome genes cause disorders that present with severe cognitive deficits and variable neuropsychiatric phenotypes. GWAS data has implicated many genes in schizophrenia. We have shown that seven schizophrenia risk genes encode proteins with centrosomal functions. Of these, SDCCAG8 is also associated with educational attainment in GWAS and the genome-wide significant SNPs for the two phenotypes are in high linkage disequilibrium indicating a pleiotropic effect. We have found that a schizophrenia risk SNP in SDCCAG8 is significantly associated with poorer performance in a social cognition task, in a large Irish dataset of schizophrenia patients and controls (p=0.001). To analyse the molecular function of SDCCAG8 we have used genome editing to knock it out in neuronal and retinal cells. Preliminary data shows that loss of SDCCAG8 impairs cells’ ability to make primary cilia and that their capacity to repair genome damage is reduced. Current work is addressing whether SDCCAG8 affects activities that may contribute to schizophrenia, including cell migration and cell signalling. This could identify molecular mechanisms by which SDCCAG8 mutations contribute to schizophrenia risk and cognition, and help uncover the processes that implicate centrosome genes in neurodevelopmental phenotypes., Multiple genetic loci have been identified for non-melanoma skin cancer (NMSC) in the general population. Polygenic risk score (PRS) was defined as the sum of all alleles associated with a trait weighted by the effect size of that allele as determined by a previous genome-wide association study (GWAS). We tested whether PRS, calculated using a GWAS of NMSC in a non-transplant population, can be used to determine risk of developing and time to NMSC post-transplant. Post-kidney transplant NMSC cases (n=155) and controls (n=442) were collected from Tennessee, Ireland and Scotland. Genetic variants that reached pre-defined levels of significance were chosen from a squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) GWAS, both conducted in non-transplant populations. Using these GWAS results, BCC and SCC PRSs were calculated at each p-value threshold (pT) for each sample. PRSs were tested as a predictor of case:control status using logistic regression and time to NMSC post-transplant in a survival model. SCC PRS calculated at pT 1x10-6 was the most significant predictor of case: control status of NMSC post-transplant (OR per 1 stdev increase in PRS=2.3; corrected P (Pc)=0.04). When NMSC was subdivided into SCC and BCC, SCC PRS pT 1x10-6 significantly predicted case:control SCC (OR=2.5, Pc=0.02) and BCC status (OR=7.6, Pc=0.02). SCC PRS pT 1x10-5 also significantly predicted time to BCC (Pc=0.007, HR=1.8) and SCC (Pc=0.05, HR=1.4). PRS of non-transplant NMSC can be used to predict case:control status of post-transplant NMSC, SCC and BCC as well as time to developing BCC and SCC post-transplant., Introduction: Rare diseases are diseases, which affect a small number of people compared to the general population. In Europe, a disease is considered rare when it affects no more than 5 per 10,000 individuals. A disease can be rare in one region but common in another. The objective of this study was to derive a proxy estimate the number of childhood onset rare diseases through referrals to the country’s only Genetics center, as the Republic of Ireland does not have a centralized rare disease registry. Methods: A retrospective review of referrals to cytogenetics and clinical genetics for the years 2000-2016 for patients born in the year 2000 was undertaken. Anonymized data was catalogued into rare, common, normal, likely rare & unclassifiable by review of records, and assigned Orphacodes based on diagnosis. Census live birth data was used as the denominator. Results: 54,7891 live births were recorded by the census in 2000. 1872 referrals to Genetics (representing 1749 individuals born in 2000) were retrieved for review. 1007 had cytogenetic testing only, of which 51 had rare chromosomal anomalies. Review of 742 referrals to clinical genetics yielded 581 with a rare disease (78%), 7 with a likely rare disease, 56 with a common disorder, 83 who were normal (at risk relative) & 15 unclassified (hadn’t yet been seen). Of the 53/1749 who had died (3%), 51 had a rare disease with congenital malformations (24) the most common cause., Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant genetic condition, with an incidence of around 1 in 3000. All NF1 patients attend our regional NF1 clinic intermittently and our departmental database records clinical details. Currently, we have 468 living patients affected with NF1 in Northern Ireland. NF1 is caused by mutations, or occasionally deletions, of the neurofibromin tumour suppressor gene, which leads to over-activation of the RAS-MAPK pathway, and tumour formation. These vary from benign lesions, such as neurofibromas, through to malignant peripheral nerve sheath tumours (MPNSTs) and tumours in other sites, particularly the central nervous system, that can be associated with significant morbidity and mortality. MEK inhibitors have recently been shown to be an effective treatment modality in the tumours associated with NF1. We have studied our population to determine the number of patients with plexiform neurofibromas, who are at risk of MPNSTs, and the proportions of patients with tumours elsewhere. This will allow us to identify which patients could benefit from MEK inhibitors in the future., Tuberous Sclerosis complex (TSC) is an autosomal dominant genetic condition which results, in the majority of patients, from a mutation in the TSC1 or TSC2 genes. Many of the patients are affected by angiomyolipomas and sub-ependymal giant cell astrocytomas. There is evidence that mTOR inhibitors, particularly Everolimus, shrink such tumours. In addition, the recent EXIST-3 study showed that Everolimus led to a significant reduction in seizure frequency in TSC patients whose seizures had previously proved resistant to anti-epileptic drug treatment. Consequently, a European licence has been granted to prescribe Everolimus for this indication. In order to determine the potential number of patients who may be eligible for consideration of this treatment, we undertook a complete population survey of epilepsy in our TSC patients. Information was extracted from our database and descriptive statistics were carried out. We were particularly interested in obtaining numbers of those whose seizures were poorly-controlled, defined as requiring 3 or more anti-epileptic drugs to manage their seizures, or requiring neurosurgical intervention. Many of the TSC patients with a diagnosis of epilepsy were also diagnosed with learning difficulties. The possibility of an association between degree of seizure control and severity of learning difficulties was explored. Finally, the annual cost of prescribing Everolimus to Northern Ireland’s TSC patients with poorly-controlled seizures was estimated., Charcot neuroarthropathy is associated with neurological deficit and is often seen in patients with a history of diabetes. Zygodactyly is a common congenital malformation with cutaneous webbing of the second and third toes. To determine the frequency of Zygodactyly in midfoot (tarso-metatarsal) Charcot neuropathy due to diabetes, we analysed a prospective series of twenty-five patients with Charcot neuropathy referred to podiatry clinics from diabetes and vascular departments. Twenty-nine patients with diabetes (but no Charcot neuropathy) were used as controls. Nineteen of the twenty-five patients with type 2 diabetes, peripheral neuropathy, and midfoot Charcot neuroarthropathy, exhibited Zygodactyly as did one of the twenty-nine controls. There was a significant difference between the two groups (Chi squared test p< 0.001). None of the cases or controls had any dysmorphic features or other limb malformations. Zygodactyly occurred in association with midfoot Charcot neuroarthropathy (diabetic neuropathy) in 76% of cases. No association between Zygodactyly, diabetes and Charcot neuropathy has previously been recognised. Genes such as OPG and RANKL affect foot and bone development and MSX1 and PLA2G6 affect spinal and distal nerve development. The possibility of a genetic contribution in patients who develop type 2 diabetes, peripheral neuropathy and Charcot neuroarthropathy must be considered. Zygodactyly may act as a predictive marker for Charcot neuropathy and further identification of regulatory genes may be possible. Until then, recognition of Zygodactyly may allow early intervention and a reduction of complications in patients with Charcot neuropathy., Development of an unusual clinical phenotype across both common and rare cancer types presents a significant challenge from a diagnostic and therapeutic perspective. We describe two distinct cases involving an Ovarian adenocarcinoma and a Medullary Thyroid cancer (MTC) patient and wherein both patients presented with metastases at highly unusual locations, followed by development of an aggressive disease. In first case involving a patient diagnosed with ovarian adenocarcinoma presented with a rare solitary extracranial brain metastases with no other associated metastases after 2 years post-hysterectomy and chemotherapy. Despite surgical removal of the metastatic lesion and stereotactic radiotherapy, the patient showed a further relapse at the initial as well as two additional extracranial regions. Our current analysis of whole-genome sequencing of primary tumour and extracranial lesion, reveal a remarkable difference in the genomic aberration landscape between the primary tumour and the metastases. In addition, we also identify several structural variants including novel gene fusions as well as gross chromosomal abnormalities, which could be potentially utilized as targets for treating this patient further. In the second case, whole-exome sequencing of primary tumour and bone-marrow metastases in the MTC patient identified three germline single nucleotide polymorphisms (SNPs) within the RET proto-oncogene that remained undetected using routine hospital genetic testing procedures. More importantly, we report for the first time in thyroid cancer on the occurrence of a “chromothripsis-like pattern”, which involved shattering of chromosome 4 leading to complete abrogation of normal chromosomal function, along with dramatic widespread copy number aberrations across both primary tumour and bone marrow samples. These results provide a rationale for the application of comprehensive genomic analysis of cancers presenting with unusual and aggressive phenotypes to facilitate more appropriate therapeutic options and diagnoses., Transient Neonatal Diabetes (TNDM) is characterised by diabetes that develops in the first 6 weeks of life and resolves by 18 months. Approximately 70% of cases are classified as TNDM Type-1 (TNDM1), caused by methylation defects on chromosome 6q24. It is associated with some congenital anomalies, however associated hepatobiliary abnormalities are not described. Choledochal cysts are congenital dilations of part or all of the bile duct, occurring in 100,000-150,000 live births. The 5 major types are classified according to the extent of hepatobiliary involvement. Surgical excision of the cyst is indicated to prevent complications such as stone formation, malignancy, cyst rupture and pancreatitis. We describe a case of TNDM1 due to whole chromosome paternal uniparental disomy 6, with co-existence of a type 1a choledochal cyst in a female born following intrauterine growth retardation. Hyperglycaemia soon after birth led to insulin treatment and a diagnosis of TNDM1, with resolution of the diabetes by 4 months of life. Follow up of antenatal findings of a cystic anomaly demonstrated the presence of a type 1a choledochal cyst on ultrasound and magnetic resonance cholangiopancreatography. Sucessful surgical excision of the cyst and a roux-en-Y hepaticojejunostomy was undertaken at 6 months of age. To our knowledge the co-existence of these disorders has not previously been reported. Further genetic analysis by whole exome sequencing is now in progress to determine if a mutation in the PKHD1 gene, unmasked by the paternal UPD of the entire chromosome 6, explains the associated choledochal cyst in this case., Mosaic mutations can go unnoticed, underlie genetic disease or normal human variation, and may be transmitted as constitutional variants to future generations. Marfan syndrome (MFS) is a clinically variable systemic connective tissue disorder involving ocular, skeletal, and cardiovascular systems. The risk to siblings of an identified de novo variant in a proband remains above population risk but less than the 50% risk attributed probands (~75%) who have an affected parent. This is due to somatic and germline mutations reported in rare cases. We describe the phenotypic variability in three siblings with a confirmed heterozygous pathogenic exon 52 fibrillin1 (FBN1) gene variant with clinically unaffected parents Parental leucocyte DNA was tested and did not identify the FBN1 gene variant. Paternity has been unequivocally confirmed and subsequent testing of parental buccal samples failed to detect the variant. One brother had aortic valve replacement and aortic aneurysm repair at 35 while another brother had surgery of aortic dilatation at the sinuses of Valsalva at 32. The brothers had variable joint hypermobility, patellar dislocations and ophthalmic presentations involving subluxed lenses, myopia and ambylopia. Early onset of varicose veins as a teenager in one and thoracolumbar scolosis in another brother were present. Their 42 year old sister has apparently normal aortic and cardiac imaging and ophthalmology but has mild Marfanoid facial features. To our knowledge this is the first reported family in the literature of 3 siblings as a result of parental mosaicism for a FBN1 gene variant and highlights the impact for genetic counselling., The inherited retinal degeneration (IRD) patient cohort used in the study has been obtained via a collaborative network of opthamoloogists whereby if an IRD is suspected given consent, a DNA sample is taken and provided to a central laboratory for genetic analysis. The study seeks to detect previously identified, together with as yet undiscovered, pathological mutations in a panel of known retinal degeneration genes utilizing target capture next generation sequencing (NGS) for 264 IRD genes. The study to date includes over 700 IRD patients from more than 500 pedigrees. While clinical trials are in progress for patients with IRDs, many such trials require patients to have a known causative mutation to participate in these trials. The Target 5000 research project aims to genetically characterise the estimated 5,000 people in Ireland with IRDs. To date, as part of Target 5000, over 10% of the Irish IRD population has been sequenced providing real insights into the genetic architecture of IRDs in Ireland. Target 5000 offers not only a chance to discover new relevant and pathogenic mutations, but is vital to providing patients with information regarding the underlying genetic pathogenesis of their disease. Thus far, during the course of the study, genetic analysis of IRD patients has helped to resolve ambiguous phenotypes and to identify causative mutations in approximately 60% of IRD cases. The growing body of data from NGS studies of IRDs globally should facilitate better correlations between genotype and phenotype and refine methods for diagnoses and prognoses., Overgrowth syndromes are characterized by tall stature, macrocephaly and other congenital features. These disorders typically arise sporadically through de novo dominant mutations in a growing list of genes. Although whole-exome sequencing (WES) allows us to examine all genes at once in a cost effective manner, we are left with a very large number of possible disease-causing variants to sift through. In addition, we must identify at least two patients with mutations in the same novel gene for the finding to be significant. To address this, we utilized detailed phenotyping of patients with undiagnosed overgrowth to group patients with significant phenotypic overlap and to help us interpret and prioritize the variants identified via WES. We performed WES for 12 undiagnosed patients from our overgrowth cohort. For most patients, there were no obvious causative variants in genes that were previously associated with human overgrowth. Therefore we analysed the participants’ clinical records to look for phenotypic traits that may lead us to new candidate genes. After further mining of the WES data, we prioritized possible disease causing variants based on a number of factors including biological function of the gene, predicted effect on protein function and a minor allele frequency, Living the ‘high life’ presents challenging conditions of extreme cold, hypobaric hypoxia and a restrictive diet that forces populations to adapt to survive. The Quechua are an indigenous high altitude population of Peru and Bolivia. They have resided at altitudes greater than 2500 meters above sea level (m.a.s.l) for the past 10,000 years, following their arrival in South America. Previous studies have characterised their adaptive physiology and identified genes under natural selection (ref). However our understanding of their genetic adaptation to hypoxia is incomplete, as previous studies focused on common genetic variation and applied a limited number of selection tests. To shed further light on genetic adaptation in the Quechua, we established a cohort of 43 Quechua individuals from Cerro de Pasco, Peru (4330 m.a.s.l). We performed whole genome sequencing to a mean depth of 34X. We detailed the demographic history of Quechua using principal components analysis, Admixture and Treemix. We performed five tests of selection, (iHS, XP-EHH, ΔiHH, FST and ΔDAF) on real, and simulated Quechua data incorporating details of the demographic history of the population. We performed a composite of multiple signals (CMS), which aggregates information from the five tests of selection, and identified robust signals of positive selection in high altitude Quechua individuals. The Quechua appear as a relatively homogenous population, with 10% European ancestry. We report the top 1% of genes under selection identified by CMS. We identify putative hypoxia associated genes under selection as well as the previously reported well-characterised hypoxia gene EGLN1., DNA methylation is an important epigenetic mechanism of regulating gene expression that is affected in certain human diseases including imprinting disorders and cancer. In mouse, UHRF1 is an essential cofactor of DNMT1, the enzyme responsible for maintaining methylation patterns. To investigate the effects of loss of UHRF1 on methylation patterns in human cells, UHRF1 levels were decreased in immortalized hTERT fibroblast cell lines using short hairpin RNA. Genome-wide effects on methylation were investigated by the Illumina Infinium HumanMethylation450 BeadChip array. Online bioinformatics software tools were used to identify FDR-significant hypomethylated gene classes, which were then verified by pyrosequencing. Transcriptional effects on these gene classes were investigated by the genome-wide Illumina HumanHT-12 v4 Expression BeadChip array, and verified by RT-qPCR. While UHRF1 depletion caused widespread demethylation, the replication-dependent histone gene cluster and the cancer testis antigen genes were identified as most significantly hypomethylated in UHRF1 knockdown cells. Pyrosequencing confirmed hypomethylation in promoter regions of cancer testis antigen genes TSPY2, MAGEC1, MAGEC2 and MAGEA12, and histone gene HIST2H2AA4 in knockdown cell lines. Hypomethylation in these gene classes correlated with an increase in expression in the knockdown cell line. In addition, cells were rescued using UHRF1 cDNA and showed a return to wild type transcription levels in the rescue cell line. We have shown that these genes are regulated by promoter DNA methylation, confirming the sensitivity of cancer-testis genes to demethylation, supporting possible use of methyltransferase inhibitors to boost antigen presentation in cancers, and the crucial role of UHRF1 in cell cycle regulation., X-linked Retinitis Pigmentosa (XLRP) is a severe, early-onset form of inherited retinal degeneration (IRD). It is estimated that approximately 15% of XLRP cases are due to mutations in RP2 (Retinitis Pigmentosa 2). The ubiquitously expressed RP2 protein is involved in ciliary trafficking of lipid-modified proteins – a process vital for photoreceptor function and survival. Most pathogenic RP2 mutations are suggested to result in truncation or complete loss of the protein. The most common stop mutation, R120X, appears to trigger nonsense-mediated decay of the transcript. RP2 is therefore an excellent candidate for gene augmentation therapy. In recent years, personalised cell models have emerged as invaluable tools for the elucidation of disease pathogeneses and have greatly enhanced pre-clinical proof of concept studies. Through the Target 5000 programme, a project focused on genetic characterisation of the 5,000 IRD patients in Ireland, a male patient harbouring the R120X RP2 mutation was identified. A patient-derived dermal fibroblast cell model of the disease was thus generated and characterised. The transduction efficiencies of AAV vectors of various serotypes in fibroblasts were tested and compared, after which it was decided to proceed with an AAV2/2.CAG.RP2 vector to explore RP2 delivery in this patient-derived cell model. In addition, the effects of RP2 overexpression in vivo in murine photoreceptors and retinal pigment epithelium cells were analysed., Mitochondrial dysfunction leads to a lack of energy production and ultimately the death of the cell. Recently a number of disorders have been shown to have mitochondrial dysfunction including but not limited to; Multiple Sclerosis, Parkinson’s and Leber’s Hereditary Optic Neuropathy (LHON). In LHON, Complex I of the Electron Transport Chain (ETC) is affected which leads to a severe shortage of energy in the cell and eventually cell death. In particular retinal ganglion cells (RGCs) are affected, leading to retinal dysfunction and blindness. These observations have prompted interest in exploring innovative therapeutics to modulate mitochondrial disorders involving complex I deficiency. The team has explored candidate gene therapies for complex I deficiency, which could classically be delivered via Adeno Associated Viruses (AAV) such as AAV serotype 2 (AAV2), among other vectors. As such the team has developed novel in vitro methods for the analysis of complex I deficiency and the evaluation of novel candidate therapies, allowing us to monitor the efficacy of these therapeutics. Assays include a suite of methods to enable evaluation of Complex I activity and oxidative phosphorylation efficiency among other mitochondrial biomarkers. Such assays in principle would be of value for future in vitro and or in vivo studies involving therapies directed towards targeting complex I deficiencies., Background: Imprinted loci are paradigms of epigenetic regulation and are associated with a number of genetic disorders in human. A key characteristic of imprints is the presence of a gametic differentially methylated region (gDMR). Previous studies have indicated that DNA methylation lost from gDMRs could not be restored by DNMT1, or the de novo enzymes DNMT3A or 3B in stem cells, indicating that imprinted regions must instead undergo passage through the germline for reprogramming. However new putative gDMR have recently been described, along with an improved delineation of the existing gDMR locations. We therefore aimed to re-examine the dependence of methylation at gDMRs on the activities of the methyltransferases in mouse embryonic stem cells (ESCs). Method: We examined the most complete current set of imprinted gDMRs that could be assessed using quantitative pyrosequencing assays in two types of ESCs: those lacking DNMT1 (1KO) and cells lacking a combination of DNMT3A and DNMT3B (3abKO). Results: Loss of methylation was approximately equivalent in both cell types. 1KO cells rescued with a cDNA-expressing DNMT1 could not restore methylation at the imprinted gDMRs, confirming previous observations. However, nearly all gDMRs were remethylated in 3abKO cells rescued with a DNMT3A2 expression construct (3abKO + 3a2). Transcriptional activity at the H19/ Igf2 locus also tracked with the methylation pattern, confirming functional reprogramming in the latter. Conclusions: DNMT3A/B plays a vital role in methylation maintenance at imprints as the rescue with DNMT3A2 can restore imprints in these cells. This provides a useful system to explore factors influencing imprint reprogramming., SATB2, BCL11B and GATAD2A map to regions containing genomewide significant SNPs for schizophrenia and regulate key stages of neurodevelopment via epigenetic mechanisms. SATB2 mediates the projection of neurons across the cerebral hemispheres by regulating the activity of BCL11B via the NuRD nucleosome remodelling complex, which contains. GATAD2A. We hypothesized that genes within the NuRD complex and genes regulated by SATB2 in the pre- and post-natal brain may contribute to schizophrenia etiology. To test, we developed three gene-sets. 1.)Genes reported in mouse knockout studies of SATB2 during cortical development (SATB2_ Cortical). 2.)Genes mapping to SATB2 ChIP-seq peaks generated from mouse cortices at E15.5 (SATB2_Pre-natal). 3.)Genes mapping to SATB2 ChIP-seq peaks generated from mouse P0 hippocampal neurons (SATB2_Post-natal). We performed competitive gene set analysis (GSA) using MAGMA to test if genes within a gene-set were more strongly associated with schizophrenia than other genes in the genome. We applied GSA to schizophrenia GWAS (n=150,064). We also investigated these gene-sets for a genetic contribution to educational attainment (EA; proxy for cognition) using GWAS (n=405,072). After multiple test correction, we observed significant associations for (1)SATB2_Cortical with schizophrenia (P=8.65x10-05) and EA (P=0.00049), (2)SATB2_Pre-natal with EA (P=0.0068) and (3)SATB2_Post-natal with schizophrenia (P=0.0069) and EA (P=2.03x10-06). Further GSA established that effect sizes are stronger for these gene-sets when analysis is limited to genes that are highly expressed in neurons or at different key timepoints during neurodevelopment of the cortex or hippocampus. These data support a role for the NuRD complex and genes regulated by SATB2 in schizophrenia and EA, Background: Dacogen (5-aza-2’deoxycitidine) is currently used to treat Acute Myeloid Leukaemia (AML) and is in trials for myeloid dysplastic syndrome and some solid cancers. As a hypomethylating agent it is thought to act by inhibiting the enzymes which add methyl groups to DNA, chief among them DNMT1. Improved targeting has been hindered by a lack of understanding with respect to the exact mechanism of action on DNMT1 and of the gene targets affected by altered methylation following treatment. Methods: We performed a comparative treatment of the same normosomic, non-transformed fibroblast cell line hTERT1604 over three days with either pharmacological 5-aza-2’deoxycitidine (Dacogen) or with SMARTpool siRNA directly targeting DNMT1. DNA was collected for analysis of methylation levels using Illumina 450k BeadChip methylation arrays. Data was analysed in R using the tailored RnBeads pipeline and in-house scripts. Results: Both Dacogen and DNMT1 siRNA caused overall hypomethylation in the treated cells, with the latter proving more efficient at demethylation at genes in particular. Amongst the targets experiencing demethylation, some hypomethylated promoters were unique to Dacogen treatment and therefore off-target with respect to the reduction in DNMT1. However an unexpected phenomenon almost exclusively caused by 5-Aza-2’-deoxycytidine treatment was gain in methylation. Therefore we also compared our findings to an independent published 450k dataset of Dacogen treated AML cells (KG1a). Our results suggest Dacogen is also having an important effect on methylation unrelated to the inhibition of DNMT1 thus suggesting further avenues for therapeutic improvements., Disruptive, damaging ultra-rare variants (dURVs) are more abundant in schizophrenia (SZ) patients than controls and are more concentrated in neuronally-expressed genes with synaptic functions. dURVs in highly constrained genes influence educational attainment (EA; a proxy for cognition) in the general population. We used MAGMA to perform gene set analysis of the largest available GWAS datasets to investigate if association signals for SZ and EA similarly mapped to highly constrained genes and to neuronally-expressed genes with synaptic functions. We investigated if SZ and EA associations were enriched in brain regions at different timepoints from early development through to adulthood. Highly constrained genes (probability of being loss-of-function intolerant; pLI>0.9; n=3,230) are strongly enriched for association with SZ(p=3.14E-08) and EA(p=1.27E-09) in comparison to genes under less constraint (0.1, Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease affecting 45,000 people in Ireland. Prolonged joint inflammation results in tissue damage with consequent reduced functional capacity and quality of life. Damage to the joints of hands and feet, assessed by x-ray, is an important outcome measure that has genetic input of around 60%. Recent studies have identified single nucleotide polymorphisms (SNPs) in immune-related genes that are associated with severity of tissue damage in RA. One of our studies identified an association with C5orf30, a previously uncharacterized regulator of tissue damage and inflammation (1, 2). However a more comprehensive genome wide analysis is required to more fully characterize the genetic basis of RA severity. This project will identify genetic variants, and their synergistic combinations, that are associated with severity of RA. We will analyse genomewide SNP data in 1,007 RA patients using state-of-the-art genetic epidemiology and computational techniques, including negative binomial modelling, to identify variants linked with joint damage severity. The study population is uniquely large and detailed clinical and genetic datasets will be used for validation studies using five European early RA cohorts. Simulations for statistical power indicate excellent power will be achieved for moderately frequent alleles, for effect sizes (IRR) over 1.4. The aim is to develop both a genetic prognostic score for RA, and to identify novel mediators of tissue destruction. The earlier identification of RA patients at risk of poorer outcome would facilitate patient stratification and inform therapeutic targeting with more aggressive regimes whilst avoiding such treatment in patients likely to have a better outcome, Bloodstream infection and sepsis are often instigated by the bacterium Staphylococcus aureus. Upon accessing the bloodstream, S. aureus binds to the endothelium triggering vascular leakage, inflammation and oedema. These characteristics are difficult to treat pharmacologically as the nature of signalling guiding this host response remains unclear. microRNAs (miRNAs) regulate ~60% of the human genome through post-transcriptional silencing/ degradation of target genes. Previously, bacteria were shown to profoundly affect miRNA expression via up-regulation of dendritic miR-99b elicited by M. tuberculosis infection. This study investigates contributions of S. aureus induced endothelial miRNA dysregulation to sustained and excessive host responses in sepsis. Sheared (10dynes/cm2) human endothelial cells were treated with plasma and TNFα to mimic sepsis conditions. Infection induced miRNA alterations were uncovered using Taqman cards to generate miRNA profiles of uninfected and infected cells (RQ = 2-ΔΔCt). Potential mRNA targets were established bioinformatically and confirmed by RNAseq, western blots and qPCR. Following infection, 58 endothelial miRNA were significantly downand 35 significantly up-regulated, including miR-330 (p, DNA methylation is a critical mechanism for regulating gene expression and ensuring genomic stability. However, loss of function mutations of methyltransferase enzymes such as DNMT1 in normal differentiated cells result in a lethal phenotype. Consequently, existing investigations have only assessed DNMT1 knockdowns in embryonic stem cells or cancer cell lines. Here, isogenic lines of hypomorphic, normal, immortalised fibroblasts have instead been generated via stable integration with short hairpin RNA. Enrichment analysis of epigenome-wide methylation arrays indicated widespread demethylation within promoter and gene body regions. In addition, four specific gene categories were highlighted as most affected; protocadherins, genes regulating body mass, olfactory receptors and cancer/testis antigens. Comparison of short-term siRNA and long-term shRNA-mediated depletion of DNMT1 indicated that many regions recover methylation as shRNA-containing cell lines adapt to lowered levels of DNMT1. Interestingly, polycomb-regulated genes are refractory to de novo DNA methylation in these cells following recovery, reinforcing the concept of mutually-exclusive domains that are regulated by these two major epigenetic mechanisms., Background: The MTHFR C677T is a common polymorphism of the folate metabolising enzyme methylene tetrahydrofolate reductase (MTHFR) associated with hypertension. Riboflavin is a cofactor to MTHFR in the one-carbon cycle for generating methyl groups important for biological reactions such as DNA methylation. Supplementation with riboflavin has previously been shown to reduce blood pressure specifically in individuals with the homozygous MTHFR 677TT genotype. The mechanisms underlying the blood pressure lowering effect of riboflavin are currently unknown however aberrant DNA methylation has been implicated in the development of hypertension. The aims of this study were to examine global DNA methylation on hypertension in adults stratified by MTHFR genotype and in response to intervention with 1.6mg/ day of riboflavin in individuals with the MTHFR 677TT genotype. Methods: Stored peripheral blood leukocyte samples from participants who had consented and participated in targeted RCTs at Ulster University’s Nutrition Innovation Centre for food and HEalth (NICHE) and previously screened for the MTHFR C677T polymorphism were accessed for this study. Bisulphite conversion and pyrosequencing was used to analyse global and gene-specific DNA methylation. Results: Preliminary results show that methylation at the repeat element, LINE-1, and imprinted gene, IGF2 was not significantly different between the MTHFR C677T genotypes at baseline. However, subsequent supplementation with riboflavin resulted in a decrease in global methylation and an increase in IGF2 methylation in MTHFR 677TT participants. Conclusion: This is the largest study to date examining the interaction between the MTHFR C677T genotypes, riboflavin supplementation and DNA methylation. Riboflavin supplementation influenced repeat element and imprinted gene methylation in MTHFR 677TT genotype individuals. Further work will provide insights into the mechanism of riboflavin action in lowering blood pressure in these genetically at risk adults., Background: microRNAs are small, non-coding RNAs which are potentially valuable markers of cardiovascular disease (CVD) risk, including hypertension. This novel investigation aims to profile circulating serum concentrations of microRNAs in premature CVD patients to identify microRNAs that correlate best with hypertension. Methods: Serum samples from an existing cohort of 75 premature CVD patients were analysed for expression of 68 CVD-related microRNAs. Patients had been screened for the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T, a risk factor for hypertension. Samples had been collected at baseline and following intervention with riboflavin, co-factor for the MTHFR enzyme, as part of a placebo-controlled double-blind, randomized trial. The associations between miRNA expression and blood pressure at baseline and post-intervention were investigated. Comparisons of data between CC and TT MTHFR genotype groups, and in response to intervention, were assessed using ANOVA, Pearson’s correlation and corrected t-test statistical analyses. Results: microRNA expression was successfully detected and quantified in all samples. At baseline miR-199a-5p expression was inversely correlated (r=-0.51;p, Background: Hypoxia in prostate tumours has been associated with disease progression and metastasis. MicroRNAs are short non-coding RNA molecules which are important in several cell processes, but their role in hypoxic signalling is still poorly understood. miR-210 has been linked with hypoxic mechanisms, but this relationship has not been extensively studied in a prostate cancer setting. Therefore, in this study, we investigate the link between hypoxia and miR-210 in prostate cancer cells. Methods: In this study we have used prostate cancer models of hypoxia to investigate the functionality of miR-210. Expression levels of miR-210 have been measured by qPCR in in vitro and in vivo samples. Functional bioassays were used to examine its effect on prostate cancer cell behaviour. Target genes have been identified and bioinformatic analysis has been employed to investigate a clinical significance for miR-210 in prostate cancer. Results: miR-210 is induced by hypoxia in prostate cancer cells. Over-expression of miR-210 impacts upon target genes which in turn may affect cell proliferation. Data-mining of online repositories of clinical prostate sample data shows that miR-210 is significantly correlated with Gleason grade and other clinical markers of prostate cancer progression. Further in silico analysis of miR-210 cellular networks reveal that miR-210 plays a key role in a number of important cell processes, the dysregulation of which can promote the development of prostate cancer. Conclusions: We propose that miR-210 is an important regulator of cell response to hypoxic stress and may play an important role in the pathogenesis of prostate cancer. Further study will focus on determining its function in prostate cancer and its potential as a biomarker in this disease.
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- 2018
15. Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22
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Lambert, D, Middle, F, Hamshere, M L, Segurado, R, Raybould, R, Corvin, A, Green, E, O'Mahony, E, Nikolov, I, Mulcahy, T, Haque, S, Bort, S, Bennett, P, Norton, N, Owen, M J, Kirov, G, Lendon, C, Jones, L, Jones, I, Holmans, P, Gill, M, and Craddock, N
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- 2005
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16. The Wellcome trust UK–Irish bipolar affective disorder sibling-pair genome screen: first stage report
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Bennett, P, Segurado, R, Jones, I, Bort, S, McCandless, F, Lambert, D, Heron, J, Comerford, C, Middle, F, Corvin, A, Pelios, G, Kirov, G, Larsen, B, Mulcahy, T, Williams, N, O'Connell, R, O'Mahony, E, Payne, A, Owen, M, Holmans, P, Craddock, N, and Gill, M
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- 2002
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17. EP19.10: Reference ranges for fetal volumes in the late first trimester, obtained using 9‐degree rotation steps
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Durkan, J.M., primary, Segurado, R., additional, Kelleher, M., additional, Kennelly, M., additional, Moran, M., additional, and Stuart, B., additional
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- 2019
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18. The association between benzodiazepine use and falls, and the impact of sleep quality on this association: data from the TILDA study
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Marron, L, primary, Segurado, R, additional, Kenny, R A, additional, and McNicholas, T, additional
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- 2019
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19. WS16-2 Comparison of direct healthcare costs in the first 2 years of life between screened and clinically diagnosed children with cystic fibrosis: the ICOS study
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Somerville, R., primary, Fitzgerald, C., additional, George, S., additional, Linnane, B., additional, Segurado, R., additional, Kapur, K., additional, O'Ceilleachair, A., additional, Staines, A., additional, and Fitzpatrick, P., additional
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- 2019
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20. The association between benzodiazepine use and falls, and the impact of sleep quality on this association: data from the TILDA study.
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Marron, L, Segurado, R, Kenny, R A, and McNicholas, T
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- *
OLDER people , *DATA quality , *SLEEP , *ODDS ratio , *LOGISTIC regression analysis - Abstract
Background Benzodiazepines (BZD) are associated with adverse effects, particularly in older adults. Aim This study assesses the association between BZD use and falls, and the impact of sleep quality on this association, in community dwelling adults aged over 50. Design Cross-sectional analysis of data from wave 1 of The Irish Longitudinal Study on Ageing. Methods Participants were classed as BZD users or non-users and asked if they had fallen in the last year, and whether any falls were unexplained. Sleep quality was assessed via self-reported trouble falling asleep, daytime somnolence and early-rising. Logistic regression assessed for an association between BZD use and falls, and the impact of sleep quality on this association was assessed by categorizing based on BZD use and sleep quality variables. Results Of 8175 individuals, 302 (3.69%) reported taking BZDs. BZD use was associated with falls, controlling for confounders [Odds Ratio (OR) 1.40; 1.08, 1.82; P -value 0.012]. There was no significant association between BZDs and unexplained falls, controlling for confounders [OR 1.41; 95% Confidence Interval (CI) 0.95, 2.10; P -value 0.09]. Participants who use BZDs and report daytime somnolence (OR 1.93; 95% CI 1.12, 3.31; P -value 0.017), early-rising (OR 1.93; 95% CI 1.20, 3.11; P -value 0.007) or trouble falling asleep (OR 1.83; 95% CI 1.12, 2.97; P -value 0.015), have an increased odds of unexplained falls. Conclusion BZD use is associated with falls, with larger effect size in those reporting poor sleep quality in community dwelling older adults. Appropriate prescription of medications such as BZDs is an important public health issue. [ABSTRACT FROM AUTHOR]
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- 2020
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21. Evaluation of the behavioural process and secondary outcomes of the self-management of osteoarthritis and low back pain through activity and skills cluster randomised controlled feasibility trial
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Hurley, D.A., primary, Jeffares, I., additional, Segurado, R., additional, and Matthews, J., additional
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- 2018
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22. 140 Co-colonisation of the cystic fibrosis airways with A. fumigatus and P. aeruginosa is associated with poorer health: an Irish registry analysis
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Reece, E., primary, Renwick, J., additional, Segurado, R., additional, Clean, S.M., additional, and Greally, P., additional
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- 2017
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23. Optimization of a wind powered desalination and pumped hydro storage system
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Segurado, R., primary, Madeira, J.F.A., additional, Costa, M., additional, Duić, N., additional, and Carvalho, M.G., additional
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- 2016
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24. Maternal Nutrient Intake during Pregnancy and Asthma Risk in Offspring Over a 10-year Period.
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Viljoen, K., primary, Segurado, R., additional, O'Brien, J., additional, Murrin, C., additional, and Kelleher, C. C., additional
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- 2015
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25. Parental age, birth order and neurodevelopmental disorders
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Merikangas, A K, primary, Segurado, R, additional, Kelleher, E, additional, Hogan, D, additional, Delaney, C, additional, Gill, M, additional, Gallagher, L, additional, Corvin, A P, additional, and Heron, E A, additional
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- 2015
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26. A genome-wide scan for common alleles affecting risk for autism
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Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Devlin, B. Ennis, S. Hallmayer, J.
- Abstract
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 3 10-28. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10-28 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. © The Author 2010. Published by Oxford University Press. All rights reserved.
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- 2010
27. Functional impact of global rare copy number variation in autism spectrum disorders
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Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.
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mental disorders - Abstract
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (
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- 2010
28. The phenotypic manifestations of rare genic CNVs in autism spectrum disorder
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Merikangas, A K, primary, Segurado, R, additional, Heron, E A, additional, Anney, R J L, additional, Paterson, A D, additional, Cook, E H, additional, Pinto, D, additional, Scherer, S W, additional, Szatmari, P, additional, Gill, M, additional, Corvin, A P, additional, and Gallagher, L, additional
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- 2014
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29. Is valve choice a significant determinant of paravalular leak post-transcatheter aortic valve implantation? A systematic review and meta-analysis
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O'Sullivan, K. E., primary, Gough, A., additional, Segurado, R., additional, Barry, M., additional, Sugrue, D., additional, and Hurley, J., additional
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- 2013
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30. Determinants and patterns of primary healthcare utilisation in children: Findings from the Lifeways Cross-Generation Cohort Study in the Republic of Ireland 2002-2013
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Viljoen, K, primary, Murrin, C, additional, Segurado, R, additional, O'Brien, J, additional, and Kelleher, CC, additional
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- 2013
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31. PP30 Primary Care Utilisation and its Socio-Economic Determinants: findings from the Lifeways Cross-Generation Cohort Study During the Recession Period in the Republic of Ireland
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Viljoen, K, primary, Murrin, C, additional, Segurado, R, additional, O’Brien, J, additional, Somerville, R, additional, Khalil, H, additional, and Kelleher, C C, additional
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- 2013
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32. Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms
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Badner, J A, primary, Koller, D, additional, Foroud, T, additional, Edenberg, H, additional, Nurnberger, J I, additional, Zandi, P P, additional, Willour, V L, additional, McMahon, F J, additional, Potash, J B, additional, Hamshere, M, additional, Grozeva, D, additional, Green, E, additional, Kirov, G, additional, Jones, I, additional, Jones, L, additional, Craddock, N, additional, Morris, D, additional, Segurado, R, additional, Gill, M, additional, Sadovnick, D, additional, Remick, R, additional, Keck, P, additional, Kelsoe, J, additional, Ayub, M, additional, MacLean, A, additional, Blackwood, D, additional, Liu, C-Y, additional, Gershon, E S, additional, McMahon, W, additional, Lyon, G J, additional, Robinson, R, additional, Ross, J, additional, and Byerley, W, additional
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- 2011
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33. Exploration of empirical Bayes hierarchical modeling for the analysis of genome-wide association study data
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Heron, E. A., primary, O'dushlaine, C., additional, Segurado, R., additional, Gallagher, L., additional, and Gill, M., additional
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- 2011
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34. A genome-wide scan for common alleles affecting risk for autism
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Anney, R., primary, Klei, L., additional, Pinto, D., additional, Regan, R., additional, Conroy, J., additional, Magalhaes, T. R., additional, Correia, C., additional, Abrahams, B. S., additional, Sykes, N., additional, Pagnamenta, A. T., additional, Almeida, J., additional, Bacchelli, E., additional, Bailey, A. J., additional, Baird, G., additional, Battaglia, A., additional, Berney, T., additional, Bolshakova, N., additional, Bolte, S., additional, Bolton, P. F., additional, Bourgeron, T., additional, Brennan, S., additional, Brian, J., additional, Carson, A. R., additional, Casallo, G., additional, Casey, J., additional, Chu, S. H., additional, Cochrane, L., additional, Corsello, C., additional, Crawford, E. L., additional, Crossett, A., additional, Dawson, G., additional, de Jonge, M., additional, Delorme, R., additional, Drmic, I., additional, Duketis, E., additional, Duque, F., additional, Estes, A., additional, Farrar, P., additional, Fernandez, B. A., additional, Folstein, S. E., additional, Fombonne, E., additional, Freitag, C. M., additional, Gilbert, J., additional, Gillberg, C., additional, Glessner, J. T., additional, Goldberg, J., additional, Green, J., additional, Guter, S. J., additional, Hakonarson, H., additional, Heron, E. A., additional, Hill, M., additional, Holt, R., additional, Howe, J. L., additional, Hughes, G., additional, Hus, V., additional, Igliozzi, R., additional, Kim, C., additional, Klauck, S. M., additional, Kolevzon, A., additional, Korvatska, O., additional, Kustanovich, V., additional, Lajonchere, C. M., additional, Lamb, J. A., additional, Laskawiec, M., additional, Leboyer, M., additional, Le Couteur, A., additional, Leventhal, B. L., additional, Lionel, A. C., additional, Liu, X.-Q., additional, Lord, C., additional, Lotspeich, L., additional, Lund, S. C., additional, Maestrini, E., additional, Mahoney, W., additional, Mantoulan, C., additional, Marshall, C. R., additional, McConachie, H., additional, McDougle, C. J., additional, McGrath, J., additional, McMahon, W. M., additional, Melhem, N. M., additional, Merikangas, A., additional, Migita, O., additional, Minshew, N. J., additional, Mirza, G. K., additional, Munson, J., additional, Nelson, S. F., additional, Noakes, C., additional, Noor, A., additional, Nygren, G., additional, Oliveira, G., additional, Papanikolaou, K., additional, Parr, J. R., additional, Parrini, B., additional, Paton, T., additional, Pickles, A., additional, Piven, J., additional, Posey, D. J., additional, Poustka, A., additional, Poustka, F., additional, Prasad, A., additional, Ragoussis, J., additional, Renshaw, K., additional, Rickaby, J., additional, Roberts, W., additional, Roeder, K., additional, Roge, B., additional, Rutter, M. L., additional, Bierut, L. J., additional, Rice, J. P., additional, Salt, J., additional, Sansom, K., additional, Sato, D., additional, Segurado, R., additional, Senman, L., additional, Shah, N., additional, Sheffield, V. C., additional, Soorya, L., additional, Sousa, I., additional, Stoppioni, V., additional, Strawbridge, C., additional, Tancredi, R., additional, Tansey, K., additional, Thiruvahindrapduram, B., additional, Thompson, A. P., additional, Thomson, S., additional, Tryfon, A., additional, Tsiantis, J., additional, Van Engeland, H., additional, Vincent, J. B., additional, Volkmar, F., additional, Wallace, S., additional, Wang, K., additional, Wang, Z., additional, Wassink, T. H., additional, Wing, K., additional, Wittemeyer, K., additional, Wood, S., additional, Yaspan, B. L., additional, Zurawiecki, D., additional, Zwaigenbaum, L., additional, Betancur, C., additional, Buxbaum, J. D., additional, Cantor, R. M., additional, Cook, E. H., additional, Coon, H., additional, Cuccaro, M. L., additional, Gallagher, L., additional, Geschwind, D. H., additional, Gill, M., additional, Haines, J. L., additional, Miller, J., additional, Monaco, A. P., additional, Nurnberger, J. I., additional, Paterson, A. D., additional, Pericak-Vance, M. A., additional, Schellenberg, G. D., additional, Scherer, S. W., additional, Sutcliffe, J. S., additional, Szatmari, P., additional, Vicente, A. M., additional, Vieland, V. J., additional, Wijsman, E. M., additional, Devlin, B., additional, Ennis, S., additional, and Hallmayer, J., additional
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- 2010
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35. Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22.
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Lambert, D, Middle, F, Hamshere, M L, Segurado, R, Raybould, R, Corvin, A, Green, E, O'Mahony, E, Nikolov, I, Mulcahy, T, Haque, S, Bort, S, Bennett, P, Norton, N, Owen, M J, Kirov, G, Lendon, C, Jones, L, Jones, I, and Holmans, P
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GENETICS - Abstract
A correction to the article "Stage 2 of the Wellcome Trust UK-Irish Bipolar Affective Disorder Sibling-Pair Genome Screen: Evidence for Linkage on Chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22" that was published in the 2005 issue is presented.
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- 2006
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36. A genome-wide scan for common alleles affecting risk for autism
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Veronica J. Vieland, Stephen W. Scherer, Elizabeth A. Heron, Barbara Parrini, Jeremy R. Parr, Louise Gallagher, Jeff Munson, Annemarie Poustka, Susan E. Folstein, Irene Drmic, Gudrun Nygren, John P. Rice, Jeff Salt, Simon Wallace, Geraldine Dawson, Daniel H. Geschwind, Annette Estes, Sean Brennan, Alistair T. Pagnamenta, Nancy J. Minshew, Christina Corsello, Jonathan Green, William M. McMahon, Christopher Gillberg, Kathryn Roeder, Lambertus Klei, Anath C. Lionel, Bridget A. Fernandez, Thomas Bourgeron, Ellen M. Wijsman, Gerard D. Schellenberg, Wendy Roberts, Jeremy Goldberg, Frederico Duque, Ghazala Mirza, Sean Ennis, Joana Almeida, Nadine M. Melhem, Jillian P. Casey, Roberta Igliozzi, Ricardo Segurado, Carine Mantoulan, Katy Renshaw, Kai Wang, Andrew D. Paterson, Raffaella Tancredi, Matthew Nicholas Hill, Richard Anney, Christian R. Marshall, Anthony P. Monaco, Linda Lotspeich, Marion Leboyer, Richard Holt, Andrew Pickles, Vlad Kustanovich, William M. Mahoney, Jessica Brian, Inês Sousa, Peter Szatmari, Vanessa Hus, Janine A. Lamb, Hakon Hakonarson, Lonnie Zwaigenbaum, John Tsiantis, David J. Posey, Olena Korvatska, Guillermo Casallo, Rita M. Cantor, Bhooma Thiruvahindrapduram, Nadia Bolshakova, Sven Bölte, Alison K. Merikangas, Brian L. Yaspan, Cecilia Kim, Andrew Crossett, Fritz Poustka, Danielle Zurawiecki, Agatino Battaglia, Sabata C. Lund, Ann P. Thompson, Bennett L. Leventhal, Jessica Rickaby, Zhouzhi Wang, John I. Nurnberger, Astrid M. Vicente, Maretha de Jonge, Tiago R. Magalhaes, Michael L. Cuccaro, Val C. Sheffield, Nuala Sykes, Elena Maestrini, Guiomar Oliveira, Joseph D. Buxbaum, Fred R. Volkmar, Shawn Wood, Magdalena Laskawiec, Katherine Sansom, Herman van Engeland, Jane McGrath, Thomas H. Wassink, Su H. Chu, Elena Bacchelli, Carolyn Noakes, Ann Le Couteur, Catarina Correia, Ohsuke Migita, Bernie Devlin, Hilary Coon, Gillian Baird, Joseph Piven, Tom Berney, Ana Tryfon, Abdul Noor, Patrick Bolton, Latha Soorya, Vera Stoppioni, Stephen J. Guter, Joseph T. Glessner, Michael Gill, Christopher J. McDougle, Anthony J. Bailey, Margaret A. Pericak-Vance, Joachim Hallmayer, Christine M. Freitag, Penny Farrar, Kirsty Wing, Katherine E. Tansey, Bernadette Rogé, Michael Rutter, Christina Strawbridge, Brett S. Abrahams, Kerstin Wittemeyer, Laura J. Bierut, Tara Paton, Emily L. Crawford, Jonathan L. Haines, Alexander Kolevzon, Gillian Hughes, Lili Senman, James S. Sutcliffe, John B. Gilbert, Katerina Papanikolaou, Andrew R. Carson, Lynne E Cochrane, Regina Regan, Judith Miller, Susanne Thomson, Helen McConachie, Daisuke Sato, Richard Delorme, Jiannis Ragoussis, Eric Fombonne, Clara Lajonchere, Judith Conroy, Dalila Pinto, Aparna Prasad, Naisha Shah, Stanley F. Nelson, Sabine M. Klauck, Catalina Betancur, John B. Vincent, Eftichia Duketis, Jennifer L. Howe, Edwin H. Cook, Xiao-Qing Liu, Catherine Lord, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry, University of Oxford [Oxford]-Warneford Hospital, Newcomen Centre, Guy's Hospital [London], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Child and Adolescent Mental Health, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Child and Adolescent Psychiatry, Institute of psychiatry, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Autism Research Unit, University of Toronto-The Hospital for sick children [Toronto] (SickKids), Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Scientific Affairs, Autism Speaks, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Speech and Hearing Sciences [Washington], University of Washington [Seattle], Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), University of Gothenburg (GU), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario], Manchester Academic Health Sciences Centre, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Department of Medicine, Autism Genetic Resource Exchange, Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nathan Kline Institute for Psychiatric Research (NKI), Nathan Kline Institute for Psychiatric Research, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU)-NYU Child Study Center, Centre d'Etudes et de Recherches en PsychoPathologie, Université Toulouse - Jean Jaurès (UT2J), Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Departments of Psychiatry and Neurology, Department of Psychiatry and Behavioral Sciences, Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), Centre for Addiction and Mental Health, Clarke Institute, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Institutes of Neuroscience and Health and Society, Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Carolina Institute for Developmental Disabilities, Social, Genetic and Developmental Psychiatry Centre, Washington University in Saint Louis (WUSTL), Howard Hughes Medical-Institute Carver College of Medicine-University of Iowa [Iowa City], Neuropsichiatria Infantile, Ospedale Santa Croce, Child Study Centre, Yale University School of Medicine, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], University of Alberta, Physiopathologie des Maladies du Système Nerveux Central, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Departments of Biostatistics and Medicine, This research was primarily supported by Autism Speaks (USA), the Health Research Board (HRB, Ireland), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health [HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH057881, MH061009, MH06359, MH066673, MH077930, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261], the Canadian Institutes for Health Research (CIHR), Assistance Publique-Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant: Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), GlaxoSmithKline-CIHR Pathfinder Chair (Canada), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health [convention 181 of 19.10.2001], the John P Hussman Foundation (USA), McLaughlin Centre (Canada), Netherlands Organization for Scientific Research [Rubicon 825.06.031], Ontario Ministry of Research and Innovation (Canada), Royal Netherlands Academy of Arts and Sciences [TMF/DA/5801], the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award [075491/Z/04 UK]. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422)., University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of Oxford-Warneford Hospital, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Université de Toulouse (UT)-Université de Toulouse (UT), University of Pennsylvania, Betancur, Catalina, Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, and Hallmayer J.
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Genome-wide association study ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,MESH: Genotype ,0302 clinical medicine ,Risk Factors ,MESH: Risk Factors ,Databases, Genetic ,Copy-number variation ,MESH: Genetic Variation ,Genetics (clinical) ,MESH: Databases, Genetic ,Genetics ,0303 health sciences ,education.field_of_study ,MESH: Polymorphism, Single Nucleotide ,Association Studies Articles ,MESH: Genetic Predisposition to Disease ,General Medicine ,MESH: European Continental Ancestry Group ,Autism spectrum disorders ,MESH: DNA Copy Number Variations ,Genotyping ,DNA Copy Number Variations ,Genotype ,Population ,MESH: Autistic Disorder ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,Genetic variation ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Allele ,Autistic Disorder ,SNP association ,education ,Molecular Biology ,Alleles ,MESH: Genome, Human ,030304 developmental biology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,Genome, Human ,MESH: Alleles ,Haplotype ,Genetic Variation ,Genetic architecture ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,MESH: Genome-Wide Association Study ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. Author has checked copyright TS 14.06.13 The subscript characters from the abstract have not copied across properly. TS
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37. Bystander defibrillation for out-of-hospital cardiac arrest in Ireland.
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Barry T, Kasemiire A, Quinn M, Deasy C, Bury G, Masterson S, Segurado R, and Murphy AW
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Aims: To describe and explore predictors of bystander defibrillation in Ireland during the period 2012 to 2020. To examine the relationship between bystander defibrillation and health system developments., Methods: National level Out of Hospital Cardiac Arrest (OHCA) registry data were interrogated, focusing on patients who had defibrillation performed. Bystander defibrillation (as compared to EMS initiated defibrillation) was the key outcome of concern. Logistic regression models were built and refined by fitting predictors, performing stepwise variable selection and by adding pairwise interactions that improved fit., Results: The data included 5,751 cases of OHCA where defibrillation was performed. Increasing year over time (OR 1.17, 95% CI 1.13, 1.21) was associated with increased adjusted odds of bystander defibrillation. Non-cardiac aetiology was associated with reduced adjusted odds of bystander defibrillation (OR 0.30, 95% CI 0.21, 0.42), as were increasing age in years (OR 0.99, 95% CI 0.987, 0.996) and night-time occurrence of OHCA (OR 0.67, 95% CI 0.53, 0.83). Six further variables in the final model (sex, call response interval, incident location (home or other), who witnessed collapse (bystander or not witnessed), urban or rural location, and the COVID period) were involved in significant interactions. Bystander defibrillation was in general less likely in urban settings and at home locations. Whilst women were less likely to receive bystander defibrillation overall, in witnessed OHCAs, occurring outside the home, in urban areas and outside of the COVID-19 period women were more likely, to receive bystander defibrillation., Conclusions: Defibrillation by bystanders has increased incrementally over time in Ireland. Interventions to address sex and age-based disparities, alongside interventions to increase bystander defibrillation at night, in urban settings and at home locations are required., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘TB has research, clinical and educational roles in resuscitation care. He is a member of the Pre-Hospital Emergency Care Council (Ireland). All authors declare no conflict of interest’., (© 2024 The Author(s).)
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- 2024
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38. Health systems developments and predictors of bystander CPR in Ireland.
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Barry T, Kasemiire A, Quinn M, Deasy C, Bury G, Masterson S, Segurado R, and Murphy AW
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Aims: To explore predictors of bystander CPR (i.e. any CPR performed prior to EMS arrival) in Ireland over the period 2012-2020. To examine the relationship between bystander CPR and key health system developments during this period., Methods: National level out-of-hospital cardiac arrest (OHCA) registry data relating to unwitnessed, and bystander witnessed OHCA were interrogated. Logistic regression models were built, then refined by fitting predictors, performing stepwise variable selection and by adding pairwise interactions that improved fit. Missing data sensitivity analyses were conducted using multiple imputation., Results: The data included 18,177 OHCA resuscitation attempts of whom 77% had bystander CPR. The final model included ten variables. Four variables (aetiology, incident location, time of day, and who witnessed collapse) were involved in interactions. The COVID-19 period was associated with reduced adjusted odds of bystander CPR (OR 0.77, 95% CI 0.65, 0.92), as were increasing age in years (OR 0.992, 95% CI 0.989, 0.994) and urban location (OR 0.52, 95% CI 0.47, 0.57). Increasing year over time (OR 1.23, 95% CI 1.16, 1.29), and an increased call response interval in minutes (OR 1.017, 95% CI 1.012, 1.022) were associated with increased adjusted odds of bystander CPR., Conclusions: Bystander CPR increased over the study period, and it is likely that health system developments contributed to the yearly increases observed. However, COVID-19 appeared to disrupt this positive trend. Urban OHCA location was associated with markedly decreased odds of bystander CPR compared to rural location. Given its importance bystander CPR in urban areas should be an immediate target for intervention., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘TB has research, clinical and educational roles in resuscitation care. He is a member of the Pre-Hospital Emergency Care Council (Ireland). All authors declare no conflict of interest.’., (© 2024 The Authors.)
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- 2024
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39. Resuscitation for out-of-hospital cardiac arrest in Ireland 2012-2020: Modelling national temporal developments and survival predictors.
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Barry T, Kasemiire A, Quinn M, Deasy C, Bury G, Masterson S, Segurado R, and Murphy AW
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Aim: To explore potential predictors of national out-of-hospital cardiac arrest (OHCA) survival, including health system developments and the COVID pandemic in Ireland., Methods: National level OHCA registry data from 2012 through to 2020, relating to unwitnessed, and bystander witnessed OHCA were interrogated. Logistic regression models were built by including predictors through stepwise variable selection and enhancing the models by adding pairwise interactions that improved fit. Missing data sensitivity analyses were conducted using multiple imputation., Results: The data included 18,177 cases. The final model included seventeen variables. Of these nine variables were involved in pairwise interactions. The COVID-19 period was associated with reduced survival (OR 0.61, 95%CI 0.43, 0.87), as were increasing age in years (OR 0.96, 95% CI 0.96, 0.97) and call response interval in minutes (OR 0.97, 95% CI 0.96, 0.99). Amiodarone administration (OR 3.91, 95% CI 2.80, 5.48), urban location (OR 1.40, 95% CI 1.12, 1.77), and chronological year over time (OR 1.14, 95% CI 1.08, 1.20) were associated with increased survival., Conclusions: National survival from OHCA has significantly increased incrementally over time in Ireland. The COVID-19 pandemic was associated with decreased survival even after accounting for potential disruption to key elements of bystander and EMS care. Further research is needed to understand and address the discrepancy between urban and rural OHCA survival. Information concerning pre-event patient health status and inpatient care process may yield important additional insights in future., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘TB has research, clinical and educational roles in resuscitation care. He is a member of the Pre-Hospital Emergency Care Council (Ireland). All authors declare no conflict of interest.’., (© 2024 The Author(s).)
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- 2024
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40. The effectiveness of a combined exercise and psychological treatment programme on measures of nervous system sensitisation in adults with chronic musculoskeletal pain - a systematic review and meta-analysis.
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Deegan O, Fullen BM, Segurado R, and Doody C
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- Adult, Humans, Combined Modality Therapy, Exercise Therapy, Pain Measurement, Pain Threshold, Treatment Outcome, Central Nervous System Sensitization physiology, Chronic Pain therapy, Chronic Pain psychology, Musculoskeletal Pain therapy, Musculoskeletal Pain psychology, Musculoskeletal Pain diagnosis
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Background: Quantitative sensory testing (QST) offers information regarding underlying mechanisms contributing to chronic pain (CP) in adults with musculoskeletal disorders. This review examined the use of QST measures in adults with CP following participation in a combined exercise and psychological intervention., Methods: The review was conducted in accordance with the PRISMA guidelines. Five databases were searched from inception to November 2022. All study designs which evaluated the effects of a combined exercise and psychological treatment on measures of nervous system sensitivity in adults with chronic musculoskeletal pain were included., Results: A total of 13 studies met the selection criteria, 10 of which were included in a meta-analysis. Local pressure pain thresholds were the most frequently used measure (n = 12 studies). Meta-analysis revealed statistically significantly improvements in favour of the combined exercise and psychological intervention group, compared to a control group, for local pressure pain threshold measures [SMD = 0.44, 95% CI 0.08-0.81, I
2 = 84%], pain intensity scores [SMD=-0.89, 95% CI -1.66- -0.13, I2 = 94%] and the Central Sensitisation Inventory [SMD=-0.69, 95% CI -1.37- -0.02, I2 = 87%]. There were no significant differences found between groups for remote pressure pain thresholds, temporal summation or conditioned pain modulation., Conclusions: The results suggest that a combined exercise and psychological intervention may lead to greater improvements in local pressure pain threshold, pain intensity and Central Sensitisation Inventory scores when compared to a control intervention in adults with CP, however these findings must be interpreted with caution as a large degree of heterogeneity was present in these results (I2 : 84-94%). Further large, longitudinal studies are required using standardised QST measurement procedures and patient reported outcome measures to explore changes in nervous system sensitisation., Trial Registration: This systematic review is registered with PROSPERO, ID Number CRD42022380464., (© 2024. The Author(s).)- Published
- 2024
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41. Epidemiological transition: a historical analysis of immigration patterns by country of origin (1861-1986) related to circulatory system diseases and all-cause mortality in twentieth-century Australia.
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Kelleher CC, Kelly GE, Segurado R, Briody J, Sellers AM, and McCalman J
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- Humans, Female, Male, Emigration and Immigration, Risk Factors, Australia epidemiology, Mortality, Cardiovascular Diseases, Cardiovascular System
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Background and Objectives: Circulatory system disease (CSD) patterns vary over time and between countries, related to lifestyle risk factors, associated in turn with socioeconomic circumstances. Current global CSD epidemics in developing economies are similar in scale to those observed previously in the USA and Australasia. Australia exhibits an important macroeconomic phenomenon as a rapidly transitioning economy with high immigration throughout the nineteenth and twentieth centuries. We wished to examine how that historical immigration related to CSD patterns subsequently., Methods and Setting: We provide a novel empirical analysis employing census-derived place of birth by age bracket and sex from 1891 to 1986, in order to map patterns of immigration against CSD mortality rates from 1907 onwards. Age-specific generalised additive models for both CSD mortality in the general population, and all-cause mortality for the foreign-born (FB) only, from 1910 to 1980 were also devised for both males and females., Results: The percentage of FB fell from 32% in 1891 to 9.8% in 1947. Rates of CSD rose consistently, particularly from the 1940s onwards, peaked in the 1960s, then declined sharply in the 1980s and showed a strong period effect across age groups and genders. The main effects of age and census year and their interaction were highly statistically significant for CSD mortality for males (p<0.001, each term) and for females (p<0.001, each term). The main effect of age and year were statistically significant for all-cause mortality minus net migration rates for the FB females (each p<0.001), and for FB males, age (p<0.001) was significant., Conclusions: We argue our empirical calculations, supported by historical and socioepidemiological evidence, employing immigration patterns as a proxy for epidemiological transition, affirm the life course hypothesis that both early life circumstances and later life lifestyle drive CSD patterns., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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42. Outcomes of out-of-hospital cardiac arrest in Ireland 2012-2020: Protocol for an observational study.
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Barry T, Kasemiire A, Quinn M, Deasy C, Bury G, Masterson S, Segurado R, and Murphy A
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Background: Out-of-hospital cardiac arrest (OHCA) is a leading cause of preventable mortality that now affects almost 3,000 people each year in Ireland. Survival is low at 6-7%, compared to a European average of 8%. The Irish Out-of-Hospital Cardiac Registry (OHCAR) prospectively gathers data on all OHCA in Ireland where emergency medical services attempted resuscitation.The Irish health system has undergone several developments that are relevant to OHCA care in the period 2012-2020. OHCAR data provides a means of exploring temporal trends in OHCA incidence, care, and outcomes over time. It also provides a means of exploring whether system developments were associated with a change in key outcomes.This research aims to summarise key trends in available OHCAR data from the period 2012 - 2020, to explore and model predictors of bystander CPR, bystander defibrillation, and survival, and to explore the hypothesis that significant system level temporal developments were associated with improvements in these outcomes., Methods: The following protocol sets out the relevant background and research approach for an observational study that will address the above aims. Key trends in available OHCAR data (2012 - 2020) will be described and evaluated using descriptive summaries and graphical displays. Multivariable logistic regression will be used to model predictors of 'bystander CPR', 'bystander defibrillation' and 'survival to hospital discharge' and to explore the effects (if any) of system level developments in 2015/2016 and the COVID-19 pandemic (2020) on these outcomes., Discussion: The findings of this research will be used to understand temporal trends in the care processes and outcomes for OHCA in Ireland over the period 2012-2020. The results can further be used to optimise future health system developments for OHCA in both Ireland and internationally., Competing Interests: Competing interests: TB has research, clinical and educational roles in resuscitation care. He is a member of the Pre-Hospital Emergency Care Council (Ireland)., (Copyright: © 2023 Barry T et al.)
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- 2023
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43. Exploring the psychological impact of contact tracing work on staff during the COVID-19 pandemic.
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Fulham-McQuillan H, O'Donovan R, Buckley CM, Crowley P, Gilmore B, Martin J, McAuliffe E, Martin G, Moore G, Morrissey M, Nicholson E, Shé ÉN, O'Hara MC, Segurado R, Sweeney MR, Wall P, and De Brún A
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- Humans, Contact Tracing, Longitudinal Studies, Pandemics, Burnout, Psychological, Health Personnel, COVID-19 epidemiology
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Background: Contact tracing is a key control measure in the response to the COVID-19 pandemic. While quantitative research has been conducted on the psychological impact of the pandemic on other frontline healthcare workers, none has explored the impact on contact tracing staff., Methods: A longitudinal study was conducted using two repeated measures with contact tracing staff employed in Ireland during the COVID-19 pandemic using two-tailed independent samples t tests and exploratory linear mixed models., Results: The study sample included 137 contact tracers in March 2021 (T1) and 218 in September 2021 (T3). There was an increase from T1 to T3 in burnout related exhaustion (p < 0·001), post-traumatic stress disorder (PTSD) symptom scores (p < 0·001), mental distress (p < 0·01), perceived stress (p < 0·001) and tension and pressure (p < 0·001). In those aged 18-30, there was an increase in exhaustion related burnout (p < 0·01), PTSD symptoms (p < 0·05), and tension and pressure scores (p < 0·05). Additionally, participants with a background in healthcare showed an increase in PTSD symptom scores by T3 (p < 0·001), reaching mean scores equivalent to those of participants who did not have a background in healthcare., Conclusions: Contact tracing staff working during the COVID-19 pandemic experienced an increase in adverse psychological outcomes. These findings highlight a need for further research on psychological supports required by contact tracing staff with differing demographic profiles., (© 2023. The Author(s).)
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- 2023
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44. Socio-ecological predictors of dietary inflammatory scores and associations with childhood and adolescent adiposity: A protocol for a rapid scoping review of observational studies.
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Vingrys K, McCarthy H, Segurado R, Hébert JR, and Phillips CM
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- Child, Adolescent, Humans, Diet, Risk Factors, Inflammation, Research Design, Systematic Reviews as Topic, Review Literature as Topic, Adiposity, Obesity
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Introduction: Diet-related inflammation is associated with adiposity. Obesity and inflammation in early life may have adverse health outcomes in later life; however, the socio-ecological predictors of a pro-inflammatory diet in childhood and adolescence are not well understood. This rapid scoping review aims to summarise the current state of research from observational studies investigating socio-ecological predictors (childhood, parental, familial, demographic and chronobiological risk factors) and their association with diet-associated inflammation and adiposity in children and adolescents., Methods: This scoping review will be conducted using the frameworks based on the Joanna Briggs Institute and Arksey and O'Malley and the Population, Concept and Context (PCC) mnemonic. Searches were conducted in OVID Medline, Cinahl and Embase, with adaptations as required. The piloted study selection process will utilise two reviewers for study selection, with reference lists checked for included studies. A third reviewer will moderate disagreements. Data will be extracted by one reviewer and calibrated by a second reviewer., Results: The results will be reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and PRISMA-ScR flow diagram. The main findings will be synthesised into themes and concepts narratively. Tables and graphs will present frequencies, study details and categorical descriptions., Discussion: This scoping review will provide an overview of the research conducted to date regarding predictors of diet-related inflammation in childhood and their associations with adiposity. Better understanding of the factors associated with a more inflammatory diet in childhood may be useful for clinicians and policy makers when designing and implementing health interventions., Competing Interests: KV, HMc, RS, CMP - no conflict of interest to declare. JH: Dr. James R. Hébert owns controlling interest in Connecting Health Innovations LLC (CHI), a company that has licensed the right to his invention of the dietary inflammatory index (DII®) from the University of South Carolina in order to develop computer and smart phone applications for patient counselling and dietary intervention in clinical settings. CHI owns exclusive right to the E-DIITM and C-DIITM. The subject matter of this paper has no direct bearing on that work, nor has any CHI-related activity exerted any influence on this project. This did not and will not alter our adherence to PLoS ONE policies on sharing data and materials. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Vingrys et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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45. Associations between maternal dietary scores during early pregnancy with placental outcomes.
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Teo SM, Murrin CM, Mehegan J, Douglas A, Hébert JR, Segurado R, Kelleher CC, and Phillips CM
- Abstract
Background and Aims: Individual macronutrient and micronutrient effects on placental growth have been widely investigated. However, the influence of overall maternal diet is relatively unknown. Therefore, the aim of this study is to examine associations between a range of maternal dietary scores during early pregnancy with placental outcomes, and to investigate whether there is evidence of sexual dimorphism., Methods: This analysis of the Lifeways Cross-Generational Cohort includes 276 mother-child pairs. A validated 148-item semi-quantitative food frequency questionnaire assessed maternal diet in early pregnancy. Dietary scores reflecting dietary quality [Healthy Eating Index (HEI-2015), Dietary Approaches to Stop Hypertension (DASH)], dietary inflammatory potential [Dietary Inflammatory Index (DII) and the energy adjusted DII (E-DII)], dietary antioxidant status [Dietary Antioxidant Quality (DAQ)], and glycemic and insulinemic loads/indices (GL/GI, IL/II) were calculated. Linear regression analyses assessed maternal dietary score relationships with untrimmed placental weight (PW) and birth weight:placental weight (BW:PW) ratio., Results: In fully adjusted models, maternal E-DII and GI were positively associated, and HEI-2015 and DAQ were negatively associated with PW (B: 12.31, 95% CI: 0.41, 24.20, p = 0.04, B: 4.13, 95% CI: 0.10, 8.17, p = 0.04, B: -2.70, 95% CI: -5.03, -0.35, p = 0.02 and B: -15.03, 95% CI: -28.08, -1.98, p = 0.02, for E-DII, GI, HEI-2015 and DAQ respectively). Maternal DAQ associations with BW:PW ratio were attenuated. When stratified by sex, maternal GI and pregnancy-specific DAQ were associated with PW in female offspring (B: 5.61, 95% CI: 0.27, 10.96, p = 0.04 and B: -15.31, 95% CI: -30.35, -0.27, p = 0.046). Maternal E-DII and HEI-2015 were associated with PW in males (B: 24.31, 95% CI: 5.66, 42.96, p = 0.01 and B: -3.85, 95% CI: -7.47, -0.35, p = 0.03 respectively)., Conclusion: The results of this novel investigation suggest that maternal diet may influence placental development. Female fetuses may be more sensitive to increased glucose levels whereas male fetuses may be more susceptible to in-utero stresses that are regulated by inflammatory pathways and overall diet quality. Hence, early pregnancy offers an opportune time for a mother to prioritize dietary changes that focus on reducing inflammatory and glycemic responses., Competing Interests: We wish to disclose that JH owns controlling interest in Connecting Health Innovations LLC (CHI), a company that has licensed the right to his invention of the dietary inflammatory index (DII) from the University of South Carolina to develop computer and smartphone applications for patient counseling and dietary intervention in clinical settings. The subject matter of this paper will not have any direct bearing on that work, nor has that activity exerted any influence on this project.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Teo, Murrin, Mehegan, Douglas, Hébert, Segurado, Kelleher and Phillips.)
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- 2023
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46. The effect of combined Action Observation Therapy with eccentric exercises in the treatment of mid-portion Achilles-tendinopathy: a feasibility pilot randomised controlled trial.
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Ryan D, O'Donoghue G, Rio E, Segurado R, and O'Sullivan C
- Abstract
Background: Mid-portion Achilles Tendinopathy (AT) is a common musculoskeletal condition with varying rehabilitation success rates. Despite the prevalence of this condition, a considerable proportion of individuals experience persisting pain and functional deficits. Current treatment approaches bias the biomedical model which emphasises physically treating and loading the tendon. Overall, there is a lack of consideration for the central nervous system that is commonly implicated in chronic injuries. The aim of this pilot study was to explore the feasibility of combining Action Observation Therapy (AOT), a treatment technique which targets central changes and influences motor learning, with eccentric exercises in the treatment of mid-portion AT. AOT involves the observation of movements and is commonly followed by the physical performance of these same movements., Methodology: This was a double-blinded randomised controlled pilot feasibility study. All participants underwent the 12-week Alfredson eccentric training protocol. The intervention group watched videos of the exercises prior to performing these exercises, whilst the control group watched nature videos before performing the same exercises. Study feasibility was the primary outcome measure, with the Victorian Institute of Sports Assessment- Achilles (VISA-A) selected as the primary clinical outcome measure., Results: Thirty participants were recruited, reflecting a 75% eligibility rate and 100% of eligible participants enrolled in the study. The retention rate at week 12 was 80%. At week six the mean VISA-A score improved by 18.1 (95% CI 10.2-26.0) in the intervention group and 7.7 (95% CI 0.3-14.9) in the control group, and 75% and 33% of participants in the intervention and control group respectively exceeded the minimal clinically important difference (MCID). At week 12 the mean VISA-A score from baseline improved by 22.25 (95% CI 12.52-31.98) in the intervention group and 16.5-(95% CI 8.47-24.53) in the control group, equating to 75% and 58% in each group respectively exceeding the MCID., Conclusion: The positive feasibility outcomes and exploratory data from the clinical outcome measures suggest that a larger scaled RCT is warranted to further investigate the impact of AOT in the rehabilitation of mid-portion AT. Trial registration ISRCTN58161116, first registered on the 23/12/2020., (© 2022. The Author(s).)
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- 2022
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47. Plasma neurofilament light levels associate with muscle mass and strength in middle-aged and older adults: findings from GenoFit.
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Pratt J, De Vito G, Segurado R, Pessanha L, Dolan J, Narici M, and Boreham C
- Subjects
- Absorptiometry, Photon, Aged, Female, Humans, Intermediate Filaments, Male, Middle Aged, Muscle Strength physiology, Muscle, Skeletal, Sarcopenia diagnosis
- Abstract
Background: Efforts to enhance diagnostic measures for sarcopenia have led to an increased focus on the screening utility of blood-based biomarkers. In this regard, circulating neurofilament light chain (NfL) levels are a potent indicator of axonal damage and have been linked with several neurological disorders. However, despite the strong neurogenic contribution to skeletal muscle health, no studies have explored the relevance of NfL concentrations to sarcopenia. With that in mind, this study aimed to examine the association between plasma NfL concentration and sarcopenic domains., Methods: Three hundred adults aged between 50 and 83 years participated to this study (male participants, n = 150; mean age: 64.2 ± 8.7 years and female participants, n = 150; mean age: 63.9 ± 8.3 years). Body composition was assessed using dual-energy X-ray absorptiometry, and a skeletal muscle index (SMI) was calculated. Muscle strength was assessed with hand dynamometry. Sarcopenia was classified using the European Working Group on Sarcopenia in Older People criteria. Plasma NfL concentration was determined using a highly sensitive, enzyme-linked immunosorbent assay., Results: Neurofilament light chain levels were associated with grip strength and SMI (P = 0.005 and P = 0.045, respectively) and were significantly elevated in sarcopenic individuals, compared with non-sarcopenic participants (P < 0.001). Individuals with pre-sarcopenia (either low grip strength or low SMI) had significantly higher NfL levels, compared with healthy controls (P = 0.001 and P = 0.006, respectively). Male participants with either low grip strength or low SMI had significantly raised NfL levels (P = 0.006 and P = 0.002, respectively), while in female participants, NfL concentrations were significantly elevated only in those with low grip strength (P = 0.049). NfL concentration displayed acceptable diagnostic accuracy for sarcopenia (area under the curve = 0.726, P < 0.001)., Conclusions: Our study clearly demonstrates the indicative pertinence of circulating NfL levels to sarcopenic domains, supporting its potential use as a biomarker of sarcopenia. More studies are needed, however, to further illuminate the diagnostic value of circulating NfL. Future research should explore whether NfL levels are more powerfully linked with muscle strength than mass and whether sex mediates the relevance of NfL concentrations to sarcopenic phenotypes., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
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- 2022
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48. Assessment of an Aujeszky's Disease Control Strategy in a Highly Prevalent Pig Farm Based on Systematic Vaccination With an Inactivated gE-Negative Marker Vaccine.
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Aznar MN, Bessone FA, Segurado R, and Duffy SJ
- Abstract
Aujeszky's disease (AD) is endemic in Argentina. In 2016, an inactivated gE- negative marker Bartha K61 vaccine (AUSKIPRA
® BK) was launched for use, making Argentina the only country to carry out a control strategy plan with it. In the present article, we describe the results of a control program in a farrow-to-finishing farm with high initial AD prevalence (33% in sows), based on the systematic vaccination, detection, and elimination of seropositive pigs, the replacement of sows with vaccinated gilts, and the instauration of artificial insemination. The program was suitable for diminishing the incidence and the prevalence at levels consistent with virus eradication. This situation has been sustained over time. This is the first report of AUSKIPRA® BK efficacy under field conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aznar, Bessone, Segurado and Duffy.)- Published
- 2022
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49. Combined online interactive mindfulness and exercise programme (MOVE-Online) compared with a self-management guide for adults with chronic pain: protocol for a randomised controlled feasibility trial.
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Deegan O, Fullen BM, Casey MB, Segurado R, Hearty C, and Doody CM
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- Adult, Exercise Therapy, Feasibility Studies, Humans, Randomized Controlled Trials as Topic, Chronic Pain therapy, Mindfulness methods, Self-Management
- Abstract
Introduction: Online pain management programmes (PMP) have growing evidence as effective interventions for individuals with chronic pain (CP). Mindfulness-based stress reduction (MBSR) is a psychological intervention proven to be effective in the management of CP. There is also a large body of evidence for the efficacy of exercise in the management of CP however, there are limited studies combining both these interventions and none to date delivering a combined intervention in the form of an online PMP. This study aims to explore the acceptability and feasibility of delivering a combined MBSR and exercise online PMP for adults with CP, and will examine the feasibility of conducting a randomised controlled trial of a combined MBSR and exercise online programme compared with an online self-management guide., Methods and Analysis: A parallel-group, feasibility randomised controlled trial (RCT) will be conducted among participants in Ireland, which will include an embedded qualitative study. Seventy-five participants will complete an online consent form and be individually randomised to one of two groups. Group A will participate in live online MBSR and supervised exercise sessions (2 hours MBSR, 1 hour exercise) once a week for 8 weeks. Group B will receive access to an 8-week online self-management guide, released biweekly and containing eight self-directed modules. Analyses of the feasibility study will be descriptive and will address the outcomes relating to the feasibility and acceptability of the interventions and procedures of the study including recruitment and eligibility, data collection methods, intervention adherence, engagement and attrition rates, intervention acceptability and participants' subjective perceptions of the programmes. Comparisons of clinical treatment effects, using validated patient-reported outcome measures will be explored descriptively to consider the viability of investigating a combined online MBSR and exercise intervention in a future fully powered RCT., Ethics and Dissemination: This study was approved by the Mater Misericordiae University Hospital Institutional Review Board (1/378/2124) and the University College Dublin Human Research Ethics Committee (LS-20-76-Deegan-Doody). Informed consent will be obtained from each participant prior to randomisation. The results of this feasibility study will be published in peer-reviewed academic journals and presented at national and international conferences., Trial Registration: NCT04899622., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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50. Factors influencing the statistical planning, design, conduct, analysis and reporting of trials in health care: A systematic review.
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Zaki M, O'Sullivan L, Devane D, Segurado R, and McAuliffe E
- Abstract
Background: Trials in health care are prospective human research studies designed to test the effectiveness and safety of health care interventions, such as medications, surgeries, medical devices and other treatment or prevention interventions. Statistics is an important and powerful tool in trials. Inappropriately designed trials and/or inappropriate statistical analysis produce unreliable results and a lack of transparency when reported, with limited clinical use., Aim: This systematic literature review aimed to identify, describe and synthesise factors contributing to or influencing the statistical planning, design, conduct, analysis and reporting of trials., Methods: Information sources were retrieved from the following electronic citation databases: PubMed, Web of Science, PsycINFO, and CINAHL and the grey literature repository: OpenGrey. 90 articles and guidelines were included in this review. A narrative, thematic synthesis identified the key factors influencing the statistical planning, design, conduct, analysis and reporting of trials in health care., Findings and Conclusion: We identified three analytical themes within which factors are grouped. These are: "what makes a statistician?", "the need for dynamic statistical involvement and collaboration throughout a trial - it's not just about the numbers", "and the "accountability of statisticians in ensuring the safety of trial participants and the integrity of trial data". While important insights emerged about the qualifications, training, roles, and responsibilities of statisticians and their collaboration with other team members in a trial, further empirical research is warranted to elicit the perceptions of trial team members at the centre of statistics in trials., Competing Interests: ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (© 2022 The Authors.)
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- 2022
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