A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Association of adiposity genetic variants with menarche timing in 92,105 women of European descent.

Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.

Audit of the Irish health system for value for money

In April 2000, Deloitte & Touche in conjunction with the York Health Economics Consortium were chosen by The Department of Health & Children to carry out an examination of the health services over the past ten years Download the Report here

Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1.

The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.1 associated with major mood disorders (rs2251219, P = 3.63 x 10(-8); odds ratio = 0.87; 95% confidence interval, 0.83-0.92), with supportive evidence for association observed in two out of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for bipolar disorder and MDD.

Improved immunogenicity against HIV-1 clade C antigens by using NYVAC-C with restored replication competence

Background: In order to improve the immunogenicity of currently available non-replicating pox virus HIV vaccine vectors, NYVAC was genetically modified through re-insertion of two host range genes (K1L and C7L), resulting in restored replicative capacity in human cells. Methods: In the present study these vectors, expressing either a combination of the HIV-1 clade C antigens Env, Gag, Pol, Nef, or a combination of Gal, Pol, Nef were evaluated for safety and immunogenicity in rhesus macaques, which were immunized at weeks 0, 4 and 12 either by scarification (conventional poxvirus route of immunization), intradermal or by intramuscular injection (route used in previous vaccine studies). Results: Replication competent NYVAC-C-KC vectors induced higher HIV-specific responses, as measured by IFN-g ELISpot assay, than the replication defective NYVAC-C vectors. Application through scarification only required one immunization to induce maximum HIV-specific immune responses. This method simultaneously induced relatively lower anti-vector responses. In contrast, two to three immunizations were required when the NYVAC-C-KC vectors were given by intradermal or intramuscular injection and this method tended to generate slightly lower responses. Responses were predominantly directed against Env in the animals that received NYVAC-C-KC vectors expressing HIV-1 Env, Gag, Pol, Nef, while Gag responses were dominant in the NYVAC-C-KC HIV-1 Gag, Pol, Nef immunized animals. Conclusion: The current study demonstrates that NYVAC replication competent vectors were well tolerated and showed increased immunogenicity as compared to replication defective vectors. Further studies are needed to evaluate the most efficient route of immunization and to explore the use of these replication competent NYVAC vectors in prime/boost combination with gp120 proteinbased vaccine candidates. This study was performed within the Poxvirus T-cell Vaccine Discovery Consortium (PTVDC) which is part of the CAVD program.

Eligibility for renal denervation: experience at 11 European expert centers.

Based on the SYMPLICITY studies and CE (Conformité Européenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure-lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center's criteria was 42.5% (95% confidence interval, 38.0%-47.0%) and 39.7% (36.2%-43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.

Genome-wide meta-analysis of common variant differences between men and women.

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.

Monitoring de la problématique du cannabis en Suisse: étude sentinelle 2004-2009

Le monitoring de la problématique du cannabis en Suisse constitue un ensemble de travaux qui permettent le suivi de la situation au niveau national et qui sont mis en oeuvre par un consortium d'institutions de recherche. Ce monitoring comprend l'étude présentée dans ce rapport, l'étude sentinelle. Celle-ci s'intéresse à l'évolution de la situation en matière de cannabis ainsi qu'à la gestion de cette situation au niveau local. Il s'agit de répondre aux questions suivantes : - quelle est la situation en matière de consommation de cannabis et de marché et quelle est son évolution ? - quels sont les principaux problèmes rencontrés sur le terrain ? - quelles sont les mesures et interventions qui ont été développées dans ce domaine ? Pour y répondre, on a choisi de suivre la situation dans quatre cantons suisses dits "sentinelle" (St-Gall, Tessin, Vaud, Zurich). Les critères de choix de ces cantons font appel à leur taille, au rapport ville/campagne et à la présence de frontière avec des états voisins, à la langue, au type de politique drogue pratiqué. Dans chaque canton on a constitué des panels d'experts formés par des profes-sionnels de terrain dans trois domaines différents (santé et social, école, police et justice). Leurs observations ainsi que les données cantonales disponibles sont récoltées et discutées lors d'un workshop et analysées sur plusieurs années. Le présent rapport fait état des résultats des quatre workshops de suivi (2005, 2006, 2008, 2009). [Résumé, p. 5]

Poots launches £18m state-of-the-art Telemonitoring NI service

Health Minister Edwin Poots today marked the roll-out of a ground-breaking hi-tech scheme which will enable more patients to monitor their health in their own homes. Following funding of £18m from the Department of Health, the newly named Centre for Connected Health and Social Care (CCHSC), part of the Public Health Agency, worked in partnership with business consortium TF3to establish the innovative Telemonitoring NI service. The service is now being delivered by the TF3 consortium in partnership with the Health and Social Care Trusts.Remote telemonitoring combines technology and services that enable patients with chronic diseases to test their vital signs such as pulse, blood pressure, body weight, temperature, blood glucose and oxygen levels at home on a daily basis. The service will now be rolled out to 3,500 patients across Northern Ireland per annum for a period of six years.Mr Poots today visited the home of Larne pensioner Michael Howard who has Chronic Pulmonary Obstructive Disorder (COPD) to hear how Telemonitoring NI has changed his life.During the visit Mr Poots said: "Chronic diseases such as heart disease, diabetes and COPD affect around three quarters of people over the age of 75. This is the generation from whom transport and mobility pose the biggest problems. The Telemonitoring NI service will allow thousands to monitor their vital signs without having to leave their own homes."It means that patients are able to understand and manage their condition better. Many say it has improved their confidence and given them peace of mind. With a health professional monitoring each patient's health on a daily basis, there is less need for hospital admission. Carers are also better informed with the pro-active support provided. It means earlier intervention in, and the prevention of, deterioration of condition, acute illness and hospital admissions."Telemonitoring NI is an excellent example of how the Health Service can innovateusing modern technology to deliver a better service for our patients."Eddie Ritson, Programme Director of CCHSC, PHA, said: "The roll-out of Telemonitoring NI represents a significant step towards providing quality care for the growing number of people with heart disease, stroke, some respiratory conditions and diabetes who want to live at home while having their conditions safely managed."This new service will give people more information which combined with timely advice will enable patients to gain more control over their health while supporting them to live independently in their own homes for longer."A patient will take their vital sign measurements at home, usually on a daily basis. and these will automatically be transmited to the Tf3 system. The resulting readings are monitored centrally by a healthcare professional working in the Tf3 triage team. If the patient's readings show signs of deterioration to an unacceptable level, they will be contacted by phone by a nurse working in a central team and if appropriate a healthcare professional in the patient's local Trust will be alerted to enable them to take appropriate action."Families and carers will also benefit from the reassurance that chronic health conditions are being closely monitored on an ongoing basis. The information collected through the service can also be used by doctors, nurses and patients in making decisions on how individual cases should be managed. "Using the service, Mr Howard, 71, who has emphysema - a long-term, progressive disease of the lungs that primarily causes shortness of breath - monitors his vital signs using the new technology every weekday morning. The information is monitored centrally and if readings show signs of deterioration to an unacceptable level, Mr Howard's local healthcare professional is alerted."Taking my readings is such a simple process but one that gives me huge benefits as it is an early warning system to me and also for the specialist nurses in charge of my care. Without the remote telemonitoring I would be running back and forward to the GPs' surgery all the time to have things checked out," he explained."Having my signs monitored by a nurse means any changes in my condition are dealt with immediately and this has prevented me from being admitted to hospital - in the past I've had to spend six days in hospital any time I'm admitted with a chest infection."The telemonitoring is not only reassuring for me, it also gives me more control over managing my own condition and as a result I have less upheaval in my life, and I'm less of a cost to the health care system. Most importantly, it gives me peace of mind and one less thing to worry about at my age."Patients seeking further information about the new telemonitoring service should contact their healthcare professional.

O2 : Estudi d'accessibilitat del repositori documental de la UOC

Els repositoris de documents són una font important d'informació per a in­vestigadors, universitaris, docents, i per qualsevol persona que vulgui ac­cedir a informació contrastada sobre qualsevol temàtica. És important que aquesta informació sigui accessible a tothom, i gràcies a Internet s'ha trobat el mitjà vehicular perquè això sigui possible. Ara bé, un cop tenim el mitjà per arribar-­hi, cal que el destí, els programaris contenidors dels repositoris, també siguin accessibles. Amb aquest propòsit, aquest treball recull la informació recaptada de l'avaluació d'una mostra de pàgines del repositori de la UOC. Aquesta avaluació s'ha fet seguint les directrius marcades per la W3C (World Wide Web Consortium), mitjançant el seu grup de treball WAI (Web Accessibility Initiative) i amb la versió 2.0 del recull de directrius WCAG (Web Content Accessibility Guidelines).

Gestión en el territorio de una empresa de seguridad mediante estándares GIS e integración de datos con Google Maps.

Estudi teòric sobre els Sistemes d'Informació Geogràfica (GIS) i sobre les especificacions que està publicant el Open Geospatial Consortium (OGC) com estàndards oberts que permetin les comunicacions entre distints GIS.

Web semántica: RDF y SGBD que lo soportan

En aquest treball es fa una breu introducció a la web semàntica i el seu estat actual. S'analitzen els llenguatges que hi ha a la base del munt de recomanacions del World Wide Web Consortium (XML, XML Schema, RDF i RDF Schema) i s'examinen diferents sistemes de gestió de bases de dades que donen suport a les metadades, que són la base de la web semàntica.

Improvement of the HIV/AIDS vaccine candidate NYVAC-C by deletion of the viral type I IFN inhibitor and/or acquisition of replication competence

Background: Recombinant viruses based on the attenuated vaccinia virus strain NYVAC are promising HIV vaccine candidates as phase I/II clinical trials have shown good safety and immunogenicity profiles. However, this NYVAC strain is non-replicating in most human cell lines and encodes viral inhibitors of the immune system. Methods: With the aim to increase the immune potency of the current NYVAC-C vector (expressing the codon optimized clade C HIV-1 genes encoding gp120 and Gag-Pol-Nef polyprotein), we have generated and characterized three NYVAC-C-based vectors by, 1) deletion of the viral type I IFN inhibitor gene (NYVAC-CdeltaB19R), 2) restoration of virus replication competence in human cells by re-inserting K1L and C7L host range genes (NYVAC-C-KC) and, 3) combination of both strategies (NYVACC- KC-deltaB19R). Results: Insertion of the KC fragment restored the replication competence of the viruses in human cells (HeLa cells and primary dermal fibroblasts and keratinocytes), increased the expression of HIV antigens by more than 3-fold compared to the non-replicating homologs, inhibited apoptosis induced by the parental NYVAC-C and retained attenuation in a newborn mouse model. In adult mice, replication-competent viruses showed a limited capacity to replicate in tissues surrounding the inoculation site (ovaries and lymph nodes). After infection of keratinocytes, PBMCs and dendritic cells these viruses induced differential modulation in specific host cell signal transduction pathways, triggering genes important in immune modulation. Conclusion: We have developed improved NYVAC-C-based vectors with enhanced HIV-1 antigen expression, with the ability to replicate in cultured human cells and partially in some tissues, with an induced expression of cellular genes relevant to immune system activation, and which trigger IFN-dependent and independent signalling pathways, while maintaining a safety phenotype. These new vectors are promising new HIV vaccine candidates. These studies were performed within the Poxvirus Tcell Vaccine Discovery Consortium (PTVDC) which is part of the CAVD program.

Multi-ethnic fine-mapping of 14 central adiposity loci.

The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ± 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.

Growing up in Ireland. Key findings: infant cohort (at 3 years).

 The latest results from the study paint a picture of how these families are faring across a range of areas in their lives including their health, family life and financial and economic circumstances. In general the findings show that three-year-olds in Ireland are in good health with a few notable public health and related issues (including overweight and obesity), there is overall stability in family structures over the short term and that the recession has had a substantial effect on families with young children over the last number of years. These are the first longitudinal findings from the study. The first wave of fieldwork with the families of the Infant Cohort included approximately 11,100 nine-month-olds, their parents and carers. Interviews began in September 2008 and were completed in March 2009. Interviews for the second round of interviews with this cohort took place between January and August 2011. A total of 90% of the original sample of nine-month-olds were successfully re-interviewed. (A full download of the results released today, presented in three briefing documents can be found by clicking here. Key findings include: Health â?¢ Most of the children were described as being in good health; 75% were rated as very healthy and a further 23% were rated as healthy, but a few minor problems. Girls were more likely to be reported as very healthy (78%) compared with boys (72%). â?¢ One in four or almost one quarter of three-year-old children were overweight (19%) or obese (6%). â?¢ Childrenâ?Ts weight was related to household social class. 5% of children in families in the professional/managerial group were classified as obese at three years of age compared with 9% of those in the most disadvantaged social class group. However, at least one-fifth of children in every social class were overweight. â?¢ Childrens consumption of energy-dense foods such as crisps, sweets, chips, and non-diet fizzy drinks increased as parental education fell. 63% of children whose mother had a lower secondary education or less ate at least one portion of crisps compared with 36% of those from degree-level backgrounds, although consumption of biscuits/chocolates was over 70% for both groups of children. â?¢ Two-thirds (66%) of three-year-olds had received at least one course of antibiotics in the 12 months preceding the interview. Children with a full medical card (35% of the sample) or a GP-only medical card (5% of the sample) were more likely to have received a course of antibiotics than â?¢ Children with a full medical card received a higher number of antibiotic courses on average (2.6) compared with those without a medical card (2.1). â?¢ Just under 16% of three-year-old children were reported as having at least one longstanding illness, condition or disability. The most commonly reported illness types included Asthma (5.8%), Eczema/Skin allergies (3.9%) and Food/digestive allergies (1.2%) Family Life and Childcare â?¢ While the overall distribution of family structure was stable, there have been transitions from one-parent families to two-parent families and vice-versa over the 27 months between interview â?" approximately 2 to 3 percent in each direction. â?¢ 50% of three year olds were in some form of non-parental childcare for eight or more hours a week. The most common form used was centre-based childcare which almost tripled between nine months and three years, from 11% to 30%. â?¢ A similar percentage of grandparents were caring for children at both nine months and three years, 12% and 11% respectively. A total of 10% of three-year-olds were being minded by a childminder, an increase of 3 percentage points from when the children were nine months of age. â?¢ Children who were in some form of non-parental childcare were spending an average of 23 hours a week in their main type of childcare. â?¢ At time of interview the vast majority of mothers reported that they had regular contact with the Study Childâ?Ts grandparents (91%). In offering support to parents, grandparents were most likely to babysit (50%), and buy clothes (40%) at least on a monthly basis. One-parent families were more likely than two-parent families to receive financial support from grandparents with just under one-third (66%) of one-parent families receiving financial support from grandparents at least once every three months. â?¢ The most frequently used discipline technique was â?~discussing or explaining why the behaviour was wrongâ?T, with 63% of mothers saying they always did this. â?¢ 12% of mothers said they used â?~smackingâ?T as a form of discipline now and again and less than 1% used â?~smackingâ?T as a form of discipline more frequently. Over half reported that they never smacked the Study Child. Financial and Economic Circumstances â?¢ Just over half (53%) of mothers of three-year-olds worked outside the home, 38% said they were on home duties and 6% said they were unemployed. â?¢ The biggest change in terms of the work status of three-year-oldsâ?T parents was an increase in the percentage of unemployed fathers â?" 6% when the child was nine months rising to almost 14% when s/he was three years of age. â?¢ 61% of families of three-year-olds reported experiencing difficulties in making â?~ends meetâ?T. This was a substantial increase from 44% in the first round of interviews when the children were nine-months-old. â?¢ Almost two thirds (63%) of all families with three-year-olds reported that the recession had had a very significant or significant effect on them. â?¢ The most frequently recorded effects were: a reduction in wages (63%); canâ?Tt afford luxuries (54%), social welfare reduction (53%) and canâ?Tt afford/cut back on basics (32%). Growing Up in Ireland is a Government funded study tracking the development of two nationally representative cohorts of children: an Infant Cohort which was interviewed initially at nine months and subsequently at three years of age; and a Child Cohort which was interviewed initially at nine years and subsequently at 13 years of age. The study is being conducted by a consortium of researchers led by the Economic and Social Research Institute (ESRI) and Trinity College Dublin. For Further Information Please Contact: Jillian Heffernan Communications Officer, Growing Up in Ireland Tel: 01 896 3378 Mobile: 087 9016880This resource was contributed to our repository by the National Documentation Centre on Drug Use.