Cognitive development and risk for psychopathology in 22q11.2 Deletion Syndrome

22q11.2 Deletion Syndrome (22q11.2DS) is one of the strongest known genetic risk factors for schizophrenia and is a valuable model for understanding cognitive trajectories which may be associated with vulnerability for later psychosis. This thesis examined cognition and psychopathology over development in 22q11.2DS through cross-sectional and longitudinal approaches. First, in a large multi-site cross-sectional sample, I investigated whether the presence of Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) or anxiety disorder was associated with cognitive performance in children and adolescents with 22q11.2DS. In adults, I examined whether cognition was associated with presence of psychotic disorder. Psychopathology was associated with cognitive profile of individuals with 22q11.2DS in an age- and domain-specific manner. I also found that magnitude of cognitive impairment differed by developmental stage (child, adolescent or adult) in 22q11.2DS and the pattern differed by domain. Next, I longitudinally examined the trajectories of a range of cognitive domains over three timepoints in children and adolescents with 22q11.2DS as compared to a control group of siblings without the deletion. There was no evidence for cognitive deterioration, but mostly initial impairment which remained stable over time, or additional lags in some domains whereby individuals with 22q11.2DS were not progressing at the same rate as controls. Lastly, I compared the prevalence of prodromal psychotic symptoms in adolescents aged 15 years old with 22q11.2DS to control siblings, and whether longitudinal cognitive trajectories differed in individuals with 22q11.2DS and prodromal symptoms compared to those without. I found higher rates of prodromal symptoms in 22q11.2DS compared to controls, and that individuals with 22q11.2DS and prodromal positive psychotic symptoms displayed different antecedent cognitive development to those without psychotic symptoms in the form of initial deficits or lags over time. vi This thesis extends knowledge of cognitive development in 22q11.2DS and how this relates to psychopathology in both clinical and high-risk stages

Effect of suckler cow vaccination against glycoprotein E (gE)-negative bovine herpesvirus type 1 (BoHV-1) on passive immunity and physiological response to subsequent bovine respiratory disease vaccination of their progeny

peer-reviewedThe study objectives were: 1) to characterise the development of immunocompetence in beef suckler calves from birth to three months of age, and 2) to trace glycoprotein E (gE)-negative bovine herpesvirus type 1 (BoHV-1) antibodies from dam to calf and subsequent vaccination against pneumonia. Thirty multiparous beef suckler, spring-calving cows, consisting of two genotypes were involved; Limousin × Friesian (LF) and Charolais × Limousin (CL). Cows were immunised against the inactivated antigen strain of BoHV-1 (gE- (IBR marker vaccine) at day − 84 and received a booster at day − 56 relative to the expected calving date (d 0). Calves were immunised at 14 and 42 days of age against PI-3 virus, BRSV and Mannheimia (Pasteurella) haemolytica serotype A1 using a commercial vaccine administered subcutaneously. Additionally, calves were immunised against BoHV-1 at 42 days of age, using 1 dose of a live commercial vaccine administered intranasally. Blood samples were collected from all calves (n = 30) via jugular venipuncture at birth, prior to colostrum feeding (0 h), at 12 h (h), 24 h, 72 h and 168 h after the initial feeding of colostrum, and at d 7, 14, 28, 42, 56 and 84 post birth. The mean ratio of gE negative antibodies circulating in the blood of LF and CL dams pre-partum scored negative to gE ab (S/N ≥ 0.70). Antibody levels of BoHV-1 (wild type (wt)) peaked at 12 h post-birth in calves and declined thereafter, as the maternal antibodies decayed. There was no difference in BoHV-1 and BRSV antibody levels in calves post vaccination.This research was funded by the Irish Government under the National Development Plan 2007-2013, Department of Agriculture, Food and the Marine (DAFM) Research Stimulus Fund ((Grant number: 11/S/131) (B. Earley, Principal Investigator)). Katie Tiernan was in receipt of a post-graduate fellowship as part of 11/S/131

Blood immune transcriptome analysis of artificially fed dairy calves and naturally suckled beef calves from birth to 7 days of age

peer-reviewedNeonatal calves possess a very immature and naïve immune system and are reliant on the intake of maternal colostrum for passive transfer of immunoglobulins. Variation in colostrum management of beef and dairy calves is thought to affect early immune development. Therefore, the objective of this study was to examine changes in gene expression and investigate molecular pathways involved in the immune-competence development of neonatal Holstein dairy calves and naturally suckled beef calves using next generation RNA-sequencing during the first week of life. Jugular whole blood samples were collected from Holstein (H) dairy calves (n = 8) artificially fed 5% B.W. colostrum, and from beef calves which were the progenies of Charolais-Limousin (CL; n = 7) and Limousin-Friesian beef suckler cows (LF; n = 7), for subsequent RNA isolation. In dairy calves, there was a surge in pro-inflammatory cytokine gene expression possibly due to the stress of separation from the dam. LF calves exhibited early signs of humoral immune development with observed increases in the expression genes coding for Ig receptors, which was not evident in the other breeds by 7 days of age. Immune and health related DEGs identified as upregulated in beef calves are prospective contender genes for the classification of biomarkers for immune-competence development, and will contribute towards a greater understanding of the development of an immune response in neonatal calves

Exercise prescription improves exercise tolerance in young children with CHD:a randomised clinical trial

Objective The main objective of this study was to ascertain if a structured intervention programme can improve the biophysical health of young children with congenital heart disease (CHD). The primary end point was an increase in measureable physical activity levels following the intervention.Methods Patients aged 5–10 years with CHD were identified and invited to participate. Participants completed a baseline biophysical assessment, including a formal exercise stress test and daily activity monitoring using an accelerometer. Following randomisation, the intervention group attended a 1 day education session and received an individual written exercise plan to be continued over the 4-month intervention period. The control group continued with their usual level of care. After 4 months, all participants were reassessed in the same manner as at baseline.Results One hundred and sixty-three participants (mean age 8.4 years) were recruited, 100 of whom were male (61.3%). At baseline, the majority of the children were active with good exercise tolerance. The cyanotic palliated subgroup participants, however, were found to have lower levels of daily activity and significantly limited peak exercise performance compared with the other subgroups. One hundred and fifty-two participants (93.2%) attended for reassessment. Following the intervention, there was a significant improvement in peak exercise capacity in the intervention group. There was also a trend towards increased daily activity levels.Conclusion Overall physical activity levels are well preserved in the majority of young children with CHD. A structured intervention programme significantly increased peak exercise capacity and improved attitudes towards positive lifestyle changes

Cognitive deficits in childhood, adolescence and adulthood in 22q11.2 deletion syndrome and association with psychopathology

22q11.2 Deletion Syndrome (22q11.2DS) is associated with high risk of psychiatric disorders and cognitive impairment. It remains unclear to what extent key cognitive skills are associated with psychopathology, and whether cognition is stable over time in 22q11.2DS. 236 children, adolescents and adults with 22q11.2DS and 106 typically developing controls were recruited from three sites across Europe. Measures of IQ, processing speed, sustained attention, spatial working memory and psychiatric assessments were completed. Cognitive performance in individuals was calculated relative to controls in different age groups (children (6–9 years), adolescents (10–17 years), adults (18+ years)). Individuals with 22q11.2DS exhibited cognitive impairment and higher rates of psychiatric disorders compared to typically developing controls. Presence of Autism Spectrum Disorder symptoms was associated with greater deficits in processing speed, sustained attention and working memory in adolescents but not children. Attention deficit hyperactivity disorder in children and adolescents and psychotic disorder in adulthood was associated with sustained attention impairment. Processing speed and working memory were more impaired in children and adults with 22q11.2DS respectively, whereas the deficit in sustained attention was present from childhood and remained static over developmental stages. Psychopathology was associated with cognitive profile of individuals with 22q11.2DS in an age-specific and domain-specific manner. Furthermore, magnitude of cognitive impairment differed by developmental stage in 22q11.2DS and the pattern differed by domain

Pan-European landscape of research into neurodevelopmental copy number variants: a survey by the MINDDS consortium

Background Several rare copy number variants have been identified to confer risk for neurodevelopmental disorders (NDD-CNVs), and increasingly NDD-CNVs are being identified in patients. There is a clinical need to understand the phenotypes of NDD-CNVs. However due to rarity of NDD-CNVs in the population, within individual countries there is a limited number of NDD-CNV carriers who can participate in research. The pan-european MINDDS (Maximizing Impact of Research in Neurodevelopmental Disorders) consortium was established in part to address this issue. Methodology A survey was developed to scope out the current landscape of NDD-CNV research across member countries of the MINDDS consortium, and to identify clinical cohorts with potential for future research. Results 36 centres from across 16 countries completed the survey. We provide a list of centres who can be contacted for future collaborations. 3844 NDD-CNV carriers were identified across clinical and research centres spanning a range of medical specialties, including psychiatry, paediatrics, medical genetics. A broad range of phenotypic data was available; including medical history, developmental history, family history and anthropometric data. In 12/16 countries, over 75% of NDD-CNV carriers could be recontacted for future studies. Conclusion This survey has highlighted the potential within Europe for large multi-centre studies of NDD-CNV carriers, to improve knowledge of the complex relationship between NDD-CNV and clinical phenotype. The MINNDS consortium is in a position to facilitate collaboration, data-sharing and knowledge exchange on NDD-CNV phenotypes across Europe

Plasma viral loads during early HIV-1 infection are similar in subtype C- and non-subtype C-infected African seroconverters.

Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C-infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens