Impact of Neighborhood Quality and Recent Life Stressors on Sleep Problems: A Longitudinal Study of Adolescents at Risk for Maltreatment

It is estimated that around 70% of adolescents are not getting sufficient sleep. The impact of poor sleep during adolescence is related to both increased psychopathology and poorer academic and social functioning. While studies have established a link at the community level between earlier school start times and poorer sleep, there remain open questions about other aspects of community such as neighborhood factors and stressful life events. In this study, we investigated the impact of three neighborhood factors (chaos, stability, and efficacy) and recent life stressors on adolescent (n = 1354) sleep habits at ages 12, 14, and 16 in a sample of children at who were either maltreated or at a high risk for maltreatment via the Longitudinal Survey on Child Abuse and Neglect (LONGSCAN). Overall, greater life stressors before age 12, led to greater sleep difficulties. Additionally, while neighborhood stability did not seem to predict more sleep problems, increased neighborhood chaos and lower collective efficacy predicted more sleep problems. These findings suggest it is important to assess the impact of various neighborhood factors separately, as the granular approach provided more nuance in understanding risk factors to poor sleep in adolescents. On a policy level, one implication is to intervene in reducing factors that lead to increased neighborhood chaos (e.g., vandalism, open drug activities) and promote collective neighborhood efficacy (e.g., developing neighborhood programs to increase interactions and trust between neighbors)

Dynamics of Change and Change in Dynamics

A framework is presented for building and testing models of dynamic regulation by categorizing sources of differences between theories of dynamics. A distinction is made between the dynamics of change, i.e., how a system self–regulates on a short time scale, and change in dynamics, i.e., how those dynamics may themselves change over a longer time scale. In order to clarify the categories, models are first built to estimate individual differences in equilibrium value and equilibrium change. Next, models are presented in which there are individual differences in parameters of dynamics such as frequency of fluctuations, damping of fluctuations, and amplitude of fluctuations. Finally, models for within–person change in dynamics over time are proposed. Simulations demonstrating feasibility of these models are presented and OpenMx scripts for fitting these models have been made available in a downloadable archive along with scripts to simulate data so that a researcher may test a selected models’ feasibility within a chosen experimental design

Mothers\u27 Sleep Deficits and Cognitive Performance: Moderation by Stress and Age

There are well-known associations between stress, poor sleep, and cognitive deficits, but little is known about their interactive effects, which the present study explored in a sample of mothers of toddlers. Since certain types of cognitive decline start during the 20s and continue into later ages, we also explored whether mothers\u27 age interacted with stress and sleep in the prediction of cognitive functioning. We hypothesized that poorer sleep [measured using one week of 24-hour wrist actigraphy data] and having more chronic stressors [e.g., life events, household chaos, work/family role conflict] would be linked with poorer cognitive performance [both executive function and standardized cognitive ability tasks], and that the interactive combination of poorer sleep and more stressors would account for the effect. We also explored whether this process operated differently for younger versus older women. In a socioeconomically and geographically diverse community sample of 227 women with toddler-age children [age, M = 32.73 yrs, SD = 5.15 yrs], poorer cognitive performance was predicted by greater activity during the sleep period, shorter sleep duration, and lower night-to-night consistency in sleep; it was not associated with higher levels of stress. The interactive effects hypothesis was supported for sleep activity [fragmented sleep] and sleep timing [when mothers went to bed]. The combination of more exposure to stressors and frequent night waking was particularly deleterious for older women\u27s performance. For younger women, going to bed late was associated with poorer performance if they were experiencing high levels of stress; for those experiencing low levels of stress, going to bed late was associated with better performance

Leading Disability Research and Workforce Development: A Western Sydney Collaboration

In this White Paper we draw attention to the potential of excellence in research and workforce development as a means, in part, to foster greater inclusion and participation for people with disability. We present a critique of the current limitations in research and workforce development and highlight the urgency to address such shortcomings to realise inclusion within our communities. We demonstrate that Western Sydney University is well positioned as a leading institution to address many of these concerns. This White paper showcases the innovative work of our team, and calls for seven key actions, to advance inclusion and participation for people and communities in Greater Western Sydney, Australia, and beyond

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)