61 research outputs found
Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2):An open-label randomised trial and updated meta-analysis
BackgroundPreterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.Methods and findingsWe conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.ConclusionsThese results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.Trial registrationISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181
Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel
Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants
TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Tiina Paunio on työryhmän UK10K jäsen.The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.Peer reviewe
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)
Restructuring the public service - the integration of data entry and clerical areas. by Sue Whyte
The 1987 second-tier wage agreement between the federal public service and the government provided for the restructuring of employment in the public service, including the integration of job classifications and extensive job design
The role of heterozygous lysosomal storage disorder alleles as risk factors for dementia
Alzheimer’s disease, the most common form of dementia, is characterised by extracellular amyloid beta plaques and intraneuronal tau tangles. While it is not fully understood why these pathological hallmarks develop, several biological systems are believed to be involved. Of these, lysosomal network dysfunction is an increasingly recognised pathogenic factor. Lysosomal network disruptions, including upregulated endocytosis, aberrant trafficking and storage of undegraded substrates, commence from the earliest stages of Alzheimer’s disease. The importance of the lysosomal network for neuronal health is underscored by the existence of more than 50 lysosomal storage disorders, which arise from the deficiency of an enzyme or other protein required for lysosomal function. Many lysosomal storage disorders have a severe neurodegenerative phenotype, most are recessively inherited, and until recently, heterozygotes were considered asymptomatic carriers. However, there is increasing evidence of some pathophysiology in heterozygotes, especially during ageing. This study aimed to investigate the impact of a heterozygous lysosomal storage disorder allele (Hexb+/-) in an Alzheimer’s mouse model (AppNL-G-F/NL-G-F). We hypothesised Hexb heterozygosity would hasten and/or exacerbate pathology and disease-related signs in AppNL-G-F/NL-G-F mice. The AppNL-G-F/NL-GF knock-in mouse was novel and not extensively characterised at the beginning of this PhD study. We therefore performed a behavioural test battery, and examined the lysosomal network, in six-monthold AppNL-G-F/NL-G-F mice. AppNL-G-F/NL-G-F mice did not have memory impairments detectable in a Y-maze, novel object recognition test or Morris water maze at six-months. They did, however, exhibit reduced open field activity and lysosomal network disruptions. Lysosome-associated membrane protein 1 and cathepsins B, L and D accumulated at amyloid beta plaques in AppNL-G-F/NL-G-F mice, presenting at the earliest and smallest plaques observed. AppNL-G-F/NL-G-F mice also exhibited elevated activity of β- hexosaminidase and cathepsins D/E and elevated levels of cathepsin D and LC3-II in the cerebral cortex, as determined by Western blot. AppNL-G-F/NL-G-F mice were intercrossed with Hexb+/- mice to determine the effect of heterozygosity of Hexb in the Alzheimer’s mouse. No substantial memory impairments or increases in key neuropathological markers of Alzheimer’s disease were found. However, AppNL-G-F/NL-G-F; Hexb+/- mice demonstrated subtle impairments in behavioural flexibility during the reversal phase of the Morris water maze. AppNL-G-F/NL-G-F; Hexb+/+ mice had reduced activity in an open field and on the Y-maze. This phenotype was not exacerbated in AppNL-G-F/NL-G-F; Hexb+/- mice, but was reproduced by Hexb heterozygosity alone, in Appwt/wt; Hexb+/- mice. Heterozygosity of Hexb in AppNL-G-F/NL-G-F mice did not increase glial fibrillary acidic protein or ionised calcium binding adaptor molecule 1, markers of astrocytes and microglia, respectively. Nor did it lead to increased GM2 ganglioside (the substrate degraded by the enzyme encoded by Hexb), or related gangliosides, GM1 or GM3. Surprisingly, heterozygosity of Hexb resulted in less amyloid beta plaques in the orbital cortex and hippocampus of 46-week-old AppNL-G-F/NL-G-F mice and less Aβ42 in the hippocampus. In summary, Hexb heterozygosity in AppNL-G-F/NL-G-F mice did not induce substantial memory impairments or increase key neuropathological markers of Alzheimer’s disease, but led to subtle phenotypic alterations, suggesting that Hexb haploinsufficiency is not a dominant factor in the progression of Alzheimer’s disease.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202
Looking back: Dance education in schools
This article investigates significant issues in dance education in schools. The first section of this article begins with a reprint of an interview originally published in Dance News 33 (December 1985), the quarterly magazine of the New Zealand Dance Federation Inc. Raewyn Whyte interviewed dance educators Shirley Ririe and Joan Woodbury from Utah in the United States, who were visiting New Zealand as Fullbright artists at the time of the interview. Ririe’s and Woodbury’s experiences added to growing momentum in Aotearoa New Zealand for developing dance in schools and provided an opportunity for New Zealand educators to learn from others. In the second and third sections of this article, current teacher educators respond to the reprint of this interview as a ‘back issue’. Liz Melchior provides an overview of dance in schools over the last thirty years and particularly considers the development of dance education in the years following the introduction of The Arts in the New Zealand Curriculum (Ministry of Education, 2000, 2007). Sue Cheesman offers reflections and insights into the challenges and successes of the new curriculum as it has been implemented into schools. Further consideration is given to the future of dance education, including specific issues relating to the role of artists working in schools
Why isn't there a plan? Community vulnerability and resilience in the Latrobe Valley's open cut coal mine towns
On February 9, 2014, the town of Morwell in Victoria, Australia, was confronted with several bushfires, resulting in a blaze at the Morwell open cut coal mine adjacent to the Hazelwood power station. For 45 days, the local communities were impacted by smoke, ash, and reports of raised carbon monoxide levels. The duration of the crisis placed an unprecedented strain on the capacity of the community and the authorities to adequately respond. Many see Morwell as vulnerable to future events because it is surrounded by coal mines, power stations, forests, and pine plantations. Drawing on interviews from key stakeholders in the community and a detailed analysis of media reports and social media, this chapter examines the factors that both harm and promote community resilience. It emphasizes the complexity of resilience and the importance of communal narratives as community members react to and recover from traumatic experiences and unknown futures
Clinical Practice Guideline on Adult Domiciliary Oxygen Therapy: Executive summary from the Thoracic Society of Australia and New Zealand
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