Rescue of severely affected dystrophin/utrophin-deficient mice through scAAV-U7snRNA-mediated exon skipping

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional protein. Antisense-mediated exon skipping is one of the most promising approaches for the treatment of DMD and recent clinical trials have demonstrated encouraging results. However, antisense oligonucleotide-mediated exon skipping for DMD still faces major hurdles such as extremely low efficacy in the cardiac muscle, poor cellular uptake and relatively rapid clearance from circulation, which means that repeated administrations are required to achieve some therapeutic efficacy. To overcome these limitations, we previously proposed the use of small nuclear RNAs (snRNAs), especially U7snRNA to shuttle the antisense sequences after vectorization into adeno-associated virus (AAV) vectors. In this study, we report for the first time the efficiency of the AAV-mediated exon skipping approach in the utrophin/dystrophin double-knockout (dKO) mouse which is a very severe and progressive mouse model of DMD. Following a single intravenous injection of scAAV9-U7ex23 in dKO mice, near-normal levels of dystrophin expression were restored in all muscles examined, including the heart. This resulted in a considerable improvement of their muscle function and dystrophic pathology as well as a remarkable extension of the dKO mice lifespan. These findings suggest great potential for AAV-U7 in systemic treatment of the DMD phenotype

Intergenerational Associations of Chronic Disease and Polycystic Ovary Syndrome

Extent: 4p.Background: Polycystic ovary syndrome (PCOS) is a common female endocrine disorder of heterogeneous clinical presentation, high disease burden, and unknown aetiology. The disease and associated conditions cluster in families, suggesting that PCOS may be the reproductive consequence of underlying chronic disease susceptibility. Objective: To determine whether parents of young women with PCOS were more likely to have a history of diabetes or cardiovascular disease in later adult life. Design, Setting and Participants: Structured interviews with 715 members of a cohort constructed by tracing female infants born at a single general hospital in Adelaide between 1973 and 1975. Participants were asked whether they had a pre-existing medical diagnosis of PCOS, and whether each parent had ever had high blood pressure, high cholesterol, diabetes, stroke, or heart disease. Maternal high blood pressure during pregnancy was taken from the medical record of the pregnancy with the study participant. Results and Conclusions: Mothers of women with PCOS were more likely than mothers of other women to have any cardiovascular disease (RR 1.78, 95% CI 1.29, 2.47), and nearly twice as likely to have high blood pressure (RR 1.95, 95% CI 1.38, 2.76). Fathers of women with PCOS were more than twice as likely to have heart disease (RR 2.36, 95% CI 1.44, 3.88) and over four times as likely to have had a stroke (RR 4.37, 95% CI 1.97, 9.70). Occurrence of cardiovascular disease in both mother and father are associated with the risk of PCOS in daughters. Further detailed study is required to elucidate the precise pathways that may be causally related to the observations.Michael J. Davies, Jennifer L. Marino, Kristyn J. Willson, Wendy A. March and Vivienne M. Moor

Evolution of system embedded optical interconnect in sub-top of rack data center systems

This research was funded by the EU FP7 project “PhoxTrot”, for which it has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 318240, the Horizon2020 Nephele project (Grant No. 645212), the Horizon2020 COSMICC project (Grant No. 688516).In this paper we review key technological milestones in system embedded optical interconnects in data centers that have been achieved between 2014 and 2020 on major European Union research and development projects. This includes the development of proprietary optically enabled data storage and switch systems and optically enabled data storage and compute subsystems. We report on four optically enabled data center system demonstrators: LightningValley, ThunderValley2, Pegasus and Aurora, which include advanced optical circuits based on polymer waveguides and fibers and proprietary electro-optical connectors. We also report on optically enabled subsystems including Ethernet-connected hard disk drives and microservers. Both are designed in the same pluggable carrier form factor and with embedded optical transceiver and connector interfaces, thus allowing, for the first time, both compute and storage nodes to be optically interchangeable and directly interconnectable over long distances. Finally, we present the Nexus platform, which allows different optically enabled data center test systems and subsystems to be interconnected and comparatively characterized within a data center test environment.Publisher PDFPeer reviewe

Holocene deglaciation and glacier readvances on the Fildes Peninsula and King George Island (Isla 25 de Mayo), South Shetland Islands, NW Antarctic Peninsula

To provide insights into glacier-climate dynamics of the South Shetland Islands (SSI), NW Antarctic Peninsula, we present a new deglaciation and readvance model for the Bellingshausen Ice Cap (BIC) on Fildes Peninsula and for King George Island/Isla 25 de Mayo (KGI) ~62°S. Deglaciation on KGI began after c. 15 ka cal BP and had progressed to within present-day limits on the Fildes Peninsula, its largest ice-free peninsula, by c. 6.6–5.3 ka cal BP. Probability density phase analysis of chronological data constraining Holocene glacier advances on KGI revealed up to eight 95% probability ‘gaps’ during which readvances could have occurred. These are grouped into four stages – Stage 1: a readvance and marine transgression, well-constrained by field data, between c. 7.4–6.6 ka cal BP; Stage 2: four probability ‘gaps’, less well-constrained by field data, between c. 5.3–2.2 ka cal BP; Stage 3: a well-constrained but restricted ‘readvance’ between c. 1.7–1.5 ka; Stage 4: two further minor ‘readvances’, one less well-constrained by field data between c. 1.3–0.7 ka cal BP (68% probability), and a ‘final’ well-constrained ‘readvance’ after 1950 CE) is associated with recent warming/more positive SAM-like conditions

Mothers' views on feeding infants around the time of weaning

OBJECTIVE: To describe women's views about aspects of infants' diets around the time of weaning, making comparisons with national guidelines. DESIGN: A survey of women with a 9-month-old child. SETTING: Adelaide, South Australia. SUBJECTS: Five hundred and five women who joined a longitudinal study during pregnancy. RESULTS: Sources of information varied, with written material most commonly used (37%). Cows' milk was considered suitable as the main drink for weaned infants by 14% of women. There were divergent views about the suitability of eggs, with many women concerned about allergy. The majority of women (84%) viewed fruit juice as suitable although many qualified their response, often by stating that fruit juice should be diluted. Almost all women considered the amount of sugar mattered, primarily because of tooth decay, and that salt mattered although the reason was often uncertain. It was widely believed (77%) that additives in food could cause health problems, in particular hyperactivity and allergies, and half of the women reported avoiding specific foods because of concerns about allergies. Many women thought that giving their child food that was high in fat would encourage a liking for ‘junk’ food or lead to fatness in adulthood. CONCLUSIONS: There is considerable diversity in the views women express about aspects of infant feeding that have been the subject of guidelines. Further health promotion efforts are needed to achieve greater consistency with recommendations and to address other concerns women have. This will entail greater engagement with parents and shared development of responses.Ruth B Walker, Jennifer A Conn, Michael J Davies and Vivienne M Moor

Prevalence of self-reported polycystic ovary syndrome and profiles of health among women of different generations: a cross sectional study

Published 6 September 2019Objective: Although polycystic ovary syndrome (PCOS) is considered a lifelong disorder, very little is understood about the diagnosis and impact of this condition in women outside of the peak reproductive years. We examined the frequency of diagnosed PCOS and concurrent health conditions in women across the lifespan. Methods: Data were analysed from 1509 women aged 15–95 years participating in a cross-sectional, face-to-face population survey in South Australia, 2015. We assessed the prevalence of PCOS in 10-year age groups and the frequency of comorbidities in women with and without PCOS subgrouped by age (< 45, ≥ 45 years). The main outcome measures were Diagnosed PCOS and other chronic conditions; lifestyle factors. Logistic regression analyses determined the risk of comorbidities in women with PCOS adjusting for age and BMI. Results: Overall prevalence of PCOS was 5.6% (95% confidence interval (CI) 4.6–6.9%), peaking in the 35–44 year age group (9.1%), and lowest in those aged 15–24 (4.1%) or ≥ 65 (3.7%) years. Women with PCOS and aged < 45 years were more likely to report diabetes (16.7% vs. 3.8%), cardiovascular disease (15.5% vs. 7.2%) and arthritis (15.5% vs. 7.2%) than their peers; these differences were diminished in the ≥ 45 year age group. The odds of diabetes and cardiovascular disease were more than doubled among women with PCOS (adjOR 2.23, 95% CI 1.49–4.31; adjOR 3.18, 95% CI 1.31–7.68). Conclusion: PCOS is underdiagnosed in young and post-menopausal women. Diabetes and cardiovascular disease are key comorbidities requiring greater attention in younger women with PCOS.Jodie C. Avery, Lisa J. Moran, Vivienne Moore, Renae C. Fernandez, Melissa Whitrow, Nigel Stocks, Tiffany K. Gill, Michael Musker, Michael Davies, Alice Rumbol

Sleep disturbances in women with polycystic ovary syndrome: prevalence, pathophysiology, impact and management strategies

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting the reproductive, metabolic and psychological health of women. Clinic-based studies indicate that sleep disturbances and disorders including obstructive sleep apnea and excessive daytime sleepiness occur more frequently among women with PCOS compared to comparison groups without the syndrome. Evidence from the few available population-based studies is supportive. Women with PCOS tend to be overweight/obese, but this only partly accounts for their sleep problems as associations are generally upheld after adjustment for body mass index; sleep problems also occur in women with PCOS of normal weight. There are several, possibly bidirectional, pathways through which PCOS is associated with sleep disturbances. The pathophysiology of PCOS involves hyperandrogenemia, a form of insulin resistance unique to affected women, and possible changes in cortisol and melatonin secretion, arguably reflecting altered hypothalamic–pituitary–adrenal function. Psychological and behavioral pathways are also likely to play a role, as anxiety and depression, smoking, alcohol use and lack of physical activity are also common among women with PCOS, partly in response to the distressing symptoms they experience. The specific impact of sleep disturbances on the health of women with PCOS is not yet clear; however, both PCOS and sleep disturbances are associated with deterioration in cardiometabolic health in the longer term and increased risk of type 2 diabetes. Both immediate quality of life and longer-term health of women with PCOS are likely to benefit from diagnosis and management of sleep disorders as part of interdisciplinary health care

Complex diseases and co-morbidities: polycystic ovary syndrome and type 2 diabetes mellitus

Objective: Many complex diseases exhibit co-morbidities often requiring management by more than one health specialist. We examined cross-speciality issues that ultimately affect the health and wellbeing of patients with polycystic ovary syndrome (PCOS). PCOS was originally described as a reproductive condition but is now recognised to also be a metabolic and psychological condition affecting 8–13% of women of reproductive age. With a four-fold increased risk of type 2 diabetes (DM2), the Population Attributable Risk of DM2 that could be avoided if PCOS were eliminated is a substantial 19–28% of women of reproductive age. To determine the extent to which PCOS is an important consideration in diabetes development, we examined publications, funding, guidelines and predictors of risk of developing DM2. Results: We found that the topic of PCOS appeared in specialist diabetes journals at only 10% the rate seen in endocrinology journals – about 1 in 500 articles. We found research funding to be substantially less than for diabetes and found that diabetes guidelines and predictive tools for DM2 risk mostly ignore PCOS. This is surprising since insulin resistance in women with PCOS has a different aetiology and additionally women with PCOS are at increased risk of becoming overweight or obese – high risk factors for DM2. Conclusions: We consider the causes of these concerning anomalies and discuss current activities to address the co-morbidities of PCOS, including the recent development of international guidelines, an international PCOS awareness program and potentially changing the name of PCOS to better reflect its metabolic consequences

Lower age at menarche affects survival in older Australian women: results from the Australian Longitudinal Study of Ageing

Extent: 10p.Background: While menarche indicates the beginning of a woman's reproductive life, relatively little is known about the association between age at menarche and subsequent morbidity and mortality. We aimed to examine the effect of lower age at menarche on all-cause mortality in older Australian women over 15 years of follow-up. Methods: Data were drawn from the Australian Longitudinal Study of Ageing (n = 1,031 women aged 65-103 years). We estimated the hazard ratio (HR) associated with lower age at menarche using Cox proportional hazards models, and adjusted for a broad range of reproductive, demographic, health and lifestyle covariates. Results: During the follow-up period, 673 women (65%) died (average 7.3 years (SD 4.1) of follow-up for decedents). Women with menses onset < 12 years of age (10.7%; n = 106) had an increased hazard of death over the follow-up period (adjusted HR 1.28; 95%CI 0.99-1.65) compared with women who began menstruating aged ≥ 12 years (89.3%; n = 883). However, when age at menarche was considered as a continuous variable, the adjusted HRs associated with the linear and quadratic terms for age at menarche were not statistically significant at a 5% level of significance (linear HR 0.76; 95%CI 0.56 - 1.04; quadratic HR 1.01; 95%CI 1.00-1.02). Conclusion: Women with lower age at menarche may have reduced survival into old age. These results lend support to the known associations between earlier menarche and risk of metabolic disease in early adulthood. Strategies to minimise earlier menarche, such as promoting healthy weights and minimising family dysfunction during childhood, may also have positive longer-term effects on survival in later life.Lynne C Giles, Gary FV Glonek, Vivienne M Moore, Michael J Davies and Mary A Luszc