Diabetes affects more than 330 million people worldwide and causes elevated cardiovascular disease risk. Mitochondria are critical for vascular function, generate cellular reactive oxygen species ...(ROS), and are perturbed by diabetes, representing a novel target for therapeutics. We hypothesized that adaptive mitochondrial plasticity in response to nutrient stress would be impaired in diabetes cellular physiology via a nitric oxide synthase- (NOS-) mediated decrease in mitochondrial function. Primary smooth muscle cells (SMCs) from aorta of the nonobese, insulin resistant rat diabetes model Goto-Kakizaki (GK) and the Wistar control rat were exposed to high glucose (25 mM). At baseline, significantly greater nitric oxide evolution, ROS production, and respiratory control ratio (RCR) were observed in GK SMCs. Upon exposure to high glucose, expression of phosphorylated eNOS, uncoupled respiration, and expression of mitochondrial complexes I, II, III, and V were significantly decreased in GK SMCs (p<0.05). Mitochondrial superoxide increased with high glucose in Wistar SMCs (p<0.05) with no change in the GK beyond elevated baseline concentrations. Baseline comparisons show persistent metabolic perturbations in a diabetes phenotype. Overall, nutrient stress in GK SMCs caused a persistent decline in eNOS and mitochondrial function and disrupted mitochondrial plasticity, illustrating eNOS and mitochondria as potential therapeutic targets.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The Born in Bradford's Better Start (BiBBS) interventional birth cohort study was designed as an innovative cohort platform for efficient evaluation of early life interventions delivered through the ...Better Start Bradford programme. There are a growing number of interventional cohorts being implemented internationally. This paper provides an interim analysis of BiBBS in order to share learning about the feasibility and value of this method.
Recruitment began in January 2016 and will complete in December 2023 with a target sample of 5,000 pregnancies. An interim analysis was completed for all pregnancies recruited between January 2016 and November 2019 with an expected due date between 1
April 2016 and 8
March 2020. Descriptive statistics were completed on the data.
Of 4,823 eligible pregnancies, 2,626 (54%) pregnancies were recruited, resulting in 2,392 mothers and 2,501 children. The sample are representative of the pregnant population (61% Pakistani heritage; 12% White British; 8% other South Asian and 6% Central and Eastern European ethnicity). The majority of participants (84%) live in the lowest decile of the Index of Multiple Deprivation, and many live in vulnerable circumstances. A high proportion (85%) of BiBBS families have engaged in one or more of the Better Start Bradford interventions. Levels of participation varied by the characteristics of the interventions, such as the requirement for active participation and the length of commitment to a programme.
We have demonstrated the feasibility of recruiting an interventional cohort that includes seldom heard families from ethnic minority and deprived backgrounds. The high level of uptake of interventions is encouraging for the goal of evaluating the process and outcomes of multiple early life interventions using the innovative interventional cohort approach. BiBBS covers a period before, during and after the coronavirus disease 2019 (COVID-19) pandemic which adds scientific value to the cohort.
General education preservice teachers' (PSTs') views about inclusion have been well documented, yet PSTs' views about the nature of disability, which are less understood, could reveal limitations of ...an inclusion-only focus. We investigated general education PSTs' (N = 59) views of disability and inclusion at the beginning and end of a one-semester introductory course about special education. Using multiple modes of measurement, quantitative and qualitative data revealed that despite changing their definitions of disability and increasing their pro-inclusion stance, PSTs retained the use of deficit language, which complicates our interpretation of their views. Implications for teacher preparation include a necessary attention to both inclusion and disability.
The tidal energy industry is progressing rapidly, but there are still barriers to overcome to realise the commercial potential of this sector. Large magnitude and highly variable loads caused by ...waves acting on the turbine are of particular concern. Composite blades with in-built bend-twist elastic response may reduce these peak loads, by passively feathering with increasing thrust. This could decrease capital costs by lowering the design loads, and improve robustness through the mitigation of pitch mechanisms. In this study, the previous research is extended to examine the performance of bend-twist blades in combined wave–current flow, which will frequently be encountered in the field. A scaled 3 bladed turbine was tested in the flume at IFREMER with bend-twist composite blades and equivalent rigid blades, sequentially under current and co-directional wave–current cases. In agreement with previous research, when the turbine was operating in current alone at higher tip speed ratios the bend-twist blades reduced the mean thrust and power compared to the rigid blades. Under the specific wave–current condition tested the average loads were similar on both blade sets. Nevertheless, the bend-twist blades substantially reduced the magnitudes of the average thrust and torque fluctuations per wave cycle, by up to 10% and 14% respectively.
•Laboratory tests demonstrated the bend-twist response of composite blades.•Bend-twist response increases with tip speed ratio.•Average loads on the rotor are similar in current and wave–current conditions.•Composite bend-twist blades damp the wave induced fluctuations in thrust and torque.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BackgroundThere are limited data on detection disparities of common mentaldisorders in minority ethnic women.AimsDescribe the natural history of common mental disorders in primary carein the maternal ...period, characterise women with, and explore ethnicdisparities in, detected and potentially missed common mentaldisorders.MethodSecondary analyses of linked birth cohort and primary care data involving8991 (39.4% White British) women in Bradford. Common mental disorderswere characterised through indications in the electronic medical record.Potentially missed common mental disorders were defined as an elevatedGeneral Health Questionnaire (GHQ-28) score during pregnancy with nocorresponding common mental disorder markers in the medical record.ResultsEstimated prevalence of pre-birth common mental disorders was 9.5%,rising to 14.0% 3 years postnatally. Up to half of cases were potentiallymissed. Compared with White British women, minority ethnic women weretwice as likely to have potentially missed common mental disorders andhalf as likely to have a marker of screening for common mentaldisorders.ConclusionsCommon mental disorder detection disparities exist for minority ethnicwomen in the maternal period.
Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare ...setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.
We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.
Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.
Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
49.
Screening and Breast Cancer Mortality—Response Nickson, Carolyn; Mason, Kate E.; English, Dallas R. ...
Cancer epidemiology, biomarkers & prevention,
12/2012, Volume:
21, Issue:
12
Journal Article
Economic, physical, built, cultural, learning, social and service environments have a profound effect on lifelong health. However, policy thinking about health research is dominated by the ...'biomedical model' which promotes medicalisation and an emphasis on diagnosis and treatment at the expense of prevention. Prevention research has tended to focus on 'downstream' interventions that rely on individual behaviour change, frequently increasing inequalities. Preventive strategies often focus on isolated leverage points and are scattered across different settings. This paper describes a major new prevention research programme that aims to create City Collaboratory testbeds to support the identification, implementation and evaluation of upstream interventions within a whole system city setting. Prevention of physical and mental ill-health will come from the cumulative effect of multiple system-wide interventions. Rather than scatter these interventions across many settings and evaluate single outcomes, we will test their collective impact across multiple outcomes with the goal of achieving a tipping point for better health. Our focus is on early life (ActEarly) in recognition of childhood and adolescence being such critical periods for influencing lifelong health and wellbeing.
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