PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia

Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1α dependent target gene activation. Mechanistically, PITX1 associates with HIF-1β and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1α-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1α dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers

Investigating the effects of long-term dornase alfa use on lung function using registry data.

BACKGROUND: Dornase alfa (DNase) is one of the commonest cystic fibrosis (CF) treatments and is often used for many years. However, studies have not evaluated the effectiveness of its long-term use. We aimed to use UK CF Registry data to investigate the effects of one-, two-, three-, four- and five-years of DNase use on lung function to see if the benefits of short-term treatment use are sustained long term. METHODS: We analysed data from 4,198 people in the UK CF Registry from 2007 to 2015 using g-estimation. By controlling for time-dependent confounding we estimated the effects of long-term DNase use on percent predicted FEV1 (ppFEV1) and investigated whether the effect differed by ppFEV1 at treatment initiation or by age. RESULTS: Considering the population as a whole, there was no significant effect of one-year's use of DNase; change in ppFEV1 over one year was -0.1% in the treated compared to the untreated (p = 0.51) and this did not change with long-term use. However, treatment was estimated to be more beneficial in people with lower lung function (p  70%

Temporal trends in muscular fitness of English 10-year-olds 1998-2014: an allometric approach

Objectives To identify temporal trends in muscular fitness of English children using allometric scaling for height and weight to adjust for the influence of body size. Design Repeated cross-sectional study. Methods We measured; height, weight, standing broad-jump, handgrip, sit-ups and bent-arm hang in 10-year-old boys and girls from Chelmsford, England in: 2014 (n = 306), 2008 (n = 304) and 1998 (n = 310). Physical activity was (PAQ-C) was assessed in 2008 and 2014. Muscular fitness was allometrically scaled for height and weight. We assessed temporal trends using General Linear Models (fixed factors: wave and sex) and reported effect sizes using partial eta squared (ηP²). We compared percentage change per year 1998-2008 with 2008-2014. Results Ten-year-olds in 2014 were taller and heavier than in 2008 and 1998 but there were no differences in BMI. Compared with 2008, physical activity was lower in boys (ηP² = 0.012) and girls (ηP² = 0.27) assessed in 2014. There were significant main effects of wave for handgrip (ηP² = 0.060), sit-ups (ηP² = 0.120) and bent-arm hang (ηP² = 0.204). Pairwise comparisons showed muscular fitness of both sexes was significantly lower in 2014 than in 1998. From 2008 to 2014 percent change per year in handgrip (1.6%) and sit-ups (3.9%) were greater than for the preceding decade (handgrip 0.6%, sit-ups 2.6%). Conclusions Downward temporal trends in muscular fitness appear independent of secular changes in body size. We found a decrease in self-reported physical activity concurrent with the accelerated declines in fitness from 2008 to 2014. These findings suggest the declines in children are not engaging in physical activities which support development of muscular fitness

The Relationship between Socioeconomic Status, Family Income, and Measures of Muscular and Cardiorespiratory Fitness in Colombian Schoolchildren

Objective To determine the associations between socioeconomic status (SES) and physical fitness in a sample of Colombian youth. Study design Prueba SER is cross-sectional survey of schoolchildren in Bogota, Colombia. Mass, stature, muscular fitness (standing long-jump, handgrip), and cardiorespiratory fitness (20-m shuttle run) were measured in 52 187 schoolchildren 14-16 years of age. Area-level SES was categorized from 1 (very low) to 4 (high) and parent-reported family income was categorized as low, middle, or high. Results Converting measures into z scores showed stature, muscular, and cardiorespiratory fitness were significantly (z = 0.3-0.7) below European values. Children in the mid- and high SES groups jumped significantly further than groups with very low SES. Differences were independent of sex but became nonsignificant when adjusted for anthropometric differences. Participants in the mid-SES and high-SES groups had better handgrip scores when adjusted for body dimension. There were, however, no significant between-group differences in cardiorespiratory fitness, which was strongly clustered by school and significantly greater in students from private schools. Conclusions Area-level SES is associated with measures of muscular fitness in Colombian schoolchildren. These associations were largely explained by the large differences in body dimensions observed between SES groups. When area-level SES is considered, there was no evidence that family income influenced fitness. The clustering of outcomes reaffirms the potential importance of schools and area-level factors in promoting fitness through opportunities for physical activity. Interventions implemented in schools, can improve academic attainment; a factor likely to be important in promoting the social mobility of children from poorer families

Who is meeting the strengthening physical activity guidelines by definition: A cross-sectional study of 253 423 English adults?

The current UK physical activity guidelines recommend that adults aged 19 to 65 years perform activity to strengthen muscle and bone a minimum of twice weekly. The number of adults meeting strengthening activity guidelines is lower than for aerobic activity, but estimates vary between studies partly due to differences in how muscle-strengthening activity is defined. We aimed to provide estimates for strengthening activity prevalence in English adults based on a nationally representative sample of n = 253,423 18-65-year-olds. We attempted to quantify the variation in estimates attributable to differences in the way strengthening activity is defined. Finally, we aim to provide a brief descriptive epidemiology of the factors associated with strengthening activity. Adults met guidelines for aerobic activity if they reported the activity equivalent to >150 min/week moderate-intensity exercise. Respondents met strengthening guidelines if they reported at least two bouts per week of strengthening activity. We defined strengthening activity, first, according to criteria used in the Health Survey for England (HSE). Second, we counted bouts of strengthening activities for which we could find evidence of health-related benefits (Evidence). Third, we included bouts of strengthening activity as defined in current UK physical activity guidelines (Guideline). Two-thirds (67%) of adults met guidelines for aerobic activity (69% of men, 65% of women). Less than one-third (29% of men and 24% of women) met guidelines for the HSE definition of strengthening activity. Under the Evidence definition, 16% of men and 9% of women met strengthening guidelines. Using the most-stringent definition (Guideline) just 7.3% of men and 4.1% of women achieved the recommendations for strengthening activity. We found females and older adults (50–65 years) were less likely to meet guidelines for aerobic, strengthening, and combined aerobic plus strengthening activity. The prevalence of meeting activity guidelines was lower in adults from more deprived areas (compared with the least deprived); Adults with lower academic qualifications (Level 1) were less likely to meet activity guidelines than those educated to Level 4 (Degree Level) or higher. Having a limiting disability was associated with a lower prevalence of meeting activity guidelines. Associations between socio-demographic measures and the prevalence of adults meeting activity guidelines were stronger for strengthening activity than for aerobic 51(or combined aerobic plus strengthening) activity Compared with aerobic activity, fewer adults engage in strengthening activity regardless of how it is defined. The range in estimates for how many adults meet strengthening activity guidelines can be explained by variations in the definition of ‘strengthening’ that are used and the specific sports or activities identified as strengthening exercise. When strengthening activity is included, the proportion of English adults meeting current physical activity guidelines could be as high as 1 in 3 but possibly as low as just 1 in 20. A harmonized definition of strengthening activity, that is aligned with physical activity guidelines, is required to provide realistic and comparable prevalence estimates

The LSST DESC data challenge 1: Generation and analysis of synthetic images for next-generation surveys

Data Challenge 1 (DC1) is the first synthetic data set produced by the Rubin Observatory Legacy Survey of Space and Time (LSST) Dark Energy Science Collaboration (DESC). DC1 is designed to develop and validate data reduction and analysis and to study the impact of systematic effects that will affect the LSST data set. DC1 is comprised of r-band observations of 40 deg2 to 10 yr LSST depth. We present each stage of the simulation and analysis process: (a) generation, by synthesizing sources from cosmological N-body simulations in individual sensor-visit images with different observing conditions; (b) reduction using a development version of the LSST Science Pipelines; and (c) matching to the input cosmological catalogue for validation and testing. We verify that testable LSST requirements pass within the fidelity of DC1. We establish a selection procedure that produces a sufficiently clean extragalactic sample for clustering analyses and we discuss residual sample contamination, including contributions from inefficiency in star-galaxy separation and imperfect deblending. We compute the galaxy power spectrum on the simulated field and conclude that: (i) survey properties have an impact of 50 per cent of the statistical uncertainty for the scales and models used in DC1; (ii) a selection to eliminate artefacts in the catalogues is necessary to avoid biases in the measured clustering; and (iii) the presence of bright objects has a significant impact (2-6) in the estimated power spectra at small scales (> 1200), highlighting the impact of blending in studies at small angular scales in LSST

Ethnic variation in outcome of people hospitalised during the first COVID-19 epidemic wave in Wales (UK):an analysis of national surveillance data using Onomap, a name-based ethnicity classification tool

Objective To identify ethnic differences in proportion positive for SARS-CoV-2, and proportion hospitalised, proportion admitted to intensive care and proportion died in hospital with COVID-19 during the first epidemic wave in Wales.Design Descriptive analysis of 76 503 SARS-CoV-2 tests carried out in Wales to 31 May 2020. Cohort study of 4046 individuals hospitalised with confirmed COVID-19 between 1 March and 31 May. In both analyses, ethnicity was assigned using a name-based classifier.Setting Wales (UK).Primary and secondary outcomes Admission to an intensive care unit following hospitalisation with a positive SARS-CoV-2 PCR test. Death within 28 days of a positive SARS-CoV-2 PCR test.Results Using a name-based ethnicity classifier, we found a higher proportion of black, Asian and ethnic minority people tested for SARS-CoV-2 by PCR tested positive, compared with those classified as white. Hospitalised black, Asian and minority ethnic cases were younger (median age 53 compared with 76 years; p<0.01) and more likely to be admitted to intensive care. Bangladeshi (adjusted OR (aOR): 9.80, 95% CI 1.21 to 79.40) and ‘white – other than British or Irish’ (aOR: 1.99, 95% CI 1.15 to 3.44) ethnic groups were most likely to be admitted to intensive care unit. In Wales, older age (aOR for over 70 years: 10.29, 95% CI 6.78 to 15.64) and male gender (aOR: 1.38, 95% CI 1.19 to 1.59), but not ethnicity, were associated with death in hospitalised patients.Conclusions This study adds to the growing evidence that ethnic minorities are disproportionately affected by COVID-19. During the first COVID-19 epidemic wave in Wales, although ethnic minority populations were less likely to be tested and less likely to be hospitalised, those that did attend hospital were younger and more likely to be admitted to intensive care. Primary, secondary and tertiary COVID-19 prevention should target ethnic minority communities in Wales

Immunization coverage and risk factors for failure to immunize within the Expanded Programme on Immunization in Kenya after introduction of new Haemophilus influenzae type b and hepatitis b virus antigens

Background: Kenya introduced a pentavalent vaccine including the DTP, Haemophilus influenzae type b and hepatitis b virus antigens in Nov 2001 and strengthened immunization services. We estimated immunization coverage before and after introduction, timeliness of vaccination and risk factors for failure to immunize in Kilifi district, Kenya. Methods: In Nov 2002 we performed WHO cluster-sample surveys of > 200 children scheduled for vaccination before or after introduction of pentavalent vaccine. In Mar 2004 we conducted a simple random sample (SRS) survey of 204 children aged 9 - 23 months. Coverage was estimated by inverse Kaplan-Meier survival analysis of vaccine- card and mothers' recall data and corroborated by reviewing administrative records from national and provincial vaccine stores. The contribution to timely immunization of distance from clinic, seasonal rainfall, mother's age, and family size was estimated by a proportional hazards model. Results: Immunization coverage for three DTP and pentavalent doses was 100% before and 91% after pentavalent vaccine introduction, respectively. By SRS survey, coverage was 88% for three pentavalent doses. The median age at first, second and third vaccine dose was 8, 13 and 18 weeks. Vials dispatched to Kilifi District during 2001 - 2003 would provide three immunizations for 92% of the birth cohort. Immunization rate ratios were reduced with every kilometre of distance from home to vaccine clinic (HR 0.95, CI 0.91 - 1.00), rainy seasons ( HR 0.73, 95% CI 0.61 - 0.89) and family size, increasing progressively up to 4 children ( HR 0.55, 95% CI 0.41 - 0.73). Conclusion: Vaccine coverage was high before and after introduction of pentavalent vaccine, but most doses were given late. Coverage is limited by seasonal factors and family siz