The Bandim TBscore – reliability, further development, and evaluation of potential uses

Background: The tuberculosis (TB) case detection rate has stagnated at 60% due to disorganized case finding and insensitivity of sputum smear microscopy. Of the identified TB cases, 4% die while being treated, monitored with tools that insufficiently predict failure/mortality. Objective: To explore the TBscore, a recently proposed clinical severity measure for pulmonary TB (PTB) patients, and to refine, validate, and investigate its place in case finding. Design: The TBscore's inter-observer agreement was assessed and compared to the Karnofsky Performance Score (KPS) (paper I). The TBscore's variables underlying constructs were assessed, sorting out unrelated items, proposing a more easily assessable TBscoreII, which was validated internally and externally (paper II). Finally, TBscore and TBscoreII's place in PTB-screening was examined in paper III. Results: The inter-observer variability when grading PTB patients into severity classes was moderate for both TBscore (κ W=0.52, 95% CI 0.46–0.56) and KPS (κ W=0.49, 95% CI 0.33–0.65). KPS was influenced by HIV status, whereas TBscore was unaffected by it. In paper II, proposed TBscoreII was validated internally, in Guinea-Bissau, and externally, in Ethiopia. In both settings, a failure to bring down the score by ≥25% from baseline to 2 months of treatment predicted subsequent failure (p=0.007). Finally, in paper III, TBscore and TBscoreII were assessed in health-care-seeking adults and found to be higher in PTB-diagnosed patients, 4.9 (95% CI 4.6–5.2) and 3.9 (95% CI 3.8–4.0), respectively, versus patients not diagnosed with PTB, 3.0 (95% CI 2.7–3.2) and 2.4 (95% CI 2.3–2.5), respectively. Had we referred only patients with cough >2 weeks to sputum smear, we would have missed 32.1% of the smear confirmed cases in our cohort. A TBscoreII>=2 missed 8.6%. Conclusions: TBscore and TBscoreII are useful monitoring tools for PTB patients on treatment, as they could fill the void which currently exists in risk grading of patients. They may also have a role in PTB screening; however, this requires our findings to be repeated elsewhere

Obesity and caries in four-to-six year old English children: a cross-sectional study.

BACKGROUND: Obesity and caries are common conditions in childhood and can have significant implications on children's wellbeing. Evidence into their association remains conflicting. Furthermore, studies examining the ssociation between obesity and caries commonly focus on individual-level determinants. The present study aimed to examine the association between obesity and caries in young English children and to determine the impact of deprivation and area-level characteristics on the distribution of the two conditions. METHODS: This was a cross-sectional study among children in Plymouth city aged four-to-six years. Anthropometric measurements included weight and height (converted to Body Mass Index centiles and z-scores), and waist circumference. Caries was assessed by using the sum of the number of teeth that were decayed, missing or filled. A questionnaire was used to obtain information on children's demographic characteristics, oral hygiene, and dietary habits. The impact of deprivation on anthropometric variables and caries was determined using Linear and Poisson regression models, respectively. Multiple logistic regression was used to assess the association between different anthropometric measures and caries. Logistic regression models were also used to examine the impact of several demographic characteristics and health behaviours on the presence of obesity and caries. RESULTS: The total sample included 347 children aged 5.10 ± 0.31 (mean ± SD). Deprivation had a significant impact on caries and BMI z-scores (p < 0.05). Neither BMI- nor waist circumference z-scores were shown to be significantly associated with dental caries. Among the neighbourhood characteristics examined, the percentage of people dependent on benefits was found to have a significant impact on caries rates (p < 0.05). Household's total annual income was inversely related to caries risk and parental educational level affected children's tooth brushing frequency. CONCLUSIONS: No associations between any measure of obesity and caries were found. However, deprivation affected both obesity and caries, thus highlighting the need to prioritise disadvantaged children in future prevention programmes

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients

A Meta-Analysis of Global Urban Land Expansion

The conversion of Earth's land surface to urban uses is one of the most irreversible human impacts on the global biosphere. It drives the loss of farmland, affects local climate, fragments habitats, and threatens biodiversity. Here we present a meta-analysis of 326 studies that have used remotely sensed images to map urban land conversion. We report a worldwide observed increase in urban land area of 58,000 km2 from 1970 to 2000. India, China, and Africa have experienced the highest rates of urban land expansion, and the largest change in total urban extent has occurred in North America. Across all regions and for all three decades, urban land expansion rates are higher than or equal to urban population growth rates, suggesting that urban growth is becoming more expansive than compact. Annual growth in GDP per capita drives approximately half of the observed urban land expansion in China but only moderately affects urban expansion in India and Africa, where urban land expansion is driven more by urban population growth. In high income countries, rates of urban land expansion are slower and increasingly related to GDP growth. However, in North America, population growth contributes more to urban expansion than it does in Europe. Much of the observed variation in urban expansion was not captured by either population, GDP, or other variables in the model. This suggests that contemporary urban expansion is related to a variety of factors difficult to observe comprehensively at the global level, including international capital flows, the informal economy, land use policy, and generalized transport costs. Using the results from the global model, we develop forecasts for new urban land cover using SRES Scenarios. Our results show that by 2030, global urban land cover will increase between 430,000 km2 and 12,568,000 km2, with an estimate of 1,527,000 km2 more likely

Activation of the AMP-Activated Protein Kinase by Eicosapentaenoic Acid (EPA, 20:5 n-3) Improves Endothelial Function In Vivo

The aim of the present study was to test the hypothesis that the cardiovascular-protective effects of eicosapentaenoic acid (EPA) may be due, in part, to its ability to stimulate the AMP-activated protein kinase (AMPK)-induced endothelial nitric oxide synthase (eNOS) activation. The role of AMPK in EPA-induced eNOS phosphorylation was investigated in bovine aortic endothelial cells (BAEC), in mice deficient of either AMPKα1 or AMPKα2, in eNOS knockout (KO) mice, or in Apo-E/AMPKα1 dual KO mice. EPA-treatment of BAEC increased both AMPK-Thr172 phosphorylation and AMPK activity, which was accompanied by increased eNOS phosphorylation, NO release, and upregulation of mitochondrial uncoupling protein-2 (UCP-2). Pharmacologic or genetic inhibition of AMPK abolished EPA-enhanced NO release and eNOS phosphorylation in HUVEC. This effect of EPA was absent in the aortas isolated from either eNOS KO mice or AMPKα1 KO mice fed a high-fat, high-cholesterol (HFHC) diet. EPA via upregulation of UCP-2 activates AMPKα1 resulting in increased eNOS phosphorylation and consequent improvement of endothelial function in vivo

Distribution and medical impact of loss-of-function variants in the Finnish founder population

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5–5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10−8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10−117). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10−4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers

Relationships between psychosocial outcomes in adolescents who are obese and their parents during a multi-disciplinary family-based healthy lifestyle intervention: One-year follow-up of a waitlist controlled trial (Curtin University's Activity, Food and Attitudes Program)

Background: Limited studies have investigated relationships in psychosocial outcomes between adolescents who are obese and their parents and how psychosocial outcomes change during participation in a physical activity and healthy eating intervention. This study examined both adolescent and parent psychosocial outcomes while participating in a one - year multi-disciplinary family-based intervention: Curtin University’s Activity, Food, and Attitudes Program (CAFAP). Methods: Following a waitlist control period, the intervention was delivered to adolescent (n = 56, ages 11–16) and parent participants over 8 weeks, with one-year maintenance follow-up. Adolescent depression and quality of life, family functioning, and parent depression, anxiety, and stress were assessed at six time points: baseline and prior to intervention (e.g., waitlist control period), immediately following intervention, and at 3, 6, and 12 months post-intervention. Relationships between adolescent and parent psychosocial outcomes were assessed using Spearman correlations and changes in both adolescent and parent outcomes were assessed using linear mixed models. Changes in adolescent psychosocial outcomes were compared to changes in behavioural (physical activity and healthy eating) and physical (weight) outcomes using independent samples t-tests.Results: The majority of psychosocial outcomes were significantly correlated between adolescents and parents across the one-year follow-up. Adolescent depression, psychosocial and physical quality of life outcomes significantly improved before or following intervention and were maintained at 6-months or one-year follow-up. Parent symptoms of depression, anxiety, and stress were reduced during waitlist and primarily remained improved. Changes in adolescent psychosocial outcomes were shown to be partially associated with behavioural changes and independent of physical changes. Conclusions: Adolescents in CAFAP improved psychosocial and physical quality of life and reversed the typical trajectory of depressive symptoms in adolescents who are obese during a one-year maintenance period. CAFAP was also effective at maintaining reductions in parent symptoms of depression, anxiety, and stress demonstrated during the waitlist period. Trial Registration: The trial was registered with the Australian and New Zealand Clinical Trials Registry (No. 12611001187932)

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

The 5T4 oncofoetal antigen is a heavily glycosylated cell surface protein found on human placental trophoblast and on diverse types of human cancer but is not expressed at significant levels on adult human tissues in health. It therefore satisfies the criteria for a tumour-associated antigen and is an ideal target for the immunotherapy of cancer. We report here that 5T4 is strongly expressed on the majority of renal cell carcinomas and therefore this population of patients is suitable for trials of 5T4-targeted therapies. In particular, we have shown that T cells from renal cell carcinoma patients can be genetically modified to kill 5T4 expressing renal cancer cell lines by introduction of a chimeric-signalling protein. This protein consists of a single chain antibody fragment capable of binding antigen directly at the cell surface and then activating the T cell by virtue of a CD3ζ-signalling domain. This is a powerful tool that bypasses a number of mechanisms that allow tumours to escape T-cell killing and can be readily scaled up for clinical use

Coastal urban and peri-urban Indigenous people’s adaptive capacity to climate change

This chapter discusses the adaptive capacity of coastal urban and peri-urban Indigenous People&rsquo;s to climate change. It is based on the findings of a National Climate Change Adaptation Research Facility (NCCARF) funded project that utilised a series of case studies that engaged key representatives from Indigenous organisations in five coastal locations in three states of south-eastern Australia (Low Choy D, Clarke P, Jones D, Serrao-Neumann S, Hales R, Koschade O et al., Aboriginal reconnections: understanding coastal urban and peri-urban Indigenous people&rsquo;s vulnerability and adaptive capacity to climate change, National Climate Change Adaptation Research Facility, Gold Coast, 139 pp, 2013). The study has highlighted the social, economic and environmental impacts on urban and peri-urban Indigenous communities inhabiting coastal areas throughout south-eastern Australia. These impacts include a loss of community and environmental assets, such as cultural heritage sites, with significant impacts on their quality of life and the establishment of potential favourable conditions for the spread of plant diseases, weeds and pests. The study also found that opportunities did not readily exist for engagement with climate change adaptation policy and initiatives and this was further exacerbated by acute shortages of qualified/experienced Indigenous members that could represent their communities&rsquo; interests in climate change adaptation forums. The evidence emerging from this research clearly demonstrates that Aboriginal people&rsquo;s consideration of the future, even with the overlay of climate change and the requirements for serious considerations of adaptation, are significantly influenced and dominated by economic aspirations which are seen as fundamental survival strategies for their communities