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Sökning: WFRF:(Costello Anthony)

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  • Clark, Andrew G., et al. (författare)
  • Evolution of genes and genomes on the Drosophila phylogeny.
  • 2007
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
  • Tidskriftsartikel (refereegranskat)abstract
    • Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
  • Aughton, Karen, et al. (författare)
  • hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA
  • 2021
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:22
  • Tidskriftsartikel (refereegranskat)abstract
    • Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.Simple Summary:Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.
  • Colbourn, Tim, et al. (författare)
  • Cost-effectiveness and affordability of community mobilisation through women's groups and quality improvement in health facilities (MaiKhanda trial) in Malawi
  • 2015
  • Ingår i: Cost Effectiveness and Resource Allocation. - : BioMed Central (BMC). - 1478-7547. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Understanding the cost-effectiveness and affordability of interventions to reduce maternal and newborn deaths is critical to persuading policymakers and donors to implement at scale. The effectiveness of community mobilisation through women's groups and health facility quality improvement, both aiming to reduce maternal and neonatal mortality, was assessed by a cluster randomised controlled trial conducted in rural Malawi in 2008-2010. In this paper, we calculate intervention cost-effectiveness and model the affordability of the interventions at scale.METHODS: Bayesian methods are used to estimate the incremental cost-effectiveness of the community and facility interventions on their own (CI, FI), and together (FICI), compared to current practice in rural Malawi. Effects are estimated with Monte Carlo simulation using the combined full probability distributions of intervention effects on stillbirths, neonatal deaths and maternal deaths. Cost data was collected prospectively from a provider perspective using an ingredients approach and disaggregated at the intervention (not cluster or individual) level. Expected Incremental Benefit, Cost-effectiveness Acceptability Curves and Expected Value of Information (EVI) were calculated using a threshold of $780 per disability-adjusted life-year (DALY) averted, the per capita gross domestic product of Malawi in 2013 international $.RESULTS: The incremental cost-effectiveness of CI, FI, and combined FICI was $79, $281, and $146 per DALY averted respectively, compared to current practice. FI is dominated by CI and FICI. Taking into account uncertainty, both CI and combined FICI are highly likely to be cost effective (probability 98% and 93%, EVI $210,423 and $598,177 respectively). Combined FICI is incrementally cost effective compared to either intervention individually (probability 60%, ICER $292, EIB $9,334,580 compared to CI). Future scenarios also found FICI to be the optimal decision. Scaling-up to the whole of Malawi, CI is of greatest value for money, potentially averting 13.0% of remaining annual DALYs from stillbirths, neonatal and maternal deaths for the equivalent of 6.8% of current annual expenditure on maternal and neonatal health in Malawi.CONCLUSIONS: Community mobilisation through women's groups is a highly cost-effective and affordable strategy to reduce maternal and neonatal mortality in Malawi. Combining community mobilisation with health facility quality improvement is more effective, more costly, but also highly cost-effective and potentially affordable in this context.
  • Fottrell, Edward, et al. (författare)
  • The effect of increased coverage of participatory women's groups on neonatal mortality in Bangladesh : A cluster randomized trial
  • 2013
  • Ingår i: JAMA pediatrics. - : American Medical Association. - 2168-6211 .- 2168-6203. ; 167:9, s. 816-25
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE: Community-based interventions can reduce neonatal mortality when health systems are weak. Population coverage of target groups may be an important determinant of their effect on behavior and mortality. A women's group trial at coverage of 1 group per 1414 population in rural Bangladesh showed no effect on neonatal mortality, despite a similar intervention having a significant effect on neonatal and maternal death in comparable settings.OBJECTIVE: To assess the effect of a participatory women's group intervention with higher population coverage on neonatal mortality in Bangladesh.DESIGN: A cluster randomized controlled trial in 9 intervention and 9 control clusters.SETTING: Rural Bangladesh.PARTICIPANTS: Women permanently residing in 18 unions in 3 districts and accounting for 19 301 births during the final 24 months of the intervention.INTERVENTIONS: Women's groups at a coverage of 1 per 309 population that proceed through a participatory learning and action cycle in which they prioritize issues that affected maternal and neonatal health and design and implement strategies to address these issues.MAIN OUTCOMES AND MEASURES: Neonatal mortality rate.RESULTS: Analysis included 19 301 births during the final 24 months of the intervention. More than one-third of newly pregnant women joined the groups. The neonatal mortality rate was significantly lower in the intervention arm (21.3 neonatal deaths per 1000 live births vs 30.1 per 1000 in control areas), a reduction in neonatal mortality of 38% (risk ratio, 0.62 [95% CI, 0.43-0.89]) when adjusted for socioeconomic factors. The cost-effectiveness was US $220 to $393 per year of life lost averted. Cause-specific mortality rates suggest reduced deaths due to infections and those associated with prematurity/low birth weight. Improvements were seen in hygienic home delivery practices, newborn thermal care, and breastfeeding practices.CONCLUSIONS AND RELEVANCE: Women's group community mobilization, delivered at adequate population coverage, is a highly cost-effective approach to improve newborn survival and health behavior indicators in rural Bangladesh.TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN01805825.
  • Krishnan, Jerry A., et al. (författare)
  • Prevalence and characteristics of asthma-chronic obstructive pulmonary disease overlap in routine primary care practices
  • 2019
  • Ingår i: Annals of the American Thoracic Society. - : American Thoracic Society. - 2325-6621. ; 16:9, s. 1143-1150
  • Tidskriftsartikel (refereegranskat)abstract
    • Rationale: Adults may exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD), a situation recently described as asthma-COPD overlap (ACO). There is a paucity of information about ACO in primary care. Objectives: To estimate the prevalence and describe characteristics of individuals withACOin primary care practices among patients currently diagnosed with asthma, COPD, or both; and to compare the prevalence and characteristics of ACO among the three source populations. Methods: The Respiratory Effectiveness Group conducted a crosssectional study of individuals ≥40 years old and with ≥2 outpatient primary care visits over a 2-year period in theUKOptimum Patient Care Research Database. Patients were classified into one of three source populations based on diagnostic codes: 1) COPD only, 2) both asthma and COPD, or 3) asthma only.ACOwas defined as the presence of all of the following 1) age ≥40 years, 2) current or former smoking, 3) postbronchodilator airflow limitation (forced expiratory volume in 1 second/ forced vital capacity <0.7), and 4) ≥12% and ≥200 ml reversibility in post-bronchodilator forced expiratory volume in 1 second. Results: Among 2,165 individuals (1,015 COPD only, 395 with both asthma and COPD, and 755 asthma only), the overall prevalence of ACO was 20% (95% confidence interval, 18-23%). Patients with ACO had a mean age of 70 years (standard deviation, 11 yr), 60% were men, 73% were former smokers (the rest were current smokers), and 66% were overweight or obese. Comorbid conditions were common in patients with ACO, including diabetes (53%), cardiovascular disease (36%), hypertension (30%), eczema (23%), and rhinitis (21%). The prevalence of ACO was higher in patients with a diagnosis of both asthma and COPD (32%) compared with a diagnosis of COPD only (20%; P<0.001) or asthma only (14%; P<0.001). Demographic and clinical characteristics of ACO varied across these three source populations. Conclusions: One in five individuals with a diagnosis of COPD, asthma, or both asthma and COPD in primary care settings have ACO based on the Respiratory Effectiveness Group ACO Working group criteria. The prevalence and characteristics of patients with ACO varies across the three source populations.
  • Lewycka, Sonia, et al. (författare)
  • Effect of women's groups and volunteer peer counselling on rates of mortality, morbidity, and health behaviours in mothers and children in rural Malawi (MaiMwana) : a factorial, cluster-randomised controlled trial
  • 2013
  • Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 381:9879, s. 1721-35
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Women's groups and health education by peer counsellors can improve the health of mothers and children. We assessed their effects on mortality and breastfeeding rates in rural Malawi.METHODS: We did a 2×2 factorial, cluster-randomised trial in 185,888 people in Mchinji district. 48 equal-sized clusters were randomly allocated to four groups with a computer-generated number sequence. 24 facilitators guided groups through a community action cycle to tackle maternal and child health problems. 72 trained volunteer peer counsellors made home visits at five timepoints during pregnancy and after birth to support breastfeeding and infant care. Primary outcomes for the women's group intervention were maternal, perinatal, neonatal, and infant mortality rates (MMR, PMR, NMR, and IMR, respectively); and for the peer counselling were IMR and exclusive breastfeeding (EBF) rates. Analysis was by intention to treat. The trial is registered as ISRCTN06477126.FINDINGS: We monitored outcomes of 26,262 births between 2005 and 2009. In a factorial model adjusted only for clustering and the volunteer peer counselling intervention, in women's group areas, for years 2 and 3, we noted non-significant decreases in NMR (odds ratio 0.93, 0.64-1.35) and MMR (0.54, 0.28-1.04). After adjustment for parity, socioeconomic quintile, and baseline measures, effects were larger for NMR (0.85, 0.59-1.22) and MMR (0.48, 0.26-0.91). Because of the interaction between the two interventions, a stratified analysis was done. For women's groups, in adjusted analyses, MMR fell by 74% (0.26, 0.10-0.70), and NMR by 41% (0.59, 0.40-0.86) in areas with no peer counsellors, but there was no effect in areas with counsellors (1.09, 0.40-2.98, and 1.38, 0.75-2.54). Factorial analysis for the peer counselling intervention for years 1-3 showed a fall in IMR of 18% (0.82, 0.67-1.00) and an improvement in EBF rates (2.42, 1.48-3.96). The results of the stratified, adjusted analysis showed a 36% reduction in IMR (0.64, 0.48-0.85) but no effect on EBF (1.18, 0.63-2.25) in areas without women's groups, and in areas with women's groups there was no effect on IMR (1.05, 0.82-1.36) and an increase in EBF (5.02, 2.67-9.44). The cost of women's groups was US$114 per year of life lost (YLL) averted and that of peer counsellors was $33 per YLL averted, using stratified data from single intervention comparisons.INTERPRETATION: Community mobilisation through women's groups and volunteer peer counsellor health education are methods to improve maternal and child health outcomes in poor rural populations in Africa.
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