The Crystal Structure of 5-Aminouracil and the Ambiguity of Alternative Polymorphs

The nucleobase derivative 5-aminouracil (AUr, C4H5N3O2) is of interest for its biological activity, yet the solid state structure of this compound has remained elusive owing to its propensity to crystallize as aggregates of microcrystalline particles. Here we report the first single-crystal structure of AUr determined from synchrotron x-ray diffraction data. An early crystal structure prediction effort, which assumed that AUr was rigid in the isolated molecule optimized conformation, provided several poor matches to the simulated PXRD pattern. Revisiting these crystal structures, by periodic electronic level modelling (PBE-TS optimization) gave more realistic relative lattice energies, but a good match to the experimental powder pattern required using the experimental cell parameters. PXRD and Raman spectroscopy suggest that phase impurities may be present in the bulk crystallization product, though the identity of alternative polymorphs could not be confirmed on the basis of the data available

PROPEL: implementation of an evidence based pelvic floor muscle training intervention for women with pelvic organ prolapse: a realist evaluation and outcomes study protocol

Abstract Background Pelvic Organ Prolapse (POP) is estimated to affect 41%–50% of women aged over 40. Findings from the multi-centre randomised controlled “Pelvic Organ Prolapse PhysiotherapY” (POPPY) trial showed that individualised pelvic floor muscle training (PFMT) was effective in reducing symptoms of prolapse, improved quality of life and showed clear potential to be cost-effective. However, provision of PFMT for prolapse continues to vary across the UK, with limited numbers of women’s health physiotherapists specialising in its delivery. Implementation of this robust evidence from the POPPY trial will require attention to different models of delivery (e.g. staff skill mix) to fit with differing care environments. Methods A Realist Evaluation (RE) of implementation and outcomes of PFMT delivery in contrasting NHS settings will be conducted using multiple case study sites. Involving substantial local stakeholder engagement will permit a detailed exploration of how local sites make decisions on how to deliver PFMT and how these lead to service change. The RE will track how implementation is working; identify what influences outcomes; and, guided by the RE-AIM framework, will collect robust outcomes data. This will require mixed methods data collection and analysis. Qualitative data will be collected at four time-points across each site to understand local contexts and decisions regarding options for intervention delivery and to monitor implementation, uptake, adherence and outcomes. Patient outcome data will be collected at baseline, six months and one year follow-up for 120 women. Primary outcome will be the Pelvic Organ Prolapse Symptom Score (POP-SS). An economic evaluation will assess the costs and benefits associated with different delivery models taking account of further health care resource use by the women. Cost data will be combined with the primary outcome in a cost effectiveness analysis, and the EQ-5D-5L data in a cost utility analysis for each of the different models of delivery. Discussion Study of the implementation of varying models of service delivery of PFMT across contrasting sites combined with outcomes data and a cost effectiveness analysis will provide insight into the implementation and value of different models of PFMT service delivery and the cost benefits to the NHS in the longer term

Women’s experiences of receiving care for pelvic organ prolapse: a qualitative study

Background Pelvic organ prolapse is a common urogenital condition affecting 41–50% of women over the age of 40. To achieve early diagnosis and appropriate treatment, it is important that care is sensitive to and meets women’s needs, throughout their patient journey. This study explored women’s experiences of seeking diagnosis and treatment for prolapse and their needs and priorities for improving person-centred care. Methods Twenty-two women receiving prolapse care through urogynaecology services across three purposefully selected NHS UK sites took part in three focus groups and four telephone interviews. A topic guide facilitated discussions about women’s experiences of prolapse, diagnosis, treatment, follow-up, interactions with healthcare professionals, overall service delivery, and ideals for future services to meet their needs. Data were analysed thematically. Results Three themes emerged relating to women’s experiences of a) Evaluating what is normal b) Hobson’s choice of treatment decisions, and c) The trial and error of treatment and technique. Women often delayed seeking help for their symptoms due to lack of awareness, embarrassment and stigma. When presented to GPs, their symptoms were often dismissed and unaddressed until they became more severe. Women reported receiving little or no choice in treatment decisions. Choices were often influenced by health professionals’ preferences which were subtly reflected through the framing of the offer. Women’s embodied knowledge of their condition and treatment was largely unheeded, resulting in decisions that were inconsistent with women’s preferences and needs. Physiotherapy based interventions were reported as helping women regain control over their symptoms and life. A need for greater awareness of prolapse and physiotherapy interventions among women, GPs and consultants was identified alongside greater focus on prevention, early diagnosis and regular follow-up. Greater choice and involvement in treatment decision making was desired. Conclusions As prolapse treatment options expand to include more conservative choices, greater awareness and education is needed among women and professionals about these as a first line treatment and preventive measure, alongside a multi-professional team approach to treatment decision making. Women presenting with prolapse symptoms need to be listened to by the health care team, offered better information about treatment choices, and supported to make a decision that is right for them

Generating synthetic fjord bathymetry for coastal Greenland

Bed topography is a critical boundary for the numerical modelling of ice sheets and ice-ocean interactions. A persistent issue with existing topography products for the bed of the Greenland Ice Sheet and surrounding sea floor is the poor representation of coastal bathymetry, especially in regions of floating ice and near the grounding line. Sparse data coverage, and the resultant coarse resolution at the ice-ocean boundary, poses issues in our ability to model ice flow advance and retreat from the present position. In addition, as fjord bathymetry is known to exert strong control on ocean circulation and ice-ocean forcing, the lack of bed data leads to an inability to model these processes adequately. Since the release of the last complete Greenland bed topography-bathymetry product, new observational bathymetry data have become available. These data can be used to constrain bathymetry, but many fjords remain completely unsampled and therefore poorly resolved. Here, as part of the development of the next generation of Greenland bed topography products, we present a new method for constraining the bathymetry of fjord systems in regions where data coverage is sparse. For these cases, we generate synthetic fjord geometries using a method conditioned by surveys of terrestrial glacial valleys as well as existing sinuous feature interpolation schemes. Our approach enables the capture of the general bathymetry profile of a fjord in north-west Greenland close to Cape York, when compared to observational data. We validate our synthetic approach by demonstrating reduced overestimation of depths compared to past attempts to constrain fjord bathymetry. We also present an analysis of the spectral characteristics of fjord centrelines using recently acquired bathymetric observations, demonstrating how a stochastic model of fjord bathymetry could be parameterised and used to create different realisations.This study was supported by UK NERC grant NE/M000869/1

Evaluation of benazepril in cats with heart disease in a prospective, randomized, blinded, placebo-controlled clinical trial

© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine. Background: Heart disease is an important cause of morbidity and mortality in cats, but there is limited evidence of the benefit of any medication. Hypothesis: The angiotensin-converting enzyme inhibitor benazepril would delay the time to treatment failure in cats with heart disease of various etiologies. Animals: One hundred fifty-one client-owned cats. Methods: Cats with heart disease, confirmed by echocardiography, with or without clinical signs of congestive heart failure, were recruited between 2002 and 2005 and randomized to benazepril or placebo in a prospective, multicenter, parallel-group, blinded clinical trial. Benazepril (0.5-1.0 mg/kg) or placebo was administered PO once daily for up to 2 years. The primary endpoint was treatment failure. Analyses were conducted separately for all-cause treatment failure (main analysis) and heart disease-related treatment failure (supportive analysis). Results: No benefit of benazepril versus placebo was detected for time to all-cause treatment failure (P =.42) or time to treatment failure related to heart disease (P =.21). Hazard ratios (95% confidence interval [CI]) from multivariate analysis for benazepril compared with placebo were 1.00 (0.57-1.74) for all-cause failure, and 0.99 (0.50-1.94) for forward selection and 0.93 (0.48-1.81) for bidirectional selection models for heart disease-related failure. There were no significant differences between groups over time after administration of the test articles in left atrium diameter, left ventricle wall thickness, quality of life scores, adverse events, or plasma biochemistry or hematology variables. Conclusions and Clinical Relevance: Benazepril was tolerated well in cats with heart disease, but no evidence of benefit was detected

Foot pain and foot health in an educated population of adults: results from the Glasgow Caledonian University Alumni Foot Health Survey

Abstract Background Foot pain is common amongst the general population and impacts negatively on physical function and quality of life. Associations between personal health characteristics, lifestyle/behaviour factors and foot pain have been studied; however, the role of wider determinants of health on foot pain have received relatively little attention. Objectives of this study are i) to describe foot pain and foot health characteristics in an educated population of adults; ii) to explore associations between moderate-to-severe foot pain and a variety of factors including gender, age, medical conditions/co-morbidity/multi-morbidity, key indicators of general health, foot pathologies, and social determinants of health; and iii) to evaluate associations between moderate-to-severe foot pain and foot function, foot health and health-related quality-of-life. Methods Between February and March 2018, Glasgow Caledonian University Alumni with a working email address were invited to participate in the cross-sectional electronic survey (anonymously) by email via the Glasgow Caledonian University Alumni Office. The survey was constructed using the REDCap secure web online survey application and sought information on presence/absence of moderate-to-severe foot pain, patient characteristics (age, body mass index, socioeconomic status, occupation class, comorbidities, and foot pathologies). Prevalence data were expressed as absolute frequencies and percentages. Multivariate logistic and linear regressions were undertaken to identify associations 1) between independent variables and moderate-to-severe foot pain, and 2) between moderate-to-severe foot pain and foot function, foot health and health-related quality of life. Results Of 50,228 invitations distributed, there were 7707 unique views and 593 valid completions (median age [inter-quartile range] 42 [31–52], 67.3% female) of the survey (7.7% response rate). The sample was comprised predominantly of white Scottish/British (89.4%) working age adults (95%), the majority of whom were overweight or obese (57.9%), and in either full-time or part-time employment (82.5%) as professionals (72.5%). Over two-thirds (68.5%) of the sample were classified in the highest 6 deciles (most affluent) of social deprivation. Moderate-to-severe foot pain affected 236/593 respondents (39.8%). High body mass index, presence of bunions, back pain, rheumatoid arthritis, hip pain and lower occupation class were included in the final multivariate model and all were significantly and independently associated with moderate-to-severe foot pain (p < 0.05), except for rheumatoid arthritis (p = 0.057). Moderate-to-severe foot pain was significantly and independently associated lower foot function, foot health and health-related quality of life scores following adjustment for age, gender and body mass index (p < 0.05). Conclusions Moderate-to-severe foot pain was highly prevalent in a university-educated population and was independently associated with female gender, high body mass index, bunions, back pain, hip pain and lower occupational class. Presence of moderate-to-severe foot pain was associated with worse scores for foot function, foot health and health-related quality-of-life. Education attainment does not appear to be protective against moderate-to-severe foot pain

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE-Glycated hemoglobin (HbA(1c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA(1c) levels.RESEARCH DESIGN AND METHODS-We studied associations with HbA(1c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.RESULTS-Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10(-26)), HFE (rs1800562/P = 2.6 x 10(-20)), TMPRSS6 (rs855791/P = 2.7 x 10(-14)), ANK1 (rs4737009/P = 6.1 x 10(-12)), SPTA1 (rs2779116/P = 2.8 x 10(-9)) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10(-9)), and four known HbA(1c) loci: HK1 (rs16926246/P = 3.1 x 10(-54)), MTNR1B (rs1387153/P = 4.0 X 10(-11)), GCK (rs1799884/P = 1.5 x 10(-20)) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10(-18)). We show that associations with HbA(1c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (%HbA(1c)) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA(1c).CONCLUSIONS-GWAS identified 10 genetic loci reproducibly associated with HbA(1c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1c) Diabetes 59: 3229-3239, 201

Metal release from contaminated estuarine sediment under pH changes in the marine environment

The contaminant release from estuarine sediment due to pH changes was investigated using a modified CEN/TS 14429 pH-dependence leaching test. The test is performed in the range of pH values of 0-14 using deionised water and seawater as leaching solutions. The experimental conditions mimic different circumstances of the marine environment due to the global acidification, carbon dioxide (CO2) leakages from carbon capture and sequestration technologies, and accidental chemical spills in seawater. Leaching test results using seawater as leaching solution show a better neutralisation capacity giving slightly lower metal leaching concentrations than when using deionised water. The contaminated sediment shows a low base-neutralisation capacity (BNCpH 12 = -0.44 eq/kg for deionised water and BNCpH 12 = -1.38 eq/kg for seawater) but a high acid-neutralisation capacity when using deionised water (ANCpH 4 = 3.58 eq/ kg) and seawater (ANCpH 4 = 3.97 eq/kg). Experimental results are modelled with the Visual MINTEQ geochemical software to predict metal release from sediment using both leaching liquids. Surface adsorption to iron- and aluminium- (hydr)oxides was applied for all studied elements. The consideration of the metal-organic matter binding through the NICA-Donnan model and Stockholm Humic Model for lead and copper, respectively, improves the former metal release prediction. Modelled curves can be useful for the environmental impact assessment of seawater acidification due to its match with the experimental values.This work was supported by the Spanish Ministry of Economy and Competitiveness, Project No. CTM 2011-28437-C02-01, ERDF included. M. C. Martı´n-Torre was funded by the Spanish Ministry of Economy and Competitiveness by means of FPI. Fellowship No. BES-2012-053816

Training in childhood obesity management in the United States: a survey of pediatric, internal medicine-pediatrics and family medicine residency program directors

<p>Abstract</p> <p>Background</p> <p>Information about the availability and effectiveness of childhood obesity training during residency is limited.</p> <p>Methods</p> <p>We surveyed residency program directors from pediatric, internal medicine-pediatrics (IM-Peds), and family medicine residency programs between September 2007 and January 2008 about childhood obesity training offered in their programs.</p> <p>Results</p> <p>The response rate was 42.2% (299/709) and ranged by specialty from 40.1% to 45.4%. Overall, 52.5% of respondents felt that childhood obesity training in residency was extremely important, and the majority of programs offered training in aspects of childhood obesity management including prevention (N = 240, 80.3%), diagnosis (N = 282, 94.3%), diagnosis of complications (N = 249, 83.3%), and treatment (N = 242, 80.9%). However, only 18.1% (N = 54) of programs had a formal childhood obesity curriculum with variability across specialties. Specifically, 35.5% of IM-Peds programs had a formal curriculum compared to only 22.6% of pediatric and 13.9% of family medicine programs (p < 0.01). Didactic instruction was the most commonly used training method but was rated as only somewhat effective by 67.9% of respondents using this method. The most frequently cited significant barrier to implementing childhood obesity training was competing curricular demands (58.5%).</p> <p>Conclusions</p> <p>While most residents receive training in aspects of childhood obesity management, deficits may exist in training quality with a minority of programs offering a formal childhood obesity curriculum. Given the high prevalence of childhood obesity, a greater emphasis should be placed on development and use of effective training strategies suitable for all specialties training physicians to care for children.</p