Inter-individual variation in nucleotide excision repair in young adults: effects of age, adiposity, micronutrient supplementation and genotype

Nucleotide excision repair (NER) is responsible for repairing bulky helix-distorting DNA lesions and is essential for the maintenance of genomic integrity. Severe hereditary impairment of NER leads to cancers such as those in xeroderma pigmentosum, and more moderate reductions in NER capacity have been associated with an increased cancer risk. Diet is a proven modifier of cancer risk but few studies have investigated the potential relationships between diet and NER. In the present study, the plasmid-based host cell reactivation assay was used to measure the NER capacity in peripheral blood mononuclear cells from fifty-seven volunteers aged 18–30 years before and after 6 weeks of supplementation with micronutrients (selenium and vitamins A, C and E). As a control, nine individuals remained unsupplemented over the same period. Volunteers were genotyped for the following polymorphisms in NER genes: ERCC5 Asp1104His (rs17655); XPC Lys939Gln (rs2228001); ERCC2 Lys751Gnl (rs13181); XPC PAT (an 83 bp poly A/T insertion–deletion polymorphism in the XPC gene). NER capacity varied 11-fold between individuals and was inversely associated with age and endogenous DNA strand breaks. For the first time, we observed an inverse association between adiposity and NER. No single polymorphism was associated with the NER capacity, although significant gene–gene interactions were observed between XPC Lys939Gln and ERCC5 Asp1104His and XPC Lys939Gln and ERCC2 Lys751Gnl. While there was no detectable effect of micronutrient supplementation on NER capacity, there was evidence that the effect of fruit intake on the NER capacity may be modulated by the ERCC2 Lys751Gnl single nucleotide polymorphism

Establishing the Effects of Quality in Early Childhood: Comparing Evidence from England

This is the final version. Available from Early Education via the URL in this record.This occasional paper examines the robustness of a paper published by Blanden, Hansen and McNally in February 2017 which sought to investigate the effects of quality within early education and care settings in England (Quality in Early Years Settings and Children's School Achievement, CEP Discussion Paper 1468, The London School of Economics). The authors question the validity of the conclusions reached by Blanden et al about the impact of quality in early childhood education in England

Potential influence of selection criteria on the demographic composition of students in an Australian medical school

<p>Abstract</p> <p>Background</p> <p>Prior to 1999 students entering our MBBS course were selected on academic performance alone. We have now evaluated the impact on the demographics of subsequent cohorts of our standard entry students (those entering directly from high school) of the addition to the selection process of an aptitude test (UMAT), a highly structured interview and a rural incentive program.</p> <p>Methods</p> <p>Students entering from 1985 to 1998, selected on academic performance alone (N = 1402), were compared to those from 1999 to 2011, selected on the basis of a combination of academic performance, interview score, and UMAT score together with the progressive introduction of a rural special entry pathway (N = 1437).</p> <p>Results</p> <p>Males decreased from 57% to 45% of the cohort, students of NE or SE Asian origin decreased from 30% to 13%, students born in Oceania increased from 52% to 69%, students of rural origin from 5% to 21% and those from independent high schools from 56% to 66%. The proportion of students from high schools with relative socio-educational disadvantage remained unchanged at approximately 10%. The changes reflect in part increasing numbers of female and independent high school applicants and the increasing rural quota. However, they were also associated with higher interview scores in females vs males and lower interview scores in those of NE and SE Asian origin compared to those born in Oceania or the UK. Total UMAT scores were unrelated to gender or region of origin.</p> <p>Conclusions</p> <p>The revised selection processes had no impact on student representation from schools with relative socio-educational disadvantage. However, the introduction of special entry quotas for students of rural origin and a structured interview, but not an aptitude test, were associated with a change in gender balance and ethnicity of students in an Australian undergraduate MBBS course.</p

Addressing the pitfalls when designing intervention studies to discover and validate biomarkers of habitual dietary intake

Introduction Dietary exposure monitoring within populations is reliant on self-reported measures such as Food Frequency Questionnaires and diet diaries. These methods often contain inaccurate information due to participant misreporting, non-compliance and bias. Urinary metabolites derived from individual foods could provide additional objective indicators of dietary exposure. For biomarker approaches to have utility it is essential that they cover a wide-range of commonly consumed foods and the methodology works in a real-world environment. Objectives To test that the methodology works in a real-world environment and to consider the impact of the major sources of likely variance; particularly complex meals, different food formulations, processing and cooking methods, as well as the dynamics of biomarker duration in the body. Methods We designed and tested a dietary exposure biomarker discovery and validation strategy based on a food intervention study involving free-living individuals preparing meals and collecting urine samples at home. Two experimental periods were built around three consecutive day menu plans where all foods and drinks were provided (n = 15 and n = 36). Results The experimental design was validated by confirming known consumption biomarkers in urinary samples after the first menu plan. We tested biomarker performance with different food formulations and processing methods involving meat, wholegrain, fruits and vegetables. Conclusion It was demonstrated that spot urine samples, together with robust dietary biomarkers, despite major sources of variance, could be used successfully for dietary exposure monitoring in large epidemiological studies

What Can We Conclude from Death Registration? Improved Methods for Evaluating Completeness

Julie Rajaratnam and colleagues evaluate the performance of a suite of demographic methods that estimate the fraction of deaths registered and counted by civil registration systems, and identify three variants that generally perform the best

What Will Happen If We Do Nothing To Control Trachoma: Health Expectancies for Blinding Trachoma in Southern Sudan

Summary measures of population health attempt to express disease burden in terms of a common “currency” and are useful in establishing public health priorities. Disability adjusted life years (DALYs), a health gap measure, have previously been used to estimate burden due to trachoma; however, their methods and results have limitations. This study demonstrates the application of the health expectancies to estimate burden due to trachoma. The study illustrates the future burden associated with doing nothing to control trachoma in Southern Sudan: a substantial proportion of remaining life expectancy spent with trichiasis and low vision or blindness for both men and women, with a disproportionate burden falling on women. The results presented are intuitively meaningful for policy makers and a non-technical audience and compare favourably with other indicators such as mortality and incidence rates or DALYs, which are not generally easily understood. Unless action is taken by further delivery of trachoma control interventions, then populations in Southern Sudan can expect to spend a substantial proportion of their life with low vision or blindness due to trachoma

The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries.

The contribution of psychological disorders to the burden of skin disease has been poorly explored, and this is a large-scale study to ascertain the association between depression, anxiety, and suicidal ideation with various dermatological diagnoses. This international multicenter observational cross-sectional study was conducted in 13 European countries. In each dermatology clinic, 250 consecutive adult out-patients were recruited to complete a questionnaire, reporting socio-demographic information, negative life events, and suicidal ideation; depression and anxiety were assessed with the Hospital Anxiety and Depression Scale. A clinical examination was performed. A control group was recruited among hospital employees. There were 4,994 participants--3,635 patients and 1,359 controls. Clinical depression was present in 10.1% patients (controls 4.3%, odds ratio (OR) 2.40 (1.67-3.47)). Clinical anxiety was present in 17.2% (controls 11.1%, OR 2.18 (1.68-2.82)). Suicidal ideation was reported by 12.7% of all patients (controls 8.3%, OR 1.94 (1.33-2.82)). For individual diagnoses, only patients with psoriasis had significant association with suicidal ideation. The association with depression and anxiety was highest for patients with psoriasis, atopic dermatitis, hand eczema, and leg ulcers. These results identify a major additional burden of skin disease and have important clinical implications.Peer reviewedFinal Published versio

Effect and Safety of Meropenem\u2013Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial

Introduction: Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem\u2013vaborbactam monotherapy versus best available therapy (BAT) for CRE. Methods: A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem\u2013vaborbactam (2&nbsp;g/2&nbsp;g over 3&nbsp;h, q8h for 7\u201314&nbsp;days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings. Results: Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, 12 44.7% to 9.3%) for meropenem\u2013vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem\u2013vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk\u2013benefit analyses of composite clinical failure or nephrotoxicity favored meropenem\u2013vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, 12 74.6% to 12 22.9%; P &lt; 0.001). Conclusions: Monotherapy with meropenem\u2013vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT. Clinical Trials Registration: NCT02168946. Funding: The Medicines Company

Incorporating scale dependence in disease burden estimates:the case of human African trypanosomiasis in Uganda

The WHO has established the disability-adjusted life year (DALY) as a metric for measuring the burden of human disease and injury globally. However, most DALY estimates have been calculated as national totals. We mapped spatial variation in the burden of human African trypanosomiasis (HAT) in Uganda for the years 2000-2009. This represents the first geographically delimited estimation of HAT disease burden at the sub-country scale.Disability-adjusted life-year (DALY) totals for HAT were estimated based on modelled age and mortality distributions, mapped using Geographic Information Systems (GIS) software, and summarised by parish and district. While the national total burden of HAT is low relative to other conditions, high-impact districts in Uganda had DALY rates comparable to the national burden rates for major infectious diseases. The calculated average national DALY rate for 2000-2009 was 486.3 DALYs/100 000 persons/year, whereas three districts afflicted by rhodesiense HAT in southeastern Uganda had burden rates above 5000 DALYs/100 000 persons/year, comparable to national GBD 2004 average burden rates for malaria and HIV/AIDS.These results provide updated and improved estimates of HAT burden across Uganda, taking into account sensitivity to under-reporting. Our results highlight the critical importance of spatial scale in disease burden analyses. National aggregations of disease burden have resulted in an implied bias against highly focal diseases for which geographically targeted interventions may be feasible and cost-effective. This has significant implications for the use of DALY estimates to prioritize disease interventions and inform cost-benefit analyses