Sebomic identification of sex- and ethnicity-specific variations in residual skin surface components (RSSC) for bio-monitoring or forensic applications

Background: “Residual skin surface components” (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of “normal” RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity. Methods: Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography–atmospheric pressure chemical ionisation–mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis. Results: The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride. Conclusions: The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.Peer reviewedFinal Published versio

In vitro selection of miltefosine resistance in promastigotes of Leishmania donovani from Nepal: genomic and metabolomic characterization.

In this study, we followed the genomic, lipidomic and metabolomic changes associated with the selection of miltefosine (MIL) resistance in two clinically derived Leishmania donovani strains with different inherent resistance to antimonial drugs (antimony sensitive strain Sb-S; and antimony resistant Sb-R). MIL-R was easily induced in both strains using the promastigote-stage, but a significant increase in MIL-R in the intracellular amastigote compared to the corresponding wild-type did not occur until promastigotes had adapted to 12.2 μM MIL. A variety of common and strain-specific genetic changes were discovered in MIL-adapted parasites, including deletions at the LdMT transporter gene, single-base mutations and changes in somy. The most obvious lipid changes in MIL-R promastigotes occurred to phosphatidylcholines and lysophosphatidylcholines and results indicate that the Kennedy pathway is involved in MIL resistance. The inherent Sb resistance of the parasite had an impact on the changes that occurred in MIL-R parasites, with more genetic changes occurring in Sb-R compared with Sb-S parasites. Initial interpretation of the changes identified in this study does not support synergies with Sb-R in the mechanisms of MIL resistance, though this requires an enhanced understanding of the parasite's biochemical pathways and how they are genetically regulated to be verified fully.This study was supported by as part of the FP7 EC K aladrug-R project (http://cordis.europa.eu/project/rcn/88823_en.html, grant number: 222895). JAC and MJS are supported by the Wellcome Trust via their core support for the Wellcome Trust Sanger Institute (grant number 098051) . TMF was funded by a BBSRC Research Experience Placement (grant number BB/J014540/1). CJRI was supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 101239/Z/13/Z). This research was supported in part by the National Science Foundation (grant number: NSF PHY11-25915) and by the Belgian Science Policy Office (TRIT, contract P7/41, to J-C.D.).This is the final version of the article. It was first available from Wiley via http://dx.doi.org/10.1111/mmi.1329

The longitudinal NIHR ARC North West Coast Household Health Survey: exploring health inequalities in disadvantaged communities.

BACKGROUND: The Household Health Survey (HHS) was developed to understand the socioeconomic determinants of mental and physical health, and health inequalities in health and social care. This paper aims to provide a detailed rationale of the development and implementation of the survey and explore socio-economic variations in physical and mental health and health care. METHODS: This comprehensive longitudinal public health survey was designed and piloted in a disadvantaged area of England, comprising questions on housing, physical health, mental health, lifestyle, social issues, environment, work, and finances. After piloting, the HHS was implemented across 28 neighbourhoods - 10 disadvantaged neighbourhoods for learning (NfLs), 10 disadvantaged comparator sites, and eight relatively advantaged areas, in 2015 and 2018. Participants were recruited via random sampling of households in pre-selected neighbourhoods based on their areas of deprivation. RESULTS: 7731 residents participated in Wave 1 (N = 4319) and 2 (n = 3412) of the survey, with 871 residents having participated in both. Mental health, physical health, employment, and housing quality were poorer in disadvantaged neighbourhoods than in relatively advantaged areas. CONCLUSIONS: This survey provides important insights into socio-economic variations in physical and mental health, with findings having implications for improved care provision to enable residents from any geographical or socio-economic background to access suitable care

A Good Samaritan inspired foundation for a fair health care system

Distributive justice on the income and on the service aspects is the most vexing modern day problem for the creation and maintenance of an all inclusive health care system. A pervasive problem of all current schemes is the lack of effective cost control, which continues to result in increasing burdens for all public and private stakeholders. This proposal posits that the responsibility and financial obligation to achieve an ideal outcome of equal and affordable access and benefits for all citizens is misplaced. The Good Samaritan demonstrated basic ethical principles, which are revisited, elaborated and integrated into a new approach to health care. The participants are limited to individual contributors and beneficiaries and organized as a citizen carried, closed, independent, and self-sufficient self-governing cooperative for their own and the benefit of a minority of disadvantaged health care consumers. The government assumes oversight, provides arbitration, enforces democratic decision making, a scheme of progressive taxation, a separate and transparent accounting system, and a balance between income and reinvestment in health care. The results are a fair distribution of cost, its effective control, and increased individual motivation to take on responsibility for personal health as a private good and a sharpened focus towards community health. At the sociopolitical level the government as well as employers are released from the inappropriate burden of catering to individual health

Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background

The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability

Public involvement in the dissemination of the North West Coast Household Health Survey: Experiences and lessons of co-producing research together

Background: Engaging with the public is a key element of health research; however, little work has examined experiences of public involvement in research dissemination. The aim of this paper is to assess the extent of public involvement, experiences of public advisers, and resulting changes in the dissemination of the North West Coast Household Health Survey (HHS). Methods: Three writing groups allowed public advisers to contribute to the dissemination of the HHS. A public workshop was set up to aid the co-production of the research evidence and discuss the experiences of public advisers involved with the survey in March 2018. A focus group with public advisers was conducted in August 2018 to understand their experiences of involvement. Data were analysed using thematic analysis and coded by two researchers. Writing groups are still ongoing. Results: Fourteen public advisers contributed via three face-to-face writing groups, by actively interpreting findings and helping in the write-up of research articles, and by presenting talks at the public workshop. At the workshop, seven public advisors contributed to setting priorities for data analysis from the HHS. Five public advisers took part in the focus group, which highlighted that whilst public advisers were generally satisfied with their involvement, they would like to be involved in more activities. Conclusions: Members of the public shaped the dissemination of evidence and provided guidance for future steps. Public advisers were mostly positive about their involvement in the dissemination of the HHS, but highlighted the need for more transparency and support from researchers

Rectal cancer in old age –is it appropriately managed? Evidence from population-based analysis of routine data across the English national health service

Background: There is significant debate as to where to draw the line between undertreating older rectal cancer patients and minimising treatment risks. This study sought to examine the use of radical rectal cancer treatments and associated outcomes in relation to age across the English NHS. Methods: Patient, tumour and treatment characteristics for all patients diagnosed with a first primary rectal cancer in England between 1st April 2009 and 31st December 2014 were obtained from the CORECT-R data repository. Descriptive analyses and adjusted logistic regression models were undertaken to examine any association between age and the use of major resection and post-surgical outcomes. Funnel plots were used to show variation in adjusted rates of major resection. Results: The proportion of patients who underwent a major surgical resection fell from 66.5% to 31.7%, amongst those aged <70 and aged ≥80 respectively. After adjustment, 30-day post-operative mortality, failure to rescue and prolonged length of stay were significantly higher among the oldest group when compared to the youngest. Patient reported outcomes were not significantly worse amongst older patients. Significant variation was observed in adjusted surgical resection rates in the oldest patients between NHS Trusts. The probability of death due to cancer was comparable across all age groups. Conclusions: Older patients who are selected for surgery have good outcomes, often comparable to their younger counterparts. Significant variation in the treatment of older patients could not be explained by differences in measured characteristics and required further investigation

The experience of linking Victorian emergency medical service trauma data

<p>Abstract</p> <p>Background</p> <p>The linking of a large Emergency Medical Service (EMS) dataset with the Victorian Department of Human Services (DHS) hospital datasets and Victorian State Trauma Outcome Registry and Monitoring (VSTORM) dataset to determine patient outcomes has not previously been undertaken in Victoria. The objective of this study was to identify the linkage rate of a large EMS trauma dataset with the Department of Human Services hospital datasets and VSTORM dataset.</p> <p>Methods</p> <p>The linking of an EMS trauma dataset to the hospital datasets utilised deterministic and probabilistic matching. The linking of three EMS trauma datasets to the VSTORM dataset utilised deterministic, probabilistic and manual matching.</p> <p>Results</p> <p>There were 66.7% of patients from the EMS dataset located in the VEMD. There were 96% of patients located in the VAED who were defined in the VEMD as being admitted to hospital. 3.7% of patients located in the VAED could not be found in the VEMD due to hospitals not reporting to the VEMD. For the EMS datasets, there was a 146% increase in successful links with the trauma profile dataset, a 221% increase in successful links with the mechanism of injury only dataset, and a 46% increase with sudden deterioration dataset, to VSTORM when using manual compared to deterministic matching.</p> <p>Conclusion</p> <p>This study has demonstrated that EMS data can be successfully linked to other health related datasets using deterministic and probabilistic matching with varying levels of success. The quality of EMS data needs to be improved to ensure better linkage success rates with other health related datasets.</p

Standard setting: Comparison of two methods

BACKGROUND: The outcome of assessments is determined by the standard-setting method used. There is a wide range of standard – setting methods and the two used most extensively in undergraduate medical education in the UK are the norm-reference and the criterion-reference methods. The aims of the study were to compare these two standard-setting methods for a multiple-choice question examination and to estimate the test-retest and inter-rater reliability of the modified Angoff method. METHODS: The norm – reference method of standard -setting (mean minus 1 SD) was applied to the 'raw' scores of 78 4th-year medical students on a multiple-choice examination (MCQ). Two panels of raters also set the standard using the modified Angoff method for the same multiple-choice question paper on two occasions (6 months apart). We compared the pass/fail rates derived from the norm reference and the Angoff methods and also assessed the test-retest and inter-rater reliability of the modified Angoff method. RESULTS: The pass rate with the norm-reference method was 85% (66/78) and that by the Angoff method was 100% (78 out of 78). The percentage agreement between Angoff method and norm-reference was 78% (95% CI 69% – 87%). The modified Angoff method had an inter-rater reliability of 0.81 – 0.82 and a test-retest reliability of 0.59–0.74. CONCLUSION: There were significant differences in the outcomes of these two standard-setting methods, as shown by the difference in the proportion of candidates that passed and failed the assessment. The modified Angoff method was found to have good inter-rater reliability and moderate test-retest reliability

Treatment of reducible unstable fractures of the distal radius in adults: a randomised controlled trial of De Palma percutaneous pinning versus bridging external fixation

Background: At present, there is no conclusive evidence regarding the best treatment method for reducible unstable fractures of the distal radius. This study compared the effectiveness of two methods used in surgical treatment of such fractures: percutaneous pinning and external fixation.Methods: We randomly allocated 100 patients into two groups treated surgically with modified de Palma percutaneous pinning and bridging external fixation. Independent but not blinded evaluators administered the DASH quality-of-life questionnaire at postoperative months 6 and 24, performed functional assessment of pain, range of motion, and palm grip strength, and radiographic examinations (volar and radial angle, and height of the radius) before the operation, immediately afterwards, and at 6 and 24 months postoperative. Modified de Palma percutaneous pinning patients used an above-elbow cast whereas external fixation group had unrestricted elbow motion after surgery. Patients who for any reason demonstrated treatment failure or required additional interventions were followed up and their results were included in the group into which these patients had initially been randomised according to the intention-to-treat principle. A significance level of 5% (alpha = 0.05). was used for all statistical tests, such that tests presenting a p-value less than 0.05 were considered statistically significant.Results: Ninety one (58.8 mean age and 66 participants were female) were included in the final assessment at 24 months. the DASH questionnaire evaluation showed a statistically significant result favouring the de Palma group (mean difference = -7.1 p = 0.044) after six months, but this was not maintained at 24 months. There were no statistically differences between the groups with respect to palm grip strength. Analysis of the range-of-motion limitation index (uninjured side minus affected side motion of) showed a statistical difference (mean difference = 2.4 p = 0.043) favoring the external fixator group with regard to the supination movement 6 months after the operation; however, this was not maintained at 24 months. the final results of the radiographic evaluation were similar for the two groups. Overall, five patients developed complications: two with de Palma pinning and three with external fixation.Conclusion: There was a small statistically significant difference favouring the de Palma method in early functional at 6 months according to the DASH questionnaire, and for supination movement favouring the fixator group. However, both were not clinical relevant. By 24 months the groups were similar for all outcome