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

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

Metabolomic analyses of Leishmania reveal multiple species differences and large differences in amino acid metabolism

Comparative genomic analyses of Leishmania species have revealed relatively minor heterogeneity amongst recognised housekeeping genes and yet the species cause distinct infections and pathogenesis in their mammalian hosts. To gain greater information on the biochemical variation between species, and insights into possible metabolic mechanisms underpinning visceral and cutaneous leishmaniasis, we have undertaken in this study a comparative analysis of the metabolomes of promastigotes of L. donovani, L. major and L. mexicana. The analysis revealed 64 metabolites with confirmed identity differing 3-fold or more between the cell extracts of species, with 161 putatively identified metabolites differing similarly. Analysis of the media from cultures revealed an at least 3-fold difference in use or excretion of 43 metabolites of confirmed identity and 87 putatively identified metabolites that differed to a similar extent. Strikingly large differences were detected in their extent of amino acid use and metabolism, especially for tryptophan, aspartate, arginine and proline. Major pathways of tryptophan and arginine catabolism were shown to be to indole-3-lactate and arginic acid, respectively, which were excreted. The data presented provide clear evidence on the value of global metabolomic analyses in detecting species-specific metabolic features, thus application of this technology should be a major contributor to gaining greater understanding of how pathogens are adapted to infecting their hosts

Concordant Gene Expression in Leukemia Cells and Normal Leukocytes Is Associated with Germline cis-SNPs

The degree to which gene expression covaries between different primary tissues within an individual is not well defined. We hypothesized that expression that is concordant across tissues is more likely influenced by genetic variability than gene expression which is discordant between tissues. We quantified expression of 11,873 genes in paired samples of primary leukemia cells and normal leukocytes from 92 patients with acute lymphoblastic leukemia (ALL). Genetic variation at >500,000 single nucleotide polymorphisms (SNPs) was also assessed. The expression of only 176/11,783 (1.5%) genes was correlated (p<0.008, FDR = 25%) in the two tissue types, but expression of a high proportion (20 of these 176 genes) was significantly related to cis-SNP genotypes (adjusted p<0.05). In an independent set of 134 patients with ALL, 14 of these 20 genes were validated as having expression related to cis-SNPs, as were 9 of 20 genes in a second validation set of HapMap cell lines. Genes whose expression was concordant among tissue types were more likely to be associated with germline cis-SNPs than genes with discordant expression in these tissues; genes affected were involved in housekeeping functions (GSTM2, GAPDH and NCOR1) and purine metabolism

Sustainable drainage system site assessment method using urban ecosystem services

The United Kingdom's recently updated approach to sustainable drainage enhanced biodiversity and amenity objectives by incorporating the ecosystem approach and the ecosystem services concept. However, cost-effective and reliable methods to appraise the biodiversity and amenity values of potential sustainable drainage system (SuDS)sites and their surrounding areas are still lacking, as is a method to enable designers to distinguish and link the amenity and biodiversity benefits that SuDS schemes can offer. In this paper, therefore, the authors propose two ecosystem services- and disservices-based methods (i.e. vegetation structure cover-abundance examination and cultural ecosystem services and disservices variables appraisal) to aid SuDS designers to distinguish and link amenity and biodiversity benefits, and allow initial site assessments to be performed in a cost-effective and reliable fashion. Forty-nine representative sites within Greater Manchester were selected to test the two methods. Amenity and biodiversity were successfully assessed and habitat for species, carbon sequestration, recreation and education ecosystem services scores were produced,which will support SuDS retrofit design decision-making. Large vegetated SuDS sites with permanent aquatic features were found to be most capable of enhancing biodiversity- and amenity-related ecosystem services. Habitat for species and recreation ecosystem services were also found to be positively linked to each other. Finally, waste bins on site were found to help reduce dog faeces and litter coverage. Overall, the findings presented here enable future SuDS retrofit designs to be more wildlife friendly and socially inclusive

The Application of NCaRBS to the Trendelenburg Test and Total Hip Arthroplasty Outcome

This paper compares the frontal plane hip func- tion of subject’s known to have had hip arthroplasty via either the lateral (LA) or posterior (PA) surgical approaches and a group of subjects associated with no pathology (NP). This is investigated through the Trendelenburg test using 3D motion analysis and classification. Here, a recent develop- ment on the Classification and Ranking Belief Simplex (CaRBS) technique, able to undertake n-state classification, so termed NCaRBS is employed. The relationship between post-operative hip function measured during a Trendelen- burg Test using three patient characteristics (pelvic obliquity, frontal plane hip moment and frontal plane hip power) of LA, PA and NP subjects are modelled together. Using these characteristics, the classification accuracy was 93.75% for NP, 57.14% for LA, 38.46% for PA. There was a clear distinction between NP and post-surgical function. 3/6 LA subjects and 6/8 PA subjects were misclassified as having NP function, implying that greater function is restored following the PA to surgery. NCaRBS achieved a higher accuracy (65.116%) than through a linear discriminant analysis (48.837%). A Neural Network with two-nodes achieved the same accuracy (65.116%) and as expected was further improved with three-nodes (69.767%). A valuable benefit to the employment of the NCaRBS technique is the graphical exposition of the contribution of patient characteristics to the classification analysis

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference