Miracle-dz/UniFAR-FTUs huggingface dataset:
Health economic analysis of ticagrelor in patients with acute coronary syndromes intended for non-invasive therapy

Objective To investigate the cost effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) in the Platelet Inhibition and Patient Outcomes (PLATO) study who were scheduled for non-invasive management. Methods A previously developed cost effectiveness model was used to estimate long-term costs and outcomes for patients scheduled for non-invasive management. Healthcare costs, event rates and health-related quality of life under treatment with either ticagrelor or clopidogrel over 12 months were estimated from the PLATO study. Long-term costs and health outcomes were estimated based on data from PLATO and published literature sources. To investigate the importance of different healthcare cost structures and life expectancy for the results, the analysis was carried out from the perspectives of the Swedish, UK, German and Brazilian public healthcare systems. Results Ticagrelor was associated with lifetime quality-adjusted life-year (QALY) gains of 0.17 in Sweden, 0.16 in the UK, 0.17 in Germany and 0.13 in Brazil compared with generic clopidogrel, with increased healthcare costs of €467, €551, €739 and €574, respectively. The cost per QALY gained with ticagrelor was €2747, €3395, €4419 and €4471 from a Swedish, UK, German and Brazilian public healthcare system perspective, respectively. Probabilistic sensitivity analyses indicated that the cost per QALY gained with ticagrelor was below conventional threshold values of cost effectiveness with a high probability. Conclusions Treatment of patients with ACS scheduled for 12 months’ non-invasive management with ticagrelor is associated with a cost per QALY gained below conventional threshold values of cost effectiveness compared with generic clopidogrel. Trial registration number NCT000391872.
Regulation of 7-Dehydrocholesterol Reductase by Vitamin D3

OF DISSERTATION Regulation of 7-Dehydrocholesterol Reductase by Vitamin D3 7-Dehydrocholesterol (7-DHC) is the substrate of 7-dehydrocholesterol reductase (DHCR7) in the cholesterol synthesis pathway. Keratinocytes in human skin possess the enzymes necessary for cholesterol synthesis but are also responsible for vitamin D3 synthesis from 7-DHC by exposure to UVB irradiation. It has been well established that DHCR7 is regulated by the SREBP pathway in the regulation of cholesterol synthesis, but little is known about the regulation of DHCR7 by the vitamin D pathway. In this study, the regulation of DHCR7 activity by vitamin D was explored. Treatment of adult human epidermal keratinocyte (HEKa) cells with vitamin D3 resulted in a rapid decrease in DHCR7 activity which was not due to changes in the amount of enzyme present. This suppression of activity was observed only in HEKa cells, a primary cell line cultured from normal human skin, and not in an immortalized skin cell line (HaCaT cells) nor in two liver-derived hepatoma cell lines. Because vitamin D3 treatment of HEKa cells did not change the content of lanosterol nor 7-DHC, these results suggest that vitamin D3 rapidly down-regulates the entire cholesterolgenesis pathway, presumably at a very early step in the pathway. 25-Hydroxyvitamin D3, the first metabolite and circulating form of vitamin D3, had a lesser effect on DHCR7 activity, while 1,25-dihydroxyvitamin D3, the activated form of the vitamin, had no effect on DHCR7, indicating that the vitamin D receptor is not involved. The decrease in DHCR7 activity was due neither to the dephosphorylation of the enzyme, an established mechanism of inactivation, nor to direct inhibition by vitamin D3. Vitamin D3 markedly inhibited proliferation and induced differentiation of HEKa cells, suggesting a possible role for hedgehog signaling in the decrease in DHCR7 activity.
The influence of host HLA on antiretroviral drug resistance mutation in HIV-1

Background: Antiretroviral treatment (ART) to induced mutations in HIV-1 reverse transcriptase (RT) and protease that allow viral escape from drug suppression are well characterised. Similarly, host CTL responses select viral variants that can escape CTL responses. We have shown in a large population study, that CTL escape mutations are evident as HLA allele-specific mutations. We examined the hypothesis that selection pressures of both host HLA-restricted CTL responses and ART interact at specific sites, causing variable susceptibility to drug resistance mutation between HLA-diverse individuals. Methods: 492 subjects with antiretroviral drug exposure, HLA-A and -B typing, pre- and post-ART RT(20-228) and protease(1-99) sequences over 2303 patient-years were studied. Multivariate logistic regression models were used to analyse associations between the development of ART-resistance mutations (as the outcomes) and ART (as covariates). We then analysed the effects of HLA alleles in these models. Results: Associations between ZDV, 3TC, ddI, ddC, ABC, NVP, EFV, IDV, RTV, SQV, NFV, and one or more of their corresponding, known primary and secondary drug resistance mutations were demonstrable using this population-based approach (e.g. M184V in RT, was associated with use of 3TC(OR=69, p<0.001) and L90M in protease was associated with use of NFV [OR=3.1, p=0.003]). At other sites (46 RT and 12 protease residues) drug exposures decreased risk of mutation. In models incorporating HLA alleles, there were 57 residues in RT and 33 in protease at which mutation was associated with specific HLA-A and -B alleles (p<0.05). Like drug resistance mutations, HLA-specific mutations (putative CTL escape mutations) were site-specific, associated with stereotypic amino acid substitutions and secondary mutations. At 8 RT and 7 protease drug mutation sites, we detected HLA associations independently increasing or decreasing the risk of mutation (e.g., T215Y in RT was associated with ZDV [OR=3.7, p<0.001] and HLA-B7 [OR=2.3, p=0.007], but was less likely in those with HLA-B13 [OR=0.2, p=0.03]). In protease, V82A/T/F was associated with IDV (OR=4.3, p<0.001) and HLA-A2 (OR=5.4, p=0.002). Conclusions: Knowledge of characteristic HLA-specific effects on viral sequence, including on drug resistance mutations may help explain variable susceptibility to drug resistance and be useful for individualisation of HIV therapy.
Antigenic and Molecular Characterization of Avian Influenza A(H9N2) Viruses, Bangladesh

Human infection with avian influenza A(H9N2) virus was identified in Bangladesh in 2011. Surveillance for influenza viruses in apparently healthy poultry in live-bird markets in Bangladesh during 2008–2011 showed that subtype H9N2 viruses are isolated year-round, whereas highly pathogenic subtype H5N1 viruses are co-isolated with subtype H9N2 primarily during the winter months. Phylogenetic analysis of the subtype H9N2 viruses showed that they are reassortants possessing 3 gene segments related to subtype H7N3; the remaining gene segments were from the subtype H9N2 G1 clade. We detected no reassortment with subtype H5N1 viruses. Serologic analyses of subtype H9N2 viruses from chickens revealed antigenic conservation, whereas analyses of viruses from quail showed antigenic drift. Molecular analysis showed that multiple mammalian-specific mutations have become fixed in the subtype H9N2 viruses, including changes in the hemagglutinin, matrix, and polymerase proteins. Our results indicate that these viruses could mutate to be transmissible from birds to mammals, including humans.
The effect of sulphur fertilisation on grass growth and animal performance

A previous study of S deficiency in Irish grassland was based on cutting trials carried out at 150 locations throughout the country. In order to determine if S deficiency would occur under grazing and affect animal performance, a grazing experiment with beef cattle was carried out on an S-deficient soil between 1981 and 1985. Results showed that when S was applied to pasture, the stock-carrying capacity was in creased, especially in late season. Samples of herbage taken prior to each grazing, together with data from a cutting experiment carried out nearby, showed that S fertilisation increased herbage yield by about 20% and also improved herbage quality as measured by its N / S ratio. These factors were probably responsible for the extra stock-carrying capacity of the S-treated areas. Sulphur fertilisation significantly decreased the molybdenum concentration in herbage from 1.85 to 0.87 mg/kg and significantly decreased blood copper of the grazing cattle from 0.56 to 0.49 |xg/ml.
Respiratory Syncytial Virus Surveillance in the United States, 2007–2012

Background: Annual respiratory syncytial virus (RSV) outbreaks throughout the US exhibit variable patterns in onset, peak month of activity and duration of season. RSVAlert®, a US surveillance system, collects and characterizes RSV test data at national, regional, state and local levels. Methods: RSV test data from 296 to 666 laboratories from 50 states, the District of Columbia and Puerto Rico (as of 2010) were collected during the 2007–2008 to 2011–2012 RSV seasons. Data were collected in early August/September to the following August/September each season. Participating laboratories provided the total number and types of RSV tests performed each week and test results. RSV season onset and offset were defined as the first and last, respectively, of 2 consecutive weeks during which the mean percentage of specimens testing positive for RSV was ≥10%. Results: Nationally, the RSV season onset occurred in October/November of each year with offset occurring in March/April of the following year. The RSV season averaged 20 weeks and typically occurred earliest in the South and latest in the West. The onset, offset and duration varied considerably within the US Department of Health and Human Services regions. RSV activity in Puerto Rico was elevated throughout the 2-year period studied. Median onset in core-based statistical areas ranged from 2 weeks earlier to 5 weeks later than those in their corresponding states. Conclusions: Substantial variability existed in the timing of RSV activity at all geographic strata analyzed. RSV actively circulated (ie, ≥10%) in many areas outside the traditionally defined RSV epidemic period of November to March.
CCR 5 A novel player in the adipose tissue inflammation and insulin resistance ?

Commentary to: Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 2012; 61:168090; PMID:22474027; http://dx.doi. org/10.2337/ db11-1506
Pertussis

B. pertussis produces multiple antigenic and biologically active products, including pertussis toxin (PT), filamentous hemagglutinin (FHA), agglutinogens, adenylate cyclase, pertactin, and tracheal cytotoxin. These products are responsible for the clinical features of pertussis disease, and an immune response to one or more produces immunity following infection. Immunity following B. pertussis infection does not appear to be permanent.
Altered balance of GABAergic and glutamatergic afferent inputs in PVN‐RVLM neurons of renovascular hypertensive rats

Altered hypothalamic synaptic function contributes to exacerbated neurohumoral drive in hypertension. Using immunohistochemistry and tract‐tracing techniques, we determined if remodeling of afferent GABAergic and glutamatergic inputs in PVN‐RVLM neurons contributes to the imbalanced excitatory/inhibitory function observed in renovascular hypertensive rats (RVH). The density of GAD67ir and VGLUT2ir boutons increased in PVN‐RVLM neurons from RVH rats (P< 0.001). Despite this concomitant increase, time‐dependent and compartment‐specific differences in their reorganization resulted in an altered balance of excitatory/inhibitory inputs. In SHAM and early stage RVH rats (3 weeks), cell body VGLUT2ir predominated over GAD67ir (P< 0.001); no differences were observed in proximal dendrites. Conversely, in late‐stage RVH rats (6 weeks), the somatic VGLUT2/GAD67 predominance diminished (P>0.5), while this relationship in proximal dendrites increased (P< 0.05). Our results support that anatomical remodeling of GABA and glutamate afferent inputs in the PVN, resulting in a net predominance of excitatory over inhibitory inputs, may contribute as an underlying mechanism to enhanced neurohumoral drive in renovascular hypertension. This work was supported by NIH HL090948‐01 to Stern JE and CAPES BEX0325/03‐1 (Brazil).
Subjective Sleepiness and Sleep Quality in Adolescents are Related to Objective and Subjective Measures of School Performance

This study investigated the relation between sleep and school performance in a large sample of 561 adolescents aged 11–18 years. Three subjective measures of sleep were used: sleepiness, sleep quality, and sleep duration. They were compared to three measures of school performance: objective school grades, self-reported school performance, and parent-reported school performance. Sleepiness – “I feel sleepy during the first hours at school” – appeared to predict both school grades and self-reported school performance. Sleep quality on the other hand – as a measure of (un)interrupted sleep and/or problems falling asleep or waking up – predicted parent-reported school performance. Self- and parent-reported school performance correlated only moderately with school grades. So it turns out that the measures used to measure either sleep or school performance impacts whether or not a relation is found. Further research on sleep and school performance should take this into account. The findings do underscore the notion that sleep in adolescence can be important for learning. They are compatible with the hypothesis that a reduced sleep quality can give rise to sleepiness in the first hours at school which results in lower school performance. This notion could have applied value in counseling adolescents and their parents in changing adolescents’ sleep behavior.
Phonocardiography

In the second half of the nineteenth century several observers tried to relate the time of occurrence of the heart sounds to the apical pulsation ? f the heart. A tambour was applied to the prsecordium in the region of the apex-beat and this tambour was connected by rubber tubing to a second tambour, movements of which were recorded by a lever writing ? n a rotating smoked drum. The prsecordial movements which occur during the cardiac cycle were thus recorded as an apical cardiogram. lvhe observer listened to the proecordium adjacent to the apical tambour and made a mark on the corresponding point of the cardiogram every time he heard a heart sound. Most observers indicated the first sound ? n the ascending limb of the principal wave of the cardiogram, corresPonding to the onset of ventricular systole, but such gross disagreement occurred regarding the time of occurrence of the second sound that the Method fell into disrepute. The first objective recording of the time of occurrence of the heart sound in the cardiac cycle was achieved by Hiirthle (1893). His apparatus ls shown in Fig. 1. The sounds were picked up from the front of the chest by a simple carbon microphone in series with a source of electric current and the Primary windings of an induction coil. The secondary windings were
Adaptation of cyanobacteria and microalgae to extreme environmental changes derived from anthropogenic pollution

Estamos en un periodo de extincion global consecuencia de las actividades humanas y que estan alterando los procesos de la biasfera. Las poblaciones de microalgas estan siendo expuestas por primera vez a estos productos fruto de la actividad antropagenica y sus mecanismos de adaptacion son muy poco conocidos. Las cianobacterias y microalgas pueden adaptarse a nuevas condiciones ambientales a traves de mutaciones espontaneas o a traves de respuestas individuales (p.e. los organismos resistentes se pueden producir por mutaciones que ocurren antes de la exposicion al agente selectivo, o por una respuesta especifica y directa al contaminante). Nosotros hemos trabajado en los mecanismos de adaptacion de estos organismos al cambio ambiental brusco debido a contaminantes del agua. El analisis de fluctuacion es el procedimiento adecuado para el estudio del proceso adaptativo. Las especies de cianobacterias y microalgas expuestas a distintos contaminantes (herbicidas, antibioticos, metales pesados, aguas sulfurosas y otros . .) muestran variantes resistentes que se producen por raras mutaciones espontaneas que ocurren antes de la exposicion al contaminante. Estos mutantes resistentes mostraron una disminucion del crecimiento y de la fotosintesis respecto a la poblacion sensible. Las mutaciones espontaneas pueden ser suficientes para asegurar la adaptacion en las enormes poblaciones de microalgas.
OrbId

MicroRNAs coordinate networks of mRNAs, but predicting specific sites of interactions is complicated by the very few bases of complementarity needed for regulation. Although efforts to characterize the specific requirements for microRNA (miR) regulation have made some advances, no general model of target recognition has been widely accepted. In this work, we describe an entirely novel approach to miR target identification. The genomic events responsible for the creation of individual miR loci have now been described with many miRs now known to have been initially formed from transposable element (TE) sequences. In light of this, we propose that limiting miR target searches to transcripts containing a miR’s progenitor TE can facilitate accurate target identification. In this report we outline the methodology behind OrbId (Origin-based identification of microRNA targets). In stark contrast to the principal miR target algorithms (which rely heavily on target site conservation across species and are therefore most effective at predicting targets for older miRs), we find OrbId is particularly efficacious at predicting the mRNA targets of miRs formed more recently in evolutionary time. After defining the TE origins of > 200 human miRs, OrbId successfully generated likely target sets for 191 predominately primate-specific human miR loci. While only a handful of the loci examined were well enough conserved to have been previously evaluated by existing algorithms, we find ~80% of the targets for the oldest miR (miR-28) in our analysis contained within the principal Diana and TargetScan prediction sets. More importantly, four of the 15 OrbId miR-28 putative targets have been previously verified experimentally. In light of OrbId proving best-suited for predicting targets for more recently formed miRs, we suggest OrbId makes a logical complement to existing, conservation based, miR target algorithms.
ORIGINAL ARTICLE

BACKGROUND: The socioeconomic determinants of health can be understood as the social conditions in which people live and work. The objective of the study was to explore the socioeconomic determinants of health in adults aged 18 years and above with the Ethiopian context for possible policy directives and intervention. METHODS: A community based survey was conducted in Kersa District, Jimma Zone on a sample of 422 adults, who were residing in a randomly selected ten kebeles (nine rural and 1 urban). Data were collected through facetoface interview. The outcome variable was self rated general health state which is measured in a single five point Likert item, which is dichotomized as “poor health” and “good health” for subsequent analysis. RESULTS: Household asset index was constructed as a proxy measure for socioeconomic status a single household asset index was constructed for the whole sample using principal component analysis (PCA). Majority of the respondents 378 (89.6%) rated their health state as good and 44 (10.4%) rated their health state as poor. The Bivariate analysis exhibited association of statistical significance with age (P value for trend = <0.001), moderate physical activity OR(95%CI:0.22-0.81), place of residence OR(95%CI:1.33-6.33) and alcohol consumption OR (95%CI: 0.07-0.83) but the independent predictors of poor health state were sufficient physical activity of moderate intensity OR (95%CI :0.19-0.77) ,age OR (95%CI: 1.02-1.07) and sex OR ( 95%CI: 1.12-4.79). CONCLUSIONS: The socioeconomic determinants of health in this study converged mainly on to negative lifestyle practice such as level of physical activity and the socio demographic characteristics sex and increasing age which signifies upcoming intervention strategies in the future should emphasize health problems of females and the elderly. And also equipping the community with the right information about the benefits of sufficient physical activity deserves special attention.
A novel genotyping approach to improve transfusion support for patients with HLA and/or HPA alloantibodies

Patients who require platelet transfusion support but have become sensitised to Human Leucocyte Antigens (HLA) or Human Platelet Antigens (HPA) require suitably matched or selected products to avoid adverse transfusion reactions resulting from antibodies reacting with the transfused product. Provision of compatible products for these patients is often challenging, and requires significant resources from the blood service. This study set out to develop and implement next generation sequencing (NGS) technology to enhance the HLA and HPA definition of both platelet donors and recipients. An NGS based method was designed and developed for high throughput, allele level HLA class I genotyping and used to evaluate the impact of NGS technology on the selection of platelet donors using HLA epitope matching (HEM). In addition, an alternative NGS approach was designed to simultaneously sequence the six genes that code for glycoproteins expressing HPA in order to define all known HPA systems in both donor and patient samples. Allele level HLA-A, -B and –C genotypes were generated for 519 platelet donors by NGS. A critical evaluation of algorithms used to predict alleles from low to medium resolution HLA types demonstrated that NGS was more accurate when determining HLA epitopes for the selection of platelets by HEM. The HLA genotyping data obtained was used to establish previously undefined HLA allele and haplotype frequencies at third field resolution in the English platelet donor population. This thesis also includes the first reported NGS based method for the simultaneous genotyping of HPA-1 to HPA-29, with the additional capability of novel HPA detection. NGS has been shown to significantly improve the definition of both HLA and HPA genetic systems and will provide a number of future benefits for laboratories and the patients they support, including provision of well matched transfusion products, the detection of rare or novel polymorphisms and increased knowledge of HLA and HPA frequencies.
Inflammatory arthritis in systemic sclerosis: What to do?

Musculoskeletal involvement, including arthritis and tendinopathy, is a common and important determinant of disability and impaired quality of life in systemic sclerosis. However, the treatment of arthritis in systemic sclerosis has not been studied as a primary outcome in randomized controlled trials, and arthritis-specific outcome measures for systemic sclerosis have not been sufficiently validated to date. Rheumatologists caring for patients with systemic sclerosis must address these complaints regularly despite the fact that the level of evidence for the treatment of systemic sclerosis–related inflammatory arthritis is limited. Consensus statements, based on treatments for related musculoskeletal aspects of rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune diseases, support the use of methotrexate and hydroxychloroquine. Newer biologics, which have efficacy in the treatment of other autoimmune conditions, may show promise in the treatment of arthritis in systemic sclerosis. In this article, we review the current literature on the assessment and treatment of systemic sclerosis arthritis in order to address management considerations.