Skewed X-chromosome inactivation in scleroderma.

Scleroderma is a female-prevalent autoimmune disease of unclear etiology. Two fundamental gender differences, skewed X-chromosome inactivation (XCI) and pregnancy-related microchimerism, have been implicated in scleroderma. We investigated the XCI patterns of female scleroderma patients and the parental origin of the inactive X chromosome in those patients having skewed XCI patterns (>80%). In addition, we investigated whether a correlation exists between XCI patterns and microchimerism in a well-characterized cohort. About 195 female scleroderma patients and 160 female controls were analyzed for the androgen receptor locus to assess XCI patterns in the DNA extracted from peripheral blood cells. Skewed XCI was observed in 67 (44.9%) of 149 informative patients and in 10 of 124 healthy controls (8.0%) [odds ratio (OR) = 9.3 (95% confidence interval (CI) 4.3-20.6, P 90%) was present in 44 of 149 patients (29.5%) but only in 3 of 124 controls (2.4%; OR = 16.9; 95% CI 4.8-70.4, P < 0.0001). Parental origin of the inactive X chromosome was investigated for ten patients for whom maternal DNA was informative, and the inactive X chromosome was of maternal origin in eight patients and of paternal origin in two patients. Skewed XCI mosaicism could be considered as an important risk factor in scleroderma

Quels enjeux pour la gestion des eaux urbaines ? Contribution à la formulation des services attendus par le système de gestion des eaux urbaines

International audienceLe système d'assainissement dont nous héritons s'est développé en couches successives, répondant chacune à des enjeux différents, et qui présentent une valeur patrimoniale très importante. Ces systèmes doivent aujourd'hui répondre à des enjeux de plus en plus diversifiés. Les techniques mises en ½uvre deviennent également de plus en plus diversifiées. Cette multiplication des fonctions et des dispositifs concourt à accroître le nombre d'organisations concernées et actives dans la gestion du système. Se pose alors la question de la coordination d'une pluralité d'organisations, gérant une pluralité d'ouvrages dans une grande diversité d'objectifs et d'intérêts. L'enjeu principal devient donc le développement d'un système durable de gestion des eaux urbaines qui se compose de dispositifs techniques et spatiaux, d'organisations en charge de ces dispositifs, et du bassin versant naturel correspondant au domaine d'influence. Cependant, pour gérer ce système, il faut dans un premier temps identifier les enjeux liés aux eaux urbaines. La multiplication des dispositifs et organisations, et le changement d'échelle pour considérer le système (ville + bassin versant naturel) nécessite en effet de repenser les services qu'il doit rendre. Cette communication propose une réponse sous forme de " marguerite des fonctions ". Les fonctions de service liées à la gestion des eaux urbaines et le mode d'obtention de la marguerite sont détaillés

Cost-effectiveness of HBV and HCV screening strategies:a systematic review of existing modelling techniques

Introduction: Studies evaluating the cost-effectiveness of screening for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are generally heterogeneous in terms of risk groups, settings, screening intervention, outcomes and the economic modelling framework. It is therefore difficult to compare cost-effectiveness results between studies. This systematic review aims to summarise and critically assess existing economic models for HBV and HCV in order to identify the main methodological differences in modelling approaches. Methods: A structured search strategy was developed and a systematic review carried out. A critical assessment of the decision-analytic models was carried out according to the guidelines and framework developed for assessment of decision-analytic models in Health Technology Assessment of health care interventions. Results: The overall approach to analysing the cost-effectiveness of screening strategies was found to be broadly consistent for HBV and HCV. However, modelling parameters and related structure differed between models, producing different results. More recent publications performed better against a performance matrix, evaluating model components and methodology. Conclusion: When assessing screening strategies for HBV and HCV infection, the focus should be on more recent studies, which applied the latest treatment regimes, test methods and had better and more complete data on which to base their models. In addition to parameter selection and associated assumptions, careful consideration of dynamic versus static modelling is recommended. Future research may want to focus on these methodological issues. In addition, the ability to evaluate screening strategies for multiple infectious diseases, (HCV and HIV at the same time) might prove important for decision makers

Neurofilament light chain predicts future dementia risk in cerebral small vessel disease.

OBJECTIVES: Serum neurofilament light chain (NfL) has been proposed as prognostic markers in neurogenerative disease. A cross-sectional study in cerebral small vessel disease (SVD) reported an association with cognition and disability. If NfL is to be used to predict outcome, studies are required to demonstrate baseline NfL predicts future dementia risk. Furthermore, if it is to be used as a surrogate marker in clinical trials, change in NfL over time periods typical of a clinical trial must be linked to clinical progression. In a longitudinal study of patients with lacunar stroke and confluent white matter hyperintensities, we determined whether both baseline, and change, in NfL levels were linked to changes in MRI markers, cognitive decline and dementia risk. METHODS: Patients underwent MRI, cognitive testing and blood taking at baseline and annually for 3 years. Clinical and cognitive follow-up continued for 5 years. RESULTS: NfL data were available for 113 subjects for baseline analysis, and 90 patients for the longitudinal analysis. Baseline NfL predicted cognitive decline (global cognition β=-0.335, SE=0.094, p=0.001) and risk of converting to dementia (HR=1.676 (95% CI 1.183 to 2.373), p=0.004). In contrast to imaging, there was no change in NfL values over the follow-up period. CONCLUSIONS: Baseline NfL predicts changes in MRI markers, cognitive decline and dementia rate over a 5 years follow-up period in SVD, suggesting NfL may be a useful prognostic marker. However, change in NfL values was not detected, and therefore NfL may not be a useful surrogate marker in clinical trials in SVD.European Union’s Horizon 2020 research and innovation programme under grant agreement No 667375 (CoSTREAM) Priority Programme Grant from the Stroke Association (award reference PPA 2015/02

Europeans’ willingness to pay for ending homelessness: A contingent valuation study

The purpose of this study is to assess the utility value European citizens put on an innovative social program aimed at reducing homelessness. The Housing First (HF) model involves access to regular, scattered, independent and integrated housing in the community with the support of a multidisciplinary team. Currently, HF is not implemented by most European countries or funded by healthcare or social plans, but randomised controlled trials have stressed significant results for improved housing stability, recovery and healthcare services use. The broader implementation of HF across Europe would benefit from a better understanding of citizens' preferences and “willingness to pay” (WTP) for medico-social interventions like HF. We conducted a representative telephone survey between March and December 2017 in eight European countries (France, Ireland, Italy, the Netherlands, Poland, Portugal, Spain, and Sweden). Respondent's WTP for HF (N = 5631) was assessed through a contingent valuation method with a bidding algorithm. 42.3% of respondents were willing to pay more taxes to reduce homelessness through the HF model, and significant differences were found between countries (p < 0.001); 30.4% of respondents who did not value the HF model were protest zeros (either contested the payment vehicle-taxes- or the survey instrument). Respondents were willing to pay €28.2 (±11) through annual taxation for the HF model. Respondents with higher educational attainment, who paid national taxes, reported positive attitudes about homelessness, or reported practices to reduce homelessness (donations, volunteering) were more likely to value the HF model, with some countries' differences also related to factors at the environmental level. These findings inform key stakeholders that European citizens are aware of the issue of homelessness in their countries and that scaling up the HF model across Europe is both feasible and likely to have public support

MCT8 expression in human fetal cerebral cortex is reduced in severe intrauterine growth restriction

The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study, we sought to quantify changes in cortical MCT8 expression with IUGR. First, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections obtained from appropriately grown for gestational age (AGA) human fetuses between 19 weeks of gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24–28 weeks of gestation was objectively compared with that in the occipital cortex of gestationally matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, in the epithelium of the choroid plexus and ependyma, and in microvessel wall. When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios (r(2)=0.28; P<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development

Lower Rate of Restenosis and Reinterventions With Covered vs Bare Metal Stents Following Innominate Artery Stenting

PURPOSE: To determine any difference between bare metal stents (BMS) and balloon-expandable covered stents in the treatment of innominate artery atheromatous lesions. MATERIALS AND METHODS: A multicenter retrospective study involving 13 university hospitals in France collected 93 patients (mean age 63.2±11.1 years; 57 men) treated over a 10-year period. All patients had systolic blood pressure asymmetry &gt;15 mm Hg and were either asymptomatic (39, 42%) or had carotid (20, 22%), vertebrobasilar (24, 26%), and/or brachial (20, 22%) symptoms. Innominate artery stenosis ranged from 50% to 70% in 4 (4%) symptomatic cases and between 70% and 90% in 52 (56%) cases; 28 (30%) lesions were preocclusive and 8 (9%) were occluded. One (1%) severely symptomatic patient had a &lt;50% stenosis. Demographic characteristics, operative indications, and procedure details were compared between the covered (36, 39%) and BMS (57, 61%) groups. Multivariate analysis was performed to determine relative risks of restenosis and reinterventions [reported with 95% confidence intervals (CI)]. RESULTS: The endovascular procedures were performed mainly via retrograde carotid access (75, 81%). Perioperative strokes occurred in 4 (4.3%) patients. During the mean 34.5±31.2-month follow-up, 30 (32%) restenoses were detected and 13 (20%) reinterventions were performed. Relative risks were 6.9 (95% CI 2.2 to 22.2, p=0.001) for restenosis and 14.6 (95% CI 1.8 to 120.8, p=0.004) for reinterventions between BMS and covered stents. The severity of the treated lesions had no influence on the results. CONCLUSION: Patients treated with BMS for innominate artery stenosis have more frequent restenoses and reinterventions than patients treated with covered stents

Pregnancy, Microchimerism, and the Maternal Grandmother

A WOMAN OF REPRODUCTIVE AGE OFTEN HARBORS A SMALL NUMBER OF FOREIGN CELLS, REFERRED TO AS MICROCHIMERISM: a preexisting population of cells acquired during fetal life from her own mother, and newly acquired populations from her pregnancies. An intriguing question is whether the population of cells from her own mother can influence either maternal health during pregnancy and/or the next generation (grandchildren).Microchimerism from a woman's (i.e. proband's) own mother (mother-of-the-proband, MP) was studied in peripheral blood samples from women followed longitudinally during pregnancy who were confirmed to have uncomplicated obstetric outcomes. Women with preeclampsia were studied at the time of diagnosis and comparison made to women with healthy pregnancies matched for parity and gestational age. Participants and family members were HLA-genotyped for DRB1, DQA1, and DQB1 loci. An HLA polymorphism unique to the woman's mother was identified, and a panel of HLA-specific quantitative PCR assays was employed to identify and quantify microchimerism. Microchimerism from the MP was identified during normal, uncomplicated pregnancy, with a peak concentration in the third trimester. The likelihood of detection increased with advancing gestational age. For each advancing trimester, there was a 12.7-fold increase in the probability of detecting microchimerism relative to the prior trimester, 95% confidence intervals 3.2, 50.3, p<0.001. None of the women with preeclampsia, compared with 30% of matched healthy women, had microchimerism (p = 0.03).These results show that microchimerism from a woman's own mother is detectable in normal pregnancy and diminished in preeclampsia, supporting the previously unexplored hypothesis that MP microchimerism may be a marker reflecting healthy maternal adaptation to pregnancy

Cost-Effectiveness of Early Versus Standard Antiretroviral Therapy in HIV-Infected Adults in Haiti

This cost-effectiveness study comparing early versus standard antiretroviral treatment (ART) for HIV, based on randomized clinical trial data from Haiti, reveals that the new WHO guidelines for early ART initiation can be cost-effective in resource-poor settings

Financing equitable access to antiretroviral treatment in South Africa

<p>Abstract</p> <p>Background</p> <p>While South Africa spends approximately 7.4% of GDP on healthcare, only 43% of these funds are spent in the public system, which is tasked with the provision of care to the majority of the population including a large proportion of those in need of antiretroviral treatment (ART). South Africa is currently debating the introduction of a National Health Insurance (NHI) system. Because such a universal health system could mean increased public healthcare funding and improved access to human resources, it could improve the sustainability of ART provision. This paper considers the minimum resources that would be required to achieve the proposed universal health system and contrasts these with the costs of scaled up access to ART between 2010 and 2020.</p> <p>Methods</p> <p>The costs of ART and universal coverage (UC) are assessed through multiplying unit costs, utilization and estimates of the population in need during each year of the planning cycle. Costs are from the provider’s perspective reflected in real 2007 prices.</p> <p>Results</p> <p>The annual costs of providing ART increase from US$1 billion in 2010 to US$3.6 billion in 2020. If increases in funding to public healthcare only keep pace with projected real GDP growth, then close to 30% of these resources would be required for ART by 2020. However, an increase in the public healthcare resource envelope from 3.2% to 5%-6% of GDP would be sufficient to finance both ART and other services under a universal system (if based on a largely public sector model) and the annual costs of ART would not exceed 15% of the universal health system budget.</p> <p>Conclusions</p> <p>Responding to the HIV-epidemic is one of the many challenges currently facing South Africa. Whether this response becomes a “resource for democracy” or whether it undermines social cohesiveness within poor communities and between rich and poor communities will be partially determined by the steps that are taken during the next ten years. While the introduction of a universal system will be complex, it could generate a health system responsive to the needs of all South Africans.</p