Quantitative identification of functional connectivity disturbances in neuropsychiatric lupus based on resting-state fMRI: a robust machine learning approach

Neuropsychiatric systemic lupus erythematosus (NPSLE) is an autoimmune entity comprised of heterogenous syndromes affecting both the peripheral and central nervous system. Research on the pathophysiological substrate of NPSLE manifestations, including functional neuroimaging studies, is extremely limited. The present study examined person-specific patterns of whole-brain functional connectivity in NPSLE patients (n = 44) and age-matched healthy control participants (n = 39). Static functional connectivity graphs were calculated comprised of connection strengths between 90 brain regions. These connections were subsequently filtered through rigorous surrogate analysis, a technique borrowed from physics, novel to neuroimaging. Next, global as well as nodal network metrics were estimated for each individual functional brain network and were input to a robust machine learning algorithm consisting of a random forest feature selection and nested cross-validation strategy. The proposed pipeline is data-driven in its entirety, and several tests were performed in order to ensure model robustness. The best-fitting model utilizing nodal graph metrics for 11 brain regions was associated with 73.5% accuracy (74.5% sensitivity and 73% specificity) in discriminating NPSLE from healthy individuals with adequate statistical power. Closer inspection of graph metric values suggested an increased role within the functional brain network in NSPLE (indicated by higher nodal degree, local efficiency, betweenness centrality, or eigenvalue efficiency) as compared to healthy controls for seven brain regions and a reduced role for four areas. These findings corroborate earlier work regarding hemodynamic disturbances in these brain regions in NPSLE. The validity of the results is further supported by significant associations of certain selected graph metrics with accumulated organ damage incurred by lupus, with visuomotor performance and mental flexibility scores obtained independently from NPSLE patients. View Full-Text Keywords: neuropsychiatric systemic lupus erythematosus; rs-fMRI; graph theory; functional connectivity; surrogate data; machine learning; visuomotor ability; mental flexibilit

Irrational prescribing of over-the-counter (OTC) medicines in general practice: testing the feasibility of an educational intervention among physicians in five European countries

Background: Irrational prescribing of over-the-counter (OTC) medicines in general practice is common in Southern Europe. Recent findings from a research project funded by the European Commission (FP7), the “OTC SOCIOMED”, conducted in seven European countries, indicate that physicians in countries in the Mediterranean Europe region prescribe medicines to a higher degree in comparison to physicians in other participating European countries. In light of these findings, a feasibility study has been designed to explore the acceptance of a pilot educational intervention targeting physicians in general practice in various settings in the Mediterranean Europe region. Methods: This feasibility study utilized an educational intervention was designed using the Theory of Planned Behaviour (TPB). It took place in geographically-defined primary care areas in Cyprus, France, Greece, Malta, and Turkey. General Practitioners (GPs) were recruited in each country and randomly assigned into two study groups in each of the participating countries. The intervention included a one-day intensive training programme, a poster presentation, and regular visits of trained professionals to the workplaces of participants. Reminder messages and email messages were, also, sent to participants over a 4-week period. A pre- and post-test evaluation study design with quantitative and qualitative data was employed. The primary outcome of this feasibility pilot intervention was to reduce GPs’ intention to provide medicines following the educational intervention, and its secondary outcomes included a reduction of prescribed medicines following the intervention, as well as an assessment of its practicality and acceptance by the participating GPs. Results: Median intention scores in the intervention groups were reduced, following the educational intervention, in comparison to the control group. Descriptive analysis of related questions indicated a high overall acceptance and perceived practicality of the intervention programme by GPs, with median scores above 5 on a 7-point Likert scale. Conclusions: Evidence from this intervention will estimate the parameters required to design a larger study aimed at assessing the effectiveness of such educational interventions. In addition, it could also help inform health policy makers and decision makers regarding the management of behavioural changes in the prescribing patterns of physicians in Mediterranean Europe, particularly in Southern European countries

Dietary and other lifestyle correlates of serum folate concentrations in a healthy adult population in Crete, Greece: a cross-sectional study

BACKGROUND: Folate has emerged as a key nutrient for optimising health. Impaired folate status has been identified as a risk factor for cardiovascular disease, various types of cancers, and neurocognitive disorders. The study aimed at examining the distribution and determinants of serum folate concentrations in a healthy adult population in Crete, Greece. METHODS: A cross-sectional sample of 486 healthy adults (250 men, 236 women) aged 39 ± 14 years, personnel of the Medical School and the University Hospital of Crete in Greece, was examined. Serum folate and vitamin B(12 )concentrations were measured by microbiological assay, and total homocysteine was determined fluorometrically and by high-pressure liquid chromatography. Lifestyle questionnaires were completed, and nutrient intakes and food consumption were assessed by 24-h dietary recalls. Multivariate analyses were performed using SPSS v10.1. RESULTS: The geometric mean (95% confidence interval) concentrations of serum folate were 15.6 μmol/l (14.6–16.8) in men and 19.2 μmol/l (17.9–20.7) in women (p < 0.001). Inadequate folate levels (≤7 nmol/l) were present in 6.8% of men and 2.1% of women (p < 0.001). Approximately 76% of men and 87% of women did not meet the reference dietary intake for folate (400 μg/day). Serum folate was inversely related to total homocysteine levels (p < 0.001). Increased tobacco and coffee consumption were associated with lower folate concentrations (p < 0.05 for both) but these associations disappeared after controlling for nutrient intakes. In multivariate analysis, intakes of MUFA, fibre, calcium, magnesium, folate, and vitamins A, E, C, B(1), and B(6 )were positively associated with serum folate. Consumption of potatoes, legumes, fruits, and vegetables were favourably related to the serum folate status. CONCLUSION: Serum folate concentrations were associated with various demographic, lifestyle and dietary factors in healthy Cretan adults. Large-scale epidemiological studies should be conducted within the general Greek adult population to assess the prevalence of impaired folate status and further examine associations with dietary patterns and chronic disease risk. Considering the importance of folate in health maintenance, it is important to increase the public's awareness of modifiable lifestyle patterns and diet and tobacco use in particular, which may be associated with improved folate status

2019 update of the EULAR recommendations for the management of systemic lupus erythematosus

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion

ps3 54 characteristic features of haematological involvement and its effect on damage accrual in patients with systemic lupus erythematousus preliminary results from a multicenter european cohort

Background and aim We studied haematological manifestations (HM) and their impact on the progression of damage in systemic lupus erythematosus (SLE) using a multicenter European cohort of patients. Methods We examined the observational data of a SLE patients with serial clinical and laboratory measurements of every 6 months for 2 years gathered from 4 different countries. Each collaborative centre was asked for a contribution of fifty or more consecutive SLE patients. We compared clinical features, antibody profiles, SLEDAI-2K and SDI in patients with and without HM using Chi-Square and Student's t-tests for categorical and continuous variables, respectively. Multivariate Cox Proportional hazards regression was used the investigate the quartiles of leukocytes, lymphocytes and platelets at every time point (at 0,6,12,18,24 months) in relation to the damage characterised by the SDI scores. Probability of change in damage index (from SDI=0 to SDI equal or greater than 1) was calculated using mixed models logistic regression. Adjustments ma Results are presented as odds ratios (ORs) with their 95% CIs; results were defined significant as a p 0.05. Results So far, 751 measurements of 159 patients were examined. Mean age was 44.9 (13.5) vs 44.0 (12.9) for patients with and without HM, respectively (p=NS). Mean disease duration at the time of cohort created was 11.1 (6.2) vs 10.8 (4.9) in patients with or without HM. Demographic features, clinical characteristics of patients with HM at SLE diagnosis or during the follow up are demonstrated in table 1. Sex, ethnicity and baseline autoantibodies showed no influence on damage. SLEDAI-2K was associated with an increased OR of 2.1 [95% CI: 1.29 to 3.42] for damage. Conclusion Preliminary results imply that disease activity predicts future damage accrual in patients with haematological manifestations

The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus

IntroductionAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE).MethodsWe performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients.ResultsWe report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy.DiscussionWe conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy

Overweight and obesity in relation to cardiovascular disease risk factors among medical students in Crete, Greece

BACKGROUND: Recent data indicate increasing rates of adult obesity and mortality from cardiovascular disease (CVD) in Greece. No data, however, are available on prevalence of overweight and obesity in relation to CVD risk factors among young adults in Greece. METHODS: A total of 989 third-year medical students (527 men, 462 women), aged 22 ± 2 years, were recruited from the University of Crete during the period 1989–2001. Anthropometric measures and blood chemistries were obtained. The relationships between obesity indices (body mass index [BMI], waist circumference [WC], waist-to-hip ratio [WHpR], waist-to-height ratio [WHtR]) and CVD risk factor variables (blood pressure, glucose, serum lipoproteins) were investigated. RESULTS: Approximately 40% of men and 23% of women had BMI ≥ 25.0 kg/m(2). Central obesity was found in 33.4% (average percentage corresponding to WC ≥ 90 cm, WHpR ≥ 0.9 and WHtR ≥ 50.0) of male and 21.7% (using WC ≥ 80 cm, WHpR ≥ 0.8, WHtR ≥ 50.0) of female students. Subjects above the obesity indices cut-offs had significantly higher values of CVD risk factor variables. BMI was the strongest predictor of hypertension. WHtR in men and WC in women were the most important indicators of dyslipidaemia. CONCLUSION: A substantial proportion of Greek medical students were overweight or obese, obesity status being related to the presence of hypertension and dyslipidaemia. Simple anthropometric indices can be used to identify these CVD risk factors. Our results underscore the need to implement health promotion programmes and perform large-scale epidemiological studies within the general Greek young adult population

First nationwide survey on cardiovascular risk factors in Grand-Duchy of Luxembourg (ORISCAV-LUX)

BACKGROUND: The ORISCAV-LUX study is the first baseline survey of an on-going cardiovascular health monitoring programme in Grand-Duchy of Luxembourg. The main objectives of the present manuscript were 1) to describe the study design and conduct, and 2) to present the salient outcomes of the study, in particular the prevalence of the potentially modifiable and treatable cardiovascular disease risk factors in the adult population residing in Luxembourg. METHOD: ORISCAV-LUX is a cross-sectional study based on a random sample of 4496 subjects, stratified by gender, age categories and district, drawn from the national insurance registry of 18-69 years aged Luxembourg residents, assuming a response rate of 30% and a proportion of 5% of institutionalized subjects in each stratum. The cardiovascular health status was assessed by means of a self-administered questionnaire, clinical and anthropometric measures, as well as by blood, urine and hair examinations. The potentially modifiable and treatable risk factors studied included smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Both univariate and multivariate statistical analyses used weighted methods to account for the stratified sampling scheme. RESULTS: A total of 1432 subjects took part in the survey, yielding a participation rate of 32.2%. This figure is higher than the minimal sample size of 1285 subjects as estimated by power calculation. The most predominant cardiovascular risk factors were dyslipidemia (69.9%), hypertension (34.5%), smoking (22.3%), and obesity (20.9%), while diabetes amounted 4.4%. All prevalence rates increased with age (except smoking) with marked gender differences (except diabetes). There was a significant difference in the prevalence of hypertension and of lipid disorders by geographic region of birth. The proportion of subjects cumulating two or more cardiovascular risk factors increased remarkably with age and was more predominant in men than in women (P<0.0001). Only 14.7% of men and 23.1% of women were free of any cardiovascular risk factor. High prevalence of non-treated CVRF, notably for hypertension and dyslipidemia, were observed in the study population. CONCLUSION: The population-based ORISCAV-LUX survey revealed a high prevalence of potentially modifiable and treatable cardiovascular risk factors among apparently healthy subjects; significant gender and age-specific differences were seen not only for single but also for combined risk factors. From a public health perspective, these preliminary findings stress the urgent need for early routine health examinations, preventive interventions and lifestyle behavioural changes, even in young asymptomatic adults, to decrease cardiovascular morbidity and mortality in Luxembourg