Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways

An online expert network for high quality information on occupational safety and health: cross-sectional study of user satisfaction and impact

<p>Abstract</p> <p>Background</p> <p>Many people have difficulties finding information on health questions, including occupational safety and health (OSH) issues. One solution to alleviate these difficulties could be to offer questioners free-of-charge, online access to a network of OSH experts who provide tailored, high-quality information. The aim of this study was to assess whether network quality, respectively information quality, as perceived by the questioners, is associated with questioners' overall satisfaction and to explore the impact of the information received on questioners' knowledge, work and work functioning.</p> <p>Methods</p> <p>We evaluated the experiences of OSH questioners with the online network ArboAntwoord.com over a two-year period. In this network, approximately 80 qualified experts are available to answer OSH questions. By means of a questionnaire, we assessed questioners' overall satisfaction with the network, whether the network was user-friendly, easily accessible and easy to handle and whether the information provided was complete, applicable and received in a timely manner. The impact of the information on questioners' knowledge, work or work functioning was explored with seven questions. In the study period, 460 unique OSH questioners asked 851 OSH questions. In total, 205 of the 460 questioners completed the questionnaire (response rate 45%).</p> <p>Results</p> <p>Of the responders, 71% were satisfied with the ArboAntwoord network. Multiple logistic regression analysis showed that the applicability of the information had a positive influence on the questioners' overall satisfaction (OR = 16.0, 95% CI: 7.0-36.4). Also, user friendliness of the network (OR = 3.3, 95% CI: 1.3-8.6) and completeness of the information provided (OR = 3.0, 95% CI: 1.3-6.8) were positively related to the questioners' satisfaction. For 74% of the questioners, the information helped to increase their knowledge and understanding. Overall, 25% of the questioners indicated that the received information improved their work, work functioning or health.</p> <p>Conclusions</p> <p>A free-of-charge, online expert network in the field of OSH can be a useful strategy to provide OSH questioners with applicable, complete and timely information that may help improve safety and health at work. This study provides more insight in how to satisfy network questioners and about the potential impact of provided information on OSH.</p

Early- Onset Stroke and Vasculopathy Associated with Mutations in ADA2

Adenosine deaminase 2 (ADA2) is an enzyme involved in purine metabolism and a growth factor that influences the development of endothelial cells and leukocytes. This study shows that defects in ADA2 cause recurrent fevers, vascular pathologic features, and mild immunodeficiency. Patients with autoinflammatory disease sometimes present with clinical findings that encompass multiple organ systems.(1) Three unrelated children presented to the National Institutes of Health (NIH) Clinical Center with intermittent fevers, recurrent lacunar strokes, elevated levels of acute-phase reactants, livedoid rash, hepatosplenomegaly, and hypogammaglobulinemia. Collectively, these findings do not easily fit with any of the known inherited autoinflammatory diseases. Hereditary or acquired vascular disorders can have protean manifestations yet be caused by mutations in a single gene. Diseases such as the Aicardi-Goutieres syndrome,(2),(3) polypoidal choroidal vasculopathy,(4) sickle cell anemia,(5) livedoid vasculopathy,(6) and the small-vessel vasculitides(7),(8) are examples of systemic ...</p

The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California Teachers Study cohort

Abstract Introduction The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy. Methods We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (P ACT). Results The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (P ACT = 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene P ACT = 0.002; overall P ACT = 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women. Conclusions We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT

Life cycle environmental impacts of convenience food: Comparison of ready and home-made meals

This paper compares the life cycle environmental impacts of ready-made meals manufactured industrially with meals prepared at home from scratch. A typical roast dinner consisting of chicken meat, vegetables and tomato sauce is considered. The results suggest that the impacts of the home-made meal are lower than for the equivalent ready-made meal. For example, the global warming and human toxicity potentials are up to 35% lower and eutrophication, photochemical smog and ozone layer depletion are up to 3 times lower. The main reasons for this are the avoidance of meal manufacturing, reduced refrigeration and a lower amount of waste in the life cycle of the home-made meal. For the ready-made meal, the lowest impacts are found for the frozen meal prepared from fresh ingredients and heated at home in a microwave. The worst option for most impacts is the frozen ready-made meal with frozen ingredients that is heated in an electric oven. For the same cooking method, chilled ready-made meals have higher impacts than the frozen. The type of refrigerant used in the supply chain influences the impacts, particularly global warming and ozone layer depletion. The contribution of packaging is important for some impacts, including global warming, fossil fuel depletion and human toxicity. The main hotspots for both types of meal are the ingredients, waste and cooking method chosen by the consumer. Using organic instead of conventional ingredients leads to higher impacts. Sourcing chicken and tomatoes from Brazil and Spain, respectively, reduces environmental impacts of the meals compared to sourcing them from the UK, despite the long-distance transport. The findings of the study are used to make recommendations to producers, retailers and consumers on reducing the environmental impacts from food production and consumption.The authors are grateful to RCUK (grant no. EP/K011820) and BECAS Chile for sponsoring this research

HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force.

PROBLEM: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. WHAT WE DID: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The overarching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.[Please see the Supplementary Note for acknowledgments.]This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.337

Correction:How the COVID-19 pandemic highlights the necessity of animal research (vol 30, pg R1014, 2020)

(Current Biology 30, R1014–R1018; September 21, 2020) As a result of an author oversight in the originally published version of this article, a number of errors were introduced in the author list and affiliations. First, the middle initials were omitted from the names of several authors. Second, the surname of Dr. van Dam was mistakenly written as “Dam.” Third, the first name of author Bernhard Englitz was misspelled as “Bernard” and the surname of author B.J.A. Pollux was misspelled as “Pullox.” Finally, Dr. Keijer's first name was abbreviated rather than written in full. These errors, as well as various errors in the author affiliations, have now been corrected online