Effectiveness of Influenza Vaccine in Preventing Medically-Attended Influenza Virus Infection in Primary Care, Israel, Influenza Seasons 2014/15 and 2015/16

IntroductionInfluenza vaccine is recommended for the entire population in Israel. We assessed influenza vaccine effectiveness (VE) for the 2014/15 and 2015/16 seasons in Israel, for the first time. Methods: Combined nose and throat swab specimens were collected from patients with influenza-like illness (ILI) presenting to sentinel primary care clinics and tested for influenza virus by RT-PCR. VE of the trivalent inactivated vaccine (TIV) was assessed using test-negative case-control design. Results: During the 2014/15 season 1,142 samples were collected; 327 (28.6%) were positive for influenza, 83.8% A(H3N2), 5.8% A(H1N1)pdm09, 9.2% B and 1.2% A un-subtyped. Adjusted VE against all influenza viruses for this influenza season was -4.8% (95% confidence interval (CI): -54.8 to 29.0) and against influenza A(H3N2), it was -15.8% (95% CI: -72.8 to 22.4). For the 2015/16 season, 1,919 samples were collected; 853 (44.4%) were positive for influenza, 43.5% A(H1N1)pdm09, 57% B, 0.7% A(H3N2) and 11 samples positive for both A(H1N1)pdm09 and B. Adjusted VE against all influenza viruses for this influenza season was 8.8% (95% CI: -25.1 to 33.5), against influenza A(H1N1)pdm09, it was 32.3% (95% CI: (-4.3 to 56.1) and against influenza B, it was -2.2% (95% CI: (-47.0 to 29.0). Conclusions: Using samples from patients with ILI visiting sentinel clinics in Israel, we demonstrated the feasibility of influenza VE estimation in Israel

Waist circumference and waist-to-height ratio of Hong Kong Chinese children

<p>Abstract</p> <p>Background</p> <p>Central body fat is a better predictor than overall body fat for cardiovascular (CV) risk factors in both adults and children. Waist circumference (WC) has been used as a proxy measure of central body fat. Children at high CV risk may be identified by WC measurements. Waist-to-height ratio (WHTR) has been proposed as an alternative, conveniently age-independent measure of CV risk although WHTR percentiles have not been reported. We aim to provide age- and sex-specific reference values for WC and WHTR in Hong Kong Chinese children.</p> <p>Methods</p> <p>Cross sectional study in a large representative sample of 14,842 children aged 6 to 18 years in 2005/6. Sex-specific descriptive statistics for whole-year age groups and smoothed percentile curves of WC and WHTR were derived and presented.</p> <p>Results</p> <p>WC increased with age, although less after age 14 years in girls. WHTR decreased with age (particularly up to age 14). WHTR correlated less closely than WC with BMI (r = 0.65, 0.59 cf. 0.93, 0.91, for boys and girls respectively).</p> <p>Conclusion</p> <p>Reference values and percentile curves for WC and WHRT of Chinese children and adolescents are provided. Both WC and WHTR are age dependent. Since the use of WHRT does not obviate the need for age-related reference standards, simple WC measurement is a more convenient method for central fat estimation than WHRT.</p

Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015

Background Exposure to ambient air pollution increases morbidity and mortality, and is a leading contributor to global disease burden. We explored spatial and temporal trends in mortality and burden of disease attributable to ambient air pollution from 1990 to 2015 at global, regional, and country levels. Methods We estimated global population-weighted mean concentrations of particle mass with aerodynamic diameter less than 2·5 μm (PM2·5) and ozone at an approximate 11 km × 11 km resolution with satellite-based estimates, chemical transport models, and ground-level measurements. Using integrated exposure–response functions for each cause of death, we estimated the relative risk of mortality from ischaemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infections from epidemiological studies using non-linear exposure–response functions spanning the global range of exposure. Findings Ambient PM2·5 was the fifth-ranking mortality risk factor in 2015. Exposure to PM2·5 caused 4·2 million (95% uncertainty interval [UI] 3·7 million to 4·8 million) deaths and 103·1 million (90·8 million 115·1 million) disability-adjusted life-years (DALYs) in 2015, representing 7·6% of total global deaths and 4·2% of global DALYs, 59% of these in east and south Asia. Deaths attributable to ambient PM2·5 increased from 3·5 million (95% UI 3·0 million to 4·0 million) in 1990 to 4·2 million (3·7 million to 4·8 million) in 2015. Exposure to ozone caused an additional 254 000 (95% UI 97 000–422 000) deaths and a loss of 4·1 million (1·6 million to 6·8 million) DALYs from chronic obstructive pulmonary disease in 2015. Interpretation Ambient air pollution contributed substantially to the global burden of disease in 2015, which increased over the past 25 years, due to population ageing, changes in non-communicable disease rates, and increasing air pollution in low-income and middle-income countries. Modest reductions in burden will occur in the most polluted countries unless PM2·5 values are decreased substantially, but there is potential for substantial health benefits from exposure reduction

Preferential binding to elk-1 by sle-associated il10 risk allele upregulates il10 expression

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans

Desmoplastic fibroma of the mandible - review of the literature and presentation of a rare case

Desmoplastic fibroma (DF) is a rare, benign but locally aggressive, intraosseous lesion with a high tendency of local recurrence. In this report the actual literature is reviewed regarding epidemiological data, pathology, clinical diagnostic criterias, therapy and prognosis. Moreover, a report of an interesting case is included localized in the mandibular corpus

Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10-8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10-7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10-7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10-4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE

Type 2 Diabetes Modifies the association of Cad Genomic Risk Variants With Subclinical atherosclerosis

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC

A Framework For Detecting Noncoding Rare-Variant associations of Large-Scale Whole-Genome Sequencing Studies

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 toPMed samples. We also analyze five non-lipid toPMed traits

Functional network resilience to pathology in presymptomatic genetic frontotemporal dementia

© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)The presymptomatic phase of neurodegenerative diseases are characterized by structural brain changes without significant clinical features. We set out to investigate the contribution of functional network resilience to preserved cognition in presymptomatic genetic frontotemporal dementia. We studied 172 people from families carrying genetic abnormalities in C9orf72, MAPT, or PGRN. Networks were extracted from functional MRI data and assessed using graph theoretical analysis. We found that despite loss of both brain volume and functional connections, there is maintenance of an efficient topological organization of the brain's functional network in the years leading up to the estimated age of frontotemporal dementia symptom onset. After this point, functional network efficiency declines markedly. Reduction in connectedness was most marked in highly connected hub regions. Measures of topological efficiency of the brain's functional network and organization predicted cognitive dysfunction in domains related to symptomatic frontotemporal dementia and connectivity correlated with brain volume loss in frontotemporal dementia. We propose that maintaining the efficient organization of the brain's functional network supports cognitive health even as atrophy and connectivity decline presymptomatically.This work was funded by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant [grant number CoEN015]. JBR was supported by the Wellcome Trust [grant number 103838]. JBR, RB, TR, and SJ were supported by the NIHR Cambridge Biomedical Research Centre and Medical Research Council [grant number G1100464]. The Dementia Research Centre at UCL is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation, NIHR Queen Square Dementia Biomedical Research Unit, NIHR UCL/H Biomedical Research Centre and Dementia Platforms UK. JDR is supported by an MRC Clinician Scientist Fellowship [grant number MR/M008525/1] and has received funding from the NIHR Rare Disease Translational Research Collaboration [grant number BRC149/NS/MH]. MM is supported by the Canadian Institutes of Health Research, Department of Medicine at Sunnybrook Health Sciences Centre and the University of Toronto, and the Sunnybrook Research Institute. RL is supported by Réseau de médecine génétique appliquée, Fonds de recherche du Québec—Santé [grant number FRQS]. FT is supported by the Italian Ministry of Health. DG is supported by the Fondazione Monzino and Italian Ministry of Health, Ricerca Corrente. SS is supported by Cassa di Risparmio di Firenze [grant number CRF 2013/0199] and the Ministry of Health [grant number RF-2010-2319722]. JvS is supported by The Netherlands Organisation for Health Research and Development Memorable grant [grant number 733050103] and Netherlands Alzheimer Foundation Memorable grant [grant number 733050103].info:eu-repo/semantics/publishedVersio

Disease-related cortical thinning in presymptomatic granulin mutation carriers

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.The authors thank all the volunteers for their participation in this study. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3, Spain (grant no. 20143810 to RSV). The GENFI study has been supported by the Medical Research Council UK, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimer’s Society PhD studentship. JDR acknowledges support from the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the UK Dementia Research Institute, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation. JCvS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG have received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG has received support from the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. MS was supported by a grant 779257 “Solve-RD” from the Horizon 2020 research and innovation programme.info:eu-repo/semantics/publishedVersio