Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016

Respiratory syncytial virus (RSV) is considered the major pathogen causing severe lower respiratory tract infections among infants and young children [1]. RSV is the most common cause of hospitalisation for acute lower respiratory tract infection in children younger than 5 years and is estimated to cause between 66,000 and 199,000 deaths worldwide every year [2]. Its significance in causing substantial morbidity and hospitalisation in the first year of life has been affirmed in a recent study and a meta-analysis [3,4]. In England, average annual hospital admission rates are 35.1 per 1,000 children younger than 1 year and 5.31 per 1,000 children aged 1–4 years [5]. In addition to children, RSV causes a substantial disease burden in elderly people and patients with chronic obstructive pulmonary disease [6,7]. RSV causes seasonal epidemics worldwide [8], with one to two epidemics each year [9] following latitudinal gradients in timing, duration, seasonal amplitude and between-year variability [8,9]. In some studies, the seasonal periodicity has been connected to climatic factors [9-11], but a common factor that explains all observed periodicity has not been established. Meteorological conditions such as temperature and high relative humidity have been reported as important predictors of RSV epidemics [9,12]. In the United States (US) and Japan, annual national and regional variation of RSV season onset and end has been reported [13-15]. In the Nordic countries, a major outbreak often alternates with a minor one, with the minor peak in the spring and a major one the following winter [16-19], a phenomenon reported also in Croatia [20], Denmark [21] and Germany [22]. RSV antigenic groups A and B alternate in two-year cycles in Finland, with dominance of the group A viruses in years 1981–82, 1985–86 and 1989–90 and the group B viruses 1983–84 and 1987–88 [17,19], and different genotypes dominate the circulation in consecutive epidemics in Korea [23]. In Spain, no biennial rhythm has been detected but rather a stable annual epidemic with a peak between week 52 and week 1 and circulation 2–8 weeks earlier than influenza viruses [24]. Similarly, in the United Kingdom (UK), one stable epidemic per year is observed [5]. Immunoprophylaxis to prevent RSV infection with a neutralising monoclonal antibody, palivizumab, has been developed for administration to target groups on a monthly basis during the RSV season [25]. However, this drug is limited to high-risk infants, the cost prohibits its use in low- and middle-income countries and the data on effectiveness of the drug in children at high risk other than infants born at gestational age < 33 weeks and in children with chronic lung and heart diseases are limited [26]. The demonstrated high disease burden of RSV infection has created a longstanding interest in RSV vaccines. Approximately 60 RSV vaccine candidates are in preclinical to phase III clinical trials [27,28], with potential target groups including elderly people, pregnant women and infants. A vaccine is expected to enter the market within 5–10 years, presumably by 2025 [29]. As natural infection provides only limited protective immunity owing to evolution of the surface protein G and alternating dominance of antigenic groups A and B [30], most of the vaccine candidates target the fusion protein F, which is cross-reactive across RSV subtypes [27]. To circumvent issues with alternating strains, it has been also suggested to consider inclusion of both RSV A and B in a future RSV vaccine [30]. To plan optimal future vaccination strategies, it is critically important to understand who is affected by RSV and to identify which groups are at risk of more severe RSV infection requiring hospitalisation or intensive care. RSV infection is not notifiable in the European Union (EU) and European Economic Area (EEA), except in Ireland, but many countries have a long tradition of reporting laboratory-confirmed RSV infections at national and international level. The European Influenza Surveillance Network (EISN) collects RSV data for the purpose of interpreting the reports of influenza-like-illness (ILI); these data can also be used to analyse seasonality of RSV [31]. Inter-country comparative analysis of seasonal circulation of RSV across Europe is lacking as most of the published literature focuses on individual countries. Our study describes the seasonality of RSV in 15 countries in the EU/EEA, specifically the start and peak of the season, length of the season and geographical spread, as a baseline description of RSV circulation in Europe. We further aimed to test if the data reported through influenza surveillance systems in use in EU/EEA countries are appropriate to analyse RSV seasonality, including more countries and a more detailed analysis than previous studies.Peer Reviewe

Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA) alone.</p> <p>Aims</p> <p>The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR).</p> <p>Methods</p> <p>Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC) before PCR amplification (LightCycler) and melting point analysis.</p> <p>Results</p> <p>The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation.</p> <p>Conclusion</p> <p>CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.</p

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: A multinational self-controlled case series in Europe

Background: The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: A European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases