Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium

Funding text The authors are grateful for the vital contributions of the participating study volunteers, clinicians, nurses, and laboratory technicians at the Surrey study site. The work by Roberto Leone, laboratory technician at Humanitas Clinical and Research Center, is gratefully acknowledged. Finally, they thank Ellen Oe (GSK) for scientific writing assistance. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115308, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. The contribution of the European Commission to the Advanced Immunization Technologies (ADITEC) project (grant agreement n° 280873) is also gratefully acknowledged. Publisher Copyright: © 2019, The Author(s).Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.Peer reviewe

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

A comprehensive fracture prevention strategy in older adults : The European union geriatric medicine society (EUGMS) statement

Published also in Aging Clinical and Experimental Research, Vol.28, No.4, WOS: 000379034800030Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest group on falls and fracture prevention of the European union geriatric medicine society (EUGMS), in collaboration with the International association of gerontology and geriatrics for the European region (IAGG-ER), the European union of medical specialists (EUMS), the Fragility fracture network (FFN), the International osteoporosis foundation (IOF) - European society for clinical and economic aspects of osteoporosis and osteoarthritis (ECCEO), outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people. (C) 2016 Published by Elsevier Masson SAS.Peer reviewe

Sequence variant at 4q25 near PITX2 associates with appendicitis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesAppendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10(-11)). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk

Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesPersistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10-8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.Netherlands Organization for Scientific Research NWO Brain & Cognition 433-09-228 European Research Council ERC-ADG-2014-671084 INSOMNIA Netherlands Scientific Organization (NWO) VU University (Amsterdam, the Netherlands) Dutch Brain Foundation Helmholtz Zentrum Munchen - German Federal Ministry of Education and Research state of Bavaria German Migraine & Headache Society (DMKG) Almirall AstraZeneca Berlin Chemie Boehringer Boots Health Care GlaxoSmithKline Janssen Cilag McNeil Pharma MSD Sharp Dohme Pfizer Institute of Epidemiology and Social Medicine at the University of Munster German Ministry of Education and Research (BMBF) German Restless Legs Patient Organisation (RLS Deutsche Restless Legs Vereinigung) Swiss RLS Patient Association (Schweizerische Restless Legs Selbsthilfegruppe

Similar decline in mortality rate of older persons with and without type 2 diabetes between 1993 and 2004 the Icelandic population-based Reykjavik and AGES-Reykjavik cohort studies.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.A decline in mortality rates due to cardiovascular diseases and all-cause mortality has led to increased life expectancy in the Western world in recent decades. At the same time, the prevalence of type 2 diabetes, a disease associated with a twofold excess risk of cardiovascular disease and mortality, has been increasing. The objective of this study was to estimate the secular trend of cardiovascular and all-cause mortality rates in two population-based cohorts of older persons, with and without type 2 diabetes, examined 11 years apart.1506 participants (42% men) from the population-based Reykjavik Study, examined during 1991-1996 (median 1993), mean age 75.0 years, and 4814 participants (43% men) from the AGES-Reykjavik Study, examined during 2002-2006 (median 2004), mean age 77.2 years, age range in both cohorts 70-87 years. The main outcome measures were age-specific mortality rates due to cardiovascular disease and all causes, over two consecutive 5.7- and 5.3-year follow-up periods.A 32% decline in cardiovascular mortality rate and a 19% decline in all-cause mortality rate were observed between 1993 and 2004. The decline was greater in those with type 2 diabetes, as illustrated by the decline in the adjusted hazard ratio of cardiovascular mortality in individuals with diabetes compared to those without diabetes, from 1.88 (95% CI 1.24-2.85) in 1993 to 1.46 (95% CI 1.11-1.91) in 2004. We also observed a concurrent decrease in major cardiovascular risk factors in both those with and without diabetes. A higher proportion of persons with diabetes received glucose-lowering, hypertensive and lipid-lowering medication in 2004.A decline in cardiovascular and all-cause mortality rates was observed in older persons during the period 1993-2004, in both those with and without type 2 diabetes. This decline may be partly explained by improvements in cardiovascular risk factors and medical treatment over the period studied. However, type 2 diabetes still persists as an independent risk factor for cardiovascular mortality.National Institute of Health/N01-AG-1-2100 NIA Intramural Research Program Icelandic Heart Association (Hjartavernd) Icelandic Parliament (Althingi

The association of degree of polypharmacy before and after among hospitalised internal medicine patients and clinical outcomes: a retrospective, population-based cohort study

OBJECTIVES: To determine the prevalence and incidence of polypharmacy/hyperpolypharmacy and which medications are most prescribed to patients with varying burden of polypharmacy. DESIGN: Retrospective, population-based cohort study. SETTING: Iceland. PARTICIPANTS: Including patients (≥18 years) admitted to internal medicine services at Landspitali – The National University Hospital of Iceland, between 1 January 2010 with a follow-up of clinical outcomes through 17 March 2022. MAIN OUTCOME MEASURES: Participants were categorised into medication use categories of non-polypharmacy (&lt;5), polypharmacy (5–10) and hyperpolypharmacy (&gt;10) based on the number of medications filled in the year predischarge and postdischarge. The primary outcome was prevalence and incidence of new polypharmacy. Secondary outcomes were mortality, length of hospital stay and re-admission. RESULTS: Among 85 942 admissions (51% male), the median (IQR) age was 73 (60–83) years. The prevalence of preadmission non-polypharmacy was 15.1% (95% CI 14.9 to 15.3), polypharmacy was 22.9% (95% CI 22.6 to 23.2) and hyperpolypharmacy was 62.5% (95% CI 62.2 to 62.9). The incidence of new postdischarge polypharmacy was 33.4% (95% CI 32.9 to 33.9), and for hyperpolypharmacy was 28.9% (95% CI 28.3 to 29.5) for patients with preadmission polypharmacy. Patients with a higher level of medication use were more likely to use multidose drug dispensing and have a diagnosis of adverse drug reaction. Other comorbidities, including responsible subspeciality and estimates of comorbidity and frailty burden, were identical between groups of varying polypharmacy. There was no difference in length of stay, re-admission rate and mortality. CONCLUSIONS: Preadmission polypharmacy/hyperpolypharmacy and postdischarge new polypharmacy/hyperpolypharmacy is common amongst patients admitted to internal medicine. A higher level of medication use category was not found to be associated with demographic, comorbidity and clinical outcomes. Medications that are frequently inappropriately prescribed were among the most prescribed medications in the group. An increased focus on optimising medication usage is needed after hospital admission. TRIAL REGISTRATION NUMBER: NCT05756400

Characterization of Antioxidant Potential of Seaweed Extracts for Enrichment of Convenience Food

In recent years, there has been a growing interest in natural antioxidants as replacements of synthetic compounds because of increased safety concerns and worldwide trend toward the usage of natural additives in foods. One of the richest sources of natural antioxidants, nowadays largely studied for their potential to decrease the risk of diseases and to improve oxidative stability of food products, are edible brown seaweeds. Nevertheless, their antioxidant mechanisms are slightly evaluated and discussed. The aims of this study were to suggest possible mechanism(s) of Fucus vesiculosus antioxidant action and to assess its bioactivity during the production of enriched rye snacks. Chemical and cell-based assays indicate that the efficient preventive antioxidant action of Fucus vesiculosus extracts is likely due to not only the high polyphenol content, but also their good Fe2+-chelating ability. Moreover, the data collected during the production of Fucus vesiculosus-enriched rye snacks show that this seaweed can increase, in appreciable measure, the antioxidant potential of enriched convenience cereals. This information can be used to design functional foods enriched in natural antioxidant ingredients in order to improve the health of targeted consumers

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesA meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.Swedish Research Council Knut and Alice Wallenberg Foundation AFA Foundation Swedish Brain Foundatio

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P= 1.2 × 10−4). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7–2.3 for lung cancer(LC;P= 4.0 × 10−4), chronic obstructive pulmonary disease (COPD;P= 9.3 × 10−4), peripheral artery disease (PAD;P= 0.090) and abdominal aortic aneurysms (AAAs; P= 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49,P= 2.2 × 10−4), COPD (OR = 3.22,P= 2.9 × 10−4), PAD (OR = 3.47,P= 9.2 × 10−3) and AAA (OR = 6.44, P= 6.3 × 10−3). Joint analysis of the four smoking-related diseases reveals significant association (P= 6.8 × 10−5), particularly for early-onset cases (P=2.1 × 10−7). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation