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• Increased inflammatory response is associated with childhood trauma and cognitive impairments. • Latent variable of inflammation mediates the association between physical neglect, inflammatory response and cognition. • Genetic risk for schizophrenia moderates the direct pathway between physical neglect and cognition. Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants. [ABSTRACT FROM AUTHOR]

Background & Aims Celiac disease is an immune-mediated enteropathy characterized with high heterogeneity in presentation among genetically predisposed individuals. In recent years, a change in the phenotypic presentation of celiac disease has been reported. We studied clinical presentation, from 1960 through 2015, in Ireland, which has a high incidence of celiac disease. Methods We performed a retrospective analysis of medical charts from patients diagnosed with celiac disease at 5 secondary referral centers in Ireland from 1960 through 2015 (n = 749; median age, 56 years; age range, 18–91 years). The cohort was divided into 5 groups based on year of diagnosis (≤1985, 1986–1995, 1996–2005, 2006–2010, or 2011 and later). We collected findings from clinical presentation at diagnosis; serology tests; small intestinal biopsy analyses; and patients’ demographic, clinical, and family data. Presentations at diagnosis were classified according to the Oslo criteria as follows: classical (patients presenting with malabsorption), nonclassical (no signs or symptoms of malabsorption at presentation), or subclinical (below the threshold of clinical detection). The primary outcome was change in clinical presentation of celiac disease over time. Results Of the 749 patients studied, 512 were female and 237 were male (ratio of 2.2:1). Female patients were diagnosed at younger ages than male patients (42 vs 47 years, respectively; P = .004), and had more immune-mediated conditions than male patients (35.7% for female patients vs 21.5% for male patients; P < .001). For patients diagnosed as adults (after the age of 18 years), the median age of diagnosis increased from 34.0 years during the period ≤1985 to median ages of 44–46 years after 1985 ( P < .002). A smaller proportion of patients presented with classical features of celiac disease after 2010 (48.4%) than ≤1985 (85.2%); the proportion of patients with nonclassical or subclinical celiac disease increased from 14.8% ≤1985 to 51.6% after 2010 ( P = .006 for each). Biopsies categorized as Marsh 3c decreased, from 52.2% in the period 1996–2005 to 22.5% in the period after 2010 ( P = .003). The prevalence of associated thyroid disease has decreased during the study period, from 36.6% ≤1985 to 17.1% after 2010 ( P = .039), whereas body mass index at diagnosis increased from 21.5 kg/m 2 ≤1985 to 24.8 kg/m 2 after 2010 ( P < .001). Conclusions We found the clinical presentation of celiac disease changed significantly in Ireland from 1960 through 2015. The age of presentation in adulthood increased over this time period, as did the proportions of patients with nonclassical or subclinical disease. [ABSTRACT FROM AUTHOR]

A letter to the editor and a response is presented regarding the development of algorithms based on cytokine gene expression in the March 2011 issue.

The article comments on the research by J.A. Kellum and colleagues on the systemic cytokine response to pneumonia in a cohort study of 1886 subjects hospitalized for community-acquired pneumonia. The authors concludes that mortality is highest when both anti-inflammatory and pro-inflammatory cytokine levels are high. It mentions that it may worthwhile reconsidering the conclusions of the authors that an unbalanced cytokine response to infection is uncommon and alternatively considering whether sepsis-related mortality in humans is related to an uncompensated anti-inflammatory response to infection.

The Inhibitor of NF Kappa B like (IKBL/NFkBIL1) gene encodes a protein homologous to members of the IKB family. IKBL is situated in the MHC and a number of different polymorphisms in the gene have been associated with diseases such as Myocardial Infarction, Rheumatoid Arthritis, Diabetes Mellitus, Celiac Disease and Crohns Disease. The function of IKBL protein has not yet been reported. We have demonstrated, by both EMSA and Luciferase Assays, that over-expression of IKBL inhibits the activity of NF kappa B. We have further demonstrated that IKBL inhibits NF kappa B activation by both TLR 2 and TLR 4 pathways. mRNA and protein expression of IL8, a NF kappa B regulated pro-inflammatory cytokine, was also inhibited by IKBL. We show that IKBL and HDAC3 may co-localise in the nucleus offering a possible mechanism since HDAC3 is a known regulator of transcription factors. Our study suggests that IKBL is a member of the novel inhibitors of NF kappa B such as MAIL that are located in the nucleus and may inhibit the activity of NF kappa B by regulating the activity of other proteins that bind to NF kappa B within the nucleus. [ABSTRACT FROM AUTHOR]

Background: The risk of skin cancer is determined by environmental factors like ultraviolet radiation (UVR), personal habits like time spent outdoors and genetic factors. This review aimed to survey existing studies in gene–environment (GxE) interaction on skin cancer risk, and report on GxE effect estimates. Methods: We searched Embase, Medline (Ovid) and Web of Science (Core Collection) and included only primary research that reported on GxE on the risk of the three most common types of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. Quality assessment followed the Newcastle–Ottawa Scale. Meta‐analysis was not possible because no two studies examined the same interaction. This review was registered on PROSPERO (CRD42021238064). Results: In total 260 records were identified after exclusion of duplicates. Fifteen studies were included in the final synthesis—12 used candidate gene approach. We found some evidence of GxE interactions with sun exposure, notably, with MC1R, CAT and NOS1 genes in melanoma, HAL and IL23A in BCC and HAL and XRCC1 in SCC. Conclusion: Sun exposure seems to interact with genes involved in pigmentation, oxidative stress and immunosuppression, indicating that excessive UV exposure might exhaust oxidative defence and repair systems differentially, dependent on genetic make‐up. Further research is warranted to better understand skin cancer epidemiology and develop sun exposure recommendations. A genome‐wide approach is recommended as it might uncover unknown disease pathways dependent on UV radiation. [ABSTRACT FROM AUTHOR]

Background and objectives Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-human leucocyte antigen (HLA) CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. The authors hypothesised that there are additional shared risk alleles, and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. Materials and methods The authors performed a meta-analysis of two published GWAS on CD (4533 cases and 10 750 controls) and RA (5539 cases and 17 231 controls), and genotyping the top associated single-nucleotide polymorphisms (SNPs) in independent set of 2169 CD cases and 2255 controls, and 2845 RA cases and 4944 controls. The authors used the gene-expression dataset of peripheral blood mononuclear cell of 1469 individuals to investigate the genotype-expression correlation of associated variants. The authors also analysed the results using various pathway analysis tools. Results Above already established six shared loci, eight additional SNPs demonstrated p<5×10 in a combined analysis of all 50 266 samples. From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium block around the SNP. Pathway analysis tools indicate remarkable overrepresentation of T cell signalling molecules among the shared genes. Conclusions The authors identified 14 shared CD-RA risk loci. These associations implicate antigen presentation and T cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases. [ABSTRACT FROM PUBLISHER]

Background & Aims: Celiac disease (CD) is a common chronic disorder of the small intestine, resulting from aberrant cellular responses to gluten peptides, and often remains undiagnosed. It is a complex genetic disorder, although 95% of the patients carry the risk heterodimer human leukocyte antigen (HLA)-DQ2. Genome-wide association studies on CD have identified 9 non-HLA loci that also contribute to CD risk, most of which are shared with other immune-related diseases. Our aim is to predict the genetic risk for CD using HLA and non-HLA risk alleles. Methods: We selected 10 independent polymorphisms in 2,308 cases and 4,585 controls from Dutch, UK, and Irish populations and categorized the individuals into 3 risk groups, based on their HLA-DQ2 genotype. We used the summed number of non-HLA risk alleles per individual to analyze their cumulative effect on CD risk, adjusting for gender and population group in logistic regression analysis. We validated our findings in 436 Italian cases and 532 controls. Results: CD cases carried more non-HLA risk alleles than controls: individuals carrying ≥13 risk alleles had a higher CD risk (odds ratio, 6.2; 95% confidence interval, 4.1–9.3) compared with those carrying 0–5 risk alleles. Combining HLA and non-HLA risk genotypes in one model increases sensitivity by 6.2% compared with using only HLA for identification of high-risk individuals with slight decrease in specificity. Conclusions: We can use non-HLA risk factors for CD to improve identification of high-risk individuals. Our risk model is a first step toward better diagnosis and prognosis in high-risk families and population-based screening. [Copyright &y& Elsevier]

Psoriasis is an inflammatory disease of the skin and joints with a prevalence of up to 2% in European populations. IL18 is a pro-inflammatory cytokine, which promotes Th1 T-cell development by inducing γ-interferon. Genetic variation in this gene has been implicated in the pathogenesis of several autoimmune conditions, including inflammatory bowel disease, type 1 diabetes, atopic eczema and asthma. There is some evidence that IL18 may play a role in psoriasis. rs6840968 is a single nucleotide polymorphism (SNP) within the IL2/IL21 region of chromosome 4q27, which has recently been associated with Type I Diabetes, Rheumatoid Arthritis, Graves' Disease and Celiac Disease. The functional relevance of the IL2 and IL21 genes in inflammatory and autoimmune conditions is highlighted by the role of these cytokines in T-cell activation and development. We have genotyped IL18 rs187238 (IL18-137) and IL2/IL21 rs6840968 in 231 ethnically uniform Irish patients with psoriasis and 871 Irish controls. Both loci conformed to HWE in both populations. Both loci showed evidence of association with psoriasis in this population (IL18 rs187238, Odds Ratio 0.61 [0.44 - 0.86], χ² = 8.99, P = 0.0027; IL2/IL21 rs6840978, Odds Ratio 0.67 [0.48 - 0.92], χ² = 6.41, P = 0.01134, for carrier status of the minor allele in both cases). This latter value for IL2/IL21 rs6840978 is similar to a recent study of psoriasis susceptibility for the same SNP in UK and US populations (OR = 0.77 [0.62 - 0.95] and OR = 0.81 [0.68 - 0.96], respectively), for the same allele and direction, substantiating existing evidence that the IL2/IL21 haplotype block represents a risk factor for the development of psoriasis. [ABSTRACT FROM AUTHOR]

High levels of inter-population differentiation at the coagulation F13B locus may be interpreted as evidence of localised natural selection. However, a neutral explanation is also possible. We re-sequenced 4.6kb of the gene, encompassing all exons, splice junctions and 1.4kb of the promoter in African, European and Asian samples. This revealed three major lineages, which correspond to the common protein alleles and differ from each other at a non-synonymous substitution in exon 3 and a novel splice acceptor in intron K. There is evidence that these lineages are not functionally equivalent, a pre-requisite for the action of natural selection. Furthermore, our case-control analyses confirm that variability at this locus modifies susceptibility to myocardial infarct (OR = 1.88 [1.18 - 2.99], P = 0.0047). When our sequence data were combined with additional sequences from the SeattleSNPs database, Fu and Li's test for selection suggested a significant departure from neutral expectations (D* = -2.92556, P = 0.02). Patterns of extended haplotype homozygosity from HapMap populations also provide evidence of adaptation (P < 0.05). Thus, several independent lines of evidence suggest that the F13B locus has been subjected to localised natural selection during recent human evolution. Possible causes of this selection are discussed. [ABSTRACT FROM AUTHOR]

The article presents information on celiac disease. The disease, also known as celiac spure and gluten-sensitive enteropathy, is an autoimmune condition caused by ingesting one of several proteins found in wheat, barley and rye which are gliadins, hordeins and secalins. Symptoms of the disease include diarrhea and depression. According to the author, the ingested proteins may have epitopes with them capable of activating T cells. The author states that the pattern of inheritance of celiac disease is complex.

Ankylosing spondylitis (AS) is a seronegative, chronic inflammatory arthritis with high genetic burden. A strong association with HLA-B27 has long been established, but to date its contribution to disease aetiology remains unresolved. Recent insights through genome wide studies reveal an increasing array of immunogenetic risk variants extraneous to the HLA complex in AS cohorts. These genetic traits build a complex profile of disease causality, highlighting several molecular pathways associated with the condition. This and other evidence strongly implicates T-cell-driven pathology, revolving around the T helper 17 cell subset as an important contributor to disease. This prominence of the T helper 17 cell subset has presented the opportunity for therapeutic intervention through inhibition of interleukins 17 and 23 which drive T helper 17 activity. While targeting of interleukin 17 has proven effective, this success has not been replicated with interleukin 23 inhibition in AS patients. Evidence points to significant genetic diversity between AS patients which may, in part, explain the observed refractoriness among a proportion of patients. In this review we discuss the impact of genetics on our understanding of AS and its relationship with closely linked pathologies. We further explore how genetics can be used in the development of therapeutics and as a tool to assist in the diagnosis and management of patients. This evidence indicates that genetic profiling should play a role in the clinician's choice of therapy as part of a precision medicine strategy towards disease management. [ABSTRACT FROM AUTHOR]

Objectives: Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous‐only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models. Methods: Genome‐wide meta‐analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single‐nucleotide polymorphism (SNP)–based heritability estimate (h2SNP) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation. Results: We identified a novel genome‐wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10−9), and key pathways that differentiate PsA from PsC, including NF‐κB signaling (adjusted P = 1.4 × 10−45) and Wnt signaling (adjusted P = 9.5 × 10−58). The heritability of PsA in this cohort was found to be moderate (h2SNP = 0.63), which was similar to the heritability of PsC (h2SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data. Conclusion: Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care. [ABSTRACT FROM AUTHOR]

Fat mass and obesity-associated (FTO) is the strongest genetic determinant of obesity identified to date. Dietary fat is a key environmental factor that may interact with genotype to affect risk of obesity and metabolic syndrome (MetS). This study investigated associations among FTO rs9939609, obesity measures, and MetS phenotypes in adults and determined potential modulation by dietary fat intake at baseline and after a 7.5-y follow-up when MetS cases and controls were selected. FTO rs9939609 genotype, biochemical, dietary, and lifestyle measurements were determined in the LIPGENE-SU.VI.MAX study (n = 1754). FTO rs9939609 A allele carriers had a higher risk of being overweight or obese [OR = 1.66 (95% CI: 1.07, 2.57); P = 0.02] and of having a larger abdominal circumference [OR = 1.42 (95% CI: 1.01, 1.99); P = 0.04] compared with the TT homozygotes. These associations were independent of physical activity and energy intake and were maintained over the follow-up period, particularly in the MetS individuals. High dietary SFA intake (⩾15.5% energy) and a low dietary PUFA:SFA intake ratio (<0.38) further accentuated the risk of having a BMI ⩾25 kg/m2 and being abdominally obese. Non-risk allele carriers appeared to be unresponsive to dietary SFA intake or to the dietary PUFA:SFA intake ratio with respect to obesity measures. In conclusion, FTO rs9939609 was associated with obesity measures, especially in those with the MetS, which was further exacerbated by high dietary SFA intake at baseline and 7.5 y later. These data indicate important novel modulation of genetic risk by dietary fat exposure in individuals with increased cardiometabolic risk. [ABSTRACT FROM AUTHOR]

Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: β indirect −0.0234, 95% CI: −0.0573 to −0.0074; CTQ physical neglect: β indirect = −0.0316, 95% CI: −0.0741 to −0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (β indirect = −0.0618, 95% CI: −0.1523 to −0.285). This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6′s association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted. [ABSTRACT FROM AUTHOR]

Individual genetic architecture is considered central to susceptibility and progression of disease in chronic pancreatitis. The study aimed to evaluate the presence of common pancreatic gene mutations in a defined cohort of idiopathic and alcohol-induced chronic pancreatitis patients in Ireland. The study comprised patients with idiopathic and alcohol-induced chronic pancreatitis and historic controls. Variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, cationic trypsinogen (PRSS1) gene and serine protease inhibitor kazal type-1 (SPINK1) gene, were assessed by Taqman© genotyping assay. Of n = 126 patients and n = 167 controls, mutations were detected in 23 (20%) and in 10 (6%) respectively (P < 0.001). The majority of mutations found were in the SPINK1 gene variant N34S (13%) which increased disease risk almost six-fold (OR 5.9). Neither CFTR severe mutation (F508del) (P = 0.649) nor mild variant (R117H) (P = 0.327) were over-represented amongst patients compared to control subjects. PRSS1 variants were not detected in either patient or control subjects. There was a significant prevalence of chronic pancreatitis-associated gene mutations in this well-phenotyped cohort. In patients with alcohol-related or idiopathic chronic pancreatitis, the possibility of genetic mutations in the SPINK 1 gene should be considered as a contributing aetiology factor. [ABSTRACT FROM AUTHOR]

Collagens and elastin are 'building blocks' of tissues and extracellular matrix. Mutations in these proteins cause severe congenital syndromes. Adverse genetic variations may accelerate the aging process in adults contributing to premature morbidity, disability and/or mortality. Favorable variants may contribute to longevity and/or healthy aging, but this is much less studied. We reviewed the association between variation in the genes of collagens and elastin and premature aging, accelerated aging, age-related diseases and/or frailty; and the association between genetic variation in those and longevity and/or healthy aging in humans. A systematic search was conducted in MEDLINE and other online databases (OMIM, Genetics Home Reference, Orphanet, ClinVar). Results suggest that genetic variants lead to aging phenotypes of known congenital disease, but also to association with common age-related diseases in adults without known congenital disease. This may be due to the variable penetrance and expressivity of many variants. Some collagen variants have been associated with longevity or healthy aging. A limitation is that most studies had <1000 participants and their criterion for statistical significance was p < 0.05. Results highlight the importance of adopting a lifecourse approach to the study of the genomics of aging. Gerontology can help with new methodologies that operationalize biological aging. • Genetic mutations in collagens and elastin lead to lethal congenital diseases. • Mutations can also cause disease and disability that accelerates the aging process. • There is some evidence for genetic variations being associated with healthy aging. • Research on aging genomics requires a health determinants and lifecourse approach. • Gerontology can help with methodologies that operationalize biological aging. [ABSTRACT FROM AUTHOR]

Objective Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. Methods Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. Results Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 × 10−8 by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.15-1.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris ( P = 5.89 × 10−2; OR 1.13 [95% CI 1.00-1.28]), indicating a role in the skin manifestations of psoriasis. Conclusion Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cell-mediated diseases. [ABSTRACT FROM AUTHOR]

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-?B signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. [ABSTRACT FROM AUTHOR]

Summary: Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system. [ABSTRACT FROM AUTHOR]

The article discusses a study of the association between the occurrence of hospital-acquired pneumonia (HAP) after lung resection surgery and characteristic expression of cytokines. Sixty patients with a thoracotomy were included in the study in Dublin, Ireland. It cites the immediate alteration of cytokine gene expression after surgery in patients who developed HAP. Results show a link between the onset of infection and a deficiency in the expression of genes encoding proinflammatory proteins.

Abstract: Introduction: The occurrence of severe sepsis may be associated with deficient pro-inflammatory cytokine production. Transforming growth factor β-1 (TGFβ-1) predominantly inhibits inflammation and may simultaneously promote IL-17 production. Interleukin-17 (IL-17) is a recently described pro-inflammatory cytokine, which may be important in auto-immunity and infection. We investigated the hypothesis that the onset of sepsis is related to differential TGFβ-1 and IL-17 gene expression. Methods: A prospective observational study in a mixed intensive care unit (ICU) and hospital wards in a university hospital. Patients (59) with severe sepsis; 15 patients with gram-negative bacteraemia but without critical illness and 10 healthy controls were assayed for TGFβ-1, IL-17a, IL-17f, IL-6 and IL-1β mRNA in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR and serum protein levels by ELISA. Results: TGFβ-1 mRNA levels are reduced in patients with bacteraemia and sepsis compared with controls (p =0.02). IL-6 mRNA levels were reduced in bacteraemic patients compared with septic patients and controls (p =0.008). IL-1β mRNA levels were similar in all groups, IL-17a and IL-17f mRNA levels are not detectable in peripheral blood mononuclear cells. IL-6 protein levels were greater in patients with sepsis than bacteraemic and control patients (p <0.0001). Activated TGFβ-1 and IL-17 protein levels were similar in all groups. IL-1β protein was not detectable in the majority of patients. Conclusions: Down regulation of TGFβ-1 gene transcription was related to the occurrence of infection but not the onset of sepsis. Interleukin-17 production in PBMC may not be significant in the human host response to infection. [Copyright &y& Elsevier]

The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, and MetS risk and whether plasma fatty acids, a biomarker of dietary fatty acids, modulate this. LEPR polymorphisms (rs10493380, rsl 137100, rsl 137101, rs12067936, rs1805096, rs2025805, rs3790419, rs3790433, rs6673324, and rs8179183), biochemical measurements, and plasma fatty acid profiles were determined in the LIPGENE-SU.Vl.MAX study of MetS cases and matched controls In = 1754). LEPR rs3790433 GG homozygotes had increased MetS risk compared with the minor A allele carriers Eodds ratio (OR) = 1.65; 95% Cl: 1.05-2.57; P= 0.0281, which may be accounted for by their increased risk of elevated insulin concentrations (OR 2.40; 95% Cl: 1.28-4.50; P= 0.006) and insulin resistance (OR = 2.15; 95% Cl: 1.18-3.90; P= 0.012). Low (less than median) plasma (n-3) and high (n-6) PUFA status exacerbated the genetic risk conferred by GG homozygosity to hyperinsulinemia (OR 2.92-2.94) and insulin resistance (OR 3.40-3.47). Interestingly, these associations were abolished against a high (n-3( or low (n-6) PUFA background. Importantly, we replicated some of these findings in an independent cohort. Homozygosity for the LEPR rs3790433 G allele was associated with insulin resistance, which may predispose to increased MetS risk. Novel gene-nutrient interactions between LEPR rs3790433 and PUFA suggest that these genetic influences were more evident in individuals with (ow plasma (n-3( or high plasma (n-6) PUPA. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) plays a key role in body weight regulation and glucose homeostasis, 2 important determinants of metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genotype to affect MetS risk. In this study, we investigated the relationship between STAT3 polymorphisms and MetS phenotypes and determined potential interactions with dietary fatty acids. STAT3 polymorphisms (rs8069645, rs744166, rs2306580, rs2293152, and rs10530050), biochemical measurements, and dietary fat composition were determined in the LIPGENE-SU.Vl.MAX study of MetS cases and matched controls (n = 1754). STAT3 polymorphisms were not associated with MetS risk. However, minor G allele carriers for rs8069645, rs744166, and rs1053005 and major GG homozygotes for rs2293152 had increased risk of abdominal obesity compared with noncarriers [odds ratio (OR) = 2.22, P= 0.0005; OR = 2.08, P= 0.0017; OR = 2.00, P= 0.0033; and OR = 1.95, P= 0.028, respectively[. The number of risk alleles additively increased obesity risk (P = 0.00031. Dietary SFA intake exacerbated these effects; among all participants with the highest SFA intake (⩾15.5% of energy), individuals carrying >2 risk alleles had further increased risk of obesity (OR = 3.30; 95% Cl = 1.50-7.28; P= 0.0079) compared with those carrying ⩽1 risk allele. Interaction analysis confirmed this gene-nutrient interaction whereby increasing SFA intake was predictive of increased waist circumference (P = 0.038). In conclusion, STAT3 gene polymorphisms influenced the risk of abdominal obesity, which is modulated by dietary SFA intake, suggesting novel gene-nutrient interactions. [ABSTRACT FROM AUTHOR]

Background: Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. Methods: We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent–child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects. Results: Three celiac disease loci — RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25 — were associated with type 1 diabetes (P<1.00×10−4). The 32-bp insertion–deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81×10−8) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease. Conclusions: A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases. N Engl J Med 2008;359:2767-77. [ABSTRACT FROM AUTHOR]

The development and progression of severe sepsis is related to a deficiency in pro-inflammatory cytokine production, characterised by lesser IFNγ levels, which are not explained by variations in levels of the main putative regulator of IFNγ, namely IL-12. As alternative regulators of IFNγ may be of greater importance in human sepsis, we investigated the hypothesis that the development of severe sepsis is related to variations in IL-18, IL-23 and IL-27 gene expression. A prospective observational trial in a mixed intensive care unit (ICU) and hospital wards in a university teaching hospital. Sixty-two ICU patients with severe sepsis, 13 bacteraemic patients with no acute critical illness, and 10 healthy controls. All subjects were assayed for IL-18, IL-23 and IL-27 mRNA levels in peripheral blood. IL-27 mRNA levels distinguished between the three groups, with levels highest in the ICU group, intermediate in the bacteraemic group and lowest in the control group. IL-23 distinguished between the groups, with levels lowest in the ICU group. In late sepsis IL-23 and TNFα mRNA levels were directly related. IL-18 mRNA levels did not distinguish between the patient groups. We conclude that the deficient pro-inflammatory response in patients with sepsis is expansive and includes deficient IL-23 and excessive IL-27 gene expression. This provides further evidence that upregulation of a cytokine-based immune response is beneficial in sepsis. [ABSTRACT FROM AUTHOR]

Psoriasis is a common skin disease with an etiology consistent with a multifactorial trait. Several psoriasis susceptibility loci are known, a number of which are also implicated in a predisposition to atopic dermatitis (AD), including the epidermal differentiation complex on chromosome 1q21. It has recently been shown in several replicate studies that prevalent null alleles for the filaggrin gene (FLG) on 1q21 are an important genetic factor in AD. Here, we examined the role of these FLG variants in psoriasis using case:control association studies comparing Irish and UK psoriasis cohorts (combined n=691) to ethnically matched populations (combined n=2117). No association was present for the two common European FLG mutations R501X and 2282del4 (combined χ2 P=0.989). In addition, the 3′ end of the FLG open-reading frame was sequenced in a number of patients with differing types of psoriasis (plaque, guttate, palmoplantar, and late-onset), which excluded the possibility of a gain-of-function frameshift mutation such as those found in loricrin or certain keratin genes. These data suggest that FLG mutations are unlikely to be involved in genetic susceptibility to psoriasis and implies that there may be within-locus heterogeneity in chromosomal regions involved in both AD and psoriasis.Journal of Investigative Dermatology (2007) 127, 1878–1882; doi:10.1038/sj.jid.5700817; published online 5 April 2007 [ABSTRACT FROM AUTHOR]

Introduction: Axial spondyloarthritis (AxSpA) is a chronic inflammatory condition primarily affecting the axial skeleton. Peripheral features such as peripheral arthritis (PA) and dactylitis are common in AxSpA disease. This study aimed to investigate the independent impact of these manifestations on patient presentation and disease outcomes within an Irish AxSpA cohort., Methods: 912 Irish AxSpA patients were analyzed in this study. Disease outcomes in patients with and without peripheral arthritis or dactylitis were compared using univariate and multivariate methods. The prevalence of extra-spinal manifestations was further assessed in relation to AxSpA disease duration., Results: 30.2% of patients reported PA, while 6.6% had dactylitis. PA and dactylitis were strongly linked, with 70% of patients presenting with dactylitis also showing features of PA. Psoriasis was more common in both patients with PA (OR 2.2, P < 0.001) and dactylitis (OR 3.38, P < 0.001). Dactylitis, but not PA was strongly linked to uveitis (OR 2.91, P < 0.001) and inflammatory bowel disease (OR 3.15, P < 0.001), while PA was associated with worse patient functioning and reduced quality of life. PA, but not dactylitis was linked with increased AxSpA disease duration., Discussion: Despite high concurrence of PA and dactylitis in AxSpA patients, each manifestation is independently associated with worse outcomes. While some of these overlapped, several outcomes are specific to either PA or dactylitis. Due to its strong association with uveitis and inflammatory bowel disease, an early presentation of dactylitis may represent a unique subset of patients and serve as a valuable predictive marker for the later onset of these conditions., (© 2024. The Author(s).)

Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related., (© 2023. The Author(s).)

Background: Both low-grade systemic inflammation and functional connectivity of the default mode network (DMN) during rest have recently been observed to mediate the association between childhood trauma (CT) and behavioural performance on an emotion recognition task. Whether inflammation also mediates the association between CT and functional connectivity of the DMN during social cognitive task performance is unknown., Methods: 51 patients with schizophrenia (SZ) or schizoaffective disorder (SZA) and 176 healthy participants completed a theory of mind (ToM) task during fMRI. IL-6 was measured in plasma using ELISA. DMN connectivity was measured during performance of the fMRI ToM task. To examine DMN connectivity, we selected 4 a priori seeds of the DMN, i.e., the medial prefrontal cortex (PFC), right lateral parietal (LP), left LP, and posterior cingulate cortex (PCC) according to the Harvard-Oxford Cortical and Subcortical Atlas (http://www.cma.mgh.harvard.edu/fsl&#95;atlas.html) as implemented in CONN., Results: Patients showed significantly increased DMN connectivity compared to healthy participants between each of the four seeds of the DMN and with other clusters in the brain. Across the entire sample, higher levels of IL-6 predicted increased connectivity between the mPFC and regions encompassing the cerebellum (<0.001 FWE). IL-6 mediated the association between physical neglect and weaker suppression of the posterior cingulate cortex (PCC) DMN seed -left precentral and postcentral gyrus (β INDIRECT  = .0170, CI: 0.0008 to.0506) connectivity during ToM performance., Discussion: This is the first study to our knowledge that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during ToM task performance. Consistent with our previous study that IL-6 mediated the association between early life stress exposure and reduced connectivity of the DMN during rest, here IL-6 mediated the association between early life stress and increased connectivity of the DMN during ToM based cognitive processing. These findings suggest a biological mechanism for how chronic stress impacts social cognitive processing., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (© 2022 The Authors.)

Vitamin D is essential for good health. Dermal vitamin D production is dependent on environmental factors such as season and latitude, and personal factors such as time spent outdoors and genetics. Varying heritability of vitamin D status by season has been reported, suggesting that gene-environment interactions (GxE) may play a key role. Thus, understanding GxE might significantly improve our understanding of determinants of vitamin D status. The objective of this review was to survey the existing methods in GxE on vitamin D studies and report on GxE effect estimates. We searched the Embase, Medline (Ovid), and Web of Science (Core Collection) databases. We included only primary research that reported on GxE effects on vitamin D status using 25-hydroxyvitamin D as a biomarker. Sun exposure was the only environmental exposure identified in these studies. The quality assessment followed the Newcastle-Ottawa Scale for cohort studies. Seven studies were included in the final narrative synthesis. We evaluate the limitations and findings of the available GxE in vitamin D research and provide recommendations for future GxE research. The systematic review was registered on PROSPERO (CRD42021238081).

Background : The current coronavirus disease 2019 (COVID-19) pandemic began in Ireland with the first confirmed positive case in March 2020. In the early stages of the pandemic clinicians and researchers in two affiliated Dublin hospitals identified the need for a COVID-19 biobanking initiative to support and enhance research into the disease. Through large scale analysis of clinical, regional, and genetic characteristics of COVID-19 patients, biobanks have helped identify, and so protect, at risk patient groups The STTAR Bioresource has been created to collect and store data and linked biological samples from patients with SARS-CoV-2 infection and healthy and disease controls. Aim : The primary objective of this study is to build a biobank, to understand the clinical characteristics and natural history of COVID-19 infection with the long-term goal of research into improved disease understanding, diagnostic tests and treatments. Methods : This is a prospective dual-site cohort study across two tertiary acute university teaching hospitals. Patients are recruited from inpatient wards or outpatient clinics. Patients with confirmed COVID-19 infection as well as healthy and specific disease control groups are recruited.  Biological samples are collected and a case report form detailing demographic and medical background is entered into the bespoke secure online Dendrite database. Impact : The results of this study will be used to inform national and international strategy on health service provision and disease management related to COVID-19. In common with other biobanks, study end points  evolve over time as new research questions emerge. They currently include patient survival, occurrence of severe complications of the disease or its therapy, occurrence of persistent symptoms following recovery from the acute illness and vaccine responses., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 O'Doherty L et al.)

Background: Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood., Methods: Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance., Results: Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, t max  = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, t max  = 4.40) (p < 0.05, family-wise error corrected across the whole brain at the cluster level)., Conclusions: These findings suggest that higher peripheral IL-6 levels predict altered neural response within brain regions involved in social cognition and emotion during facial emotion recognition. This is consistent with recent neuroimaging research on IL-6 and suggesting a possible neural mechanism by which this cytokine might affect facial emotion recognition accuracy., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: the role of innate immunity in human sepsis must be fully clarified to identify potential avenues for novel immune adjuvant sepsis therapies. Methods: A prospective observational study was performed including patients with sepsis (septic group), infection without sepsis (infection group), and healthy controls (control group) in the setting of acute medical wards and intensive care units in a 1000-bed university hospital. A total of 42 patients with sepsis, 30 patients with infection, and 30 healthy controls were studied. The differentiation states of circulating mucosal associated invariant T (MAIT) cells and Natural Killer T (NKT) cells were characterised as naive (CD45RA + , CD197 + ), central memory (CD45RA - , CD197 + ), effector memory (CD45RA - , CD197 - ), or terminally differentiated (CD45RA + , CD197 - ). The differentiation states of circulating gamma-delta T lymphocytes were characterised as naive (CD45RA + , CD27 + ), central memory (CD45RA - , CD27 + ), effector memory (CD45RA - , CD27 - ), or terminally differentiated (CD45RA + , CD27 - ). The expression of IL-12 and IL-23 receptors, the transcription factors T-Bet and RORγt, and interferon-γ and IL-17a were analysed. Results: MAIT cell counts were lower in the septic group ( p = 0.002) and the infection group ( p < 0.001) than in the control group. The MAIT cell T-Bet expression in the infection group was greater than in the septic group ( p = 0.012). The MAIT RORγt expression in the septic group was lower than in the control group ( p = 0.003). The NK cell counts differed in the three groups ( p < 0.001), with lower Natural Killer (NK) cell counts in the septic group ( p < 0.001) and in the infection group ( p = 0.001) than in the control group. The NK cell counts increased in the septic group in the 3 weeks following the onset of sepsis ( p = 0.028). In lymphocyte stimulation experiments, fewer NK cells expressed T-Bet in the septic group than in the infection group ( p = 0.002), and fewer NK cells expressed IFN-γ in the septic group than in the control group ( p = 0.002). The NKT cell counts were lower in the septic group than both the control group ( p = 0.05) and the infection group ( p = 0.04). Fewer NKT cells expressed T-Bet in the septic group than in the infection group ( p = 0.004). Fewer NKT cells expressed RORγt in the septic group than in the control group ( p = 0.003). Fewer NKT cells expressed IFN-γ in the septic group than in both the control group ( p = 0.002) and the infection group ( p = 0.036). Conclusion: The clinical presentation of infection and or sepsis in patients is linked with a mosaic of changes in the innate lymphocyte Th1 and Th17 phenotypes. The manipulation of the innate lymphocyte phenotype offers a potential avenue for immune modulation in patients with sepsis.

Background: Coeliac disease (CD) is associated with an increased risk of other immune-mediated conditions. Aim : To investigate the prevalence of coexistent immune-mediated diseases in CD patients, and changes in the prevalence of autoimmune thyroidal diseases over the last 50 years., Methods: Medical record data were collected retrospectively from 749 CD patients in Ireland. Prevalence of autoimmune diseases was compared with previously published results from general populations. Patients were divided into four groups based on the year of diagnosis to analyse changes in the prevalence of autoimmune thyroidal disease over time., Results: Median age at the time of CD diagnosis was 56 years (range 18-91 years). A total of 233 (31.1%) patients had a coexistent immune-mediated condition (IMC). Autoimmune thyroidal diseases were seen in 149 (19.9%) patients, hypothyroidism in 110 (14.7%), type 1 diabetes in 27 (3.6%), psoriasis in 20 (2.7%), inflammatory bowel disease in 14 (1.9%) and rheumatoid arthritis in 12 (1.6%). All conditions were more common in CD patients than in the general population. Type 1 diabetes was diagnosed mainly before CD, whereas there was no such trend in other conditions. Autoimmune thyroidal diseases became less common in female CD patients over time., Conclusions: Prevalence of autoimmune diseases is increased in adult CD patients compared with the general population. However, concomitant autoimmune thyroidal diseases became less common over time in women.

Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, with a strong heritable component, affecting patients with psoriasis. Here we attempt to identify genetic variants within the major histocompatibility complex (MHC) that differentiate patients with PsA from patients with cutaneous psoriasis alone (PsC)., Methods: 2808 patients with PsC, 1945 patients with PsA and 8920 population controls were genotyped. We imputed SNPs, amino acids and classical HLA alleles across the MHC and tested for association with PsA compared to population controls and the PsC patient group. In addition we investigated the impact of the age of disease onset on associations., Results: HLA-C*06:02 was protective of PsA compared to PsC (p=9.57×10 -66 , OR 0.37). The HLA-C*06:02 risk allele was associated with a younger age of psoriasis onset in all patients (p=1.01×10 -59 ). After controlling for the age of psoriasis onset no association of PsA to HLA-C*06:02 (p=0.07) was observed; instead, the most significant association was to amino acid at position 97 of HLA-B (p=1.54×10 -9 ) where the presence of asparagine or serine residue increased PsA risk. Asparagine at position 97 of HLA-B defines the HLA-B*27 alleles., Conclusions: By controlling for the age of psoriasis onset, we show, for the first time, that HLA-C*06:02 is not associated with PsA and that amino acid position 97 of HLA-B differentiates PsA from PsC. This amino acid also represents the largest genetic effect for ankylosing spondylitis, thereby refining the genetic overlap of these two spondyloarthropathies. Correcting for bias has important implications for cross-phenotype genetic studies., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)