Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Extreme Evolutionary Disparities Seen in Positive Selection across Seven Complex Diseases

Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01×10−5) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update

Objectives: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. Methods: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. Results: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. Conclusions: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost

Invertebrates – a forgotten group of animals in infrastructure planning? Butterflies as tools and model organisms in Sweden

There is a growing concern about the ecological effects of roads and railways on animals. There is increased mortality due to road kills, changes in movement patterns and changes in the physical environment in areas affected by infrastructure. A majority of all studies have been on larger mammals. There are also a growing number of studies on smaller animals like birds, amphibians and small mammals. However, the studies of invertebrates are few in comparison with vertebrates, and the knowledge of the effects of infrastructure on this group is limited. The importance of also including invertebrates in the studies of infrastructure is evident. First of all, this group of animals is the richest of species that exists. They are also ecologically important. In Sweden, a majority of the red-listed species are invertebrates. Of 4,120 red-listed species, fully 2,337 are invertebrates. Their generation times are fast, which also makes the response on changes in their environment fast, compared to mammals and birds. For that reason, invertebrates can be expected to give an indication earlier than mammals if an area is negatively affected by infrastructure. Butterflies have several traits that make them suitable as model organisms to represent the invertebrates when studying problems due to infrastructure. In Sweden, they inhabit one of the most species-rich habitats: floral-rich semi-natural grasslands and open deciduous forests. This habitat has decreased 82 percent since 1880. Today it contains more than 1,000 red-listed species in Sweden. The habitat is sensitive to further fragmentation due to effects of infrastructure. There is a need to identify species that are dependent on these landscapes and that are possible to monitor. Butterflies are good candidates. It is relatively easy and cheap to catch and mark a large number of butterflies. They are active in daytime, and it is easy to put marks on their wings with simple equipment. Since some butterfly species are sensitive to habitat fragmentation and occur in species-rich habitats they may act as indicators of biologically rich landscapes and, therefore, as model organisms in infrastructure planning. Many butterflies are dependent on systems of patches, and that contact between them and the area of the patches are key elements in the preservation. In one study we examined the changes in the butterfly fauna across a gradient from an intensively managed agricultural landscape with a large amount of open fields to a landscape rich in semi-natural grasslands and deciduous forests. The study took place in the province of Östergötland in southeast of Sweden. About 70 percent of the species showed a positive response to the amount of semi-natural grasslands and open deciduous forests in the landscape. More species showed a significant response at the landscape level compared to at the site-level (e.g., site area). There seems to be clear thresholds in area demands where a small increase in the amount of habitats has large effect on occupancy probability. If you look at single species, the value for 50 percent probability of occurrence varied between 3-10 percent grasslands and deciduous forests for the seven species where the landscape factor was positively significant. For these species, there was a sharp drop in probability of occurrence at the thresholds. The individual species and groups of species that show clear thresholds in area demands can be used as indicators of biologically rich landscapes. In this study the whole group of the family Zygaenidae and the fritillaries may be used as indicators. In another study we investigated the barrier effect by marking and recapturing butterflies along the motorway E4 in southeast Sweden. The motorway was surrounded by semi-natural pastures with portions of deciduous trees on both sides. Every capture of an individual was positioned by GPS, and by plotting the data in a GIS application we could analyze the dispersal ability and the flight direction of most of the species. The results showed that there were large differences between species regarding the dispersal ability. We used the data set to simulate a new data set of random movements. For the Ringlet (Aphantopus hyperantus) we expected 12 percent crossings of the motorway but (we) found only 3 percent in our field data. The barrier effect was therefore calculated to 75 percent for the Ringlet. The migratory species Green-veined white (Pieris napi) showed another pattern, and we both expected and found 14 percent crossings. The main conclusions from this study of using butterflies in the planning process are: • Butterflies can be used to identify rich landscapes. • There exist critical thresholds, and infrastructure has probably the largest impact around the thresholds (3-10% of natural habitat left). • Indicator species may be used to identify rich landscapes. • Roads may act as barriers to some species. • Invertebrates are a significant group to consider in infrastructure planning. In the future the results can be used to identify potentially species rich areas without expensive field surveys, before the start of road and railway projects. Using data from aerial photos or satellites and analyzing them with thresholds for groups of species in a GIS application could give us a tool to prevent further fragmentation by infrastructure. The development of this tool is the next challenge, but there is also a need to confirm our findings in other landscapes as well. The thresholds in this study should be interpreted with some caution as the landscapes around some sites sometimes overlap each other

Statistics and Data Analysis for Social Workers

160 p.; 21 cm

Fladdermöss i Östergötland : Resultat från inventeringar utförda 1978-2004

denna rapport redovisas resultat från olika fladdermusinventeringar som utförts i Östergötland under åren1978-2004. Från 1994 och framåt har det genomförts en mer systematisk inventering av fladdermöss. Undersenare år har inventeringen skett inom ramen för den inventeringsverksamhet som Länsstyrelsen Östergötlandpåbörjade 1993 under benämningen Projekt hotade arter. Projektet är ett samarbete mellan lokala, regionala ochcentrala myndigheter och organisationer. Syftet med projektet är att öka kunskapen om de rödlistade arternasutbredning, liksom att erhålla ett bättre underlag för naturvårdsarbetet i länet. Fladdermössen utgör här en viktigoch intressant del av faunan i kulturlandskapet, då rik artförekomst av fladdermöss indikerar miljöer med storbiologisk mångfald. 213 lokaler har hittills inventerats. Gemensamt för flertalet av de 13 artrikaste lokalerna, med sju till nio arter, äratt det är heterogena miljöer bestående av trädbärande betesmarker med gamla, ihåliga träd i ett gammalt odlingslandskap,oftast i närhet till vatten och med anknytning till större gårdar eller gods rika på gamla byggnader. Av de 16 arter som regelbundet finns i landet har 11 påträffats i Östergötland. Av landets sex rödlistade arterförekommer fyra i länet. Dessa är barbastell, Barbastella barbastellus (EN), fransfladdermus, Myotis nattereri (VU),mustaschfladdermus, Myotis mystacinus (VU) och trollfladdermus, Pipistrellus nathusii (NT). Fyndlokalerna förbarbastell är, med ett undantag, koncentrerade till den allra sydligaste delen av länet. Fransfladdermusen har påträffatsföreträdesvis på artrika lokaler. 84 % av fynden har gjort på lokaler med fem till nio arter. På två lokaler ilänet har mustaschfladdermus konstaterats med hjälp av fångst. Under 2004 påträffades för första gången trollfladdermuspå en lokal i norra delen av länet. Stor fladdermus var tidigare både internationellt och nationelltrödlistad, men har tagits bort från listorna på grund av nya kriterier från den internationella naturvårdsunionenIUCN. Arten har också strukits från listan över regionalt hotade arter. För en fortsatt kunskapsuppbyggnad på området är det angeläget att utveckla metodiken så att svårdetekteradearter lättare kan hittas. För att få klarlagt huruvida fransfladdermus kan betraktas som en indikatorart för artrikamiljöer eller ej bör artrika lokaler där arten ännu ej påträffats återinventeras, liksom även artfattigare lokaler där ejbelagda indikationer om artens förekomst finns

Statistic and data analysis for social workers

160 p.; 23 cm

Extreme weather affects colonization : extinction dynamics and the persistence of a threatened butterfly

Extreme weather events can be expected to increase in frequency in the future. Our knowledge on how this may affect species persistence is, however, very limited. For reliable projections of future persistence we need to understand how extreme weather affects species' population dynamics.We analysed the effect of extreme droughts on the host plant Succisa pratensis, colonization-extinction dynamics, and future persistence of the threatened marsh fritillary Euphydryas aurinia. Specifically, we studied a metapopulation inhabiting a network of 256 patches on Gotland (Sweden), where the summer of 2018 was the driest ever recorded. We analysed how the frequency and leaf size of host plants changed between 2017 and 2019, based on 6,833 records in 0.5-m(2) sample plots. Using turnover data on the butterfly from 2018 to 2019 we modelled local extinction and colonization probabilities. Moreover, we projected future population dynamics with an increasing frequency of extreme years under three different management strategies that regulate the grazing regime.Our results show a substantial decrease in both frequency (46%) and size (20%) of host plants due to the drought, which taken together may constitute a 57% loss of food resources. The butterfly occupancy decreased by over 30% between 2018 and 2019 (from 0.36 to 0.27). The extinction probability increased with increasing 'effective area' of the patch (taking quality reduction due to grazing into account), and the colonization probability increased with increasing connectivity and ground moisture.Projections of future dynamics showed an increasing risk of metapopulation extinction with increasing frequency of years with extreme droughts. The risk, however, clearly differed between management strategies. Less grazing in years with droughts decreased the extinction risk considerably.Synthesis and applications. Extreme weather events can have profound negative impacts on butterflies and their host plants. For the marsh fritillary, an increased frequency of extreme droughts can lead to extinction of the entire metapopulation, even in a large and seemingly viable metapopulation. Increased grazing, due to fodder deficiency in dry years, may lead to cascading negative effects, while active management that reduce grazing in years with droughts can almost completely mitigate these effects.Data are available via the Dryad Digital Repository https://doi.org/10.5061/dryad.s1rn8pk4k (Johansson, Kindvall, Askling, &amp; Franzén, 2020).</p

Immunogenicity and safety of the tick-borne encephalitis vaccination (2009-2019): A systematic review

BACKGROUND Tick-borne encephalitis (TBE) is increasing in Europe. We aimed to evaluate the immunogenicity and safety of TBE-vaccination. METHODS This systematic review was registered at PROSPERO (#CRD42020155737) and conducted in accordance with PRISMA guidelines. We searched CINAHL, Cochrane, Embase, PubMed, and Scopus using specific terms. Original articles, case reports and research abstracts in English, French, German and Italian were included for screening and extracting (JER; PS). RESULTS Of a total of 2464 records, 49 original research publications were evaluated for immunogenicity and safety. TBE-vaccines showed adequate immunogenicity, good safety and interchangeability in adults and children with some differences in long-term protection (Seropositivity in 90.6-100% after primary vaccination; 84.9%-99.4% at 5 year follow up). Primary conventional vaccination schedule (days 0, 28, and 300) demonstrated the best immunogenic results (99-100% of seropositivity). Mixed brand primary vaccination presented adequate safety and immunogenicity with some exceptions. After booster follow-ups, accelerated conventional and rapid vaccination schedules were shown to be comparable in terms of immunogenicity and safety. First booster vaccinations five years after primary vaccination were protective in adults aged 50 years, lower protective antibody titers were found. Allergic individuals showed an adequate response and immunosuppressed individuals a diminished response to TBE-vaccination. CONCLUSIONS The TBE-vaccination is generally safe with rare serious adverse events. Schedules should, if possible, use the same vaccine brand (non-mixed). TBE-vaccines are immunogenic in terms of antibody response but less so when vaccination is started after the age of 50 years. Age at priming is a key factor in the duration of protection