Efficacy of foot orthoses for the treatment of plantar heel pain:a systematic review and meta-analysis

BackgroundPlantar heel pain (PHP) is common. Foot orthoses are often applied as treatment for PHP, even though there is little evidence to support this.ObjectiveTo investigate the effects of different orthoses on pain, function and self-reported recovery in patients with PHP and compare them with other conservative interventions.DesignSystematic review and meta-analysis.Data sourcesA systematic literature search was conducted in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, CINAHL and Google Scholar up to January 2017.Eligibility criteria for selecting studiesRandomised controlled trials comparing foot orthoses with a control (defined as no intervention, sham or other type of conservative treatment) reporting on pain, function or self-reported recovery in patients with PHP.ResultsTwenty studies investigating eight different types of foot orthoses were included in the review. Most studies were of high quality. Pooled data from six studies showed no difference between prefabricated orthoses and sham orthoses for pain at short term (mean difference (MD) of 0.26 (95% CI −0.09 to 0.60)). No difference was found between sham orthoses and custom orthoses for pain at short term (MD 0.22 (95% CI −0.05 to 0.50)), nor was there a difference between prefabricated orthoses and custom orthoses for pain at short term (MD 0.03 (95% CI −0.15 to 0.22)). For the majority of other interventions, no significant differences were found.ConclusionsFoot orthoses are not superior for improving pain and function compared with sham or other conservative treatment in patients with PHP.PROSPERO registration numberCRD42015029659.</jats:sec

Open science in archaeology

No abstract available

A computational model of postprandial adipose tissue lipid metabolism derived using human arteriovenous stable isotope tracer data

Given the association of disturbances in non-esterified fatty acid (NEFA) metabolism with the development of Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, computational models of glucose-insulin dynamics have been extended to account for the interplay with NEFA. In this study, we use arteriovenous measurement across the subcutaneous adipose tissue during a mixed meal challenge test to evaluate the performance and underlying assumptions of three existing models of adipose tissue metabolism and construct a new, refined model of adipose tissue metabolism. Our model introduces new terms, explicitly accounting for the conversion of glucose to glyceraldehye-3-phosphate, the postprandial influx of glycerol into the adipose tissue, and several physiologically relevant delays in insulin signalling in order to better describe the measured adipose tissues fluxes. We then applied our refined model to human adipose tissue flux data collected before and after a diet intervention as part of the Yoyo study, to quantify the effects of caloric restriction on postprandial adipose tissue metabolism. Significant increases were observed in the model parameters describing the rate of uptake and release of both glycerol and NEFA. Additionally, decreases in the model’s delay in insulin signalling parameters indicates there is an improvement in adipose tissue insulin sensitivity following caloric restriction.</p

The behaviour of political parties and MPs in the parliaments of the Weimar Republic

Copyright @ 2012 The Authors. This is the author's accepted manuscript. The final published article is available from the link below.Analysing the roll-call votes of the MPs of the Weimar Republic we find: (1) that party competition in the Weimar parliaments can be structured along two dimensions: an economic left–right and a pro-/anti-democratic. Remarkably, this is stable throughout the entire lifespan of the Republic and not just in the later years and despite the varying content of votes across the lifespan of the Republic, and (2) that nearly all parties were troubled by intra-party divisions, though, in particular, the national socialists and communists became homogeneous in the final years of the Republic.Zukunftskolleg, University of Konstan

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

Lithic technological responses to Late Pleistocene glacial cycling at Pinnacle Point Site 5-6, South Africa

There are multiple hypotheses for human responses to glacial cycling in the Late Pleistocene, including changes in population size, interconnectedness, and mobility. Lithic technological analysis informs us of human responses to environmental change because lithic assemblage characteristics are a reflection of raw material transport, reduction, and discard behaviors that depend on hunter-gatherer social and economic decisions. Pinnacle Point Site 5-6 (PP5-6), Western Cape, South Africa is an ideal locality for examining the influence of glacial cycling on early modern human behaviors because it preserves a long sequence spanning marine isotope stages (MIS) 5, 4, and 3 and is associated with robust records of paleoenvironmental change. The analysis presented here addresses the question, what, if any, lithic assemblage traits at PP5-6 represent changing behavioral responses to the MIS 5-4-3 interglacial-glacial cycle? It statistically evaluates changes in 93 traits with no a priori assumptions about which traits may significantly associate with MIS. In contrast to other studies that claim that there is little relationship between broad-scale patterns of climate change and lithic technology, we identified the following characteristics that are associated with MIS 4: increased use of quartz, increased evidence for outcrop sources of quartzite and silcrete, increased evidence for earlier stages of reduction in silcrete, evidence for increased flaking efficiency in all raw material types, and changes in tool types and function for silcrete. Based on these results, we suggest that foragers responded to MIS 4 glacial environmental conditions at PP5-6 with increased population or group sizes, 'place provisioning', longer and/or more intense site occupations, and decreased residential mobility. Several other traits, including silcrete frequency, do not exhibit an association with MIS. Backed pieces, once they appear in the PP5-6 record during MIS 4, persist through MIS 3. Changing paleoenvironments explain some, but not all temporal technological variability at PP5-6.Social Science and Humanities Research Council of Canada; NORAM; American-Scandinavian Foundation; Fundacao para a Ciencia e Tecnologia [SFRH/BPD/73598/2010]; IGERT [DGE 0801634]; Hyde Family Foundations; Institute of Human Origins; National Science Foundation [BCS-9912465, BCS-0130713, BCS-0524087, BCS-1138073]; John Templeton Foundation to the Institute of Human Origins at Arizona State Universit

A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273]

BACKGROUND: Etoricoxib is a highly selective COX-2 inhibitor which was evaluated for the treatment of rheumatoid arthritis (RA). METHODS: Double-blind, randomized, placebo and active comparator-controlled, 12-week study conducted at 67 sites in 28 countries. Eligible patients were chronic NSAID users who demonstrated a clinical worsening of arthritis upon withdrawal of prestudy NSAIDs. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures included direct assessment of arthritis by counts of tender and swollen joints, and patient and investigator global assessments of disease activity. Key secondary measures included the Stanford Health Assessment Questionnaire, patient global assessment of pain, and the percentage of patients who achieved ACR20 responder criteria response (a composite of pain, inflammation, function, and global assessments). Tolerability was assessed by adverse events and routine laboratory evaluations. RESULTS: 1171 patients were screened, 891 patients were randomized (N = 357 for placebo, N = 353 for etoricoxib, and N = 181 for naproxen), and 687 completed 12 weeks of treatment (N = 242 for placebo, N = 294 for etoricoxib, and N = 151 for naproxen). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p<0.05). Treatment responses were similar between the etoricoxib and naproxen groups for all endpoints. The percentage of patients who achieved ACR20 responder criteria response was 41% in the placebo group, 59% in the etoricoxib group, and 58% in the naproxen group. Etoricoxib and naproxen were both generally well tolerated. CONCLUSIONS: In this study, etoricoxib 90 mg once daily was more effective than placebo and similar in efficacy to naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in RA patients

Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein

Background: The recent emergence of a novel pandemic influenza A(H1N1) strain in humans exemplifies the rapid and unpredictable nature of influenza virus evolution and the need for effective therapeutics and vaccines to control such outbreaks. However, resistance to antivirals can be a formidable problem as evidenced by the currently widespread oseltamivir- and adamantane-resistant seasonal influenza A viruses (IFV). Additional antiviral approaches with novel mechanisms of action are needed to combat novel and resistant influenza strains. DAS181 (Fludase)™) is a sialidase fusion protein in early clinical development with in vitro and in vivo preclinical activity against a variety of seasonal influenza strains and highly pathogenic avian influenza strains (A/H5N1). Here, we use in vitro, ex vivo, and in vivo models to evaluate the activity of DAS181 against several pandemic influenza A(H1N1) viruses. Methods and Findings: The activity of DAS181 against several pandemic influenza A(H1N1) virus isolates was examined in MDCK cells, differentiated primary human respiratory tract culture, ex-vivo human bronchi tissue and mice. DAS181 efficiently inhibited viral replication in each of these models and against all tested pandemic influenza A(H1N1) strains. DAS181 treatment also protected mice from pandemic influenza A(H1N1)-induced pathogenesis. Furthermore, DAS181 antiviral activity against pandemic influenza A(H1N1) strains was comparable to that observed against seasonal influenza virus including the H274Y oseltamivir-resistant influenza virus. Conclusions: The sialidase fusion protein DAS181 exhibits potent inhibitory activity against pandemic influenza A(H1N1) viruses. As inhibition was also observed with oseltamivir-resistant IFV (H274Y), DAS181 may be active against the antigenically novel pandemic influenza A(H1N1) virus should it acquire the H274Y mutation. Based on these and previous results demonstrating DAS181 broad-spectrum anti-IFV activity, DAS181 represents a potential therapeutic agent for prevention and treatment of infections by both emerging and seasonal strains of IFV.published_or_final_versio

Construction of a large scale integrated map of macrophage pathogen recognition and effector systems

<p>Abstract</p> <p>Background</p> <p>In an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme.</p> <p>Results</p> <p>The diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges.</p> <p>Conclusions</p> <p>The pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways.</p

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery