Treatment for inclusion body myositis

Background Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment. Objectives To assess the effects of treatment for IBM. Search methods On 7 October 2014 we search ed the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials. Selection criteria We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews. Data collection and analysis We used standard Cochrane methodological procedures. Main results The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events. Authors\u27 conclusions Trials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures

Ecosystem respiration: Drivers of daily variability and background respiration in lakes around the globe

We assembled data from a global network of automated lake observatories to test hypotheses regarding the drivers of ecosystem metabolism. We estimated daily rates of respiration and gross primary production (GPP) for up to a full year in each lake, via maximum likelihood fits of a free‐water metabolism model to continuous high‐frequency measurements of dissolved oxygen concentrations. Uncertainties were determined by a bootstrap analysis, allowing lake‐days with poorly constrained rate estimates to be down‐weighted in subsequent analyses. GPP and respiration varied considerably among lakes and at seasonal and daily timescales. Mean annual GPP and respiration ranged from 0.1 to 5.0 mg O2 L−1 d−1 and were positively related to total phosphorus but not dissolved organic carbon concentration. Within lakes, significant day‐to‐day differences in respiration were common despite large uncertainties in estimated rates on some lake‐days. Daily variation in GPP explained 5% to 85% of the daily variation in respiration after temperature correction. Respiration was tightly coupled to GPP at a daily scale in oligotrophic and dystrophic lakes, and more weakly coupled in mesotrophic and eutrophic lakes. Background respiration ranged from 0.017 to 2.1 mg O2 L−1 d−1 and was positively related to indicators of recalcitrant allochthonous and autochthonous organic matter loads, but was not clearly related to an indicator of the quality of allochthonous organic matter inputs

Factors affecting the local distribution of <i>Polystigma rubrum</i> stromata on <i>Prunus spinosa</i>

Background and aims – Polystigma rubrum forms orange-red stromata on the surface of living leaves of Prunus spinosa and P. domestica. Records suggests that this fungus now has a much more limited distribution in Britain than recorded in the 19th and early 20th century. Methods – We studied the local distribution of the fungus in the Burren Hills of western Ireland where it remains very common. Key results – Assessment of the local distribution of the fungus over two years found stromata to occur more frequently on P. spinosa leaves in hedgerows than woodlands. On individual trees in areas of open limestone pavement, the frequency of stromata was ten times higher in 2016 than 2015, possibly related to interannual rainfall differences. On hedgerow trees subjected to winter flooding, stromata were much less abundant, whereas stromata were more abundant on leaves also infected by the gall mite Eriophyes prunispinosae. The identity of Po. rubrum was confirmed by ITS sequencing.Conclusion – At a field location where Po. rubrum stromata are present in unusually high abundance, the distribution of stromata on trees in different habitats showed high levels of variation linked to both habitat and the presence of gall mites. Further work is required to determine whether variation in leaf surface and soil moisture are the key determinants of the observed distribution. Such investigations may reveal why Po. rubrum, once common in northern Europe is now restricted mainly to westerly, coastal locations

The Global Lake Ecological Observatory Network (GLEON): the evolution of grassroots network science

Nine years later, with over 380 members from 40 countries, and 50 publications to its credit, GLEON is growing at a rapid pace and pushing the boundaries of the practice of network science. GLEON is really three networks: a network of lakes, data, and peopl

Insights from the Global Lake Ecological Observatory Network (GLEON)

The Global Lake Ecological Observatory Network (GLEON) is a grass-roots network of people, data, and observatories. The network represents a unique effort to bring together a diverse community of scientists, engineers, information technology experts, and engaged stakeholders to understand, conserve, and predict the state of lakes and reservoirs globally. Individuals and teams in GLEON have generated a range of scientific, educational, and outreach products, from software tools to scientific publications to education modules and programs. This special issue of Inland Waters brings together a series of papers generated from the network. Here, we discuss the foundations of GLEON that have facilitated these publications and others like them in terms of network structure, research areas, and the threads that tie the network together. GLEON is underpinned by sophisticated analytical tools and a network of high-frequency in situ observatories that exploit advanced sensors and associated technologies. This approach expands the space and time domains available to inquiry and analysis of lake processes. Using team science, the network has also established a culture of collaboration, sharing, and trust. This flexible framework allows GLEON members to advance research on a range of topics and has led to an increasing number of collaborative cross-site products. Future success will depend on the network&rsquo;s ability to continue to facilitate the successes of its members while also being responsive to evolving member needs, technologies, and societal priorities

Dysregulation of Angiopoietins Is Associated with Placental Malaria and Low Birth Weight

BACKGROUND: Placental malaria (PM) is associated with adverse pregnancy outcomes including low birth weight (LBW). However, the precise mechanisms by which PM induces LBW are poorly defined. Based on the essential role of angiopoietin (ANG)-1 and -2 in normal placental vascular development, we hypothesized that PM may result in the dysregulation of angiopoietins and thereby contribute to LBW outcomes. METHODS AND FINDINGS: In a mouse model of PM, we show that Plasmodium berghei ANKA infection of pregnant mice resulted in dysregulated angiopoietin levels and fetal growth restriction. PM lead to decreased ANG-1, increased ANG-2, and an elevated ratio of ANG-2/ANG-1 in the placenta and the serum. These observations were extended to malaria-exposed pregnant women: In a study of primigravid women prospectively followed over the course of pregnancy, Plasmodium falciparum infection was associated with a decrease in maternal plasma ANG-1 levels (P = 0.031) and an increase in the ANG-2:ANG-1 ratio (P = 0.048). ANG-1 levels recovered with successful treatment of peripheral parasitemia (P = 0.010). In a cross-sectional study of primigravidae at delivery, angiopoietin dysregulation was associated with PM (P = 0.002) and LBW (P = 0.041). Women with PM who delivered LBW infants had increased ANG-2:ANG-1 ratios (P = 0.002) compared to uninfected women delivering normal birth weight infants. CONCLUSIONS: These data support the hypothesis that dysregulation of angiopoietins is associated with PM and LBW outcomes, and suggest that ANG-1 and ANG-2 levels may be clinically informative biomarkers to identify P. falciparum-infected mothers at risk of LBW deliveries

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Advances in the Production and Batch Reformatting of Phage Antibody Libraries

Phage display antibody libraries have proven an invaluable resource for the isolation of diagnostic and potentially therapeutic antibodies, the latter usually being antibody fragments converted into IgG formats. Recent advances in the production of highly diverse and functional antibody libraries are considered here, including for Fabs, scFvs and nanobodies. These advances include codon optimisation during generation of CDR diversity, improved display levels using novel signal sequences, molecular chaperones and isomerases and the use of highly stable scaffolds with relatively high expression levels. In addition, novel strategies for the batch reformatting of scFv and Fab phagemid libraries, derived from phage panning, into IgG formats are described. These strategies allow the screening of antibodies in the end-use format, facilitating more efficient selection of potential therapeutics

A Global lake ecological observatory network (GLEON) for synthesising high-frequency sensor data for validation of deterministic ecological models

A Global Lake Ecological Observatory Network (GLEON; www.gleon.org) has formed to provide a coordinated response to the need for scientific understanding of lake processes, utilising technological advances available from autonomous sensors. The organisation embraces a grassroots approach to engage researchers from varying disciplines, sites spanning geographic and ecological gradients, and novel sensor and cyberinfrastructure to synthesise high-frequency lake data at scales ranging from local to global. The high-frequency data provide a platform to rigorously validate processbased ecological models because model simulation time steps are better aligned with sensor measurements than with lower-frequency, manual samples. Two case studies from Trout Bog, Wisconsin, USA, and Lake Rotoehu, North Island, New Zealand, are presented to demonstrate that in the past, ecological model outputs (e.g., temperature, chlorophyll) have been relatively poorly validated based on a limited number of directly comparable measurements, both in time and space. The case studies demonstrate some of the difficulties of mapping sensor measurements directly to model state variable outputs as well as the opportunities to use deviations between sensor measurements and model simulations to better inform process understanding. Well-validated ecological models provide a mechanism to extrapolate high-frequency sensor data in space and time, thereby potentially creating a fully 3-dimensional simulation of key variables of interest