Exercise therapy for chronic low back pain:protocol for an individual participant data meta-analysis

<p>Abstract</p> <p>Background</p> <p>Low back pain (LBP) is one of the leading causes of disability and has a major socioeconomic impact. Despite a large amount of research in the field, there remains uncertainty about the best treatment approach for chronic LBP, and identification of relevant patient subgroups is an important goal. Exercise therapy is a commonly used strategy to treat chronic low back pain and is one of several interventions that evidence suggests is moderately effective.</p> <p>In parallel with an update of the 2005 Cochrane review, we will undertake an individual participant data (IPD) meta-analysis, which will allow us to standardize analyses across studies and directly derive results, and to examine differential treatment effects across individuals to estimate how patients’ characteristics modify treatment benefit.</p> <p>Methods/design</p> <p>We will use standard systematic review methods advocated by the Cochrane Collaboration to identify relevant trials. We will include trials evaluating exercise therapy compared to any or no other interventions in adult non-specific chronic LBP. Our primary outcomes of interest include pain, functional status, and return-to-work/absenteeism. We will assess potential risk of bias for each study meeting selection criteria, using criteria and methods recommended by the Cochrane BRG.</p> <p>The original individual participant data will be requested from the authors of selected trials having moderate to low risk of bias. We will test original data and compile a master dataset with information about each trial mapped on a pre-specified framework, including reported characteristics of the study sample, exercise therapy characteristics, individual patient characteristics at baseline and all follow-up periods, subgroup and treatment effect modifiers investigated. Our analyses will include descriptive, study-level meta-analysis and meta-regression analyses of the overall treatment effect, and individual-level IPD meta-analyses of treatment effect modification. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modeled simultaneously while accounting for the clustering of participants with studies.</p> <p>Discussion</p> <p>We will analyze IPD across a large number of LBP trials. The resulting larger sample size and consistent presentation of data will allow additional analyses to explore patient-level heterogeneity in treatment outcomes and prognosis of chronic LBP.</p

CLEC5A Regulates Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality

CLEC5A/MDL-1, a member of the myeloid C-type lectin family expressed on macrophages and neutrophils, is critical for dengue virus (DV)-induced hemorrhagic fever and shock syndrome in Stat1−/− mice and ConA-treated wild type mice. However, whether CLEC5A is involved in the pathogenesis of viral encephalitis has not yet been investigated. To investigate the role of CLEC5A to regulate JEV-induced neuroinflammation, antagonistic anti-CLEC5A mAb and CLEC5A-deficient mice were generated. We find that Japanese encephalitis virus (JEV) directly interacts with CLEC5A and induces DAP12 phosphorylation in macrophages. In addition, JEV activates macrophages to secrete proinflammatory cytokines and chemokines, which are dramatically reduced in JEV-infected Clec5a−/− macrophages. Although blockade of CLEC5A cannot inhibit JEV infection of neurons and astrocytes, anti-CLEC5A mAb inhibits JEV-induced proinflammatory cytokine release from microglia and prevents bystander damage to neuronal cells. Moreover, JEV causes blood-brain barrier (BBB) disintegrity and lethality in STAT1-deficient (Stat1−/−) mice, whereas peripheral administration of anti-CLEC5A mAb reduces infiltration of virus-harboring leukocytes into the central nervous system (CNS), restores BBB integrity, attenuates neuroinflammation, and protects mice from JEV-induced lethality. Moreover, all surviving mice develop protective humoral and cellular immunity against JEV infection. These observations demonstrate the critical role of CLEC5A in the pathogenesis of Japanese encephalitis, and identify CLEC5A as a target for the development of new treatments to reduce virus-induced brain damage

VLPs and particle strategies for cancer vaccines

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Behavioral genetics and taste

This review focuses on behavioral genetic studies of sweet, umami, bitter and salt taste responses in mammals. Studies involving mouse inbred strain comparisons and genetic analyses, and their impact on elucidation of taste receptors and transduction mechanisms are discussed. Finally, the effect of genetic variation in taste responsiveness on complex traits such as drug intake is considered. Recent advances in development of genomic resources make behavioral genetics a powerful approach for understanding mechanisms of taste

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Allele-Independent Turnover of Human Leukocyte Antigen (HLA) Class Ia Molecules.

Major histocompatibility complex class I (MHCI) glycoproteins present cytosolic peptides to CD8+ T cells and regulate NK cell activity. Their heavy chains (HC) are expressed from up to three MHC gene loci (human leukocyte antigen [HLA]-A, -B, and -C in humans), whose extensive polymorphism maps predominantly to the antigen-binding groove, diversifying the bound peptide repertoire. Codominant expression of MHCI alleles is thus functionally critical, but how it is regulated is not fully understood. Here, we have examined the effect of polymorphism on the turnover rates of MHCI molecules in cell lines with functional MHCI peptide loading pathways and in monocyte-derived dendritic cells (MoDCs). Proteins were labeled biosynthetically with heavy water (2H2O), folded MHCI molecules immunoprecipitated, and tryptic digests analysed by mass spectrometry. MHCI-derived peptides were assigned to specific alleles and isotypes, and turnover rates quantified by 2H incorporation, after correcting for cell growth. MHCI turnover half-lives ranged from undetectable to a few hours, depending on cell type, activation state, donor, and MHCI isotype. However, in all settings, the turnover half-lives of alleles of the same isotype were similar. Thus, MHCI protein turnover rates appear to be allele-independent in normal human cells. We propose that this is an important feature enabling the normal function and codominant expression of MHCI alleles

NK cells and cancer: you can teach innate cells new tricks

Natural killer (NK) cells are the prototype innate lymphoid cells endowed with potent cytolytic function that provide host defence against microbial infection and tumours. Here, we review evidence for the role of NK cells in immune surveillance against cancer and highlight new therapeutic approaches for targeting NK cells in the treatment of cancer