Abdominal functional electrical stimulation to improve respiratory function after spinal cord injury: a systematic review and meta-analysis

Objectives: Abdominal functional electrical stimulation (abdominal FES) is the application of a train of electrical pulses to the abdominal muscles, causing them to contract. Abdominal FES has been used as a neuroprosthesis to acutely augment respiratory function and as a rehabilitation tool to achieve a chronic increase in respiratory function after abdominal FES training, primarily focusing on patients with spinal cord injury (SCI). This study aimed to review the evidence surrounding the use of abdominal FES to improve respiratory function in both an acute and chronic manner after SCI. Settings: A systematic search was performed on PubMed, with studies included if they applied abdominal FES to improve respiratory function in patients with SCI. Methods: Fourteen studies met the inclusion criteria (10 acute and 4 chronic). Low participant numbers and heterogeneity across studies reduced the power of the meta-analysis. Despite this, abdominal FES was found to cause a significant acute improvement in cough peak flow, whereas forced exhaled volume in 1 s approached significance. A significant chronic increase in unassisted vital capacity, forced vital capacity and peak expiratory flow was found after abdominal FES training compared with baseline. Conclusions: This systematic review suggests that abdominal FES is an effective technique for improving respiratory function in both an acute and chronic manner after SCI. However, further randomised controlled trials, with larger participant numbers and standardised protocols, are needed to fully establish the clinical efficacy of this technique

Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes

<p>Abstract</p> <p>Background</p> <p>Development of a standardized platform for the rapid expansion of tumor-infiltrating lymphocytes (TILs) with anti-tumor function from patients with limited TIL numbers or tumor tissues challenges their clinical application.</p> <p>Methods</p> <p>To facilitate adoptive immunotherapy, we applied genetically-engineered K562 cell-based artificial antigen presenting cells (aAPCs) for the direct and rapid expansion of TILs isolated from primary cancer specimens.</p> <p>Results</p> <p>TILs outgrown in IL-2 undergo rapid, CD28-independent expansion in response to aAPC stimulation that requires provision of exogenous IL-2 cytokine support. aAPCs induce numerical expansion of TILs that is statistically similar to an established rapid expansion method at a 100-fold lower feeder cell to TIL ratio, and greater than those achievable using anti-CD3/CD28 activation beads or extended IL-2 culture. aAPC-expanded TILs undergo numerical expansion of tumor antigen-specific cells, remain amenable to secondary aAPC-based expansion, and have low CD4/CD8 ratios and FOXP3+ CD4+ cell frequencies. TILs can also be expanded directly from fresh enzyme-digested tumor specimens when pulsed with aAPCs. These "young" TILs are tumor-reactive, positively skewed in CD8+ lymphocyte composition, CD28 and CD27 expression, and contain fewer FOXP3+ T cells compared to parallel IL-2 cultures.</p> <p>Conclusion</p> <p>Genetically-enhanced aAPCs represent a standardized, "off-the-shelf" platform for the direct ex vivo expansion of TILs of suitable number, phenotype and function for use in adoptive immunotherapy.</p

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Lymphodepletion and infusion of autologous expanded tumour-infiltrating lymphocytes is effective therapy for patients with malignant melanoma. Antitumour responses are likely to be mediated by HLA class I- and II-restricted immune responses directed at tumour antigens. We assessed whether the peripheral blood of normal HLA-matched siblings of patients with melanoma could be used to generate lymphocytes with antimelanoma activity for adoptive immunotherapy after allogeneic blood or marrow transplantation. Melanoma cell lines were derived from two donors and were used to stimulate the mononuclear cells of three HLA-identical siblings. CD4+ clones dominated cultures. Of these, approximately half were directly cytotoxic towards recipient melanoma cells and secreted interferon-γ in response to tumour stimulation. More than half of the noncytotoxic clones also secreted interferon-γ after melanoma stimulation. No CD4+ clones responded to stimulation with recipient haemopoietic cells. The majority of CD8+ clones directly lysed recipient melanoma, but did not persist in long-term culture in vitro. No crossreactivity with recipient haemopoietic cells was observed. The antigenic target of one CD4+ clone was determined to be an HLA-DR11-restricted MAGE-3 epitope. Antigenic targets of the remaining clones were not elucidated, but appeared to be restricted through a non-HLA-DR class II molecule. We conclude that the blood of allogeneic HLA-matched sibling donors contains melanoma-reactive lymphocyte precursors directed at tumour-associated antigens. Adoptive immunotherapy with unselected or ex vivo-stimulated donor lymphocytes after allogeneic stem cell transplantation has a rational basis for the treatment of malignant melanoma

Gold Mining in the Peruvian Amazon: Global Prices, Deforestation, and Mercury Imports

Many factors such as poverty, ineffective institutions and environmental regulations may prevent developing countries from managing how natural resources are extracted to meet a strong market demand. Extraction for some resources has reached such proportions that evidence is measurable from space. We present recent evidence of the global demand for a single commodity and the ecosystem destruction resulting from commodity extraction, recorded by satellites for one of the most biodiverse areas of the world. We find that since 2003, recent mining deforestation in Madre de Dios, Peru is increasing nonlinearly alongside a constant annual rate of increase in international gold price (∼18%/yr). We detect that the new pattern of mining deforestation (1915 ha/year, 2006–2009) is outpacing that of nearby settlement deforestation. We show that gold price is linked with exponential increases in Peruvian national mercury imports over time (R2 = 0.93, p = 0.04, 2003–2009). Given the past rates of increase we predict that mercury imports may more than double for 2011 (∼500 t/year). Virtually all of Peru's mercury imports are used in artisanal gold mining. Much of the mining increase is unregulated/artisanal in nature, lacking environmental impact analysis or miner education. As a result, large quantities of mercury are being released into the atmosphere, sediments and waterways. Other developing countries endowed with gold deposits are likely experiencing similar environmental destruction in response to recent record high gold prices. The increasing availability of satellite imagery ought to evoke further studies linking economic variables with land use and cover changes on the ground

Selecting effective incentive structures in health care: A decision framework to support health care purchasers in finding the right incentives to drive performance

<p>Abstract</p> <p>Background</p> <p>The Ontario health care system is devolving planning and funding authority to community based organizations and moving from steering through rules and regulations to steering on performance. As part of this transformation, the Ontario Ministry of Health and Long-Term Care (MOHLTC) are interested in using incentives as a strategy to ensure alignment – that is, health service providers' goals are in accord with the goals of the health system. The objective of the study was to develop a decision framework to assist policymakers in choosing and designing effective incentive systems.</p> <p>Methods</p> <p>The first part of the study was an extensive review of the literature to identify incentives models that are used in the various health care systems and their effectiveness. The second part was the development of policy principles to ensure that the used incentive models are congruent with the values of the Ontario health care system. The principles were developed by reviewing the Ontario policy documents and through discussions with policymakers. The validation of the principles and the suggested incentive models for use in Ontario took place at two meetings. The first meeting was with experts from the research and policy community, the second with senior policymakers from the MOHLTC. Based on the outcome of those two meetings, the researchers built a decision framework for incentives. The framework was send to the participants of both meetings and four additional experts for validation.</p> <p>Results</p> <p>We identified several models that have proven, with a varying degree of evidence, to be effective in changing or enabling a health provider's performance. Overall, the literature suggests that there is no single best approach to create incentives yet and the ability of financial and non-financial incentives to achieve results depends on a number of contextual elements. After assessing the initial set of incentive models on their congruence with the four policy principles we defined nine incentive models to be appropriate for use in Ontario and potentially other health care systems that want to introduce incentives to improve performance. Subsequently, the models were incorporated in the resulting decision framework.</p> <p>Conclusion</p> <p>The design of an incentive must reflect the values and goals of the health care system, be well matched to the performance objectives and reflect a range of contextual factors that can influence the effectiveness of even well-designed incentives. As a consequence, a single policy recommendation around incentives is inappropriate. The decision framework provides health care policymakers and purchasers with a tool to support the selection of an incentive model that is the most appropriate to improve the targeted performance.</p

Factors affecting glomerular filtration rate, as measured by iohexol disappearance, in men with or at risk for HIV infection

Objective: Formulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD). Design: Cross-sectional measurement of iohexol-based GFR (iGFR) in HIV(+) men (n = 455) receiving antiretroviral therapy, and HIV-uninfected (HIV(-)) men (n = 258) in the Multicenter AIDS Cohort Study. Methods: iGFR was calculated from disappearance of infused iohexol from plasma. Determinants of GFR and the presence of CKD were compared using iGFR and GFR estimated by the CKD-Epi equation (eGFR). Results: Median iGFR was higher among HIV(+) than HIV(-) men (109 vs. 106 ml/min/1.73 m2, respectively, p = .046), and was 7 ml/min higher than median eGFR. Mean iGFR was lower in men who were older, had chronic hepatitis C virus (HCV) infection, or had a history of AIDS. Low iGFR (≤90 ml/min/1.73 m2) was associated with these factors and with black race. Other than age, factors associated with low iGFR were not observed with low eGFR. CKD was more common in HIV(+) than HIV(-) men; predictors of CKD were similar using iGFR and eGFR. Conclusions: iGFR was higher than eGFR in this population of HIV-infected and -uninfected men who have sex with men. Presence of CKD was predicted equally well by iGFR and eGFR, but associations of chronic HCV infection and history of clinically-defined AIDS with mildly decreased GFR were seen only with iGFR. © 2014 Margolick et al

Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise

Protected areas and poverty

Protected areas are controversial because they are so important for conservation and because they distribute fortune and misfortune unevenly. The nature of that distribution, as well as the terrain of protected areas themselves, have been vigorously contested. In particular, the relationship between protected areas and poverty is a long-running debate in academic and policy circles. We review the origins of this debate and chart its key moments. We then outline the continuing flashpoints and ways in which further evaluation studies could improve the evidence base for policy-making and conservation practice

Mining for genotype-phenotype relations in Saccharomyces using partial least squares

<p>Abstract</p> <p>Background</p> <p>Multivariate approaches are important due to their versatility and applications in many fields as it provides decisive advantages over univariate analysis in many ways. Genome wide association studies are rapidly emerging, but approaches in hand pay less attention to multivariate relation between genotype and phenotype. We introduce a methodology based on a BLAST approach for extracting information from genomic sequences and Soft- Thresholding Partial Least Squares (ST-PLS) for mapping genotype-phenotype relations.</p> <p>Results</p> <p>Applying this methodology to an extensive data set for the model yeast <it>Saccharomyces cerevisiae</it>, we found that the relationship between genotype-phenotype involves surprisingly few genes in the sense that an overwhelmingly large fraction of the phenotypic variation can be explained by variation in less than 1% of the full gene reference set containing 5791 genes. These phenotype influencing genes were evolving 20% faster than non-influential genes and were unevenly distributed over cellular functions, with strong enrichments in functions such as cellular respiration and transposition. These genes were also enriched with known paralogs, stop codon variations and copy number variations, suggesting that such molecular adjustments have had a disproportionate influence on <it>Saccharomyces </it>yeasts recent adaptation to environmental changes in its ecological niche.</p> <p>Conclusions</p> <p>BLAST and PLS based multivariate approach derived results that adhere to the known yeast phylogeny and gene ontology and thus verify that the methodology extracts a set of fast evolving genes that capture the phylogeny of the yeast strains. The approach is worth pursuing, and future investigations should be made to improve the computations of genotype signals as well as variable selection procedure within the PLS framework.</p