A critical assessment of the WHO responsiveness tool: lessons from voluntary HIV testing and counselling services in Kenya

<p>Abstract</p> <p>Background</p> <p>Health, fair financing and responsiveness to the user's needs and expectations are seen as the essential objectives of health systems. Efforts have been made to conceptualise and measure responsiveness as a basis for evaluating the non-health aspects of health systems performance. This study assesses the applicability of the responsiveness tool developed by WHO when applied in the context of voluntary HIV counselling and testing services (VCT) at a district level in Kenya.</p> <p>Methods</p> <p>A mixed method study was conducted employing a combination of quantitative and qualitative research methods concurrently. The questionnaire proposed by WHO was administered to 328 VCT users and 36 VCT counsellors (health providers). In addition to the questionnaire, qualitative interviews were carried out among a total of 300 participants. Observational field notes were also written.</p> <p>Results</p> <p>A majority of the health providers and users indicated that the responsiveness elements were very important, e.g. confidentiality and autonomy were regarded by most users and health providers as very important and were also reported as being highly observed in the VCT room. However, the qualitative findings revealed other important aspects related to confidentiality, autonomy and other responsiveness elements that were not captured by the WHO tool. Striking examples were inappropriate location of the VCT centre, limited information provided, language problems, and concern about the quality of counselling.</p> <p>Conclusion</p> <p>The results indicate that the WHO developed responsiveness elements are relevant and important in measuring the performance of voluntary HIV counselling and testing. However, the tool needs substantial revision in order to capture other important dimensions or perspectives. The findings also confirm the importance of careful assessment and recognition of locally specific aspects when conducting comparative studies on responsiveness of HIV testing services.</p

Trihydrophobin 1 Phosphorylation by c-Src Regulates MAPK/ERK Signaling and Cell Migration

c-Src activates Ras-MAPK/ERK signaling pathway and regulates cell migration, while trihydrophobin 1 (TH1) inhibits MAPK/ERK activation and cell migration through interaction with A-Raf and PAK1 and inhibiting their kinase activities. Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1. Further study reveals that Tyr-6 phosphorylation of TH1 reduces its inhibition on MAPK/ERK signaling, enhances c-Src mediated cell migration. Moreover, induced tyrosine phosphorylation of TH1 has been found by EGF and estrogen treatments. Taken together, our findings demonstrate a novel mechanism for the comprehensive regulation of Ras/Raf/MEK/ERK signaling and cell migration involving tyrosine phosphorylation of TH1 by c-Src

Measuring capacity building in communities: a review of the literature

<p>Abstract</p> <p>Background</p> <p>Although communities have long been exhorted to make efforts to enhance their own health, such approaches have often floundered and resulted in little or no health benefits when the capacity of the community has not been adequately strengthened. Thus being able to assess the capacity building process is paramount in facilitating action in communities for social and health improvement. The current review aims to i) identify all domains used in systematically documented frameworks developed by other authors to assess community capacity building; and ii) to identify the dimensions and attributes of each of the domains as ascribed by these authors and reassemble them into a comprehensive compilation.</p> <p>Methods</p> <p>Relevant published articles were identified through systematic electronic searches of selected databases and the examination of the bibliographies of retrieved articles. Studies assessing capacity building or community development or community participation were selected and assessed for methodological quality, and quality in relation to the development and application of domains which were identified as constituents of community capacity building. Data extraction and analysis were undertaken using a realist synthesis approach.</p> <p>Results</p> <p>Eighteen articles met the criteria for this review. The various domains to assess community capacity building were identified and reassembled into nine comprehensive domains: "learning opportunities and skills development", "resource mobilization", "partnership/linkages/networking", "leadership", "participatory decision-making", "assets-based approach", "sense of community", "communication", and "development pathway". Six sub-domains were also identified: "shared vision and clear goals", "community needs assessment", "process and outcome monitoring", "sustainability", "commitment to action" and "dissemination".</p> <p>Conclusions</p> <p>The set of domains compiled in this review serve as a foundation for community-based work by those in the field seeking to support and nurture the development of competent communities. Further research is required to examine the robustness of capacity domains over time and to examine capacity development in association with health or other social outcomes.</p

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

<p>Abstract</p> <p>Background</p> <p>Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.</p> <p>Methods</p> <p>In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.</p> <p>Results</p> <p>Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.</p> <p>Conclusions</p> <p>Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.</p

Extending Epigenesis: From Phenotypic Plasticity to the Bio-Cultural Feedback

The paper aims at proposing an extended notion of epigenesis acknowledging an actual causal import to the phenotypic dimension for the evolutionary diversification of life forms. Section 1 offers introductory remarks on the issue of epigenesis contrasting it with ancient and modern preformationist views. In Section 2 we propose to intend epigenesis as a process of phenotypic formation and diversification a) dependent on environmental influences, b) independent of changes in the genomic nucleotide sequence, and c) occurring during the whole life span. Then, Section 3 focuses on phenotypic plasticity and offers an overview of basic properties (like robustness, modularity and degeneracy) that allows biological systems to be evolvable – i.e. to have the potentiality of producing phenotypic variation. Successively (Section 4), the emphasis is put on environmentally-induced modification in the regulation of gene expression giving rise to phenotypic variation and diversification. After some brief considerations on the debated issue of epigenetic inheritance (Section 5), the issue of culture (kept in the background of the preceding sections) is considered. The key point is that, in the case of humans and of the evolutionary history of the genus Homo at least, the environment is also, importantly, the cultural environment. Thus, Section 6 argues that a bio-cultural feedback should be acknowledged in the “epigenic” processes leading to phenotypic diversification and innovation in Homo evolution. Finally, Section 7 introduces the notion of “cultural neural reuse”, which refers to phenotypic/neural modifications induced by specific features of the cultural environment that are effective in human cultural evolution without involving genetic changes. Therefore, cultural neural reuse may be regarded as a key instance of the bio-cultural feedback and ultimately of the extended notion of epigenesis proposed in this work

The Neuronal Correlates of Digits Backward Are Revealed by Voxel-Based Morphometry and Resting-State Functional Connectivity Analyses

Digits backward (DB) is a widely used neuropsychological measure that is believed to be a simple and effective index of the capacity of the verbal working memory. However, its neural correlates remain elusive. The aim of this study is to investigate the neural correlates of DB in 299 healthy young adults by combining voxel-based morphometry (VBM) and resting-state functional connectivity (rsFC) analyses. The VBM analysis showed positive correlations between the DB scores and the gray matter volumes in the right anterior superior temporal gyrus (STG), the right posterior STG, the left inferior frontal gyrus and the left Rolandic operculum, which are four critical areas in the auditory phonological loop of the verbal working memory. Voxel-based correlation analysis was then performed between the positive rsFCs of these four clusters and the DB scores. We found that the DB scores were positively correlated with the rsFCs within the salience network (SN), that is, between the right anterior STG, the dorsal anterior cingulate cortex and the right fronto-insular cortex. We also found that the DB scores were negatively correlated with the rsFC within an anti-correlation network of the SN, between the right posterior STG and the left posterior insula. Our findings suggest that DB performance is related to the structural and functional organizations of the brain areas that are involved in the auditory phonological loop and the SN