Discussion of off-target and tentative genomic findings may sometimes be necessary to allow evaluation of their clinical significance

We discuss a case where clinical genomic investigation of muscle weakness unexpectedly found a genetic variant that might (or might not) predispose to kidney cancer. We argue that despite its off-target and uncertain nature, this variant should be discussed with the man who had the test, not because it is medical information, but because this discussion would allow the further clinical evaluation that might lead it to becoming so. We argue that while prominent ethical debates around genomics often take 'results' as a starting point and ask questions as to whether to look for and how to react to them, the construction of genomic results is fraught with ethical complexity, although often couched as a primarily technical problem. We highlight the need for greater focus on, and appreciation of, the ethical work undertaken daily by scientists and clinicians working in genomic medicine and discuss how public conversations around genomics need to adapt to prepare future patients for potentially uncertain and unexpected outcomes from clinical genomic tests

Speech and communication in Parkinson’s disease: a cross-sectional exploratory study in the UK

Objective: To assess associations between cognitive status, intelligibility, acoustics and functional communication in PD. Design: Cross-sectional exploratory study of functional communication, including a within-participants experimental design for listener assessment. Setting: A major academic medical centre in the East of England, UK. Participants: Questionnaire data were assessed for 45 people with Parkinson’s disease (PD), who had self-reported speech or communication difficulties and did not have clinical dementia. Acoustic and listener analyses were conducted on read and conversational speech for 20 people with PD and 20 familiar conversation partner controls without speech, language or cognitive difficulties. Main outcome measures: Functional communication assessed by the Communicative Participation Item Bank (CPIB) and Communicative Effectiveness Survey (CES). Results: People with PD had lower intelligibility than controls for both the read (mean difference 13.7%, p=0.009) and conversational (mean difference 16.2%, p=0.04) sentences. Intensity and pause were statistically significant predictors of intelligibility in read sentences. Listeners were less accurate identifying the intended emotion in the speech of people with PD (14.8% point difference across conditions, p=0.02) and this was associated with worse speaker cognitive status (16.7% point difference, p=0.04). Cognitive status was a significant predictor of functional communication using CPIB (F=8.99, p=0.005, η2 = 0.15) but not CES. Intelligibility in conversation sentences was a statistically significant predictor of CPIB (F=4.96, p=0.04, η2 = 0.19) and CES (F=13.65, p=0.002, η2 = 0.43). Read sentence intelligibility was not a significant predictor of either outcome. Conclusions: Cognitive status was an important predictor of functional communication—the role of intelligibility was modest and limited to conversational and not read speech. Our results highlight the importance of focusing on functional communication as well as physical speech impairment in speech and language therapy (SLT) for PD. Our results could inform future trials of SLT techniques for PD

CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma

Metabolic adjustments are necessary for the initiation, proliferation, and spread of cancer cells. Although mitochondria have been shown to move to cancer cells from their microenvironment, the metabolic consequences of this phenomenon have yet to be fully elucidated. Here we report that multiple myeloma (MM) cells use mitochondrial-based metabolism as well as glycolysis when located within the bone marrow microenvironment (BMM). The reliance of MM cells on oxidative phosphorylation was caused by intercellular mitochondrial transfer to MM cells from neighboring non-malignant bone marrow stromal cells (BMSC). This mitochondrial transfer occurred through tumor-derived tunneling nanotubes (TNT). Moreover, shRNA mediated knockdown of CD38 inhibits mitochondrial transfer and TNT formation in-vitro and blocks mitochondrial transfer and improves animal survival in vivo. This study describes a potential treatment strategy to inhibit mitochondrial transfer for clinical benefit and scientifically expands the understanding of the functional effects of mitochondrial transfer on tumor metabolism

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Towards building equitable health systems in Sub-Saharan Africa: lessons from case studies on operational research

<p>Abstract</p> <p>Background</p> <p>Published practical examples of how to bridge gaps between research, policy and practice in health systems research in Sub Saharan Africa are scarce. The aim of our study was to use a case study approach to analyse how and why different operational health research projects in Africa have contributed to health systems strengthening and promoted equity in health service provision.</p> <p>Methods</p> <p>Using case studies we have collated and analysed practical examples of operational research projects on health in Sub-Saharan Africa which demonstrate how the links between research, policy and action can be strengthened to build effective and pro-poor health systems. To ensure rigour, we selected the case studies using pre-defined criteria, mapped their characteristics systematically using a case study development framework, and analysed the research impact process of each case study using the RAPID framework for research-policy links. This process enabled analysis of common themes, successes and weaknesses.</p> <p>Results</p> <p>3 operational research projects met our case study criteria: HIV counselling and testing services in Kenya; provision of TB services in grocery stores in Malawi; and community diagnostics for anaemia, TB and malaria in Nigeria. <b>Political context and external influences: </b>in each case study context there was a need for new knowledge and approaches to meet policy requirements for equitable service delivery. Collaboration between researchers and key policy players began at the inception of operational research cycles. <b>Links</b>: critical in these operational research projects was the development of partnerships for capacity building to support new services or new players in service delivery. <b>Evidence: </b>evidence was used to promote policy dialogue around equity in different ways throughout the research cycle, such as in determining the topic area and in development of indicators.</p> <p>Conclusion</p> <p>Building equitable health systems means considering equity at different stages of the research cycle. Partnerships for capacity building promotes demand, delivery and uptake of research. Links with those who use and benefit from research, such as communities, service providers and policy makers, contribute to the timeliness and relevance of the research agenda and a receptive research-policy-practice interface. Our study highlights the need to advocate for a global research culture that values and funds these multiple levels of engagement.</p

CTL Responses of High Functional Avidity and Broad Variant Cross-Reactivity Are Associated with HIV Control

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI