106 research outputs found

    Identification of complex health interventions suitable for evaluation: development and validation of the 8-step scoping framework

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    Background: There is extensive literature on the methodology of evaluation research and the development and evaluation of complex interventions but little guidance on the formative stages before evaluation and how to work with partner organizations that wish to have their provision evaluated. It is important to be able to identify suitable projects for evaluation from a range of provision and describe the steps required, often with academic institutions working in partnership with external organizations, in order to set up an evaluation. However, research evaluating programs or interventions rarely discusses these stages. Objective: This study aimed to extend work on evaluability assessment and pre-evaluation planning by proposing an 8-Step Scoping Framework to enable the appraisal of multiple programs in order to identify interventions suitable for evaluation. We aimed to add to the literature on evaluability assessment and more recent evaluation guidance by describing the processes involved in working with partner organizations. Methods: This paper documents the steps required to identify multiple complex interventions suitable for process and outcome evaluation. The steps were developed using an iterative approach by working alongside staff in a local government organization, to build an evidence base to demonstrate which interventions improve children’s outcomes. The process of identifying suitable programs for evaluation, thereby establishing the pre-evaluation steps, was tested using all Flying Start provision. Results: The 8-Step Scoping Framework was described using the example of the local government organization Flying Start to illustrate how each step contributes to finding projects suitable for process and outcome evaluation: (1) formulating overarching key questions that encompass all programs offered by an organization, (2) gaining an in-depth understanding of the work and provision of an organization and engaging staff, (3) completing a data template per project/program offered, (4) assessing the robustness/validity of data across all programs, (5) deciding on projects suitable for evaluation and those requiring additional data, (6) negotiating with chosen project leads, both within and outside the organization, (7) developing individual project evaluation protocols, and (8) applying for ethical approval from the university and partner organization. Conclusions: This paper describes the processes involved in identifying suitable projects for evaluation. It adds to the existing literature on the assessment of specific programs suitable for evaluation and guidance for conducting evaluations by establishing the formative steps required to identify suitable programs from a range of provision. This scoping framework particularly relates to academic partners and organizations tasked with delivering evidence-based services designed to meet local needs. The steps identified have been described in the context of early years provision but can be applied to a range of community-based evaluations, or more generally, to cases where an academic partner is working with external stakeholders to identify projects suitable for academic evaluation

    An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

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    BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1–5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan–Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16–82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up

    Direct Binding of a Hepatitis C Virus Inhibitor to the Viral Capsid Protein

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    Over 130 million people are infected chronically with hepatitis C virus (HCV), which, together with HBV, is the leading cause of liver disease. Novel small molecule inhibitors of Hepatitis C virus (HCV) are needed to complement or replace current treatments based on pegylated interferon and ribavirin, which are only partially successful and plagued with side-effects. Assembly of the virion is initiated by the oligomerization of core, the capsid protein, followed by the interaction with NS5A and other HCV proteins. By screening for inhibitors of core dimerization, we previously discovered peptides and drug-like compounds that disrupt interactions between core and other HCV proteins, NS3 and NS5A, and block HCV production. Here we report that a biotinylated derivative of SL209, a prototype small molecule inhibitor of core dimerization (IC50 of 2.80 µM) that inhibits HCV production with an EC50 of 3.20 µM, is capable of penetrating HCV-infected cells and tracking with core. Interaction between the inhibitors, core and other viral proteins was demonstrated by SL209–mediated affinity-isolation of HCV proteins from lysates of infected cells, or of the corresponding recombinant HCV proteins. SL209-like inhibitors of HCV core may form the basis of novel treatments of Hepatitis C in combination with other target-specific HCV drugs such as inhibitors of the NS3 protease, the NS5B polymerase, or the NS5A regulatory protein. More generally, our work supports the hypothesis that inhibitors of viral capsid formation might constitute a new class of potent antiviral agents, as was recently also shown for HIV capsid inhibitors

    Financial incentives for return of service in underserved areas: a systematic review

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    <p>Abstract</p> <p>Background</p> <p>In many geographic regions, both in developing and in developed countries, the number of health workers is insufficient to achieve population health goals. Financial incentives for return of service are intended to alleviate health worker shortages: A (future) health worker enters into a contract to work for a number of years in an underserved area in exchange for a financial pay-off.</p> <p>Methods</p> <p>We carried out systematic literature searches of PubMed, the Excerpta Medica database, the Cumulative Index to Nursing and Allied Health Literature, and the National Health Services Economic Evaluation Database for studies evaluating outcomes of financial-incentive programs published up to February 2009. To identify articles for review, we combined three search themes (health workers or students, underserved areas, and financial incentives). In the initial search, we identified 10,495 unique articles, 10,302 of which were excluded based on their titles or abstracts. We conducted full-text reviews of the remaining 193 articles and of 26 additional articles identified in reference lists or by colleagues. Forty-three articles were included in the final review. We extracted from these articles information on the financial-incentive programs (name, location, period of operation, objectives, target groups, definition of underserved area, financial incentives and obligation) and information on the individual studies (authors, publication dates, types of study outcomes, study design, sample criteria and sample size, data sources, outcome measures and study findings, conclusions, and methodological limitations). We reviewed program results (descriptions of recruitment, retention, and participant satisfaction), program effects (effectiveness in influencing health workers to provide care, to remain, and to be satisfied with work and personal life in underserved areas), and program impacts (effectiveness in influencing health systems and health outcomes).</p> <p>Results</p> <p>Of the 43 reviewed studies 34 investigated financial-incentive programs in the US. The remaining studies evaluated programs in Japan (five studies), Canada (two), New Zealand (one) and South Africa (one). The programs started between 1930 and 1998. We identified five different types of programs (service-requiring scholarships, educational loans with service requirements, service-option educational loans, loan repayment programs, and direct financial incentives). Financial incentives to serve for one year in an underserved area ranged from year-2000 United States dollars 1,358 to 28,470. All reviewed studies were observational. The random-effects estimate of the pooled proportion of all eligible program participants who had either fulfilled their obligation or were fulfilling it at the time of the study was 71% (95% confidence interval 60–80%). Seven studies compared retention in the <it>same </it>(underserved) area between program participants and non-participants. Six studies found that participants were less likely than non-participants to remain in the same area (five studies reported the difference to be statistically significant, while one study did not report a significance level); one study did not find a significant difference in retention in the same area. Thirteen studies compared provision of care or retention in <it>any </it>underserved area between participants and non-participants. Eleven studies found that participants were more likely to (continue to) practice in any underserved area (nine studies reported the difference to be statistically significant, while two studies did not provide the results of a significance test); two studies found that program participants were significantly less likely than non-participants to remain in any underserved area. Seven studies investigated the satisfaction of participants with their work and personal lives in underserved areas.</p> <p>Conclusion</p> <p>Financial-incentive programs for return of service are one of the few health policy interventions intended to improve the distribution of human resources for health on which substantial evidence exists. However, the majority of studies are from the US, and only one study reports findings from a developing country, limiting generalizability. The existing studies show that financial-incentive programs have placed substantial numbers of health workers in underserved areas and that program participants are more likely than non-participants to work in underserved areas in the long run, even though they are less likely to remain at the site of original placement. As none of the existing studies can fully rule out that the observed differences between participants and non-participants are due to selection effects, the evidence to date does not allow the inference that the programs have caused increases in the supply of health workers to underserved areas.</p

    The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours

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    Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists (90)Y-DOTATOC ([(90)Y-DOTA(0),Tyr(3)]-octreotide) or (177)Lu-DOTATATE ([(177)Lu-DOTA(0),Tyr(3),Thr(8)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving (177)Lu-DOTATATE or (90)Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency

    Hormones of the Adrenal Medulla

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