Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility

We were supported by the Biotechnology and Biological Sciences Research Council grant BB/H001123/1 (P.W.), the Medical Research Council grants G0601498 and G1100546/2 (P.W.), Tenovus Scotland Grant G09/17 (A.J.M.) and the University of Aberdeen (P.W.). We thank O. Tüscher for discussion, P. Teismann and the microscopy core facility at the University of Aberdeen for the use of microscopy equipment, L. Strachan, A. Plano, S. Deiana for help with behavioral testing.

Effects of allergic diseases and age on the composition of serum IgG glycome in children

Glycan analysis was partly supported by European Commission GlycoBioM (contract #259869), IBD-BIOM (contract #305479), HighGlycan (contract #278535), MIMOmics (contract #305280), HTP-GlycoMet (contract #324400) and IntegraLife (contract #315997) grants. The SEATON cohort was partly funded by the UK Medical Research Council (contract #80219) and Asthma UK (contract #00/011 and 02/017) grants.

Habitual chocolate consumption and the risk of incident heart failure among healthy men and women

Acknowledgments The authors would like to thank the participants of the EPIC-Norfolk cohort. We thank the nutritionist team and data management team of the EPIC-Norfolk cohort. The EPIC-Norfolk study was supported by grants from the Medical Research Council and Cancer Research UK. Funders had no role in study design or interpretation of the findings.

Functional analysis of the 5′ flanking region of the human G6PC3 gene: regulation of promoter activity by glucose, pyruvate, AMP kinase and the pentose phosphate pathway

G6PC3 is a widely expressed isoform of glucose-6-phosphatase, found in many foetal and adult tissues. Mutations in this gene cause developmental abnormalities and severe neutropenia due to abolition of glucose recycling between the cytoplasm and endoplasmic reticulum. Low G6PC3 expression as a result of promoter polymorphisms or dysregulation could produce similar outcomes. Here we investigated the regulation of human G6PC3 promoter activity. HeLa and H4IIE cells were transiently transfected with G6PC3 promoter coupled to the firefly luciferase gene, and promoter activity was measured by dual luciferase assay. Activity was highest in a 453 bp segment of the G6PC3 promoter, from − 455 to − 3 relative to the transcriptional start site. This promoter was unresponsive to glucostatic hormones. Its activity increased significantly between 1 and 5.5 mM glucose, and was not elevated further by glucose concentrations up to 25 mM. Pyruvate increased its activity, but β-hydroxybutyrate and sodium acetate did not. Promoter activity was reduced by inhibitors of hexokinase, glyceraldehyde phosphate dehydrogenase and the oxidative branch of the pentose phosphate pathway, but not by a transketolase inhibitor. Deletion of two adjacent Enhancer-boxes (− 274 to − 279 and − 299 to − 304) reduced promoter activity and abolished the glucose effect, suggesting they could function as a glucose response element. Deletion of an additional downstream 140 bp (− 140 to − 306) restored activity, but not the glucose response, suggesting the presence of repressor elements in this region. 5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) reduced promoter activity, showing dependence on AMP-kinase. Regulation of the G6PC3 promoter is thus radically different to that of the hepatic isoform, G6PC. It is sensitive to carbohydrate, but not to fatty acid metabolites, and at much lower physiological concentrations. Based on these findings, we speculate that reduced G6PC3 expression could occur during hypoglycemic episodes in vivo, which are common in utero and in the postnatal period. If such episodes lower G6PC3 expression they could place the foetus or infant at risk of impaired immune function and development, and this possibility requires further examination both in vitro and in vivo.

A rehabilitation intervention to promote physical recovery following intensive care: a detailed description of construct development, rationale and content together with proposed taxonomy to capture processes in a randomised controlled trial.

Background: increasing numbers of patients are surviving critical illness, but survival may be associated with a constellation of physical and psychological sequelae that can cause on going disability and reduced health-related quality of life. Limited evidence currently exists to guide the optimum structure, timing, and content of rehabilitation programmes. There is a need to both develop and evaluate interventions to support and expedite recovery during the post-ICU discharge period. This paper describes the construct development for a complex rehabilitation intervention intended to promote physical recovery following critical illness. The intervention is currently being evaluated in a randomised trial (ISRCTN09412438; funder Chief Scientists Office, Scotland). Methods: the intervention was developed using the Medical Research Council (MRC) framework for developing complex healthcare interventions. We ensured representation from a wide variety of stakeholders including content experts from multiple specialties, methodologists, and patient representation. The intervention construct was initially based on literature review, local observational and audit work, qualitative studies with ICU survivors, and brainstorming activities. Iterative refinement was aided by the publication of a National Institute for Health and Care Excellence guideline (No. 83), publicly available patient stories (Healthtalkonline), a stakeholder event in collaboration with the James Lind Alliance, and local piloting. Modelling and further work involved a feasibility trial and development of a novel generic rehabilitation assistant (GRA) role. Several rounds of external peer review during successive funding applications also contributed to development. Results: the final construct for the complex intervention involved a dedicated GRA trained to pre-defined competencies across multiple rehabilitation domains (physiotherapy, dietetics, occupational therapy, and speech/language therapy), with specific training in post-critical illness issues. The intervention was from ICU discharge to 3 months post-discharge, including inpatient and post-hospital discharge elements. Clear strategies to provide information to patients/families were included. A detailed taxonomy was developed to define and describe the processes undertaken, and capture them during the trial. The detailed process measure description, together with a range of patient, health service, and economic outcomes were successfully mapped on to the modified CONSORT recommendations for reporting non-pharmacologic trial interventions. Conclusions: the MRC complex intervention framework was an effective guide to developing a novel post-ICU rehabilitation intervention. Combining a clearly defined new healthcare role with a detailed taxonomy of process and activity enabled the intervention to be clearly described for the purpose of trial delivery and reporting. These data will be useful when interpreting the results of the randomised trial, will increase internal and external trial validity, and help others implement the intervention if the intervention proves clinically and cost effective.

On the Problems of Mixing RCTs with Qualitative Research: The Case of the MRC Framework for the Evaluation of Complex Healthcare Interventions

In the perceived hierarchy of research designs, the results from randomized controlled trials are considered to provide the highest level of evidence. Indeed these trials have been upheld as the gold standard in research. The benefits and limitations of the randomized controlled trial as a method of evaluating the effectiveness of healthcare interventions are presented. The article then examines the different levels of complexity within healthcare interventions and the problems this poses in determining effectiveness. In an effort to provide a solution to this problem, the Medical Research Council produced a framework to assist investigators to develop and evaluate complex healthcare interventions. The framework is described with reference to an example of implementing and evaluating protocols for weaning patients in the intensive care unit. The framework is critiqued on the basis that it involves an ambiguous or contradictory ontology, which fails to articulate the relationship between the positivism of randomized controlled trials with the relativism of qualitative approaches. It is concluded that the use of realist strategies in combination with randomized controlled trials provides the most coherent solution to this quandary

Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center

Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch–Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death (‘primary refractoriness’). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML.

National Research Council of Thailand Visit

Agenda for the National Research Council of Thailand's Visit to Florida International University on May 17 and 18, 2007.

Lifting the lifegiving dollar : case samples of creative practice in health and medical research philanthropy

This study aims to stimulate thought, debate and action for change on this question of more vigorous philanthropic funding of Australian health and medical research (HMR). It sharpens the argument with some facts and ideas about HMR funding from overseas sources. It also reports informed opinions from those working, giving and innovating in this area. It pinpoints the range of attitudes to HMR giving, both positive and negative. The study includes some aspects of Government funding as part of the equation, viewing Government as major HMR givers, with particular ability to partner, leverage and create incentives. Stimulating new philanthropy takes active outreach. The opportunity to build more dialogue between the HMR industry and the wider community is timely given the ‘licence to practice’ issues and questioned trust that applies currently somewhat both to science and to the charitable sector. This interest in improving HMR philanthropy also coincides with the launch last year by the Federal Government of Nonprofit Australia Limited (NAL), a group currently assessing infrastructure improvements to the charitable sector. History suggests no one will create this change if Research Australia does not. However, interest in change exists in various quarters. For Research Australia to successfully change the culture of Australian HMR giving, the process will drive the outcomes. Obviously stakeholder buy-in and partners will be needed and the ultimate blueprint for greater philanthropic HMR funding here will not be this document. Instead it will be the one that wears the handprint and ‘mindprint’ of the many architects and implementers interested in promoting HMR philanthropy, from philanthropists to nonprofit peaks to government policy arms. As the African proverb says, ‘If you want to go fast, go alone; but if you want to go far, go with others’.

Securing medical research data with a rights management system

We propose a digital rights management approach for sharing electronic health records for research purposes and argue advantages of the approach. We give an outline of our implementation, discuss challenges that we faced and future directions.

Using digital rights management for securing data in a medical research environment

We propose a digital rights management approach for sharing electronic health records in a health research facility and argue advantages of the approach. We also give an outline of the system under development and our implementation of the security features and discuss challenges that we faced and future directions.

Funding grant proposals for scientific research : retrospective analysis of scores by members of grant review panel

Objectives: To quantify randomness and cost when choosing health and medical research projects for funding. Design: Analysis of retrospective data from grant review panels. Setting: The National Health & Medical Research Council of Australia. Participants/Data: All panel members’ scores for grant proposals submitted in 2009. Main outcome measure: The proportion of grant proposals that were always, sometimes and never funded after accounting for random variability arising from variation in panel members’ scores; the cost-effectiveness of different size assessment panels. Results: 59% of 620 funded grants were sometimes not funded when random variability was accounted for. Only 9% of grant proposals were always funded, 61% were never funded and 29% were sometimes funded. The extra cost per grant effectively funded from the most effective system was $18,541. Conclusions: Allocating funding for scientific research in health and medicine is costly and somewhat random. There are many useful research questions to be addressed that could improve current processes.

Ethical review in creative industries and other practice-based research

The processes used in Australian universities for reviewing the ethics of research projects are based on the traditions of research and practice from the medical and health sciences. The national guidelines for ethical conduct in research are heavily based on presumptions that the researcher–participant relationship is similar to a doctor–patient relationship. The National Health and Medical Research Council, Australian Research Council and Australian Vice-Chancellors’ Committee have made a laudable effort to fix this problem by releasing the National Statement on Ethical Conduct in Human Research in 2007, to replace the 1999 National Statement on Ethical Conduct in Research Involving Humans. The new statement better encompasses the needs of the humanities, social sciences and creative industries. However, this paper argues that the revised National Statement and ethical review processes within universities still do not fully encompass the definitions of ‘research’ and the requirements, traditions, codes of practice and standards of the humanities, social sciences and creative industries. The paper argues that scholars within these disciplines often lack the language to articulate their modes of practice and risk management strategies to university-level ethics committees. As a consequence, scholars from these disciplines may find their research is delayed or stymied. The paper focuses on creative industries researchers, and explores the issues that they face in managing the ethical review process, particularly when engaging in practice-based research. Although the focus is on the creative industries, the issues are relevant to most fields in the humanities and social sciences.

Sri Lanka in global medical research: a scientific analysis of the Sri Lankan research output during 2000-2009

Background Scientific research is an essential component in guiding improvements in health systems. There are no studies examining the Sri Lankan medical research output at international level. The present study evaluated the Sri Lankan research performance in medicine as reflected by the research publications output between years 2000-2009. Methods This study was based on Sri Lankan medical research publication data, retrieved from the SciVerse Scopus® from January 2000 to December 2009. The process of article selection was as follows: Affiliation - 'Sri Lanka' or 'Ceylon', Publication year - 'January 2000 to December 2009' and Subject area - 'Life and Health Sciences'. The articles identified were classified according to disease, medical speciality, institutions, major international collaborators, authors and journals. Results Sri Lanka's cumulative medical publications output between years 2000-2009 was 1,740 articles published in 160 different journals. The average annual publication growth rate was 9.1%. Majority of the articles were published in 'International' (n = 950, 54.6%) journals. Most articles were descriptive studies (n = 611, 35.1%), letters (n-345, 19.8%) and case reports (n = 311, 17.9%). The articles were authored by 148 different Sri Lankan authors from 146 different institutions. The three most prolific local institutions were Universities of; Colombo (n = 547), Kelaniya (n = 246) and Peradeniya (n = 222). Eighty four countries were found to have published collaborative papers with Sri Lankan authors during the last decade. UK was the largest collaborating partner (n = 263, 15.1%). Malaria (n = 75), Diabetes Mellitus (n = 55), Dengue (n = 53), Accidental injuries (n = 42) and Lymphatic filariasis (n = 40) were the major diseases studied. The 1,740 publications were cited 9,708 times, with an average citation of 5.6 per paper. The most cited paper had 203 citations, while there were 597 publications with no citations. The Sri Lankan authors' contribution to the global medical research output during the last decade was only 0.086%. Conclusion The Sri Lankan medical research output during the last decade is only a small fraction of the global research output. There it is a necessity to setup an enabling environment for research, with a proper vision, support, funds and training. In addition, collaborations across the region need to be strengthened to face common regional health challenges. Keywords: Sri Lanka, Medical research, Publication, Analysis