Showing papers by "University of London published in 2008"

Developing and evaluating complex interventions: The new Medical Research Council guidance

Abstract: Evaluating complex interventions is complicated. The Medical Research Council9s evaluation framework (2000) brought welcome clarity to the task. Now the council has updated its guidance

IL-10: The Master Regulator of Immunity to Infection

Abstract: IL-10 is an anti-inflammatory cytokine. During infection it inhibits the activity of Th1 cells, NK cells, and macrophages, all of which are required for optimal pathogen clearance but also contribute to tissue damage. In consequence, IL-10 can both impede pathogen clearance and ameliorate immunopathology. Many different types of cells can produce IL-10, with the major source of IL-10 varying in different tissues or during acute or chronic stages of the same infection. The priming of these various IL-10-producing populations during infections is not well understood and it is not clear whether the cellular source of IL-10 during infection dictates its cellular target and thus its outcome. In this article we review the biology of IL-10, its cellular sources, and its role in viral, bacterial, and protozoal infections.

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Abstract: To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

Cyberbullying: Another main type of bullying?

Abstract: Cyberbullying has recently emerged as a new form of bullying and harassment. 360 adolescents (12–20 years), were surveyed to examine the nature and extent of cyberbullying in Swedish schools. Four categories of cyberbullying (by text message, email, phone call and picture/video clip) were examined in relation to age and gender, perceived impact, telling others, and perception of adults becoming aware of such bullying. There was a significant incidence of cyberbullying in lower secondary schools, less in sixth-form colleges. Gender differences were few. The impact of cyberbullying was perceived as highly negative for picture/video clip bullying. Cybervictims most often chose to either tell their friends or no one at all about the cyberbullying, so adults may not be aware of cyberbullying, and (apart from picture/video clip bullying) this is how it was perceived by pupils. Findings are discussed in relation to similarities and differences between cyberbullying and the more traditional forms of bullying.

Heat Stress and Public Health: A Critical Review

Abstract: Heat is an environmental and occupational hazard. The prevention of deaths in the community caused by extreme high temperatures (heat waves) is now an issue of public health concern. The risk of heat-related mortality increases with natural aging, but persons with particular social and/or physical vulnerability are also at risk. Important differences in vulnerability exist between populations, depending on climate, culture, infrastructure (housing), and other factors. Public health measures include health promotion and heat wave warning systems, but the effectiveness of acute measures in response to heat waves has not yet been formally evaluated. Climate change will increase the frequency and the intensity of heat waves, and a range of measures, including improvements to housing, management of chronic diseases, and institutional care of the elderly and the vulnerable, will need to be developed to reduce health impacts.

Epidemiology and etiology of childhood pneumonia

Abstract: Childhood pneumonia is the leading single cause of mortality in children aged less than 5 years. The incidence in this age group is estimated to be 0.29 episodes per child-year in developing and 0.05 episodes per child-year in developed countries. This translates into about 156 million new episodes each year worldwide, of which 151 million episodes are in the developing world. Most cases occur in India (43 million), China (21 million) and Pakistan (10 million), with additional high numbers in Bangladesh, Indonesia and Nigeria (6 million each). Of all community cases, 7-13% are severe enough to be life-threatening and require hospitalization. Substantial evidence revealed that the leading risk factors contributing to pneumonia incidence are lack of exclusive breastfeeding, undernutrition, indoor air pollution, low birth weight, crowding and lack of measles immunization. Pneumonia is responsible for about 19% of all deaths in children aged less than 5 years, of which more than 70% take place in sub-Saharan Africa and south-east Asia. Although based on limited available evidence, recent studies have identified Streptococcus pneumoniae, Haemophilus influenzae and respiratory syncytial virus as the main pathogens associated with childhood pneumonia.

Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

Abstract: Summary Background Mutations in LRRK2 , the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2 -associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2 ? Methods Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2 -associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Findings Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2 -associated PD were more benign than those of idiopathic PD. Interpretation Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. Funding UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

Cancer survival in five continents: a worldwide population-based study (CONCORD)

Abstract: Summary Background Cancer survival varies widely between countries. The CONCORD study provides survival estimates for 1·9 million adults (aged 15–99 years) diagnosed with a first, primary, invasive cancer of the breast (women), colon, rectum, or prostate during 1990–94 and followed up to 1999, by use of individual tumour records from 101 population-based cancer registries in 31 countries on five continents. This is, to our knowledge, the first worldwide analysis of cancer survival, with standard quality-control procedures and identical analytic methods for all datasets. Methods To compensate for wide international differences in general population (background) mortality by age, sex, country, region, calendar period, and (in the USA) ethnic origin, we estimated relative survival, the ratio of survival noted in the patients with cancer, and the survival that would have been expected had they been subject only to the background mortality rates. 2800 life tables were constructed. Survival estimates were also adjusted for differences in the age structure of populations of patients with cancer. Findings Global variation in cancer survival was very wide. 5-year relative survival for breast, colorectal, and prostate cancer was generally higher in North America, Australia, Japan, and northern, western, and southern Europe, and lower in Algeria, Brazil, and eastern Europe. CONCORD has provided the first opportunity to estimate cancer survival in 11 states in USA covered by the National Program of Cancer Registries (NPCR), and the study covers 42% of the US population, four-fold more than previously available. Cancer survival in black men and women was systematically and substantially lower than in white men and women in all 16 states and six metropolitan areas included. Relative survival for all ethnicities combined was 2–4% lower in states covered by NPCR than in areas covered by the Surveillance Epidemiology and End Results (SEER) Program. Age-standardised relative survival by use of the appropriate race-specific and state-specific life tables was up to 2% lower for breast cancer and up to 5% lower for prostate cancer than with the census-derived national life tables used by the SEER Program. These differences in population coverage and analytical method have both contributed to the survival deficit noted between Europe and the USA, from which only SEER data have been available until now. Interpretation Until now, direct comparisons of cancer survival between high-income and low-income countries have not generally been available. The information provided here might therefore be a useful stimulus for change. The findings should eventually facilitate joint assessment of international trends in incidence, survival, and mortality as indicators of cancer control. Funding Centers for Disease Control and Prevention (Atlanta, GA, USA), Department of Health (London, UK), Cancer Research UK (London, UK).

Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset

Abstract: Since the discovery of T helper type 1 and type 2 effector T cell subsets 20 years ago, inducible regulatory T cells and interleukin 17 (IL-17)-producing T helper cells have been added to the 'portfolio' of helper T cells. It is unclear how many more effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Here we show that transforming growth factor-beta, a cytokine at the center of the differentiation of IL-17-producing T helper cells and inducible regulatory T cells, 'reprograms' T helper type 2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drives the differentiation of 'T(H)-9' cells directly. Thus, transforming growth factor-beta constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways.

Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics.

Abstract: Background Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors. Methods and Findings Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial. Conclusions Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.

Functionalized carbon nanotubes in drug design and discovery.

Abstract: Carbon nanotubes (CNTs) have been proposed and actively explored as multipurpose innovative carriers for drug delivery and diagnostic applications. Their versatile physicochemical features enable the covalent and noncovalent introduction of several pharmaceutically relevant entities and allow for rational design of novel candidate nanoscale constructs for drug development. CNTs can be functionalized with different functional groups to carry simultaneously several moieties for targeting, imaging, and therapy. Among the most interesting examples of such multimodal CNT constructs described in this Account is one carrying a fluorescein probe together with the antifungal drug amphotericin B or fluorescein and the antitumor agent methotrexate. The biological action of the drug in these cases is retained or, as in the case of amphotericin B constructs, enhanced, while CNTs are able to reduce the unwanted toxicity of the drug administered alone. Ammonium-functionalized CNTs can also be considered very promising vectors for gene-encoding nucleic acids. Indeed, we have formed stable complexes between cationic CNTs and plasmid DNA and demonstrated the enhancement of the gene therapeutic capacity in comparison to DNA alone. On the other hand, CNTs conjugated with antigenic peptides can be developed as a new and effective system for synthetic vaccine applications. What makes CNTs quite unique is their ability, first shown by our groups in 2004, to passively cross membranes of many different types of cells following a translocation mechanism that has been termed the nanoneedle mechanism. In that way, CNTs open innumerable possibilities for future drug discovery based on intracellular targets that have been hard to reach until today. Moreover, adequately functionalized CNTs as those shown in this Account can be rapidly eliminated from the body following systemic administration offering further encouragment for their development. CNT excretion rates and accumulation in organs and any reactivity with the immune system will determine the CNT safety profile and, consequently, any further pharmaceutical development. Caution is advised about the need for systematic data on the long-term fate of these very interesting and versatile nano-objects in correlation with the type of CNT material used. CNTs are gradually plyaing a bigger and more important role in the emerging field of nanomedicine; however, we need to guarantee that the great opportunities they offer will be translated into feasible and safe constructs to be included in drug discovery and development pipelines.

Entrepreneurial Orientation, Learning Orientation, and Firm Performance

Abstract: Entrepreneurial orientation (EO) is a key ingredient for firm success. Nonetheless, an important message from past findings is that simply examining the direct effect of EO on firm performance prov...

Birth Weight and Risk of Type 2 Diabetes: A Systematic Review

Abstract: Context Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. Objective To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. Data Sources and Study Selection Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. Data Extraction Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. Data Synthesis Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight–type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I 2 = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight–type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. Conclusion In most populations studied, birth weight was inversely related to type 2 diabetes risk.

Plasmodium knowlesi Malaria in Humans Is Widely Distributed and Potentially Life Threatening

Abstract: Background. Until recently, Plasmodium knowlesi malaria in humans was misdiagnosed as Plasmodium malariae malaria. The objectives of the present study were to determine the geographic distribution of P. knowlesi malaria in the human population in Malaysia and to investigate 4 suspected fatal cases. Methods. Sensitive and specific nested polymerase chain reaction was used to identify all Plasmodium species present in (1) blood samples obtained from 960 patients with malaria who were hospitalized in Sarawak, Malaysian Borneo, during 2001-2006; (2) 54 P. malariae archival blood films from 15 districts in Sabah, Malaysian Borneo (during 2003-2005), and 4 districts in Pahang, Peninsular Malaysia (during 2004-2005); and (3) 4 patients whose suspected cause of death was P. knowlesi malaria. For the 4 latter cases, available clinical and laboratory data were reviewed. Results. P. knowlesi DNA was detected in 266 (27.7%) of 960 of the samples from Sarawak hospitals, 41 (83.7%) of 49 from Sabah, and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 patients who died. All were hyperparasitemic and developed marked hepatorenal dysfunction. Conclusions. Human infection with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 h, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for P. knowlesi malaria, we recommend that patients who reside in or have traveled to Southeast Asia and who have received a "P. malariae" hyperparasitemia diagnosis by microscopy receive intensive management as appropriate for severe falciparum malaria.

Conducting a meta-ethnography of qualitative literature: Lessons learnt

Abstract: Qualitative synthesis has become more commonplace in recent years. Meta-ethnography is one of several methods for synthesising qualitative research and is being used increasingly within health care research. However, many aspects of the steps in the process remain ill-defined. We utilized the seven stages of the synthesis process to synthesise qualitative research on adherence to tuberculosis treatment. In this paper we discuss the methodological and practical challenges faced; of particular note are the methods used in our synthesis, the additional steps that we found useful in clarifying the process, and the key methodological challenges encountered in implementing the meta-ethnographic approach. The challenges included shaping an appropriate question for the synthesis; identifying relevant studies; assessing the quality of the studies; and synthesising findings across a very large number of primary studies from different contexts and research traditions. We offer suggestions that may assist in undertaking meta-ethnographies in the future. Meta-ethnography is a useful method for synthesising qualitative research and for developing models that interpret findings across multiple studies. Despite its growing use in health research, further research is needed to address the wide range of methodological and epistemological questions raised by the approach.

Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis.

Abstract: Clinically isolated syndromes (CIS), such as optic neuritis, brainstem or spinal cord syndromes are frequently the first clinical presentations of multiple sclerosis However, not all CIS patients develop multiple sclerosis and in those who do, disability is highly variable In previous follow-up studies, brain lesions on T2-weighted MRI are associated with increased risk of multiple sclerosis and to an extent disability We evaluated the longitudinal relationships between the MRI lesions and clinical course over a period of 20 years CIS patients were recruited between 1984 and 1987 and previously followed up after 1, 5, 10 and 14 years Of the 140 subjects who were initially recruited with a CIS for a baseline MRI study, we followed up 107 patients after a mean of 202 years (range 18-277) Multiple sclerosis was diagnosed as clinically definite on clinical grounds only and disability determined using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) score Clinically definite multiple sclerosis developed in 67 out of 107 (63%) overall: 60 out of 73 (82%) with abnormal and 7 out of 34 (21%) with normal baseline MRI Multiple sclerosis was still relapsing-remitting in 39 (58%)--including 26 (39%) with a 'benign' course (EDSS < or = 3)--whilst 28 (42%) had developed secondary progression T2 lesion volume at all time-points correlated moderately with 20-year EDSS (r(s) values 048 to 067; P < 0001) and MSFC z-score [r(s) values (-050) to (-061); P < 0001] In those developing multiple sclerosis, a concurrent correlation of change in T2 lesion volume with change in EDSS was most evident in years 0-5 (r(s) = 069, P < 0001) The estimated rate of lesion growth over 20 years was 080 cm3/year in those who retained a relapsing remitting multiple sclerosis course, and 289 cm3/year in those who developed secondary progressive multiple sclerosis, a difference of 209 cm3/year (95% CI: 077, 296; P < 0001) This study extends previous follow-up of CIS patients and sheds new light on how the lesions evolve according to the natural history Baseline MRI findings are predictive for development of clinically definite multiple sclerosis Lesion volume and its change at earlier time points are correlated with disability after 20 years Lesion volume increases for at least 20 years in relapse-onset multiple sclerosis and the rate of lesion growth is three times higher in those who develop secondary progressive than in those who remain relapsing remitting multiple sclerosis

Undue reliance on I(2) in assessing heterogeneity may mislead.

Abstract: The heterogeneity statistic I 2, interpreted as the percentage of variability due to heterogeneity between studies rather than sampling error, depends on precision, that is, the size of the studies included. Based on a real meta-analysis, we simulate artificially 'inflating' the sample size under the random effects model. For a given inflation factor M = 1, 2, 3,... and for each trial i, we create a M-inflated trial by drawing a treatment effect estimate from the random effects model, using /M as within-trial sampling variance. As precision increases, while estimates of the heterogeneity variance τ 2 remain unchanged on average, estimates of I 2 increase rapidly to nearly 100%. A similar phenomenon is apparent in a sample of 157 meta-analyses. When deciding whether or not to pool treatment estimates in a meta-analysis, the yard-stick should be the clinical relevance of any heterogeneity present. τ 2, rather than I 2, is the appropriate measure for this purpose.

The epidemiology of obesity: the size of the problem.

Abstract: The epidemic of obesity took off from about 1980 and in almost all countries has been rising inexorably ever since. Only in 1997 did WHO accept that this was a major public health problem and, even then, there was no accepted method for monitoring the problem in children. It was soon evident, however, that the optimum population body mass index is about 21 and this is particularly true in Asia and Latin America where the populations are very prone to developing abdominal obesity, type 2 diabetes and hypertension. These features are now being increasingly linked to epigenetic programming of gene expression and body composition in utero and early childhood, both in terms of fat/lean tissue ratios and also in terms of organ size and metabolic pathway regulation. New Indian evidence suggests that insulin resistance at birth seems linked to low birth weight and a higher proportion of body fat with selective B12 deficiency and abnormalities of one carbon pool metabolism potentially responsible and affecting 75% of Indians and many populations in the developing world. Biologically there are also adaptive biological mechanisms which limit weight loss after weight gain and thereby in part account for the continuing epidemic despite the widespread desire to slim. Logically, the burden of disease induced by inappropriate diets and widespread physical inactivity can be addressed by increasing physical activity (PA), but simply advocating more leisure time activity is unrealistic. Substantial changes in urban planning and diet are needed to counter the removal of any every day need for PA and the decades of misdirected food policies which with free market forces have induced our current 'toxic environment'. Counteracting this requires unusual policy initiatives.

Reliability, repeatability and reproducibility: analysis of measurement errors in continuous variables

Abstract: Clinical practice involves measuring quantities for a variety of purposes, such as aiding diagnosis, predicting future patient outcomes, and serving as endpoints in studies or randomized trials. Measurements are almost always prone to various sorts of errors, which cause the measured value to differ from the true value; accordingly, studies investigating measurement error frequently appear in this and other journals. The importance of measurement error depends upon the context in which the measurements in question are to be used. For example, a certain degree of measurement error may be acceptable if measurements are to be used as an outcome in a comparative study such as a clinical trial, but the same measurement errors may be unacceptably large to make measurements usable in individual patient management, such as screening or risk prediction. In the past 20 years many papers have been published advocating how studies of measurement error should be analyzed, with a paper by Bland and Altman1 being one of the most cited and well known examples. There has been much controversy concerning the choice of parameter to be estimated and reported, and consequently confusion surrounding the meaning and interpretation of results from studies investigating measurement error. In this paper we first distinguish between the general concepts of agreement and reliability to aid researchers in considering which are relevant for their particular application. We then review the statistical methods that can be used to investigate and quantify agreement and reliability, dealing separately with the different types of measurement error study, while emphasizing the largely common techniques that should be used for data analysis. We reiterate that the judgment of whether agreement or reliability are acceptable must be related to the clinical application, and cannot be proven by a statistical test. We highlight the fact that reliability depends on the population in which measurements are made, and not just on the measurement errors of the measurement method. We discuss the advantages of method comparison studies making at least two measurements with each measurement method on each subject. A key advantage is that the cause of a correlation between paired differences and means in the so-called Bland–Altman plot can be determined, in contrast to when only a single measurement is made with each method. Throughout the paper, we try to emphasize that calculated values of agreement and reliability from measurement error studies are estimates of parameters, and as such we should report such estimates with CIs to indicate the uncertainty with which they have been estimated. We restrict our attention to measurements of a continuous quantity; alternative methods are required for categorical data2.

Outcomes for COPD pharmacological trials: From lung function to biomarkers

Abstract: The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Doing health policy analysis: methodological and conceptual reflections and challenges

Abstract: The case for undertaking policy analysis has been made by a number of scholars and practitioners. However, there has been much less attention given to how to do policy analysis, what research designs, theories or methods best inform policy analysis. This paper begins by looking at the health policy environment, and some of the challenges to researching this highly complex phenomenon. It focuses on research in middle and low income countries, drawing on some of the frameworks and theories, methodologies and designs that can be used in health policy analysis, giving examples from recent studies. The implications of case studies and of temporality in research design are explored. Attention is drawn to the roles of the policy researcher and the importance of reflexivity and researcher positionality in the research process. The final section explores ways of advancing the field of health policy analysis with recommendations on theory, methodology and researcher reflexivity.

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Abstract: Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD)(1-4) and type 2 diabetes (T2D)(5-7), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial

Abstract: Summary Background Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia; however, the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting, and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence. The Hypertension in the Very Elderly trial (HYVET) was designed to assess the risks and benefits of treatment of hypertension in elderly patients and included an assessment of cognitive function. Methods Patients with hypertension (systolic pressure 160–200 mm Hg; diastolic pressure Findings 3336 HYVET participants had at least one follow-up assessment (mean 2·2 years) and were included: 1687 participants were randomly assigned to the treatment group and 1649 to the placebo group. Only five reports of adverse effects were attributed to the medication: three in the placebo group and two in the treatment group. The mean decrease in systolic blood pressure between the treatment and placebo groups at 2 years was systolic −15 mm Hg, p Interpretation Antihypertensive treatment in elderly patients does not statistically reduce incidence of dementia. This negative finding might have been due to the short follow-up, owing to the early termination of the trial, or the modest effect of treatment. Nevertheless, the HYVET findings, when included in a meta-analysis, might support antihypertensive treatment to reduce incident dementia. Funding The British Heart Foundation; the Institute de Recherches Internationales Servier.

Malaria: progress, perils, and prospects for eradication

Abstract: There are still approximately 500 million cases of malaria and 1 million deaths from malaria each year. Yet recently, malaria incidence has been dramatically reduced in some parts of Africa by increasing deployment of anti-mosquito measures and new artemisinin-containing treatments, prompting renewed calls for global eradication. However, treatment and mosquito control currently depend on too few compounds and thus are vulnerable to the emergence of compound-resistant parasites and mosquitoes. As discussed in this Review, new drugs, vaccines, and insecticides, as well as improved surveillance methods, are research priorities. Insights into parasite biology, human immunity, and vector behavior will guide efforts to translate parasite and mosquito genome sequences into novel interventions.

Newly identified genetic risk variants for celiac disease related to the immune response

Abstract: Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

Content-Based Music Information Retrieval: Current Directions and Future Challenges

Abstract: The steep rise in music downloading over CD sales has created a major shift in the music industry away from physical media formats and towards online products and services. Music is one of the most popular types of online information and there are now hundreds of music streaming and download services operating on the World-Wide Web. Some of the music collections available are approaching the scale of ten million tracks and this has posed a major challenge for searching, retrieving, and organizing music content. Research efforts in music information retrieval have involved experts from music perception, cognition, musicology, engineering, and computer science engaged in truly interdisciplinary activity that has resulted in many proposed algorithmic and methodological solutions to music search using content-based methods. This paper outlines the problems of content-based music information retrieval and explores the state-of-the-art methods using audio cues (e.g., query by humming, audio fingerprinting, content-based music retrieval) and other cues (e.g., music notation and symbolic representation), and identifies some of the major challenges for the coming years.