NHS Tayside

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

RATIONALE: There are no risk stratification tools for morbidity and mortality in bronchiectasis. Identifying patients at risk of exacerbations, hospital admissions, and mortality is vital for future research. OBJECTIVES: This study describes the derivation and validation of the Bronchiectasis Severity Index (BSI). METHODS: Derivation of the BSI used data from a prospective cohort study (Edinburgh, UK, 2008-2012) enrolling 608 patients. Cox proportional hazard regression was used to identify independent predictors of mortality and hospitalization over 4-year follow-up. The score was validated in independent cohorts from Dundee, UK (n = 218); Leuven, Belgium (n = 253); Monza, Italy (n = 105); and Newcastle, UK (n = 126). MEASUREMENTS AND MAIN RESULTS: Independent predictors of future hospitalization were prior hospital admissions, Medical Research Council dyspnea score greater than or equal to 4, FEV1 < 30% predicted, Pseudomonas aeruginosa colonization, colonization with other pathogenic organisms, and three or more lobes involved on high-resolution computed tomography. Independent predictors of mortality were older age, low FEV1, lower body mass index, prior hospitalization, and three or more exacerbations in the year before the study. The derived BSI predicted mortality and hospitalization: area under the receiver operator characteristic curve (AUC) 0.80 (95% confidence interval, 0.74-0.86) for mortality and AUC 0.88 (95% confidence interval, 0.84-0.91) for hospitalization, respectively. There was a clear difference in exacerbation frequency and quality of life using the St. George's Respiratory Questionnaire between patients classified as low, intermediate, and high risk by the score (P < 0.0001 for all comparisons). In the validation cohorts, the AUC for mortality ranged from 0.81 to 0.84 and for hospitalization from 0.80 to 0.88. CONCLUSIONS: The BSI is a useful clinical predictive tool that identifies patients at risk of future mortality, hospitalization, and exacerbations across healthcare systems.

OBJECTIVES: To undertake a systematic review of the long-term effects of obesity treatments on body weight, risk factors for disease, and disease. METHODS: The study encompassed three systematic reviews that examined different aspects of obesity treatments. (1) A systematic review of obesity treatments in adults where the methods of the Cochrane Collaboration were applied and randomised controlled trials (RCTs) with a follow-up of at least 1 year were evaluated. (2) A systematic epidemiological review, where studies were sought on long-term effects of weight loss on morbidity and/or mortality, and examined through epidemiological modelling. (3) A systematic economic review that sought reports with both costs and outcomes of treatment, including recent reports that assessed the cost-effectiveness of pharmaceutical and surgical interventions. A Markov model was also adopted to examine the cost-effectiveness of a low-fat diet and exercise intervention in adults with obesity and impaired glucose tolerance. RESULTS: The addition of the drugs orlistat or sibutramine was associated with weight loss and generally improved risk factors, apart from diastolic blood pressure for sibutramine. Metformin was associated with decreased mortality after 10 years in obese people with type 2 diabetes. Low-fat diets were associated with continuing weight loss for 3 years and improvements in risk factors, as well as prevention of type 2 diabetes and improved control of hypertension. Insufficient evidence was available to demonstrate the benefits of low calorie or very low calorie diets. The addition of an exercise or behaviour programme to diet was associated with improved weight loss and risk factors for at least 1 year. Studies combining low-fat diets, exercise and behaviour therapy suggested improved hypertension and cardiovascular disease. Family therapy was associated with improved weight loss for 2 years compared to individual therapy. There was insufficient evidence to conclude that individual therapy was more beneficial than group therapy. Weight lost more quickly (within 1 year), from the epidemiology review, may be more beneficial with respect to the risk of mortality. The effects of intentional weight loss need further investigation. Weight loss from surgical and non-surgical interventions for people suffering from obesity was associated with decreased risk of development of diabetes, and a reduction in low-density lipoprotein cholesterol, total cholesterol and blood pressure, in the long term. Targeting high-risk individuals with drugs or surgery was likely to result in a cost per additional life-year or quality-adjusted life-year (QALY) of no more than 13,000 British pounds. There was also suggestive evidence of cost saving from treatment of people with type 2 diabetes with metformin. Targeting surgery on people with severe obesity and impaired glucose tolerance was likely to be more cost-effective at 2329 British pounds per additional life-year. Economic modelling over 6 years for diet and exercise for people with impaired glucose tolerance was associated with a high initial cost per additional QALY, but by the sixth year the cost per QALY was 13,389 British pounds. Results did not include cost savings from diseases other than diabetes, and therefore may be conservative. CONCLUSIONS: The drugs orlistat and sibutramine appear beneficial for the treatment of adults with obesity, and metformin for obese patients with type 2 diabetes. Exercise and/or behaviour therapy appear to improve weight loss when added to diet. Low-fat diets with exercise, or with exercise and behaviour therapy are associated with the prevention of type 2 diabetes and hypertension. Long-term weight loss in epidemiological studies was associated with reduced risk of type 2 diabetes, and may be beneficial for cardiovascular disease. Low-fat diets and exercise interventions in individuals at risk of obesity-related illness are of comparable cost to drug treatments. Long-term pragmatic RCTs of obesity treatments in populations with obesity-related illness or at high risk of developing such illness are needed (to include an evaluation of risk factors, morbidity, quality of life and economic evaluations). Drug trials that include dietary advice, plus exercise and/or behaviour therapy are also needed. Research exploring effective types of exercise, diet or behaviour and also interventions to prevent obesity in adults is required.

BACKGROUND: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).

BACKGROUND: The escalating use of prescribed drugs has increasingly raised concerns about polypharmacy. This study aims to examine changes in rates of polypharmacy and potentially serious drug-drug interactions in a stable geographical population between 1995 and 2010. METHODS: This is a repeated cross-sectional analysis of community-dispensed prescribing data for all 310,000 adults resident in the Tayside region of Scotland in 1995 and 2010. The number of drug classes dispensed and the number of potentially serious drug-drug interactions (DDIs) in the previous 84 days were calculated, and age-sex standardised rates in 1995 and 2010 compared. Patient characteristics associated with receipt of ≥ 10 drugs and with the presence of one or more DDIs were examined using multilevel logistic regression to account for clustering of patients within primary care practices. RESULTS: Between 1995 and 2010, the proportion of adults dispensed ≥ 5 drugs doubled to 20.8%, and the proportion dispensed ≥ 10 tripled to 5.8%. Receipt of ≥ 10 drugs was strongly associated with increasing age (20-29 years, 0.3%; ≥ 80 years, 24.0%; adjusted OR, 118.3; 95% CI, 99.5-140.7) but was also independently more common in people living in more deprived areas (adjusted OR most vs. least deprived quintile, 2.36; 95% CI, 2.22-2.51), and in people resident in a care home (adjusted OR, 2.88; 95% CI, 2.65-3.13). The proportion with potentially serious drug-drug interactions more than doubled to 13% of adults in 2010, and the number of drugs dispensed was the characteristic most strongly associated with this (10.9% if dispensed 2-4 drugs vs. 80.8% if dispensed ≥ 15 drugs; adjusted OR, 26.8; 95% CI 24.5-29.3). CONCLUSIONS: Drug regimens are increasingly complex and potentially harmful, and people with polypharmacy need regular review and prescribing optimisation. Research is needed to better understand the impact of multiple interacting drugs as used in real-world practice and to evaluate the effect of medicine optimisation interventions on quality of life and mortality.

BACKGROUND: Process evaluations are recommended to open the 'black box' of complex interventions evaluated in trials, but there is limited guidance to help researchers design process evaluations. Much current literature on process evaluations of complex interventions focuses on qualitative methods, with less attention paid to quantitative methods. This discrepancy led us to develop our own framework for designing process evaluations of cluster-randomised controlled trials. METHODS: We reviewed recent theoretical and methodological literature and selected published process evaluations; these publications identified a need for structure to help design process evaluations. We drew upon this literature to develop a framework through iterative exchanges, and tested this against published evaluations. RESULTS: The developed framework presents a range of candidate approaches to understanding trial delivery, intervention implementation and the responses of targeted participants. We believe this framework will be useful to others designing process evaluations of complex intervention trials. We also propose key information that process evaluations could report to facilitate their identification and enhance their usefulness. CONCLUSION: There is no single best way to design and carry out a process evaluation. Researchers will be faced with choices about what questions to focus on and which methods to use. The most appropriate design depends on the purpose of the process evaluation; the framework aims to help researchers make explicit their choices of research questions and methods. TRIAL REGISTRATION: Clinicaltrials.gov NCT01425502.

OBJECTIVE: To determine the incidence, predisposing factors, and costs of emergency treatment of severe hypoglycemia in people with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Over a 12-month period, routinely collected datasets were analyzed in a population of 367,051 people, including 8,655 people with diabetes, to measure the incidence of severe hypoglycemia that required emergency assistance from Ninewells Hospital and Medical School (NHS) personnel including those in primary care, ambulance services, hospital accident and emergency departments, and inpatient care. Associated costs with these episodes were calculated. RESULTS: A total of 244 episodes of severe hypoglycemia were recorded in 160 patients, comprising 69 (7.1%) people with type 1 diabetes, 66 (7.3%) with type 2 diabetes treated with insulin, and 23 (0.8%) with type 2 diabetes treated with sulfonylurea tablets. Incidence rates were 11.5 and 11.8 events per 100 patient-years for type 1 and type 2 patients treated with insulin, respectively. Age, duration, and socioeconomic status were identified as risk factors for severe hypoglycemia. One in three cases were treated solely by the ambulance service with no other contact from health care professionals. The total estimated cost of emergency treatment of severe hypoglycemia was </= pound 92,078 in one year. CONCLUSIONS: Hypoglycemia requiring emergency assistance from health service personnel is as common in people with type 2 diabetes treated with insulin as in people with type 1 diabetes. It is associated with considerable NHS resource use that has a significant economic and personal cost.

BACKGROUND: It has been suggested that the known poorer survival from cancer in the United Kingdom, compared with other European countries, can be attributed to more advanced cancer stage at presentation. There is, therefore, a need to understand the diagnostic process, and to ascertain the risk factors for increased time to presentation. METHODS: We report the results from two worldwide systematic reviews of the literature on patient-mediated and practitioner-mediated delays, identifying the factors that may influence these. RESULTS: Across cancer sites, non-recognition of symptom seriousness is the main patient-mediated factor resulting in increased time to presentation. There is strong evidence of an association between older age and patient delay for breast cancer, between lower socio-economic status and delay for upper gastrointestinal and urological cancers and between lower education level and delay for breast and colorectal cancers. Fear of cancer is a contributor to delayed presentation, while sanctioning of help seeking by others can be a powerful mediator of reduced time to presentation. For practitioner delay, 'misdiagnosis' occurring either through treating patients symptomatically or relating symptoms to a health problem other than cancer, was an important theme across cancer sites. For some cancers, this could also be linked to inadequate patient examination, use of inappropriate tests or failing to follow-up negative or inconclusive test results. CONCLUSION: Having sought help for potential cancer symptoms, it is therefore important that practitioners recognise these symptoms, and examine, investigate and refer appropriately.

BACKGROUND: Lack of consensus on the meaning of eHealth has led to uncertainty among academics, policymakers, providers and consumers. This project was commissioned in light of the rising profile of eHealth on the international policy agenda and the emerging UK National Programme for Information Technology (now called Connecting for Health) and related developments in the UK National Health Service. OBJECTIVES: To map the emergence and scope of eHealth as a topic and to identify its place within the wider health informatics field, as part of a larger review of research and expert analysis pertaining to current evidence, best practice and future trends. METHODS: Multiple databases of scientific abstracts were explored in a nonsystematic fashion to assess the presence of eHealth or conceptually related terms within their taxonomies, to identify journals in which articles explicitly referring to eHealth are contained and the topics covered, and to identify published definitions of the concept. The databases were Medline (PubMed), the Cumulative Index of Nursing and Allied Health Literature (CINAHL), the Science Citation Index (SCI), the Social Science Citation Index (SSCI), the Cochrane Database (including Dare, Central, NHS Economic Evaluation Database [NHS EED], Health Technology Assessment [HTA] database, NHS EED bibliographic) and ISTP (now known as ISI proceedings). We used the search query, "Ehealth OR e-health OR e*health". The timeframe searched was 1997-2003, although some analyses contain data emerging subsequent to this period. This was supplemented by iterative searches of Web-based sources, such as commercial and policy reports, research commissioning programmes and electronic news pages. Definitions extracted from both searches were thematically analyzed and compared in order to assess conceptual heterogeneity. RESULTS: The term eHealth only came into use in the year 2000, but has since become widely prevalent. The scope of the topic was not immediately discernable from that of the wider health informatics field, for which over 320000 publications are listed in Medline alone, and it is not explicitly represented within the existing Medical Subject Headings (MeSH) taxonomy. Applying eHealth as narrative search term to multiple databases yielded 387 relevant articles, distributed across 154 different journals, most commonly related to information technology and telemedicine, but extending to such areas as law. Most eHealth articles are represented on Medline. Definitions of eHealth vary with respect to the functions, stakeholders, contexts and theoretical issues targeted. Most encompass a broad range of medical informatics applications either specified (eg, decision support, consumer health information) or presented in more general terms (eg, to manage, arrange or deliver health care). However the majority emphasize the communicative functions of eHealth and specify the use of networked digital technologies, primarily the Internet, thus differentiating eHealth from the field of medical informatics. While some definitions explicitly target health professionals or patients, most encompass applications for all stakeholder groups. The nature of the scientific and broader literature pertaining to eHealth closely reflects these conceptualizations. CONCLUSIONS: We surmise that the field -- as it stands today -- may be characterized by the global definitions suggested by Eysenbach and Eng.

Abstract The partitioning of nitrate assimilation between root and shoot of higher plant species is indicated by the relative proportions of total plant nitrate reductase activity (NRA) in the two plant parts and the relative concentrations of nitrate and reduced N in the xylem sap. These have been collated here from the literature and temperate and tropical species compared. Both the distribution of NRA and xylem sap nitrate: reduced N indicate that the following four generalizations can be made. Temperate, perennial species growing in low external nitrate concentrations (about 1 mol m −3 ) carry out most of their nitrate assimilation in the root. As external nitrate concentration increases (in the range found in agricultural soils, 1–20 mol m −3 ), shoot nitrate assimilation becomes increasingly important. Temperate, annual legume species growing in low external nitrate concentrations carry out most of their nitrate assimilation in the root. Shoot nitrate assimilation increases in importance as external nitrate concentration is increased. Temperate, annual non‐legume species vary greatly in their partitioning of nitrate assimilation between root and shoot when growing in low external nitrate concentrations. Regardless of the proportion carried out in the root at low external nitrate concentrations, nitrate assimilation in the shoot becomes increasingly important as external nitrate concentration is increased. Tropical and subtropical species, annual and perennial, carry out a substantial proportion of their nitrate assimilation in the shoot when growing in low external nitrate concentrations. The partitioning of nitrate assimilation between root and shoot remains constant as external nitrate concentration increases. It is proposed that a greater proportion of nitrate assimilation occurs in the shoot when an increase in the rate of nitrate uptake does not induce an increase in NR level in the root. Thus, a greater proportion of the nitrate taken up remains unassimilated and is passed into the xylem. A constant partitioning of nitrate assimilation between root and shoot is achieved by balancing NR levels in the root with rates of nitrate uptake. The advantages and disadvantages of assimilating nitrate in either the root or shoot are discussed in relation to temperate and tropical habitats.

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

AIMS: To evaluate the patterns and predictors of adherence in all patients with Type 2 diabetes in the community receiving treatment with a single oral hypoglycaemic drug. In particular, to test the hypothesis that one tablet per day is associated with better adherence than more than one. METHODS: The study design was a retrospective cohort study set in the Tayside region of Scotland (population approx. 400 000). Participants were residents of Tayside from 1 January 1993 until 31 December 1995 with at least 12 months of prescriptions of oral hypoglycaemic drugs (OHDs). The main outcome measures were adherence indices for sulphonylureas and metformin separately, adjusting for prescribing while hospitalized. RESULTS: Of the total 2920 subjects identified, adequate adherence (> or = 90%) was found in 31% of those prescribed sulphonylureas alone (n = 1329, median adherence = 300 days per year), and in 34% of those prescribed metformin alone (n = 528, median = 302 days per year). There were significant linear trends of poorer adherence with each increase in the daily number of tablets taken (p = 0.001) and increase in co-medication (p = 0.0001) for sulphonylureas alone after adjustment for other factors. CONCLUSIONS: In the community only one in three with Type 2 diabetes had adequate adherence to OHDs. One tablet per day administration was associated with greater adherence than multiple tablets. Poor adherence is a major obstacle to the benefit of complex drug regimens in the treatment of Type 2 diabetes.

BACKGROUND: Recruiting participants to trials can be extremely difficult. Identifying strategies that improve trial recruitment would benefit both trialists and health research. OBJECTIVES: To quantify the effects of strategies to improve recruitment of participants to randomised controlled trials. SEARCH STRATEGY: We searched the Cochrane Methodology Review Group Specialised Register - CMR (The Cochrane Library (online) Issue 1 2008) (searched 20 February 2008); MEDLINE, Ovid (1950 to date of search) (searched 06 May 2008); EMBASE, Ovid (1980 to date of search) (searched 16 May 2008); ERIC, CSA (1966 to date of search) (searched 19 March 2008); Science Citation Index Expanded, ISI Web of Science (1975 to date of search) (searched 19 March 2008); Social Sciences Citation Index, ISI Web of Science (1975 to date of search) (searched 19 March 2008); and National Research Register (online) (Issue 3 2007) (searched 03 September 2007); C2-SPECTR (searched 09 April 2008). We also searched PubMed (25 March 2008) to retrieve "related articles" for 15 studies included in a previous version of this review. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of methods to increase recruitment to randomised controlled trials. This includes non-healthcare studies and studies recruiting to hypothetical trials. Studies aiming to increase response rates to questionnaires or trial retention, or which evaluated incentives and disincentives for clinicians to recruit patients were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted on the method evaluated; country in which the study was carried out; nature of the population; nature of the study setting; nature of the study to be recruited into; randomisation or quasi-randomisation method; and numbers and proportions in each intervention group. We used risk ratios and their 95% confidence intervals to describe the effects in individual trials, and assessed heterogeneity of these ratios between trials. MAIN RESULTS: We identified 27 eligible trials with more than 26,604 participants. There were 24 studies involving interventions aimed directly at trial participants, while three evaluated interventions aimed at people recruiting participants. All studies were in health care. Some interventions were effective in increasing recruitment: telephone reminders to non-respondents (RR 2.66, 95% CI 1.37 to 5.18), use of opt-out, rather than opt-in, procedures for contacting potential trial participants (RR 1.39, 95% CI 1.06 to 1.84) and open designs where participants know which treatment they are receiving in the trial (RR 1.25, 95% CI 1.18 to 1.34). However, some of these strategies have disadvantages, which may limit their widespread use. For example, opt-out procedures are controversial and open designs are by definition unblinded. The effects of many other recruitment strategies are unclear; examples include the use of video to provide trial information to potential participants and modifying the training of recruiters. Many studies looked at recruitment to hypothetical trials and it is unclear how applicable these results are to real trials. AUTHORS' CONCLUSIONS: Trialists can increase recruitment to their trials by using the strategies shown to be effective in this review: telephone reminders; use of opt-out, rather than opt-in; procedures for contacting potential trial participants and open designs. Some strategies (e.g. open trial designs) need to be considered carefully before use because they also have disadvantages. For example, opt-out procedures are controversial and open designs are by definition unblinded.

BACKGROUND: Clinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of routinely prescribed chemotherapy drugs are poorly understood. METHODS: We created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil and elacridar and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461. ABCB1 expression was assessed by qRT-PCR, copy number, western blotting and immunohistochemical analysis and ABCB1 activity assessed by the Vybrant and P-glycoprotein-Glo assays. RESULTS: Paclitaxel-resistant cells were cross-resistant to olaparib, doxorubicin and rucaparib but not to veliparib or AZD2461. Resistance correlated with increased ABCB1 expression and was reversible following treatment with the ABCB1 inhibitors verapamil and elacridar. Active efflux of paclitaxel, olaparib, doxorubicin and rucaparib was confirmed in drug-resistant cells and in ABCB1-expressing bacterial membranes. CONCLUSIONS: We describe a common ABCB1-mediated mechanism of paclitaxel and olaparib resistance in ovarian cancer cells. Optimal choice of PARP inhibitor may therefore limit the progression of drug-resistant disease, while routine prescription of first-line paclitaxel may significantly limit subsequent chemotherapy options in ovarian cancer patients.

BACKGROUND: Positron emission tomography using 18F-fluorodeoxyglucose (18F-FDG PET) has been proposed to enhance preoperative assessment of cervical lymph node status in patients with head and neck squamous cell carcinoma (HNSCC). Management is most controversial for patients with a clinically negative (cN0) neck. We aimed to assess the diagnostic accuracy of 18F-FDG PET in detecting lymph node metastases in patients with HNSCC. METHODS: We performed a meta-analysis of all available studies of the diagnostic performance of 18F-FDG PET in patients with HNSCC. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves using hierarchical regression models. We also compared the performance of 18F-FDG PET with that of conventional diagnostic methods (ie, computed tomography, magnetic resonance imaging, and ultrasound with fine-needle aspiration) by analyzing studies that had also used these diagnostic methods on the same patients. RESULTS: Across 32 studies (1236 patients), 18F-FDG PET sensitivity was 79% (95% confidence interval [CI] = 72% to 85%) and specificity was 86% (95% CI = 83% to 89%). For cN0 patients, sensitivity of 18F-FDG PET was only 50% (95% CI = 37% to 63%), whereas specificity was 87% (95% CI = 76% to 93%). Overall, LR+ was 5.84 (95% CI = 4.59 to 7.42) and LR- was 0.24 (95% CI = 0.17 to 0.33). In studies in which both 18F-FDG PET and conventional diagnostic tests were performed, sensitivity and specificity of 18F-FDG PET were 80% and 86%, respectively, and of conventional diagnostic tests were 75% and 79%, respectively. CONCLUSION: 18F-FDG PET has good diagnostic performance in the overall pretreatment evaluation of patients with HNSCC but still does not detect disease in half of the patients with metastasis and cN0.

Randomised trials are a central component of all evidence-informed health care systems and the evidence coming from them helps to support health care users, health professionals and others to make more informed decisions about treatment. The evidence available to trialists to support decisions on design, conduct and reporting of randomised trials is, however, sparse. Trial Forge is an initiative that aims to increase the evidence base for trial decision-making and in doing so, to improve trial efficiency.One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. This guidance document provides a brief definition of SWATs, an explanation of why they are important and some practical 'top tips' that come from existing experience of doing SWATs. We hope the guidance will be useful to trialists, methodologists, funders, approvals agencies and others in making clear what a SWAT is, as well as what is involved in doing one.

INTRODUCTION: International guidelines recommend a severity-based approach to management in community-acquired pneumonia. CURB65, CRB65 and the Pneumonia Severity Index (PSI) are the most widely recommended severity scores. The aim of this study was to compare the performance characteristics of these scores for predicting mortality in community-acquired pneumonia. METHODS: A systematic review and meta-analysis was conducted according to MOOSE (meta-analysis of observational studies in epidemiology) guidelines. PUBMED and EMBASE were searched (1980-2009). 40 studies reporting prognostic information for the PSI, CURB65 and CRB65 severity scores were identified. Performance characteristics were pooled using a random effects model. Relationships between sensitivity and specificity were plotted using summary receiver operator characteristic (sROC) curves. RESULTS: All three scores predicted 30 day mortality. The PSI had the highest area under the sROC curve, 0.81 (SE 0.008), compared with CURB65, 0.80 (SE 0.008), p=0.1, and CRB65, 0.79 (0.01), p=0.09. These differences were not statistically significant. Performance characteristics were similar across comparable cut-offs for low, intermediate and high risk for each score. In identifying low risk patients, PSI (groups I and II) had the best negative likelihood ratio 0.08 (0.06-0.12) compared with CURB65 (score 0-1) 0.21 (0.15-0.30) and CRB65 (score 0), 0.15 (0.10-0.22). CONCLUSION: There were no significant differences in overall test performance between PSI, CURB65 and CRB65 for predicting mortality from community-acquired pneumonia.

OBJECTIVES: To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD. DESIGN: Up to four serial qualitative interviews were conducted with each patient and nominated carer over 18 months. Interviews were transcribed and analysed both thematically and as narratives. PARTICIPANTS: 21 patients, and 13 informal carers (a family member, friend, or neighbour) and 18 professional carers (a key health or social care professional) nominated by the patients. SETTING: Primary and secondary care in Lothian, Tayside, and Forth Valley, Scotland, during 2007-9. RESULTS: Eleven patients died during the study period. Our final dataset comprised 92 interviews (23 conducted with patient and informal carer together). Severe symptoms that caused major disruption to normal life were described, often in terms implying acceptance of the situation as a "way of life" rather than an "illness." Patients and their informal carers adapted to and accepted the debilitating symptoms of a lifelong condition. Professional carers' familiarity with the patients' condition, typically over many years, and prognostic uncertainty contributed to the difficulty of recognising and actively managing end stage disease. Overall, patients told a "chaos narrative" of their illness that was indistinguishable from their life story, with no clear beginning and an unanticipated end described in terms comparable with attitudes to death in a normal elderly population. CONCLUSIONS: Our findings challenge current assumptions underpinning provision of end of life care for people with COPD. The policy focus on identifying a time point for transition to palliative care has little resonance for people with COPD or their clinicians and is counter productive if it distracts from early phased introduction of supportive care. Careful assessment of possible supportive and palliative care needs should be triggered at key disease milestones along a lifetime journey with COPD, in particular after hospital admission for an exacerbation.

RATIONALE: Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. OBJECTIVES: The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. METHODS: We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. MEASUREMENTS AND MAIN RESULTS: Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patient's management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. CONCLUSIONS: Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.