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Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67LI-gemininLI; (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2LI-Ki67LI; (P=0.01)) and accelerated cell cycle progression (gemininLI/ Ki67LI; (P= 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication. \u00a9 2007 Cancer Research.
\n \n\n \n \nBackground: Passive leg raising (PLR) is a so called self-volume challenge used to test for fluid responsiveness. Changes in cardiac output (CO) or stroke volume (SV) measured during PLR are used to predict the need for subsequent fluid loading. This requires a device that can measure CO changes rapidly. The Vigileo\u2122 monitor, using third-generation software, allows continuous CO monitoring. The aim of this study was to compare changes in CO (measured with the Vigileo device) during a PLR manoeuvre to calculate the accuracy for predicting fluid responsiveness. Methods: This is a prospective study in a 20-bedded mixed general critical care unit in a large non-university regional referral hospital. Fluid responders were defined as having an increase in CO of greater than 15 % following a fluid challenge. Patients meeting the criteria for circulatory shock with a Vigileo\u2122 monitor (Vigileo\u2122; FloTrac; Edwards\u2122; Lifesciences, Irvine, CA, USA) already in situ, and assessed as requiring volume expansion by the clinical team based on clinical criteria, were included. All patients underwent a PLR manoeuvre followed by a fluid challenge. Results: Data was collected and analysed on stroke volume variation (SVV) at baseline and CO and SVV changes during the PLR manoeuvre and following a subsequent fluid challenge in 33 patients. The majority had septic shock. Patient characteristics, baseline haemodynamic variables and baseline vasoactive infusion requirements were similar between fluid responders (10 patients) and non-responders (23 patients). Peak increase in CO occurred within 120 s during the PLR in all cases. Using an optimal cut point of 9 % increase in CO during the PLR produced an area under the receiver operating characteristic curve of 0.85 (95 % CI 0.63 to 1.00) with a sensitivity of 80 % (95 % CI 44 to 96 %) and a specificity of 91 % (95 % CI 70 to 98 %). Conclusions: CO changes measured by the Vigileo\u2122 monitor using third-generation software during a PLR test predict fluid responsiveness in mixed medical and surgical patients with vasopressor-dependent circulatory shock.
\n \n\n \n \nBackground: Each year, infection with Plasmodium causes millions of clinical cases of malaria and hundreds of thousands of deaths. Resistance to different antimalarial medications continues to develop and spread, threatening effective prophylaxis and treatment. Surveillance of resistance is required to inform health policy and preserve effective antimalarial drugs; molecular methods can be used to surveil likely parasite resistances. However, there is no consensus on the most accurate molecular methods, and large variation exists in practice. The objective of this update to this systematic review is to improve and update identification of the sensitivity and specificity of each molecular method for detecting selected antimalarial drug resistance markers. Methods: We will include diagnostic accuracy studies that compare at least two of any molecular methods to examine blood samples from patients diagnosed with, or suspected of having malaria, to detect at least one selected marker of antimalarial drug resistance. We will search PubMed, EMBASE, BIOSIS, and Web of Science from 2000 to present. Two reviewers will independently screen all results, extract data, consider applicability, and evaluate the methodological quality of included studies using QUADAS-2. We will carry out a meta-analysis and use statistical methods to compare results from homogenous studies. We will use narrative to synthesise and compare results of heterogeneous studies. Discussion: This review will help to identify sub-optimal molecular methods for antimalarial marker detection which may be discontinued and identify more sensitive and specific methods which may be adopted. More sensitive and specific detection of drug resistance can be used to improve the breadth and accuracy of surveillance. This would enable the identification of previously undiscovered areas of antimalarial resistances and susceptibilities, improve the precision of estimates of the prevalence of resistances, and improve our ability to detect smaller changes in these patterns. Higher-quality evidence generated by more accurate and detailed surveillance can be used to inform guidelines on the use of antimalarial drugs, leading to better outcomes for more patients. Systematic review registration: This systematic review protocol was registered with PROSPERO on 22 November 2017 (registration number CRD42017082101).
\n \n\n \n \nBackground. Pneumococcal conjugate vaccines (PCVs) provide direct protection against disease in those vaccinated, and interrupt transmission through the prevention of nasopharyngeal (NP) carriage. Methods. We analyzed immunogenicity data from 5224 infants who received PCV in prime-boost schedules. We defned any increase in antibody between the 1-month postpriming visit and the booster dose as an indication of NP carriage (\"seroincidence\"). We calculated antibody concentrations using receiver operating characteristic curves, and used generalized additive models to compute their protective efcacy against seroincidence. To support seroincidence as a marker of carriage, we compared seroincidence in a randomized immunogenicity trial in Nepal with the serotype-specifc prevalence of carriage in the same community. Results. In Nepalese infants, seroincidence of carriage closely correlated with serotype-specifc carriage prevalence in the community. In the larger data set, antibody concentrations associated with seroincidence were lowest for serotypes 6B and 23F (0.50 \u03bcg/mL and 0.63 \u03bcg/mL, respectively), and highest for serotypes 19F and 14 (2.54 \u03bcg/mL and 2.48 \u03bcg/mL, respectively). Te protective efcacy of antibody at these levels was 62% and 74% for serotypes 6B and 23F, and 87% and 84% for serotypes 19F and 14. Protective correlates were on average 2.15 times higher in low/lower middle-income countries than in high/upper middle-income countries (geometric mean ratio, 2.15 [95% confdence interval, 1.46-3.17]; P =.0024). Conclusions. Antibody concentrations associated with protection vary between serotypes. Higher antibody concentrations are required for protection in low-income countries. Tese fndings are important for global vaccination policy, to interrupt transmission by protecting against carriage.
\n \n\n \n \nBackground: Declining physical activity is associated with a rising burden of global disease. Efforts to reverse this trend have not been successful. We aimed to assess the efficacy of a facilitated behavioural intervention to increase the physical activity of sedentary individuals at familial risk of diabetes. Methods: We enrolled 365 sedentary adults who had a parental history of type 2 diabetes. They were recruited from either diabetes or family history registers at 20 general practice clinics in the UK. Eligible participants were randomly assigned to one of two intervention groups, or to a comparison group. All participants were posted a brief advice leaflet. One intervention group was offered a 1-year behaviour-change programme, to be delivered by trained facilitators in participants' homes, and the other the same programme by telephone. The programme was designed to alter behavioural determinants, as defined by the theory of planned behaviour, and to teach behaviour-change strategies. The principal outcome at 1 year was daytime physical activity, which was objectively measured as a ratio to resting energy expenditure. Analysis was by intention to treat. This study is registered as ISRCTN61323766. Findings: Of 365 patients, we analysed primary endpoints for 321 (88%) for whom we had data after 1 year of follow-up. At 1 year, the physical-activity ratio of participants who received the intervention, by either delivery route, did not differ from the ratio in those who were given a brief advice leaflet. The mean difference in daytime physical-activity ratio, adjusted for baseline, was -0\u00b704 (95% CI -0\u00b716 to 0\u00b708). The physical-activity ratio did not differ between participants who were delivered the intervention face-to-face or by telephone (mean difference -0\u00b705; 95% CI -0\u00b719 to 0\u00b710). Interpretation: A facilitated theory-based behavioural intervention was no more effective than an advice leaflet for promotion of physical activity in an at-risk group; therefore health-care providers should remain cautious about commissioning behavioural programmes into individual preventive health-care services. \u00a9 2008 Elsevier Ltd. All rights reserved.
\n \n\n \n \nIntroduction A significant percentage of patients admitted to hospital have undiagnosed hypertension. However, present hypertension guidelines in the UK, Europe and USA do not define a blood pressure threshold at which hospital inpatients should be considered at risk of hypertension, outside of the emergency setting. The objective of this study is to identify the optimal in-hospital mean blood pressure threshold, above which patients should receive postdischarge blood pressure assessment in the community. Methods and analysis Screening for Hypertension in the INpatient Environment is a prospective diagnostic accuracy study. Patients admitted to hospital whose mean average daytime blood pressure after 24 hours or longer meets the study eligibility threshold for mean daytime blood pressure (\u2265120/70 mm Hg) and who have no prior diagnosis of, or medication for hypertension will be eligible. At 8 weeks postdischarge, recruited participants will wear an ambulatory blood pressure monitor for 24 hours. Mean daytime ambulatory blood pressure will be calculated to assess for the presence or absence of hypertension. Diagnostic performance of in-hospital blood pressure will be assessed by constructing receiver operator characteristic curves from participants' in-hospital mean systolic and mean diastolic blood pressure (index test) versus diagnosis of hypertension determined by mean daytime ambulatory blood pressure (reference test). Ethics and dissemination Ethical approval has been provided by the National Health Service Health Research Authority South Central-Oxford B Research Ethics Committee (19/SC/0026). Findings will be disseminated through national and international conferences, peer-reviewed journals and social media.
\n \n\n \n \nScalable and transparent methods for risk assessment are increasingly required in criminal justice to inform decisions about sentencing, release, parole, and probation. However, few such approaches exist and their validation in external settings is typically lacking. A total national sample of all offenders (9072 released from prisoners and 6329 individuals on probation) from 2011\u20132012 in the Netherlands were followed up for violent and any reoffending over 2 years. The sample was mostly male (n = 574 [6%] were female prisoners and n = 784 [12%] were female probationers), and median ages were 30 in the prison sample and 34 in those on probation. Predictors for a scalable risk assessment tool (OxRec) were extracted from a routinely collected dataset used by criminal justice agencies, and outcomes from official criminal registers. OxRec\u2019s predictive performance in terms of discrimination and calibration was tested. Reoffending rates in the Dutch prisoner cohort were 16% for 2-year violent reoffending and 44% for 2-year any reoffending, with lower rates in the probation sample. Discrimination as measured by the c-index was moderate, at 0.68 (95% CI: 0.66\u20130.70) for 2-year violent reoffending in prisoners and between 0.65 and 0.68 for other outcomes and the probation sample. The model required recalibration, after which calibration performance was adequate (e.g. calibration in the large was 1.0 for all scenarios). A recalibrated model for OxRec can be used in the Netherlands for individuals released from prison and individuals on probation to stratify their risk of future violent and any reoffending. The approach that we outline can be considered for external validations of criminal justice and clinical risk models.
\n \n\n \n \nAssessment of suicide risk in individuals with severe mental illness is currently inconsistent, and based on clinical decision-making with or without tools developed for other purposes. We aimed to develop and validate a predictive model for suicide using data from linked population-based registers in individuals with severe mental illness. A national cohort of 75,158 Swedish individuals aged 15\u201365 with a diagnosis of severe mental illness (schizophrenia-spectrum disorders, and bipolar disorder) with 574,018 clinical patient episodes between 2001 and 2008, split into development (58,771 patients, 494 suicides) and external validation (16,387 patients, 139 suicides) samples. A multivariable derivation model was developed to determine the strength of pre-specified routinely collected socio-demographic and clinical risk factors, and then tested in external validation. We measured discrimination and calibration for prediction of suicide at 1 year using specified risk cut-offs. A 17-item clinical risk prediction model for suicide was developed and showed moderately good measures of discrimination (c-index 0.71) and calibration. For risk of suicide at 1 year, using a pre-specified 1% cut-off, sensitivity was 55% (95% confidence interval [CI] 47\u201363%) and specificity was 75% (95% CI 74\u201375%). Positive and negative predictive values were 2% and 99%, respectively. The model was used to generate a simple freely available web-based probability-based risk calculator (Oxford Mental Illness and Suicide tool or OxMIS) without categorical cut-offs. A scalable prediction score for suicide in individuals with severe mental illness is feasible. If validated in other samples and linked to effective interventions, using a probability score may assist clinical decision-making.
\n \n\n \n \nAims The demand for test requests from general practice to laboratory services remains high. Tests performed at the point of care could reduce turnaround time and speed up clinical decision making. Replicating laboratory testing in the community would require panels of tests to be performed simultaneously, which is now approaching technological feasibility. We assessed frequencies and combinations of test requests from community settings to inform the potential future development of multiplex point-of-care panels. Methods We assessed all laboratory test requests made from general practice in Oxfordshire, UK, from January 2014 to March 2017. We summarised test request frequency overall and in combination, using heatmaps and hierarchical cluster analysis. Results are also presented by age/sex subgroups. We further assessed patterns of tests requested within 7 and 14 days after an initial test request. Results 11 763 473 test requests were made for 413 073 individuals (28% age >65). Of more than 500 test types, 62 were requested at least 5000 times, most commonly renal function tests (approximately 296 000/ year), full blood count (278 000/year) and liver function tests (237 000/year). Cluster analysis additionally identified a clear grouping of tests commonly used to investigate anaemia. Follow-up test frequency was much lower than the frequency of multiple tests ordered at initial presentation. Conclusions The current high volume of single and combination test requests highlights an opportunity for reliable multiplex point-of-care panels to cover a core set of frequently requested tests. The impact on test use of introducing such panels to general practice requires additional research.
\n \n\n \n \nBackground A stepped wedge cluster randomised trial (SWCRT) is a multicentred study which allows an intervention to be rolled out at sites in a random order. Once the intervention is initiated at a site, all participants within that site remain exposed to the intervention for the remainder of the study. The time since the start of the study (\u201ccalendar time\u201d) may affect outcome measures through underlying time trends or periodicity. The time since the intervention was introduced to a site (\u201cexposure time\u201d) may also affect outcomes cumulatively for successful interventions, possibly in addition to a step change when the intervention began. Methods Motivated by a SWCRT of self-monitoring for bipolar disorder, we conducted a simulation study to compare model formulations to analyse data from a SWCRT under 36 different scenarios in which time was related to the outcome (improvement in mood score). The aim was to find a model specification that would produce reliable estimates of intervention effects under different scenarios. Nine different formulations of a linear mixed effects model were fitted to these datasets. These models varied in the specification of calendar and exposure times. Results Modelling the effects of the intervention was best accomplished by including terms for both calendar time and exposure time. Treating time as categorical (a separate parameter for each measurement time-step) achieved the best coverage probabilities and low bias, but at a cost of wider confidence intervals compared to simpler models for those scenarios which were sufficiently modelled by fewer parameters. Treating time as continuous and including a quadratic time term performed similarly well, with slightly larger variations in coverage probability, but narrower confidence intervals and in some cases lower bias. The impact of misspecifying the covariance structure was comparatively small. Conclusions We recommend that unless there is a priori information to indicate the form of the relationship between time and outcomes, data from SWCRTs should be analysed with a linear mixed effects model that includes separate categorical terms for calendar time and exposure time. Prespecified sensitivity analyses should consider the different formulations of these time effects in the model, to assess their impact on estimates of intervention effects.
\n \n\n \n \nIntroduction: Previous studies suggest that many systematic reviews contain meta-analyses that display temporal trends, such as the first study's result being more extreme than later studies' or a drift in the pooled estimate. We assessed the extent and characteristics of temporal trends using all Cochrane intervention reports published 2008-2012. Methods: We selected the largest meta-analysis within each report and analysed trends using methods including a Z-test (first versus subsequent estimates); generalised least squares; and cumulative sum charts. Predictors considered include meta-analysis size and review group. Results: Of 1288 meta-analyses containing at least 4 studies, the point estimate from the first study was more extreme and in the same direction as the pooled estimate in 738 (57%), with a statistically significant difference (first versus subsequent) in 165 (13%). Generalised least squares indicated trends in 717 (56%); 18% of fixed effects analyses had at least one violation of cumulative sum limits. For some methods, meta-analysis size was associated with temporal patterns and use of a random effects model, but there was no consistent association with review group. Conclusions: All results suggest that more meta-analyses demonstrate temporal patterns than would be expected by chance. Hence, assuming the standard meta-analysis model without temporal trend is sometimes inappropriate. Factors associated with trends are likely to be context specific.
\n \n\n \n \nBackground Various lipid measurements in monitoring/screening programmes can be used, alone or in cardiovascular risk scores, to guide treatment for prevention of cardiovascular disease (CVD). Because some changes in lipids are due to variability rather than true change, the value of lipid-monitoring strategies needs evaluation. Objective To determine clinical value and cost-effectiveness of different monitoring intervals and different lipid measures for primary and secondary prevention of CVD. Data sources We searched databases and clinical trials registers from 2007 (including the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the Clinical Trials Register, the Current Controlled Trials register, and the Cumulative Index to Nursing and Allied Health Literature) to update and extend previous systematic reviews. Patient-level data from the Clinical Practice Research Datalink and St Luke\u2019s Hospital, Japan, were used in statistical modelling. Utilities and health-care costs were drawn from the literature. Methods In two meta-analyses, we used prospective studies to examine associations of lipids with CVD and mortality, and randomised controlled trials to estimate lipid-lowering effects of atorvastatin doses. Patient-level data were used to estimate progression and variability of lipid measurements over time, and hence to model lipid-monitoring strategies. Results are expressed as rates of true-/false-positive and true-/false-negative tests for high lipid or high CVD risk. We estimated incremental costs per quality-adjusted life-year. Results A total of 115 publications reported strength of association between different lipid measures and CVD events in 138 data sets. The summary adjusted hazard ratio per standard deviation of total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio was 1.25 (95% confidence interval 1.15 to 1.35) for CVD in a primary prevention population but heterogeneity was high (I2\u2009=\u200998%); similar results were observed for non-HDL cholesterol, apolipoprotein B and other ratio measures. Associations were smaller for other single lipid measures. Across 10 trials, low-dose atorvastatin (10 and 20\u2009mg) effects ranged from a TC reduction of 0.92\u2009mmol/l to 2.07\u2009mmol/l, and low-density lipoprotein reduction of between 0.88\u2009mmol/l and 1.86\u2009mmol/l. Effects of 40\u2009mg and 80\u2009mg were reported by one trial each. For primary prevention, over a 3-year period, we estimate annual monitoring would unnecessarily treat 9 per 1000 more men (28 vs. 19 per 1000) and 5 per 1000 more women (17 vs. 12 per 1000) than monitoring every 3 years. However, annual monitoring would also undertreat 9 per 1000 fewer men (7 vs. 16 per 1000) and 4 per 1000 fewer women (7 vs. 11 per 1000) than monitoring at 3-year intervals. For secondary prevention, over a 3-year period, annual monitoring would increase unnecessary treatment changes by 66 per 1000 men and 31 per 1000 women, and decrease undertreatment by 29 per 1000 men and 28 per 1000 men, compared with monitoring every 3 years. In cost-effectiveness, strategies with increased screening/monitoring dominate. Exploratory analyses found that any unknown harms of statins would need utility decrements as large as 0.08 (men) to 0.11 (women) per statin user to reverse this finding in primary prevention. Limitation Heterogeneity in meta-analyses. Conclusions While acknowledging known and potential unknown harms of statins, we find that more frequent monitoring strategies are cost-effective compared with others. Regular lipid monitoring in those with and without CVD is likely to be beneficial to patients and to the health service. Future research should include trials of the benefits and harms of atorvastatin 40 and 80\u2009mg, large-scale surveillance of statin safety, and investigation of the effect of monitoring on medication adherence. Study registration This study is registered as PROSPERO CRD42013003727. Funding The National Institute for Health Research Health Technology Assessment programme.
\n \n\n \n \nAlthough the lymphatic system is clearly linked to the metastasis of most human carcinomas, the mechanisms by which lymphangiogenesis occurs in response to the presence of carcinoma remain unclear. Hierarchical models are presented to investigate the properties of lymphatic vessel production in 2997 fields taken from 20 individuals with invasive carcinoma, 21 individuals with cervical intraepithelial neoplasia and 21 controls. Such data demonstrate a high degree of correlation within tumour samples from the same individual. Joint hierarchical models utilising shared random effects are discussed and fitted in a Bayesian framework to allow for the correlation between two key outcome measures: a random cluster size (the number of lymphatic vessels in a tissue sample) and a continuous outcome (vessel size). Results show that invasive carcinoma samples are associated with increased production of smaller and more irregularly-shaped lymphatic vessels and suggest a mechanistic link between carcinoma of the cervix and lymphangiogenesis.
\n \n\n \n \nAims: To assess the cardiovascular disease (CVD) risk of people with screen-detected Type 2 diabetes and to estimate the risk reduction achievable through early intensive pharmacological intervention. Methods: In ADDITION-Cambridge, diabetic patients were identified among people aged 40-69 years through a stepwise screening procedure including a risk score, random and fasting capillary blood glucose, HbA1c and oral glucose tolerance test. In those without prior macrovascular disease, 10-year CVD risk was computed using UK Prospective Diabetes Study (UKPDS) and Framingham engines. The absolute risk reduction achievable and its plausible range were predicted using relative risk reductions for individual therapies from published trials and sensitivity analysis. Results: Of the 867 individuals with undiagnosed diabetes, 19% had pre-existing CVD, 97% were overweight or obese, 86% had hypertension, 75% had dyslipidaemia, 20% had microalbuminuria and 18% were smokers. Of those with hypertension, 35% were not prescribed drugs and 42% were suboptimally treated. Of participants with dyslipidaemia, 68% were not prescribed medications and 22% were poorly controlled. Median 10-year CVD risk was 34.0% [interquartile range (IQR) 26.2-44.6] in men and 21.5% (IQR 15.7-28.7) in women using the UKPDS engine; 38.6% (IQR 27.8-53.0) in men and 24.6% (IQR 17.2-32.9) in women using Framingham equations. In the most conservative scenario (no additive effect of therapies), the absolute risk reduction achievable through multifactorial therapy ranged from 4.9 to 9.5% (UKPDS) and from 5.4 to 10.5% (Framingham). The corresponding ranges of numbers needed to treat were 11-20 and 10-19. Conclusions: People with screen-detected diabetes have an adverse cardiovascular risk profile, which is potentially modifiable through application of existing treatment recommendations. \u00a9 2008 The Authors.
\n \n\n \n \nPsychological models of bipolar disorder (BD), such as the self-regulation model (SRM; Leventhal, Nerenz, & Steele, 1984), highlight the crucial role of beliefs about mood in relapse vulnerability. To date, no studies have directly compared these beliefs between people with and without BD. Based on the SRM, the current research examined beliefs about mood in people with and without BD and explored the impact of current affect on these beliefs. Fifty euthymic people with a diagnosis of BD and 50 controls were recruited through an online screening study, clinical services, and support organizations. Experience sampling methodology (ESM) was used to assess beliefs (according to the Brief Illness Perceptions Questionnaire; Broadbent, Petrie, Main, & Weinman, 2006) across a typical week of everyday life. Data were analysed using multilevel modelling. Forty-two people with a diagnosis of BD and 50 controls were included in the analyses. Results indicated that the BD group reported less control over mood, a shorter duration of mood, and less understanding of mood and were more likely to report the cause of depressive symptoms as something internal, compared with controls. When controlling for current affect, the BD group also reported more positive consequences, made more internal attributions for hypomanic symptoms, and reported less concern about mood, compared with controls. Findings suggest important differences in beliefs about mood between people with and without BD that are not the result of current affect. These beliefs may be particularly important in understanding underlying vulnerability to future relapse into depression and/or mania.
\n \n\n \n \nBackground & Objectives: The aim of this study was to apply three simple risk - scoring systems to prospectively collected data on all elective open Abdominal Aortic Aneurysm (AAA) operations in the Cambridge Academic Vascular Unit over a 6 - year period (January 1998 to January 2004), to compare their predictive values and to evaluate their validity with respect to prediction of mortality and post-operative complications. Methods: 204 patients underwent elective open infra-renal AAA repair. Data were prospectively collected and risk assessment scores were calculated for mortality and morbidity according to the Glasgow Aneurysm Score (GAS), VBHOM (Vascular Biochemistry and Haematology Outcome Models) and Estimation of Physiologic Ability and Surgical Stress (E-PASS). Results: The mortality rate was 6.3% (13/204) and 59% (121/204) experienced a post-operative complication (30-day outcome). For GAS, VBHOM and E-PASS the receiver operating characteristics (ROC) curve analysis for prediction of in-hospital mortality showed area under the curve (AUC) of 0.84 (95% confidence interval [CI], 0.76 to 0.92; p < 0.0001), 0.82 (95% CI, 0.68 to 0.95; p = 0.0001) and 0.92 (95% CI, 0.87 to 0.97; p < 0.0001) respectively. There were also significant correlations between post-operative complications and length of hospital stay and each of the three scores, but the correlation was substantially higher in the case of E-PASS. Conclusions: All three scoring systems accurately predicted the risk of mortality and morbidity in patients undergoing elective open AAA repair. Among these, E-PASS seemed to be the most accurate predictor in this patient population. \u00a9 2007 European Society for Vascular Surgery.
\n \n\n \n \nObjective: Low disease prevalence poses challenges for diagnostic accuracy studies because of the large sample sizes that are required to obtain sufficient precision. The aim is to collate and discuss designs of diagnostic accuracy studies suited for use in low-prevalence situations. Study Design and Setting: We conducted a literature search including backward citation tracking and expert consultation. Two reviewers independently selected studies on designs for estimating diagnostic accuracy in a low-prevalence situation. During a 1-day expert meeting, all designs were discussed and recommendations were formulated. Results: We identified six designs for diagnostic accuracy studies that are suitable in low-prevalence situations because they reduced the total sample size or the number of patients undergoing the index test or reference standard depending on which poses the highest burden. We described the advantages and limitations of these designs and evaluated efficiencies in sample sizes, risk of bias, and alignment with the clinical pathway for applicability in routine care. Conclusion: Choosing a study design for diagnostic accuracy studies in low-prevalence situations should depend on whether the aim is to limit the number of patients undergoing the index test or reference standard, and the risk of bias associated with a particular design type.
\n \n\n \n \nBackground Internal appraisal styles, in addition to circadian and social rhythm instability, have been implicated in the development of mood experiences in bipolar disorder (BD), yet potential interactions between these variables remain under researched. Methods This study used online questionnaires to examine relationships between social and circadian rhythm instability, appraisal style and mood within populations at varying vulnerability for BD. Results Participants with BD (n=51), and those at behavioural high-risk (BHR; n=77), exhibited poor sleep quality and a stronger tendency to form internal appraisals of both positive and negative experiences compared to non-clinical controls (n=498) and participants with fibromyalgia (n=80). Participants with BD also exhibited a stronger tendency to adopt an internal, negative appraisal style compared to individuals at BHR. Sleep disturbance and internal appraisal styles were significantly associated with low mood in BD. Limitations Sleep quality and social rhythm stability were assessed using self-report measures only, which may differ from objective measures. Causal relationships between constructs could not be examined due to the cross-sectional design. Conclusions The findings suggest the importance of attending to internal appraisal styles and sleep quality when working therapeutically with individuals diagnosed with BD. Potential differences in the effect of appraisal style at the state and trait level warrant further exploration.
\n \n\n \n \nThis cross-sectional survey explored paediatric physician perspectives regarding diagnostic errors. All paediatric consultants and specialist registrars in Ireland were invited to participate in this anonymous online survey. The response rate for the study was 54\u00a0% (n\u00a0=\u00a0127). Respondents had a median of 9-year clinical experience (interquartile range (IQR) 4\u201320\u00a0years). A diagnostic error was reported at least monthly by 19 (15.0\u00a0%) respondents. Consultants reported significantly less diagnostic errors compared to trainees (p value\u00a0=\u00a00.01). Cognitive error was the top-ranked contributing factor to diagnostic error, with incomplete history and examination considered to be the principal cognitive error. Seeking a second opinion and close follow-up of patients to ensure that the diagnosis is correct were the highest-ranked, clinician-based solutions to diagnostic error. Inadequate staffing levels and excessive workload were the most highly ranked system-related and situational factors. Increased access to and availability of consultants and experts was the most highly ranked system-based solution to diagnostic error. Conclusion: We found a low level of self-perceived diagnostic error in an experienced group of paediatricians, at variance with the literature and warranting further clarification. The results identify perceptions on the major cognitive, system-related and situational factors contributing to diagnostic error and also key preventative strategies.What is Known:\u2022 Diagnostic errors are an important source of preventable patient harm and have an estimated incidence of 10\u201315\u00a0%.\u2022 They are multifactorial in origin and include cognitive, system-related and situational factors.What is New:\u2022 We identified a low rate of self-perceived diagnostic error in contrast to the existing literature.\u2022 Incomplete history and examination, inadequate staffing levels and excessive workload are cited as the principal contributing factors to diagnostic error in this study.
\n \n\n \n \n