Katrina Sharples

Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database

Objective To examine the risk of non-fatal idiopathic venous thromboembolism in current users of a combined oral contraceptive containing drospirenone, relative to current users of preparations containing levonorgestrel. Design Nested case-control study. Setting UK General Practice Research Database. Participants Women aged 15-44 years without major risk factors for venous thromboembolism who started a new episode of use of an oral contraceptive containing 30 µg oestrogen in combination with either drospirenone or levonorgestrel between May 2002 and September 2009. Cases were women with a first diagnosis of venous thromboembolism; up to four controls, matched by age, duration of recorded information, and general practice, were randomly selected for each case. Main outcome measures Odds ratios and 95% confidence intervals estimated with conditional logistic regression; age adjusted incidence rate ratio estimated with Poisson regression. Results 61 cases of idiopathic venous thromboembolism and 215 matched controls were identified. In the case-control analysis, current use of the drospirenone contraceptive was associated with a threefold higher risk of non-fatal idiopathic venous thromboembolism compared with levonorgestrel use; the odds ratio adjusted for body mass index was 3.3 (95% confidence interval 1.4 to 7.6). Subanalyses suggested that referral, diagnostic, first time user, duration of use, and switching biases were unlikely explanations for this finding. The crude incidence rate was 23.0 (95% confidence interval 13.4 to 36.9) per 100 000 woman years in current users of drospirenone and 9.1 (6.6 to 12.2) per 100 000 woman years in current users of levonorgestrel oral contraceptives. The age adjusted incidence rate ratio was 2.7 (1.5 to 4.7). Conclusions These findings contribute to emerging evidence that the combined oral contraceptive containing drospirenone carries a higher risk of venous thromboembolism than do formulations containing levonorgestrel.

Effect of premanipulative tests on vertebral artery and internal carotid artery blood flow: A pilot study

BACKGROUND Neck manipulation occasionally causes stroke after trauma to the vertebral or internal carotid artery. Premanipulativ e tests involving cervical spine rotation or extension have been recommended to detect patients at risk of neurovascular ischemia. However, the effect of these procedures on extracranial blood flow is not well established, and their validity is thus controversial. OBJECTIVE To determine the effect of premanipulative tests involving cervical spine rotation or extension on vertebral artery and internal carotid artery blood flow parameters. DESIGN Two-group experimental study. SUBJECTS Twenty subjects consisting of 16 patients treated with physiotherapy and four volunteers. METHODS Subjects were tested with a recommended premanipulative protocol by both an independent physiotherapist and an investigator. One group consisted of 10 subjects with signs or symptoms indicative of neurovascular ischemia on premanipulative testing, with 10 subjects with no signs or symptoms indicative of neurovascular ischemia on premanipulative testing comprising the second group. Hemodynamic measurements for both vertebral and both internal carotid arteries were taken by use of duplex Doppler ultrasonography with color-flow imaging with the subjects in the following positions: neutral, end-range extension, 45 degrees contralateral rotation, end-range contralateral rotation, and combined end-range contralateral rotation/extension. RESULTS The reliability of premanipulative testing was supported. Significant changes in flow velocity of the vertebral artery (and to a lesser extent of the internal carotid artery) were shown in end-range positions involving rotation and extension. No meaningful significant differences were found between the two groups. CONCLUSIONS Screening procedures that use rotation and extension may be useful tests of the adequacy of collateral circulation. A larger study is needed to determine whether subjects testing positive significantly differ from those testing negative.

Regression analysis of correlated binary data: some small sample results for the estimating equation approach

Liang and Zeger (1986Biometrika 73 13-22) and Zeger and Liang (1986Biometrics 42 121-30) proposed a generalized estimating equation approach to the estimation of covariate effects on correlated binary outcomes. They showed that estimates of the regression parameters are consistent and asymp¬totically normal even if the correlation structure is misspecified. We present the results of a simulation study designed to evaluate the small sample properties of the estimating equations and to make some comparisons with maximum likelihood. We consider the situation where the block sizes are small and the covariates (block and sub-unit level) are binary. The generalized estimating equations are shown to estimate the regression parameters well in small samples of this type, but estimation of the correlation parameters is more difficult. Misspecification of the correlation structure has some effect on bias and efficiency for small samples (100) but the effect is negligible for larger samples. In these cases, use of th...

Pseudomonas aeruginosa Uses Multiple Pathways To Acquire Iron during Chronic Infection in Cystic Fibrosis Lungs

ABSTRACT Pseudomonas aeruginosa chronically infects the lungs of more than 80% of adult patients with cystic fibrosis (CF) and is a major contributor to the progression of disease pathology. P. aeruginosa requires iron for growth and has multiple iron uptake systems that have been studied in bacteria grown in laboratory culture. The purpose of this research was to determine which of these are active during infection in CF. RNA was extracted from 149 sputum samples obtained from 23 CF patients. Reverse transcription–quantitative real-time PCR (RT-qPCR) was used to measure the expression of P. aeruginosa genes encoding transport systems for the siderophores pyoverdine and pyochelin, for heme, and for ferrous ions. Expression of P. aeruginosa genes could be quantified in 89% of the sputum samples. Expression of genes associated with siderophore-mediated iron uptake was detected in most samples but was at low levels in some samples, indicating that other iron uptake mechanisms are active. Expression of genes encoding heme transport systems was also detected in most samples, indicating that heme uptake occurs during infection in CF. feoB expression was detected in all sputum samples, implying an important role for ferrous ion uptake by P. aeruginosa in CF. Our data show that multiple P. aeruginosa iron uptake mechanisms are active in chronic CF infection and that RT-qPCR of RNA extracted from sputum provides a powerful tool for investigating bacterial physiology during infection in CF.

A Multigene Urine Test for the Detection and Stratification of Bladder Cancer in Patients Presenting with Hematuria

PURPOSE We investigated whether the RNA assay uRNA® and its derivative Cxbladder® have greater sensitivity for the detection of bladder cancer than cytology, NMP22™ BladderChek™ and NMP22™ ELISA, and whether they are useful in risk stratification. MATERIALS AND METHODS A total of 485 patients presenting with gross hematuria but without a history of urothelial cancer were recruited prospectively from 11 urology clinics in Australasia. Voided urine samples were obtained before cystoscopy. The sensitivity and specificity of the RNA tests were compared to cytology and the NMP22 assays using cystoscopy as the reference. The ability of Cxbladder to distinguish between low grade, stage Ta urothelial carcinoma and more advanced urothelial carcinoma was also determined. RESULTS uRNA detected 41 of 66 urothelial carcinoma cases (62.1% sensitivity, 95% CI 49.3-73.8) compared with NMP22 ELISA (50.0%, 95% CI 37.4-62.6), BladderChek (37.9%, 95% CI 26.2-50.7) and cytology (56.1%, 95% CI 43.8-68.3). Cxbladder, which was developed on the study data, detected 82%, including 97% of the high grade tumors and 100% of tumors stage 1 or greater. The cutoffs for uRNA and Cxbladder were prespecified to give a specificity of 85%. The specificity of cytology was 94.5% (95% CI 91.9-96.5), NMP22 ELISA 88.0%, (95% CI 84.6-91.0) and BladderChek 96.4% (95% CI 94.2-98.0). Cxbladder distinguished between low grade Ta tumors and other detected urothelial carcinoma with a sensitivity of 91% and a specificity of 90%. CONCLUSIONS uRNA and Cxbladder showed improved sensitivity for the detection of urothelial carcinoma compared to the NMP22 assays. Stratification with Cxbladder provides a potential method to prioritize patients for the management of waiting lists.

Maintaining confidentiality of interim data to enhance trial integrity and credibility

Background For clinical trials of interventions that could affect mortality or major morbidity, Data Monitoring Committees have an important role in safeguarding patient interests and enhancing trial integrity and credibility. In trials overseen by an independent DMC it is widely recognized that interim data should remain confidential to the DMC and to the statistical group preparing reports. However, we have found that the principle of confidentiality is not always followed in practice, particularly where the interim data include complete results on a short-term outcome measure. Purpose To discuss the reasoning and evidence supporting the principle of confidentiality of interim data with emphasis on the setting where the interim data include complete results on a short-term outcome. Methods We review the reasons why wider access to interim data can increase the risk of false positive or false negative conclusions and discuss the types of harm which can occur. We provide illustrations and insights from recent experiences and discuss the level of consensus in the research community. Results The arguments in favor of early release of interim data include the need to provide reliable data in a timely manner to patients and physicians, the potential to increase the enthusiasm of trial investigators, and to restore equipoise. However interim data, even where these include complete results on a short-term outcome measure, provide an unreliable and biased assessment of the overall benefit-to-risk profile of the trial treatments. Pre-judgment based on over-interpretation of such interim data can affect recruitment, treatment delivery, and follow-up, risking the ability of the trial to achieve its goals. Conclusions In order to preserve the integrity of a trial and safeguard the interests of patients, interim data, including complete data on short-term outcomes, should remain confidential to the DMC and the statistical group responsible for preparing interim reports until the trial has achieved its primary objectives. Clinical Trials 2008; 5: 157—167. http://ctj.sagepub.com

CYP2C19 pharmacogenetics in advanced cancer: compromised function independent of genotype

CYP2C19 is a drug-metabolising enzyme involved in the metabolism of a number of chemotherapeutic agents including cyclophosphamide. Variants of the CYP2C19 gene result in a loss of function polymorphism, which affects approximately 3% of the Caucasian population. These individuals are poor metabolisers (PM) of a wide range of medications including omeprazole (OMP). In healthy subjects PM can be identified through homozygous variant genotype. However, a discordance between CYP2C19 genotype and phenotype has been reported previously in a small study of cancer patients. To investigate whether CYP2C19 activity was decreased in patients with advanced cancer, CYP2C19 genotype was determined in 33 advanced cancer patients using PCR-RFLP analysis for the two important allelic variants (*2,681G>A and *3,636G>A) and the activity of the enzyme was evaluated using the CYP2C19 probe drug OMP. The activity of the drug-metabolising enzyme CYP2C19 was severely compromised in advanced cancer patients, resulting in a PM status in 37% of the patients who had normal genotype. This is significantly (P<0.0005) higher than that would be predicted from the genotypic status of these patients. There was no evidence of a correlation between compromised CYP2C19 activity and any of the proinflammatory cytokines or acute phase response proteins studied. However, there was preliminary evidence of an association between PM status and low body mass (P=0.03). There is increasing interest in using pharmacogenetics to ‘individualise medicine’, however, the results of this study indicate that in a cancer population genotyping for CYP2C19 would significantly underestimate the number of phenotypic PM of drugs, such as cyclophosphamide, which may be metabolised by this enzyme.

Late presentation of HIV infection among adults in New Zealand: 2005-2010.

Early diagnosis of HIV infection is important for the individual and for disease control. A consensus was recently reached among European countries on definitions of timing of presentation for care: ‘Late presentation’ refers to entering care with a CD4 count <350 cells/μL or an AIDS‐defining event, regardless of the CD4 count. Presentation with ‘advanced HIV disease’ is a subset having a CD4 count <200 cells/μL and also includes all who have an AIDS‐defining event regardless of CD4 count. This study examines timing of presentation in New Zealand from 2005 to 2010.

Temporal patterns of injury during a rugby season.

The aim of this study was to describe temporal patterns in the frequency, nature and circumstances of injuries occurring among a cohort of 356 rugby players during a club rugby season in New Zealand. It was found that the rate of injury in games decreased significantly over time in both males and females. The reduction in injury rate over the season was more pronounced in some grades, but no differences were found when examined by gender. playing position, age, ethnicity or by health and fitness types. Trends in injury rate were consistent over the rugby season and did not appear to be the result of a bias involving under-reporting of end-of-season injuries. The types and severity of injury remained relatively constant, but the proportion of injuries occurring in back play fell significantly over the season and injuries were more likely to occur in the trunk body region as the season progressed. This study supported the hypothesis that higher rates of injury occur at the start of the rugby season and decrease over the course of the season. This reduction is consistent over time and across player types, and is not attributable either to decreasing injury severity or to increasing player fitness.

Unlinked anonymous HIV prevalence among New Zealand sexual health clinic attenders : 2005-2006

This unlinked anonymous study aimed at determining the prevalence of HIV among sexual health clinic attenders having blood samples taken for syphilis and/or hepatitis B serology in six major New Zealand cities over a 12-month period in 2005–2006. Overall, seroprevalence was five per 1000 (47/9439). Among men who have sex with men (MSM), the overall prevalence and that of previously undiagnosed HIV were 44.1 and 20.1 per 1000, respectively. In heterosexual men, the overall prevalence was 1.2 per 1000 and in women 1.4 per 1000. HIV remains to be concentrated among homosexual and bisexual men. Comparison with a previous survey in 1996–1997 suggests an increase in the prevalence of undiagnosed HIV among MSM and also an increase in the number of MSM attending sexual health clinics. The low prevalence of HIV among heterosexuals suggests no extensive spread into the groups identified at risk of other sexually transmitted infections.