Estimating the number of people with hepatitis C virus who have ever injected drugs and have yet to be diagnosed: an evidence synthesis approach for Scotland.

AIMS: To estimate the number of people who have ever injected drugs (defined here as PWID) living in Scotland in 2009 who have been infected with the hepatitis C virus (HCV) and to quantify and characterize the population remaining undiagnosed. METHODS: Information from routine surveillance (n=22616) and survey data (n=2511) was combined using a multiparameter evidence synthesis approach to estimate the size of the PWID population, HCV antibody prevalence and the proportion of HCV antibody prevalent cases who have been diagnosed, in subgroups defined by recency of injecting (in the last year or not), age (15-34 and 35-64 years), gender and region of residence (Greater Glasgow and Clyde and the rest of Scotland). RESULTS: HCV antibody-prevalence among PWID in Scotland during 2009 was estimated to be 57% [95% CI=52-61%], corresponding to 46657 [95% credible interval (CI)=33812-66803] prevalent cases. Of these, 27434 (95% CI=14636-47564) were undiagnosed, representing 59% [95% CI=43-71%] of prevalent cases. Among the undiagnosed, 83% (95% CI=75-89%) were PWID who had not injected in the last year and 71% (95% CI=58-85%) were aged 35-64 years. CONCLUSIONS: The number of undiagnosed hepatitis C virus-infected cases in Scotland appears to be particularly high among those who have injected drugs more than 1 year ago and are more than 35 years old.

Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22.

BACKGROUND: Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22. METHODS: 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit. RESULTS: Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62-75%) and 93% negative predictive value (95% CI = 92-95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71-0.79) and 0.72 (95% CI = 0.67-0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88-99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69-74%). CONCLUSIONS: The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.

Performance of anal cytology in a clinical setting when measured against histology and high-resolution anoscopy findings.

OBJECTIVES: The success of cervical cytology in screening for cervical neoplasia has led to the concept of anal cytology screening for anal neoplasia. Our objective is to study the performance of anal cytology as a screening tool. DESIGN: We assessed anal cytology against histology and high-resolution anoscopy in a clinical setting. METHODS: Anal pap test was obtained prior to high-resolution anoscopy examinations and biopsies. The results were analysed against a number of patient variables. RESULTS: From 395 individuals (93% men), 584 anal pap tests were obtained. HIV status was positive in 212 (54%) and negative in 156 (39%) individuals. On the basis of 288 histology results, the sensitivity of anal cytology to detect disease was 70% [95% confidence interval (CI) 64-75], whereas the specificity was 67% (95% CI 38-88). For high-grade disease (anal intraepithelial neoplasia 2/3), sensitivity of anal cytology was 81% (95% CI 70-90), and the negative predictive value was 85% (95% CI 76-92). Sensitivity was dependent on the area of disease (86% for two or more quadrants vs. 69% for one or more quadrants, P = 0.002) and HIV positivity (76% in HIV positive vs. 59% in HIV negative, P = 0.009). Amongst HIV-positive patients, the sensitivity was 90% when CD4 cell count was 400 cells/microl or less compared with 67% when CD4 cell count was above 400 cells/microl (P = 0.005). CONCLUSION: Anal cytology performs similar to cervical cytology in a clinical setting. Sensitivity of anal smear is dependent on the area (quadrants) of disease present. Sensitivity of anal cytology is enhanced when CD4 cell count is less than 400 cells/microl in HIV-positive men. Our results may explain the variable sensitivity reported in the literature.

Symptomatic venous thromboembolism following a hip fracture.

BACKGROUND AND PURPOSE: Venous thromboembolism (VTE) remains a substantial cause of morbidity and mortality following hip fracture. Previous work has not identified any risk factors associated with the type of hip fracture. We report the incidence of and risk factors for development of symptomatic VTE in patients following a hip fracture. PATIENTS AND METHODS: In this prospective study, we collected information on 5,300 consecutive patients who were admitted to a single unit with a hip fracture-in terms of their pre-admission status, details of any operation performed, and details of complications in the form of symptomatic venous thromboembolism. All patients received thromboprophylaxis with heparin. RESULTS: The incidence of symptomatic VTE was 2.2% (95% CI: 1.8-2.6). 85% of these events occurred within 5 weeks of the fracture. The statistically significant risk factors for symptomatic VTE were better preoperative mobility, living in one's own home, high mental test score, high preoperative hemoglobin, inter-trochanteric fractures, and fixation with a dynamic hip screw. In multivariate analysis adjusting for sex and age, type of residence on admission, type of fracture, and hemoglobin values on admission remained independently significant. INTERPRETATION: We found that the rate of symptomatic VTE using thromboprophylaxis with heparin was low but that there were a number of groups that were at a significantly higher risk of developing VTE. The patients who are particularly at risk appear to be those with a subtrochanteric or intertrochanteric hip fracture; here, the incidence of symptomatic VTE was twice that of intracapsular hip fractures.

Prospective estimation of rates of change in mammographic parenchymal patterns: influence of age and of hormone replacement therapy.

The objective of this study was to assess the effect of age, breast size and use of hormone replacement therapy (HRT) on the rate of change of mammographic parenchymal patterns, and the effect of age on the probability of misclassification between patterns. It was designed as a longitudinal study of the members of the treatment arm of a non-randomized screening trial in which subjects were assigned to screening or not by year of birth. The subjects were women in the Kotka district of Finland, each of whom attended for four or five mammographic screens. Participants were all women living in the district who were born in the relevant years and accepted an invitation to screening. A model was fitted to the longitudinal data comprising the observed Wolfe patterns on each woman, with age and breast size as predictors of breast density at first screen, age and HRT use as predictors of change in density at future screens, and age as a predictor of misclassification of true density between favourable (non-dense) and unfavourable (dense) patterns (according to the Wolfe classification). Relevant posterior probability estimates (with 95% credible intervals) were as follows. The probability that a woman of age 43.5 is truly in the favourable state ranged from 0.35 (0.34-0.37) for smallest breast size to 0.74 (0.72-0.76) for the largest. The probability that a woman is truly in the favourable state at first screen increased from 0.37 (0.36-0.38) at age 40 to 0.59 (0.58-0.60) at age 47. The probability that a woman having a later screen who had truly been in the unfavourable state at her previous screen changed to the favourable state increased from 0.12 (0.11-0.13) at age 42 to 0.48 (0.46-0.50) at age 55 for a woman not taking HRT, and from 0.10 (0.09-0.11) to 0.43 (0.40-0.45) at the same ages for a woman taking HRT. The probability that a woman would have changed from being truly in the favourable state to the unfavourable state was 0.003 (0.001-0.003) for any age and HRT use. The probability that a woman truly in a favourable state would be correctly classified rose from 0.87 (0.85-0.89) at age 40 to 0.998 (0.997-0.998) at age 55. The probability that a woman truly in the unfavourable state would be correctly classified decreased from 0.96 (0.95-0.97) to 0.93 (0.91-0.94) between the same ages. The probability of being in a non-dense, favourable state increases with age, as does the rate of change from dense to non-dense patterns. These are consistent with previous work. The probability of non-dense patterns and the rate of change to non-dense patterns are reduced with HRT use. Errors of classification are relatively rare, but are dependent on the age of the subject.

Misclassification in a matched case-control study with variable matching ratio: application to a study of c-erbB-2 overexpression and breast cancer.

We provide a simple analytic correction for risk factor misclassification in a matched case-control study with variable numbers of controls per case. The method is an extension of existing methodology, and involves estimating the corrected proportions of controls and cases in risk factor categories within each matched set. These estimates are then used to calculate the Mantel-Haenszel odds ratio estimate corrected for misclassification. A simulation-based interval estimate is developed. An example is given from a study of risk factors for progression of benign breast disease to breast cancer, in which the risk factor is a biological marker measured with poor sensitivity.