Prospective Study of the Diagnostic Accuracy of the In Vivo Laser Scanning Confocal Microscope for Severe Microbial Keratitis.

PURPOSE: To determine the diagnostic accuracy of in vivo confocal microscopy (IVCM) for moderate to severe microbial keratitis (MK). DESIGN: Double-masked prospective cohort study. PARTICIPANTS: Consecutive patients presenting to Aravind Eye Hospital, Madurai, India, between February 2012 and February 2013 with MK (diameter ≥3 mm, excluding descemetocele, perforation, or herpetic keratitis). METHODS: Following examination, the corneal ulcer was scanned by IVCM (HRT3/RCM, Heidelberg Engineering, Heidelberg, Germany). Images were graded for the presence or absence of fungal hyphae or Acanthamoeba cysts by the confocal microscopist who performed the scan (masked to microbial diagnosis) and 4 other experienced confocal graders (masked to clinical features and microbiology). The regrading of the shuffled image set was performed by 3 graders, 3 weeks later. Corneal-scrape samples were collected for microscopy and culture. MAIN OUTCOME MEASURES: The main outcome measures were sensitivity, specificity, and positive and negative predictive values of IVCM compared with those of a reference standard of positive culture or light microscopy. Sensitivities and specificities for multiple graders were pooled and 95% confidence intervals calculated using a bivariate random-effects regression model. RESULTS: The study enrolled 239 patients with MK. Fungal infection was detected in 176 (74%) and Acanthamoeba in 17 (7%) by microbiological methods. IVCM had an overall pooled (5 graders) sensitivity of 85.7% (95% confidence interval [CI]: 82.2%-88.6%) and pooled specificity of 81.4% (95% CI: 76.0%-85.9%) for fungal filament detection. For Acanthamoeba, the pooled sensitivity was 88.2% (95% CI: 76.2%-94.6%) and pooled specificity was 98.2% (95% CI: 94.9%-99.3%). Intergrader agreement was good: κ was 0.88 for definite fungus; κ was 0.72 for definite Acanthamoeba. Intragrader repeatability was high for both definite fungus (κ: 0.88-0.95) and definite Acanthamoeba classification (κ: 0.63-0.90). IVCM images from 11 patients were considered by all 5 graders to have a specific organism present (10 fungus, 1 Acanthamoeba) but had negative results via culture and light microscopy. CONCLUSIONS: Laser scanning IVCM performed with experienced confocal graders has high sensitivity, specificity, and test reproducibility for detecting fungal filaments and Acanthamoeba cysts in moderate to large corneal ulcers in India. This imaging modality was particularly useful for detecting organisms in deep ulcers in which culture and light microscopy results were negative.

Human papillomavirus infection and increased risk of HIV acquisition. A systematic review and meta-analysis.

OBJECTIVES: Human papillomavirus (HPV), one of the commonest sexually transmitted infections, may be a cofactor in HIV acquisition. We systematically reviewed the evidence for an association of HPV infection with HIV acquisition in women, heterosexual men and men who have sex with men (MSM). DESIGN: : Systematic review and meta-analysis. METHODS: Studies meeting inclusion criteria in Pubmed, Embase and conference abstracts up to 29 July 2011 were identified. Random effects meta-analyses were performed to calculate summary hazard ratios (HR). Publication bias and statistical heterogeneity were evaluated and population attributable fractions (PAFs) calculated. RESULTS: Eight articles were included, with previously unpublished data from five authors. Seven studies found an association between prevalent HPV and HIV acquisition. Risk of HIV acquisition in women doubled with prevalent HPV infection with any genotype [HR = 2.06 (95% CI = 1.44-2.94), I = 0%], although adjustment for confounders was often inadequate. The effect was similar for high-risk [HR = 1.99 (95% CI = 1.54-2.56), I = 8.4%] and low-risk [HR = 2.01 (95% CI = 1.27-3.20), I = 0%] HPV genotypes with weak evidence of publication bias (P = 0.06). Two studies in men were identified: both showed an association between HPV infection and HIV acquisition. Unpublished data from one of two studies in women indicated an association between genotypes targeted by HPV vaccines and HIV acquisition. PAFs for HIV attributable to infection with any HPV genotype ranged between 21 and 37%. CONCLUSION: If further studies validate the association between HPV infection and HIV acquisition, HPV vaccines may reduce HIV incidence in high HPV prevalence populations, in addition to preventing cervical cancer. HIV surveillance studies during implementation of HPV vaccine programmes are warranted.

Male circumcision and penile cancer: a systematic review and meta-analysis.

OBJECTIVE: We systematically reviewed the evidence of an association between male circumcision and penile cancer. METHODS: Databases were searched using keywords and text terms for the epidemiology of penile cancer. Random effects meta-analyses were used to calculate summary odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: We identified eight papers which evaluated the association of circumcision with penile cancer, of which seven were case-control studies. There was a strong protective effect of childhood/adolescent circumcision on invasive penile cancer (OR = 0.33; 95% CI 0.13-0.83; 3 studies). In two studies, the protective effect of childhood/adolescent circumcision on invasive cancer no longer persisted when analyses were restricted to boys with no history of phimosis. In contrast, there was some evidence that circumcision in adulthood was associated with an increased risk of invasive penile cancer (summary OR = 2.71; 95% CI 0.93-7.94; 3 studies). There was little evidence for an association of penile intra-epithelial neoplasia and in situ penile cancer with circumcision performed at any age. CONCLUSIONS: Men circumcised in childhood/adolescence are at substantially reduced risk of invasive penile cancer, and this effect could be mediated partly through an effect on phimosis. Expansion of circumcision services in sub-Saharan Africa as an HIV prevention strategy may additionally reduce penile cancer risk.

Design of epidemiological studies measuring genital and plasma HIV-1 outcomes: lessons from a randomised controlled trial.

OBJECTIVE: HIV-1 genital viral loads have not been extensively used as markers of HIV transmissibility. We set out to determine whether the variability of genital HIV-1 RNA over time necessitates design adjustments in studies measuring genital shedding to account for this variability. METHODS: We used data from a completed trial of HSV suppressive therapy to estimate the correlation of plasma and genital HIV-1 RNA quantities sampled at different times. These correlation estimates were used to estimate the relative sample sizes needed to detect an impact on HIV-1 genital and plasma quantities assuming a variable number of pre- and post-randomisation repeated measurements. The treatment effect on quantities of genital and plasma HIV-1 RNA were analysed using random effects linear regression. RESULTS: Post-randomisation plasma HIV-1 RNA was highly correlated within-women, while genital HIV-1 RNA was less strongly correlated. Related to this, the sample size required to detect a treatment effect on genital HIV-1 RNA decreased with increasing numbers of post-randomisation measurements up to 6-7 measurements, but varied less for plasma HIV-1 RNA. In contrast, repeated pre-randomisation measurements of plasma HIV-1 RNA increased study power more than genital HIV-1 RNA because of the high correlation of plasma HIV-1 RNA measurements between the pre- and post-randomisation samples. Re-analysis of the trial data illustrated the increased precision of the treatment effect on genital HIV-1 with increasing post-randomisation measurements. CONCLUSIONS: Designs allowing for repeated post-randomisation measures should be used to increase the precision in estimates of genital HIV-1 RNA. Repeated post-randomisation measurements of plasma HIV-1 RNA are of limited benefit.