A systematic review and meta-analysis of studies evaluating the performance of point-of-care tests for human papillomavirus screening.

BACKGROUND: High-risk human papillomavirus (HPV) is a necessary cause of high-grade cervical intraepithelial neoplasia (grade 2 or higher, CIN2+). Simplified and rapid HPV DNA assays designed for use in resource-limited settings have recently become available. METHODS: We performed a systematic review and meta-analysis by searching Medline, Embase, Global Health and CINAHL databases for studies from 1 January 2004 to 25 February 2017 that reported the performance of careHPV or OncoE6 for the detection of histological CIN2+ in cervical cancer screening. We used bivariate models to estimate pooled sensitivity and specificity for CIN2+ and CIN3+. RESULTS: A total of 29 657 women were included from seven studies evaluating the performance of careHPV for the detection of CIN2+ and four studies among 27 845 women for the detection of CIN3+. The pooled prevalence for CIN2+ and CIN3+ was 2.3% and 1.1%, respectively. careHPV had sensitivity and specificity of 88.1% (95% CI 81.4 to 92.7) and 83.7% (95% CI 74.9 to 89.8), respectively, for CIN2+ and 90.3% (95% CI 83.4 to 94.5) and 85.3% (95% CI 73.1 to 92.5), respectively, for CIN3+, using clinician-collected cervical specimen. The corresponding pooled estimates using self-collected vaginal swabs were 73.6% (95% CI 64.9 to 80.8) and 88.0% (95% CI 79.1 to 93.5) for CIN2+ and 75.2% (95% CI 66.8 to 82.0) and 90.6% (95% CI 83.4 to 94.9) for CIN3+. Two studies using OncoE6 reported sensitivity and specificity ranging from 31.3% to 42.4% and 99.1%-99.4% for CIN2+, and 53.5% and 98.9% for CIN3+ for one study. CONCLUSION: CareHPV has good sensitivity and specificity for the detection of CIN2+ and CIN3+, but sensitivity was lower using self-collected vaginal samples. The specificity is lower in high HPV prevalence populations such as women living with HIV. OncoE6 assay warrants further evaluation

Rapid and point-of-care tests for the diagnosis of Trichomonas vaginalis in women and men.

BACKGROUND: Trichomonasvaginalis (TV) is a highly prevalent parasitic infection worldwide. It is associated with many adverse reproductive health outcomes. Many infections are asymptomatic and syndromic management leads to underdetection of TV. Traditional methods of TV detection such as wet preparation are insensitive. New rapid, point-of-care (POC) tests can enhance the diagnosis of trichomoniasis. METHODS: The authors reviewed the literature and discuss older POC tests for TV detection, as well as the OSOM lateral flow test, the AmpliVue test, the Solana test and the GeneXpert test as well as the limitations of wet preparation and culture for detection of TV. RESULTS: The OSOM test is easy to perform, compared with other POC tests, and is Clinical Laboratory Improvement Amendments (CLIA)-waived, equipment-free, has sensitivities of 83%-86% compared with nucleic acid amplification tests (NAATs) and can be performed in 15 min. The AmpliVue and the Solana tests are not CLIA waived and require small pieces of equipment. They are molecular amplified assays and can be completed in <1 hour. AmpliVue demonstrated a sensitivity for vaginal swabs of 100% compared with wet preparation/culture and 90.7% compared with NAATs. Solana demonstrated a sensitivity of 98.6%-100% for vaginal swabs and 92.9%-98% for female urines, compared with wet preparation/culture. Compared with other NAATs, the sensitivity for Solana was 89.7% for swabs and 100% for urine. The GeneXpert TV test for women and men is a moderately complex test, requires a small platform and can be performed in <1 hour. The sensitivity compared with wet preparation/culture for self-collected vaginal swabs was 96.4%, 98.9% for endocervical specimens and 98.4% for female urine. For men, sensitivity for urines was excellent (97.2%). The specificity for all assays was excellent. CONCLUSIONS: Several rapid POC tests have the potential to rapidly diagnose trichomoniasis in women and one is available for detection of TV in men

Systematic reviews of point-of-care tests for the diagnosis of urogenital Chlamydia trachomatis infections.

BACKGROUND: WHO estimates that 131 million new cases of urogenital Chlamydia trachomatis (CT) infections occur globally every year. Most infections are asymptomatic. Untreated infection in women can lead to severe complications. Screening and treatment of at-risk populations is a priority for prevention and control. OBJECTIVES: To summarise systematic reviews of the performance characteristics of commercially available point-of-care tests (POCT) for screening and diagnosis of urogenital CT infection. METHODS: Two separate systematic reviews covering the periods 2004-2013 and 2010-2015 were conducted on rapid CT POCTs. Studies were included if tests were evaluated against a valid reference standard. RESULTS: In the first review, 635 articles were identified, of which 11 were included. Nine studies evaluated the performance of eight antigen detection rapid POCTs on 10 280 patients and two studies evaluated a near-patient nucleic acid amplification test (NAAT) on 3518 patients. Pooled sensitivity of antigen detection tests was 53%, 37% and 63% for cervical swabs, vaginal swabs and male urine, and specificity was 99%, 97% and 98%, respectively. The pooled sensitivity and specificity of the near-patient NAAT for all specimen types were >98% and 99.4%, respectively. The second review identified two additional studies on four antigen detection POCTs with sensitivities and specificities of 22.7%-37.7% and 99.4%-100%, respectively. A new two-step 15 min rapid POCT using fluorescent nanoparticles showed performance comparable to that of near-patient NAATs. CONCLUSIONS: The systematic reviews showed that antigen detection POCTs for CT, although easy to use, lacked sufficient sensitivity to be recommended as a screening test. A near-patient NAAT shows acceptable performance as a screening or diagnostic test but requires electricity, takes 90 min and is costly. More affordable POCTs are in development

Evaluation of the Prognostic Value of IFN-γ Release Assay and Tuberculin Skin Test in Household Contacts of Infectious Tuberculosis Cases in Senegal

BACKGROUND: Chemoprophylaxis of contacts of infectious tuberculosis (TB) cases is recommended for TB control, particularly in endemic countries, but is hampered by the difficulty to diagnose latent TB infection (LTBI), classically assessed through response to the Tuberculin Skin Test (TST). Interferon-gamma release assays (IGRA) are proposed new tools to diagnose LTBI, but there are limited data on their ability to predict the development of active TB disease. To address this, we investigated the response to TST and IGRA in household contacts of infectious TB cases in a TB high-burden country and the potential correlation with development of TB. METHODOLOGY/PRINCIPAL FINDINGS: Prospective household contacts study conducted in two health centres in Dakar, Senegal. A total of 2679 household contacts of 206 newly detected smear and/or culture positive index TB cases aged 18 years or greater were identified A TST was performed in each contact and an ESAT6/CFP10 ELISPOT assay performed in a random sample of those. Contacts were followed-up for 24 months. TB was diagnosed in 52 contacts, an incidence rate of 9.27/1000 person-years. In univariable analysis, the presence of positive TST (> or = 10 mm) and ELISPOT (>32 SFC/million PBMC) responses at baseline were associated with active TB during follow-up: Rate Ratio [RR] = 2.32 (95%CI:1.12-4.84) and RR = 2.09 (95%CI:0.83-5.31), respectively. After adjustment for age, sex and proximity to index case, adjusted RRs were 1.51 (95%CI:0.71-3.19) and 1.98 (95%CI:0.77-5.09), respectively. Restricting analysis to the 40 microbiologically confirmed cases, the adjusted RR for positive ELISPOT was 3.61 (95%CI:1.03-12.65). The median ELISPOT response in contacts who developed TB was 5-fold greater than in those who did not develop TB (p = 0.02). CONCLUSIONS/SIGNIFICANCE: TST and IGRAs are markers of a contact of the immune system with tubercle bacilli. In a TB endemic area, a high ELISPOT response may reflect increased bacterial replication that may subsequently be associated with development of TB disease and may have a prognostic value. Further longitudinal data are needed to assess whether IGRAs are reliable markers to be used for targeting chemoprophylaxis

Probing the electron capture dissociation mass spectrometry of phosphopeptides with traveling wave ion mobility spectrometry and molecular dynamics simulations

Electron capture dissociation mass spectrometry offers several advantages for the analysis of peptides, most notably that backbone c and z fragments typically retain labile modifications such as phosphorylation. We have shown previously that, in some cases, the presence of phosphorylation has a deleterious effect on peptide sequence coverage, and hypothesized that intramolecular interactions involving the phosphate group were preventing separation of backbone fragments. In the present work, we seek to rationalize the observed ECD behavior through a combination of ECD of model peptides, traveling wave ion mobility mass spectrometry and molecular dynamics simulations. The results suggest that for doubly protonated ions of phosphopeptide APLpSFRGSLPKSYVK a salt-bridge structure is favored, whereas for the doubly-protonated ions of APLSFRGSLPKpSYVK ionic hydrogen bonds predominate. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13361-015-1094-1) contains supplementary material, which is available to authorized users

Risk Factors Associated with Positive QuantiFERON-TB Gold In-Tube and Tuberculin Skin Tests Results in Zambia and South Africa

INTRODUCTION: The utility of T-cell based interferon-gamma release assays for the diagnosis of latent tuberculosis infection remains unclear in settings with a high burden of tuberculosis. OBJECTIVES: To determine risk factors associated with positive QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) results and the level of agreement between the tests; to explore the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST. METHODS: Adult household contacts of tuberculosis patients were invited to participate in a cross-sectional study across 24 communities in Zambia and South Africa. HIV, QFT-GIT and TST tests were done. A questionnaire was used to assess risk factors. RESULTS: A total of 2,220 contacts were seen. 1,803 individuals had interpretable results for both tests, 1,147 (63.6%) were QFT-GIT positive while 725 (40.2%) were TST positive. Agreement between the tests was low (kappa = 0.24). QFT-GIT and TST results were associated with increasing age (adjusted OR [aOR] for each 10 year increase for QFT-GIT 1.15; 95% CI: 1.06-1.25, and for TST aOR: 1.10; 95% CI 1.01-1.20). HIV positivity was less common among those with positive results on QFT-GIT (aOR: 0.51; 95% CI: 0.39-0.67) and TST (aOR: 0.61; 95% CI: 0.46-0.82). Smear positivity of the index case was associated with QFT-GIT (aOR: 1.25; 95% CI: 0.90-1.74) and TST (aOR: 1.39; 95% CI: 0.98-1.98) results. We found little evidence in our data to support our hypotheses. CONCLUSION: QFT-GIT may not be more sensitive than the TST to detect risk factors associated with tuberculous infection. We found little evidence to support the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST

Homologous recombination repair intermediates promote efficient de novo telomere addition at DNA double-strand breaks

The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stabilit

Annual Risk of Tuberculous Infection Using Different Methods in Communities with a High Prevalence of TB and HIV in Zambia and South Africa

BACKGROUND: The annual risk of tuberculous infection (ARTI) is a key epidemiological indicator of the extent of transmission in a community. Several methods have been suggested to estimate the prevalence of tuberculous infection using tuberculin skin test data. This paper explores the implications of using different methods to estimate prevalence of infection and ARTI. The effect of BCG vaccination on these estimates is also investigated. METHODOLOGY/PRINCIPAL FINDINGS: Tuberculin surveys among school children in 16 communities in Zambia and 8 in South Africa (SA) were performed in 2005, as part of baseline data collection and for randomisation purposes of the ZAMSTAR study. Infection prevalence and ARTI estimates were calculated using five methods: different cut-offs with or without adjustments for sensitivity, the mirror method, and mixture analysis. A total of 49,835 children were registered for the surveys, of which 25,048 (50%) had skin tests done and 22,563 (90%) of those tested were read. Infection prevalence was higher in the combined SA than Zambian communities. The mirror method resulted in the least difference of 7.8%, whereas that estimated by the cut-off methods varied from 12.2% to 17.3%. The ARTI in the Zambian and SA communities was between 0.8% and 2.8% and 2.5% and 4.2% respectively, depending on the method used. In the SA communities, the ARTI was higher among the younger children. BCG vaccination had little effect on these estimates. CONCLUSIONS/SIGNIFICANCE: ARTI estimates are dependent on the calculation method used. All methods agreed that there were substantial differences in infection prevalence across the communities, with higher rates in SA. Although TB notification rates have increased over the past decades, the difference in cumulative exposure between younger and older children is less dramatic and a rise in risk of infection in parallel with the estimated incidence of active tuberculosis cannot be excluded

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB