A proposed approach may help systematic reviews retain needed expertise while minimizing bias from nonfinancial conflicts of interest.

OBJECTIVES: Groups such as the Institute of Medicine emphasize the importance of attention to financial conflicts of interest. Little guidance exists, however, on managing the risk of bias for systematic reviews from nonfinancial conflicts of interest. We sought to create practical guidance on ensuring adequate clinical or content expertise while maintaining independence of judgment on systematic review teams. STUDY DESIGN AND SETTING: Workgroup members built on existing guidance from international and domestic institutions on managing conflicts of interest. We then developed practical guidance in the form of an instrument for each potential source of conflict. RESULTS: We modified the Institute of Medicine's definition of conflict of interest to arrive at a definition specific to nonfinancial conflicts. We propose questions for funders and systematic review principal investigators to evaluate the risk of nonfinancial conflicts of interest. Once risks have been identified, options for managing conflicts include disclosure followed by no change in the systematic review team or activities, inclusion on the team along with other members with differing viewpoints to ensure diverse perspectives, exclusion from certain activities, and exclusion from the project entirely. CONCLUSION: The feasibility and utility of this approach to ensuring needed expertise on systematic reviews and minimizing bias from nonfinancial conflicts of interest must be investigated.

Community health workers, social support and cervical cancer screening among high-risk groups in rural Mexico.

BACKGROUND: Rural Mexico has a low screening prevalence and high burden of cervical cancer. One strategy to increase screening coverage utilizes community health workers (CHWs) to recruit high-risk women and address barriers. METHODS: We conducted a systematic cross-sectional survey of 196 women residing in Chiapas, Mexico who were recruited by either CHWs or traditional means for screening. This analysis compares 110 rural women's risk factors, attitudes and knowledge of cervical cancer and socioeconomic factors stratified by type of recruitment. RESULTS: Women who were informed of screening by CHWs were more likely to be of high risk sub-groups and report higher scores of social support but were also more likely to endorse difficulty with access and fatalistic attitudes about cancer. DISCUSSION: Utilizing CWHs results in increased screening among high-risk women and increased social support for screening among rural women, addressing a significant barrier, but may have limited effects on other barriers.

The Peru Cervical Cancer Prevention Study (PERCAPS): the technology to make screening accessible.

OBJECTIVE: This study utilized a combination of HPV self-sampling, iFTA elute specimen cards, and long distance transport for centralized processing of specimens to determine the feasibility of large-scale screening in remote and transient populations. METHODS: This study was performed in two locations in Peru (Manchay and Iquitos). The "Just For Me" cervico-vaginal brush and iFTA elute cards were used for the collection and transport of specimens. Samples were shipped via FedEx to China and tested for 14 types of high-risk HPV using PCR based MALDI-TOF. HPV positive women were treated with cryotherapy after VIA triage, and followed-up with colposcopy, biopsy, ECC, and repeat HPV testing at 6 months. RESULTS: Six hundred and forty three women registered, and 632 returned a sample over a 10 day period. Within 2 weeks, specimens were shipped, samples tested, and results received by study staff. Sixty-eight women (10.8%) tested positive, and these results were delivered over 4 days. Fifty-nine HPV positive women (87%) returned for evaluation and treatment, and 2 had large lesions not suitable for cryotherapy. At 6 months, 42 women (74%) returned for follow-up, and 3 had CIN 2 (all positive samples from the endocervical canal). Ninety eight percent of participants reported that they would participate in this type of program again. CONCLUSIONS: Utilizing HPV self-sampling, solid media specimen cards for long distance transport, and centralized high throughput processing, we achieved rapid delivery of results, high satisfaction levels, and low loss to follow-up for cervical cancer screening in remote and transient populations.

Cervical epithelial brightness by optical coherence tomography can determine histological grades of cervical neoplasia.

OBJECTIVE: The study aimed to determine if the difference in cervical epithelium brightness, as measured by optical coherence tomography (OCT), has potential as a distinguishing characteristic of normal, low-grade, high-grade (cervical intraepithelial neoplasia 2+), and cancer histological findings. MATERIALS AND METHODS: Information from 476 women was available for analysis. Demographic information was collected through in-person interview. All participants were human papillomavirus positive and/or had abnormal cytological finding and underwent colposcopy or unaided visual inspection and examination by OCT by quadrant. All women had a minimum of 4 OCT-matched cervical biopsies and endocervical curettage. Two sample t tests were used to measure differences in OCT image brightness by histological grades. RESULTS: Mean OCT image brightness differed significantly between each preinvasive histological grade and invasive cancer (p < .01 for all comparisons). Brightness as measured by OCT was also able to differentiate between squamous metaplasia and cervical intraepithelial neoplasia 3/cancer; p values were .004 and .003, respectively. CONCLUSIONS: Epithelial brightness is an important component of cervical epithelium diagnosis by OCT, and we plan to add it to our diagnostic mathematical algorithm in all future versions of OCT software.

The Peru cervical cancer prevention study (PERCAPS): community-based participatory research in Manchay, Peru.

OBJECTIVE: Cervical cancer is a preventable disease which causes significant morbidity and mortality, particularly in developing countries. Although technology for early detection continues to improve, prevention programs suffer from significant barriers. Community-based participatory research is an approach to research which focuses on collaboration with the community to surmount these barriers. The objective of this study was to evaluate the utility of community-based participatory research techniques in a mother-child screen/treat and vaccinate program for cervical cancer prevention in Manchay, Peru. MATERIALS AND METHODS: Human papillomavirus (HPV) self-sampling and cryotherapy were used for the screen/treat intervention, and the Gardasil vaccine was used for the vaccine intervention. Community health workers from Manchay participated in a 3-day educational course, designed by the research team. The community health workers then decided how to implement the interventions in their community. The success of the program was measured by (1) the ability of the community health workers to determine an implementation plan, (2) the successful use of research forms provided, (3) participation and retention rates, and (4) satisfaction of the participants. RESULTS: (1) The community health workers used a door-to-door approach through which participants were successfully registered and both interventions were successfully carried out; (2) registration forms, consent forms, and result forms were used correctly with minimal error; (3) screen/treat intervention: 97% of registered participants gave an HPV sample, 94% of HPV-positive women were treated, and 90% returned for 6-month follow-up; vaccine intervention: 95% of registered girls received the first vaccine, 97% of those received the second vaccine, and 93% the third; (4) 96% of participants in the screen/treat intervention reported high satisfaction. CONCLUSIONS: Community-based participatory research techniques successfully helped to implement a screen/treat and vaccinate cervical cancer prevention program in Manchay, Peru. These techniques may help overcome barriers to large-scale preventive health-care interventions.

Improved sensitivity of vaginal self-collection and high-risk human papillomavirus testing.

Self-collected vaginal specimens tested for high-risk human papillomavirus (HR-HPV) have been shown to be less sensitive for the detection of cervical intraepithelial neoplasia or cancer (≥CIN 3) than physician-collected endocervical specimens. To increase the sensitivity of self-collected specimens, we studied a self-sampling device designed to obtain a larger specimen from the upper vagina (POI/NIH self-sampler) and a more sensitive polymerase chain reaction (PCR)-based HR-HPV assay. Women (10,000) were screened with cervical cytology and HR-HPV testing of vaginal self-collected and endocervical physician-collected specimens. Women were randomly assigned to use either a novel self-collection device (POI/NIH self-sampler) or conical-shaped brush (Qiagen). The self-collected and clinician-collected specimens were assayed by Cervista (Hologic) and the research only PCR-based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF). Women with any abnormal screening test underwent colposcopy and biopsy. Women (8,556), mean age of 38.9, had complete data; 1.6% had ≥ CIN 3. For either HR-HPV assay, the sensitivity was similar for the two self-collection devices. Tested with Cervista, the sensitivity for ≥CIN 3 of self-collected specimens was 70.9% and for endocervical specimens was 95.0% (p = 0.0001). Tested with MALDI-TOF, the sensitivity for ≥CIN 3 of self-collected specimens was 94.3% and for endocervical specimens was also 94.3% (p = 1.0). A self-collected sample using a PCR-based assay with the capability of very high throughput has similar sensitivity as a direct endocervical specimen obtained by a physician. Large population-based screening "events" in low-resource settings could be achieved by promoting self-collection and centralized high-throughput, low-cost testing by PCR-based MALDI-TOF.

A new PCR-based mass spectrometry system for high-risk HPV, part II: clinical trial.

This was a population-based clinical trial of a polymerase chain reaction-based multiplex high-risk human papillomavirus (HR-HPV) assay using mass spectrometry (MassARRAY [Sequenom, San Diego, CA] matrix-assisted laser desorption/ionization time-of-flight mass spectrometry system [MALDI-TOF]). Participants were 10,000 women between the ages of 25 and 59 years in Guangdong Province, China (SHENCCAST II Study). All women collected a self-sample (tested with Cervista [Hologic, Marlborough, MA] and MALDI-TOF) followed by a clinician-collected cervical sample (for cytology, Hybrid Capture 2 [HC2; Qiagen, Gaithersburg, MD], Cervista, and MALDI-TOF). Patients with any abnormal result were asked to return for colposcopy and biopsies. This analysis included the data for 8,556 women. The sensitivity values for cervical intraepithelial neoplasia (CIN) 3 or worse for a direct cervical sample were 97.9%, 95.1%, and 94.3 for HC2, Cervista, and MALDI-TOF, respectively (P > .05). The sensitivity for CIN 3 or worse for a self-collected sample tested with MALDI-TOF was also 94.3%, which was similar to a clinician-obtained endocervical sample assayed with the 3 HR-HPV assays. MALDI-TOF combined with a self-collected sample provides a highly sensitive, high-throughput, low-cost-per-case assay for mass screening.

A population-based clinical trial comparing endocervical high-risk HPV testing using hybrid capture 2 and Cervista from the SHENCCAST II Study.

Our objective was to directly compare the accuracy of the high-risk human papillomavirus (HPV) assays, Hybrid Capture 2 (hc2; Qiagen, Gaithersburg, MD) and Cervista (Hologic, Bedford, MA), in diagnosing cervical intraepithelial neoplasia (CIN) 3 or worse (cancer). A population-based, cross-sectional study (The Shenzhen Cervical Cancer Screening Trial II) was conducted in Guangdong Province in China. Three high-risk HPV assays, self and direct cervical sampling and cytology, were studied. Abnormal results on any of 6 study tests (33%) resulted in referral to colposcopy. At colposcopy, every patient had at least 5 cervical biopsy specimens obtained. For 8,556 women between the ages of 25 and 59 years (mean, 38.9 years), the rate for CIN 3 or worse was 1.6% (141/8,556). The sensitivity (confidence interval) values for CIN 3 or worse were 97.9% (94.0%-99.6%) and 95.1% (90.0%-98.0%) for hc2 and Cervista, respectively (P > .05). The specificity (confidence interval) values were 87.8% (87.1%-88.5%) and 90.3% (89.6%-90.9%), respectively (P < .05). Differences in accuracy in diagnosing CIN 3 or worse with the hc2 and Cervista tests are minor and result from the decisions made in selecting the cut points.

SNIPER: a novel assay for human papillomavirus testing among women in Guizhou, China.

OBJECTIVE: Clinically validate the SNIPER human papillomavirus (HPV) DNA assay for the detection of cervical intraepithelial neoplasia (CIN)2 or higher and CIN2 or higher in a prospective cross-sectional screening study in Guizhou Province, China. METHODS: Between March and April, 2008, 1000 nonpregnant women aged 30 or older were recruited in Guizhou Province, China. Women positive by SNIPER or cytological examination were requested to return for follow-up. A biopsy of all colposcopically detected abnormalities was performed by quadrant. In normal quadrants, biopsies were obtained at the squamocolumnar junction (2-, 4-, 8-, and 10-o'clock positions depending on the quadrant). Samples were placed in 2 mL of saline solution and maintained between 2 degrees C and 30 degrees C for up to 1 week. One milliliter of this suspension was then prepared and tested. For polymerase chain reaction amplification, a pool of HPV primers was designed to amplify HPV DNA from 13 high-risk-HPV genotypes (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). Test characteristics were calculated according to standard definitions. RESULTS: One thousand women were screened; 175 tested HPV positive, 36 women tested negative but had positive Papanicolaou test results. All but 21 (90%) returned for follow-up. Median age and proportions having CIN2 or higher and CIN3 or higher differed by HPV status. Twenty-five women had CIN2 or higher and 16 had CIN3 or higher. The SNIPER assay was 93.3% and 94% sensitive and 86% and 85% specific for the detection of CIN2 or higher and CIN3 or higher, respectively. The positive predictive value was 17.4 % and 9.9% for CIN2 or higher and CIN3 or higher, respectively. Negative predictive value approached 100% for CIN2 or higher and CIN3 or higher. CONCLUSION: The SNIPER assay is functionally competitive and in terms of cost holds an advantage over Hybrid Capture 2 in a Chinese healthcare market, and potentially others, around the world.

Human papillomavirus DNA testing for cervical cancer screening: practical aspects in developing countries.

Cervical cancer is the second most common cancer in women worldwide, and the most common cause of death from cancer in women in the developing world. Cervical cancer represents the only gynecologic cancer that can be prevented through regular screening. Although there are established screening programs in the Western world that have effectively reduced the burden of cervical cancer, these programs have relied on insensitive screening technologies that depend on the long preinvasive phase of cervical carcinogenesis. The developing world faces specific additional challenges in implementing a successful cervical cancer screening program. The association between cervical cancers and human papillomavirus (HPV) make testing for the presence of HPV DNA a valuable screening tool. This review focuses on practical aspects of the implementation and delivery of HPV testing as the primary cervical cancer screening strategy in the developing world, and attempts to offer some solutions to the real-world challenges faced in these regions.

Study of the diagnostic efficacy of real-time optical coherence tomography as an adjunct to unaided visual inspection with acetic acid for the diagnosis of preinvasive and invasive neoplasia of the uterine cervix.

OBJECTIVES: To determine the sensitivity and specificity of optical coherence tomography (OCT) as an adjunct to unaided visual inspection using acetic acid (VIA) in the detection of cervical intraepithelial neoplasia 2 (CIN 2) in a real-time clinical evaluation. BACKGROUND: This clinical study was a prospective cross-sectional comparative trial that screened 1000 patients (aged 30-50 years) in a low-resource setting. Women with abnormal cervical cytology or positive human papillomavirus (HPV) tests were referred for further evaluation including VIA, OCT imaging, colposcopy, and cervical biopsies. METHODS: The VIA diagnoses were coded by quadrant. The OCT was then performed in all VIA-positive areas and at the squamocolumnar junction in all 4 quadrants. All patients were colposcoped; assessed by quadrant with biopsies at 2, 4, 8, and 10 o'clock; all abnormal areas were biopsied; and endocervical curettage was performed. Data were analyzed using generalized estimating equations and logistic regression. RESULTS: Of the 1000 patients, 175 (17.5%) were HPV positive, 93 (9.3%) had abnormal cervical cytology greater than or equal to atypical squamous cells of undetermined significance, and 211 (21.1%) were either HPV positive or had abnormal cytology. The VIA, OCT, colposcopy, and biopsies were completed on 183 (86.7%) of 211 women. For VIA alone, the sensitivity and specificity in detecting lesions greater than or equal to CIN 2 was 43% and 96%. With the addition of OCT, the sensitivity increases to 62% with a specificity of 80%. CONCLUSIONS: With the addition of OCT, the sensitivity of VIA increased in all analyses for the detection of greater than or equal to CIN II, with a loss in specificity. We hope that the potential of this technology will be realized when a computer algorithm is generated to aid in image interpretation.

Diagnostic efficacy of real-time optical coherence tomography in the management of preinvasive and invasive neoplasia of the uterine cervix.

OBJECTIVE: Determine the sensitivity and specificity of optical coherence tomography (OCT) as an adjunct to colposcopy in the detection of cervical intraepithelial neoplasia (CIN) grade 2 or higher in a real-time clinical evaluation. BACKGROUND: Optical coherence tomography (OCT) uses infrared light similar to ultrasound pulse-echo imaging. Image resolution is optimal in the 1-to-3-mm range. This study is the third in our series of OCT investigations and our first real-time clinical trial. The study was conducted at the Peking University Shenzhen Hospital, Shenzhen, China. METHODS: Nonpregnant women 18 years or older with abnormal cervical cytologic findings or a positive high-risk human papillomavirus test result were recruited. Women were assessed; and diagnoses, recorded by cervical quadrant first with colposcopy, followed by colposcopic directed OCT. A biopsy of the abnormal areas was performed. In normal quadrants, biopsy specimens were obtained at the 2-, 4-, 8-, and 10-o'clock positions at the squamocolumnar junction depending on the quadrant. An endocervical curettage was also done. Individual OCT diagnoses were paired with colposcopic impressions and biopsy specimens to assess its role as a paired secondary screen. Data were analyzed using generalized estimating equations to control for correlation within a woman. RESULTS: One thousand two hundred thirty-seven paired diagnoses from 299 women were analyzed. Median age was 36 years. Ninety-six women (8%) had a diagnosis of CIN 2 or higher. Evaluation by quadrant showed that the sensitivity for CIN 2 or higher decreased by adding OCT to colposcopy, but the specificity increased from 83% to 93%. CONCLUSIONS: We continue to try to improve sensitivity by improving the near-infrared light source, decreasing the scan time to 8 frames per second, and using a larger diameter (5 mm) fiberoptic probe with a newly designed application specific probe sheath.

The Mexican Cervical Cancer Screening Trial: self-sampling for human papillomavirus with unaided visual inspection as a secondary screen.

The Mexican Cervical Cancer Screening (MECCS) study took place in the State of Michoacán. Primary screening was by self-sampling for high-risk human papillomavirus (HR-HPV). The objectives were to increase the specificity of primary HPV screening by requiring 2 positive HPV tests 1 year apart in women whose secondary screen was negative according to an acetic acid-aided visual inspection (VIA). In addition, we postulated that the sensitivity of VIA would be sufficient to identify large preinvasive lesions and cancers unsuitable for cryotherapy if applied in a see-and-treat algorithm.A total of 8621 women (aged 30-50 years) were screened, and 14.3% were positive for HR-HPV. In phase 1, 11.9% of the HPV-positive women were VIA-positive and were referred for colposcopy with directed and random biopsies. If VIA-negative, women repeated the self-sample 1 year later to detect persistent HR-HPV (25.2% were positive). If persistently HR-HPV-positive in phase 2, patients again had VIA, then all women (both VIA-positive and -negative) received directed and random biopsies. If cryotherapy had been used to treat HPV- and VIA-positive women in phase 1 or persistent HR-HPV-positive (phase 2), the potential risk of undertreatment would have been 4.1%, and 66.4% of the treated patients would have had normal or cervical intraepithelial neoplasia I on biopsy. The VIA triage would refer 0.73% of the patients to colposcopy owing to the lesion size, location, or the presence of a cancer. On the basis of this pilot study, we are encouraged to explore and evaluate a rapid, more sensitive, and more specific self-test.

Mitochondrial disorders among infants exposed to HIV and antiretroviral therapy.

Although antiretroviral therapy (ART) is critical for preventing mother-to-child transmission of HIV, concern has been raised about the possibility that it may cause mitochondrial dysfunction in infants. There is adequate evidence for a mechanism by which exposure to nucleoside reverse transcriptase inhibitors (NRTIs) could lead to mitochondrial dysfunction; animal studies have shown evidence of mitochondrial dysfunction in the offspring of animals treated with NRTIs and mitochondrial disorders occur in adults treated with NRTIs. This systematic review synthesises the published research on mitochondrial dysfunction and disorders in infants exposed to HIV and antiretrovirals. We found conflicting evidence regarding the possible association of in utero ART exposure with mortality and morbidity due to mitochondrial dysfunction. ART exposure in utero or postpartum was associated with persistent decreases in lymphocytes, neutrophils and platelets as well as an increased risk of transient lactic acidaemia, anaemia and mitochondrial DNA depletion, although these laboratory findings were generally not associated with clinical symptoms. We conclude that large, prospective studies of HIV-exposed infants are needed to resolve the discrepant results regarding morbidity and mortality related to mitochondrial disorders, to ascertain the clinical significance of effects on laboratory values, to determine whether or not the incidence of mitochondrial disorders differs by regimen and to develop predictive models that might identify which infants are at the greatest risk. The challenges that remain to be addressed include the development of a sensitive but affordable screening algorithm in combination with specific diagnostic criteria; consistent collection of data on ART exposure and other risk factors, long-term follow-up of HIV-exposed but uninfected children and implementation in resource-limited settings.