Determinants of Acquisition, Persistence, and Clearance of Oncogenic Cervical Human Papillomavirus Infection in the Philippines Using a Multi-Omics Approach: DEFEAT HPV Study Protocol.

HPV infection is one of the most studied risk factors in cervical cancer-the second most common cancer site and cause of death due to cancer in the Philippines. However, there is a lack of population-based epidemiological data on cervical HPV infection in the Philippines. Local reports on co-infections with other lower genital tract pathogens, commonly reported globally, are also lacking, which emphasizes the need to increase efforts in targeting HPV prevalence, genotype, and distribution. Hence, we aim to determine the molecular epidemiology and natural history of HPV infection among reproductive-age Filipino women using a community-based prospective cohort design. Women from rural and urban centers will be screened until the target sample size of 110 HPV-positive women (55 from rural sites and 55 from urban sites) is reached. Cervical and vaginal swabs will be collected from all screened participants. For HPV-positive patients, HPV genotypes will be determined. One hundred ten healthy controls will be selected from previously screened volunteers. The cases and controls will comprise the multi-omics subset of participants and will be followed up after 6 and 12 months for repeat HPV screening. Metagenomic and metabolomic analyses of the vaginal swabs will also be performed at baseline, after 6 months, and after 12 months. The results of this study will update the prevalence and genotypic distribution of cervical HPV infection among Filipino women, determine whether the current vaccines used for HPV vaccination programs capture the most prevalent high-risk HPV genotypes in the country, and identify vaginal community state types and bacterial taxa associated with the natural history of cervical HPV infection. The results of this study will be used as the basis for developing a biomarker that can help predict the risk of developing persistent cervical HPV infection in Filipino women.

Improving diagnostic strategies for ovarian cancer in Filipino women using ultrasound imaging and a multivariate index assay.

OBJECTIVE: To evaluate the clinical performance and overall utility of imaging and biomarker assays in discriminating between benign and malignant ovarian masses in a Filipino population. METHODS: This is a prospective cohort study among Filipino women undergoing assessment for an ovarian mass in a tertiary center. All included patients underwent a physical examination before level III specialist ultrasonographic and Doppler evaluation, multivariate index assay (MIA2G), and surgery for an adnexal mass. Ovarian tumors were classified as high-risk for malignancy based on the International Ovarian Tumour Analysis (IOTA) - Logistic Regression 2 (LR2) score. The ovarian imaging and biomarker results were correlated with the reference standard: histological findings. RESULTS: Among the 379 women with adnexal masses enrolled in this study, 291 were evaluable with ultrasound imaging, biomarker assays, and histopathological results. The risk of malignancy was higher for women classified as high-risk based on IOTA-LR2 (≥10%). The sensitivity, specificity, and diagnostic accuracy for the prediction of malignancy were 81.2%, 81%, and 0.81 (95% CI: 0.77-0.86) for IOTA-LR2; 77.5%, 66.7%, and 0.72 (95% CI: 0.67-0.77) for CA-125; and 91.3%, 41.2%, and 0.66 (95% CI: 0.62-0.71) for MIA2G. A combination of IOTA-LR2 and MIA2G significantly influenced the diagnostic performance and the result. When MIA2G was combined with IOTA-LR2 in parallel, the sensitivity (94.2%) and NPV (87.7%) increased, but the specificity (37.3%) decreased. When combined with IOTA-LR2 in series, there were fewer false positives, which resulted in improved specificity (85%). CONCLUSION: This study determined the utility of ovarian imaging and a second-generation multivariate index assay in predicting the risk of ovarian malignancy. IOTA-LR2 and MIA2G were useful in classifying patients with a high risk for ovarian malignancy.

Clinical Performance of a Multivariate Index Assay in Detecting Early-Stage Ovarian Cancer in Filipino Women.

This study evaluated the clinical performance and overall utility of a multivariate index assay in detecting early-stage ovarian cancer in a Filipino population. This is a prospective cohort study among Filipino women undergoing assessment for an ovarian mass in a tertiary center. Patients diagnosed with early-stage ovarian cancer and who underwent a physical examination before level III specialist ultrasonographic and Doppler evaluation, multivariate index assay (MIA2G), and surgery for an adnexal mass were included in this study. Ovarian tumors were classified as high-risk for malignancy based on the IOTA-LR2 score. The ovarian imaging and biomarker results were correlated with the reference standard: surgico-pathologic findings. The MIA2G exhibited the best overall performance among individual classifiers with a sensitivity of 91.7% and NPV of 84.7%, with a concomitant higher sensitivity in early-stage disease, whether as an individual classifier (93.5%) or in serial combination with ultrasound (85.5%). The performance of biomarkers (specificity, positive predictive values, and AUROC) such as MIA2G and CA-125 significantly improved when combined with an ultrasound risk scoring approach (p < 0.01). MIA2G showed a higher sensitivity for detecting lesions among EOC and late-stage ovarian cancers than otherwise. The application of biomarkers for evaluating ovarian masses in our local setting is secondary to ultrasound but adopting multivariate index assays rather than CA-125 would increase the detection of early-stage ovarian cancers regardless of menopausal status. This is most relevant in areas where level III sonographers or gynecologic oncologists are limited and preoperative referrals to these specialists can improve the survival of our patients.

Current Status of Human Papillomavirus Infection and Cervical Cancer in the Philippines.

Cervical cancer is estimated to cause 341,831 deaths each year, with 9 of 10 deaths occurring in developing countries. Over the past decade, there has been a significant increase in cervical cancer incidence among women in the Philippines. Persistent infection with high-risk human papillomavirus (HPV) is the well-established necessary cause of cervical cancer. Based on limited studies conducted in the Philippines, the prevalence of infection with any HPV genotype was 93.8% for cervical squamous cell carcinoma and 90.9% for cervical adenocarcinomas. HPV types 16 and 18 were the most common HPV genotypes among Filipino patients with cervical cancer. On the other hand, the incidence of HPV infection among Filipino women with normal cervices was 9.2%. The World Health Organization has launched a global agenda of eliminating HPV infection by 2030. One of its key milestones is to vaccinate 90% of girls with the HPV vaccine by 15 years. However, the HPV vaccination rate among Filipino women remains to be unsatisfactory. HPV vaccination has only been included in the Philippine Department of Health's community-based National Immunization Program in 2015. Despite these efforts, the Philippines currently ranks last on HPV program coverage among low-middle income countries, with coverage of only 23% of the target female population for the first dose and 5% for the final dose. The principal reason for the non-acceptance of HPV vaccines was the perceived high cost of vaccination. The low utilization of available cervical cancer screening tests such as Pap smear and visual inspection with acetic acid hampered the Philippines' control and prevention of HPV infection and cervical cancer. Among those diagnosed with cervical cancer in the Philippines, only an estimated 50% to 60% receive some form of treatment. To this end, we summarize the burden of HPV infection and cervical cancer on Filipinos and the risk factors associated with the disease. We present the current screening, diagnostics, treatment, and prevention of HPV-related diseases in the Philippines. Lastly, we also propose solutions on how each building block in health systems can be improved to eliminate HPV infection and reduce the burden of cervical cancer in the Philippines.

Diagnostic Performances of Ultrasound-Based Models for Predicting Malignancy in Patients with Adnexal Masses.

This study compared the diagnostic performance of different ultrasound-based models in discriminating between benign and malignant ovarian masses in a Filipino population. This was a prospective cohort study in women with findings of an ovarian mass on ultrasound. All included patients underwent a physical examination before level III specialist ultrasonographic and Doppler evaluation using the different International Ovarian Tumor Analysis (IOTA) Group's risk models. Serum CA-125 and a second-generation multivariate index assay (MIA2G) were also determined for all patients. The ovarian imaging and biomarker results were correlated with the histological findings. A total of 260 patients with completed ultrasound, CA-125, MIA2G, and histopathologic results was included in the study. The presence of papillae with blood flow and irregular cyst walls during the ultrasound were significantly associated with a 20-fold (OR: 20.13, CI: 8.69−46.67, p < 0.01) and 10-fold (OR: 10.11, CI: 5.30−19.28, p < 0.01) increase in the likelihood of a malignant lesion, respectively. All individual sonologic procedures performed well in discerning malignant and benign ovarian lesions. IOTA-LR1 showed the highest accuracy (82.6%, 95% CI: 77.5−87%) for identifying ovarian cancer. IOTA-ADNEX showed the highest sensitivity (93.3%, 95% CI: 87.2−97.1%) while IOTA-LR2 exhibited the highest specificity (84.4%, 95% CI: 77.3−90%). Among the different serial test combinations, IOTA-LR1 with MIA2G and IOTA-LR2 with MIA2G showed the highest diagnostic accuracy (AUROC = 0.82). This study showed that all individual ultrasound-based models performed well in discerning malignant and benign ovarian lesions, with IOTA-LR1 exhibiting the highest accuracy.

The role of genital mycoplasma infection in female infertility: A systematic review and meta-analysis.

PROBLEM: Recent studies show that lower genital tract infection with genital mycoplasma may be associated with the pathology of female infertility. However, this association remains controversial due to the variable prevalence, sample sizes, and different methods used to diagnose genital mycoplasma infection. The aim of the present meta-analysis was to gain better understanding of the specific impact of genital mycoplasma on female infertility. METHOD OF STUDY: A systematic review of literature on the association of genital mycoplasma (Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum) infection and female infertility was performed using three electronic databases: PubMed, Scopus, and CINAHL, from January 2000 to January 2020. Pooled odds ratio (OR) and 95% confidence intervals for genital mycoplasma infection and female infertility were derived from a fixed effects model. RESULTS: This meta-analysis included eight studies conducted in six countries. Based on the results, women with infertility had a statistically higher odds of having any genital mycoplasma infection (p < .0001) compared to the control group. The pooled OR of all the included studies was 3.82 (95% CI: 2.55, 5.72). There was an unremarkable heterogeneity in all the studies included in this meta-analysis (I2  = 0%, p = .48). A subgroup analysis also showed that M. genitalium, M. hominis, and U. urealyticum infections are significantly associated with female infertility. CONCLUSION: Our meta-analysis showed a significant association between M. genitalium, M. hominis, and U. urealyticum infections and female infertility. This evidence supports the development of guidelines for the diagnosis and treatment of genital mycoplasma infections to prevent female infertility.

Evaluation of Abdominal Fetal Electrocardiography in Early Intrauterine Growth Restriction.

Objectives: This descriptive study was performed to evaluate the capability of a non-invasive transabdominal electrocardiographic system to extract clear fetal electrocardiographic (FECG) measurements from intrauterine growth restricted (IUGR) fetuses and to assess whether abdominal FECG parameters can be developed as markers for evaluating the fetal cardiac status in IUGR. Methods: Transabdominal FECG was attempted in 20 controls and 15 IUGR singleton pregnancies at 20+0-33+6 weeks gestation. Standard ECG parameters were compared between the study groups and evaluated for their correlation. Accuracy for the prediction of IUGR by cut off values of the different FECG parameters was also determined. Results: Clear P-QRST complexes were recognized in all cases. In the IUGR fetuses, the QT and QTc intervals were significantly prolonged (p = 0.017 and p = 0.002, respectively). There was no correlation between ECG parameters and Doppler or other indices to predict IUGR. The generation of cut off values for detecting IUGR showed increasing sensitivities but decreasing specificities with the prolongation of ECG parameters. Conclusion: The study of fetal electrocardiophysiology is now feasible through a non-invasive transabdominal route. This study confirms the potential of FECG as a clinical screening tool to aid diagnosis and management of fetuses after key limitations are addressed. In the case of IUGR, both QT and QTc intervals were significantly prolonged and thus validate earlier study findings where both these parameters were found to be markers of diastolic dysfunction. This research is a useful prelude to a test of accuracy and Receiver Operating Characteristics (ROC) study.

Ultrasound Imaging of Mouse Fetal Intracranial Hemorrhage Due to Ischemia/Reperfusion.

Despite vast improvement in perinatal care during the 30 years, the incidence rate of neonatal encephalopathy remains unchanged without any further Progress towards preventive strategies for the clinical impasse. Antenatal brain injury including fetal intracranial hemorrhage caused by ischemia/reperfusion is known as one of the primary triggers of neonatal injury. However, the mechanisms of antenatal brain injury are poorly understood unless better predictive models of the disease are developed. Here we show a mouse model for fetal intracranial hemorrhage in vivo developed to investigate the actual timing of hypoxia-ischemic events and their related mechanisms of injury. Intrauterine growth restriction mouse fetuses were exposed to ischemia/reperfusion cycles by occluding and opening the uterine and ovarian arteries in the mother. The presence and timing of fetal intracranial hemorrhage caused by the ischemia/reperfusion were measured with histological observation and ultrasound imaging. Protein-restricted diet increased the risk of fetal intracranial hemorrhage. The monitoring of fetal brains by ultrasound B-mode imaging clarified that cerebral hemorrhage in the fetal brain occurred after the second ischemic period. Three-dimensional ultrasound power Doppler imaging visualized the disappearance of main blood flows in the fetal brain. These indicate a breakdown of cerebrovascular autoregulation which causes the fetal intracranial hemorrhage. This study supports the fact that the ischemia/reperfusion triggers cerebral hemorrhage in the fetal brain. The present method enables us to noninvasively create the cerebral hemorrhage in a fetus without directly touching the body but with repeated occlusion and opening of the uterine and ovarian arteries in the mother.

Aberrant behavior of mouse embryo development after blastomere biopsy as observed through time-lapse cinematography.

OBJECTIVE: To analyze whether blastomere biopsy affects early embryonal growth as observed through time-lapse cinematography. DESIGN: Comparative prospective study between embryos in which a blastomere was removed and embryos in which a blastomere was not removed. SETTING: An experimental laboratory of the university. MAIN OUTCOME MEASURE(S): We calculated the time between blastocele formation and the end of hatching, the time between the start and end of hatching, the number of contractions and expansions between blastocyst formation and the end of hatching, and the maximum diameter of the expanded blastocyst. RESULT(S): In blastomere removal embryos, compaction began at the six-cell stage instead of at the eight-cell stage. We also found that hatching was delayed in these embryos as compared with matched controls. Moreover, the frequency of contraction and expansion movements after blastocyst formation was significantly higher in the blastomere removal group as compared with the control group. Finally, the maximum diameter of the expanded blastocyst just before hatching was not significantly different between both groups. CONCLUSION(S): These findings suggested that blastomere removal has an adverse effect on embryonic development around the time of hatching. Thus, future developments in preimplantation genetic diagnosis and screening should involve further consideration and caution in light of the influence of blastomere biopsy on embryonal growth.