Differential Effects of the Hormonal and Copper Intrauterine Device on the Endometrial Transcriptome.

The contraceptive effectiveness of intrauterine devices (IUDs) has been attributed in part to a foreign body reaction in the endometrium. We performed this study to better understand mechanisms of action of contraceptives of by studying their effects on endometrial and cervical transcriptomes. We collected endometrial and cervical biopsies from women using the levonorgestrel-releasing intrauterine system (LNG-IUS, n = 11), copper intrauterine device (cu-IUD, n = 13) or levonorgestrel-containing combined oral contraceptives (COC, n = 12), and from women not using contraceptives (control group, n = 11). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. In endometrial samples from cu-IUD users, there were no genes with statistically significant differential expression compared to controls. In LNG-IUS users, 2509 genes were differentially expressed and mapped predominantly onto immune and inflammatory pathways. The cervical samples showed no statistically significant differential gene expression compared to controls. Hormonal and copper IUDs have significantly different effects on the endometrial transcriptome, with the LNG-IUS transcriptome showing pronounced inflammation and immune activation compared to controls whereas the cu-IUD transcriptome was indistinguishable from luteal phase endometrium. These findings argue against a foreign body reaction as a common mechanism of action of IUDs

Performance of p16INK4a ELISA as a primary cervical cancer screening test among a large cohort of HIV-infected women in western Kenya: a 2-year cross-sectional study.

ObjectiveA biomarker with increased specificity for cervical dysplasia compared with human papillomavirus (HPV) testing would be an attractive option for cervical cancer screening among HIV-infected women in resource-limited settings. p16(INK4a) has been explored as a biomarker for screening in general populations.DesignA 2-year cross-sectional study.Setting2 large HIV primary care clinics in western Kenya.Participants1054 HIV-infected women in western Kenya undergoing cervical cancer screening as part of routine HIV care from October 2010 to November 2012.InterventionsParticipants underwent p16(INK4a) specimen collection and colposcopy. Lesions with unsatisfactory colposcopy or suspicious for cervical intraepithelial neoplasia 2+ (CIN2+; including CIN2/3 or invasive cervical cancer) were biopsied. Following biopsy, disease status was determined by histopathological diagnosis.Primary and secondary outcome measuresWe measured the sensitivity, specificity and predictive values of p16(INK4a) ELISA for CIN2+ detection among HIV-infected women and compared them to the test characteristics of current screening methods used in general as well as HIV-infected populations.ResultsAverage p16(INK4a) concentration in cervical samples was 37.4 U/mL. After colposcopically directed biopsy, 127 (12%) women were determined to have CIN2+. Receiver operating characteristic analysis showed an area under the curve of 0.664 for p16(INK4a) to detect biopsy-proven CIN2+. At a p16(INK4a) cut-off level of 9 U/mL, sensitivity, specificity, positive and negative predictive values were 89.0%, 22.9%, 13.6% and 93.8%, respectively. The overall p16(INK4a) positivity at a cut-off level of 9 U/mL was 828 (78.6%) women. There were 325 (30.8%) cases of correct p16(INK4a) prediction to detect or rule out CIN2+, and 729 (69.2%) cases of incorrect p16(INK4a) prediction.Conclusionsp16(INK4a) ELISA did not perform well as a screening test for CIN2+ detection among HIV-infected women due to low specificity. Our study contributes to the ongoing search for a more specific alternative to HPV testing for CIN2+ detection

Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions.

Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P4) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E2) to each progestin influenced the number of differentially expressed genes and biofunctions in P4 and MPA, while LNG and NETA signatures were more independent of E2. Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E2. Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use

Effects of the levonorgestrel-releasing intrauterine device on the immune microenvironment of the human cervix and endometrium

There is little information regarding the impact of the intrauterine device on immune parameters of the upper female reproductive tract related to risk of HIV acquisition

Social capital and pet ownership – A tale of four cities☆

Highlights • Pet ownership is significantly associated with higher levels of social capital. • Social capital was associated with pet ownership in the U.S. and Australia. • Results are not confined to dog owners nor dog walkers. • Pets are an under-recognized conduit for building social capital

Investigating Potential Associations between Cervical Procedures and HIV Acquisition

Objective. Cervical human papillomavirus (HPV) infection has been associated with human immunodeficiency virus (HIV) acquisition in populations with a high prevalence of both infections. Procedures performed in the management of cervical dysplasia may facilitate HIV entry via mechanical injury. We sought to investigate the association between cervical procedures and incident HIV. Methods. Data on cervical cancer screening and procedures were collected in a cohort study evaluating the diaphragm for HIV prevention in 2040 women. In this secondary analysis, we investigated the association between cervical procedures and HIV acquisition. Results. Out of 2027 HIV-negative women at baseline, 199 underwent cervical procedures. Cumulative risk of HIV was 4.3% over 21 months of median followup (n = 88). Compared with women without cervical procedures, we observed no difference in HIV incidence after a cervical biopsy (RR 0.92, 95% CI 0.39–2.16), endocervical curettage (RR 0.29, 95% CI 0.07–1.22), or loop electrosurgical excision procedure (RR 1.00, 95% CI 0.30–3.30). Conclusions. In this cohort, cervical procedures were not associated with HIV incidence. This lack of association could be due to the small number of events

Induction of MHC Class I Expression on Immature Thymocytes in HIV-1-Infected SCID-hu Thy/Liv Mice: Evidence of Indirect Mechanisms

The SCID-hu Thy/Liv mouse and human fetal thymic organ culture (HF-TOC) models have been used to explore the pathophysiologic mechanisms of HIV-1 infection in the thymus. We report here that HIV-1 infection of the SCID-hu Thy/Liv mouse leads to the induction of MHC class I (MHCI) expression on CD4+CD8+ (DP) thymocytes, which normally express low levels of MHCI. Induction of MHCI on DP thymocytes in HIV-1-infected Thy/Liv organs precedes their depletion and correlates with the pathogenic activity of the HIV-1 isolates. Both MHCI protein and mRNA are induced in thymocytes from HIV-1-infected Thy/Liv organs, indicating induction of MHCI gene expression. Indirect mechanisms are involved, because only a fraction (<10%) of the DP thymocytes were directly infected by HIV-1, although the majority of DP thymocytes are induced to express high levels of MHCI. We further demonstrate that IL-10 is induced in HIV-1-infected thymus organs. Similar HIV-1-mediated induction of MHCI expression was observed in HF-TOC assays. Exogenous IL-10 in HF-TOC induces MHCI expression on DP thymocytes. Therefore, HIV-1 infection of the thymus organ leads to induction of MHCI expression on immature thymocytes via indirect mechanisms involving IL-10. Overexpression of MHCI on DP thymocytes can interfere with thymocyte maturation and may contribute to HIV-1-induced thymocyte depletion

Type-Specific Cervico-Vaginal Human Papillomavirus Infection Increases Risk of HIV Acquisition Independent of Other Sexually Transmitted Infections

Sexually transmitted infections (STIs) such as herpes simplex virus (HSV)-2 are associated with an increased risk of HIV infection. Human papillomavirus (HPV) is a common STI, but little is know about its role in HIV transmission. The objective of this study was to determine whether cervico-vaginal HPV infection increases the risk of HIV acquisition in women independent of other common STIs.This prospective cohort study followed 2040 HIV-negative Zimbabwean women (average age 27 years, range 18-49 years) for a median of 21 months. Participants were tested quarterly for 29 HPV types (with L1 PCR primers) and HIV (antibody testing on blood samples with DNA or RNA PCR confirmation). HIV incidence was 2.7 per 100 woman-years. Baseline HPV prevalence was 24.5%, and the most prevalent HPV types were 58 (5.0%), 16 (4.7%), 70 (2.4%), and 18 (2.3%). In separate regression models adjusting for baseline variables (including age, high risk partner, positive test for STIs, positive HSV-2 serology and condom use), HIV acquisition was associated with having baseline prevalent infection with HPV 58 (aHR 2.13; 95% CI 1.09-4.15) or HPV 70 (aHR 2.68; 95% CI 1.08-6.66). In separate regression models adjusting for both baseline variables and time-dependent variables (including HSV-2 status, incident STIs, new sexual partner and condom use), HIV acquisition was associated with concurrent infection with any non-oncogenic HPV type (aHR 1.70; 95% CI 1.02-2.85), any oncogenic HPV type (aHR 1.96; 95% CI 1.16-3.30), HPV 31 (aHR 4.25; 95% CI 1.81-9.97) or HPV 70 (aHR 3.30; 95% CI 1.50-7.20). Detection of any oncogenic HPV type within the previous 6 months was an independent predictor of HIV acquisition, regardless of whether HPV status at the HIV acquisition visit was included (aHR 1.95; 95% CI 1.19-3.21) or excluded (aHR 1.96; 95% CI 1.02-2.85) from the analysis.Cervico-vaginal HPV infection was associated with an increased risk of HIV acquisition in women, and specific HPV types were implicated in this association. The observational nature of our study precludes establishment of causation between HPV infection and HIV acquisition. However, given the high prevalence of HPV infection in women, further investigation of the role of HPV in HIV transmission is warranted

Integration of palliative and supportive care in the management of advanced liver disease:development and evaluation of a prognostic screening tool and supportive care intervention

BACKGROUND AND OBJECTIVES: Patients with decompensated cirrhosis rarely receive palliative and supportive care interventions, which are routine in other life-limiting diseases. We aimed to design and evaluate a prognostic screening tool to routinely identify inpatients with decompensated cirrhosis at high risk of dying over the coming year, alongside the development of a supportive care intervention. DESIGN: Clinical notes from consecutive patients admitted as an emergency to University Hospitals Bristol with a diagnosis of cirrhosis over two distinct 90-day periods were scrutinised retrospectively for the presence or absence of five evidence-based factors associated with poor prognosis. These were analysed against their ability to predict mortality at 1 year. ‘Plan-Do-Study-Act’ (PDSA) methodology was used to incorporate poor-prognosis screening into the routine assessment of patients admitted with cirrhosis, and develop a supportive care intervention. RESULTS: 73 admissions were scrutinised (79.5% male, 63% alcohol-related liver disease, median age 54). The presence of three or more poor-prognosis criteria at admission predicted 1-year mortality with sensitivity, specificity and positive predictive value of 72.2%, 83.8% and 81.3%, respectively, and was used as a trigger for implementing the supportive care intervention. Following modification from six PDSA cycles, prognostic screening was integrated into the assessment of all patients admitted with decompensated cirrhosis, with the supportive care intervention (developed simultaneously) instigated for appropriate patients. CONCLUSIONS: We describe a model of care which identifies inpatients with cirrhosis at significant risk of dying over the coming year, and describe development of a supportive care intervention, which can be offered to suitable patients in parallel to ongoing active management