ERα/ERß-directed CBS transcription mediates E2ß-stimulated hUAEC H2S production.

Elevated endogenous estrogens stimulate human uterine artery endothelial cell (hUAEC) hydrogen sulfide (H2S) production by selectively upregulating the expression of H2S synthesizing enzyme cystathionine ß-synthase (CBS), but the underlying mechanisms are underdetermined. We hypothesized that CBS transcription mediates estrogen-stimulated pregnancy-dependent hUAEC H2S production. Estradiol-17ß (E2ß) stimulated CBS but not cystathionine γ-lyase (CSE) expression in pregnant human uterine artery ex vivo, which was attenuated by the estrogen receptor (ER) antagonist ICI 182,780. E2ß stimulated CBS mRNA/protein and H2S production in primary hUAEC from nonpregnant and pregnant women, but with greater responses in pregnant state; all were blocked by ICI 182,780. Human CBS promoter contains multiple estrogen-responsive elements (EREs), including one ERE preferentially binding ERα (αERE) and three EREs preferentially binding ERß (ßERE), and one full ERE (α/ßERE) and one half ERE (½α/ßERE) binding both ERα and ERß. Luciferase assays using reporter genes driven by human CBS promoter with a series of 5'-deletions identified the α/ßEREs binding both ERα and ERß (α/ßERE and ½α/ßERE) to be important for baseline and E2ß-stimulated CBS promoter activation. E2ß stimulated ERα/ERß heterodimerization by recruiting ERα to α/ßEREs and ßERE, and ERß to ßERE, α/ßEREs, and αERE. ERα or ERß agonist alone trans-activated CBS promoter, stimulated CBS mRNA/protein and H2S production to levels comparable to that of E2ß-stimulated, while ERα or ERß antagonist alone abrogated E2ß-stimulated responses. E2ß did not change human CSE promoter activity and CSE mRNA/protein in hUAEC. Altogether, estrogen-stimulated pregnancy-dependent hUAEC H2S production occurs by selectively upregulating CBS expression via ERα/ERß-directed gene transcription.

Inborn Versus Outborn Delivery in Neonates With Congenital Diaphragmatic Hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a morbid and potentially fatal condition that challenges providers. The aim of this study is to compare outcomes in neonates with prenatally diagnosed CDH that are inborn (delivered in the institution where definitive care for CDH is provided) versus outborn. METHODS: Prenatally diagnosed CDH cases were identified from the Congenital Diaphragmatic Hernia Study Group (CDHSG) database between 2007 and 2019. Using risk adjustment based on disease severity, we compared inborn versus outborn status using baseline risk and multivariable logistic regression models. The primary endpoint was mortality and the secondary endpoint was need for extracorporeal life support (ECLS). RESULTS: Of 4195 neonates with prenatally diagnosed CDH, 3087 (73.6%) were inborn and 1108 (26.4%) were outborn. There was no significant difference in birth weight, gestational age, or presence of additional congenital anomalies. There was no difference in mortality between inborn and outborn infants (32.6% versus 33.8%, P = 0.44) or ECLS requirement (30.9% versus 31.5%, P = 0.73). Among neonates requiring ECLS, outborn status was a risk factor for mortality (OR 1.51, 95% CI 1.13-2.01, P = 0.006). After adjusting for post-surgical defect size, which is not known prenatally, outborn status was no longer a risk factor for mortality for infants requiring ECLS. CONCLUSIONS: Risk of mortality and need for ECLS for inborn CDH patients is not different to outborn infants. Future studies should be directed to establishing whether highest risk infants are at risk for worse outcomes based on center of birth.

The Case for Capping Residency Interviews.

OBJECTIVE: To determine 2020 residency cycle application practices and to model potential consequences in the 2021 cycle if (1) applicants scheduled an uncapped number of interviews; (2) applicants were capped to schedule 12 interviews; (3) residency programs kept their number of interview offers unchanged; and (4) programs increased their interview offers by 20%. DESIGN AND SETTING: The authors sent an anonymous survey to all obstetrics and gynecology applicants registered through the Electronic Residency Application Service in February 2020 asking respondents to share demographics and number of interview offers received and completed. Based on prior estimates that 12 interviews are needed to match in obstetrics and gynecology, respondents were divided into Group 12+ (those receiving ≥12 interview offers) and Group <12 (those receiving <12 offers). Model assumptions were (1) applicants can complete all interviews they are offered because they are virtual; (2) interview offers that applicants in Group 12+ decline are subsequently offered to applicants in Group <12; (3) the proportions of interviews offered to Group 12+ and Group <12 will remain the same if programs chose to increase their total number of interview spots. PARTICIPANTS: Among 2508 applicants, 750 (30%) provided the number of interview offers received and completed: 417 (56%) in Group 12+ and 333 (44%) in Group <12. RESULTS: In models where applicants are uncapped in the number of interviews, Group <12 applicants receive <1 interview offer, even if programs increase the number of interviews offered and performed. If applicants are capped at 12 interviews, Group <12 applicants will receive 9 interview offers on average and will reach 12 if programs increase the number of interviews offered by 20%. CONCLUSIONS: This work highlights how current inefficiencies may lead to negative consequences with virtual interviews. Interview caps and preference signaling systems need to be urgently considered.

A Model for Exploring Compatibility Between Applicants and Residency Programs: Right Resident, Right Program.

Holistic review of residency applications is touted as the gold standard for selection, yet vast application numbers leave programs reliant on screening using filters such as United States Medical Licensing Examination scores that do not reliably predict resident performance and may threaten diversity. Applicants struggle to identify which programs to apply to, and devote attention to these processes throughout most of the fourth year, distracting from their clinical education. In this perspective, educators across the undergraduate and graduate medical education continuum propose new models for student-program compatibility based on design thinking sessions with stakeholders in obstetrics and gynecology education from a broad range of training environments. First, we describe a framework for applicant-program compatibility based on applicant priorities and program offerings, including clinical training, academic training, practice setting, residency culture, personal life, and professional goals. Second, a conceptual model for applicant screening based on metrics, experiences, attributes, and alignment with program priorities is presented that might facilitate holistic review. We call for design and validation of novel metrics, such as situational judgment tests for professionalism. Together, these steps could improve the transparency, efficiency and fidelity of the residency application process. The models presented can be adapted to the priorities and values of other specialties.

Performance of a proteomic preterm delivery predictor in a large independent prospective cohort.

BACKGROUND: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. OBJECTIVE: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. STUDY DESIGN: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks' gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks' gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0-3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. RESULTS: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks' gestation and 838 noncases at ≥320/7 weeks' gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks' gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks' gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55-0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (22

Consent for the Pelvic Examination Under Anesthesia by Medical Students: Recommendations by the Association of Professors of Gynecology and Obstetrics.

The pelvic examination is a critical tool for the diagnosis of women's health conditions and remains an important skill necessary for students to master before becoming physicians. Recently, concerns regarding student involvement in pelvic examinations-specifically those performed while a woman is under anesthesia-have been raised in the scientific, professional, and lay literature. These concerns have led to calls to limit or halt the performance of pelvic examinations by students while a woman is under anesthesia. Although ensuring adequate informed consent for teaching pelvic examinations is a priority, we must not lose sight of the critical pedagogical value of teaching pelvic examination in familiarizing students with the female anatomy and instilling a physician workforce with confidence in pelvic examination skills. A compromise that addresses all of these values is possible. In this commentary, we review the educational and legal aspects of the pelvic examination under anesthesia, then provide strategies that individuals and institutions can consider to optimize processes regarding consent for pelvic examination under anesthesia.

Promoting HIV Testing for Gay and Bisexual Men: An Evaluation of the 2011-2012 Campaign in Toronto and Ottawa.

This article reports on a social marketing campaign directed toward high-risk men who have sex with men in Toronto and Ottawa to encourage testing for HIV and syphilis; improve knowledge about HIV transmission, seroconversion symptoms, and the HIV window period; and heighten awareness of syphilis transmission and its relationship to facilitating HIV transmission. Evaluation data were collected from a large-scale online pre-and postcampaign survey of sexually active men who have sex with men and from laboratory testing data. Men who turned up to be tested also filled out an exit survey. The campaign websites attracted some 15,000 unique visitors, 54% of whom had an IP address in Toronto or Ottawa. Laboratory data showed a 20% increase in HIV testing in Toronto over the campaign compared to the previous year. The overall rate of HIV-positive tests remained relatively constant. Knowledge levels about seroconversion symptoms, sexually transmitted infection and HIV transmission, and the HIV window period were significantly better among postcampaign survey respondents aware of the campaign compared to postcampaign respondents who were not aware and compared to precampaign respondents.

Cohort profile: the Ontario HIV Treatment Network Cohort Study (OCS).

The Ontario HIV Treatment Network Cohort Study (OCS) is an observational, open dynamic cohort of people who are receiving medical care for human immunodeficiency virus (HIV) infection in Ontario, Canada. Established in the mid-1990s, the OCS has its roots in AIDS activists' demands for research that would improve the quality of life of people living with HIV while respecting their privacy. It is a collaborative and community-driven study, including a Governance Committee made up of people with HIV and other stakeholders that evaluates analysis project proposals for community relevance and ethics. From 1995 to 2010, a total of 5644 participants were enrolled and 27,720 person-years of observation were accumulated; follow-up will continue until at least 2015. In the initial years of study, the focus was on clinical data from medical chart reviews. It has since evolved into a comprehensive study that collects extensive de-identified information on clinical, laboratory and psychosocial and behavioural measures based on medical chart abstractions, interviews using a standardized questionnaire and linkage with external administrative health databases in Ontario. Interested collaborators are encouraged to submit analysis project proposals as instructed on the study website (www.ohtncohortstudy.ca).

High uptake of HIV testing in pregnant women in Ontario, Canada.

In 1999, Ontario implemented a policy to offer HIV counseling and testing to all pregnant women and undertook measures to increase HIV testing. We evaluated the effectiveness of the new policy by examining HIV test uptake, the number of HIV-infected women identified and, in 2002, the HIV rate in women not tested during prenatal care. We analyzed test uptake among women receiving prenatal care from 1999 to 2010. We examined HIV test uptake and HIV rate by year, age and health region. In an anonymous, unlinked study, we determined the HIV rate in pregnant women not tested. Prenatal HIV test uptake in Ontario increased dramatically, from 33% in the first quarter of 1999 to 96% in 2010. Test uptake was highest in younger women but increased in all age groups. All health regions improved and experienced similar test uptake in recent years. The HIV rate among pregnant women tested in 2010 was 0.13/1,000; in Toronto, the rate was 0.28 per 1,000. In the 2002 unlinked study, the HIV rate was 0.62/1,000 among women not tested in pregnancy compared to 0.31/1,000 among tested women. HIV incidence among women who tested more than once was 0.05/1,000 person-years. In response to the new policy in Ontario, prenatal HIV testing uptake improved dramatically among women in all age groups and health regions. A reminder to physicians who had not ordered a prenatal HIV test appeared to be very effective. In 2002, the HIV rate in women who were not tested was twice that of tested women: though 77% of pregnant women had been tested, only 63% of HIV-infected women were tested. HIV testing uptake was estimated at 98% in 2010.

Increase in transmitted HIV drug resistance among persons undergoing genotypic resistance testing in Ontario, Canada, 2002-09.

OBJECTIVES: To characterize persons undergoing HIV genotypic resistance testing (GRT) while treatment naive and to estimate the prevalence of transmitted HIV drug resistance (TDR) among HIV-positive outpatients in Ontario, Canada. METHODS: We analysed data from a multi-site cohort of persons receiving HIV care. Data were obtained from medical chart abstractions, interviews and record linkage with the Public Health Laboratories, Public Health Ontario. The analysis was restricted to 626 treatment-naive persons diagnosed in 2002-09. TDR mutations were identified using the calibrated population resistance tool. We used descriptive statistics and regression methods to characterize treatment-naive GRT test uptake and patterns of TDR. RESULTS: Overall, 53.2% (333/626) of participants had baseline GRT. The proportion increased with year of HIV diagnosis from 30.0% in 2002 to 82.6% in 2009 (P < 0.0001). Among those tested, 13.6% (CI 9.9-17.3%) had one or more drug resistance mutations, and 8.8% (CI 5.7-11.8%), 4.8% (CI 2.5-7.2%) and 2.7% (CI 1.0-4.5%) had mutations conferring resistance to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), respectively. TDR prevalence increased from 2002-07 to 2008-09 (adjusted OR 3.7, 95% CI 1.7-8.2), driven by a higher proportion with NRTI (18.2% versus 5.9%, P = 0.0009) and NNRTI mutations (11.7% versus 2.8%, P = 0.004) in the later time period. PI TDR remained unchanged. CONCLUSIONS: Baseline GRT increased dramatically since 2002, but remains below 100%. The prevalence of overall TDR tripled due to increases in NRTI and NNRTI mutations. These findings highlight the value of routine baseline GRT for TDR surveillance and patient care.

Fetal epignathus: the case of an early EXIT (ex utero intrapartum treatment).

BACKGROUND: Fetal epignathus, a teratoma arising from the oropharynx that may be lethal, can be diagnosed prenatally. CASE: A 29-year-old woman, gravida 1, was evaluated for an elevated alpha-fetoprotein level. Imaging evaluation revealed a fetal epignathus without intracranial extension. Preterm labor necessitated delivery at 27 5/7 weeks of gestation with ex utero intrapartum treatment (EXIT) procedure using a classical incision. The neonate's small size and short umbilical cord required complete exteriorization to secure the airway. Pathology revealed an immature teratoma. CONCLUSION: Prenatal diagnosis of fetal epignathus is imperative so that all options can be discussed. An EXIT procedure may be necessary for airway management at birth. If preterm delivery is necessary, choice of uterine incision and fetal size are important factors to consider for a successful outcome.

Factors that affect HIV testing and counseling services among heterosexuals in Canada and the United Kingdom: an integrated review.

OBJECTIVE: To examine factors that affect the utilization of HIV testing and counseling (HTC) services among heterosexual populations in Canada and the U.K. METHODS: We conducted an integrated review of published and unpublished literature (1996-September 2010) using Scopus, OVID-EMBASE, CSA illumina, CINHAL, PROQuest, Web of Science, and Google. RESULTS: Twenty-seven studies met the inclusion criteria. We identified and categorized the key factors into three broad categories depending on their source. Personal-related factors included socio-demographic characteristics, risk perception, illness, HIV-related stigma, level of HIV and testing knowledge, and culture. Provider-related factors included provider-recommended HIV testing, provision of culturally and linguistically appropriate services, and doctor-patient relationship. System-related factors included integrating HIV testing with other health care services, anonymity of testing services, suitability of testing venues, technical aspects of HIV testing, and funding for immigrant health services. CONCLUSION: The findings from our review indicate that HTC behaviors of heterosexuals in the Canada and the U.K. are likely influenced by several unchangeable (socio-demographic characteristics) and amenable factors. There is need to step-up research to confirm whether these associations are causal using stronger research designs. PRACTICAL IMPLICATION: We have made several recommendations that could be used to improve existing services in Canada.

Herpes simplex and HIV infections and preterm PROM.

Maternal human immunodeficiency virus (HIV) and genital herpes simplex virus (HSV) infection in pregnancy have potential for vertical transmission that may result in death or morbidity. The risk increases with preterm delivery and prolonged ruptured membranes. When managing preterm premature rupture of membranes, the risk of transmission must be weighed against the risk of prematurity. Before 32 to 34 weeks, expectant management is preferred for patients with well controlled HIV or recurrent active genital HSV infection. For patients with advanced HIV disease or primary genital HSV infection, the risk of vertical transmission is higher and many clinical factors need to be considered.

Case-control comparison of cesarean hysterectomy with and without prophylactic placement of intravascular balloon catheters for placenta accreta.

OBJECTIVE: The objective of the study was to compare outcomes of women with placenta accreta who underwent cesarean hysterectomy with and without prophylactic intravascular balloon catheters. STUDY DESIGN: Case-control study of women at risk for placenta accreta identified using hospital databases and billing records from January 1995 to January 2006. Subjects with preoperative intravascular balloon catheter (BC) placement plus hysterectomy were compared with those that had hysterectomy alone. RESULTS: Sixty-nine subjects had cesarean hysterectomy performed for placenta accreta; 19 subjects had balloon catheters plus hysterectomy and 50 subjects had hysterectomy alone. No significant differences were noted in estimated blood loss (P = .79), transfused blood products (P = .60), operative time (P = .85), and postoperative hospital days (P = .85). There were no significant differences in secondary outcomes between groups. Three of the 19 BC subjects (15.8%) had complications from catheter placement; 2 required stent placement and/or arterial bypass. CONCLUSION: Prophylactic intravascular balloon catheters did not benefit women with placenta accreta undergoing cesarean hysterectomy.

Nonfinancial factors associated with decreased plasma viral load testing in Ontario, Canada.

OBJECTIVE: To examine whether individual characteristics were associated with differential use of viral load testing when testing is available without charge to all HIV-positive patients with provincial health insurance. METHODS: Individuals enrolled in the HIV Ontario Observational Database with complete medication records and health insurance numbers for linkage were studied. Generalized estimating equation regression models were used to examine the relationship between time-varying covariates such as plasma viral load levels, CD4 counts, and antiretroviral regimen characteristics and the number of days between viral load tests and the occurrence of an interval of >or=6 or 9 months between tests. RESULTS: A total of 1032 individuals were included in the analysis with a median follow-up of 4.6 years and a median of 18 viral load tests. In multivariate analyses, clinically important gaps in viral load testing were more likely among injection drug users (odds ratio [OR]=1.86, P<0.0001), in more recent years (P<0.01) and for individuals not using antiretrovirals (OR=1.70, P<0.0001) and less likely among individuals using >4 antiretrovirals (OR=0.62, P<0.0001). Results were similar when the outcome was the number of days between tests. CONCLUSIONS: Injection drug users, younger individuals, and residents of Toronto used fewer viral load tests than other individuals, even when financial barriers to testing were removed.

Epidemiologic modeling to evaluate prevention of mother-infant HIV transmission in Ontario.

OBJECTIVES: To evaluate the impact of the Ontario HIV screening program to reduce mother-infant HIV transmission, this study estimated the proportion of preventable transmissions that were prevented. METHODS: Using an iterative spreadsheet model, incidences of HIV infection, AIDS, and AIDS mortality in Ontario women were estimated by exposure category. The number of HIV-infected infants born to HIV-infected mothers was then estimated from conception and abortion rates of HIV-infected women of childbearing age and surveillance data. Finally, the proportion of HIV-infected mothers who received antiretroviral prophylaxis (ARP) was assessed. RESULTS: HIV prevalence in 2001 among women of childbearing age was 1.05 per 1000. From 1984-2001, 764 infants were born to HIV-infected mothers and 180 were infected. From mid-1994-2001, 214 (39%) of the estimated 544 HIV-infected mothers were diagnosed; almost all received ARP. Of 118 preventable infections among infants born in this period, 39 (33%) were prevented. In 2001, only 46% of preventable infections were prevented and 11 preventable transmissions occurred. CONCLUSIONS: HIV prevalence among women in Ontario increased >4-fold from 1990 to 2001. Fewer than half of HIV-infected mothers received ARP and preventable HIV infections continue to occur. Measures to further increase uptake of prenatal HIV screening must be instituted.

Symptomatic primary HIV infection or risk experiences? Circumstances surrounding HIV testing and diagnosis among recent seroconverters.

Our objective was to understand the circumstances surrounding HIV testing among recent HIV seroconverters (n=80) compared to HIV-negative controls (n=106) in Ontario, Canada using self-reported interview data. Diagnosis of symptomatic primary HIV infection (SPHI) was defined as diagnosis by the participant's physician. Testing in response to symptoms was reported by 42% of seroconverters vs 12% of controls. More controls than seroconverters tested in response to risk behaviour (70% vs 50%) or from a desire to know their status (34% vs 12%). Among seroconverters, 76% reported 'flu-like' illness during the time period of infection, 66% had symptoms consistent with SPHI, and 35% reported a physician's diagnosis of SPHI. Compared to seroconverters with undiagnosed SPHI, more of those diagnosed with SPHI had rash (odds ratio=4.5). SPHI plays a significant role in HIV testing and subsequent early diagnosis in this population. More seroconversions could be diagnosed with better patient and physician awareness of its symptoms.