Implementing Provider‐based Sampling for the National Children's Study: Opportunities and Challenges

Background:  The National Children's Study (NCS) was established as a national probability sample of births to prospectively study children's health starting from in utero to age 21. The primary sampling unit was 105 study locations (typically a county). The secondary sampling unit was the geographic unit (segment), but this was subsequently perceived to be an inefficient strategy. Methods and Results:  This paper proposes that second‐stage sampling using prenatal care providers is an efficient and cost‐effective method for deriving a national probability sample of births in the US. It offers a rationale for provider‐based sampling and discusses a number of strategies for assembling a sampling frame of providers. Also presented are special challenges to provider‐based sampling pregnancies, including optimising key sample parameters, retaining geographic diversity, determining the types of providers to include in the sample frame, recruiting women who do not receive prenatal care, and using community engagement to enrol women. There will also be substantial operational challenges to sampling provider groups. Conclusion:  We argue that probability sampling is mandatory to capture the full variation in exposure and outcomes expected in a national cohort study, to provide valid and generalisable risk estimates, and to accurately estimate policy (such as screening) benefits from associations reported in the NCS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94504/1/ppe12005.pd

Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p= 4.89 x 10 - 57) , high mitotic index (p= 5.25 x 10 - 28), pleomorphism (p= 6.31 x 10-19), ER negative (p= 9.02 x 10-35 ), PR negative (p= 9.24 x 10-24 ), triple negative phenotype (p= 6.67 x 10-21) , PAM50.Her2 (p=5.19 x 10-13 ), PAM50.Basal (p=2.7 x 10-41), PAM50.LumB (p=1.56 x 10-26), integrative molecular cluster 1 (intClust.1) ( p=7.47 x 10-12), intClust.5 (p=4.05 x 10-12) and intClust. 10 (p=7.59 x 10-38 ) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p=4.4 x 10-16) and multivariate analysis (p=9.19 x 10-7). At the protein level, in ER positive tumours , FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps< 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps<0.05). In ER positive as well as in ER negative tumours, FEN1 protein over expression is associated with poor survival in univariate and multivariate analysis (ps<0.01). In ovarian epithelial cancers , similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps<0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer

Cellular Active N-Hydroxyurea FEN1 Inhibitors Block Substrate Entry to the Active Site

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the first crystal structure of inhibitor-bound hFEN1 and show a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein– substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the unpairing of substrate DNA necessary for reaction. Other compounds were more competitive with substrate. Cellular thermal shift data showed engagement of both inhibitor types with hFEN1 in cells with activation of the DNA damage response evident upon treatment. However, cellular EC50s were significantly higher than in vitro inhibition constants and the implications of this for exploitation of hFEN1 as a drug target are discussed

Knowledge, attitudes, and practices regarding conception and fertility: a population-based survey among reproductive-age United States women

Objective: To assess overall knowledge, attitudes, and practices related to conception and fertility among reproductive-age women in the United States. Design: Online survey of a cross-sectional sample of 1,000 women. Setting: United States, March 2013. Patient(s): Women aged 18-40 years. Intervention(s): None. Main Outcome Measure(s): Knowledge, attitudes, and practices regarding selected topics in reproductive health. Result(s): Forty percent of women across all age groups expressed concerns about their ability to conceive. Yet one-third of women were unaware of adverse implications of sexually transmitted infections, obesity, or irregular menses for procreative success, and one-fifth were unaware of the effects of aging. Approximately 40% were unfamiliar with the ovulatory cycle. Overall, younger women (18-24 years) demonstrated less knowledge regarding conception, fertility, and ovulation, whereas older women tended to believe in common myths and misconceptions. Respondents in all age groups identified women\u27s health care providers (75%) and Web sites (40%) as top sources of reproductive health-related information; however, engagement with providers on specific factors affecting fertility is sparse. Conclusion(s): Knowledge regarding ovulation, fertility, and conception is limited among this sample of reproductive-age US women. Future initiatives should prioritize improved provider engagement and accurate information dissemination in Web-based venues. (C) 2014 by American Society for Reproductive Medicine

Effect of 2 stitches vs 1 stitch on the prevention of preterm birth in women with singleton pregnancies who undergo cervical cerclage

OBJECTIVE: This study investigates whether 2 cerclage stitches are more effective than 1 stitch in the prevention of preterm birth. STUDY DESIGN: This is a retrospective cohort study of 150 singleton pregnancies that underwent cervical cerclage. Gestational age at delivery and clinical characteristics were compared. RESULTS: One hundred twelve patients (74.7%) received 1 stitch, and 38 patients (25.3%) received 2 stitches. There were no baseline differences between the groups. Analysis showed no significant difference in gestational age at delivery between the 1 vs 2 cerclage groups overall (median, 38.0 vs 38.3 weeks of gestation, respectively; P = .356) or for a given gestational age cut-off (< 37 weeks of gestation: 37.4% vs 34.2% [P = .727]; < 34 weeks of gestation: 16.8% vs 18.4% [P = .823]; < 28 weeks of gestation: 9.4% vs 2.6% [P =.179]). CONCLUSION: This study shows no measurable benefit to the placement of 2 stitches over 1 stitch during cervical cerclage in singleton pregnancies; however, further study of preterm birth at < 28 weeks of gestation and postcerclage outcomes among a larger cohort is merited

Placenta Accreta: A Spectrum of Predictable Risk, Diagnosis, and Morbidity

Abstract Objective  Placenta accreta is a feared pathology, in part, because prenatal diagnosis is imperfect. It is not known whether clinical risk factors or sonographic features equally predict the entire graded pathological spectrum of placental overinvasion disease nor whether clinical outcomes differ along the spectrum. Study Design  We conducted a mixed methods retrospective study of a cohort of women screened sonographically for placenta accreta, cross-referenced against cases identified by pathological diagnosis ( N  = 416). Demographic, diagnostic, and outcome information were compared across the spectrum of invasive placentation: percreta, increta, accreta, and focal accreta not requiring hysterectomy. The t -test, chi-square, Mann–Whitney, and Kruskal–Wallis tests were used for statistical analysis across groups. Results  As the depth of invasion decreased, risk factors for placental overinvasion were less common, especially placenta previa and previous cesarean. There was also reduced anticipation by sonographic examination of the placenta. Rates of adverse outcomes were lower among women with focal accreta compared with those with deeper invasion. Conclusion  As the depth of invasion decreases, clinical risk factors and sonographic evaluation are less reliable in the antenatal prediction of placenta accreta. The potential for unanticipated morbidity underscores the need for improved diagnostic tools for placenta accreta spectrum