Search

Apurinic/apyrimidinic endonuclease 1 (APE1) is the predominant AP site repair enzyme in mammals. APE1 also maintains 3'-5' exonuclease and 3'-repair activities, and regulates transcription factor DNA binding through its REF-1 function. Since complete or se

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by trinucleotide repeat (TNR) expansions. We show here that somatic TNR expansions are significantly reduced in several organs of R6/1 mice lacking exon 2 of Nei-like 1 (Neil1) (R

Background/Objective: To evaluate adherence to labor arrest and failed induction of labor (IOL) criteria in nulliparous, term, singleton, and vertex (NTSV) cesarean deliveries at an academic medical center and to measure the impact of a quality-improvement educational initiative that focused on obstetric provider education of modern labor arrest and failed IOL criteria. Methods: This is a retrospective cohort study using electronic health record (EHR) data with a pre- (1 September 2018-30 September 2019) and post-intervention (1 October 2019-31 March 2020) study design of all NTSV cesarean deliveries for labor arrest or failed IOL performed at an academic medical center in the northeastern United States. The quality-improvement educational intervention consisted of the distribution of educational pocket cards outlining modern labor arrest and failed IOL criteria to obstetric providers. Outcomes included adherence to labor arrest and failed IOL criteria pre- and post-intervention with secondary outcomes evaluating adherence by provider type (Maternal-Fetal Medicine (MFM) or generalist obstetrician). Descriptive and bivariate statistics were used in the analysis. Results: Pre-intervention, 272 NTSV cesarean deliveries were performed for labor arrest or failed IOL versus 92 post-intervention. Adherence improved post-intervention amongst failed IOL (OR 6.5, CI 1.8-23.8), first-stage arrest (OR 4.5, CI 2.2-10.8) and second-stage arrest (OR 3.7, CI 1.5-9.4). When comparing provider type, MFM physicians were more likely to be adherent to labor arrest and failed IOL criteria compared to generalist obstetricians pre-intervention (OR 3.1, CI 1.7-5.5); however, post-intervention, there was no longer a difference in adherence (OR 3.3, CI 0.9-12.3). Conclusions: Adherence to labor arrest criteria was suboptimal in the pre-intervention period; however, a targeted quality-improvement educational intervention improved adherence rates to labor arrest and failed IOL criteria among obstetric providers.

Introduction: The J9 Plus (J9) maternal-child accompaniment program is based on four pillars: group antenatal care (GANC), group pediatric care, psychosocial support, and community-based care. We aimed to evaluate the impact of the J9 model of care on perinatal outcomes., Methodology: We conducted a convergent mixed methods study of maternal-newborn dyads born in 2019 at Hôpital Universitaire de Mirebalais. Quantitative data was collected retrospectively to compare dyads receiving J9 care to usual care. A secondary analysis of qualitative data described patient perspectives of J9 care., Results: Antenatal care attendance was significantly higher among women in J9 (n = 524) compared to usual care (n = 523), with 490(93%) and 189(36%) having >4 visits, respectively; p <0.001, as was post-partum visit attendance [271(52%) compared to 84(16%), p<0.001] and use of post-partum family planning methods [98(19%) compared to 47(9%), p = 0.003]. Incidence of pre-eclampsia with severe features was significantly lower in the J9 group [44(9%)] compared to the usual care group [73(14%)], p <0.001. Maternal and neonatal mortality and low birth weight did not differ across groups. Cesarean delivery [103(20%) and 82(16%), p<0.001] and preterm birth [118 (24%)] and 80 (17%), p <0.001] were higher in the J9 group compared to usual care, respectively. In the qualitative analysis, ease of access to high-quality care, meaningful social support, and maternal empowerment through education were identified as key contributors to these outcomes., Conclusion: Compared to usual care, the J9 Plus maternal-child accompaniment model of care is associated with increased engagement in antenatal and postpartum care, increased utilization of post-partum family planning, and lower incidence of pre-eclampsia with severe features, which remains a leading cause of maternal mortality in Haiti. The J9 accompaniment approach to care is an empowering model that has the potential to be replicated in similar settings to improve quality of care and outcomes globally., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Casella Jean-Baptiste et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The cesarean delivery rate in the United States is 31.9%. One of the leading indications for primary cesarean delivery is labor arrest. A modern understanding of the labor curve supports more time prior to the diagnosis of labor arrest. We conducted this study to examine the impact of adherence to the modern criteria for labor arrest and failed induction on rates of primary cesarean delivery and to identify predictors of meeting these criteria., Study Design: We analyzed rates of primary cesarean deliveries overall and primary cesarean deliveries occurring due to arrest of dilation, arrest of descent, and failed induction among the 17,877 live births at a large academic center from 2010 through 2013. Multiple logistic regression modeling identified predictors of meeting the new criteria for these indications based on guidelines published by the 2012 National Institute of Child Health and Human Development., Results: The primary cesarean delivery rate decreased from 23.5 to 21.1% ( p  = 0.026) from 2010 to 2013. Primary cesarean delivery rate for labor arrest and failed induction decreased from 8.5 to 6.7% ( p  = 0.005). The percentage of primary cesarean deliveries meeting the 2012 criteria for labor arrest increased from 18.8 to 34.9% ( p  = 0.002), and the rate of primary cesarean deliveries due to arrest of dilation decreased from 5.1 to 3.4% ( p  < 0.0005). The percentage of cases meeting the 2012 criteria for arrest of descent increased from 57.8 to 71.0% ( p  < 0.007), while primary cesarean delivery rate due to arrest of descent remained relatively unchanged, 3.1 to 2.6% ( p  = 0.330)., Conclusion: A decrease in the primary cesarean rate was attributable to a decrease in cesarean for arrest of dilation in the setting of a significant increase in meeting the 2012 criteria for arrest of dilation. At the end of the study period, 65.2% of cesareans still did not meet the criteria for arrest of dilation. Greater rates of adherence to these guidelines may yield further reductions in the cesarean rate., Key Points: · Primary cesarean delivery for labor arrest was decreased.. · Meeting criteria for labor arrest increased.. · A hospitalist provider increased odds of meeting criteria.., Competing Interests: None declared., (Thieme. All rights reserved.)

This 2023 focused update to the neonatal resuscitation guidelines is based on 4 systematic reviews recently completed under the direction of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. Systematic reviewers and content experts from this task force performed comprehensive reviews of the scientific literature on umbilical cord management in preterm, late preterm, and term newborn infants, and the optimal devices and interfaces used for administering positive-pressure ventilation during resuscitation of newborn infants. These recommendations provide new guidance on the use of intact umbilical cord milking, device selection for administering positive-pressure ventilation, and an additional primary interface for administering positive-pressure ventilation.

Objective: To evaluate if knowledge and awareness of concepts and concerns pertaining to reproductive health and fertility vary by race/ethnicity among reproductive-aged women in the United States., Methods: A 2013 cross-sectional web-based survey assessed reproductive health-related knowledge, awareness, and perceptions of 1,000 women (18-40 years). Multivariable logistic regression analyses, adjusting for age, education, income, marital status, employment, region, and pregnancy history, examined the association between race/ethnicity and subfertility-related risk factor awareness; knowledge of factors that may affect pregnancy susceptibility; and future fertility-related concerns., Results: Knowledge and awareness related to reproductive wellness and fertility differed by race/ethnicity in US women. Compared with Caucasians, Hispanic women were less likely to be aware of smoking-related harm to fertility (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.38-0.86); African American women were more aware of the implications of sexually transmitted infections on fertility (OR, 2.13; 95% CI, 1.15-3.94); and Asian women demonstrated greater awareness of a possible relationship between dysmenorrhea and subfertility (OR, 2.05; 95% CI, 1.09-3.86). Asian women consider fertility socially taboo to talk about and a private affair that is difficult to discuss (OR, 2.63; 95% CI, 1.32-5.29 and OR, 1.99; 95% CI, 1.05-3.75, respectively), were more concerned about their future fertility (OR, 2.36; 95% CI, 1.24-4.52), and more likely to perceive a need for future fertility treatment (OR, 2.36; 95% CI, 1.18-4.71)., Conclusion: Among reproductive-aged women in the United States, knowledge, awareness, and perceptions relating to reproductive health vary by race/ethnicity. Our findings suggest race/ethnicity as potential modulators of population perceptions regarding reproductive health and infertility., Clinical Trial Registration Number: NIH ZIA# HD008985., (© 2022 The Authors.)

Objective: In recent decades, there has been a call to foster effective collaborative models of practice between midwives and obstetricians/gynecologists (OB/GYNs) in the United States in order to improve clinician satisfaction and outcomes for childbearing women. Currently, there is no existing validated scale that measures the collaboration between obstetricians and midwives on labor and birth units. We sought to develop and validate a Midwifery- Obstetrics Collaboration (MOC) Scale that measures obstetricians' attitudes towards collaboration between obstetricians and midwives on labor and birth units., Design: Validation study. The items in the questionnaire to be validated were developed de novo by the authors, based on their experiences and expertise in collaborative practice as well as by incorporating key principles of effective collaborative practice documented in the literature. The questionnaire was then piloted among 13 content experts., Setting: Anonymous online survey conducted in the United States., Participants: We validated the questionnaire among 471 obstetricians in the United States from Sept 2019 to March 2020. The respondents included general obstetrician and gynecologists (OB/GYN) attendings, OB/GYN hospitalists, maternal fetal medicine (MFM) fellows and MFM attendings who practice on a labor and birth unit in the United States., Measurements and Findings: We performed reliability analysis of the a priori items. We measured concurrent validity with an existing scale that measures inter-professional collaboration between nurses and physicians. We also correlated our scale with concerns for liability when working in a collaborative practice with midwives. Lastly, we measured discriminant validity with a single item burn out scale. The novel MOC Scale demonstrated construct and concurrent validity, and high inter-item reliability (a=0.93). The MOC Scale correlated with concerns about liability (r=0.63, p <0.001) but was not associated with burnout indicating the uniqueness of the new construct., Key Conclusions: The MOC Scale is validated to assess collaboration between obstetricians and midwives on labor and birth units from an obstetrician's perspective IMPLICATIONS FOR PRACTICE: The MOC Scale can be used as a tool in clinical practice, to assess and foster effective collaboration between obstetricians and midwives from an obstetricians' perspective especially when used in conjunction with other tools that take into the account the perspectives of midwives and childbearing women., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To examine interhospital variation in admissions to neonatal intensive care units (NICU) and reasons for the variation., Study Design: 2010-2012 linked birth certificate and hospital discharge data from 35 hospitals in California on live births at 35-42 weeks gestation and ≥1500 g birth weight were used. Hospital variation in NICU admission rates was assessed by coefficient of variation. Patient/hospital characteristics associated with NICU admissions were identified by multivariable regression., Results: Among 276,489 newborns, 6.3% were admitted to NICU with 34.5% of them having mild diagnoses. There was high interhospital variation in overall risk-adjusted rate of NICU admission (coefficient of variation = 26.2) and NICU admission rates for mild diagnoses (coefficient of variation: 46.4-74.0), but lower variation for moderate/severe diagnoses (coefficient of variation: 8.8-14.1). Births at hospitals with more NICU beds had a higher likelihood of NICU admission., Conclusion: Interhospital variation in NICU admissions is mostly driven by admissions for mild diagnoses, suggesting potential overuse.

Objective: Trial of labor after cesarean delivery has been mostly studied in the setting of one prior cesarean delivery; controversy remains regarding the risks and benefits of trial of labor for women with two prior cesarean deliveries. This study aimed to examine utilization, success rate, and maternal and neonatal outcomes of trial of labor in this population., Methods: Using linked hospital discharge and birth certificate data, we retrospectively analyzed a cohort of mothers with nonanomalous, term, singleton live births in California between 2010-2012 and had two prior cesarean deliveries and no clear contraindications for trial of labor. We measured whether they attempted labor and, if so, whether they delivered vaginally. Association of patient and hospital characteristics with the likelihood of attempting labor and successful vaginal birth was examined using multivariable regressions. We compared composite severe maternal morbidities and composite severe newborn complications in those who underwent trial of labor as opposed to planned cesarean delivery using a propensity score-matching approach., Results: Among 42,771 women who met sample eligibility criteria, 1,228 (2.9%) attempted labor, of whom 484 (39.4%) delivered vaginally. There was no significant difference in the risk of composite severe maternal morbidities, but there was a modest increase in the risk of composite severe newborn complications among women who attempted labor compared with those who did not (2.0% vs 1.4%, P=.04). After accounting for differences in patient and hospital characteristics, propensity score-matched analysis showed no significant association between trial of labor and the risk of composite severe maternal morbidities (odds ratio [OR] 1.16, 95% CI 0.70-1.91), but trial of labor was associated with a higher risk for the composite of severe newborn complications (OR 1.78, 95% CI 1.04-3.04)., Conclusion: Among women with two prior cesarean deliveries, trial of labor was rarely attempted and was successful in 39.4% of attempts. Trial of labor in this population was associated with a modest increase in severe neonatal morbidity.

Objective: To evaluate the association between temporary cessation in oxytocin infusion (oxytocin rest) and mode of delivery in women undergoing induction of labor with a protracted latent phase., Methods: We conducted a retrospective cohort analysis of nulliparous women with term, vertex, singleton gestations who were undergoing induction of labor with continuous oxytocin infusion at a large academic medical center. Episodes of oxytocin rest were identified among patients who were exposed to 8 hours of continuous oxytocin yet remained in latent labor (ie, protracted latent labor). Multivariable logistic regression analysis was performed to estimate the association between duration of oxytocin rest and mode of delivery while adjusting for duration of latent phase, maternal age, gestational age, body mass index, and indications for induction and oxytocin cessation. Maternal and neonatal morbidities were also compared among patients with different durations of oxytocin rest., Results: From January 2012 to December 2016, 1,193 patients met eligibility criteria. Among these patients, 267 patients (22.4%) underwent an oxytocin rest that lasted at least 1 hour. After adjusting for potential confounders, the odds ratios of cesarean delivery for patients with oxytocin rest compared with those with no oxytocin rest were as follows: 1.12 (95% CI 0.79-1.58) for less than 1 hour, 0.78 (95% CI 0.48-1.27) for 1-2 hours, 0.60 (95% CI 0.35-1.04) for 2-8 hours, and 0.43 (95% CI 0.24-0.79) for 8 hours or more. We did not detect an association between oxytocin rest of more than 8 hours and a composite of maternal or neonatal morbidities., Conclusion: An oxytocin rest of at least 8 hours is a clinical tool that may reduce the risk of cesarean delivery among women with protracted latent labor without significantly increasing maternal or neonatal morbidity.

DNA is susceptible to a range of chemical modifications, with one of the most frequent lesions being apurinic/apyrimidinic (AP) sites. AP sites arise due to damage-induced (e.g. alkylation) or spontaneous hydrolysis of the N-glycosidic bond that links the base to the sugar moiety of the phosphodiester backbone, or through the enzymatic activity of DNA glycosylases, which release inappropriate bases as part of the base excision repair (BER) response. Unrepaired AP sites, which lack instructional information, have the potential to cause mutagenesis or to arrest progressing DNA or RNA polymerases, potentially causing outcomes such as cellular transformation, senescence or death. The predominant enzyme in humans responsible for repairing AP lesions is AP endonuclease 1 (APE1). Besides being a powerful AP endonuclease, APE1 possesses additional DNA repair activities, such as 3'-5' exonuclease, 3'-phophodiesterase and nucleotide incision repair. In addition, APE1 has been shown to stimulate the DNA-binding activity of a number of transcription factors through its 'REF1' function, thereby regulating gene expression. In this article, we review the structural and biochemical features of this multifunctional protein, while reporting on new structures of the APE1 variants Cys65Ala and Lys98Ala. Using a functional complementation approach, we also describe the importance of the repair and REF1 activities in promoting cell survival, including the proposed passing-the-baton coordination in BER. Finally, results are presented indicating a critical role for APE1 nuclease activities in resistance to the genotoxins methyl methanesulphonate and bleomycin, supporting biologically important functions as an AP endonuclease and 3'-phosphodiesterase, respectively., (Published by Oxford University Press on behalf of The UK Environmental Mutagen Society 2019.)

Objectives: Efforts to study potential overuse of NICU admissions and hospital variation in practice are often hindered by a lack of an appropriate data source. We examined the concordance of hospital-level NICU admission rates between birth certificate data and California Children's Services (CCS) data to inform the utility of birth certificate data in studying hospital variation in NICU admissions., Methods: We analyzed birth certificate data from California in 2012 and hospital-specific summary data from CCS regarding NICU admissions. NICU admission rates were calculated for both data sets while using CCS data as the gold standard. The difference between birth certificate-based and CCS-based NICU admission rates was assessed by using the Wilcoxon signed rank test, and concordance between the 2 rates was evaluated by using Lin's concordance correlation coefficient and Kendall's W concordance coefficient., Results: Among a total of 103 hospitals that were linked between the 2 data sets, birth certificate data generally underreported NICU admission rates compared with CCS data (median = 7.72% vs 11.51%; P < .001). However, in a subset of 35 hospitals where the difference in NICU admission rates between the 2 data sets was small, the birth certificate-based NICU admission rate showed good concordance with the rate from CCS data (Lin's concordance correlation coefficient = 0.91; 95% confidence interval: 0.84-0.95; Kendall's W concordance coefficient = 0.99; P < .001). Hospitals with good-concordance data did not differ from other hospitals in the institutional characteristics assessed., Conclusions: For a selected subset of hospitals, birth certificate data may offer a reasonable means to investigate hospital variation in NICU admissions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Introduction: Despite evidence supporting the safety of low-interventional approaches to intrapartum care, defined by the American College of Obstetricians and Gynecologists as "practices that facilitate a physiologic labor process and minimize intervention," little is known about how frequently such practices are utilized. We examined hospital use of low-interventional practices, as well as variation in utilization across hospitals., Methods: Data came from 185 California hospitals completing a survey of intrapartum care, including 9 questions indicating use of low- versus high-interventional practices (eg, use of intermittent auscultation, nonpharmacologic pain relief, and admission of women in latent labor). We performed a group-based latent class analysis to identify distinct groups of hospitals exhibiting different levels of utilization on these 9 measures. Multivariable logistic regression identified institutional characteristics associated with a hospital's likelihood of using low-interventional practices. Procedure rates and patient outcomes were compared between the hospital groups using bivariate analysis., Results: We identified 2 distinct groups of hospitals that tended to use low-interventional (n = 44, 23.8%) and high-interventional (n = 141, 76.2%) practices, respectively. Hospitals more likely to use low-interventional practices included those with midwife-led or physician-midwife collaborative labor management (adjusted odds ratio [aOR], 7.52; 95% CI, 2.53-22.37; P < .001) and those in rural locations (aOR, 3.73; 95% CI, 1.03-13.60; P = .04). Hospitals with a higher proportion of women covered by Medicaid or other safety-net programs were less likely to use low-interventional practices (aOR, 0.96; 95% CI, 0.93-0.99; P = .004), as were hospitals in counties with higher medical liability insurance premiums (aOR, 0.53; 95% CI, 0.33-0.85; P = .008). Hospitals in the low-intervention group had comparable rates of severe maternal and newborn morbidities but lower rates of cesarean birth and episiotomy compared with hospitals in the high-intervention group., Discussion: Only one-quarter of hospitals used low-interventional practices. Attention to hospital culture of care, incorporating the midwifery model of care, and addressing medical-legal concerns may help promote utilization of low-interventional intrapartum practices., (© 2019 by the American College of Nurse-Midwives.)

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., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Cardiovascular disease is the leading cause of pregnancy-related death in the United States. Identification of short-term indicators of cardiovascular morbidity has the potential to alter the course of this devastating disease among women. It has been established that hypertensive disorders of pregnancy are associated with increased risk of cardiovascular disease 10-30 years after delivery; however, little is known about the association of hypertensive disorders of pregnancy with cardiovascular morbidity during the delivery hospitalization., Objective: We aimed to identify the immediate risk of cardiovascular morbidity during the delivery hospitalization among women who experienced a hypertensive disorder of pregnancy., Materials and Methods: This retrospective cohort study of women, 15-55 years old with a singleton gestation between 2008 and 2012 in New York City, examined the risk of severe cardiovascular morbidity in women with hypertensive disorders of pregnancy compared with normotensive women during their delivery hospitalization. Women with a history of chronic hypertension, diabetes mellitus, or cardiovascular disease were excluded. Mortality and severe cardiovascular morbidity (myocardial infarction, cerebrovascular disease, acute heart failure, heart failure or arrest during labor or procedure, cardiomyopathy, cardiac arrest and ventricular fibrillation, or conversion of cardiac rhythm) during the delivery hospitalization were identified using birth certificates and discharge record coding. Using multivariable logistic regression, we assessed the association between hypertensive disorders of pregnancy and severe cardiovascular morbidity, adjusting for relevant sociodemographic and pregnancy-specific clinical risk factors., Results: A total of 569,900 women met inclusion criteria. Of those women, 39,624 (6.9%) had a hypertensive disorder of pregnancy: 11,301 (1.9%) gestational hypertension; 16,117 (2.8%) preeclampsia without severe features; and 12,206 (2.1%) preeclampsia with severe features, of whom 319 (0.06%) had eclampsia. Among women with a hypertensive disorder of pregnancy, 431 experienced severe cardiovascular morbidity (10.9 per 1000 deliveries; 95% confidence interval, 9.9-11.9). Among normotensive women, 1780 women experienced severe cardiovascular morbidity (3.4 per 1000 deliveries; 95% confidence interval, 3.2-3.5). Compared with normotensive women, there was a progressively increased risk of cardiovascular morbidity with gestational hypertension (adjusted odds ratio, 1.18; 95% confidence interval, 0.92-1.52), preeclampsia without severe features (adjusted odds ratio, 1.96; 95% confidence interval, 1.66-2.32), preeclampsia with severe features (adjusted odds ratio, 3.46; 95% confidence interval, 2.99-4.00), and eclampsia (adjusted odds ratio, 12.46; 95% confidence interval, 7.69-20.22). Of the 39,624 women with hypertensive disorders of pregnancy, there were 15 maternal deaths, 14 of which involved 1 or more cases of severe cardiovascular morbidity., Conclusion: Hypertensive disorders of pregnancy, particularly preeclampsia with severe features and eclampsia, are significantly associated with cardiovascular morbidity during the delivery hospitalization. Increased vigilance, including diligent screening for cardiac pathology in patients with hypertensive disorders of pregnancy, may lead to decreased morbidity for mothers., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: This study aims to examine hospital variation in both maternal and neonatal morbidities and identify institutional characteristics associated with hospital performance in a combined measure of maternal and neonatal outcomes., Methods: Using the California Linked Birth File containing data from birth certificate and hospital discharge records, we identified 1 322 713 term births delivered at 248 hospitals during 2010-2012. For each hospital, a risk-standardized rate of severe maternal morbidities and a risk-standardized rate of severe newborn morbidities were calculated after adjusting for patient clinical risk factors. Hospitals were ranked based on combined information on their maternal and newborn morbidity rates., Results: Risk-standardized severe maternal and severe newborn morbidity rates varied substantially across hospitals (10th to 90th percentile range = 67.5-148.2 and 141.8-508.0 per 10 000 term births, respectively), although there was no significant association between the two (P = 0.15). Government hospitals (non-Federal) were more likely than other hospitals to be in worse rank quartiles (P value for trend = 0.004), whereas larger volume was associated with better rank among hospitals in the first three quartiles (P = 0.004). The most prevalent morbidities that differed progressively across hospital rank quartiles were severe hemorrhage, disseminated intravascular coagulation, and heart failure during procedure/surgery for mothers, and severe infection, respiratory complication, and shock/resuscitation for neonates., Conclusions: Hospitals with low maternal morbidity rates may not have low neonatal morbidity rates and vice versa, highlighting the importance of assessing joint maternal-newborn outcomes in order to fully characterize a hospital's obstetrical performance. Hospitals with smaller volume and government ownership tend to have less desirable outcomes and warrant additional attention in future quality improvement efforts., (© 2018 Wiley Periodicals, Inc.)

Background: Evaluating trends in indications may identify targets to safely reduce the primary cesarean delivery rate., Objective: The purpose of this study was to examine physician-documented indications for cesarean delivery to identify specific factors that contribute to a decreasing cesarean delivery rate., Study Design: We analyzed rates of primary and repeat cesarean deliveries, which included indications for the procedure, among 22,265 live births at an academic tertiary center from 2009-2013. Time trends for each indication were modeled to estimate the absolute and cumulative annualized relative risk of cesarean delivery by indication over time and the relative contribution of each indication to the overall decrease in primary cesarean delivery rate., Results: From 2009-2013, the cesarean delivery rate decreased from 36.5-31.4%; 74% of the decrease was attributable to a decrease in primary cesarean deliveries, which decreased from 21.7-17.6%. Among documented indications for primary cesarean delivery, labor arrest, abnormal or indeterminate fetal heart rate, and preeclampsia decreased significantly over time (P<.001), whereas malpresentation, multiple gestation, maternal-fetal, macrosomia, and other obstetric and elective/maternal requests did not change (P>.05). Labor arrest was responsible for the largest proportion of the decrease in the primary cesarean delivery rate (44%), followed by abnormal or indeterminate fetal heart rate (23%) and preeclampsia (13%)., Conclusion: Primary cesarean births accounted for 74% of the decreasing cesarean delivery rate. Reductions in the diagnosis of labor arrest and abnormal fetal heart rate led to a decreased cesarean delivery rate at a major academic institution. Contemporaneous changes in definitions of labor arrest and approaches to fetal monitoring that were adopted at our institution may have considerable effect on the cesarean delivery rate., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To examine whether women who varied from recommended gestational weight gain guidelines by the Institute of Medicine (IOM, now known as the National Academy of Medicine) were at increased risk of severe maternal morbidity during delivery hospitalization compared with those whose weight gain remained within guidelines., Methods: We conducted a retrospective cohort study using linked 2008-2012 New York City discharge and birth certificate data sets. Cases of severe maternal morbidity were identified using International Classification of Diseases, 9th Revision, Clinical Modification codes based on the Centers for Disease Control and Prevention criteria, which consists of 21 indicators of possible life-threatening diagnoses, life-saving procedures, or death. Multivariable logistic regression was used to evaluate the association between gestational weight gain categories based on prepregnancy body mass index (BMI) and severe maternal morbidity adjusting for maternal demographics and socioeconomic status. The analysis was stratified by prepregnancy BMI categories., Results: During 2008-2012, there were 515,148 term singleton live births in New York City with prepregnancy weight and gestational weight gain information. In 24.8%, 35.1%, 32.1%, and 8.0% of these births, women gained below, within, 1-19 lbs above, and 20 lbs or more above the IOM guidelines, respectively. After adjusting for maternal demographic and socioeconomic characteristics, women who had gestational weight gain 1-19 lbs above (adjusted odds ratio [AOR] 1.08, 95% CI 1.02-1.13) or 20 lbs or more above the IOM recommendations (AOR 1.21, 95% CI 1.12-1.31) had higher odds of overall severe maternal morbidity compared with women who gained within guidelines. Although the increased odds ratios (ORs) were statistically significant, this only resulted in an absolute rate increase of 2.1 and 6 cases of severe maternal morbidity per 1,000 deliveries for those who gained 1-19 and 20 lbs or more above recommendations, respectively. Women with gestational weight gain 20 lbs or more above recommendations had significantly higher ORs of eclampsia, heart failure during a procedure, pulmonary edema or acute heart failure, transfusion, and ventilation., Conclusion: Women whose gestational weight gain is in excess of IOM guidelines are at increased risk of severe maternal morbidity, although their absolute risks remain low.

Background: Trial of labor after cesarean delivery is an effective and safe option for women without contraindications., Objectives: The objective of the study was to examine hospital variation in utilization and success of trial of labor after cesarean delivery and identify associated institutional characteristics and patient outcomes., Study Design: Using linked maternal and newborn hospital discharge records and birth certificate data in 2010-2012 from the state of California, we identified 146,185 term singleton mothers with 1 prior cesarean delivery and no congenital anomalies or clear contraindications for trial of labor at 249 hospitals. Risk-standardized utilization and success rates of trial of labor after cesarean delivery were estimated for each hospital after accounting for differences in patient case mix. Risk for severe maternal and newborn morbidities, as well as maternal and newborn length of stay, were compared between hospitals with high utilization and high success rates of trial of labor after cesarean delivery and other hospitals. Bivariate analysis was also conducted to examine the association of various institutional characteristics with hospitals' utilization and success rates of trial of labor after cesarean delivery., Results: In the overall sample, 12.5% of women delivered vaginally. After adjusting for patient clinical risk factors, utilization and success rates of trial of labor after cesarean delivery varied considerably across hospitals, with a median of 35.2% (10th to 90th percentile range: 10.2-67.1%) and 40.5% (10th to 90th percentile range: 8.5-81.1%), respectively. Risk-standardized utilization and success rates of trial of labor after cesarean delivery demonstrated an inverted U-shaped relationship such that low or excessively high use of trial of labor after cesarean delivery was associated with lower success rate. Compared with other births, those delivered at hospitals with above-the-median utilization and success rates of trial of labor after cesarean delivery had a higher risk for uterine rupture (adjusted risk ratio, 2.74, P < .001), severe newborn respiratory complications (adjusted risk ratio, 1.46, P < .001), and severe newborn neurological complications/trauma (adjusted risk ratio, 2.48, P < .001), but they had a lower risk for severe newborn infection (adjusted risk ratio, 0.80, P = .003) and overall severe unexpected newborn complications (adjusted risk ratio, 0.86, P < .001) as well as shorter length of stays (adjusted mean ratio, 0.948 for mothers and 0.924 for newborns, P < .001 for both). Teaching status, system affiliation, larger volume, higher neonatal care capacity, anesthesia availability, higher proportion of midwife-attended births, and lower proportion of Medicaid or uninsured patients were positively associated with both utilization and success of trial of labor after cesarean delivery. However, rural location and higher local malpractice insurance premium were negatively associated with the utilization of trial of labor after cesarean delivery, whereas for-profit ownership was associated with lower success rate., Conclusion: Utilization and success rates of trial of labor after cesarean delivery varied considerably across hospitals. Strategies to promote vaginal birth should be tailored to hospital needs and characteristics (eg, increase availability of trial of labor after cesarean delivery at hospitals with low utilization rates while being more selective at hospitals with high utilization rates, and targeted support for lower capacity hospitals)., (Copyright © 2018. Published by Elsevier Inc.)

Frequent oxidative modification of the neural genome is a by-product of the high oxygen consumption of the nervous system. Rapid correction of oxidative DNA lesions is essential, as genome stability is a paramount determinant of neural homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known as "APEX1" or "REF1") is a key enzyme for the repair of oxidative DNA damage, although the specific role(s) for this enzyme in the development and maintenance of the nervous system is largely unknown. Here, using conditional inactivation of murine Ape1 , we identify critical roles for this protein in the brain selectively after birth, coinciding with tissue oxygenation shifting from a placental supply to respiration. While mice lacking APE1 throughout neurogenesis were viable with little discernible phenotype at birth, rapid and pronounced brain-wide degenerative changes associated with DNA damage were observed immediately after birth leading to early death. Unexpectedly, Ape1 Nes-cre mice appeared hypothermic with persistent shivering associated with the loss of thermoregulatory serotonergic neurons. We found that APE1 is critical for the selective regulation of Fos1-induced hippocampal immediate early gene expression. Finally, loss of APE1 in combination with p53 inactivation resulted in a profound susceptibility to brain tumors, including medulloblastoma and glioblastoma, implicating oxidative DNA lesions as an etiologic agent in these diseases. Our study reveals APE1 as a major suppressor of deleterious oxidative DNA damage and uncovers specific and broad pathogenic consequences of respiratory oxygenation in the postnatal nervous system., Competing Interests: The authors declare no conflict of interest.

In this thoughtful article, medical educators in various stages of their careers (resident, mid-career clinician-educators, medical school deans) reflect upon increasing reports of harassment and mistreatment of trainees by patients. In addition to providing a general overview of the limited literature on this topic, the authors describe their own experience collecting information on trainee mistreatment by patients at their institution. They explore the universal difficulty that educators face regarding how to best address this mistreatment and support both faculty and trainees. Given the current sociopolitical climate, there has never been a more urgent need to critically examine this issue. The authors call on the greater medical education community to join them in these important conversations.

Objective: To examine hospital variation in cost of childbirth hospitalisations and identify factors that contribute to the variation., Design: Cross-sectional analysis of linked birth certificate and hospital discharge data., Setting: Two hundred and twenty hospitals in California delivering ≥ 100 births per year., Population: A total of 405 908 nulliparous term singleton vertex births during 2010-2012., Methods: Cost of childbirth hospitalisations was compared across hospitals after accounting for differences in patient clinical risk factors. Relative contributions of patient sociodemographic, obstetric intervention, birth attendant and institutional characteristics to variation in cost were assessed by further adjusting for these factors in hierarchical generalised linear models., Main Outcome Measures: Cost of childbirth hospitalisation., Results: Median risk-standardised cost of childbirth was $7149 among the hospitals (10 th -90th percentile range: $4760-$10,644). Maternal sociodemographic characteristics and type of birth attendant did not explain hospital variation in cost. Adjustment for obstetric interventions overall reduced within-hospital variance by 15.8% (P < 0.001), while adjusting for caesarean delivery alone reduced within-hospital variance by 14.4% (P < 0.001). However, obstetric interventions did not explain between-hospital variation in cost. In contrast, adjustment for institutional characteristics reduced between-hospital variance by 30.3% (P = 0.002). Hospital type of ownership, teaching/urban-rural status, neonatal care capacity and geographic region were most impactful. Risk-standardised cost was positively correlated with risk-standardised rate of severe newborn morbidities (correlation coefficient 0.22, P = 0.001), but not associated with risk-standardised rate of severe maternal morbidities., Conclusions: Cost of childbirth hospitalisations varied widely among hospitals in California. Institutional characteristics significantly contributed to this variation. Higher-cost hospitals did not have better outcomes, suggesting potential opportunities to enhance value in care., Tweetable Abstract: Hospitals vary in cost of childbirth. Institutional characteristics significantly contribute to the variation., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Background: Despite the availability of a safe and efficacious vaccine against human papillomavirus, uptake of the vaccine in the United States is low. Missed clinical opportunities to recommend and to administer human papillomavirus vaccine are considered one of the most important reasons for its low uptake in adolescents; however, little is known about the frequency or characteristics of missed opportunities in the young adult (18-26 years of age) population., Objective: The objective of the study was to assess both the rates of and the factors associated with missed opportunities for human papillomavirus immunization among young adult women who attended an urban obstetrics and gynecology clinic., Study Design: In this cross-sectional study, medical records were reviewed for all women 18-26 years of age who were underimmunized (<3 doses) and who sought care from Feb. 1, 2013, to January 31, 2014, at an urban, hospital-based obstetrics and gynecology clinic. A missed opportunity for human papillomavirus immunization was defined as a clinic visit at which the patient was eligible to receive the vaccine and a dose was due but not administered. Multivariable logistic regression was used to test associations between sociodemographic variables and missed opportunities., Results: There were 1670 vaccine-eligible visits by 1241 underimmunized women, with a mean of 1.3 missed opportunities/person. During the study period, 833 of the vaccine eligible women (67.1%) had at least 1 missed opportunity. Overall, the most common types of visits during which a missed opportunity occurred were postpartum visits (17%) or visits for either sexually transmitted disease screening (21%) or contraception (33%). Of the patients with a missed opportunity, 26.5% had a visit at which an injectable medication or a different vaccine was administered. Women who identified their race as black had higher adjusted odds of having a missed opportunity compared with white women (adjusted odds ratio, 1.61 [95% confidence interval, 1.08-2.41], P < .02). Women who reported a non-English- or non-Spanish-preferred language had lower adjusted odds of having a missed opportunity (adjusted odds ratio, 0.25 [95% confidence interval, 0.07-0.87], P = .03). No other patient characteristics assessed in this study were significantly associated with having a missed opportunity., Conclusion: A majority of young-adult women in this study had missed opportunities for human papillomavirus immunization, and significant racial disparity was observed. The greatest frequency of missed opportunities occurred with visits for either contraception or for sexually transmitted disease screening., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To assess hospital practices in obstetric quality management activities and identify institutional characteristics associated with utilization of evidence-supported practices., Methods: Data for this study came from a statewide survey of obstetric hospitals in California regarding their organization and delivery of perinatal care. We analyzed responses from 185 hospitals that completed quality assurance sections of the survey to assess their practices in a broad spectrum of quality enhancement activities. The association between institutional characteristics and adoption of evidence-supported practices (ie, those supported by prior literature or recommended by professional organizations as beneficial for improving birth outcome or patient safety) was examined using bivariate analysis and appropriate statistical tests., Results: Most hospitals regularly audited adherence to written protocols regarding critical areas of care; however, 77.7% and 16.8% reported not having written guidelines on diagnosis of labor arrest and management of abnormal fetal heart rate, respectively. Private nonprofit hospitals were more likely to have a written protocol for management of abnormal fetal heart rate (P=.002). One in 10 hospitals (9.7%) did not regularly review cases with significant morbidity or mortality, and only 69.0% regularly tracked indications for cesarean delivery. Moreover, 26.3%, 14.3%, and 8.7% of the hospitals reported never performing interprofessional simulations for eclampsia, shoulder dystocia, or postpartum hemorrhage, respectively. Teaching status was associated with more frequent simulations in these three areas (P≤.04 for all), while larger volume was associated with more frequent simulations for eclampsia (P=.04)., Conclusion: Hospitals in California engage in a wide range of practices to assure or improve quality of obstetric care, but substantial variation in practice exists among hospitals. There is opportunity for improvement in adoption of evidence-supported practices.

Objective: To evaluate the association between planned home birth and neonatal hypoxic ischemic encephalopathy (HIE)., Methods: This is a case-control study in which a database of neonates who underwent head cooling for HIE at our institution from 2007 to 2011 was linked to New York City (NYC) vital records. Four normal controls per case were then randomly selected from the birth certificate data after matching for year of birth, geographic location, and gestational age. Demographic and obstetric information was obtained from the vital records for both the cases and controls. Location of birth was analyzed as hospital or out of hospital birth. Details from the out of hospital deliveries were reviewed to determine if the delivery was a planned home birth. Maternal and pregnancy characteristics were examined as covariates and potential confounders. Logistic regression was used to determine the odds of HIE by intended location of delivery., Results: Sixty-nine neonates who underwent head cooling for HIE had available vital record data on their births. The 69 cases were matched to 276 normal controls. After adjusting for pregnancy characteristics and mode of delivery, neonates with HIE had a 44.0-fold [95% confidence interval (CI) 1.7-256.4] odds of having delivered out of hospital, whether unplanned or planned. Infants with HIE had a 21.0-fold (95% CI 1.7-256.4) increase in adjusted odds of having had a planned home birth compared to infants without HIE., Conclusion: Out of hospital birth, whether planned home birth or unplanned out of hospital birth, is associated with an increase in the odds of neonatal HIE.

Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. Environ. Mol. Mutagen. 58:84-98, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Objective: To examine hospital variation in intrapartum care and its relationship with cesarean rates., Design: Cross-sectional survey., Setting: Connecticut and Massachusetts hospitals providing obstetric services., Participants: Nurse managers or other clinical staff knowledgeable about intrapartum care., Methods: We assessed labor and delivery unit capacity and staffing, fetal monitoring, labor management, intrapartum interventions, newborn care, quality assurance, and performance review practices. Association of hospital characteristics and intrapartum practices with cesarean rate was evaluated using Wilcoxon exact rank sum test and Kendall's tau-b correlation coefficient., Results: Among 60 eligible hospitals, respondents from 39 hospitals (65%) completed the survey. Cesarean rates varied from 21% to 42% (median = 30%). Regular review of cesarean rates and indications (85%), regular provision of feedback on cesarean rates and indications to physicians (80%), and regular review of vaginal birth after cesarean rates (94%) were commonly performed at responding hospitals. These practices, however, were not associated with hospital cesarean rate. Hospitals that offered cesarean at the request of the woman (p < .01) and had more liberal indications for labor induction (p < .01) and cesarean birth (p < .01) had significantly greater cesarean rates than institutions without these practices. Routinely placing an intravenous line (p < .01) and drawing blood for complete blood count/type and antibody screen (p < .01) in low-risk women were associated with greater cesarean rates; having a certified nurse-midwife in house at all times (p = .01) and permitting women to eat during labor (p = .02) were associated with lower cesarean rates., Conclusion: Intrapartum practices of hospitals varied markedly. These different patterns of care may suggest differing levels of intrapartum intervention., (Copyright © 2017 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)

Childbirth is the leading cause of hospital admission in the United States, yet there has been little research on variation in hospital costs associated with childbirth. Using data from the 2011 Nationwide Inpatient Sample, we characterized the variation in estimated facility costs of hospitalizations for low-risk childbirth across US hospitals. We found that the average estimated facility cost per maternity stay ranged from $1,189 to $11,986 (median: $4,215), with a 2.2-fold difference between the 10th and 90th percentiles. Estimated facility costs were higher at hospitals with higher rates of cesarean delivery or serious maternal morbidity. Hospitals having government or nonprofit ownership; being a rural hospital; and having relatively low volumes of childbirths, low proportions of childbirths covered by Medicaid, and long stays also had significantly higher costs. The large variation in estimated facility cost for low-risk childbirths among hospitals suggests that hospital practices might be an important contributor to variation in cost and that there may be opportunities for cost reduction. The safe reduction of cesarean deliveries, increasing the coordination of care, and emphasizing value of care through new payment and delivery systems reforms may help reduce hospital costs and cost variation associated with childbirth in the United States., (Project HOPE—The People-to-People Health Foundation, Inc.)

Purpose: To estimate whether low-to-moderate prenatal alcohol exposure is associated with selected birth outcomes., Methods: Low-to-moderate prenatal alcohol drinking and effects on low birthweight, preterm delivery, intrauterine growth restriction, and selected neonatal outcomes were evaluated among 4496 women and singleton infants. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression, controlling for confounding variables., Results: Early pregnancy drinking was associated with reduced odds of low birthweight, OR, 0.66 (95% CI, 0.46-0.96) and birth length less than 10th percentile, OR, 0.74 (95% CI, 0.56-0.97). Drinking during the first 3 months showed lower odds for birth length and head circumference less than 10th percentile, OR, 0.56 (95% CI, 0.36-0.87) and OR, 0.69 (95% CI, 0.50-0.96), respectively. Third trimester drinking was associated with lower odds for low birthweight, OR, 0.56 (95% CI, 0.34-0.94) and preterm delivery, OR, 0.60 (95% CI, 0.42-0.87)., Conclusions: Our results suggest low-to-moderate alcohol exposure during early and late gestation is not associated with increased risk of low birthweight, preterm delivery, intrauterine growth restriction, and most selected perinatal outcomes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To explore patient and provider perspectives regarding a new Web-based contraceptive support tool., Study Design: We conducted a qualitative study at an urban Medicaid-based clinic among sexually active women interested in starting a new contraceptive method, clinic providers and staff. All participants were given the opportunity to explore Bedsider, an online contraceptive support tool developed for sexually active women ages 18-29 by the National Campaign to Prevent Teen and Unplanned Pregnancy and endorsed by the American Congress of Obstetricians and Gynecologists. Focus groups were conducted separately among patient participants and clinic providers/staff using open-ended structured interview guides to identify specific themes and key concepts related to use of this tool in an urban clinic setting., Results: Patient participants were very receptive to this online contraceptive support tool, describing it as trustworthy, accessible and empowering. In contrast, clinic providers and staff had concerns regarding the Website's legitimacy, accessibility, ability to empower patients and applicability, which limited their willingness to recommend its use to patients., Conclusion: Contrasting opinions regarding Bedsider may point to a potential disconnect between how providers and patients view contraception information tools. Further qualitative and quantitative studies are needed to explore women's perspectives on contraceptive education and counseling and providers' understanding of these perspectives., Implications Statement: This study identifies a contrast between how patients and providers in an urban clinic setting perceive a Web-based contraceptive tool. Given a potential patient-provider discrepancy in preferred methods and approaches to contraceptive counseling, additional research is needed to enhance this important arena of women's health care., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Base excision repair (BER) is a frontline defense mechanism for dealing with many common forms of endogenous DNA damage, several of which can drive mutagenic or cell death outcomes. The pathway engages proteins such as glycosylases, abasic endonucleases, polymerases and ligases to remove substrate modifications from DNA and restore the genome back to its original state. Inherited mutations in genes related to BER can give rise to disorders involving cancer, immunodeficiency and neurodegeneration. Studies employing genetically defined heterozygous (haploinsufficient) mouse models indicate that partial reduction in BER capacity can increase vulnerability to both spontaneous and exposure-dependent pathologies. In humans, measurement of BER variation has been imperfect to this point, yet tools to assess BER in epidemiological surveys are steadily evolving. We provide herein an overview of the BER pathway and discuss the current efforts toward defining the relationship of BER defects with disease susceptibility., (Published by Oxford University Press 2014.)

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 × 10(-57)), high mitotic index (p = 5.25 × 10(-28)), pleomorphism (p = 6.31 × 10(-19)), ER negative (p = 9.02 × 10(-35)), PR negative (p = 9.24 × 10(-24)), triple negative phenotype (p = 6.67 × 10(-21)), PAM50.Her2 (p = 5.19 × 10(-13)), PAM50. Basal (p = 2.7 × 10(-41)), PAM50.LumB (p = 1.56 × 10(-26)), integrative molecular cluster 1 (intClust.1) (p = 7.47 × 10(-12)), intClust.5 (p = 4.05 × 10(-12)) and intClust. 10 (p = 7.59 × 10(-38)) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 × 10(-16)) and multivariate analysis (p = 9.19 × 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 overexpression 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., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Begun in 2003, the Yale-New Haven Hospital comprehensive obstetric safety program consisted of measures to standardize care, improve teamwork and communication, and optimize oversight and quality review. Prior publications have demonstrated improvements in adverse outcomes and safety culture associated with this program. In this analysis, we aimed to assess the impact of this program on liability claims and payments at a single institution. We reviewed liability claims at a single, tertiary-care, teaching hospital for two 5-year periods (1998-2002 and 2003-2007), before and after implementing the safety program. Connecticut statute of limitations for professional malpractice is 36 months from injury. Claims/events were classified by event-year and payments were adjusted for inflation. We analyzed data for trends as well as differences between periods before and after implementation. Forty-four claims were filed during the 10-year study period. Annual cases per 1000 deliveries decreased significantly over the study period (P < .01). Claims (30 vs 14) and payments ($50.7 million vs $2.9 million) decreased in the 5-years after program inception. Compared with before program inception, median annual claims dropped from 1.31 to 0.64 (P = .02), and median annual payments per 1000 deliveries decreased from $1,141,638 to $63,470 (P < .01). Even estimating the monetary awards for the 2 remaining open cases using the median payments for the surrounding 5 years, a reduction in the median monetary amount per case resulting in payment to the claimant was also statistically significant ($632,262 vs $216,815, P = .046). In contrast, the Connecticut insurance market experienced a stable number of claims and markedly increased cost per claim during the same period. We conclude that an obstetric safety initiative can improve liability claims exposure and reduce liability payments., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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's 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., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This study estimates the effect of maternal infections during pregnancy on childhood asthma. One-thousand four-hundred and twenty-eight pregnant women were prospectively followed using structured interviews and chart review until their child's 6th year of life. Infections were identified from outpatient and hospital visits. Childhood asthma was defined as physician diagnosis with symptoms at age six. Adjusted odds ratios were calculated from multivariable logistic regression models. Six-hundred and thirty-five women experienced an infection during pregnancy. Among antepartum infections, maternal urinary tract infections were significantly associated with childhood asthma (aOR 1.60, 95 % CI 1.12-2.29). Chorioamnionitis and maternal group beta streptococcus colonization were not significantly associated with an increased risk in childhood asthma. This study found an increased risk of asthma in children of women diagnosed with urinary tract infections during pregnancy, while other maternal infections did not increase the risk.

Apurinic/apyrimidinic endonuclease 1 (APE1) is the predominant AP site repair enzyme in mammals. APE1 also maintains 3'-5' exonuclease and 3'-repair activities, and regulates transcription factor DNA binding through its REF-1 function. Since complete or severe APE1 deficiency leads to embryonic lethality and cell death, it has been hypothesized that APE1 protein variants with slightly impaired function will contribute to disease etiology. Our data indicate that except for the endometrial cancer-associated APE1 variant R237C, the polymorphic variants Q51H, I64V and D148E, the rare population variants G241R, P311S and A317V, and the tumor-associated variant P112L exhibit normal thermodynamic stability of protein folding; abasic endonuclease, 3'-5' exonuclease and REF-1 activities; coordination during the early steps of base excision repair; and intracellular distribution when expressed exogenously in HeLa cells. The R237C mutant displayed reduced AP-DNA complex stability, 3'-5' exonuclease activity and 3'-damage processing. Re-sequencing of the exonic regions of APE1 uncovered no novel amino acid substitutions in the 60 cancer cell lines of the NCI-60 panel, or in HeLa or T98G cancer cell lines; only the common D148E and Q51H variants were observed. Our results indicate that APE1 missense mutations are seemingly rare and that the cancer-associated R237C variant may represent a reduced-function susceptibility allele.

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., (© 2012 Blackwell Publishing Ltd.)

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by trinucleotide repeat (TNR) expansions. We show here that somatic TNR expansions are significantly reduced in several organs of R6/1 mice lacking exon 2 of Nei-like 1 (Neil1) (R6/1/Neil1(-/-)), when compared with R6/1/Neil1(+/+) mice. Somatic TNR expansion is measured by two different methods, namely mean repeat change and instability index. Reduced somatic expansions are more pronounced in male R6/1/Neil1(-/-) mice, although expansions are also significantly reduced in brain regions of female R6/1/Neil1(-/-) mice. In addition, we show that the lack of functional Neil1 significantly reduces germline expansion in R6/1 male mice. In vitro, purified human NEIL1 protein binds and excises 5-hydroxycytosine in duplex DNA more efficiently than in hairpin substrates. NEIL1 excision of cytosine-derived oxidative lesions could therefore be involved in initiating the process of TNR expansion, although other DNA modifications might also contribute. Altogether, these results imply that Neil1 contributes to germline and somatic HD CAG repeat expansion.