The interplay of density functional selection and crystal structure for accurate NMR chemical shift predictions.

Ab initio chemical shift prediction plays a central role in nuclear magnetic resonance (NMR) crystallography, and the accuracy with which chemical shifts can be predicted relative to experiment impacts the confidence with which structures can be assigned. For organic crystals, periodic density functional theory calculations with the gauge-including projector augmented wave (GIPAW) approximation and the PBE functional are widely used at present. Many previous studies have examined how using more advanced density functionals can increase the accuracy of predicted chemical shifts relative to experiment, but nearly all of those studies employed crystal structures that were optimized with generalized-gradient approximation (GGA) functionals. Here, we investigate how the accuracy of the predicted chemical shifts in organic crystals is affected by replacing GGA-level PBE-D3(BJ) crystal geometries with more accurate hybrid functional PBE0-D3(BJ) ones. Based on benchmark data sets containing 132 13C and 35 15N chemical shifts, plus case studies on testosterone, acetaminophen, and phenobarbital, we find that switching from GGA-level geometries and chemical shifts to hybrid-functional ones reduces 13C and 15N chemical shift errors by ∼40-60% versus experiment. However, most of the improvement stems from the use of the hybrid functional for the chemical shift calculations, rather than from the refined geometries. In addition, even with the improved geometries, we find that double-hybrid functionals still do not systematically increase chemical shift agreement with experiment beyond what hybrid functionals provide. In the end, these results suggest that the combination of GGA-level crystal structures and hybrid-functional chemical shifts represents a particularly cost-effective combination for NMR crystallography in organic systems.

Predicting primary cesarean delivery in pregnancies complicated by gestational diabetes mellitus.

BACKGROUND: Prediction models have shown promise in helping clinicians and patients engage in shared decision-making by providing quantitative estimates of individual risk of important clinical outcomes. Gestational diabetes mellitus is a common complication of pregnancy, which places patients at higher risk of primary CD. Suspected fetal macrosomia diagnosed on prenatal ultrasound is a well-known risk factor for primary CD in patients with gestational diabetes mellitus, but tools incorporating multiple risk factors to provide more accurate CD risk are lacking. Such tools could help facilitate shared decision-making and risk reduction by identifying patients with both high and low chances of intrapartum primary CD. OBJECTIVE: This study aimed to develop and internally validate a multivariable model to estimate the risk of intrapartum primary CD in pregnancies complicated by gestational diabetes mellitus undergoing a trial of labor. STUDY DESIGN: This study identified a cohort of patients with gestational diabetes mellitus derived from a large, National Institutes of Health-funded medical record abstraction study who delivered singleton live-born infants at ≥34 weeks of gestation at a large tertiary care center between January 2002 and March 2013. The exclusion criteria included previous CD, contraindications to vaginal delivery, scheduled primary CD, and known fetal anomalies. Candidate predictors were clinical variables routinely available to a practitioner in the third trimester of pregnancy found to be associated with an increased risk of CD in gestational diabetes mellitus. Stepwise backward elimination was used to build the logistic regression model. The Hosmer-Lemeshow test was used to demonstrate goodness of fit. Model discrimination was evaluated via the concordance index and displayed as the area under the receiver operating characteristic curve. Internal model validation was performed with bootstrapping of the original dataset. Random resampling with replacement was performed for 1000 replications to assess predictive ability. An additional analysis was performed in which the population was stratified by parity to evaluate the model's predictive ability among nulliparous and multiparous individuals. RESULTS: Of the 3570 pregnancies meeting the study criteria, 987 (28%) had a primary CD. Of note, 8 variables were included in the final model, all significantly associated with CD. They included large for gestational age, polyhydramnios, older maternal age, early pregnancy body mass index, first hemoglobin A1C recorded in pregnancy, nulliparity, insulin treatment, and preeclampsia. Model calibration and discrimination were satisfactory with the Hosmer-Lemeshow test (P=.862) and an area under the receiver operating characteristic curve of 0.75 (95% confidence interval, 0.74-0.77). Internal validation demonstrated similar discriminatory ability. Stratification by parity demonstrated that the model worked well among both nulliparous and multiparous patients. CONCLUSION: Using information routinely available in the third trimester of pregnancy, a clinically pragmatic model can predict intrapartum primary CD risk with reasonable reliability in pregnancies complicated by gestational diabetes mellitus and may provide quantitative data to guide patients in understanding their individual primary CD risk based on preexisting and acquired risk factors.

Frailty as a predictor of delayed initiation of adjuvant chemotherapy in patients with ovarian cancer.

OBJECTIVE: This study aimed to identify whether frailty is associated with the time between surgery and the initiation of chemotherapy for patients with ovarian cancer. METHODS: This retrospective cohort study included patients 18 years or older with stage II to IV ovarian cancer who underwent primary debulking surgery at a tertiary medical center between July 2006 and July 2015. Basic demographics and clinical information were obtained from a departmental database and the electronic medical record. The Modified Frailty Index (mFI) was calculated based on 10 comorbidities and functional status yielding 11 items total. Patients were categorized by a total score: 0-1=no frailty, 2=moderate frailty and 3+=high frailty. RESULTS: Among 451 patients, 359 had mFI scores of 0-1, 60 had a score of 2, and 32 had scores of 3+. Mean time from surgery to initiation of chemotherapy was 37 days. Mean number of days between surgery and initiation of chemotherapy increased with increasing frailty score: 36 days for the not frail group, 39 days for the moderate frailty group, and 54 days for the high frailty group (p<0.001). Time to initiation of chemotherapy of 42 days or more occurred in 23% of the no frailty group, 28% in the moderate frailty group, and 63% in the high frailty group (p<0.001). Overall survival decreased with increasing frailty scores. CONCLUSION: High mFI scores lead to a greater delay between surgery and chemotherapy initiation. Being able to predict delays in initiation of chemotherapy may allow oncologists to consider neoadjuvant chemotherapy, pre-habilitation before surgery, and improved preoperative counseling in high-risk patients.

Outcomes among Neonates after a Diagnosis of Persistent or Transient Fetal Growth Restriction Delivered at Term.

OBJECTIVE: This study aimed to evaluate whether transient fetal growth restriction (FGR) that resolves prior to delivery confers a similar risk of neonatal morbidity as uncomplicated FGR that persists at term. STUDY DESIGN: This is a secondary analysis of a medical record abstraction study of singleton live-born pregnancies delivered at a tertiary care center between 2002 and 2013. Patients with fetuses that had either persistent or transient FGR and delivered at 38 weeks or later were included. Patients with abnormal umbilical artery Doppler studies were excluded. Persistent FGR was defined as estimated fetal weight (EFW) <10th percentile by gestational age from diagnosis through delivery. Transient FGR was defined as EFW <10th percentile on at least one ultrasound, but not on the last ultrasound prior to delivery. The primary outcome was a composite of neonatal morbidity: neonatal intensive care unit admission, Apgar's score <7 at 5 minutes, neonatal resuscitation, arterial cord pH <7.1, respiratory distress syndrome, transient tachypnea of the newborn, hypoglycemia, sepsis, or death. Baseline characteristics and obstetric and neonatal outcomes were compared using Wilcoxon's rank-sum and Fisher's exact test. Log binomial regression was used to adjust for confounders. RESULTS: Of 777 patients studied, 686 (88%) had persistent FGR and 91 (12%) had transient FGR. Patients with transient FGR were more likely to have a higher body mass index, gestational diabetes, diagnosed with FGR earlier in pregnancy, have spontaneous labor, and deliver at later gestational ages. There was no difference in the composite neonatal outcome (relative risk = 1.03, 95% confidence interval [CI] 0.72, 1.47) for transient versus persistent FGR after adjusting for confounders (adjusted relative risk = 0.79, 95% CI 0.54, 1.17). There were no differences in cesarean delivery or delivery complications between groups. CONCLUSION: Neonates born at term after transient FGR do not appear to have differences in composite morbidity compared with those where uncomplicated FGR persists at term. KEY POINTS: · No differences in neonatal outcomes in uncomplicated persistent versus transient FGR at term.. · Transient FGR pregnancies more likely to deliver at later gestational ages.. · No differences in mode of delivery or obstetric complications in persistent versus transient FGR at term..

Epidemiology of Antiphospholipid Syndrome in the General Population.

PURPOSE OF REVIEW: The epidemiology of antiphospholipid syndrome (APS) is poorly understood. Here, we review the current understanding of the epidemiology of antiphospholipid syndrome in the general population and the frequency of antiphospholipid antibodies in the general population in patients with obstetric morbidity, arterial events, and venous thromboembolism. RECENT FINDINGS: There have been few population-based studies that estimated the prevalence and incidence of APS. The estimated incidence and prevalence among most these studies ranged between 1 and 2 cases per 100,000 and 40 and 50 cases per 100,000 respectively. The prevalence of antiphospholipid antibodies in patients with obstetric morbidity was 6-9%, while in arterial events and venous thromboembolism is 9-10%. However, this data remains limited. Mortality of patients with APS is 50-80% higher than the general population. The epidemiology of APS has been difficult to elucidate. Population-based studies patients with diverse age, racial, and ethnic backgrounds are needed.

Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy.

BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake-via AMP-activated protein kinase (AMPK)-after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

Risk Factors for Progression From Gestational Diabetes to Postpartum Type 2 Diabetes: A Review.

Gestational diabetes mellitus (GDM) complicates 6% to 8% of pregnancies and up to 50% of women with GDM progress to type 2 diabetes mellitus (DM) within 5 years postpartum. Clinicians have little guidance on which women are most at risk for DM progression or when evidence-based prevention strategies should be implemented in a woman's lifecycle. To help address this gap, the authors review identifiable determinants of progression from GDM to DM across the perinatal period, considering prepregnancy, pregnancy, and postpartum periods. The authors categorize evidence by pathways of risk including genetic, metabolic, and behavioral factors that influence progression to DM among women with GDM.

GDF11 Modulates Ca2+-Dependent Smad2/3 Signaling to Prevent Cardiomyocyte Hypertrophy.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-ß family, has been shown to act as a negative regulator in cardiac hypertrophy. Ca2+ signaling modulates cardiomyocyte growth; however, the role of Ca2+-dependent mechanisms in mediating the effects of GDF11 remains elusive. Here, we found that GDF11 induced intracellular Ca2+ increases in neonatal rat cardiomyocytes and that this response was blocked by chelating the intracellular Ca2+ with BAPTA-AM or by pretreatment with inhibitors of the inositol 1,4,5-trisphosphate (IP3) pathway. Moreover, GDF11 increased the phosphorylation levels and luciferase activity of Smad2/3 in a concentration-dependent manner, and the inhibition of IP3-dependent Ca2+ release abolished GDF11-induced Smad2/3 activity. To assess whether GDF11 exerted antihypertrophic effects by modulating Ca2+ signaling, cardiomyocytes were exposed to hypertrophic agents (100 nM testosterone or 50 µM phenylephrine) for 24 h. Both treatments increased cardiomyocyte size and [³H]-leucine incorporation, and these responses were significantly blunted by pretreatment with GDF11 over 24 h. Moreover, downregulation of Smad2 and Smad3 with siRNA was accompanied by inhibition of the antihypertrophic effects of GDF11. These results suggest that GDF11 modulates Ca2+ signaling and the Smad2/3 pathway to prevent cardiomyocyte hypertrophy.

Preventive behaviors and knowledge of tick-borne illnesses: results of a survey from an endemic area.

CONTEXT: Lyme disease (LD) is the most commonly reported vector-borne illness in the United States. With physically and economically burdensome effects, it is a concern of public health officials. OBJECTIVES: To assess knowledge and preventive behaviors of individuals in the endemic area of Martha's Vineyard, Massachusetts, to better understand how sociodemographic data and knowledge correlate with preventive behaviors, and to update previous island studies. DESIGN: A 30-item paper-based anonymous survey in either English or Portuguese based on language preference. SETTING: The island of Martha's Vineyard and the ferry between island and mainland. PARTICIPANTS: A total of 946 participants were recruited at 1 of 4 island locations. The majority of participants were traveling by ferry to and from Martha's Vineyard. To reach 2 populations potentially at high risk, that is, youths and outdoor workers, 3 additional venues included the island high school, an English-as-a-Second-Language class, and a local Brazilian church. OUTCOME MEASURES: Four specific preventive behaviors as well as an overall composite prevention score. RESULTS: Participants' knowledge of tick-borne illnesses was poor, and the frequency of practicing preventive behaviors was low; the most commonly reported behavior was checking one's skin for ticks (45%). Approximately one-third of respondents (37%) stated that they did not know the late symptoms of untreated LD, nor did they know early LD treatment options (49%). The 2 high-risk groups reported little participation in preventive measures. In multivariate analyses, only 4 characteristics-older age, confidence in telling deer tick from wood tick, seeing tick-borne illness as a serious threat, and certainty in ability to identify LD symptoms-attained significance associated with preventive behavior as an overall composite score. CONCLUSIONS: Public health interventions focusing on accurately communicating risk, improving knowledge both of LD symptoms and of ticks that carry the disease, as well as teaching preventive behaviors may help reduce tick-borne illness rates.

Systemic racism and Non-Hispanic Black to Non-Hispanic White disparities in infant mortality at the county level.

OBJECTIVE: To use a novel measure of systemic racism to examine its relationship with Non-Hispanic Black (NHB) to Non-Hispanic White (NHW) racial disparities in infant mortality across U.S. counties. STUDY DESIGN: In this cross-sectional study, a composite, multi-dimensional measure of systemic racism at the county level was developed using confirmatory factor analysis based on indicators across five dimensions of systemic racism. Using linear regression analysis, we examined the relationship between the systemic racism factor scores and the NHB to NHW racial disparities in county-level infant mortality rates. Additionally, we performed a multi-level analysis of infant mortality, with births nested within counties by running a random intercept model that controlled for factors at both the individual and county levels to take into account the clustered nature of the data. RESULTS: There were 325 counties that met inclusion criteria for the county level analysis and 1181 counties for the individual level analysis. Each one standard deviation increase in the Systemic Racism Index was associated with an increase of 10.4% in the Non-Hispanic Black to Non-Hispanic White infant mortality rate ratio at the county level (aOR 1.104, 95% CI [1.061-1.148]). After controlling for individual level clinical factors and county level factors, each one standard deviation increase in the systemic racism index score was associated with a decrease of 3.5% in the NHW infant mortality rate (aOR 0.965, 95% CI [0.943-0.988]). CONCLUSION: Systemic racism is significantly associated with differences between counties in the magnitude of their Non-Hispanic Black to Non-Hispanic White racial disparities in infant mortality rates.

Evidence-based surgery for cesarean hysterectomy secondary to placenta accreta spectrum: A systematic review.

OBJECTIVE: In this systematic review, we aim to propose evidence-based management for perioperative care to improve outcomes at the time of planned cesarean hysterectomy for placenta accreta spectrum, a procedure associated with significant maternal and neonatal morbidity. DATA SOURCES: We conducted a literature search for studies published in MEDLINE (via Ovid), Embase, CINAHL, and Cochrane/CENTRAL up until February 25, 2022. The search included free-text and controlled-vocabulary terms for cesarean section, cesarean delivery, and hysterectomy. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials, prospective cohort, retrospective cohort, and case-control studies published in English that reported on a perioperative intervention in the performance of a planned CH for PAS. Studies must have included a comparator group. Of the 8,907 studies screened in this systematic review, 79 met the inclusion criteria. STUDY APPRAISAL AND SYNTHESIS METHODS: Articles examining each step or intervention of the CH were grouped together and reviewed qualitatively as a group. Evidence levels and recommendations were made by consensus of all authors according to the terminology of the United States Preventive Services Task Force (USPSTF). We synthesized the results of 79 articles, and provided 28 recommendations. RESULTS: Based on USPSTF criteria, 21.4 % of the recommendations were level B (n = 6), 39.3 % were C (n = 11), 10.7 % were D (n = 3) and 28.6 % were I (n = 8). The interventions with the highest level of recommendation included delivery at a hospital with high cesarean hysterectomy volume, implementation of a standardized hospital protocol, delivery via a planned procedure, neuraxial anesthesia, and transverse skin incision (all level B recommendations by USPSTF criteria). CONCLUSIONS: Development of a standardized hospital protocol, delivery at a center with high CH surgical volume, and utilization of neuraxial anesthesia garnered B evidence levels. Recommendations were limited due to the lack of prospective trials. Further research into the technical aspects of this high-risk procedure is warranted.

Single Coil Mechano-Electromagnetic System for the Automatic 1-Axis Position Feedback 3D Locomotion Control of Magnetic Robots and Their Selective Manipulation.

3D locomotion of magnetic microrobots requires at least one pair of coils per axis and 3D feedback of the position of the microrobot. This results in voluminous systems with high-power usage and a small working space, which require complex and expensive controllers. This study presents a single-coil magneto-electromagnetic system, comprising a parallel robot and coil, capable of precise 3D locomotion control of magnetic millirobots while requiring only feedback of the vertical position of the millirobot. The coil current creates a 2D magnetic trapping point in the horizontal plane, which depends on the position and orientation of the coil and toward which the millirobot moves, eliminating the need for position feedback at such plane. The vertical position of the millirobot is controlled by varying the coil current while receiving feedback from the vertical position of the millirobot. Feedbackless 2D control and 1-axis feedback 3D automatic control of magnetic millirobots are experimentally demonstrated, achieving higher speeds and similar position errors when compared to control systems with 3D position feedback. Furthermore, selective control of two millirobots is demonstrated by matching the region of maximum vertical magnetic force and the targeted millirobot, achieving selective levitation and control of such millirobots.

Multimodal Locomotion and Active Targeted Thermal Control of Magnetic Agents for Biomedical Applications.

Magnetic microrobots can be miniaturized to a nanometric scale owing to their wireless actuation, thereby rendering them ideal for numerous biomedical applications. As a result, nowadays, there exist several mechano-electromagnetic systems for their actuation. However, magnetic actuation is not sufficient for implementation in biomedical applications, and further functionalities such as imaging and heating are required. This study proposes a multimodal electromagnetic system comprised of three pairs of Helmholtz coils, a pair of Maxwell coils, and a high-frequency solenoid to realize multimodal locomotion and heating control of magnetic microrobots. The system produces different configurations of magnetic fields that can generate magnetic forces and torques for the multimodal locomotion of magnetic microrobots, as well as generate magnetic traps that can control the locomotion of magnetic swarms. Furthermore, these magnetic fields are employed to control the magnetization of magnetic nanoparticles, affecting their magnetic relaxation mechanisms and diminishing their thermal properties. Thus, the system enables the control of the temperature increase of soft-magnetic materials and selective heating of magnetic microrobots at different positions, while suppressing the heating properties of magnetic nanoparticles located at undesired areas.

Prediction Model for Vaginal Birth After Induction of Labor in Women With Hypertensive Disorders of Pregnancy.

OBJECTIVE: To identify characteristics associated with vaginal delivery compared with cesarean delivery after labor induction among women with hypertensive disorders of pregnancy and to develop and validate a prediction model to assist in clinical care. METHODS: We studied a retrospective cohort of women with singleton pregnancies who had hypertensive disorders of pregnancy and who underwent induction of labor at 34 weeks of gestation or more from January 1, 2002, to March 31, 2013. Exclusion criteria included spontaneous labor, prelabor cesarean delivery, and known fetal anomalies. The study cohort was randomly divided into two groups; 70% of pregnancies were used to identify characteristics associated with vaginal delivery and develop a prediction model, and 30% were used to internally validate the model. Candidate predictors were limited to those associated with cesarean delivery and were available to a practitioner at time of induction. Stepwise backward logistic regression was used to build the most parsimonious model predicting cesarean delivery. Hosmer-Lemeshow test was used to assess goodness-of-fit. Model discrimination was evaluated using the concordance index and displayed through the area under the receiver operating characteristic curve (AUC). RESULTS: Of the 1,357 women meeting study criteria, 974 (71.8%) had a vaginal delivery. The final model consisted of eight variables: maternal age, body mass index, gestational age, intrapartum magnesium sulfate for seizure prophylaxis, need for cervical ripening, prior cesarean delivery and cervical dilation, and effacement. Model calibration and discrimination were satisfactory with Hosmer-Lemeshow test P=.35 and with a 95% CI, an AUC of 0.76 (0.73-0.79). Among those with predicted probability of cesarean delivery of 20% or less, 89.5% had a vaginal delivery. Internal validation demonstrated similar discriminatory ability. CONCLUSION: Using information available before labor induction, and contingent on future external validation, our model can help women better understand their likelihood of vaginal delivery success when undergoing induction of labor for hypertensive disorders of pregnancy.

Graft Detachment Pattern After Descemet Membrane Endothelial Keratoplasty Comparing Air Versus 20% SF6 Tamponade.

PURPOSE: The change from air to 20% sulfur hexafluoride (SF6) as anterior chamber tamponade for Descemet membrane endothelial keratoplasty (DMEK) significantly reduced the rebubbling rate. Nonetheless, underlying mechanisms are not completely understood. In this study, we investigate the morphology of graft detachments after DMEK depending on the tamponade and its influence on postoperative rebubbling. METHODS: In this retrospective analysis of prospective data of 204 consecutive patients who underwent DMEK with 100% air, or 20% SF6, we compared the SF6 group with the air group regarding the number, lateral and axial diameter and localization of detachments, visual acuity (BSCVA), and incidence of rebubbling after 1 week (T1), after 1 (T2), 3 (T3), 6 (T4), and 12 (T5) months postoperatively. RESULTS: The air group showed more detachments at all time points. Detachments in this group were of a larger axial diameter at T1, T4, and T5 and of a larger lateral diameter at T1, T3, T4, and T5 compared with the SF6 group. Patients receiving SF6 needed fewer rebubblings at T1 compared with patients receiving air (12.1% vs. 29.1%, P = 0.003), but not at T2 (15.1% vs. 19.1%, P = 0.56). There was no difference in postoperative BSCVA between the groups. CONCLUSIONS: Early graft attachment after DMEK, which is improved by the use of SF6 as anterior chamber tamponade, is important for the overall rebubbling rate and improves wound-healing mechanisms between the graft and recipient cornea. Faster resolving air tamponade is associated with extended detachments especially inferiorly and mid-peripherally, but has no negative effect on the long-term BSCVA.

Attempted and Successful Vacuum-Assisted Vaginal Delivery by Prepregnancy Body Mass Index.

OBJECTIVE: To examine rates of attempted and successful vacuum-assisted vaginal delivery by prepregnancy body mass index (BMI). METHODS: We conducted a retrospective cohort study of 2,084 women with singleton gestations needing operative delivery assistance and vacuum-eligible (fully dilated, +2 station or greater, 34 weeks of gestation or greater) using 2006-2014 inpatient records. Prepregnancy BMI was categorized as underweight (less than 18.5), normal weight (18.5 to less than 25), overweight (25 to less than 30), or obese (30 or greater). Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of attempted and successful vacuum-assisted vaginal delivery by prepregnancy BMI adjusted for age, race, marital status, parity, diabetes, labor induction-augmentation, episiotomy, gestational age, and neonatal birth weight. RESULTS: Thirty-nine percent of women requiring delivery assistance and eligible for a vacuum were overweight or obese, 79% had vacuum attempts, and 95.3% of attempted vacuum-assisted vaginal deliveries were successful. Compared with women who were normal weight prepregnancy (82.8%), women who were overweight or obese were less likely to have vacuum attempted (75.8%, OR 0.71, 95% CI 0.53-0.96 and 71.2%, OR 0.53, 95% CI 0.39-0.74, respectively). Among women with attempted vacuum-assisted vaginal delivery, successful delivery did not differ by prepregnancy BMI (92.6%, OR 0.54, 95% CI 0.21-1.37 for underweight; 94.5%, OR 1.07, 95% CI 0.57-2.00 for overweight; 96.3%, OR 1.09, 95% CI 0.51-2.33 for obese compared with 95.6% among normal-weight women). CONCLUSION: Among women in need of operative delivery assistance, prepregnancy obesity was associated with lower likelihood of attempted vacuum-assisted vaginal delivery but, if attempted, success rates were similar to rates among normal-weight women. With significant morbidity of second-stage cesarean delivery in obese women, research should examine whether vacuum-assisted vaginal delivery may be appropriate for additional obese patients.

Ca2+/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in Testosterone-Induced Cardiac Myocyte Hypertrophy.

Testosterone is known to induce cardiac hypertrophy through androgen receptor (AR)-dependent and -independent pathways, but the molecular underpinnings of the androgen action remain poorly understood. Previous work has shown that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and myocyte-enhancer factor 2 (MEF2) play key roles in promoting cardiac myocyte growth. In order to gain mechanistic insights into the action of androgens on the heart, we investigated how testosterone affects CaMKII and MEF2 in cardiac myocyte hypertrophy by performing studies on cultured rat cardiac myocytes and hearts obtained from adult male orchiectomized (ORX) rats. In cardiac myocytes, MEF2 activity was monitored using a luciferase reporter plasmid, and the effects of CaMKII and AR signaling pathways on MEF2C were examined by using siRNAs and pharmacological inhibitors targeting these two pathways. In the in vivo studies, ORX rats were randomly assigned to groups that were administered vehicle or testosterone (125 mg⋅kg-1⋅week-1) for 5 weeks, and plasma testosterone concentrations were determined using ELISA. Cardiac hypertrophy was evaluated by measuring well-characterized hypertrophy markers. Moreover, western blotting was used to assess CaMKII and phospholamban (PLN) phosphorylation, and MEF2C and AR protein levels in extracts of left-ventricle tissue from control and testosterone-treated ORX rats. Whereas testosterone treatment increased the phosphorylation levels of CaMKII (Thr286) and phospholambam (PLN) (Thr17) in cardiac myocytes in a time- and concentration-dependent manner, testosterone-induced MEF2 activity and cardiac myocyte hypertrophy were prevented upon inhibition of CaMKII, MEF2C, and AR signaling pathways. Notably, in the hypertrophied hearts obtained from testosterone-administered ORX rats, both CaMKII and PLN phosphorylation levels and AR and MEF2 protein levels were increased. Thus, this study presents the first evidence indicating that testosterone activates MEF2 through CaMKII and AR signaling. Our findings suggest that an orchestrated mechanism of action involving signal transduction and transcription pathways underlies testosterone-induced cardiac myocyte hypertrophy.

Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake­via AMP-activated protein kinase (AMPK)­after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.