hMG addition affects the change in progesterone level during IVF stimulation and LBR: a retrospective cohort study.

BACKGROUND: Premature progesterone (P) rise during IVF stimulation reduces endometrial receptivity and is associated with lower pregnancy rates following embryo transfer (ET), which can influence provider recommendation for fresh or frozen ET. This study aimed to determine whether change in P level between in IVF baseline and trigger (𝚫P) is predictive of pregnancy outcome following fresh ET, and whether the ratio of gonadotropins influences P rise and, as a result, clinical pregnancy outcomes: clinical pregnancy rate (CPR) and live birth rates (LBR). METHODS: Retrospective cohort study at a single fertility center at an academic institution. The peak P level and 𝚫P were modeled in relation to prediction of CPR and LBR, and the ratios of hMG:rFSH were also modeled in relation to prediction of peak P level on day of trigger, 𝚫P, and CPR/LBR in a total of 291 patients undergoing fresh embryo transfer after controlled ovarian hyperstimulation-IVF (COH-IVF). RESULTS: 𝚫P correlates with CPR, with the most predictive range for success as 𝚫P 0.7-0.85 ng/mL (p = 0.005, 95% CI 0.635, 3.636; predicting CPR of 88.9%). The optimal range for peak P in regard to pregnancy outcome was 0.15-1.349 ng/mL (p = 0.01; 95% CI for coefficient in model 0.48-3.570). A multivariable logistic model for prediction of CPR and LBR using either peak or 𝚫P supported a stronger association between 𝚫P and CPR/LBR as compared to peak P. Furthermore, an hMG:rFSH ratio of > 0.6 was predictive of lowest peak P (p = 0.010, 95% CI 0.035, 0.256) and smallest 𝚫P (p = 0.012, 95% CI 0.030, 0.243) during COH-IVF cycles. Highest CPRs were observed within hMG:rFSH ratios of 0.3-0.4 [75.6% vs. 62.5% within and outside of the range, respectively, (p = 0.023, 95% CI 0.119, 1.618)]. Highest LBRs were seen within the range of 0.3-0.6 hMG:rFSH, [LBR of 55.4% vs. 41.4% (p = 0.010, 95% CI 0.176, 1.311)]. CONCLUSIONS: Our data supports use of 𝚫P to best predict pregnancy rates and therefore can improve clinical decision making as to when fresh ET is most appropriate. Furthermore, we found optimal gonadotropin ratios can be considered to minimize P rise and to optimize CPR/LBR, emphasizing the importance of luteinizing hormone (LH) activity in COH-IVF cycles.

In Vitro Gametogenesis in Oncofertility: A Review of Its Potential Use and Present-Day Challenges in Moving toward Fertility Preservation and Restoration.

Current fertility preservation options are limited for cancer survivor patients who wish to have their own biological children. Human in vitro gametogenesis (IVG) has the hypothetical ability to offer a unique solution to individuals receiving treatment for cancer which subsequently shortens their reproductive lifespan. Through a simple skin punch biopsy, a patient's fertility could be restored via reprogramming of dermal fibroblast cells to induced pluripotent stem cells, then from primordial germ cell-like cells into viable oocytes and spermatocytes which could be used for embryogenesis. Induced pluripotent stem cells could also be used to form in vitro environments, similar to the ovary or testes, necessary for the maturation of oogonia. This would allow for the entire creation of embryos outside the body, ex vivo. While this area in stem cell biology research offers the potential to revolutionize reproduction as we know it, there are many critical barriers, both scientific and ethical, that need to be overcome to one day see this technology utilized clinically.

Recent advances in understanding primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is an uncommon yet devastating occurrence that results from a premature depletion of the ovarian pool of primordial follicles. Our understanding of both putative and plausible mechanisms underlying POI, previously considered to be largely "idiopathic", has been furthered over the past several years, largely due to advances in the field of genetics and through expansion of translational models for experimental research. In this review, our goal is to familiarize the multidisciplinary readers of the F1000 platform with the strides made in the field of reproductive medicine that hold both preventative and therapeutic implications for those women who are at risk for or who have POI.

Emerging roles for noncoding RNAs in female sex steroids and reproductive disease.

The "central dogma" of molecular biology, that is, that DNA blueprints encode messenger RNAs which are destined for translation into protein, has been challenged in recent decades. In actuality, a significant portion of the genome encodes transcripts that are transcribed into functional RNA. These noncoding RNAs (ncRNAs), which are not transcribed into protein, play critical roles in a wide variety of biological processes. A growing body of evidence derived from mouse models and human data demonstrates that ncRNAs are dysregulated in various reproductive pathologies, and that their expression is essential for female gametogenesis and fertility. Yet in many instances it is unclear how dysregulation of ncRNA expression leads to a disease process. In this review, we highlight new observations regarding the roles of ncRNAs in the pathogenesis of disordered female steroid hormone production and disease, with an emphasis on long noncoding RNAs (lncRNAs) and microRNAs (miRNAs). We will focus our discussion in the context of three ovarian disorders which are characterized in part by altered steroid hormone biology - diminished ovarian reserve, premature ovarian insufficiency, and polycystic ovary syndrome. We will also discuss the limitations and challenges faced in studying noncoding RNAs and sex steroid hormone production. An enhanced understanding of the role of ncRNAs in sex hormone regulatory networks is essential in order to advance the development of potential diagnostic markers and therapeutic targets for diseases, including those in reproductive health. Our deepened understanding of ncRNAs has the potential to uncover new applications and therapies; however, in many cases, the next steps will involve distinguishing critical ncRNAs from those which are merely changing in response to a particular disease state, or which are altogether unrelated to disease pathophysiology.

The Role of Callous-Unemotional Traits on Adolescent Positive and Negative Emotional Reactivity: A Longitudinal Community-Based Study.

Callous-unemotional (CU) traits are associated with lower emotional reactivity in adolescents. However, since previous studies have focused mainly on reactivity to negative stimuli, it is unclear whether reactivity to positive stimuli is also affected. Further, few studies have addressed the link between CU traits and emotional reactivity in longitudinal community samples, which is important for determining its generalizability and developmental course. In the current study, pupil dilation and self-ratings of arousal and valence were assessed in 100 adolescents (15-17 years) from a community sample, while viewing images with negative and positive valence from the International Affective Pictures System (IAPS). Behavioral traits (CU) were assessed concurrently, as well as at ages 12-15, and 8-9 (subsample, n = 68, low levels of prosocial behavior were used as a proxy for CU traits). The results demonstrate that CU traits assessed at ages 12-15 and 8-9 predicted less pupil dilation to both positive and negative images at ages 15-17. Further, CU traits at ages 12-15 and concurrently were associated with less negative valence ratings for negative images and concurrently to less positive valence ratings for positive images. The current findings demonstrate that CU traits are related to lower emotional reactivity to both negative and positive stimuli in adolescents from a community sample.

Implementation and Outcomes of Universal Delayed Umbilical Cord Clamping at Term.

OBJECTIVE: To evaluate the implementation of an institutional protocol for universal delayed umbilical cord clamping (DCC) at term on maternal, neonatal, and umbilical cord blood gas outcomes. STUDY DESIGN: This is a retrospective cohort study of singleton term gestations from April through July 2017. On June 1, 2017, a protocol was implemented for DCC in all deliveries. Outcomes were compared between patients delivered prior to and those delivered after implementation. The primary outcome was postpartum hemorrhage (PPH). Secondary outcomes were additional adverse maternal, neonatal, and umbilical cord blood gas outcomes. Multivariable logistic regression was used to adjust for potential confounders. RESULTS: Of 682 patients, 341 were delivered preprotocol and 341 were delivered postprotocol. After implementation, there was 91.8% adherence to the protocol. Overall, there was no significant difference in PPH between patients delivered preprotocol and those delivered postprotocol (8.2 vs. 13.2%; adjusted relative risk [aRR]: 1.26, 95% confidence interval [CI]: 0.98-1.51). There was a significant decrease in the ability to obtain paired arterial and venous umbilical cord blood gases from preprotocol to postprotocol (83 vs. 63.6%; aRR: 0.62 [95% CI: 0.50-0.76]). There were no significant differences in abnormal umbilical cord blood gases or neonatal outcomes. CONCLUSION: We did not find an increased risk of adverse outcomes associated with the widespread use of DCC.

The Role of Patient Advocacy and the Declining Rate of Clitoroplasty in 46,XX Patients With Congenital Adrenal Hyperplasia.

Prior to the 1990s, most 46,XX infants with clitoromegaly secondary to congenital adrenal hyperplasia were treated with feminizing genitoplasty to make their cosmetic appearance congruent with their genotypic sex. A 2006 consensus statement for the management of intersex disorders accepted input from patient advocates and did not support purely cosmetic surgery for clitoromegaly. This study examined the extent to which the desired change was implemented in practice. Retrospective chart review was performed at a single Midwestern tertiary care medical center for patients born between 1979 and 2013. Of 45 virilized patients, 40 had clitoromegaly and 39 had urogenital sinus or posterior labial fusion. Twenty-seven (67.5%) patients underwent clitoroplasty and 33 (84.6%) underwent perineoplasty, including vaginoplasty, urethroplasty, imperforate vagina repair, and/or posterior labial fusion repair. There was a linear decline in the rate of clitoroplasty over time for the patient cohort. This study demonstrates the power of patient advocacy to improve medical practice.

Neonatal Morbidity in the Offspring of Obese Women Without Hypertension or Diabetes.

OBJECTIVE: To compare the independent risk of neonatal morbidity between the offspring of obese and nonobese women without hypertension or diabetes. METHODS: This is a secondary analysis of a prospective single-center cohort study of singleton deliveries at or beyond 37 weeks of gestation from 2010 to 2014. Women with diabetes (pregestational or gestational) and hypertensive disorders were excluded. The primary outcomes were 1) a composite neonatal morbidity including death, mechanical ventilation, respiratory distress, meconium aspiration, suspected sepsis, confirmed sepsis, hypoxic-ischemic encephalopathy, therapeutic hypothermia, or seizures; and 2) a composite of neonatal neurologic morbidity including hypoxic-ischemic encephalopathy, therapeutic hypothermia, or seizures. The primary outcomes were compared between the offspring of obese (body mass index 30 or greater) and nonobese women. Adjusted odds ratios (ORs) were estimated using multivariable logistic regression. RESULTS: Of 6,458 women without diabetes or hypertensive disorders, 3,311 (51%) were obese. After adjusting for race, neonates of obese patients were at significantly increased risk for the composite neonatal morbidity (9.2% vs 7.2%, adjusted OR 1.39, 95% CI 1.15-1.67) and neurologic neonatal morbidity (0.7% vs 0.3%, adjusted OR 2.84, 95% CI 1.22-6.65). Specifically, neonates of obese patients were more likely to have hypoxic-ischemic encephalopathy (0.5% vs 0.2%, adjusted OR 2.80, 95% CI 1.02-7.68), hypothermia treatment (0.6% vs 0.2%, adjusted OR 2.92 95% CI 1.17-7.30), and suspected sepsis (7.6% vs 5.8%, adjusted OR 1.45, 95% CI 1.18-1.79). CONCLUSION: In patients who labor, maternal obesity is an independent risk factor for significant neonatal morbidity, even in the absence of hypertensive disorders or diabetes.

Behavioral interventions for reducing head motion during MRI scans in children.

A major limitation to structural and functional MRI (fMRI) scans is their susceptibility to head motion artifacts. Even submillimeter movements can systematically distort functional connectivity, morphometric, and diffusion imaging results. In patient care, sedation is often used to minimize head motion, but it incurs increased costs and risks. In research settings, sedation is typically not an ethical option. Therefore, safe methods that reduce head motion are critical for improving MRI quality, especially in high movement individuals such as children and neuropsychiatric patients. We investigated the effects of (1) viewing movies and (2) receiving real-time visual feedback about head movement in 24 children (5-15 years old). Children completed fMRI scans during which they viewed a fixation cross (i.e., rest) or a cartoon movie clip, and during some of the scans they also received real-time visual feedback about head motion. Head motion was significantly reduced during movie watching compared to rest and when receiving feedback compared to receiving no feedback. However, these results depended on age, such that the effects were largely driven by the younger children. Children older than 10 years showed no significant benefit. We also found that viewing movies significantly altered the functional connectivity of fMRI data, suggesting that fMRI scans during movies cannot be equated to standard resting-state fMRI scans. The implications of these results are twofold: (1) given the reduction in head motion with behavioral interventions, these methods should be tried first for all clinical and structural MRIs in lieu of sedation; and (2) for fMRI research scans, these methods can reduce head motion in certain groups, but investigators must keep in mind the effects on functional MRI data.

Risk association of congenital anomalies in patients with ambiguous genitalia: A 22-year single-center experience.

BACKGROUND: Ambiguous genitalia refers to a form of differences of sex development (DSD) wherein the appearance of the external genitalia is atypical. This rare condition presents challenges in decision-making and clinical management. Review of historical data may reveal areas for clinical research to improve care for patients with ambiguous genitalia. OBJECTIVE: This chart review was performed to identify patients with ambiguous genitalia, and to classify them as having 46,XX DSD, 46,XY DSD, or sex chromosome DSD. Within these categories, we looked at establishment of specific diagnoses, type and frequency of other congenital anomalies and neoplasms, and gender assignment, as well as incidence of gender reassignment and transition. METHODS: We performed a retrospective chart review of patients diagnosed with DSD conditions from 1995 to 2016 using ICD9 codes. For the purpose of this study, review was limited to individuals assessed to have neonatal "ambiguous genitalia" or "indeterminate sex." RESULTS: Review identified 128 patients evaluated for ambiguous genitalia from 22 years of experience (Figure). Approximately half of these (53%) had 46,XY karyotype, 35% had 46,XX, and the remaining 12% had sex chromosome aberrations. Diagnostic rate for 46,XX DSD was higher at 64%, all of which were congenital adrenal hyperplasia, while diagnostic rate for 46,XY DSD was 11.7% for a molecularly confirmed diagnosis and 24% if clinical diagnoses were included. The most common anomalies included cardiac anomalies in 28/128 (22%), skeletal anomalies in 19/128 (15%), and failure to thrive or growth problems in 19/128 (15%). Additional congenital anomalies were found in 53 out of 128 patients (41%). There were three reported neoplasms in this group: gonadoblastoma, hepatoblastoma, and myelodysplastic syndrome with monosomy 7. Gender assignment was consistent with chromosomes in approximately 90% of XX and XY patients. There were three recorded gender reassignments or transitions. DISCUSSION: Diagnostic rate for ambiguous genitalia is low, especially in 46,XY DSD. Most neonates were assigned gender consistent with their chromosomes. Given the high rate of associated anomalies, screening for cardiac or other anomalies in patients with ambiguous genitalia may be beneficial. CONCLUSION: Patients with ambiguous genitalia often have additional congenital anomalies. Establishment of a specific diagnosis is uncommon in 46,XY patients. A few patients have gender reassignment outside of the newborn period. Ongoing collection of clinical data on this population may reveal new information regarding long-term health, quality of life, and establishment of more diagnoses with improved molecular techniques.

Real-time motion analytics during brain MRI improve data quality and reduce costs.

Head motion systematically distorts clinical and research MRI data. Motion artifacts have biased findings from many structural and functional brain MRI studies. An effective way to remove motion artifacts is to exclude MRI data frames affected by head motion. However, such post-hoc frame censoring can lead to data loss rates of 50% or more in our pediatric patient cohorts. Hence, many scanner operators collect additional 'buffer data', an expensive practice that, by itself, does not guarantee sufficient high-quality MRI data for a given participant. Therefore, we developed an easy-to-setup, easy-to-use Framewise Integrated Real-time MRI Monitoring (FIRMM) software suite that provides scanner operators with head motion analytics in real-time, allowing them to scan each subject until the desired amount of low-movement data has been collected. Our analyses show that using FIRMM to identify the ideal scan time for each person can reduce total brain MRI scan times and associated costs by 50% or more.

Callous-unemotional traits affect adolescents' perception of collaboration.

BACKGROUND: How is the perception of collaboration influenced by individual characteristics, in particular high levels of callous-unemotional (CU) traits? CU traits are associated with low empathy and endorsement of negative social goals such as dominance and forced respect. Thus, it is possible that they could relate to difficulties in interpreting that others are collaborating based on a shared goal. METHODS: In the current study, a community sample of 15- to 16-year olds participated in an eye tracking task measuring whether they expect that others engaged in an action sequence are collaborating, depending on the emotion they display toward each other. Positive emotion would indicate that they share a goal, while negative emotion would indicate that they hold individual goals. RESULTS: When the actors showed positive emotion toward each other, expectations of collaboration varied with CU traits. The higher adolescents were on CU traits, the less likely they were to expect collaboration. When the actors showed negative emotion toward each other, CU traits did not influence expectations of collaboration. CONCLUSIONS: The findings suggest that CU traits are associated with difficulty in perceiving positive social interactions, which could further contribute to the behavioral and emotional problems common to those with high CU traits.

Pupillary Contagion in Infancy: Evidence for Spontaneous Transfer of Arousal.

Pupillary contagion-responding to pupil size observed in other people with changes in one's own pupil-has been found in adults and suggests that arousal and other internal states could be transferred across individuals using a subtle physiological cue. Examining this phenomenon developmentally gives insight into its origins and underlying mechanisms, such as whether it is an automatic adaptation already present in infancy. In the current study, 6- and 9-month-olds viewed schematic depictions of eyes with smaller and larger pupils-pairs of concentric circles with smaller and larger black centers-while their own pupil sizes were recorded. Control stimuli were comparable squares. For both age groups, infants' pupil size was greater when they viewed large-center circles than when they viewed small-center circles, and no differences were found for large-center compared with small-center squares. The findings suggest that infants are sensitive and responsive to subtle cues to other people's internal states, a mechanism that would be beneficial for early social development.