Uterine macrophages and NK cells exhibit population and gene-level changes after implantation but maintain pro-invasive properties.

Introduction: Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells. Methods: With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy. Results: We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC. Conclusions: This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.

Type I interferon alters invasive extravillous trophoblast function.

Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluated the consequence of elevated type I IFN exposure on implantation using a biomimetic model of human implantation in an organ-on-a-chip device. We found that type I IFN reduced extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes, we uncovered that IFN truncated endovascular EVT emergence in the implantation-on-a-chip device by stunting EVT epithelial-to-mesenchymal transition. Disruptions to the epithelial-to-mesenchymal transition is associated with the pathogenesis of preeclampsia, a life-threatening hypertensive disorder of pregnancy. Strikingly, unwarranted IFN stimulation induced genes associated with increased preeclampsia risk and a preeclamptic gene-like signature in EVTs. These dysregulated EVT phenotypes ultimately reduced EVT-mediated endothelial cell vascular remodeling in the implantation-on-a-chip device. Overall, our work indicates IFN signaling can alter EVT epithelial-to-mesenchymal transition progression which results in diminished EVT-mediated spiral artery remodeling and a preeclampsia gene signature upon sustained stimulation. Our work implicates unwarranted type I IFN as a maternal disturbance that can result in abnormal EVT function that could trigger preeclampsia.

Elevated antimüllerian hormone levels are not associated with preterm delivery after in vitro fertilization or ovulation induction.

OBJECTIVE: To investigate the association between antimüllerian hormone (AMH) and preterm birth risk in a larger cohort of patients who underwent either in vitro fertilization or ovulation induction with intrauterine insemination at a US academic fertility center. DESIGN: Retrospective cohort study. SETTING: Single academic fertility center. PATIENT(S): Live singleton births from patients who underwent in vitro fertilization or ovulation induction between 2016 and 2020 at a single academic fertility center were included in this study. Patients were excluded if they had a missing prepregnancy AMH level, a pregnancy using donor oocytes or a gestational carrier, multiple gestations, a delivery before 20 weeks gestation, or a cerclage in place. INTERVENTION(S): AMH level. MAIN OUTCOME MEASURE(S): The primary outcome was the proportion of preterm delivery. Secondary outcomes included the rate of pregnancy-induced hypertension, gestational diabetes, and small for gestational age. RESULT(S): In the entire cohort (n = 875), 8.4% of deliveries were preterm. The mean AMH values were similar between those with term and preterm births (3.9 vs. 4.2 ng/mL). Similar proportions of patients with term and preterm deliveries had AMH levels greater than the 75th percentile (25% vs. 21%). The odds of preterm birth were similar by AMH quartile after adjusting for the history of preterm birth. Similarly, in the polycystic ovary syndrome (PCOS) cohort, there was no difference between mean AMH values of term and preterm births (n = 139, 9.6 vs. 10.0 ng/mL). The proportions of patients with PCOS with AMH levels greater than the 75th percentile were similar between those with term and preterm deliveries (25% vs. 22%). The odds of preterm birth were similar by the AMH quartile after adjusting for the history of preterm birth. CONCLUSION(S): Elevated AMH levels were not associated with an increased risk of preterm birth in patients who conceived after in vitro fertilization and ovulation induction, including patients with PCOS. Although studies suggest that AMH levels may help stratify the risk of preterm birth in this population, our findings indicate that further studies are needed before clinical application.

Progression of depression and anxiety symptoms in pregnancies conceived by assisted reproductive technology in the United States.

PURPOSE: Women who utilize assisted-reproductive technology (ART) to achieve pregnancy experience unique circumstances before and during their pregnancy. This study aims to examine the progression of mental health in pregnant women who conceived via various methods of ART to understand gestational time periods of emotional stability or risk specific to these populations. METHODS: Secondary analysis of the Yale Pink and Blue Study - a prospective cohort involving women from 137 obstetrical practices in the northeastern United States between 2005-2009. Depressive and anxiety symptoms among spontaneous, planned pregnancies were compared to ART pregnancies using the Edinburgh Postnatal Depression Scale (EPDS) and its anxiety subscale (EPDS-3A), respectively. Generalized Estimating Equations were used to compare group changes (EPDS and EPDS-3A score threshold ≥10) at timepoints of <17 weeks (T1), 28(±2) weeks (T2), and 8(±4) weeks postpartum (T3). RESULTS: 1,466 spontaneous, planned pregnancies were compared to 191 pregnancies conceived via ART. Prevalence of depressive symptoms were similar between conception groups. Change in prevalence over time differed significantly between those groups (from T1 to T3 (ß 0.59), as well as between spontaneous pregnancies compared to autologous gamete ART pregnancies (from T1 to T2 (ß 0.48) and T1 to T3 (ß 0.65). Course of anxiety did not differ between conception groups. CONCLUSIONS: Women who conceive via ART have different rates of change in depressive symptoms throughout gestation compared to women with spontaneous pregnancies.

Premenstrual disorders.

Premenstrual disorders include premenstrual syndrome, premenstrual dysphoric disorder, and premenstrual worsening of another medical condition. While the underlying causes of these conditions continue to be explored, an aberrant response to hormonal fluctuations that occurs with the natural menstrual cycle and serotonin deficits have both been implicated. A careful medical history and daily symptom monitoring across 2 menstrual cycles is important in establishing a diagnosis. Many treatments have been evaluated for the management of premenstrual disorders. The most efficacious treatments for premenstrual syndrome and premenstrual dysphoric disorder include serotonin reuptake inhibitors and contraceptives with shortened to no hormone-free interval. Women who do not respond to these and other interventions may benefit from gonadotropin-releasing hormone agonist treatment.

Women's career priority is associated with attitudes towards family planning and ethical acceptance of reproductive technologies.

STUDY QUESTION: Do women who place high importance on career success have different perceptions of pregnancy planning, delayed reproduction, and the ethical acceptability of ART than women with less emphasis on their career? SUMMARY ANSWER: Career-focused women place more importance on pregnancy planning, have greater confidence in delayed childbearing, and are more ethically accepting of donor gamete ART than women who do not place as much importance on career success. WHAT IS KNOWN ALREADY: Women in high-professional careers are more likely to delay childbearing while simultaneously possessing a stronger desire for motherhood. The underlying values which enable these competing desires have not been elucidated. STUDY DESIGN, SIZE, DURATION: This cross-sectional study utilized data from the National Survey of Fertility Barriers (NSFB), a nationally representative telephone survey of US women aged 25-45. Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NSFB surveyed 4712 women from 2004 to 2007. PARTICIPANTS/MATERIALS, SETTING, METHODS: In addition to demographic data, the NSFB obtained information about the reproductive history and personal values of participants. Weighted multivariate regression analysis was used to assess reproductive values in career-focused women. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 48.8% of women considered success in work very important, while 17.3% considered it somewhat or not important. Women who placed less value on career success were less likely to consider pregnancy planning important and were less optimistic about the success of delayed childbearing than their work-centric counterparts. Women less focused on their careers were also more likely to have serious ethical concerns about donor gametes, but less likely to have ethical concerns about IUI or IVF, when compared to career-focused women. LIMITATIONS, REASONS FOR CAUTION: Intention to bear children could not be evaluated in the setting of career intentions due to a lack of data on when the participant intended on pursuing motherhood. Political preferences on reproductive health were also not evaluated. The validity of the career priority questions has not been assessed. Additionally, respondents' value statements were not matched to subsequent actions, so it remains possible that these values do not directly impact reproductive behaviors. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that reproductive counseling for career-focused women should focus on effective contraception when attempting to delay pregnancy, improved knowledge about age-related fertility decline, and the scope and limitations of current reproductive technologies. In addition, the unique reproductive views of career-focused women suggest that they may benefit from increased employer/insurer support for strategies to enable delayed childbearing, such as fertility preservation and third-party reproduction. STUDY FUNDING/COMPETING INTEREST(S): None.

Zika virus infection of Hofbauer cells.

Recent studies have linked antenatal infection with Zika virus (ZIKV) with major adverse fetal and neonatal outcomes, including microcephaly. There is a growing consensus for the existence of a congenital Zika syndrome (CZS). Previous studies have indicated that non-placental macrophages play a key role in the replication of dengue virus (DENV), a closely related flavivirus. As the placenta provides the conduit for vertical transmission of certain viruses, and placental Hofbauer cells (HBCs) are fetal-placental macrophages located adjacent to fetal capillaries, it is not surprising that several recent studies have examined infection of HBCs by ZIKV. In this review, we describe congenital abnormalities associated with ZIKV infection, the role of HBCs in the placental response to infection, and evidence for the susceptibility of HBCs to ZIKV infection. We conclude that HBCs may contribute to the spread of ZIKV in placenta and promote vertical transmission of ZIKV, ultimately compromising fetal and neonatal development and function. Current evidence strongly suggests that further studies are warranted to dissect the specific molecular mechanism through which ZIKV infects HBCs and its potential impact on the development of CZS.

Zika virus productively infects primary human placenta-specific macrophages.

The strong association of Zika virus infection with congenital defects has led to questions of how a flavivirus is capable of crossing the placental barrier to reach the fetal brain. Here, we demonstrate permissive Zika virus infection of primary human placental macrophages, commonly referred to as Hofbauer cells, and placental villous fibroblasts. We also demonstrate Zika virus infection of Hofbauer cells within the context of the tissue ex vivo using term placental villous explants. In addition to amplifying infectious virus within a usually inaccessible area, the putative migratory activities of Hofbauer cells may aid in dissemination of Zika virus to the fetal brain. Understanding the susceptibility of placenta-specific cell types will aid future work around and understanding of Zika virus-associated pregnancy complications.

Surgical management of osteochondritis dissecans lesions of the patella and trochlea in the pediatric and adolescent population.

BACKGROUND: There is a paucity of published data regarding the management of osteochondritis dissecans (OCD) lesions of the patellofemoral joint in children and adolescents. PURPOSE: To evaluate the functional outcomes of surgical management of OCD lesions of the patella and trochlea in children and adolescents. Secondary aims included elucidating predictors for higher functional outcomes and determining complication rates, surgical satisfaction, and ability to return to sports. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients aged 18 years and younger who were surgically treated for OCD of the patella or trochlea were identified. Charts were queried to record patient/lesion data, surgical procedure, results, and complications. Pre- and postoperative imaging was reviewed. Patients were asked to complete a follow-up athletic questionnaire and a Pediatric International Knee Documentation Committee (Pedi-IKDC) questionnaire. Statistical analysis was conducted to look for predictors for reoperation, residual pain, ability to return to sports, and lower Pedi-IKDC scores. RESULTS: A total of 26 children (9 females, 17 males, 3 with bilateral lesions; thus, 29 lesions) were identified. The mean age was 14.7 years (range, 9-18, years), 21 of the 29 knees with lesions (72%) had open physes, and median follow-up was 3.8 years (range, 1-9 years). The most common location was the trochlea (17/29 lesions; 59%). Twenty-two lesions (76%) underwent transarticular drilling (n = 14) or drilling with fixation (n = 8), while 7 underwent excision and marrow stimulation. Four patients (14%) required unplanned reoperation. Internal fixation was predictive of reoperation (odds ratio [OR] = 8.7; 95% CI, 2.8-26.9; P = .04). At final follow-up, 14 knees (48%) were pain free, and 14 (48%) had mild residual pain. Female sex was predictive of residual pain (OR, 9; 95% CI, 2-56; P = .02). Twenty-two patients (85%) returned to sports. Longer duration of preoperative pain negatively affected return to sports (OR, 0.32; 95% CI, 0.05-0.97; P = .04). On postoperative MRI, the lesion appeared completely healed in 2 cases (18%) and partially healed in 9 cases (82%). All 15 survey respondents were satisfied with surgery. The mean Pedi-IKDC score was 82.4 ± 17.8 (range, 40.2-100). CONCLUSION: Surgical treatment of patellofemoral OCD in children and adolescents produces a high rate of satisfaction and return to sports. Female sex, prolonged duration of symptoms, and internal fixation may be associated with worse outcomes.

Horizontal intra-articular patellar dislocation resulting in quadriceps avulsion and medial patellofemoral ligament tear: a case report.

Intra-articular patellar dislocations are rare. We present a 13-year-old boy who sustained a complete horizontal intra-articular patellar dislocation following blunt trauma to the flexed knee. Closed reduction was unsuccessful and open reduction indicated a repairable quadriceps avulsion and medial patellofemoral ligament tear. He is the youngest patient to sustain a quadriceps rupture and the only patient to sustain a medial patellofemoral ligament tear to date. His flexed knee and the horizontally positioned patella (seen on lateral radiograph) were indicative of a complete rotational injury with extensor mechanism involvement. Open reduction allowed for the repair of both injuries and a favorable outcome.

Scaled cortical impact in immature swine: effect of age and gender on lesion volume.

The piglet scaled cortical impact model creates a focal contusion using a skull-mounted, spring-loaded blunt indentation device scaled to achieve identical tissue strains in subjects with different brain sizes. Preliminary data showed that contusion size increased proportional to subject age. This study details the results from a new, larger series of subjects of three ages, and compares the effect of age and additional host and physiologic variables on injury response. Sixty-seven subjects, including infant (5- to 7-day-old), "toddler" (1-month-old), and early adolescent (4-month-old) swine underwent scaled cortical impact under strict anesthetic protocols. Serum glucose, testosterone, and 17beta-estradiol levels were measured. Lesion size was measured at 1 week post injury, as the ratio of the lesion area over the area of the contralateral hemisphere. Adolescent subjects had lesions over eight times larger than infants (p < 0.0001). Lesion volumes were larger in toddlers than in infants, most significantly for males (p < 0.05). Adolescent subjects were warmer on average, but there was no correlation between temperature and lesion volume within any age group. Serum glucose did not differ among ages. Infant males had the highest levels of circulating sex steroids. In this model, age was the most robust predictor of lesion size. Temperature had an effect, but did not explain all the variability seen among age groups. There was an interaction among gender, hormone levels, and lesion size in younger subjects. Characterization of these variables allows use of this model for treatment trials for subjects at different stages of maturation.

Elevations of endogenous kynurenic acid produce spatial working memory deficits.

Kynurenic acid (KYNA) is a tryptophan metabolite that is synthesized and released by astrocytes and acts as a competitive antagonist of the glycine site of N-methyl-D-aspartate receptors at high concentrations and as a noncompetitive antagonist of the alpha7-nicotinic acetylcholine receptor at low concentrations. The discovery of increased cortical KYNA levels in schizophrenia prompted the hypothesis that elevated KYNA concentration may underlie the working memory dysfunction observed in this population that has been attributed to altered glutamatergic and/or cholinergic transmission. The present study investigated the effect of elevated endogenous KYNA on spatial working memory function in rats. Increased KYNA levels were achieved with intraperitoneal administration of kynurenine (100 mg/kg), the precursor of KYNA synthesis. Rats were treated with either kynurenine or a vehicle solution prior to testing in a radial arm maze task at various delays. Elevations of endogenous KYNA resulted in increased errors in the radial arm maze. In separate experiments, assessment of locomotor activity in an open field and latency to retrieve food reward from one of the maze arms ruled out the possibility that deficits in the maze were attributable to altered locomotor activity or motivation to consume food. These results provide evidence that increased KYNA levels produce spatial working memory deficits and are among the first to demonstrate the influence of glia-derived molecules on cognitive function. The implications for psychopathological conditions such as schizophrenia are discussed.

Nicotine administration enhances conditioned inhibition in rats.

The effect of nicotine on conditioned inhibition was examined using a serial feature negative discrimination task. Nicotine (0.35 mg/kg) or vehicle was administered before each of the 16 training sessions. On some trials in each session, a tone was presented and followed by food reward. On other trials, the tone was preceded by a visual stimulus and not reinforced. Nicotine-treated rats exhibited greater discrimination between the two trial types as evidenced by less frequent responding during non-reinforced trials, and learned the discrimination in fewer sessions than vehicle-treated rats. In contrast, there were no group differences in responding during the reinforced trials.