Single-cell multi-ome and immune profiles of the Inspiration4 crew reveal conserved, cell-type, and sex-specific responses to spaceflight.

Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a "spaceflight signature" of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Spaceflight induces changes in gene expression profiles linked to insulin and estrogen.

Organismal adaptations to spaceflight have been characterized at the molecular level in model organisms, including Drosophila and C. elegans. Here, we extend molecular work to energy metabolism and sex hormone signaling in mice and humans. We found spaceflight induced changes in insulin and estrogen signaling in rodents and humans. Murine changes were most prominent in the liver, where we observed inhibition of insulin and estrogen receptor signaling with concomitant hepatic insulin resistance and steatosis. Based on the metabolic demand, metabolic pathways mediated by insulin and estrogen vary among muscles, specifically between the soleus and extensor digitorum longus. In humans, spaceflight induced changes in insulin and estrogen related genes and pathways. Pathway analysis demonstrated spaceflight induced changes in insulin resistance, estrogen signaling, stress response, and viral infection. These data strongly suggest the need for further research on the metabolic and reproductive endocrinologic effects of space travel, if we are to become a successful interplanetary species.

Beyond the surface: Does stage I-II endometriosis impact fertility? Exploring the challenges of mild disease.

Endometriosis is one of the most common gynecologic conditions that women face throughout their lives. Despite advances in technology, diagnosis and treatment of this relapsing and remitting condition is still challenging for many women. This review focuses on literature pertaining to minimal/mild (stage I/II) endometriosis and its impact on fertility. The effectiveness of medical interventions to improve infertility and obstetric outcomes in both natural and assisted reproductive technologies cycles remains debated. The recent ESHRE guidelines suggests that operative laparoscopy could be considered for rASRM stage I/II endometriosis as it improves ongoing pregnancy rates.

Walking on thin endometrium.

PURPOSE OF REVIEW: Endometrial thickness has been regarded a predictor of success in assisted reproductive technology cycles and it seems a common practice to cancel embryo transfer when it is below a cut-off. However, various cut-offs have been proposed without a causal relationship between endometrial thickness and embryo implantation being established, casting doubt on the current dogma. RECENT FINDINGS: Methodological limitations of the available studies on endometrial thickness are increasingly recognized and better designed studies do not demonstrate a cut-off value which requires cancelling an embryo transfer. SUMMARY: Endometrium is important for implantation and a healthy pregnancy; however, ultrasound measured thickness does not seem to be a good marker of endometrial function.

A critical appraisal of studies on endometrial thickness and embryo transfer outcome.

A receptive endometrium is required for successful embryo implantation. Endometrial thickness, as measured by ultrasonography, is the most commonly used marker of endometrial receptivity in assisted reproductive technology cycles. Several factors simultaneously affect both endometrial thickness and probability of live birth, including age, oestradiol concentration and oocyte number, among others. Most of the studies investigating a relationship between endometrial thickness and embryo transfer outcomes are retrospective and do not adequately address confounding factors, in addition to other limitations. Despite multiple meta-analyses and studies with large numbers of cycles, controversy still exists. The difference between the results from prospective and retrospective studies is also striking. This article presents a critical appraisal of the studies on endometrial thickness and embryo transfer outcomes in order to highlight methodological issues and how they can be overcome in future studies. Currently available evidence does not seem to support a modification of management just because endometrial thickness is below an arbitrary threshold.

Obesity downregulates lipid metabolism genes in first trimester placenta.

Placentas of obese women have low mitochondrial ß-oxidation of fatty acids (FA) and accumulate lipids in late pregnancy. This creates a lipotoxic environment, impairing placental efficiency. We hypothesized that placental FA metabolism is impaired in women with obesity from early pregnancy. We assessed expression of key regulators of FA metabolism in first trimester placentas of lean and obese women. Maternal fasting triglyceride and insulin levels were measured in plasma collected at the time of procedure. Expression of genes associated with FA oxidation (FAO; ACOX1, CPT2, AMPKα), FA uptake (LPL, LIPG, MFSD2A), FA synthesis (ACACA) and storage (PLIN2) were significantly reduced in placentas of obese compared to lean women. This effect was exacerbated in placentas of male fetuses. Placental ACOX1 protein was higher in women with obesity and correlated with maternal circulating triglycerides. The PPARα pathway was enriched for placental genes impacted by obesity, and PPARα antagonism significantly reduced 3H-palmitate oxidation in 1st trimester placental explants. These results demonstrate that obesity and hyperlipidemia impact placental FA metabolism as early as 7 weeks of pregnancy.

Use of anti-Müllerian hormone for understanding ovulatory dysfunction in polycystic ovarian syndrome.

PURPOSE OF REVIEW: The aim of this review is to understand how anti-Müllerian hormone (AMH) contributes to ovulatory dysfunction in polycystic ovarian syndrome (PCOS). RECENT FINDINGS: In the last few years, new findings have emerged on AMH and its role on the central nervous system causing ovulatory dysfunction. SUMMARY: Anovulation is a prominent feature of PCOS. Women with anovulatory PCOS have higher AMH levels than in ovulatory PCOS. Higher levels of AMH may contribute to the pathophysiology of PCOS through central and peripheral actions. Once universal standardization is achieved to measure serum AMH, the benefits would be significant in diagnosing women with PCOS.

Disposable paper-based microfluidics for fertility testing.

Fifteen percent of couples of reproductive age suffer from infertility globally and the burden of infertility disproportionately impacts residents of developing countries. Assisted reproductive technologies (ARTs), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), have been successful in overcoming various reasons for infertility including borderline and severe male factor infertility which consists of 20%-30% of all infertile cases. Approximately half of male infertility cases stem from suboptimal sperm parameters. Therefore, healthy/normal sperm enrichment and sorting remains crucial in advancing reproductive medicine. Microfluidic technologies have emerged as promising tools to develop in-home rapid fertility tests and point-of-care (POC) diagnostic tools. Here, we review advancements in fabrication methods for paper-based microfluidic devices and their emerging fertility testing applications assessing sperm concentration, sperm motility, sperm DNA analysis, and other sperm functionalities, and provide a glimpse into future directions for paper-based fertility microfluidic systems.

Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review.

Outer space is an extremely hostile environment for human life, with ionizing radiation from galactic cosmic rays and microgravity posing the most significant hazards to the health of astronauts. Spaceflight has also been shown to have an impact on established cancer hallmarks, possibly increasing carcinogenic risk. Terrestrially, women have a higher incidence of radiation-induced cancers, largely driven by lung, thyroid, breast, and ovarian cancers, and therefore, historically, they have been permitted to spend significantly less time in space than men. In the present review, we focus on the effects of microgravity and radiation on the female reproductive system, particularly gynecological cancer. The aim is to provide a summary of the research that has been carried out related to the risk of gynecological cancer, highlighting what further studies are needed to pave the way for safer exploration class missions, as well as postflight screening and management of women astronauts following long-duration spaceflight.

Metabolomic signatures of low- and high-adiposity neonates differ based on maternal BMI.

Maternal obesity [body mass index (BMI) > 30 kg/m2] is associated with greater neonatal adiposity, cord blood (CB) insulin levels, and a proinflammatory phenotype at birth, contributing to risk of future cardiometabolic disease in the offspring. Variation in neonatal adiposity within maternal BMI groups is underappreciated, and it remains unclear whether the metabolic impairments at birth are an outcome of maternal obesity or excess fetal fat accrual. We examined the hypothesis that CB metabolites associated with fetal fat accrual differ between offspring of normal-weight and obese women. Umbilical venous blood was collected at the time of scheduled cesarean delivery from 50 normal-weight women (LE; pregravid BMI = 22.3 ± 1.7 kg/m2) and 50 obese women (OB; BMI = 34.5 ± 3.0 kg/m2). Neonatal adiposity was estimated from flank skinfold thickness. The first (low adiposity, LA) and third (high adiposity, HA) tertiles of neonatal %body fat were used to create four groups: OBLA, OBHA, LELA, and LEHA. CB metabolites were measured via untargeted metabolomics. Broadly, the LA offspring of OB women (OBLA) metabolite signature differed from other groups. Lauric acid (C12:0) was 82-118% higher in OBLA vs. all other groups [false discovery rate (FDR) < 0.01]. Several other fatty acids, including palmitate, stearate, and linoleate, were higher in OBLA vs. OBHA groups. CB metabolites, such as lauric acid, a medium-chain fatty acid that may improve insulin sensitivity, were associated with neonatal adiposity differently between offspring of women with and without obesity. Changes in metabolically active lipids at birth may have long-term consequences for offspring metabolism.NEW & NOTEWORTHY Using untargeted metabolomics in 100 newborns, we found that cord blood metabolite signatures associated with neonatal adiposity differed between offspring of women with and without obesity.

Non-oestrogenic modalities to reverse urogenital aging.

Urogenital aging is a common process affecting all women in the post-menopausal period of their life, and it is substantially due to oestrogen deprivation after ovarian function cessation. These changes can lead to a progressive, chronic, and complex association of symptoms identified as the genitourinary syndrome of menopause, which has a significant impact on quality of life. Genitourinary syndrome and urogenital aging do not resolve spontaneously and usually recur when treatment is stopped. Therefore, appropriate long-term management is of paramount importance, and local oestrogen is the most effective treatment to reverse urogenital aging and to improve symptoms of genitourinary syndrome as replacement therapy. In some women, topical oestrogen may be inconvenient, it may not achieve complete response, or it may be contra-indicated. Several non-hormonal therapies have been investigated, but few treatments have been reported as potentially able to reverse the urogenital aging process similarly to exogenous oestrogens. Laser seems the most promising, although further studies to define its safety and efficacy are mandatory. Vitamin D and E, and phytotherapy have returned conflicting results and require further confirmation. Lifestyle modifications, physiotherapy, and electrical stimulation represent inexpensive and applicable treatments that might slow urogenital aging. Among the hormonal non-oestrogenic therapies, the use of vaginal oxytocin and dehydroepiandrosterone have been found to be effective compared to placebo, as well as the use of oral ospemifene, which partially relieves vulvovaginal atrophy.

Obesity and IVF: weighing in on the evidence.

Obesity is associated with serious health risks, and its rising prevalence represents a growing public health emergency. Ongoing research into the association of obesity and assisted reproductive technology (ART) outcomes aims to disentangle selective detrimental effects of obesity on the oocyte and the endometrium. More translational studies involving women with severe obesity and in the third-party reproduction setting will help improve the standard of care in the provision of ART services for obese patients.

Comparison of laparoendoscopic single-site (LESS) surgery and conventional multiport laparoscopic (CMPL) surgery for hysterectomy: long-term outcomes of abdominal incisional scar.

There is scarcity of data about the long-term results such as port-site hernia, body image scale and cosmesis scale outcomes between laparoendoscopic single-site (LESS) surgery and conventional multiport laparoscopy (CMPL) for hysterectomy. Eighty women, who underwent total hysterectomy by the LESS (n = 40) and CMPL (n = 40) technique due to benign and malign gynecological disorders, were evaluated with a cosmesis and body image questionnaire in an age-matched cohort study.Median follow-up time was 25 (6-30) months in both groups. The mean age of the patients was 49.3 ± 6.3 years. The mean body image scale scores were 5.3 ± 0.6 and 5.5 ± 1.2 in the LESS and CMPL groups, respectively (p = 0.268). The mean cosmesis and scar scale scores were significantly higher in the LESS group compared to the CMPL group (p = .011 and p < .001, respectively). Port-site hernia was detected in two patients in the LESS group, but not in the CMPL group. There was no cuff dehiscence in the LESS nor in the CMPL group. The LESS technique provides better cosmesis when compared with the CMPL technique. The body image perceptions in the two groups were similar. Women who wish to undergo the LESS surgery should be informed about the risk of incisional hernia.Impact statementWhat is already known on this subject? Short-term results of LESS hysterectomy such as complication rates, additional port requirement, conversion to CMPL or laparotomy, pain score and analgesic use were evaluated in various studies. Several studies have been published on the safety and efficacy of single-port laparoscopic hysterectomy (LH); however, it has been unclear whether single-port LH offers benefits over multiport LH regarding long-term patient satisfaction and cosmetic satisfaction.What do the results of this study add? In this prospective cohort study, we aimed to compare long-term results (at least six months) of abdominal incisional scar between LESS and CMPL surgery for hysterectomy. The LESS technique provides better cosmesis when compared with the CMPL technique, although, the body image perceptions in the two groups were similar.What are the implications of these findings for clinical practice and/or further research? LESS technique can be offered as an option for hysterectomy since it provides better long-term cosmesis compared to CMPL.

Efficacy of chewing gum for improving bowel function after cesarean sections: a randomized controlled trial.

Objective: To investigate the effects of chewing xylitol-free gum at different intervals after cesarean sections.Study design: One hundred fifty patients undergoing cesarean sections were randomized into a gum chewing group (n = 75) and a control group (n = 75). Patients in the gum group chewed one sugarless gum for 30 min at 3, 5, and 7 h postoperatively. The two groups were compared in terms of time to first bowel movement, first feeling of hunger, first passage of flatus, and defecation time. Postoperative satisfaction with bowel movements was rated on a scale of 1-5.Results: First bowel movement time (4.93 ± 1.05 versus 7.97 ± 2.33 h postoperatively, p = .0001), first feeling of hunger (5.51 ± 1.68 versus 6.30 ± 1.58 h postoperatively, p = .004), first passage of flatus (11.73 ± 4.61 versus 14.10 ± 2.71 h postoperatively, p = .001), and mean length of hospital stay (2.30 ± 0.49 versus 2.50 ± 0.50 d, p = .015) were significantly reduced in the gum group compared with the control group. Postoperative satisfaction scores for overall bowel function were better in the patients who chewed gum.Conclusion: Gum chewing at frequent intervals in the early postoperative period promotes the early return of bowel movements, shortens hospitalization, and increases patient satisfaction regarding bowel function.

A comparison of obstetric outcomes in adolescent pregnancies and adult pregnancies.

Introduction: Adolescent pregnancies are associated with adverse maternal and fetal outcomes including preeclampsia, preterm birth, and fetal growth restriction compared to adult pregnancies. The purpose of our study is to compare the incidents of obstetric outcomes between the adolescent pregnancies and adult pregnancies.Materials and methods: This retrospective case-control study was conducted between January 2013 and January 2018 at Kanuni Sultan Suleyman Research and Training Hospital, Istanbul, Turkey. The institutions' medical records were screened for women with pregnancies after 24 weeks of gestation. Women under 19 years of age were included as the adolescent group and women between the ages of 20 and 29 were included as the control group. Obstetric outcomes were compared between the groups.Results: There were 3875 adolescent pregnancies in the case group and 3875 adult pregnancies in the control group. Even after adjusting for confounders in our adolescent pregnant cohort, the odds of intrauterine growth restriction, preterm birth and premature rupture of membranes were higher than in our adult pregnant cohort. On the other hand, we found low incidents of preeclampsia and gestational diabetes mellitus in pregnant women younger than 19 years of age.Conclusions: Adolescent pregnancies should be closely followed up as they have higher preterm birth rates as well as the risk of intrauterine growth restriction.

Maternal serum mitofusin-2 levels in patients with preeclampsia: the possible role of mitochondrial dysfunction in preeclampsia.

Purpose: Hypoxia alters mitochondria function and our aim was to measure mitochondrial fusion protein mitofusin-2 (Mfn2) in patients with preeclampsia.Materials and methods: This cross-sectional study was conducted including 82 pregnant women, 27 with normal pregnancy and 55 with preeclampsia (27 with early-onset preeclampsia and 28 with late-onset preeclampsia). Maternal serum levels of Mfn2 were measured by using enzyme-linked immunosorbent assay kits.Results: The mean serum mitofusin-2 levels were higher in women with preeclampsia than in the control group (68.02 ± 8.7 pg/mL vs. 99.72 ± 37.27 pg/mL, p < .0001). The mean serum mitofusin-2 level was found to be the highest in the early-onset preeclampsia (EOPE) group (EOPE: 101.6 ± 38.5 pg/mL). Maternal serum mitofusin-2 levels correlated with both systolic and diastolic blood pressures as well as uterine artery pulsatility index. The optimal cutoff value of Mfn2 for determining preeclampsia was 75.3 pg/mL.Conclusion: Mfn2 has regulatory roles in stress response. Maternal serum Mfn2 is higher in patients with preeclampsia suggesting that Mfn2 increases in the maternal system as a stress response against hypoxia and endothelial dysfunction.What do the results of this study add? Hypoxia causes mitochondrial dysfunction that has been linked to the etiology of many diseases including preeclampsia. Mitofusin-2 is a mitochondrial fusion protein, and the levels can be altered in preeclampsia. For the first time, we showed that maternal levels of mitofusin-2 are higher in patients with preeclampsia. Further, we reported the correlation of mitofusin-2 with blood pressures and uterine artery pulsatility index. These findings will open up other avenues for researchers to investigate other mitochondrial molecules while under stress.

A new look at the etiology of interstitial cystitis/bladder pain syndrome: extraordinary cultivations.

PURPOSE: So far, studies have not clearly identified infectious agents as an etiological factor for interstitial cystitis (IC). Specific microbiological diagnosis for detecting the pathogen with higher sensitivity in IC may decrease the treatment costs and increase psychosocial health of the patients. METHODS: A prospective clinical study was performed in 26 IC patients and 20 controls between April and September 2017. All participants were asked to give mid-stream urine sample for routine urine cultures. Followed by the negative results, symptomatic 26 patients were evaluated for L-form pathogen existence by extraordinary cultivation methods. Biopsy samples were taken from 19 patients with ulcerative lesions in the bladder while collecting sterile urine samples from all 26 patients. PG broth, 5% sheep blood agar, EMB, Sabouraud's dextrose, LEM, and GYPA were used. Followed by the 1st day inoculations, all inoculated PG broths were subcultured into the same solid media at the 2nd and 10th days in case of any growth after incubation of 24 h under 35-37 °C. The "O'Leary Sant Symptom and Problem Index" score forms were used to evaluate response to the appropriate treatment for those patients with documented pathogens. RESULTS: Bacterial isolations were yielded from samples of 13 IC patients in PG broth. Eight (61.5%) P. aeruginosa, 2 (15.4%) K. pneumoniae, 2 (15.4%) C. mucifaciens, and 1 (7.7%) E. faecalis were isolated. Antibiotic susceptibility tests were performed. Somehow, the median symptom index and problem scores of those 13 IC patients were lower after the appropriate antibiotic treatment (p < 0.05). CONCLUSIONS: Extraordinary mediums with longer incubation periods may reveal a causative pathogen in the etiology of IC. Future culture techniques may have some value, because still some of IC/BPS patients are describing symptomatic relief by a group of antibiotics.

Gremlin-1 and gremlin-2 levels in polycystic ovary syndrome and their clinical correlations.

Objective: Gremlin 1 and 2 regulate oocyte primordial follicle transition in animal models. The main objective of this study is to measure the blood levels of Gremlin 1 and 2 in the women with Polycystic Ovary Syndrome (PCOS). We also aimed to evaluate the association of these markers with hormonal and biochemical parameters of PCOS as interrupted folliculogenesis in those women is related to metabolic dysfunction. Material and methods: Fifty women with PCOS were diagnosed according to Rotterdam criteria, and thirty age-matched female controls were included in this prospective study. Gremlin 1 and 2 levels along with hormonal and metabolic parameters were compared between PCOS and control groups. Results: Serum Gremlin 1 levels were significantly higher in the PCOS group than in the control group (p = .001). Gremlin 2 levels were similar between the groups. Besides, there was a significant positive correlation between Gremlin 1 and insulin levels, Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) and waist to hip ratio (WHR) (r = 0.305; r = 0.297; r = 0.303, respectively). Conclusion: Our data suggest that Gremlin 1 may be the key regulator in the pathogenesis of PCOS. In future, Gremlin 1 may be a novel therapeutic target for the treatment of PCOS.

Evaluation of ovarian reserve in women with psoriasis.

The aim of this study is to evaluate ovarian reserve in women with psoriasis. Thirty-six women with psoriasis and 36 healthy women were enrolled in this prospective study. On day 3 of the menstrual cycle, blood samples for AMH and other hormones were collected. On the same day, antral follicle count (AFC), and ovarian volumes were measured. A multiple regression analysis was carried out to examine the contribution of factors to the serum AMH levels in patients with psoriasis. The serum AMH levels and ovarian volumes were lower in the psoriasis group than in the control group (1.85 ± 1.13 ng/ml vs 2.46 ± 1.21 ng/ml, p = .029 and 10.43 ± 3.08 cm3 vs 11.93 ± 3.01 cm3, p = .038). However, the mean AFC between the two groups was not significantly different. The psoriasis area severity index (PASI) score did not correlate with AMH. On the other hand, the duration of the disease negatively correlated with AMH, total AFC and ovarian volume. In the multiple regression analysis, duration of disease and total AFC were the most significant contributors to the serum AMH levels in patients with psoriasis. Autoimmune diseases may affect ovarian reserve regardless of immunosuppresive treatment. Longitudinal follow-ups regarding reproductive function might be required in women with psoriasis.