Bariatric surgery for spontaneous ovulation in women living with polycystic ovary syndrome: the BAMBINI multicentre, open-label, randomised controlled trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Obesity exacerbates the reproductive complications of PCOS; however, the management of obesity in women with PCOS remains a large unmet clinical need. Observational studies have indicated that bariatric surgery could improve the rates of ovulatory cycles and prospects of fertility; however, the efficacy of surgery on ovulation rates has not yet been compared with behavioural modifications and medical therapy in a randomised trial. The aim of this study was to compare the safety and efficacy of bariatric surgery versus medical care on ovulation rates in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea. METHODS: In this multicentre, open-label, randomised controlled trial, 80 women older than 18 years, with a diagnosis of PCOS based on the 2018 international evidence-based guidelines for assessing and managing PCOS, and a BMI of 35 kg/m2 or higher, were recruited from two specialist obesity management centres and via social media. Participants were randomly assigned at a 1:1 ratio to either vertical sleeve gastrectomy or behavioural interventions and medical therapy using a computer-generated random sequence (PLAN procedure in SAS) by an independent researcher not involved with any other aspect of the clinical trial. The median age of the entire cohort was 31 years and 79% of participants were White. The primary outcome was the number of biochemically confirmed ovulatory events over 52 weeks, and was assessed using weekly serum progesterone measurements. The primary endpoint included the intention-to-treat population and safety analyses were per-protocol population. This study is registered with the ISRCTN registry (ISRCTN16668711). FINDINGS: Participants were recruited from Feb 20, 2020 to Feb 1, 2021. 40 participants were assigned to each group and there were seven dropouts in the medical group and ten dropouts in the surgical group. The median number of ovulations was 6 (IQR 3·5-10·0) in the surgical group and 2 (0·0-4·0) in the medical group. Women in the surgical group had 2.5 times more spontaneous ovulations compared with the medical group (incidence rate ratio 2·5 [95% CI 1·5-4·2], p<0·0007). There were more complications in the surgical group than the medical group, although without long-term sequelae. There were 24 (66·7%) adverse events in the surgical group and 12 (30·0%) in the medical group. There were no treatment-related deaths. INTERPRETATION: Bariatric surgery was more effective than medical care for the induction of spontaneous ovulation in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea. Bariatric surgery could, therefore, enhance the prospects of spontaneous fertility in this group of women. FUNDING: The Jon Moulton Charity Trust.

Incubator type affects human blastocyst formation and embryo metabolism: a randomized controlled trial.

STUDY QUESTION: Does the type of incubator used to culture human preimplantation embryos affect development to the blastocyst stage and alter amino acid utilization of embryos in assisted reproduction? SUMMARY ANSWER: Culturing embryos in a time lapse system (TLS) was associated with a higher Day 5 blastocyst formation rate and altered amino acid utilization when measured from Day 3 to Day 5 compared to the standard benchtop incubator. WHAT IS KNOWN ALREADY: Culture environment is known to be important for the developing preimplantation embryo. TLSs provide a stable milieu allowing embryos to be monitored in situ, whereas embryos cultured in standard benchtop incubators experience environmental fluctuations when removed for morphological assessment. STUDY DESIGN, SIZE, DURATION: A prospective clinical trial randomizing 585 sibling embryos to either the TLS (289 embryos) or the standard benchtop incubator (296 embryos) over a 23-month period in a UK University Hospital Fertility Clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were aged 42 years or under, had an antral follicle count of ≥12 and ≥6 2 pronucleate zygotes. Zygotes were cultured individually in 25 µl of medium. Randomized embryos were graded and selected for transfer or cryopreservation on Day 5. For those embryos produced by women who underwent stimulation with recombinant FSH injections and were triggered with hCG, spent medium was collected on Day 5 for amino acid analysis by high pressure liquid chromatography. Clinical pregnancy was defined as the presence of a foetal heart beat on ultrasound scan at 7 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, blastocyst formation rate on Day 5 was significantly higher in embryos cultured in the TLS (55%) compared to the standard incubator (45%; P = 0.013). Similarly, there was an increase in the number of blastocysts suitable for cryopreservation in the TLS (31%) compared to the standard incubator (23%; P = 0.032). There was a significant difference in the utilization of 12 amino acids by blastocysts cultured from Day 3 to Day 5 in the TLS compared to the standard incubator. Embryos cultured in the TLS displayed an increased total amino acid utilization (P < 0.001) and reduced amino acid production (P < 0.001) compared to those in the standard incubator. Irrespective of incubator used, embryos fertilized by ICSI depleted significantly more amino acids from the medium compared to those fertilized by conventional IVF. There was no difference in the mean score of blastocysts transferred, or the clinical pregnancy rate after transfer of embryos from either of the incubators. LIMITATIONS, REASONS FOR CAUTION: The study was not powered to discern significant effects on clinical outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The metabolism and development of preimplantation embryos is impacted by the type of incubator used for culture. Further research is required to investigate the long-term implications of these findings. STUDY FUNDING/COMPETING INTEREST(S): NIHR Southampton Biomedical Research Centre Commercial and Enterprise Incubator Fund funded this study. The TLS was provided on loan for the study by Vitrolife. The authors declare no conflict of interests. TRIAL REGISTRATION NUMBER: ISRCTN73037149. TRIAL REGISTRATION DATE: 12 January 2012. DATE OF FIRST PATIENT'S ENROLMENT: 21 January 2012.

Maternal intermittent fasting during pregnancy induces fetal growth restriction and down-regulated placental system A amino acid transport in the rat.

During Ramadan, many pregnant Muslim women fast between dawn and sunset. Although the impacts of prolonged maternal intermittent fasting (IF) on fetal growth and placental function are under-researched, reported effects include reduced placental weight and birth weight. In the present study, pregnant Wistar rats were used to model repeated cycles of IF on fetal development and placental function and to examine sex-specific effects. In the IF group, food was withdrawn daily from 17:00 to 09:00 over 21 days of gestation, while the control group received food ad libitum. Both groups had free water access. IF dams consumed less food, had significantly reduced weight compared with controls, with reduced plasma glucose and amino acids. Both fetal sexes were significantly lighter in the IF group with reduced fetal plasma amino acids. Placental weights and morphology were unchanged. The profile of placental metabolites was altered in the IF group with sex-specific responses evident. Transplacental flux of 14C-methylaminoisobutyric acid (14C-MeAIB), a system A amino acid transporter substrate, was significantly reduced in both fetal sexes in the IF group. Sodium-dependent 14C-MeAIB uptake into isolated placental plasma membrane vesicles was unchanged. The gene expression of system A transporter Slc38a1, Slc38a2 and Slc38a4 was up-regulated in IF male placentas only. No changes were observed in placental SNAT1 and SNAT2 protein expression. Maternal IF results in detrimental impacts on maternal physiology and fetal development with changes in the placental and fetal metabolite profiles. Reduced placental system A transporter activity may be responsible for fetal growth restriction in both sexes.

A randomised controlled trial of clinics in secondary schools for adolescents with asthma.

AIM: To compare a nurse-led clinic in schools versus care in general practice for adolescents with asthma. DESIGN OF STUDY: Randomised controlled trial in four schools; parallel observational study in two schools. SETTING: Six comprehensive schools. METHOD: In the randomised trial, pupils were invited to attend asthma review at a nurse-led clinic either in school, or in general practice. The parallel observational study compared pupils invited to practice care within and outside the randomised trial. Primary outcome measures were attendance for asthma review, symptom control, and quality of life. Secondary outcomes were knowledge, attitudes, inhaler technique, use of steroids, school absence, peak flow rate, preference for future care, health service utilisation, and costs. RESULTS: School clinic pupils were more likely to attend an asthma review than those randomised to practice care (90.8% versus 51.0% overall [P < 0.001, not consistent across schools]). No differences were observed in symptom control (P = 0.42) or quality of life (P = 0.63). Pupils attending school clinics had greater knowledge of asthma (difference = +0.38, 95% CI = 0.19 to 0.56), more positive attitudes (difference = +0.21, 95% CI = 0.05 to 0.36), and better inhaler technique (P < 0.001, not consistent across all schools). No differences were observed in school absence or peak flow rate. A majority (63%) of those who had received care at school preferred this model in future. Median costs of providing care at school and at the practice were 32.10 Pounds and 19.80 Pounds, respectively. No differences were observed between the groups in the observational comparison on any outcome. CONCLUSIONS: The schools asthma clinic increased uptake of asthma reviews. There were improvements in various process measures, but not in clinical outcomes.

HIF-2α regulates NANOG expression in human embryonic stem cells following hypoxia and reoxygenation through the interaction with an Oct-Sox cis regulatory element.

Low O2 tension is beneficial for human embryonic stem cell (hESC) maintenance but the mechanism of regulation is unknown. HIF-2α was found to bind directly to predicted hypoxic response elements (HREs) in the proximal promoter of OCT4, NANOG and SOX2 only in hESCs cultured under hypoxia (5% O2). This binding induced an array of histone modifications associated with gene transcription while a heterochromatic state existed at atmospheric O2. Interestingly, an enhanced euchromatic state was found when hESCs were exposed to hypoxia followed by 72 hours reoxygenation. This was sustained by HIF-2α which enhanced stemness by binding to an oct-sox cis-regulatory element in the NANOG promoter. Thus, these data have uncovered a novel role of HIF-2α as a direct regulator of key transcription factors controlling self-renewal in hESCs but also in the induction of epigenetic modifications ensuring a euchromatic conformation which enhances the regenerative potential of these cells.

Environmental oxygen tension regulates the energy metabolism and self-renewal of human embryonic stem cells.

Energy metabolism is intrinsic to cell viability but surprisingly has been little studied in human embryonic stem cells (hESCs). The current study aims to investigate the effect of environmental O2 tension on carbohydrate utilisation of hESCs. Highly pluripotent hESCs cultured at 5% O2 consumed significantly more glucose, less pyruvate and produced more lactate compared to those maintained at 20% O2. Moreover, hESCs cultured at atmospheric O2 levels expressed significantly less OCT4, SOX2 and NANOG than those maintained at 5% O2. To determine whether this difference in metabolism was a reflection of the pluripotent state, hESCs were cultured at 5% O2 in the absence of FGF2 for 16 hours leading to a significant reduction in the expression of SOX2. In addition, these cells consumed less glucose and produced significantly less lactate compared to those cultured in the presence of FGF2. hESCs maintained at 5% O2 were found to consume significantly less O2 than those cultured in the absence of FGF2, or at 20% O2. GLUT1 expression correlated with glucose consumption and using siRNA and chromatin immunoprecipitation was found to be directly regulated by hypoxia inducible factor (HIF)-2α at 5% O2. In conclusion, highly pluripotent cells associated with hypoxic culture consume low levels of O2, high levels of glucose and produce large amounts of lactate, while at atmospheric conditions glucose consumption and lactate production are reduced and there is an increase in oxidative metabolism. These data suggest that environmental O2 regulates energy metabolism and is intrinsic to the self-renewal of hESCs.