Subjective cognitive changes following premenopausal risk-reducing bilateral salpingo-oophorectomy.

OBJECTIVE: Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Cognitive symptoms during natural menopause transition are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, we explored the cognitive experiences of women within 24 months post BSO. METHODS: This observational cross-sectional sub-study is part of a larger project, the Early Menopause and Cognition Study (EM-COG). We investigated perceived cognitive experiences in Australian women (n = 16) who underwent risk-reducing BSO using qualitative interviews. Thematic analysis was undertaken to identify key themes. RESULTS: Fifteen out of 16 participants (93.75%) reported changes to cognition within 24 months post BSO. The key cognitive symptoms reported were brain fog, memory and retrieval difficulties, slower processing speed as well as attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. CONCLUSION: Findings from this study suggest that women experience subjective cognitive changes within 24 months post BSO. This period could be a vulnerable time for women's cognitive health. While these findings need to be confirmed by a large prospective study, our research indicates that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.

Prenatal exposure to maternal stressful life events and earlier age at menarche: the Raine Study.

STUDY QUESTION: Is there an association between prenatal exposure to stressful life events and age at menarche, and does childhood BMI mediate this association? SUMMARY ANSWER: Girls exposed to prenatal stress had a slightly earlier age at menarche, but this association did not show a dose-response effect and was not mediated by childhood offspring BMI. WHAT IS ALREADY KNOWN: Prenatal stress may impact on reproductive function in females including age at menarche, but human data are very limited. High childhood BMI is known to be associated with earlier age at menarche. Only one small study has measured the association between maternal stress and age at menarche and reported that childhood BMI mediated the association between maternal stress and earlier age at menarche. However, neither maternal stress nor age at menarche was prospectively recorded and the study was limited to 31 mother-daughter pairs. STUDY DESIGN, SIZE, DURATION: The Raine Study is a large prospective population-based pregnancy cohort study (n = 1414 mother-daughter pairs) continuously followed from prenatal life through to adolescence. In the present study, we examined the association between exposure to maternal stressful life events during early, late and total gestation and age at menarche in offspring using 753 mother-daughter pairs with complete case information. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mothers prospectively reported stressful life events during pregnancy at 18 and 34 weeks using a standardized 10-point questionnaire. Exact date of menarche was assessed using a purpose-designed questionnaire at 8, 10, 14 and 17 years of age. Complete information on exposure, outcome and confounding variables was obtained from 753 mothers-daughter pairs. Multivariate linear regression complete case analysis was used to examine associations between maternal stressful life event exposure and age at menarche. Potential selection bias was evaluated using multiple imputations (50 datasets). The mediating effects of offspring childhood BMI (ages 5, 8, or 10 years) on these associations were measured in separate sub-analyses. MAIN RESULTS AND ROLE OF CHANCE: Most (580/753, 77%) daughters were exposed to at least one prenatal stressful life event. Exposure to maternal stressful life events during the entire pregnancy was associated with a non-linear earlier age at menarche. Exposure to one event and two or more psychological stressful events was associated with a 3.5 and 1.7-month earlier onset of puberty, respectively when compared to the reference group with no exposure maternal stressful life events. The estimates from multiple imputation with 50 datasets were comparable with complete case analysis confirming the existence of an underlying effect. No separate significant effects were observed for exposure during early or late gestation. The association between prenatal stressful events and age at menarche was not mediated by childhood BMI in the offspring. LIMITATIONS, REASONS FOR CAUTION: Stressful life events may have affected pregnant women in different ways and self-perceived maternal stress severity may have provided a more precise estimate of gestational psychological stress. The observed non-linear U-shape of the association between maternal psychological stress and age at menarche did not reflect a dose-response. This suggests that the first exposure to prenatal stress exerts a greater effect on fetal reproductive development. A potential mechanism is via dramatic initial activation of the hypothalamic-pituitary-adrenal (HPA) axis following the first stressful life event which is greater than that observed following subsequent exposure to two or more maternal stressful life events. Whilst we adjusted for a priori chosen confounders, we cannot exclude residual confounding or confounding by factors we did not include. Maternal age at menarche was not available so the effects of familial history/genetics could not be assessed. There was a large loss due to the number of girls with no information on date of menarche and missing confounder information implying risk of selection bias and multiple imputation analyses did not fully exclude this risk (similar direction but slightly weaker estimate magnitude). WIDER IMPLICATIONS OF THE FINDINGS: Menarche is a sentinel reproductive event and earlier age at menarche carries implications for psychological, social and reproductive health and for long-term risk of common non-communicable diseases. Understanding the factors regulating age at menarche has extensive health implications. This is the first population-based cohort study in humans to demonstrate that prenatal psychological stress might directly modify age at menarche. STUDY FUNDING/COMPETING INTEREST(S): Dr. Bräuner and Trine Koch's salaries were supported by Doctor Sofus Carl Emil Friis and spouse Olga Doris Friis foundation, The Danish Cancer Society (Kræftens Bekæmpelse, RP15468, R204-A12636, Denmark) and The Danish Health Foundation (Helsefonden, F-22181-23, Denmark). Martha Hickey was funded by NHMRC Practitioner Fellowships. The funding bodies played no role in the design, collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Dr. Hart has received personal fees in his function as the Medical Director of Fertility Specialists of Western Australia and received educational sponsorship grants from MSD, Merck-Serono and from Ferring Pharmaceuticals. Dr Hart has also received personal fees from Shareholders in Western IVF outside the submitted work. TRIAL REGISTRATION NUMBER: NA.

How common is add-on use and how do patients decide whether to use them? A national survey of IVF patients.

STUDY QUESTION: What is the prevalence and pattern of IVF add-on use in Australia? SUMMARY ANSWER: Among women having IVF in the last 3 years, 82% had used one or more IVF add-on, most commonly acupuncture, preimplantation genetic testing for aneuploidy and Chinese herbal medicine. WHAT IS KNOWN ALREADY: IVF add-ons are procedures, techniques or medicines which may be considered nonessential to IVF, but usually used in attempts to improve the probability of conception and live birth. The use of IVF add-ons is believed to be widespread; however, there is little information about the prevalence and patterns of use in different settings. STUDY DESIGN, SIZE, DURATION: An online survey was distributed via social media to women in Australia who had undergone IVF since 2017. Women were excluded if they were gestational surrogates, used a surrogate, or underwent ovarian stimulation for oocyte donation or elective oocyte cryopreservation only. The survey was open from 21 June to 14 July 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survey questions included demographics, IVF and medical history, and use of IVF add-ons including details of the type of add-on, costs and information sources used. Participants were also asked about the relative importance of evidence regarding safety and effectiveness, factors considered in decision-making and decision regret. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1590 eligible responses were analysed. Overall, 82% of women had used one or more add-ons and these usually incurred an additional cost (72%). Around half (54%) had learned about add-ons from their fertility specialist, and most reported that the decision to use add-ons was equally shared with the specialist. Women placed a high level of importance on scientific evidence for safety and efficacy, and half (49%) assumed that add-ons were known to be safe. Most women experienced some regret at the decision to use IVF add-ons (66%), and this was more severe among women whose IVF was unsuccessful (83%) and who believed that the specialist had a larger contribution to the decision to use add-ons (75%). LIMITATIONS, REASONS FOR CAUTION: This retrospective survey relied on patient recall. Some aspects were particularly prone to bias such as contributions to decision-making. This approach to capturing IVF add-on use may yield different results to data collected directly from IVF clinics or from fertility specialists. WIDER IMPLICATIONS OF THE FINDINGS: There is a very high prevalence of IVF add-on use in Australia which may be generalisable to other settings with similar models of IVF provision. Although women placed high importance on scientific evidence to support add-ons, most add-ons do not have robust evidence of safety and effectiveness. This suggests that IVF patients are not adequately informed about the risks and benefits of IVF add-ons, or are not aware of the paucity of evidence to support their use. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a McKenzie Postdoctoral Fellowship Grant (University of Melbourne), a Department of Obstetrics and Gynaecology Innovation Grant (University of Melbourne) and an NHMRC Investigator Grant (APP1195189). A.P. declares that he provides fertility services at Melbourne IVF (part of Virtus Health). J.W. reports grants from Wellcome Trust, during the conduct of the study, and that publishing benefits his career. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Loss of bone density and bone strength following premenopausal risk-reducing bilateral salpingo-oophorectomy: a prospective controlled study (WHAM Study).

Prophylactic oophorectomy is recommended for women at high risk for ovarian cancer, but the associated impact on bone health is of clinical concern. This prospective, controlled study demonstrated substantial loss of bone density and bone strength following surgical menopause. Postoperative hormone therapy alleviated, but not fully prevented, spinal bone loss. INTRODUCTION: This prospective study investigated bone health in women following premenopausal oophorectomy. METHODS: Dual-energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and pQCT-based finite element analysis (pQCT-FEA) were used to assess bone health between systemic hormone therapy (HT) users and non-users after premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) compared with premenopausal controls over 24-month follow-up. RESULTS: Mean age was 42.4 ± 2.6 years (n = 30) for the surgery group and 40.2 ± 6.3 years for controls (n = 42), and baseline bone measures were similar between groups. Compromised bone variables were observed at 24 months after RRBSO, among which areal bone mineral density (aBMD) at the lumbar spine, tibial volumetric cortical density (Crt vBMD), and tibial bending stiffness (kbend) had decreased by 4.7%, 1.0%, and 12.1%, respectively (all p < 0.01). In non-HT users, significant losses in lumbar spine (5.8%), total hip (5.2%), femoral neck (6.0%) aBMD, tibial Crt vBMD (2.3%), and kbend (14.8%) were observed at 24 months (all p < 0.01). HT prevented losses in kbend, tibial Crt vBMD, and aBMD, except for modest 2.3% loss at the lumbar spine (p = 0.01). CONCLUSION: This prospective, controlled study of bone health following RRBSO or premenopausal oophorectomy demonstrated substantial loss of bone density and bone strength following RRBSO. HT prevented loss of bone density and bone stiffness, although there was still a modest decrease in lumbar spine aBMD in HT users. These findings may inform decision-making about RRBSO and clinical management following premenopausal oophorectomy.

Associations of childhood adiposity with menstrual irregularity and polycystic ovary syndrome in adulthood: the Childhood Determinants of Adult Health Study and the Bogalusa Heart Study.

STUDY QUESTION: Is high adiposity in childhood associated with menstrual irregularity and polycystic ovary syndrome (PCOS) in later life? SUMMARY ANSWER: Overall, greater childhood BMI was associated with menstrual irregularity, and greater childhood BMI and waist/height ratio (WHtR) in white but not black participants were associated with PCOS in adulthood. WHAT IS KNOWN ALREADY: Increased childhood BMI has been associated with irregular menstrual cycles and PCOS symptoms in adulthood in two longitudinal population-based studies, but no study has reported on associations with childhood abdominal obesity. Few studies have investigated whether there are racial differences in the associations of adiposity with PCOS though there has been some suggestion that associations with high BMI may be stronger in white girls than in black girls. STUDY DESIGN, SIZE, DURATION: The study included 1516 participants (aged 26-41 years) from the Australian Childhood Determinants of Adult Health study (CDAH) and 1247 participants (aged 26-57 years) from the biracial USA Babies substudy of the Bogalusa Heart Study (BBS) who were aged 7-15 years at baseline. At follow-up, questions were asked about menstruation (current for CDAH or before age 40 years for BBS), ever having had a diagnosis of PCOS and symptoms of PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: In CDAH, a single childhood visit was conducted in 1985. In BBS, multiple childhood visits occurred from 1973 to 2000 and race was reported (59% white; 41% black). In childhood, overweight and obesity were defined by international age-sex-specific standards for BMI and WHtR was considered as an indicator of abdominal obesity. Multilevel mixed-effects Poisson regression estimated relative risks (RRs) adjusting for childhood age, highest parental and own education and age at menarche. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of childhood obesity was 1.1% in CDAH and 7.5% in BBS. At follow-up, menstrual irregularity was reported by 16.7% of CDAH and 24.5% of BBS participants. The prevalence of PCOS was 7.4% in CDAH and 8.0% in BBS participants. In CDAH, childhood obesity was associated with menstrual irregularity (RR = 2.84, 95% CI: 1.63-4.96) and PCOS (RR = 4.05, 95% CI: 1.10-14.83) in adulthood. With each 0.01 unit increase in childhood WHtR there was a 6% (95% CI: 1-11%) greater likelihood of PCOS. Overall, in BBS, childhood obesity was associated with increased risk of menstrual irregularity (RR = 1.44, 95% CI: 1.08-1.92) in adulthood. Significant interaction effects between race and childhood adiposity were detected in associations with PCOS. In BBS white participants, childhood obesity was associated with PCOS (RR = 2.93, 95% CI: 1.65-5.22) and a 0.01 unit increase in childhood WHtR was associated with an 11% (95% CI: 5-17%) greater likelihood of PCOS in adulthood. In BBS black participants, no statistically significant associations of childhood adiposity measures with PCOS were observed. LIMITATIONS, REASONS FOR CAUTION: The classification of menstrual irregularity and PCOS was based on self-report by questionnaire, which may have led to misclassification of these outcomes. However, despite the limitations of the study, the prevalence of menstrual irregularity and PCOS in the two cohorts was consistent with the literature. While the study samples at baseline were population-based, loss to follow-up means the generalizability of the findings is uncertain. WIDER IMPLICATIONS OF THE FINDINGS: Greater childhood adiposity indicates a higher risk of menstrual irregularity and PCOS in adulthood. Whether this is causal or an early indicator of underlying hormonal or metabolic disorders needs clarification. The stronger associations of adiposity with PCOS in white than black participants suggest that there are racial differences in childhood adiposity predisposing to the development of PCOS and other environmental or genetic factors are also important. STUDY FUNDING/COMPETING INTEREST(S): The CDAH study was supported by grants from the Australian National Health and Medical Research Council (grants 211316, 544923 and 1128373). The Bogalusa Heart Study is supported by US National Institutes of Health grants R01HD069587, AG16592, HL121230, HD032194 and P50HL015103. No competing interests existed.

Top 10 priorities for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study† ‡.

STUDY QUESTION: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER: Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS: A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Variation in menopausal vasomotor symptoms outcomes in clinical trials: a systematic review.

BACKGROUND: There is substantial variation in how menopausal vasomotor symptoms are reported and measured among intervention studies. This has prevented meaningful comparisons between treatments and limited data synthesis. OBJECTIVES: To review systematically the outcome reporting and measures used to assess menopausal vasomotor symptoms from randomised controlled trials of treatments. SEARCH STRATEGY: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to May 2018. SELECTION CRITERIA: Randomised controlled trials with a primary outcome of menopausal vasomotor symptoms in women and a sample size of at least 20 women per study arm. DATA COLLECTION AND ANALYSIS: Data about study characteristics, primary vasomotor-related outcomes and methods of measuring them. MAIN RESULTS: The search identified 5591 studies, 214 of which were included. Forty-nine different primary reported outcomes were identified for vasomotor symptoms and 16 different tools had been used to measure these outcomes. The most commonly reported outcomes were frequency (97/214), severity (116/214), and intensity (28/114) of vasomotor symptoms or a composite of these outcomes (68/214). There was little consistency in how the frequency and severity/intensity of vasomotor symptoms were defined. CONCLUSIONS: There is substantial variation in how menopausal vasomotor symptoms have been reported and measured in treatment trials. Future studies should include standardised outcome measures which reflect the priorities of patients, clinicians, and researchers. This is most effectively achieved through the development of a Core Outcome Set. This systematic review is the first step towards development of a Core Outcome Set for menopausal vasomotor symptoms. TWEETABLE SUMMARY: Menopausal hot flushes and night sweats have been reported in 49 different ways in clinical research. A core outcome set is urgently required.

A core outcome set for future endometriosis research: an international consensus development study.

OBJECTIVE: To develop a core outcome set for endometriosis. DESIGN: Consensus development study. SETTING: International. POPULATION: One hundred and sixteen healthcare professionals, 31 researchers and 206 patient representatives. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final core outcome set includes three core outcomes for trials evaluating potential treatments for pain and other symptoms associated with endometriosis: overall pain; improvement in the most troublesome symptom; and quality of life. In addition, eight core outcomes for trials evaluating potential treatments for infertility associated with endometriosis were identified: viable intrauterine pregnancy confirmed by ultrasound; pregnancy loss, including ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy; live birth; time to pregnancy leading to live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital abnormalities. Two core outcomes applicable to all trials were also identified: adverse events and patient satisfaction with treatment. CONCLUSIONS: Using robust consensus science methods, healthcare professionals, researchers and women with endometriosis have developed a core outcome set to standardise outcome selection, collection and reporting across future randomised controlled trials and systematic reviews evaluating potential treatments for endometriosis. TWEETABLE ABSTRACT: @coreoutcomes for future #endometriosis research have been developed @jamesmnduffy.

Managing vasomotor symptoms effectively without hormones.

Vasomotor symptoms (hot flushes and/or night sweats) affect approximately 80% of women over the menopause transition and can affect quality of life, productivity, and relationships. Vasomotor symptoms are the main reason for seeking treatment during the menopausal transition. Although menopausal hormone therapy (MHT) is effective for symptom management, the majority of symptomatic women do not take MHT. In this article, we review the evidence for non-hormonal treatments for vasomotor symptoms, including pharmacological and non-pharmacological approaches, and provide a clinical algorithm for managing symptomatic women.

Cisplatin- and cyclophosphamide-induced primordial follicle depletion is caused by direct damage to oocytes.

It is well established that DNA-damaging chemotherapies can cause infertility and ovarian endocrine failure by depleting the ovarian reserve of primordial follicles. Currently, no effective pharmacological therapies exist for the preservation of long-term fertility and ovarian function in female cancer patients, due to a limited understanding of the mechanisms of chemotherapy-induced follicle depletion. This study investigated the cellular targets, molecular mechanisms, and temporal course of ovarian reserve depletion following treatment with commonly used chemotherapeutic drugs. Adult female C57BL/6 mice were injected i.p. with saline, cisplatin (5mg/kg), or cyclophosphamide (300mg/kg); ovaries were harvested after 8 or 24 hours. Follicle counts showed depletion of all follicular stages 24 hours after administration of cisplatin or cyclophosphamide. Eight hours post-treatment, H2A histone family member X (γH2AX) immunofluorescence showed DNA double-stranded breaks at all follicular stages, including within primordial follicle oocytes. This staining was resolving by 24 hours, indicating that primordial follicle oocytes begin to undergo either apoptosis or repair in this timeframe. γH2AX-positive follicles were further examined to identify the specific cell types damaged. In primordial, transitional, and primary follicles, only oocytes sustained DNA damage, whereas in secondary and antral follicles, only somatic cells were affected. TUNEL staining confirmed that apoptosis occurs in these targeted cell types. Whilst multi-drug and multi-dose regimens were not examined, this study conclusively shows that cyclophosphamide and cisplatin cause direct damage to primordial follicle oocytes, which then undergo apoptosis. Therefore, future pharmacological strategies to prevent chemotherapy-induced infertility in females must specifically prevent primordial follicle oocyte death.

The association between in-utero exposure to stressful life events during pregnancy and male reproductive function in a cohort of 20-year-old offspring: The Raine Study.

STUDY QUESTION: Is exposure to gestational stress in the critical time window for the normal differentiation and growth of male reproductive tissue associated with male reproductive function in offspring in later life? SUMMARY ANSWER: Exposure to stressful life events (SLEs) in early, but not late gestation, are associated with reduced adult male reproductive function, consistent with the hypothesis that events during early prenatal life programme adult male reproductive function. WHAT IS ALREADY KNOWN: Animal studies suggest that gestational stress may impact on the reproductive function of male offspring, but human evidence is sparse. STUDY DESIGN, SIZE, DURATION: Using a prospective longitudinal cohort, we examined the association between number and type of maternal stressors during pregnancy in both early and late gestation and reproductive function in 643 male Generation 2 (offspring) at age 20 years. Mothers and their male Generation 2 (offspring) from The Raine Study participated. Mothers prospectively reported SLEs during pregnancy recorded at gestational weeks 18 and 34 using a standardized 10-point questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 643 male Generation 2 (offspring) underwent testicular ultrasound examination and semen analysis and provided serum for reproductive hormone analysis. Multivariate linear regression analysis was used to examine associations. MAIN RESULTS AND ROLE OF CHANCE: Of 643 recruited males, 407 (63%) were exposed to at least one SLE in early gestation. Fewer SLEs were reported in late gestation (n = 343, 53%). Maternal SLE exposure in early gestation was negatively associated with total sperm count (ß = -0.31, 95% CI -0.58; -0.03), number of progressive motile sperm (ß = -0.15, 95% CI -0.31; 0.00) and morning serum testosterone concentration (ß = -0.04, 95% CI -0.09; -0.00). No similar effects of maternal SLE exposure in late pregnancy were detected. The large sample size and an objective detailed direct assessment of adult male reproductive function with strict external quality control for sperm quality, as well as detailed prospectively collected information on prenatal SLEs in two distinct time windows of pregnancy reported by the women in early and late gestation along with other risk factors, imply minimal possibility of recall, information bias and selection bias. When assessing our results, we adjusted for a priori chosen confounders, but residual confounding or confounding by factors unbeknown to us cannot be ruled out. LIMITATIONS, REASONS FOR CAUTION: It is not possible to measure how SLEs impacted differently on the mother's experience or perception of stress. Resilience (coping) gradients may alter cortisol levels and thus modify the associations we observed and the mothers' own perception of stress severity may have provided a more precise estimate of her exposure. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that exposure to SLEs in early, but not late gestation, are associated with reduced adult male reproductive function. Improved support for women with exposure to SLEs during pregnancy, particularly during the first trimester, may improve the reproductive health of their male offspring in later life. Intervention studies of improved pregnancy support could provide more insight into this association and more information is needed about the potential specific epigenetic mechanisms underlying this association. STUDY FUNDING/COMPETING INTEREST(S): The male fertility sub-study was funded by NHMRC Grant 634 457. The core management of the Raine Study is funded by University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and Raine Medical Research foundation. Dr Bräuner's salary was supported by Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis foundation in Denmark. All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Managing menopausal symptoms after cancer.

The joint burden of cancer and menopause impacts millions of women globally. This review provides an approach to management of menopausal symptoms after cancer in all settings. This includes an overview of current evidence for both hormonal and non-hormonal treatments for vasomotor symptoms and vaginal dryness after cancer. Systemic menopausal hormone therapy provides symptom control and may be used after most cancers but should be avoided after estrogen receptor-positive breast cancer and after some other estrogen-dependent cancers. Non-hormonal therapies have been minimally studied in women after a cancer diagnosis and, where they have been studied, it is usually in women with breast cancer. Non-hormonal methods to manage vasomotor symptoms include cognitive behavioral therapy, hypnosis, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, clonidine, and gabapentin. Vaginal estrogen may be useful to address vaginal dryness. However, safety data in breast cancer patients are still lacking and there is currently no consensus. Lubricants may also help with pain with sexual activity. Management of menopausal symptoms after cancer may be challenging and should include information about induced menopause and possible symptoms as well as available treatments. Management then requires a holistic and multidisciplinary approach with individualized care.

An analysis of the atmospheric propagation of underground-explosion-generated infrasonic waves based on the equations of fluid dynamics: Ground recordings.

An investigation on the propagation of underground-explosion-generated infrasonic waves is carried out via numerical simulations of the equations of fluid dynamics. More specifically, the continuity, momentum, and energy conservation equations are solved along with the Herzfeld-Rice equations in order to take into account the effects of vibrational relaxation phenomena. The radiation of acoustic energy by the ground motion caused by underground explosions is initiated by enforcing the equality, at ground level, between the component of the air velocity normal to the Earth's surface and the normal velocity of the ground layer. The velocity of the ground layer is defined semi-empirically as a function of the depth of burial and of the yield. The effects of the depth and of the source energy on the signals recorded in the epicentral zone are first discussed. The tropospheric and stratospheric infrasonic phases traveling at a long-range are then analyzed and explained. Synthesized ground waveforms are finally discussed and compared to those recorded at the I45RU station of the International Monitoring System after the 2013 North-Korean test. Good agreement is found between numerical results and experimental data, which motivates the use of infrasound technologies alongside seismic techniques for the characterization of underground explosions.

Exploring knowledge, attitudes and experience of genitourinary symptoms in women with early breast cancer on adjuvant endocrine therapy.

Clinical trials of adjuvant endocrine therapy in women with early breast cancer have consistently reported that genitourinary symptoms are common. However, little is known about women's experiences of genitourinary symptoms, their views about the symptoms and how they impact on their lives. The aim of this study was to explore knowledge, attitudes and experiences of genitourinary symptoms among women receiving adjuvant endocrine therapy for early breast cancer. Thirty-two semi-structured interviews were conducted and subjected to a rigorous qualitative analysis. Genitourinary symptoms were commonly reported to negatively impact on personal, social and physical activities, were often attributed to anxiety and stress and were a source of embarrassment. Women also commented on the limited information available or provided regarding the potential genitourinary adverse effects of adjuvant endocrine therapy. There was a general lack of awareness that their symptoms could be associated with or exacerbated by adjuvant endocrine therapy. Women indicated a preference to receive information and advice about potential management options from either their general practitioner or specialist. These findings underscore the importance of improving communication and increasing awareness among both clinicians and patients about the potential impact of adjuvant endocrine therapy on genitourinary symptoms.

Preferential incorporation of dark, coloured materials into nests by a mound-nesting stream cyprinid.

We compared size and colour characteristics of rocks used by male cutlip minnows Exoglossum maxillingua to build nests to those of streambed background materials. We found that materials used to construct conspicuous, mound-shaped nests were uniform in size and darker and more colour-saturated than background materials of the same size. To our knowledge, this phenomenon is the first reported example of fish selecting nest materials based on colour and has important implications for the conservation of mound-nesting stream cyprinid species.

Altered functioning of reward circuitry in youth offspring of parents with bipolar disorder.

BACKGROUND: Offspring of parents with bipolar disorder (BD) (BO) are at higher risk of BD than offspring of parents with non-BD psychopathology (NBO), although both groups are at higher risk than offspring of psychiatrically healthy parents (HC) for other affective and psychiatric disorders. Abnormal functioning in reward circuitry has been demonstrated previously in individuals with BD. We aimed to determine whether activation and functional connectivity in this circuitry during risky decision-making differentiated BO, NBO and HC. METHOD: BO (n = 29; mean age = 13.8 years; 14 female), NBO (n = 28; mean age = 13.9 years; 12 female) and HC (n = 23; mean age = 13.7 years; 11 female) were scanned while performing a number-guessing reward task. Of the participants, 11 BO and 12 NBO had current non-BD psychopathology; five BO and four NBO were taking psychotropic medications. RESULTS: A 3 (group) × 2 (conditions: win-control/loss-control) analysis of variance revealed a main effect of group on right frontal pole activation: BO showed significantly greater activation than HC. There was a significant main effect of group on functional connectivity between the bilateral ventral striatum and the right ventrolateral prefrontal cortex (Z > 3.09, cluster-p < 0.05): BO showed significantly greater negative functional connectivity than other participants. These between-group differences remained after removing youth with psychiatric disorders and psychotropic medications from analyses. CONCLUSIONS: This is the first study to demonstrate that reward circuitry activation and functional connectivity distinguish BO from NBO and HC. The fact that the pattern of findings remained when comparing healthy BO v. healthy NBO v. HC suggests that these neuroimaging measures may represent trait-level neurobiological markers conferring either risk for, or protection against, BD in youth.

Abstracts of the 24th international isotope society (UK group) symposium: synthesis and applications of labelled compounds 2015.

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

Development of a two-step, non-probed multiplex real-time PCR for surveilling Vibrio anguillarum in seawater.

Vibrio anguillarum is an aggressive and halophilic bacterial pathogen most commonly originating from seawater. Vibrio anguillarum presence in fisheries and aquaculture facilities causes significant morbidity and mortality among aquaculture species primarily from haemorrhaging of the body and skin of the infected fish that eventually leads to death, collectively recognized as the disease vibriosis. This study served to develop a non-probe, multiplex real-time PCR assay to rapidly detect V. anguillarum presence in seawater. Specific primers targeting genes vah1, empA and rpoN of V. anguillarum were selected for multiplex reaction among 11 different primer sets and the extension step was eliminated. Primer concentration, denaturation time as well as annealing time and temperature of DNA amplification were optimized, thus reducing reaction duration. The two-step, non-probed multiplex real-time PCR set forth by this study detects as little as 3 CFU mL(-1) of V. anguillarum presence in sea water, without enrichment cultivation, in 70 min with molecular precision and includes melting curve confirmation.

Outcomes of intravenous tissue plasminogen activator for acute ischaemic stroke in HIV-infected adults.

BACKGROUND AND PURPOSE: To our knowledge there are no studies reporting the use and short-term outcomes of intravenous tissue plasminogen activator (IV-TPA) for the treatment of acute ischaemic stroke (AIS) in people living with HIV. METHODS: The US Nationwide Inpatient Sample (NIS) (2006-2010) was searched for HIV-infected AIS patients treated with IV-TPA. RESULTS: In the NIS, 2.2% (62/2877) of HIV-infected AIS cases were thrombolyzed with IV-TPA (median age 52 years, range 27-78, 32% female, 22% Caucasian) vs. 2.1% (19 335/937 896) of HIV-uninfected cases (median age 72 years, range 17-102 years, 50% female, 74% Caucasian; P = 0.77). There were more deaths in HIV-infected versus uninfected patients with stroke (220/2877, 7.6% vs. 49 089/937 547, 5.2%, P < 0.001) but no difference in the proportion of deaths amongst IV-TPA-treated patients. The age- and sex-adjusted odds ratio for death following IV-TPA administration in HIV-infected versus uninfected patients was 2.26 (95% CI 1.12, 4.58), but the interaction on mortality between HIV and IV-TPA use was not statistically significant, indicating no difference in risk of in-hospital death by HIV serostatus with IV-TPA use. A higher number of HIV-infected patients remained in hospital versus died or were discharged at both 10 and 30 days (P < 0.01 at 10 and 30 days). No difference in the proportion of intracerebral hemorrhage in the two groups was found (P = 0.362). CONCLUSIONS: The in-hospital mortality is higher amongst HIV-infected AIS patients than HIV-uninfected patients. However, the risk of death amongst HIV-infected patients treated with IV-TPA is similar to HIV-uninfected groups.