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Study question How can cycle monitoring using a urine-based hormonal assay device improve current clinical practice in medically assisted reproduction (MAR)? Summary answer A urine-based hormonal assay has the potential to overcome the inconvenience of blood tests and reduce the frequency of appointments, waiting times and patient burden. What is known already Cycle monitoring via ultrasound and serum-based hormonal assays during MAR can provide information on the ovarian response and assist in optimising treatment strategies and reducing complications, such as ovarian hyperstimulation syndrome (OHSS). However, blood tests may cause inconvenience to patients due to repeated venepuncture and the need for frequent clinic appointments. Urine-based assays have been historically used by fertility specialists in clinics, but since got replaced by more practical and automated serum-based assays. Novel technology utilising rapid chromatographic immunoassay to test urinary reproductive hormones in a home setting could provide an alternative to current serum-based testing at clinics. Study design, size, duration A questionnaire was disseminated among 24 fertility specialists (2019–2020) on the use of ultrasound and serum-based hormone monitoring in clinical practice. In addition, the literature on the reliability of urine-based hormonal assays compared to serum-based hormonal assays during MAR was reviewed in order to examine if urine-based hormonal monitoring could be re-introduced in clinical practice using novel state-of-the-art technology. Participants/materials, setting, methods All 24 surveyed fertility specialists responded, representing 10 countries from across Europe, Asia and Latin America. Questions assessed the frequency and role of hormonal monitoring, the hormones tested and the drawbacks of blood tests. The PubMed search engine was used to search the Medline database for publications between 1960–2020 with (MeSH-) search terms related to cycle monitoring (e.g. fertility monitoring, controlled ovarian stimulation, ovulation confirmation) and hormonal assays (e.g. estrone–3-glucuronide or E1–3G). Main results and the role of chance The survey confirmed that many fertility practitioners (n = 22/24) routinely conducted hormone monitoring during MAR, primarily for guiding dose adjustments (n = 20/24) and indicating risk of OHSS (n = 20/24). The reported drawbacks of blood tests included validity of results from different service providers, long waiting times and discomfort to patients due to travelling to clinics for tests and repeated venepunctures. The hormones routinely checked were E2 (n = 22/22), P4 (n = 18/22) and LH (n = 15/22). The literature review revealed a relatively high correlation (correlation coefficients 0.85–0.95) between serum E2 and urinary E1–3G in gonadotrophin stimulated cycles (Lessing 1987, Catalan 1989, Rapi 1992 and Alper 1994). No studies assessed the correlation between serum P4 and urinary PdG or between serum LH and urinary LH in stimulated cycles. In natural cycles, the correlation coefficients between serum P4 and urinary PdG seemed to be slightly higher than those between serum E2 and urinary E1–3G (0.73–0.94 vs. 0.54–0.88) (Denari 1981, Munro 1991, Roos 2015, Stanczyk 1980). One study reported a moderate correlation coefficient (0.72) between serum and urinary LH in natural cycles (Roos 2015). Limitations, reasons for caution There is risk of selection-bias for fertility specialists included in survey, however, the 100% response rate is reassuring. The correlation coefficients between serum- and urine-based hormonal assay and the cost-effectiveness and time-efficiency of urinary assay should be confirmed in further clinical studies using a novel state-of-the-art remote urinary monitoring device. Wider implications of the findings: Remote hormonal monitoring can be part of a novel digital health solution that includes remote ultrasound and tele-counselling to link clinics and patients at home. Especially during the unprecedented times of the COVID–19 pandemic, the prospect of remote monitoring system has the potential to improve patient experience during fertility treatment. Trial registration number Not applicable

Endometriosis is a chronic oestrogen-dependent gynaecological disease present in approximately 10% of women of reproductive age and up to 30–50% of women with infertility and/or pain. It is defined as the presence of endometrial-like tissue outside the uterus. The pathogenesis remains enigmatic but the most common hypothesis is Sampson’s theory of retrograde menstruation. Over the last decade, the roles of inflammation, angiogenesis, and the immune system have been well documented. Diagnosis of endometriosis is difficult since physical examination, ultrasonography, and magnetic resonance imaging can detect but not exclude the presence of endometriosis. Therefore, the gold standard for diagnosis of endometriosis remains laparoscopic visualization with histological confirmation. Medical treatment options are combined oral contraceptives, progestogens, or gonadotropin-releasing hormone analogues. Surgical management is necessary in patients who want to become pregnant or those who are refractory to medical treatment. These complex surgical procedures, with significant risks and recurrence rates, should be performed by experienced teams only.

The nature and pace of genome mutation is largely unknown. Because standard methods sequence DNA from populations of cells, the genetic composition of individual cells is lost, de novo mutations in cells are concealed within the bulk signal and per cell cycle mutation rates and mechanisms remain elusive. Although single-cell genome analyses could resolve these problems, such analyses are error-prone because of whole-genome amplification (WGA) artefacts and are limited in the types of DNA mutation that can be discerned. We developed methods for paired-end sequence analysis of single-cell WGA products that enable (i) detecting multiple classes of DNA mutation, (ii) distinguishing DNA copy number changes from allelic WGA-amplification artefacts by the discovery of matching aberrantly mapping read pairs among the surfeit of paired-end WGA and mapping artefacts and (iii) delineating the break points and architecture of structural variants. By applying the methods, we capture DNA copy number changes acquired over one cell cycle in breast cancer cells and in blastomeres derived from a human zygote after in vitro fertilization. Furthermore, we were able to discover and fine-map a heritable inter-chromosomal rearrangement t(1;16)(p36;p12) by sequencing a single blastomere. The methods will expedite applications in basic genome research and provide a stepping stone to novel approaches for clinical genetic diagnosis. ispartof: Nucleic acids research vol:41 issue:12 pages:6119-6138 ispartof: location:England status: published

Study question: What is the effect of a legal limitation of the number of embryos that can be transferred in an assisted reproductive technology (ART) cycle on the multiple delivery rate? Summary answer: The Belgian national register shows that the introduction of reimbursement of ART laboratory costs in July 2003, and the imposition of a legal limitation of the number of embryos transferred in the same year, were associated with a >50% reduction of the multiple pregnancy rate from 27 to 11% between 2003 and the last assessment in 2010, without any reduction of the pregnancy rate per cycle. What is known already: Individual Belgian IVF centres have published their results since the implementation of the law, and these show a decrease in the multiple pregnancy rate on a centre by centre basis. However, the overall national picture remains unpublished. Study design, size, duration: Cohort study from 1990 to 2010 of all ART cycles in Belgium (2685 cycles in 1990 evolving to 19 110 cycles in 2010), with a retrospective analysis from 1990 to 2000 and prospective online data collection since 2001. Participants/materials, setting, methods: Registration evolved from paper written reports per centre to a compulsory online registration of all ART cycles. From 2001 up to mid-2009, data were collected from Excel spread sheets or MS Access files into an MS Access database. Since mid-2009, data collection is done via a remote and secured web-based system (www.belrap.be) where centres can upload their data and get immediate feedback about missing data, errors and inconsistencies. Main results and the role of chance: National Belgian registration data show that reimbursement of IVF laboratory costs in July 2003, coupled to a legal limitation in the number of embryos transferred in utero,were associated with a 50% reduction of the multiple pregnancy rate from 27 to 11% without reduction of the pregnancy rate per cycle, and with an increase in the number of fresh and frozen ART cycles due to improved access to treatment. Limitations, reasons for caution: There is potential underreporting of complications of ART treatment, pregnancy outcome and neonatal health. Wider implications of the findings: Over the 20 years of registration, the pregnancy rate has remained constant, despite the reduction in the number of embryos transferred, optimization of laboratory procedures and stimulation protocols, introduction of quality systems and implementation of the EU Tissue Directive over the period 2004–2010.

STUDY QUESTION Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER N/A.

BACKGROUND: A case-control study was designed to determine the possible association between chronic exposure to dioxins and polychlorinated biphenyls (PCBs), and the occurrence of endometriosis. The study group consisted of 42 infertile endometriosis cases and 27 mechanical infertile controls, both groups attending one of the collaborating Centres for Reproductive Medicine, enrolled between 1996-1998. METHODS: Exposure assessment to dioxin-like compounds was determined through CALUX (chemical-activated luciferase gene expression)-bioassay to measure dioxin-like total toxic equivalents (dioxins and co-planar PCBs), whereas non-co-planar PCBs were determined through chemical analysis. RESULTS: No association was found between median dioxin-like total toxic equivalents (TEQ) and the occurrence of endometriosis in infertile women [cases (n = 34): 29; controls (n = 27): 24; NS]. When patients were subdivided based on an arbitrary cut-off value of 100 pg TEQ/g serum lipids, no statistically significant association between very high exposure to dioxin-like compounds and endometriosis was found [crude odds ratio (OR) = 4.33; confidence interval (CI) 0.49-38.19; NS]. After adjusting for body mass index, and alcohol consumption, the risk increased slightly to OR = 4.6 (CI 0.48-43.62; NS). There was no confounding by age, ovulatory dysfunction, caffeine intake, smoking or exposure to non-co-planar PCBs. CONCLUSIONS: The study results showed no statistically significant association between exposure to dioxin-like compounds and the occurrence of endometriosis in infertile women.

STUDY QUESTION To what extent do the management of endometriosis and the symptoms that remain after treatment affect the quality of life in women with the disease? SUMMARY ANSWER Many women with endometriosis had impaired quality of life and continued to suffer from endometriosis-associated symptoms even though their endometriosis has been managed in tertiary care centres. WHAT IS KNOWN ALREADY The existing literature indicates that quality of life and work productivity is reduced in women with endometriosis. However, most studies have small sample sizes, are treatment related or examine newly diagnosed patients only. STUDY DESIGN, SIZE, DURATION A cross-sectional questionnaire-based survey among 931 women with endometriosis treated in 12 tertiary care centres in 10 countries. PARTICIPANTS/MATERIALS, SETTING, METHODS Women diagnosed with endometriosis who had at least one contact related to endometriosis-associated symptoms during 2008 with a participating centre were enrolled into the study. The study investigated the effect of endometriosis on education, work and social wellbeing, endometriosis-associated symptoms and health-related quality of life, by using questions obtained from the World Endometriosis Research Foundation (WERF) GSWH instrument (designed and validated for the WERF Global Study on Women's Health) and the Short Form 36 version 2 (SF-36v2). MAIN RESULTS AND THE ROLE OF CHANCE Of 3216 women invited to participate in the study, 1450 (45%) provided informed consent and out of these, 931 (931/3216 = 29%) returned the questionnaires. Endometriosis had affected work in 51% of the women and affected relationships in 50% of the women at some time during their life. Dysmenorrhoea was reported by 59%, dyspareunia by 56% and chronic pelvic pain by 60% of women. Quality of life was decreased in all eight dimensions of the SF-36v2 compared with norm-based scores from a general US population (all P < 0.01). Multivariate regression analysis showed that number of co-morbidities, chronic pain and dyspareunia had an independent negative effect on both the physical and mental component of the SF-36v2. LIMITATIONS, REASONS FOR CAUTION The fact that women were enrolled in tertiary care centres could lead to a possible over-representation of women with moderate-to-severe endometriosis, because the participating centres typically treat more complex and referred cases of endometriosis. The response rate was relatively low. Since there was no Institute Review Board approval to do a non-responder investigation on basic characteristics, some uncertainty remains regarding the representativeness of the investigated population. WIDER IMPLICATIONS OF THE FINDINGS This international multicentre survey represents a large group of women with endometriosis, in all phases of the disease, which increases the generalizability of the data. Women still suffer from frequent symptoms, despite tertiary care management, in particular chronic pain and dyspareunia. As a result their quality of life is significantly decreased. A patient-centred approach with extensive collaboration across disciplines, such as pain specialists, psychologists, sexologists and social workers, may be a valuable strategy to improve the long-term care of women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The WERF EndoCost study is funded by the World Endometriosis Research Foundation (WERF) through grants received from Bayer Schering Pharma AG, Takeda Italia Farmaceutici SpA, Pfizer Ltd and the European Society of Human Reproduction and Embryology. The sponsors did not have a role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. L.H. is the chief executive and T.D. was a board member of WERF at the time of funding. T.D. holds the Merck-Serono Chair in Reproductive Medicine and Surgery, and the Ferring Chair in Reproductive Medicine at the Katholieke Universiteit Leuven in Belgium and has served as consultant/research collaborator for Merck-Serono, Schering-Plough, Astellas and Arresto.