Natural and Anthropogenic Processes Affecting Domestic Groundwater Quality within the Northwestern Appalachian Basin.

Domestic wells serve as the primary drinking-water source for rural residents in the northern Appalachian Basin (NAB), despite a limited understanding of contaminant distributions in groundwater sources. We employ a newly collected dataset of 216 water samples from domestic wells in Ohio and West Virginia and an integrated contaminant-source attribution method to describe water quality in the western NAB and characterize key agents influencing contaminant distributions. Our results reveal arsenic and nitrate concentrations above federal maximum contaminant levels (MCLs) in 6.8 and 1.3% of samples and manganese concentrations above health advisory in 7.3% of samples. Recently recharged groundwaters beneath upland regions appear vulnerable to surface-related impacts, including nitrate pollution from agricultural activities and salinization from road salting and domestic sewage sources. Valley regions serve as terminal discharge points for long-residence-time groundwaters, where mixing with basin brines is possible. Arsenic impairments occurred in alkaline groundwaters with major-ion compositions altered by ion exchange and in low-oxygen metal-rich groundwaters. Mixing with as much as 4-10% of mine discharge-like waters was observed near coal mining operations. Our study provides new insights into key agents of groundwater impairment in an understudied region of the NAB and presents an integrated approach for contaminant-source attribution applicable to other regions of intensive resource extraction.

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.

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.

Effectiveness on fertility outcome of tubal flushing with different contrast media: systematic review and network meta-analysis.

OBJECTIVES: To compare, in women with infertility, the effectiveness and safety of tubal flushing using oil-based contrast medium, water-based contrast medium or their combination, and no tubal flushing, and to evaluate the effectiveness of tubal flushing on fertility outcome over time. METHODS: We performed a systematic review and network meta-analysis, searching the electronic databases MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, and trial registries, up to 25 September 2018. We included randomized controlled trials (RCTs) comparing the following interventions with each other or with no intervention in women with infertility: tubal flushing using water-based contrast medium, tubal flushing using oil-based contrast medium or additional tubal flushing with oil-based medium following diagnostic tubal flushing with water-based medium. The outcomes included clinical pregnancy, live birth, ongoing pregnancy, miscarriage, ectopic pregnancy and adverse events. RESULTS: Of the 283 studies identified through the search, 14 RCTs reporting on 3852 women with infertility were included. Network meta-analysis showed that tubal flushing using oil-based contrast medium was associated with higher odds of clinical pregnancy within 6 months after randomization and more subsequent live births compared with tubal flushing using water-based medium (odds ratio (OR), 1.67 (95% CI, 1.38-2.03), moderate certainty of evidence; and OR, 2.18 (95% CI, 1.30-3.65), low certainty of evidence, respectively) and compared with no intervention (OR, 2.28 (95% CI, 1.50-3.47), moderate certainty of evidence; and OR, 2.85 (95% CI, 1.41-5.74), low certainty of evidence, respectively). These results agreed with those of the pairwise meta-analysis. For clinical pregnancy within 6 months, there was insufficient evidence of a difference between tubal flushing with water-based contrast medium and no intervention (OR, 1.36 (95% CI, 0.91-2.04), low certainty of evidence). For fertility outcomes after 6 months, there was insufficient evidence of a difference in any comparison (low to very low certainty of evidence). Compared with tubal flushing using water-based contrast medium, the use of oil-based contrast medium was associated with higher odds of asymptomatic intravasation (OR, 5.06 (95% CI, 2.29-11.18), moderate certainty of evidence). CONCLUSIONS: In women with infertility undergoing fertility workup, tubal flushing using oil-based contrast medium probably increases clinical pregnancy rates within 6 months after randomization and may increase subsequent live-birth rates, compared with tubal flushing using water-based contrast medium and compared with no intervention. Evidence on fertility outcomes beyond 6 months is inadequate to draw firm conclusions. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Eficacia sobre el resultado de fertilidad del lavado de trompas con diferentes medios de contraste: revisión sistemática y metaanálisis en red OBJETIVOS: Comparar, en mujeres con infertilidad, la efectividad y seguridad del lavado de trompas con un medio de contraste a base de aceite, un medio de contraste a base de agua o una combinación, y el no lavado de trompas, y evaluar la efectividad del lavado de trompas en el resultado de la fertilidad con el tiempo. MÉTODOS: Se realizó una revisión sistemática y un metaanálisis en red, mediante búsquedas en las bases de datos electrónicas MEDLINE, EMBASE y el Registro Central Cochrane de Ensayos Controlados, y en otros registros de ensayos, hasta el 25 de septiembre de 2018. Se incluyeron ensayos controlados aleatorizados (ECA) que compararon las siguientes intervenciones entre sí o con la no intervención en mujeres con infertilidad: lavado de trompas con medio de contraste a base de agua, lavado de trompas con medio de contraste a base de aceite o lavado de trompas adicional con un medio a base de aceite después de un lavado de trompas con un medio a base de agua. Los resultados incluyeron el embarazo confirmado ecográficamente, el nacimiento vivo, el embarazo en curso, el aborto espontáneo, el embarazo ectópico y los eventos adversos. RESULTADOS: De los 283 estudios identificados mediante la búsqueda, se incluyeron 14 ECA que informaron sobre 3852 mujeres con infertilidad. El metaanálisis en red mostró que el lavado de trompas con medio de contraste a base de aceite se asoció con mayores probabilidades de embarazo confirmado ecográficamente dentro de los seis meses posteriores a la aleatorización y más nacimientos vivos posteriores en comparación con el lavado de trompas con medio a base de agua (razón de momios [RM], 1,67; IC 95%: 1,38-2,03), certeza moderada de evidencia; y RM, 2,18 (IC 95%: 1,30-3,65), certeza baja de evidencia, respectivamente) y en comparación con la no intervención (RM, 2,28 (IC 95%: 1,50-3,47), certeza moderada de evidencia; y RM, 2,85 (IC 95%: 1,41-5,74), certeza baja de evidencia, respectivamente). Estos resultados coincidieron con los del metaanálisis por pares. No hubo evidencia suficiente de una diferencia entre el lavado de trompas con medio de contraste a base de agua y la no intervención para el embarazo clínico dentro de los seis meses (RM, 1,36 (IC 95%: 0,91-2,04); certeza baja de evidencia). Para los resultados de fertilidad después de los seis meses, no hubo evidencia suficiente de diferencias en cualquier comparación (certeza de evidencia baja a muy baja). En comparación con el lavado de trompas con un medio de contraste a base de agua, el uso de un medio de contraste a base de aceite se asoció con mayores probabilidades de intravasación asintomática (RM, 5,06 (IC 95%: 2,29-11,18), certeza moderada de evidencia). CONCLUSIONES: En las mujeres con infertilidad que se someten a un examen de fertilidad, el lavado de trompas con medio de contraste a base de aceite aumenta la probabilidad de las tasas de embarazo clínico dentro de los 6 meses posteriores a la aleatorización y puede aumentar las tasas posteriores de nacimientos vivos, en comparación con el lavado de trompas con medio de contraste a base de agua y en comparación con la no intervención. La evidencia sobre los resultados de fertilidad después de los seis meses es inadecuada para establecer conclusiones firmes. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Establishment of lipiodol as a fertility treatment - prospective study of the complete innovative treatment data set.

BACKGROUND: Our randomised controlled trial (RCT) found that a hysterosalpingogram (HSG) with the oil-soluble contrast medium (OSCM) lipiodol improves pregnancy rates amongst couples with unexplained and endometriosis-related infertility. These results were supported by the findings of our observational study of the first 100 women to undergo the procedure after it was offered as an innovative treatment in New Zealand from September 2003. AIM: To further assess the safety and efficacy of lipiodol procedures and present together the complete data set of the procedures performed in our RCT and those performed as innovative procedures (n = 296) prior to it being offered as a standard fertility treatment. METHODS: Women with infertility underwent a therapeutic lipiodol procedure by HSG technique with fluoroscopy X-ray screening. Primary outcomes were clinical pregnancy within six months of the procedure and live birth. RESULTS: The overall pregnancy rate for the 296 women was 40.2%. The live birth/ongoing pregnancy rate was 31.4%. The pregnancy rates for women under the age of 40 with endometriosis and unexplained infertility were 51.1 and 31.4%, respectively. CONCLUSION: Lipiodol can now be considered a standard treatment for both unexplained and endometriosis-related infertility. The precise mechanism behind the fertility-enhancing effect of lipiodol has yet to be elucidated. This study supports a mechanism of effect on the endometrium with possible enhanced receptivity of the endometrium to embryo implantation.

A randomized controlled trial of fallopian tube sperm perfusion compared with standard intrauterine insemination for women with non-tubal infertility.

STUDY QUESTION: Does fallopian tube sperm perfusion (FSP) result in better pregnancy and live birth rates than standard intrauterine insemination (SIUI) for couples with non-tubal infertility with or without gonadotrophin or clomiphene stimulation? SUMMARY ANSWER: There was no evidence of an improvement in live birth rates with FSP compared with SIUI. WHAT IS KNOWN ALREADY: Previous randomized controlled trials have suggested improved live birth rates with FSP but these trials were small. A systematic review published in 2004 suggested heterogeneity in results. STUDY DESIGN, SIZE, AND DURATION: This pragmatic, multicentre, randomized controlled trial compared SIUI and FSP in 417 women with non-tubal infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: The patients were treated at fertility clinics in New Zealand, Australia and the United Arab Emirates. MAIN RESULTS AND THE ROLE OF CHANCE: Four hundred and seventeen women were randomized to SIUI (n = 210) or FSP (n = 207). Data were available for analysis from 198 women in the SIUI group and 198 women in the FSP group. There were 19 women with incomplete data because of cycle cancellation or withdrawals and 2 women who conceived prior to commencing treatment. There were no significant differences in live birth rates between the two groups with 27 (12.9%) in the SIUI group and 21 in the FSP group (10.1%) [Odds Ratio (OR) 1.31 (0.71, 2.39), P = 0.48]. Two ectopic pregnancies were reported in the SIUI group and one was reported in the FSP group. LIMITATIONS, REASONS FOR CAUTION: Different ovulation protocols were used in the different clinics. Approximately 10% of the cycles involved donor sperm and ∼5% of the cycles did not complete the assigned intervention. WIDER IMPLICATIONS OF THE FINDINGS: There was no evidence of an improvement in live birth rates with FSP compared with SIUI. STUDY FUNDING/COMPETING INTEREST(S): The study was funded in part by the A+ trust of the Auckland District Health Board. No commercial funding was received. TRIAL REGISTRATION NUMBER: ANZCTR Number ACTRN12612001303831.

Endometriosis classification, staging and reporting systems: a review on the road to a universally accepted endometriosis classification.

BACKGROUND: In the field of endometriosis, several classification, staging and reporting systems have been developed. However, endometriosis classification, staging and reporting systems that have been published and validated for use in clinical practice have not been systematically reviewed up to now. OBJECTIVES: The aim of the current review is to provide a historical overview of these different systems based on an assessment of published studies. MATERIALS AND METHODS: A systematic Pubmed literature search was performed. Data were extracted and summarised. RESULTS: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific and different purposes. There is still no international agreement on how to describe the disease. Studies evaluating different systems are summarised showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the Enzian system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. CONCLUSIONS: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated, in 46 studies, for the purpose for which they were developed. It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. WHAT IS NEW?: This overview of existing systems is a first step in working towards a universally accepted endometriosis classification.

An International Terminology for Endometriosis, 2021.

BACKGROUND: Different classification systems have been developed for endometriosis, using different definitions for the disease, the different subtypes, symptoms and treatments. In addition, an International Glossary on Infertility and Fertility Care was published in 2017 by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in collaboration with other organisations. An international working group convened over the development of a classification or descriptive system for endometriosis. As a basis for such system, a terminology for endometriosis was considered a condition sine qua non. OBJECTIVES: The aim of the current paper is to develop a set of terms and definitions on endometriosis that would be the basis for standardisation in disease description, classification and research. MATERIALS AND METHODS: The working group listed a number of terms relevant to be included in the terminology, documented currently used and published definitions, and discussed and adapted them until consensus was reached within the working group. Following stakeholder review, further terms were added, and definitions further clarified. Although definitions were collected through published literature, the final set of terms and definitions is to be considered consensus-based. After finalisation of the first draft, the members of the international societies and other stakeholders were consulted for feedback and comments, which led to further adaptations. RESULTS: A list of 49 terms and definitions in the field of endometriosis is presented, including a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. Endometriosis is defined as a disease characterised by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process. CONCLUSIONS: The current paper outlines a list of 49 terms and definitions in the field of endometriosis. The application of the defined terms aims to facilitate harmonisation in endometriosis research and clinical practice. Future research may require further refinement of the presented definitions. WHAT IS NEW?: A consensus based international terminology for endometriosis for clinical and research use.

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 were 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 judgement, 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. Geoffrey Adamson 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. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne 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. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger 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. Jane Stewart 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. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. Andy Vail 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 HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong 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: Not applicable.

PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene.

BACKGROUND: Ovulation induction treatment with metformin, either alone or in combination with clomiphene citrate (CC), remains controversial even though previous randomized trials have examined this. METHODS: A double blinded multi-centre randomized trial was undertaken including 171 women with anovulatory or oligo-ovulatory polycystic ovary syndrome. Women with high body mass index (BMI) > 32 kg/m(2) received placebo ('standard care') or metformin; women with BMI < or = 32 kg/m(2) received CC ('standard care'), metformin or both. Treatment continued for 6 months or until pregnancy was confirmed. Primary outcomes were clinical pregnancy and live birth. RESULTS: For women with BMI > 32 kg/m(2), clinical pregnancy and live birth rates were 22% (7/32) and 16% (5/32) with metformin, 15% (5/33) and 6% (2/33) with placebo. For women with BMI < or = 32 kg/m(2), clinical pregnancy and live birth rates were 40% (14/35) and 29% (10/35) with metformin, 39% (14/36) and 36% (13/36) with CC, 54% (19/35) and 43% (15/35) with combination metformin plus CC. CONCLUSIONS: There is no evidence that adding metformin to 'standard care' is beneficial. Pregnancy and live birth rates are low in women with BMI > 32 kg/m(2) whatever treatment is used, with no evidence of benefit of metformin over placebo. For women with BMI < or = 32 kg/m(2) there is no evidence of significant differences in outcomes whether treated with metformin, CC or both. ClinicalTrials.gov number NCT00795808; trial protocol accepted for publication November 2005: Johnson, Aust N Z Journal Obstet Gynaecol 2006;46:141-145.

Uterine bathing with sonography gel prior to IVF/ICSI-treatment in patients with endometriosis, a multicentre randomised controlled trial.

STUDY QUESTION: What is the effect of uterine bathing with sonography gel prior to IVF/ICSI-treatment on live birth rates after fresh embryo transfer in patients with endometriosis? SUMMARY ANSWER: After formal interim analysis and premature ending of the trial, no significant difference between uterine bathing using a pharmacologically neutral sonography gel compared to a sham procedure on live birth rate after fresh embryo transfer in endometriosis patients (26.7% vs. 15.4%, relative risk (RR) 1.73, 95% confidence interval (CI) 0.81-3.72; P-value 0.147) could be found, although the trial was underpowered to draw definite conclusions. WHAT IS KNOWN ALREADY: Impaired implantation receptivity contributes to reduced clinical pregnancy rates after IVF/ICSI-treatment in endometriosis patients. Previous studies have suggested a favourable effect of tubal flushing with Lipiodol® on natural conceptions. This benefit might also be explained by enhancing implantation through endometrial immunomodulation. Although recent studies showed no beneficial effect of endometrial scratching, the effect of mechanical stress by intrauterine infusion on the endometrium in endometriosis patients undergoing IVF/ICSI-treatment has not been investigated yet. STUDY DESIGN SIZE DURATION: We performed a multicentre, patient-blinded, randomised controlled trial in which women were randomly allocated to either a Gel Infusion Sonography (GIS, intervention group) or a sham procedure (control group) prior to IVF/ICSI-treatment. Since recruitment was slow and completion of the study was considered unfeasible, the study was halted after inclusion of 112 of the planned 184 women. PARTICIPANTS/MATERIALS SETTING METHODS: We included infertile women with surgically confirmed endometriosis ASRM stage I-IV undergoing IVF/ICSI-treatment. After informed consent, women were randomised to GIS with intrauterine instillation of ExEm-gel® or sonography with gel into the vagina (sham). This was performed in the cycle preceding the embryo transfer, on the day GnRH analogue treatment was started. The primary endpoint was live birth rate after fresh embryo transfer. Analysis was performed by both intention-to-treat and per-protocol. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2014 to September 2018, we randomly allocated 112 women to GIS (n = 60) or sham procedure (n = 52). The live birth rate after fresh embryo transfer was 16/60 (26.7%) after GIS versus 8/52 (15.4%) after the sham (RR 1.73, 95% CI 0.81-3.72; P-value 0.147). Ongoing pregnancy rate was 16/60 (26.7%) after GIS versus 9/52 (17.3%) in the controls (RR 1.54, 95% CI 0.74-3.18). Miscarriage occurred in 1/60 (1.7%) after GIS versus 5/52 (9.6%) in the controls (RR 0.17, 95% CI 0.02-1.44) women. Uterine bathing resulted in a higher pain score compared with a sham procedure (visual analogue scale score 2.7 [1.3-3.5] vs. 1.0 [0.0-2.0], P < 0.001). There were two adverse events after GIS compared with none after sham procedures. LIMITATIONS REASONS FOR CAUTION: The study was terminated prematurely due to slow recruitment and trial fatigue. Therefore, the trial is underpowered to draw definite conclusions regarding the effect of uterine bathing with sonography gel on live birth rate after fresh embryo transfer in endometriosis patients undergoing IVF/ICSI-treatment. WIDER IMPLICATIONS OF THE FINDINGS: We could not demonstrate a favourable effect of uterine bathing procedures with sonography gel prior to IVF/ICSI-treatment in patients with endometriosis. STUDY FUNDING/COMPETING INTERESTS: Investigator initiated study. IQ Medical Ventures provided the ExEm FOAM® kits free of charge, they were not involved in the study design, data management, statistical analyses and/or manuscript preparation, etc. C.B.L. reports receiving grants from Ferring, Merck and Guerbet, outside the submitted work. C.B.L. is Editor-in-Chief of Human Reproduction. V.M. reports grants and other from Guerbet, outside the submitted work. B.W.M. reports grants from NHMRC (GNT1176437), personal fees from ObsEva, Merck and Merck KGaA, Guerbet and iGenomix, outside the submitted work. N.P.J. reports research funding from Abb-Vie and Myovant Sciences and consultancy for Vifor Pharma, Guerbet, Myovant Sciences and Roche Diagnostics, outside the submitted work. K.D. reports personal fees from Guerbet, outside the submitted work. The other authors do not report any conflicts of interest. No financial support was provided. TRIAL REGISTRATION NUMBER: NL4025 (NTR4198). TRIAL REGISTRATION DATE: 7 October 2013. DATE OF FIRST PATIENT'S ENROLMENT: 22 July 2014.

Dynamic tests of ovarian reserve: a systematic review of diagnostic accuracy.

Despite a plethora of tests of ovarian reserve, there is no perfect test to predict pregnancy. Recent evidence points that anti-Müllerian hormone and antral follicle count may be better than other tests, although other tests continue to be used and form the basis of exclusion of women from fertility treatments. This systematic review concentrated on dynamic tests of ovarian reserve [clomifene citrate challenge test (CCCT), gonadotrophin-releasing hormone agonist stimulation test (GAST) and exogenous FSH ovarian reserve test (EFORT)] and assessed their predictability in terms of fertility outcomes. The study did not restrict itself to women undergoing IVF. The diagnostic odds of abnormal CCCT for non-pregnancy were 2.11 (95% confidence interval, 1.04-4.29) at FSH >10 IU/l (day 3 or 10). The diagnostic accuracy of GAST and EFORT could not be determined due to inconsistencies in the way these tests were conducted. This systematic review and meta-analysis was limited by heterogeneity in terms of the population sampled and the index and reference tests. There is an urgent need for consensus on the performance of these tests and the definition of normality, if their use is to be continued. However, given the present level of evidence, these tests should be completely abandoned.

Gynaecologic surgery from uncertainty to science: evidence-based surgery is no passing fad.

BACKGROUND: The randomized controlled trial (RCT) is the least biased measure of the effectiveness of interventions, including surgical interventions. The aim was to review the available evidence base in gynaecologic surgery, to assess what progress has been made and to determine gaps in the evidence for clinical decision-making. METHODS: Systematic reviews involving gynaecological surgery interventions were extracted from the Cochrane Database of Systematic Reviews (Issue 2, 2007) and data were extracted for key primary outcomes from each of the randomized trials in the reviews. The reviews were categorized as to whether they had provided evidence of effectiveness for pre-defined outcomes of most relevance to patients. RESULTS: Of 371 reviews or protocols published on the Cochrane Database of Systematic Reviews (Issue 2, 2007), only 30 were completed reviews assessing surgical interventions. Seven reviews concluded there was evidence of a significant effect (whether beneficial or harmful) of the interventions studied for pre-defined primary outcomes; 11 reviews concluded there was some evidence of significant effects for primary outcomes along with some gaps for primary outcomes; 12 reviews concluded insufficient evidence of effectiveness. Common themes of unique methodological challenges and pitfalls with trials of surgical interventions were apparent. CONCLUSIONS: Cochrane reviews have gone a long way to establishing a sound evidence base in gynaecologic surgery: some gaps in the evidence have been eliminated and others highlighted. In general, gynaecology has been a specialty where surgical interventions have been well exposed to the scrutiny of RCTs compared with other surgical specialties.

Techniques for surgical retrieval of sperm prior to intra-cytoplasmic sperm injection (ICSI) for azoospermia.

BACKGROUND: Azoospermia, the absence of sperm in ejaculated semen, is the most severe form of male-factor infertility and is present in approximately 5% of all investigated infertile couples. The advent of intra-cytoplasmic sperm injection (ICSI) has transformed treatment of this type of severe male-factor infertility. Sperm can be retrieved for ICSI from either the epididymis or the testis, depending on the type of azoospermia. OBJECTIVES: To evaluate the efficacy of the various surgical retrieval techniques for men with obstructive or non-obstructive azoospermia prior to ICSI. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (November 2007), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 4), MEDLINE (1966 to November 2007), EMBASE (1980 to November 2007), Biological Abstracts (1980 to November 2007), and reference lists of identified articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effectiveness of different sperm-retrieval techniques in men with azoospermia prior to ICSI. Due to the lack of RCTs, non-randomised trials that used the participants as their own control were also considered in the review but their results were not included in the meta-analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: The search was revised and re-run in November 2007. No new trials were located therefore the results of the updated review remain unchanged from those published in 2006. Two trials involving 98 men were included. The first small RCT had 59 participants and compared two epididymal techniques. The trial gave limited evidence that microsurgical epididymal sperm aspiration (MESA) achieved a significantly lower pregnancy rate (one pregnancy in 29 procedures compared with seven pregnancies in 30 procedures; OR 0.19, 95% CI 0.04 to 0.83) and fertilisation rate (OR 0.16, 95% CI 0.05 to 0.48) than the micropuncture with perivascular nerve stimulation technique. The other RCT comparing two testicular aspiration techniques (TSA) in 39 participants gave no statistically significant evidence for the superiority of the ultrasound-guided technique compared to the aspiration technique without ultrasound. TSA with ultrasound resulted in pregnancy in three out of 16 participants compared with four out of 23 participants (OR 1.10, 95% CI 0.21 to 5.74). AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend any specific sperm retrieval technique for azoospermic men undergoing ICSI. In the absence of evidence to support more invasive or more technically difficult methods, the review authors recommend the least invasive and simplest technique available. Further randomised trials are warranted, preferably multi-centred trials. The classification of azoospermia as obstructive and non-obstructive appears to be relevant to a successful clinical outcome and a distinction according to the cause of azoospermia is important for future clinical trials.

Asymmetric split H-shape nanoantennas for molecular sensing.

In this paper we report on a very sensitive biosensor based on gold asymmetric nanoantennas that are capable of enhancing the molecular resonances of C-H bonds. The nanoantennas are arranged as arrays of asymmetric-split H-shape (ASH) structures, tuned to produce plasmonic resonances with reflectance double peaks within the mid-infrared vibrational resonances of C-H bonds for the assay of deposited films of the molecule 17ß-estradiol (E2), used as an analyte. Measurements and numerical simulations of the reflectance spectra have enabled an estimated enhancement factor on the order of 105 to be obtained for a thin film of E2 on the ASH array. A high sensitivity value of 2335 nm/RIU was achieved, together with a figure of merit of approximately 8. Our experimental results were corroborated using numerical simulations for the C-H stretch vibrational resonances from the analyte, superimposed on the plasmonic resonances of the ASH nanoantennas.

Total versus subtotal hysterectomy for benign gynaecological conditions.

BACKGROUND: Hysterectomy using an abdominal approach removes either the uterus alone (subtotal hysterectomy) or both the uterus and the cervix (total hysterectomy). The latter is more common but outcomes have not been systematically compared. OBJECTIVES: To assess and compare outcomes with subtotal hysterectomy versus total abdominal hysterectomy for benign gynaecological conditions. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group's specialised register of controlled trials (December 2005), Central (December 2005), Medline (1966 to December 2005), EmBase (1980 to December 2005), Biological Abstracts (1980 to December 2005), the National Research Register and relevant citation lists. SELECTION CRITERIA: Only randomised controlled trials of women undergoing either total or subtotal hysterectomy for benign gynaecological conditions were included. DATA COLLECTION AND ANALYSIS: Three trials that included 733 participants were included. Independent selection of trials and data extraction were undertaken by 2 reviewers and results compared. MAIN RESULTS: There was no evidence of a difference in the rates of incontinence, constipation or measures of sexual function. In one unblinded trial, a significantly greater proportion of women indicated that they had frequent episodes of urinary incontinence after subtotal hysterectomy when compared with total hysterectomy (OR=2.1, 1.02 to 4.3), but these results were not confirmed by the other two trials that measured both stress and urge incontinence and urinary frequency. . Length of surgery and amount of blood lost during surgery were significantly reduced during subtotal hysterectomy when compared with total hysterectomy, but there was no evidence of a difference in the odds of transfusion. Febrile morbidity was less likely (OR=0.43, 0.25 to 0.75) and ongoing cyclical vaginal bleeding one year after surgery was more likely (OR=11.3, 4.1 to 31.2) after subtotal when compared with total hysterectomy. There was no evidence of a difference in the rates of other complications, recovery from surgery or readmission rates. AUTHORS' CONCLUSIONS: This review has not confirmed the perception that subtotal hysterectomy offers improved outcomes for sexual, urinary or bowel function when compared with total abdominal hysterectomy. Surgery is shorter and intraoperative blood loss and fever are reduced but women are more likely to experience ongoing cyclical bleeding up to a year after surgery with subtotal hysterectomy compared to total hysterectomy.

Techniques for surgical retrieval of sperm prior to ICSI for azoospermia.

BACKGROUND: Azoospermia, the absence of sperm in ejaculated semen, is the most severe form of male factor infertility and is present in approximately 5% of all investigated infertile couples. The advent of intra-cytoplasmic sperm injection (ICSI), however, has transformed treatment of this type of severe male factor infertility. Sperm can be retrieved for ICSI from either the epididymis or the testis depending on the type of azoospermia. OBJECTIVES: To evaluate the efficacy of the various surgical retrieval techniques for men with obstructive or non obstructive azoospermia prior to ICSI. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched 12 Jan 2005), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to Nov 2004), EMBASE (1980 to Dec 2004), and Biological Abstracts (1980 to Nov 2004) and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effectiveness of sperm retrieval techniques in men with azoospermia prior to ICSI. Due to the lack of RCTs, non-randomised trials that used the participants as their own control, were also considered in the review but not included in the meta-analysis. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Two trials involving 98 men were included. The first small RCT had 59 participants and compared two epididymal techniques. The trial gave limited evidence that microsurgical epididymal sperm aspiration (MESA) achieved significantly lower pregnancy (One pregnancy in 29 procedures compared with seven pregnancies in 30 procedures, OR 0.19, 95% CI 0.04 to 0.83) and fertilisation rates (OR 0.16, 95% CI 0.05 to 0.48) than the micropuncture with perivascular nerve stimulation technique. The other RCT comparing two testicular techniques in 39 participants gave no statistically significant evidence about the superiority of the ultrasound guided aspiration technique compared to the aspiration technique without ultrasound guidance. TSA with ultrasound resulted in pregnancy in 3 out of 16 participants and TSA without ultrasound in four pregnancies with 23 participants (OR 1.10, 95% CI 0.21 to 5.74) AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend any specific sperm retrieval technique for azoospermic men undergoing ICSI. In the absence of evidence to support more invasive or more technically difficult methods the reviewers recommend the least invasive and simplest technique available. Further randomised trials are warranted, preferably multi-centred trials. The classification of azoospermia as obstructive and non-obstructive appears to be relevant to a successful clinical outcome so a distinction according to the cause azoospermia is important for future clinical trials.

Mutagenicity, cytotoxicity, and DNA binding of platinum(II)-chloroammines in Chinese hamster ovary cells.

The cytotoxicity and mutagenicity at the six platinum(II)chloroammines have been investigated in Chinese hamster ovary cells. For these compounds, the observed slopes of the mutation-induction curves (mutants/10(6) cells/microM) were: cis-Pt(NH3)2Cl2 (31.5), K[Pt(NH3)Cl3] (2.78), [Pt(NH3)3Cl]Cl (0.11), K2[PtCl4] (0.12), trans-Pt(NH3)2Cl2 (0.013), and [Pt(NH3)4]Cl2 (0.0). The relative cytotoxicity of these compounds follows the same order and is of similar magnitude. The observed relative mutagenicities of these compounds paralleled their reported potencies in the Ames assay and their relative antitumor activities. Results indicate that Chinese hamster ovary cells are useful in quantifying low mutagenic activity of chemicals such as platinum compounds. Studies with 195mPt-labeled cis- and trans-Pt(NH3)2Cl2 showed that during treatment both compounds enter the cell and bind to the DNA with comparable efficiency. Hence, the relative mutagenicities of cis- and trans-Pt(NH3)2Cl2 are not a consequence of different initial levels of DNA binding.