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Introduction: Growing evidence suggests a role for neuroinflammation in Alzheimer's disease (AD). We investigated complement pathway activity in AD patient cerebrospinal fluid (CSF) and evaluated its modulation by the anti-tau antibody semorinemab., Methods: Immunoassays were applied to measure CSF complement proteins C4, factor B (FB), C3 and their cleavage fragments C4a, C3a, and factor Bb (Bb) in AD patients and a separate cognitively unimpaired (CU) cohort., Results: All measured CSF complement proteins were increased in AD versus CU subjects, with C4a displaying the most robust increase. Finally, semorinemab did not have a significant pharmacodynamic effect on CSF complement proteins., Discussion: Elevated levels of CSF C4a, C4, C3a, C3, Bb, and FB are consistent with complement activation in AD brains. Despite showing a reduction in CSF soluble tau species, semorinemab did not impact complement protein levels or activity. Further studies are needed to determine the value of complement proteins as neuroinflammation biomarkers in AD., Highlights: Cerebrospinal fluid (CSF) complement proteins C4a, C3a, Bb, C4, C3, and factor B levels were increased in Alzheimer's disease (AD) patients compared to a separate cognitively unimpaired (CU) cohort. Baseline CSF complement protein levels were correlated with neuro-axonal degeneration and glial activation biomarkers in AD patients. The investigational anti-tau antibody semorinemab did not impact CSF complement protein levels or activity relative to the placebo arm., (© 2024 Roche Diagnostics GmbH and Genentech, Inc. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The vaginal microbiome of trans men and menopausal women is suspected to be similar due to a lack of estrogen leading to the absence of lactobacilli. However, data are scarce. We performed an analysis of the vaginal microbiome of trans men (n = 25) in comparison to that of menopausal (n = 25) and premenopausal women (n = 25). The vaginal microbiome of trans men and menopausal women showed a higher alpha diversity than that of premenopausal women. Various beta diversity indices (e.g., Bray‒Curtis (Un-)Weigthed Unifrac), showed significant differences in community composition between trans men and premenopausal (p < 0.001) and menopausal women (p < 0.001). The vaginal microbiome of trans men is characterized by a loss of Lactobacillus and an increase in bacteria associated with the intestinal flora (e.g., Campylobacter, Anaerococcus, Dialister, Prevotella). The abundance of Dialister and Prevotella decreased with the length of hormonal therapy in trans men. The Nugent score, Pap smear and HPV status did not differ between the study groups. The vaginal microbiome of trans men differs from that of premenopausal women but shows similarities to that of menopausal women. The duration of hormonal therapy in trans men may have important impacts on the vaginal microbiome and thus possibly on the risk for STIs., (© 2024. The Author(s).)

Competing Interests: The authors report no conflicts of interest.

Aim This official guideline was published and coordinated by the DGGG, OEGGG and SGGG with the involvement of other medical societies. The aim was to provide a consensus-based overview of non-hormonal forms of contraception based on an evaluation of the relevant literature. The first part of these summarized statements and recommendations presents natural family planning methods such as lactational amenorrhea, barrier methods and coitus interruptus. The second part will focus on intrauterine devices and sterilization methods. Methods This S2k-guideline was developed by representative members from different medical professions on behalf of the guidelines commission of the DGGG, OEGGG and SGGG using a structured consensus process. Recommendations The guideline provides recommendations on the indications for, safety of use, benefits, and limitations of the different methods as well as recommendations on providing advice and other aspects of non-hormonal contraception. Natural family planning methods, lactational amenorrhea, barrier methods and coitus interruptus are discussed., Competing Interests: Conflict of Interest/Interessenkonflikt The conflicts of interest of all the authors are listed in the long German-language version of the guideline./Die Interessenkonflikte der Autor*innen sind in der Langfassung der Leitlinie aufgelistet., (Thieme. All rights reserved.)

Aim This official guideline was published and coordinated by the DGGG, OEGGG and SGGG with the involvement of other medical societies. The aim was to provide a consensus-based overview of non-hormonal forms of contraception based on an evaluation of the relevant literature. The first part of these summarized statements and recommendations presents natural family planning methods such as lactational amenorrhea, barrier methods and coitus interruptus. The second part focuses on intrauterine devices and sterilization. Methods This S2k-guideline was developed by representative members from different medical professions on behalf of the guidelines commission of the DGGG, OEGGG and SGGG using a structured consensus process. Recommendations The guideline provides recommendations on the indications for, safety of use, benefits, and limitations of the different methods as well as recommendations on providing advice and other aspects of non-hormonal contraception. This summary presents recommendations and statements about intrauterine devices and female and male sterilization., Competing Interests: Conflict of Interest/Interessenkonflikt The conflicts of interest of all the authors are listed in the long German-language version of the guideline./Die Interessenkonflikte der Autor*innen sind in der Langfassung der Leitlinie aufgelistet., (Thieme. All rights reserved.)

Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of contextual conditioned fear, we characterized distinct resilient and susceptible subpopulations based on lasting generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and ii.) expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing unsupervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Resilient subjects showed elevated prelimbic and lower ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient and non-shocked control subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) prefrontal, hippocampal and amygdalar neuronal hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024 Published by Elsevier Inc.)

Objective: To compare the success rates of medical management using a combined mifepristone and misoprostol protocol in cases of early pregnancy loss (EPL) between women who conceived without medical assistance and those who conceived through in vitro fertilization (IVF), after fresh or frozen embryo transfer, and evaluate for the predictive factors of success, time to first passage of tissue, and time to complete resolution of pregnancy., Design: Retrospective cohort study., Setting: University hospital., Patient(s): Women who presented with EPL below 13 weeks of gestation between June 2013 and July 2021 who were managed medically with mifepristone 200 mg orally and misoprostol 800 mcg vaginally were included in the study., Intervention(s): Medical management with mifepristone and misoprostol; conception without medical assistance vs. post-IVF, after fresh or frozen embryo transfer., Main Outcome Measure(s): We evaluated overall success and performed subgroup analysis according to the mode of conception and compared fresh vs. frozen-thawed embryo transfers for IVF pregnancies. In all groups, we also calculated success according to gestational age and compared the time to first passage of tissue. The potential predictive factors of treatment success were analyzed. The side effects and complications of treatment were recorded., Result(s): A total of 930 women were included in the study, 99 (11%) of whom achieved pregnancy after IVF. The overall success of medical treatment was 89% with no statistically significant difference according to the mode of conception (89% vs. 89%) or type of transfer (fresh 89% vs. frozen 89%). Only lower gestational age by sonography was independently predictive of treatment success, showing a negative regression coefficient of β = -0.333 and an odds ratio of 0.717. The mean time to first passage of tissue was 5.0 ± 2.1 hours. Altogether, 666 women (72%) showed pregnancy resolution on the day of medication administration, an additional 110 women at 1-week follow-up, and a further 74 women after ≥4 weeks on ultrasound., Conclusion(s): Medical management of EPL with mifepristone and misoprostol is a highly successful treatment option that results in completed abortion in a timely fashion in both pregnancies conceived without medical assistance and those conceived after IVF., Competing Interests: Declaration of interests V.C.-T. has nothing to disclose. M.H. has nothing to disclose. A.C.-K. has nothing to disclose. M.T. has nothing to disclose. S.M. has nothing to disclose. B.T. has nothing to disclose. B.S. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Improved survivorship in cancer patients leads to new challenging issues including potential impairment of quality of life, sexual function, and fertility. The aim of this study was to assess sexual dysfunction (SD) and psychological distress in female cancer survivors who underwent fertility preservation in the past in comparison to reviewed healthy control data from other published studies. Additionally, our focus was on the difference in SD between women with current desire to get pregnant and already completed family planning., Methods: In this prospective study, 53 female cancer survivors who underwent fertility preservation at time of cancer diagnosis between 2010 and 2020 were invited to a gynecological exam, laboratory assessment, and two questionnaires (Female Sexual Function Index (FSFI) and Hospital anxiety and depression scale (HADS)) in 2022. These scores were compared to results in the literature of healthy controls and depending on anti-Mullerian-hormone (AMH) levels, current desire to have a child, and age., Results: After a mean follow-up time of 70 ± 50 months, SD was detected in 60.4% (n = 32) of the 53 included patients. Normal results regarding HADS-D/anxiety and HADS-D/depression were found in 88.7% and 94.3% of patients, respectively. At time of follow-up, 69.9% (n = 40) regained regular menstrual cycles, 52.6% (n = 20) < 40 years showed a diminished ovarian reserve with AMH levels < 1.1 ng/ml and 28.3% (n = 15) suffered from infertility., Conclusion: Female cancer survivors may be at risk for SD. Cancer patients should be informed about possible sexual dysfunction already at the start of cancer treatment and during follow-up. In addition, contraception needs to be addressed if regular cycles occur as more than two-thirds of the women regained regular menstrual cycles., (© 2024. The Author(s).)

Endometriosis has been shown to be associated with unfavorable development and maturation of oocytes, as well as aberrancies in embryonal development, including arrest after fertilization, following in vitro fertilization (IVF). Time-lapse monitoring (TLM) enables continuous and non-invasive monitoring of embryo morphokinetics during the IVF process and might be useful in the assessment of embryos from women with endometriosis. In this review, five eligible studies were evaluated to determine if embryo morphokinetics assessed under TLM differ in patients with endometriosis and subsequently predict blastocyst quality, implantation and success of pregnancy. The studies showed overall inferior morphokinetic parameters of embryos from endometriosis patients when compared to controls, independent of the severity of endometriosis. Embryos with optimal early morphokinetic parameters (t2, s2, t5, tSB, tEB) and late developmental events (compaction, morulation, and blastulation) had better implantation rates than those who had suboptimal ranges. However, due to few studies available with mostly retrospective data, the validity of these findings and their generalizability for clinical practice needs to be further assessed. Prospective studies with larger sample sizes are needed to determine whether using TLM for embryo selection in endometriosis improves pregnancy and live birth outcomes., (© 2023. The Author(s).)

Background and Objectives: Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD., Methods: The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated., Results: Between December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated., Discussion: Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD., Classification of Evidence: This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD., Trial Registration Information: The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: The way pupils and university students talk about sex does not reflect their real understanding of reproductive health issues. Therefore, we developed a survey for pupils and students in Tyrol, Austria, to evaluate the current state of knowledge., Methods: Two questionnaires with 39 items for pupils (n = 369) and 53 items for university students (n = 537) were developed, and an online survey was carried out in Tyrol, Austria, between April and July 2022. A sum score for each correct answer to ten identical items in both questionnaires was used to compare groups (range: 0-11 points), with analysis performed using independent sample t-test, analyses of variance (ANOVAs) and chi-square test., Results: With regards to reproductive health issues and fertility awareness, female vs. male participants (p < 0.001), university students vs. pupils (p < 0.001) and medical students vs. other students (p < 0.001) had greater knowledge. Participants who had already had sexual intercourse showed a broader knowledge of contraception and fertility (p < 0.001).The age at which the decline of female fertility becomes relevant was misstated by the adolescents, who gave a mean age of 42.6 years compared to university students who asserted a mean age of 35.9 years (p < 0.001). Overall, the lowest rate of correct answers was found with respect to emergency contraception (30.7%), while knowledge of contraceptive methods was comparatively high (99.2%)., Conclusion: Substantial lack of knowledge of reproductive health issues exists, with differences found between pupils and university students, between genders, and according to field of study. Future health and fertility awareness programs at school and university should focus on gender-specific aspects to prevent unplanned pregnancies, sexually transmitted diseases, and childlessness., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: RPL and RIF are challenges in reproductive medicine. The immune system plays a pivotal role in endometrial receptivity, successful implantation, and pregnancy complications. Immunological changes have been associated with RPL and RIF. Understanding immune dysregulation especially in NK and T cell subtypes may lead to better diagnostic concepts and treatments. From July 2019 to August 2020 patients with RPL and RIF underwent a standardized diagnostic procedure including endometrial biopsies. Immune cell analysis was performed using flow cytometry. Patients were contacted in March 2023 and interviewed concerning their pregnancy outcomes following diagnostics., Results: Out of 68 patients undergoing endometrial biopsies, 49 patients were finally included. Live birth rates were high with 72% in RPL and 86% in RIF. Immune cell analysis revealed that patients with RPL had more cytotoxic CD56 dim CD16 high cells, while RIF patients had more CD56 + uNK cells. RPL patients with pregnancy complications showed increased NKT cell percentages., Conclusion: Our findings suggest specific immune changes in RPL and RIF patients, offering potential therapeutic targets. Tailored immunotherapy based on endometrial immunophenotyping might be an option, but further research is needed.

Research Question: What are the differences in menstrual blood lymphocytes between controls, patients with recurrent pregnancy loss (RPL) and patients with unexplained infertility (uINF)?, Design: Prospective study including 46 healthy controls, 28 RPL and 11 uINF patients. A feasibility study compared lymphocyte compositions of endometrial biopsies and menstrual blood collected during the first 48 h of menstruation in seven controls. In all patients, peripheral and menstrual blood from the first and subsequent 24 h were analysed separately by flow cytometry, focusing on the main lymphocyte populations and natural killer (NK) cell subsets., Results: The first 24 h of menstrual blood resembles the uterine immune milieu as tested by endometrial biopsy. RPL patients showed significantly higher menstrual blood CD56 + NK cell numbers than controls (mean ± SD: 31.13 ± 7.52% versus 36.73 ± 5.4%, P = 0.002). Menstrual blood CD56 dim CD16 bright NK cells within the CD56 + NK cell population were decreased in RPL (16.34 ± 14.65%, P = 0.011) and uINF (15.7 ± 5.91%, P = 0.02) patients versus control (20.42 ± 11.53%). uINF patients had the lowest menstrual blood CD3 + T cell counts (38.81 ± 5.04%, control versus uINF: P = 0.01) and cytotoxicity receptors NKp46 and NKG2D on CD56 bright CD16 dim cells were higher in uINF (68.12 ± 11.84%, P = 0.006; 45.99 ± 13.83%, P = 0.01, respectively) and RPL (NKp46: 66.21 ± 15.36%, P = 0.009) patients versus controls. RPL and uINF patients had higher peripheral CD56 + NK cell counts versus controls (11.42 ± 4.05%, P = 0.021; 12.86 ± 4.29%, P = 0.009 versus 8.4 ± 3.5%)., Conclusions: Compared with controls, RPL and uINF patients had a different menstrual blood-NK-subtype profile, indicating an altered cytotoxicity. In future studies, this non-invasive analysis might enable identification and monitoring of patients receiving immunomodulatory medications., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Adverse childhood experiences (ACE) have been shown to have a tremendous negative impact on health outcomes later in life. This study presents data on the prevalence of ACEs, psychological distress, and trauma-related symptoms in transgender and gender-diverse (TGD) people compared to cisgender people. TGD adults ( n = 35) and a matched sample of nonpsychiatric hospital patients ( n = 35) were surveyed between September 2018 and March 2019. Participants completed the Maltreatment and Abuse Chronology of Exposure Scale to assess ACEs, as well as the Brief Symptom Inventory and the Essener Trauma Inventory to assess psychological distress and trauma-related symptoms. TGD patients reported a higher number of ACEs than cisgender patients (0.7 vs. 2.4; p < 0.001; d = 0.94). A total of 28.6% of TGD vs. 5.7% cisgender patients reported four or more ACEs ( p < 0.001). The most common forms of ACEs were parental abuse (54.3%) and peer abuse (54.3%). No significantly increased prevalence of sexual abuse was found ( p > 0.05). TGD patients also reported a higher prevalence of depression (48.4% vs. 5.7%, p < 0.001), posttraumatic stress disorder symptoms (59.4% vs. 13.8%, p < 0.001), and anxiety (58.1% vs. 28.6%, p = 0.016). Health care providers should be aware of and assess ACEs, especially in vulnerable groups such as TGD people, and create a safe place through open-minded, affirming care.

Study Question: How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed?, Summary Answer: This is the first ESHRE good practice recommendations paper providing a definition for RIF together with recommendations on how to investigate causes and contributing factors, and how to improve the chances of a pregnancy., What Is Known Already: RIF is a challenge in the ART clinic, with a multitude of investigations and interventions offered and applied in clinical practice, often without biological rationale or with unequivocal evidence of benefit., Study Design Size Duration: This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, if available, and the results of a previously published survey on clinical practice in RIF and the expertise of the working group. A literature search was performed in PubMed and Cochrane focussing on 'recurrent reproductive failure', 'recurrent implantation failure', and 'repeated implantation failure'., Participants/materials Setting Methods: The ESHRE Working Group on Recurrent Implantation Failure included eight members representing the ESHRE Special Interest Groups for Implantation and Early Pregnancy, Reproductive Endocrinology, and Embryology, with an independent chair and an expert in statistics. The recommendations for clinical practice were formulated based on the expert opinion of the working group, while taking into consideration the published data and results of the survey on uptake in clinical practice. The draft document was then open to ESHRE members for online peer review and was revised in light of the comments received., Main Results and the Role of Chance: The working group recommends considering RIF as a secondary phenomenon of ART, as it can only be observed in patients undergoing IVF, and that the following description of RIF be adopted: 'RIF describes the scenario in which the transfer of embryos considered to be viable has failed to result in a positive pregnancy test sufficiently often in a specific patient to warrant consideration of further investigations and/or interventions'. It was agreed that the recommended threshold for the cumulative predicted chance of implantation to identify RIF for the purposes of initiating further investigation is 60%. When a couple have not had a successful implantation by a certain number of embryo transfers and the cumulative predicted chance of implantation associated with that number is greater than 60%, then they should be counselled on further investigation and/or treatment options. This term defines clinical RIF for which further actions should be considered. Nineteen recommendations were formulated on investigations when RIF is suspected, and 13 on interventions. Recommendations were colour-coded based on whether the investigations/interventions were recommended (green), to be considered (orange), or not recommended, i.e. not to be offered routinely (red)., Limitations Reasons for Caution: While awaiting the results of further studies and trials, the ESHRE Working Group on Recurrent Implantation Failure recommends identifying RIF based on the chance of successful implantation for the individual patient or couple and to restrict investigations and treatments to those supported by a clear rationale and data indicating their likely benefit., Wider Implications of the Findings: This article provides not only good practice advice but also highlights the investigations and interventions that need further research. This research, when well-conducted, will be key to making progress in the clinical management of RIF., Study Funding/competing Interests: The meetings and technical support for this project were funded by ESHRE. N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); Honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update , and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles, or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online , and Editor in Chief of Journal Gynäkologische Endokrinologie . He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update , immediate past Coordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online . B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose., Disclaimer: This Good Practice Recommendations (GPR) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation . ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type . Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE ., Competing Interests: N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update, and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online, and Editor in Chief of Journal Gynäkologische Endokrinologie. He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update, immediate past Co-ordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online. B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Introduction: Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI., Material and Methods: Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17β-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks., Results: Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p < 0.001) and OS (p = 0.039)., Conclusion: Increased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to ICI in women. These results show first clinical evidence of the potential role of sex hormones as prognostic and predictive biomarker in mUC. Further prospective analyses are needed to corroborate our findings., (© 2023. The Author(s).)

In Austria, female physicians must immediately disrupt their surgical training as soon as their pregnancy is announced. In Germany, surveys on the topic of "female surgeons performing surgery during pregnancy" led to a reform of the German Maternity Protection Act, which came into force on January 1, 2018, and allows female physicians to perform risk-adapted surgery during pregnancy at their own request. However, in Austria, such reform is still pending. The study aimed i) to assess the current situation of how pregnant female surgeons handle their training under the actual restrictive legislature in Austria, especially in context of operative activity, and ii) to identify needs for improvements. Therefore, a nation-wide online survey, initiated by the Austrian Society for Gynecology and Obstetrics and the Young Forum of the Austrian Society of Gynecology and Obstetrics, was performed from June 1 to December 24, 2021, among employed physicians working in surgical specialties. To conduct a general needs assessment, the questionnaire was made available to both female and male physicians in all positions. In total, 503 physicians participated in the survey, of which 70.4% (n = 354) were women and 29.6% (n = 149) were men. The majority of the women (61.3%) were undergoing residency training at the time of their pregnancy. The announcement of the pregnancy to the supervisor(s) occurred on average in the 13th week of gestation (week 2-40). Before that, pregnant female physicians spent an average of 10 h per trimester (first trimester: 0-120 h; second trimester: 0-100 h) in the operating room. The main reason for women to continue surgical activity despite their (yet unreported) pregnancy was "own request". 93% (n = 469) of the participants explicitly wished to be able to perform surgical activities in a safe setting during pregnancy. This response was independent of gender (p = 0.217), age (p = 0.083), specialty (p = 0.351), professional position (p = 0.619), and previous pregnancy (p = 0.142). In conclusion, there is an urgent need to offer female surgeons the possibility of continuing surgical activities during pregnancy. This handling would significantly increase the career opportunities for women who want to build up both a successful career and a family life., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction For some patients, undergoing medical treatment for infertility is a cause of major emotional stress which the couple needs to deal with together; it can be said that infertility is a shared stressor. From the literature it is known that a subjectively perceived sense of self-efficacy supports the patient's ability to cope adaptively with an illness. As the basis for this study, we assumed that high levels of self-efficacy are associated with low psychological risk scores (e.g., for anxiety or depressiveness), both in the patient themselves and in their partner. Accordingly, in infertility patients, targeted support to promote helpful self-efficacy expectations could represent a new counselling strategy that could enable psychologically vulnerable patients to better cope with the treatment procedure and treatment failures of medically assisted reproduction, making these patients less at risk with regard to psychosocial factors. Methods 721 women and men attending five fertility centers in Germany (Heidelberg, Berlin), Austria (Innsbruck), and Switzerland (St. Gallen, Basel) completed the SCREENIVF-R questionnaire to identify psychological risk factors for amplified emotional problems, as well as the ISE scale to measure self-efficacy. Using paired t-tests and the actor-partner interdependence model, we analyzed the data of 320 couples. Results Considering the study participants as couples, women had a higher risk score than men for four out of five risk factors (depressiveness, anxiety, lack of acceptance, helplessness). In all of the risk areas, it was possible to identify a protective effect from self-efficacy on the patient's own risk factors (actor effect). There was a negative correlation between the men's self-efficacy level and the women's feelings of depressiveness and helplessness (partner effect, man → woman). The women's self-efficacy levels had a positive correlation with acceptance and access to social support in the men (partner effect, woman → man). Conclusion Because infertility is generally something that a couple has to deal with together, future studies should focus on couples as the unit of analysis instead of just analyzing the men and women separately. In addition, couples therapy should be the gold standard in psychotherapy for infertility patients., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: An increasing number of persons around the world are receiving the diagnosis of gender incongruence, and most of them are in their reproductive years. Safe contraception and fertility preservation are important issues for counseling., Methods: This review is based on pertinent publications retrieved by a systematic search in the PubMed and Web of Science databases, employing the search terms "fertility," "contraception," "transgender," "gender-affirming hormone therapy" (GAHT), "ovarian reserve," and "testicular tissue." 908 studies were included, 26 of which entered the final analysis., Results: Most of the available studies on fertility in trans persons undergoing GAHT reveal a marked effect on spermatogenesis, but no impairment of ovarian reserve. No studies are available on trans women; the data show that 59-87% of trans men use contraceptives, often mainly in order to suppress menstrual bleeding. Fertility preservation measures are mainly used by trans women., Conclusion: GAHT mainly impairs spermatogenesis; thus, counseling on fertility preservation should always be given before GAHT. More than 80% of trans men use contraceptives, mainly for their other effects such as suppression of menstrual bleeding. GAHT is not in itself a reliable method of contraception, and persons about to undergo GAHT should always receive contraceptive counseling.

Synchrony has been used to describe simple beat entrainment as well as correlated mental processes between people, leading some to question whether the term conflates distinct phenomena. Here we ask whether simple synchrony (beat entrainment) predicts more complex attentional synchrony, consistent with a common mechanism. While eye-tracked, participants listened to regularly spaced tones and indicated changes in volume. Across multiple sessions, we found a reliable individual difference: some people entrained their attention more than others, as reflected in beat-matched pupil dilations that predicted performance. In a second study, eye-tracked participants completed the beat task and then listened to a storyteller, who had been previously recorded while eye-tracked. An individual's tendency to entrain to a beat predicted how strongly their pupils synchronized with those of the storyteller, a corollary of shared attention. The tendency to synchronize is a stable individual difference that predicts attentional synchrony across contexts and complexity., (© 2023. The Author(s).)

Research Question: Are outlier high values of first-measured human chorionic gonadotrophin (HCG) following embryo transfer related to pregnancy complications, specifically pre-eclampsia?, Design: This retrospective cohort study screened 3448 women aged 18-45 years who underwent IVF between 2014 and 2019 and evaluated 614 women who had an intrauterine pregnancy following single embryo transfer (SET), 423 of whom had a live birth. Pregnancy and birth outcome information was available for final analysis in 280 cases. The setting was a university-based IVF centre. HCG was measured at a standardized time after the embryo transfer and the values correlated with adverse pregnancy outcomes associated with poor placentation., Results: Women with first-measured HCG in the highest quintile had a higher incidence of pre-eclampsia than those with lower HCG concentrations (odds ratio [OR] 4.08, 95% confidence interval [CI] 1.41-11.82) even after controlling for age, body mass index, parity and type of embryo transfer. Additionally controlling for embryo stage at embryo transfer did not change the results (OR 3.97, 95% CI 1.37-11.46). No differences were found in the incidence of fetal growth restriction., Conclusions: This is the first known report that links high first-measured HCG after SET to an adverse pregnancy outcome. If confirmed by future studies, initiation of preventive interventions at a very early stage of pregnancy merits further evaluation in this cohort of patients., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Menstrual irregularities are one of the main clinical symptoms caused by polycystic ovary syndrome (PCOS). Pharmacological treatment options for non-fertility indications to restore menstrual frequency play an important role in the management of PCOS. Oral contraceptive pills are commonly prescribed for adolescents with menstrual irregularities, however, when contraindicated or poorly tolerated, further pharmacological therapy is required. This systematic literature research aims to provide an overview concerning the effects of non-hormonal pharmacological treatment options on menstrual irregularities in adolescents suffering from PCOS. A systematic literature search in PubMed, Cochrane, Embase, Bio-SISS and Web of Science was performed, including literature from January 1998 to September 2022, using specific keywords in order to find related studies. n = 265 studies were identified of which n = 164 were eligible for further evaluation. Only four placebo-controlled studies were identified, with diverging inclusion and exclusion criteria. Available data on specific non-hormonal off-label use medication primarily consisted of metformin, Glucagon-like peptide 1 receptor agonists, thiazolidinediones, anti-androgen agents (spironolactone, finasteride, flutamide) and supplements (chromium picolinate, myo-inositol). However, only a few have partly pointed out beneficial effects on improving menstrual frequency in patients diagnosed with PCOS. In summary, metformin in dosages of 1500-2550 g/day, GLP-1-analogues and supplements were effective in regulation of menstrual cycles in adolescents diagnosed with PCOS. Menstrual frequency in adolescents with PCOS is essential to prevent hypoestrogenism with long-term consequences. In this context, MET is the most effective and cost- efficient in overweight adolescent girls, also showing beneficial effects in the regulation of insulin sensitivity, especially if COCs are contraindicated or not well-tolerated. Further studies are needed to evaluate therapies in lean and normal-weight girls with PCOS.

Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols. Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out. Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM)., Competing Interests: Conflict of Interest/Interessenkonflikt The authorsʼ conflicts of interest are listed in the long version of the guideline./Die Interessenkonflikte der Autoren sind in der Langfassung der Leitlinie aufgelistet., (Thieme. All rights reserved.)

Purpose: To develop a predictive score for the success of intrauterine insemination (IUI) based on clinical parameters., Methods: We performed a retrospective cohort study evaluating the homologous IUI cycles performed at a single university-based reproductive medical center between 2009 and 2017. The primary outcome measure was pregnancy, defined as positive serum human chorionic gonadotropin (hCG) 12-14 days after IUI. Predictive factors for pregnancy after IUI were identified, and a predictive score was developed using a multivariable continuation ratio model., Results: Overall, 1437 IUI cycles in 758 couples were evaluated. We found a per cycle pregnancy rate of 10.9% and a cumulative pregnancy rate of 19.4%. In a multivariable analysis, the probability of pregnancy was negatively associated with female age ≥ 35 years (OR 0.63, 95% CI 0.41-0.97, p = 0.034), endometriosis, unilateral tubal factor, or anatomical alteration (OR 0.54, 95% CI 0.33-0.89, p = 0.016), anti-Mullerian hormone (AMH) < 1 ng/ml (OR 0.50, 95% CI 0.29-0.87, p = 0.014), and total progressive motile sperm count (TPMSC) < 5 mil (OR 0.47, 95% CI 0.19-0.72, p = 0.004). We developed a predictive clinical score ranging from 0 to 5. Following 3 cycles, couples in our cohort with a score of 5 had a cumulative probability of achieving pregnancy of nearly 45%. In contrast, couples with a score of 0 had a cumulative probability of only 5%., Conclusion: IUI success rates vary widely depending on couples' characteristics. A simple to use score could be used to estimate a couple's chance of achieving pregnancy via IUI, facilitating individualized counseling and decision-making., (© 2022. The Author(s).)

Importance: Alzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression., Objective: To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD., Design, Setting, and Participants: Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively., Interventions: Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks., Main Outcomes and Measures: The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score., Results: There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point., Conclusions and Relevance: Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD., Trial Registration: ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657.

Purpose: Quality of life (QoL) is a complex term, including mental, physical and social health, and everyone's individual environment. While transgender individuals still often report lower QoL than other individuals, they can benefit substantially from gender affirming therapy. The aim of this study was to develop a questionnaire to determine QoL in transgender individuals during gender affirming hormone therapy (GAHT)., Methods: A multi-step questionnaire development process was performed. In phase 1, a list of key issues was established by reviewing relevant literature. In phase 2, n = 38 transgender individuals as well as n = 6 practitioners evaluated the questionnaire (iTransQoL) in terms of relevance, meaning, comprehensibility and redundancy. Psychometric testing of the questionnaire was performed in phase 3 with n = 40 transgender individuals. The external validity of the iTransQoL was tested by comparison with three validated health questionnaires., Results: The exploratory factor analysis indicated an underlying four-factor solution. Psychometric testing showed acceptable to good overall reliability (α = 0.73-0.83) for the total score and the four subscales as well as good validity indices. Based on the results, a final version of the iTransQoL was established., Conclusion: The iTransQoL is a reliable and valid tool to evaluate QoL of transgender individuals during GAHT., (© 2022. The Author(s).)

Objective: To assess obstetricians' personality traits (empathy, locus of control [LoC], situational affect) and relate these to stress coping when making the diagnosis and delivering the news of late fetal death to parents., Methods: Cross-sectional questionnaire study., Results: 341 Austrian obstetricians (72.7% females) participated in this online survey. Participants' mean age was 46.4 ± 10.8 years. The majority of participants (n = 158, 46.3%) had been previously involved in the diagnosis of fetal death and subsequent breaking news up to five times. We observed no gender-specific differences in physicians' stress coping, including situational affect, perceived stress, challenge, self-concept, or perceived control, nor in internal or external LoC, and perspective taking. Female obstetricians showed significantly higher trait empathy and reported higher levels of distress regarding fetal death than males. Obstetricians with greater experience in dealing with fetal death (>11 times) reported a higher ability to cope with stress as reflected by lower situational affect, less perceived stress, less challenge, and higher situational control., Conclusion: While obstetricians' stress coping in diagnosing and communicating fetal death is independent of physicians' gender, greater ability to empathize with the parents diminishes overall sense of control and affect over the situation, whereas increased level of clinical experience with fetal death supports all domains of control and stress coping., (© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Importance: Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau., Objective: To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD., Design, Setting, and Participants: This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included., Interventions: During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter., Main Outcomes and Measures: The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo., Results: In the modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n = 126; Δ = 2.19 [95% CI, 1.74-2.63]) and semorinemab (1500 mg: n = 86; Δ = 2.36 [95% CI, 1.83-2.89]; 4500 mg: n = 126; Δ = 2.36 [95% CI, 1.92-2.79]; 8100 mg: n = 84; Δ = 2.41 [95% CI, 1.88-2.94]) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 [93.1%]) and semorinemab (1500 mg: 89 [88.8%]; 4500 mg: 132 [94.7%]; 8100 mg: 90 [92.2%]) arms., Conclusions and Relevance: In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach., Trial Registration: ClinicalTrials.gov Identifier: NCT03289143.

In contrast to the former notion of a sterile womb, sequencing techniques have proven a bacterial colonization of the uterus. However, timing of microbiota analysis regarding possible intra-cycle variations as well as specific alterations in patients with recurrent miscarriage (RM) or recurrent implantation failure (RIF) remain unknown. In total, n = 20 RM-, n = 20 RIF-patients and n = 10 healthy controls were included in this prospective study. In every subject, uterine flushing was performed during follicular, ovulatory and luteal phase. Bacterial DNA was isolated and 16S amplicon sequencing analysis of the V3-V4 region was carried out. Diversity measures were compared between samples from the disease groups and the control group separately for each timepoint of the menstrual cycle and over time. In the control group a significant decrease of species richness and evenness was shown around ovulation which remained at this lower level during the luteal phase (Shannon index), indicating a more uniform distribution of microbiota (p < 0.05). This loss of diversity during the menstrual cycle was not apparent in RIF and RM patients. A higher similarity was seen in taxonomic distribution between RM and RIF patients compared to the control group. Longitudinal dynamics included increases in Firmicutes (controls and RM only) and a concomitant loss of Proteobacteria in controls that was not present in RIF and RM. We demonstrate longitudinal intra-cycle-dependent changes in the endometrial microbiota of healthy controls. An increased diversity in both patient groups could be the cause or consequence of a micro-environment that is more prone to pregnancy failures., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Both infertility and erectile dysfunction (ED) are known long-term consequences of cancer treatment in young male cancer survivors. In the present study, we aimed to assess whether sperm quality and sexual function in male cancer survivors are associated., Methods: In this prospective study, n = 244 patients male cancer survivors who underwent sperm analysis and cryopreservation between 2008 and 2018 prior to the initiation of gonadotoxic treatment were invited. In total n = 50 had a follow-up sperm analysis and completed two questionnaires, the Aging Males' Symptom Scale (AMS) and the International Index of Erectile Function (IIEF-EF). Differences between the individual parameters were analyzed using the Wilcoxon or Mann Whitney test., Results: Azoospermia was present in n = 16/50 (32.0%) patients at time of follow-up. ED occurred in n = 9/43 (20.9%) patients and was observed more frequently in patients with oligo- or azoospermia than in those with normospermia, even though this association was not statistically significant. Sperm parameters (total sperm count, sperm concentration, progressive motility) did not differ between time of cryopreservation and time of follow-up. Mean total, somatic, psychological, and sexual AMS score was 23.6, 9.9, 6.6, and 6.8, respectively. Mean total IIEF-EF score was 27.3, indicating mainly mild ED., Conclusions: More than one-third of cancer patients suffered from azoospermia, and ED was primarily present in this subgroup. We recommend implementing the screening of sexual dysfunction in the annual sperm testing that should be offered to all men after gonadotoxic treatment. Our study highlights the importance of counseling young cancer patients on both aspects-future infertility and sexual function-prior to treatment and at follow-up visits., (© 2022. The Author(s).)

Background: Endometriosis is often associated with severe dysmenorrhea, pelvic pain and dyspareunia and has a high impact on daily life as well as sexuality. Quality of partnership positively influences the course of various diseases and ability to cope with emotional and physical distress. However, studies focusing on the male partners of endometriosis patients are rare, and even less is known about the reciprocal relationship in these couples. Therefore, this study aims to explore the interrelations in couples with endometriosis in matters of psychological distress, sexual and partnership satisfaction and social support., Methods: The cross-sectional study was conducted in two university-affiliated fertility centres in Germany and Austria with n = 104 female/male couples affected by endometriosis. Participants completed a questionnaire regarding endometriosis, partnership, sexuality, stress, anxiety, depression and social support. Both women and men were asked about the impact of women's endometriosis-related pain (IEP) on their everyday life (e.g. leisure time). Data were analysed using the Actor-Partner-Interdependence Model., Results: Significant partner effects were evident: High depression, anxiety and stress scores in women were associated with a higher IEP in men (all p ≤ 0.01), reciprocally high stress and depression scores in men were correlated with a higher IEP in women (all p ≤ 0.05). Less sexual satisfaction in women was associated with a higher IEP in men (p = 0.040). There was a significant reciprocal association between the perceived lack of understanding from the social environment and a higher IEP, for both women (p = 0.022) and men (p = 0.027)., Conclusions: The male partner should be taken into account when counselling or treating women with endometriosis. Our study shows a high interdependence and reciprocal influence from both partners-positively and negatively-concerning psychological distress and sexual satisfaction. Furthermore, there ought to be more awareness for the psychosocial impact of endometriosis, especially in regard to social support and understanding. Talking about and improving sexual satisfaction as well as enhancing stress reducing techniques may hold great benefits for dealing with endometriosis. Registration number The study is registered with the German Clinical Trials Register (DRKS), number DRKS00014362., (© 2022. The Author(s).)

Background As the COVID-19 pandemic persists and new vaccines are developed, concerns among the general public are growing that both infection with the SARS-CoV-2 virus and vaccinations against the coronavirus (mRNA vaccines) could lead to infertility or higher miscarriage rates. These fears are voiced particularly often by young adults of reproductive age. This review summarizes the current data on the impact of SARS-CoV-2 infection and corona vaccinations on female and male fertility, based on both animal models and human data. Method A systematic literature search (PubMed, Embase, Web of Science) was carried out using the search terms "COVID 19, SARS-CoV-2, fertility, semen, sperm, oocyte, male fertility, female fertility, infertility". After the search, original articles published between October 2019 and October 2021 were selected and reviewed. Results Despite the use of very high vaccine doses in animal models, no negative impacts on fertility, the course of pregnancy, or fetal development were detected. In humans, no SARS-CoV-2 RNA was found in the oocytes/follicular fluid of infected women; similarly, no differences with regard to pregnancy rates or percentages of healthy children were found between persons who had recovered from the disease, vaccinated persons, and controls. Vaccination also had no impact on live-birth rates after assisted reproductive treatment. No viral RNA was detected in the semen of the majority of infected or still infectious men; however, a significant deterioration of semen parameters was found during semen analysis, especially after severe viral disease. None of the studies found that corona vaccines had any impact on male fertility. Discussion Neither the animal models nor the human data presented in recent studies provide any indications that fertility decreases after being vaccinated against coronavirus. However, there is a growing body of evidence that severe SARS-CoV-2 infection has a negative impact on male fertility and there is clear evidence of an increased risk of complications among pregnant women with SARS-CoV-2 infection. The counseling offered to young adults should therefore take their fears and concerns seriously as well as providing a structured discussion of the current data., Competing Interests: Conflict of Interest/Interessenkonflikt The authors declare that they have no conflict of interest./Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.

Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer's disease (AD) diagnosis and treatment., Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts., Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients., Results: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET., Conclusion: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

Purpose: The diagnosis of probable multiple system atrophy relies on the presence of severe cardiovascular or urogenital autonomic failure. Erectile dysfunction is required to fulfil the latter criterion in men, whereas no corresponding item is established for women. In this study, we aimed to investigate sexual dysfunction in women with multiple system atrophy., Methods: We administered the Female Sexual Function Index questionnaire and interviewed women with multiple system atrophy and age-matched controls regarding the presence of "genital hyposensitivity.", Results: We recruited 25 women with multiple system atrophy and 42 controls. Female Sexual Function Index scores in sexually active women with multiple system atrophy were significantly lower (multiple system atrophy = 10; 15.4, 95% CI [10.1, 22.1], controls = 37; 26.1 [24.1, 28.1], p = 0.0004). The lowest scores concerned the domains of desire, arousal and lubrication. Genital hyposensitivity was reported by 56% of the patients with multiple system atrophy and 9% controls (p < 0.0001)., Conclusions: Sexual dysfunction is highly prevalent in women with multiple system atrophy. Screening for disturbances in specific sexual domains should be implemented in the clinical evaluation of women with suggestive motor symptoms., (© 2021. The Author(s).)

Only a handful of cell types, including fibroblasts, epithelial, and endothelial cells, can support human cytomegalovirus (CMV) replication in vitro, in striking contrast to the situation in vivo. While the susceptibility of epithelial and endothelial cells to CMV infection is strongly modulated by their anatomical site of origin, multiple CMV strains have been successfully isolated and propagated on fibroblasts derived from different organs. As oral mucosal cells are likely involved in CMV acquisition, we sought to evaluate the ability of infant labial fibroblasts to support CMV replication, compared to that of commonly used foreskin and fetal lung fibroblasts. No differences were found in the proportion of cells initiating infection, or in the amounts of viral progeny produced after exposure to the fibroblast-adapted CMV strain AD169 or to the endothelial cell-adapted strain TB40/E. Syncytia formation was, however, significantly enhanced in infected labial and lung fibroblasts compared to foreskin-derived cells, and did not occur after infection with AD169. Together, these data indicate that fibroblast populations derived from different tissues are uniformly permissive to CMV infection but retain phenotypic differences of potential importance for infection-induced cell-cell fusion, and ensuing viral spread and pathogenesis in different organs.

Objective: Fenebrutinib (GDC-0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo-controlled study., Methods: Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI-4) response at week 48., Results: Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI-4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group-based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK-dependent plasmablast RNA signature, anti-double-stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo., Conclusion: While fenebrutinib had an acceptable safety profile, the primary end point, SRI-4 response, was not met despite evidence of strong pathway inhibition., (© 2021, American College of Rheumatology.)

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to report that are related to the reported content of this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We aimed to compare the sperm quality in different cancer types and benign diseases before gonadotoxic treatment, and assess the usage rate of cryopreserved sperm for assisted reproductive treatment (ART). This retrospective study was conducted at two university clinics between January 2008 and July 2018. A total of 545 patients suffering from cancer or benign diseases were included in the study. The pretreatment sperm analyses were based on the World Health Organization (WHO) guidelines. Patients with testicular malignancy (TM) showed a significantly lower sperm count (median [interquartile range]: 18.7 × 10 6 [5.3 × 10 6 -43.0 × 10 6 ] ml -1 ; P = 0.03) as well as total sperm count (42.4 × 10 6 [13.3 × 10 6 -108.5 × 10 6 ] per ejaculate; P = 0.007) compared to other malignant and benign diseases. In addition, patients with nonseminomatous TM showed the lowest sperm count (14.3 × 10 6 [6.0 × 10 6 -29.9 × 10 6 ] ml -1 , vs seminomas: 16.5 × 10 6 [4.6 × 10 6 -20.3 × 10 6 ] ml -1 ; P = 0.001). With reference to the WHO 2010 guidelines, approximately 48.0% of the patients with TM and 23.0% with hematological malignancies (HM) had oligozoospermia. During the observation period, only 29 patients (5.3%) used their frozen sperms for 48 ART cycles, resulting in 15 clinical pregnancies and 10 live births. The sperm quality varies with the type of underlying disease, with TM and HM patients showing the lowest sperm counts. Due to the observed low usage rate of cryopreserved sperm, further patient interviews and sperm analyses should be included in the routine oncologic protocols to avoid unnecessary storage expenses. However, sperm banking is worth the effort as it provides hope for men who cannot reproduce naturally after gonadotoxic treatment., Competing Interests: None

Background: In chronic coronary syndromes, guidelines mandate invasive functional guidance of revascularization whenever non-invasive proof of ischemia is missing. ISIS-2 survey aimed to evaluate how the adoption of guideline recommendation on ischemia-guided revascularization has evolved over the last 5-7 years., Methods: In ISIS-2 participants assessed five complete angiograms, presenting only intermediate stenoses without information on non-invasive pre-testing. Fractional flow reserve was known for each stenosis, but remained undisclosed. Participants could determine stenosis significance either by angiography or by requesting an adjunctive invasive diagnostic method (intravascular imaging or functional tests). Primary endpoint was the rate of requesting adjunctive functional assessment. Secondary endpoints were the rate of concordance between angiography-based decisions and know functional severity. ISIS-2 utilized the same web-based platform as ISIS-1 in 2013. (NCT04001452)., Results: 334 participants performed 2059 lesion evaluations: 1202 (59%) decisions were based solely on angiography without expressed need for further evaluation. These decisions were discordant with known functional significance in 39%, mainly with potential of overtreatment. Participants requested invasive functional assessment in 643 (31%) and intravascular imaging in 214 (10%) cases. Compared to ISIS-1 the rate of purely angiography-based decisions has decreased (59% vs 66%; p < 0.001), while invasive functional tests were more frequently requested (31% vs 25%; p < 0.001)., Conclusions: ISIS-2 suggests an evolving pattern in the intention to integrate invasive coronary physiology into the revascularization decisions. However, the disconnect between recommendations and current thinking is still dominant., (Copyright © 2021. Published by Elsevier B.V.)

The final results from this multi-dose, 90-day inhalation toxicology study in the rat with life-time post-exposure observation have shown a significant fundamental difference in pathological response and tumorgenicity between brake dust generated from brake pads manufactured with chrysotile or from chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. The groups exposed to brake dust showed no significant pathological or tumorigenic response in the respiratory track compared to the air control group at exposure concentrations and deposited doses well above those at which humans have been exposed. Slight alveolar/interstitial macrophage accumulation of particles was noted. Wagner grades were 1-2 (1 = control group), similar to the TiO 2 particle control group. Chrysotile was not biopersistent, exhibiting in the lung a deterioration of its matrix which results in breakage into particles and short fibers which can be cleared by alveolar macrophages and which can continue to dissolve. Particle-laden macrophage accumulation was observed, leading to a very-slight interstitial inflammatory response (Wagner grade 1-3). There was no peribronchiolar inflammation, occasional very-slight interstitial fibrosis (Wagner grade 4), and no exposure-related tumorigenic response. The pathological response of crocidolite and amosite compared to the brake dust and chrysotile was clearly differentiated by the histopathology and the confocal analysis. Crocidolite and amosite induced persistent inflammation, microgranulomas, persistent fibrosis (Wagner grades 4), and a dose-related lung tumor response. Confocal microscopy quantified extensive inflammatory response and collagen development in the lung, visceral and parietal pleura as well as pleural adhesions. These results provide a clear foundation for differentiating the innocuous effects of brake dust exposure from the adverse effects following amphibole asbestos exposure., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the second most common dystrophy associated with predominant pelvic and shoulder girdle muscle weakness termed Limb-Girdle Muscular Dystrophy (LGMD), genetic complexity, large phenotypic variability, and clinical overlap can result in extensive diagnostic delays in certain individuals. In view of the large strides genetics has taken in this day and age, we address the question if muscle biopsies can still provide diagnostic evidence of substance for these patients. We reviewed and reanalyzed muscle biopsy characteristics in a cohort of LGMD patient pairs in which gene variants were picked up in CAPN3, FKRP, TTN, and ANO5, using histochemical-immunohistochemical-and immunofluorescent staining, and western blotting. We found that not the nature and severity of inflammatory changes, but the changed properties of the dystrophin complex were the most valuable assets to differentiate LGMD from myositis. Proteomic evaluation brought both primary and secondary deficiencies to light, which could be equally revealing for diagnosis. Though a muscle biopsy might, at present, not always be strictly necessary anymore, it still represents an irrefutable asset when the genetic diagnosis is complicated., (© 2021. Belgian Neurological Society.)

While roughly 30% of all women experience a spontaneous miscarriage in their lifetime, the incidence of recurrent (habitual) spontaneous miscarriage is 1 - 3% depending on the employed definition. The established risk factors include endocrine, anatomical, infection-related, genetic, haemostasis-related and immunological factors. Diagnosis is made more difficult by the sometimes diverging recommendations of the respective international specialist societies. The present study is therefore intended to provide a comparison of existing international guidelines and recommendations. The guidelines of the ESHRE, ASRM, the DGGG/OEGGG/SGGG and the recommendations of the RCOG were analysed. It was shown that investigation is indicated after 2 clinical pregnancies and the diagnosis should be made using a standardised timetable that includes the most frequent causes of spontaneous miscarriage. The guidelines concur that anatomical malformations, antiphospholipid syndrome and thyroid dysfunction should be excluded. Moreover, the guidelines recommend carrying out pre-conception chromosomal analysis of both partners (or of the aborted material). Other risk factors have not been included in the recommendations by all specialist societies, on the one hand because of a lack of diagnostic criteria (luteal phase insufficiency) and on the other hand because of the different age of the guidelines (chronic endometritis). In addition, various economic and consensus aspects in producing the guidelines influence the individual recommendations. An understanding of the underlying decision-making process should lead in practice to the best individual diagnosis and resulting treatment being offered to each couple., Competing Interests: Conflict of Interest/Interessenkonflikt Bettina Toth: shareholder of Reprognostics GbR, research funding: Teva, Bayer, Ferring. Fees/reimbursement of costs: Deutsche Gesellschaft für Gynäkologie und Geburtshilfe [German Society of Obstetrics and Gynecology]. Ferring, MSD, Exeltis, Merck Serono, Teva, Bayer. The remaining authors state that they have no conflicts of interest./Bettina Toth: Gesellschafterin Reprognostics GbR, Forschungsförderung: Firma Teva, Bayer, Ferring. Honorare/Kostenerstattung: Deutsche Gesellschaft für Gynäkologie und Geburtshilfe. Ferring, MSD, Exeltis, Merck Serono, Teva, Bayer. Die übrigen Autoren geben an, dass keine Interessenkonflikte bestehen., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

A substantial number of pregnant women at some point experience cardiac arrhythmia, which is mostly treated by antiarrhythmic medication. In some instances, arrhythmias can be drug-resistant and pose a relevant risk to both mother and unborn child as they can result in hemodynamic compromise. In recent years, invasive electrophysiology procedures have been carried out with ever reducing exposure to ionising radiation, and multiple techniques have been established to achieve ZERO exposure. Of course, these techniques should all be applied when contemplating an invasive mapping and ablation procedure during pregnancy. The role of the cardio-obstetrics team in planning and performing such procedures is paramount. Careful assessment of the pregnant mother and her unborn child is mandatory. Only with good preparation is a complete understanding of both cardiac anatomy and physiology achievable, which is a pre-requisite of a successful ablation outcome. Various aspects of the ablation procedure itself are discussed and evaluated from the perspective of all team members involved, including the obstetrician, the anaesthetist and the electrophysiologist. This review aims to inform the reader about the techniques available and reports on the published outcomes for ablations during pregnancy in the last decade.

The standard model of particle physics describes the vast majority of experiments and observations involving elementary particles. Any deviation from its predictions would be a sign of new, fundamental physics. One long-standing discrepancy concerns the anomalous magnetic moment of the muon, a measure of the magnetic field surrounding that particle. Standard-model predictions 1 exhibit disagreement with measurements 2 that is tightly scattered around 3.7 standard deviations. Today, theoretical and measurement errors are comparable; however, ongoing and planned experiments aim to reduce the measurement error by a factor of four. Theoretically, the dominant source of error is the leading-order hadronic vacuum polarization (LO-HVP) contribution. For the upcoming measurements, it is essential to evaluate the prediction for this contribution with independent methods and to reduce its uncertainties. The most precise, model-independent determinations so far rely on dispersive techniques, combined with measurements of the cross-section of electron-positron annihilation into hadrons 3-6 . To eliminate our reliance on these experiments, here we use ab initio quantum chromodynamics (QCD) and quantum electrodynamics simulations to compute the LO-HVP contribution. We reach sufficient precision to discriminate between the measurement of the anomalous magnetic moment of the muon and the predictions of dispersive methods. Our result favours the experimentally measured value over those obtained using the dispersion relation. Moreover, the methods used and developed in this work will enable further increased precision as more powerful computers become available.