Completed Treatment Cycles Research Articles

GnRH agonist-only trigger, compared to dual trigger, reduces oocyte retrieval rate in high responders without affecting cumulative live birth rate.

This study compared, in high responders undergoing IVF treatment, GnRH agonist-only trigger and dual trigger on oocyte retrieval rate and cumulative live birth rate (LBR). The aim was to determine if the GnRH agonist-only triggers had provided outcomes comparable to dual trigger, while minimizing the risk of ovarian hyperstimulation syndrome (OHSS). A retrospective, matched case-control study was conducted at Taichung Veterans General Hospital, Taiwan, including women who underwent IVF/ICSI between January 1, 2014, and December 31, 2022. Inclusion criteria were: GnRH antagonist protocol and estrogen level >3,000 pg/ml on trigger day. Exclusion criteria were: immune/metabolic diseases, donated oocytes, and mixed stimulation cycles. Propensity score matching was applied to balance age, AMH level, and oocyte number between the GnRH agonist-only and dual trigger groups. Outcomes were analyzed for patients who had complete treatment cycles, focusing on oocyte retrieval rate and cumulative LBR. We analyzed 116 cycles in the agonist-only group, and 232 cycles in the dual trigger group. No inter-group difference was found in their age, BMI, and AMH levels. The dual trigger group had a higher oocyte retrieval rate (93% vs. 80%; p <0.05), while fertilization rates, blastocyst formation rates, and cumulative LBR were comparable. Notably, no OHSS cases had been reported in the GnRH agonist-only group, compared with 7 cases in the dual trigger group. GnRH agonist-only triggers resulted in a lower oocyte retrieval rate compared to dual triggers but did not significantly affect cumulative LBR in high responders. This approach effectively reduces OHSS risk without compromising pregnancy outcomes, making it a preferable option in freeze-all strategies, despite a longer oocyte pick-up duration and a medium cost. GnRH agonist-only trigger, however, may not be suitable for fresh embryo transfers or patients with low serum LH levels on trigger day.

Predicting personalized cumulative live birth rate after a complete in vitro fertilization cycle: an analysis of 32,306 treatment cycles in China

BackgroundThe cumulative live birth rate (CLBR) has been regarded as a key measure of in vitro fertilization (IVF) success after a complete treatment cycle. Women undergoing IVF face great psychological pressure and financial burden. A predictive model to estimate CLBR is needed in clinical practice for patient counselling and shaping expectations.MethodsThis retrospective study included 32,306 complete cycles derived from 29,023 couples undergoing IVF treatment from 2014 to 2020 at a university-affiliated fertility center in China. Three predictive models of CLBR were developed based on three phases of a complete cycle: pre-treatment, post-stimulation, and post-treatment. The non-linear relationship was treated with restricted cubic splines. Subjects from 2014 to 2018 were randomly divided into a training set and a test set at a ratio of 7:3 for model derivation and internal validation, while subjects from 2019 to 2020 were used for temporal validation.ResultsPredictors of pre-treatment model included female age (non-linear relationship), antral follicle count (non-linear relationship), body mass index, number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, tubal factor, male factor, and scarred uterus. Predictors of post-stimulation model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. Predictors of post-treatment model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), cumulative Day-3 embryos live-birth capacity (non-linear relationship), number of previous IVF attempts, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. The C index of the three models were 0.7559, 0.7744, and 0.8270, respectively. All models were well calibrated (p = 0.687, p = 0.468, p = 0.549). In internal validation, the C index of the three models were 0.7422, 0.7722, 0.8234, respectively; and the calibration P values were all greater than 0.05. In temporal validation, the C index were 0.7430, 0.7722, 0.8234 respectively; however, the calibration P values were less than 0.05.ConclusionsThis study provides three IVF models to predict CLBR according to information from different treatment stage, and these models have been converted into an online calculator (https://h5.eheren.com/hcyc/pc/index.html#/home). Internal validation and temporal validation verified the good discrimination of the predictive models. However, temporal validation suggested low accuracy of the predictive models, which might be attributed to time-associated amelioration of IVF practice.

The Stabilizing Effect of Chitosan‐Modified Biochar (β‐CD/C‐BC) on Agricultural Soil Contaminated by the Cd‐Pyr Complex

AbstractThe composite pollution of heavy metals (HMs) and polycyclic aromatic hydrocarbons (PAHs) in agricultural soil is increasingly severe. HMs can undergo surface adsorption, complexation, or chemical reactions to transform from bioavailable species to residual species, achieving chemical morphological stability. However, these processes have no effect on PAHs. Biochar (BC), due to its inherent characteristics, can significantly enhance the stability of PAHs and is recommended as a potential co‐stabilizing material for both heavy metals and PAHs. In this study, rice husk biochar modified with β‐cyclodextrin and chitosan (β‐CD/C‐BC) was utilized to stabilize agricultural soil contaminated by Cd and Pyrene (Pyr). One‐way tests were conducted on the dosage and curing time of biochar after a complete cycle of treatment. The results demonstrated that the optimal effect was achieved when the dosage of β‐CD/C‐BC was 7.5 % or the curing time was 21 days. The removal efficiencies for Cd and Pyr were found to be 84.62 %, 64.22 % or 85.90 %, 65.78 %, respectively. Additionally, BCR testing revealed that β‐CD/C‐BC could convert HMs in soil into a residual state (from 32 % to 82 %) with the highest stabilization rate, thereby reducing their migration ability and ecological risk.

Outcome of Risk- and Response-Adapted Post-Remission Therapy in Patients with NPM1 AML Treated Intensively

Introduction: Molecular assessment of measurable residual disease (MRD) is a powerful prognostic tool to identify high risk of relapse. Specifically, large studies have shown that MRD negativity of NPM1 after two cycles of intensive chemotherapy (IC) predicts long term remission. The translation of MRD results to treatment decisions such as treatment augmentation (MRD erasing) and referral to an allogeneic stem cell transplant (allo-SCT) is still lacking. The purpose of this study is to report the outcome of AML patients with NPM1 mutation who received IC and achieved remission, in whom NPM1 MRD post cycle 2 of IC, combined with FLT3-ITD status, were used systematically to decide whether patients were to complete intensive consolidations or refer to alloSCT. Methods: This is a retrospective analysis from 3 large hospitals in Israel. Patients were treated with 7+3 for induction and a repeat induction based on day 14 marrow. Midostaurin was added for FLT3mut leukemia since 2018. Consolidation consisted of 3-4 HiDAC cycles at doses of 1-3 g/msqrX6. Gemtuzumab ozogamicin and maintenance with FLT3 inhibitors or CC486 could be added. NPM1 transcript levels (normalized to ABL copies) were collected at diagnosis, after 2 cycles of IC, at the end of IC cycles and during follow-up. Patients were transplanted if a donor was available and any of the following: NPM1 transcript level was not reduced by 3 logs by the end of second cycle chemotherapy, absolute level was &amp;gt;1%, poor risk AML (ELN 2017 guidelines) or high AR FLT3-ITD mutation was present. Patients were followed for relapse (type and timing) and whether a second remission was achieved, as well as for EFS and overall survival. Results: A database search yielded 90 patients with NPM1 AML who were treated according the abovementioned protocol between 5/2015 and 11/2022 and achieved remission, with a median follow-up of 872 days (range 103-2751). Forty-seven patients were to receive consolidation cycles without transplantation in CR1, based on the aforementioned criteria. All but one patient (death from sepsis) completed treatment cycles. During follow-up, 21 (45%) patients relapsed at a median of 343 days. Two patients died while in CR1 during follow-up (extensive burns; sudden death at home). In a subgroup analysis of patients &amp;lt;60y (N=28), there were 11 events (9 relapses and 2 deaths), whereas in patients &amp;gt;60y (N=19) there were 13 events (12 relapses and 1 death during follow-up). Of note, 4 patients &amp;gt;60y were treated with CC486, of whom only 1 relapsed. Of the 18 patients who relapsed and received further treatment (3 had palliative care only), only 1 patient did not enter CR2 (died during salvage). The other 17 patients entered CR2 after salvage regimen (N=7, 4 were qPCR MRDneg, 5 were subsequently transplanted in CR2) or after upfront alloSCT without any salvage regimen (N=10, 4 were qPCR MRDneg). Forty-three patients were planned for alloSCT at CR1 (27 - inadequate molecular response, 16 - ELN risk group). Only one of these patients failed to undergo alloSCT in CR1 as she relapsed. The other 42 patients underwent alloSCT at CR1. In this group of patients, the median progression-free survival was 5 years, with no difference in patients above or below the age of 60. One half of the events (9/18) were relapses and the other half were deaths in remission, almost all were GVHD associated (figure1). Discussion: NPM1 mut AML without FLT3 is still considered by the ELN to have favorable outcome and most patients are not being transplanted at CR1. Yet, many relapse. This study evaluated the outcome of AML patients according to molecular risk stratification and alloSCT consideration by the end of cycle 2 of IC. In line with previous publications, younger patients with standard-risk AML and with adequate molecular response had a favorable outcome, with &amp;gt;60% of them having a disease-free long-term survival without transplantation. Moreover, even in a case of relapse, patients can achieve CR2 with MRDneg and attain long-term remission (90% OS in long-term follow-up). Older patients have a less favorable outcome even when they achieve adequate molecular response with two thirds of them experiencing relapse. Hence, the potential long-term outcome without transplantation needs to be balanced by the high risk of relapse. Nevertheless, even these patients can be successfully treated with either a salvage regimen or immediate transplantation, and &amp;gt;40% of them can be long-term survivors.

Psychosocial wellbeing shortly after allocation to a freeze-all strategy compared with a fresh transfer strategy in women and men: a sub-study of a randomized controlled trial.

Psychosocial wellbeing shortly after allocation to a freeze-all strategy compared with a fresh transfer strategy in women and men: a sub-study of a randomized controlled trial.

Desensitization protocol to lenalidomide: An effective and safe treatment modality for delayed hypersensitivity-induced rash in patients with multiple myeloma.

Lenalidomide is considered a standard of care in multiple myeloma (MM) Some MM patients will develop delayed hypersensitivity to lenalidomide, which can lead to treatment discontinuation. Desensitization to lenalidomide can help these patients to complete treatment courses. Here, we aimed to review lenalidomide-treated MM patients who developed delayed hypersensitivity-induced rash and were treated with desensitization. A retrospective analysis of medical files of MM patients, who were desensitized to lenalidomide due to delayed hypersensitivity rash. Patients were treated between 2018 and 2022 at Hadassah Medical Center, Jerusalem, Israel. Search of patients yielded 16 patients that underwent desensitization to lenalidomide within the study period. The desensitization protocol consisted of a slow, 3-week-long protocol with lenalidomide's target doses of 10, 15, and 25 mg/day. Of the 16 patients, 10 (62.5%) succeeded to complete the protocol and thus were able to complete lenalidomide treatment cycles. One patient with unsuccessful desensitization was subsequently treated with first-generation IMiD thalidomide, with no rash appearing. None of the patients that were treated with desensitization had severe immune-mediated or non-dermatological adverse reactions. Desensitization to lenalidomide is safe and effective. Discontinuation of lenalidomide in MM patients with delayed hypersensitivity and no contraindication to desensitization should be discouraged. Collaboration between hematologists and allergists is needed.

Структура сплавов для постоянных магнитов типа (Sm,Zr)(Co,Cu,Fe)z и механизм формирования высококоэрцитивного состояния

Owing to the high temperature stability of hysteretic characteristics and corrosion resistance under external actions, (Sm,Zr)(Co,Cu,Fe)z-based magnets are widely used in devices operating at high temperatures, most critical constructions of aerospace engineering and defense technology, and in traction electric motors for transport engineering. A number of modern research methods are used to study in detail the structure and phase composition of the (Sm,Zr)(Co,Cu,Fe)z alloys with z = 5.5 – 7.0 in as-cast state and after heat treatment, which includes the solid solution treatment at 1150 – 1180 °С for 5 h, subsequent water quenching, isothermal aging at 800 °С for 20 h, and cooling (stepped aging) from 800 to 400 °С at an average cooling rate of 100 °С/h. The results obtained allowed us to suggest the schematic diagram of grain-boundary constituent transformation at different stages of heat treatment of (Sm,Zr)(Co,Cu,Fe)z permanent magnets prepared by powder metallurgy. The formation mechanism of high-coercivity state of (Sm,Zr)(Co,Cu,Fe)z permanent magnets in the course of complete heat treatment cycle is given as the sequence of phase transformations accompanied by redistribution of a number of alloy components.

An elevated systemic inflammation index is related to an inferior response to pomalidomide and dexamethasone treatment in patients with relapsed and refractory multiple myeloma.

The systemic inflammation index (SII) might serve as an indicator of the equilibrium between the inflammatory and immune responses. The aim of the study was to determine the clinical value and prognostic significance of SII in the cohort of multiple myeloma (MM) patients treated with a regimen of pomalidomide and dexamethasone (Pd). This retrospective, real-life study included patients who received a Pd regimen in our centre between November 2018 and July 2022. The systemic inflammation index was calculated from peripheral blood counts of platelets, neutrophils, and lymphocytes collected shortly before commencement of Pd treatment using the equation: SII = N × P/L, where N, P, and L are the respective counts per litre of peripheral blood for neutrophils, platelets, and lymphocytes. The study group consisted of 54 patients. Most patients received Pd as the third (38.9%) or fourth (37.0%) line of treatment. The median number of completed treatment cycles was 5 (IQR: 1-12). The median progression-free survival (PFS) was 6.8 months and overall survival (OS) 14.8 months. High SII (> 374) was an independent prognostic factor for PFS (HR = 3.0, 95% CI: 1.4-6.3, p < 0.01) and OS (HR = 2.2, 95% CI: 1.0-4.6, p = 0.04). In the low SII group, the respective median PFS and OS values were 9.6 and 21.7 months, compared to 2.6 (p = 0.018) and 5.5 months (p = 0.035) in the high SII group. The systemic inflammation index has prognostic significance in MM patients treated with Pd. A high SII predicts a poorer outcome in pretreated MM patients undergoing Pd treatment evaluation. As such, it may well be a key factor for guiding subsequent treatment decisions.

Final results of a phase 1 evaluation of niraparib and everolimus in advanced ovarian and metastatic breast cancer (303)

Objectives: To evaluate the safety and efficacy of the combination of niraparib and everolimus in a heavily pretreated PARP naïve population of advanced ovarian and metastatic breast cancer patients. Methods: An open-label, Phase I cohort study with a standard 3+3 design with four planned cohorts. All patients were PARP naïve. The planned schema was as follows: · Cohort 1 – Niraparib 100mg daily and everolimus 5mg MWF · Cohort 2 – Niraparib 200mg daily and everolimus 5mg MWF · Cohort 3 – Niraparib 200mg daily and everolimus 1mg daily · Cohort 4 – Niraparib 200mg daily and everolimus 5mg daily After two DLTs were experienced in cohort 2, four additional patients were enrolled at cohort 1 dose levels to confirm the safety of the combination at this dose and schedule. Results: Fourteen patients were enrolled in this study, and the safety evaluation has been completed. Three patients were not evaluable due to not completing the first cycle of treatment; two patients experienced DLTs, and one patient had rapid disease progression during the first week of cycle 1. Twelve patients had high-grade serous ovarian cancer, one patient had clear cell ovarian cancer, and one patient had breast cancer. Two dose-limiting toxicities (thrombocytopenia and hypertension) occurred in cohort 2. Of the 11 evaluable patients who received at least one complete cycle of treatment, the response rate was 18%, and the clinical benefit rate was 45%. One patient achieved a PR, and three patients had stable disease. The median progression-free survival for patients deriving clinical benefit was six months. There were 154 attributed adverse events; of these, 17 were grade 3 or grade 4 events (11%). The most common toxicities requiring intervention were thrombocytopenia (9.7%), hypertension (7.1%), nausea (4.6%), and stomatitis (3.9%). No new toxicities with this combination were evident. All patients had comprehensive molecular profiling prior to enrollment. Patient-reported outcomes were collected using the Treatment-Related Symptom Checklist (TRSC) and HRQOL-LASA and will be presented separately. Conclusions: The combination of niraparib and everolimus appears to provide some support for efficacy at the lowest doses. However, based on the DLTs experienced in cohort 2, the treatment proved to be too toxic to explore further at higher doses than niraparib 100mg daily and everolimus 5mg MWF. Objectives: To evaluate the safety and efficacy of the combination of niraparib and everolimus in a heavily pretreated PARP naïve population of advanced ovarian and metastatic breast cancer patients. Methods: An open-label, Phase I cohort study with a standard 3+3 design with four planned cohorts. All patients were PARP naïve. The planned schema was as follows: · Cohort 1 – Niraparib 100mg daily and everolimus 5mg MWF · Cohort 2 – Niraparib 200mg daily and everolimus 5mg MWF · Cohort 3 – Niraparib 200mg daily and everolimus 1mg daily · Cohort 4 – Niraparib 200mg daily and everolimus 5mg daily After two DLTs were experienced in cohort 2, four additional patients were enrolled at cohort 1 dose levels to confirm the safety of the combination at this dose and schedule. Results: Fourteen patients were enrolled in this study, and the safety evaluation has been completed. Three patients were not evaluable due to not completing the first cycle of treatment; two patients experienced DLTs, and one patient had rapid disease progression during the first week of cycle 1. Twelve patients had high-grade serous ovarian cancer, one patient had clear cell ovarian cancer, and one patient had breast cancer. Two dose-limiting toxicities (thrombocytopenia and hypertension) occurred in cohort 2. Of the 11 evaluable patients who received at least one complete cycle of treatment, the response rate was 18%, and the clinical benefit rate was 45%. One patient achieved a PR, and three patients had stable disease. The median progression-free survival for patients deriving clinical benefit was six months. There were 154 attributed adverse events; of these, 17 were grade 3 or grade 4 events (11%). The most common toxicities requiring intervention were thrombocytopenia (9.7%), hypertension (7.1%), nausea (4.6%), and stomatitis (3.9%). No new toxicities with this combination were evident. All patients had comprehensive molecular profiling prior to enrollment. Patient-reported outcomes were collected using the Treatment-Related Symptom Checklist (TRSC) and HRQOL-LASA and will be presented separately. Conclusions: The combination of niraparib and everolimus appears to provide some support for efficacy at the lowest doses. However, based on the DLTs experienced in cohort 2, the treatment proved to be too toxic to explore further at higher doses than niraparib 100mg daily and everolimus 5mg MWF.

Predicting cumulative live birth for couples beginning their second complete cycle of in vitro fertilization treatment.

STUDY QUESTIONCan we develop an IVF prediction model to estimate individualized chances of a live birth over multiple complete cycles of IVF in couples embarking on their second complete cycle of treatment?SUMMARY ANSWERYes, our prediction model can estimate individualized chances of cumulative live birth over three additional complete cycles of IVF.WHAT IS KNOWN ALREADYAfter the completion of a first complete cycle of IVF, couples who are unsuccessful may choose to undergo further treatment to have their first child, while those who have had a live birth may decide to have more children. Existing prediction models can estimate the overall chances of success in couples before commencing IVF but are unable to revise these chances on the basis of the couple’s response to a first treatment cycle in terms of the number of eggs retrieved and pregnancy outcome. This makes it difficult for couples to plan and prepare emotionally and financially for the next step in their treatment.STUDY DESIGN, SIZE, DURATIONFor model development, a population-based cohort was used of 49 314 women who started their second cycle of IVF including ICSI in the UK from 1999 to 2008 using their own oocytes and their partners’ sperm. External validation was performed on data from 39 442 women who underwent their second cycle from 2010 to 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSData about all UK IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA) database. Using a discrete time logistic regression model, we predicted the cumulative probability of live birth from the second up to and including the fourth complete cycles of IVF. Inverse probability weighting was used to account for treatment discontinuation. Discrimination was assessed using c-statistic and calibration was assessed using calibration-in-the-large and calibration slope.MAIN RESULTS AND THE ROLE OF CHANCEFollowing exclusions, 49 314 women with 73 053 complete cycles were included. 12 408 (25.2%) had a live birth resulting from their second complete cycle. Cumulatively, 17 394 (35.3%) had a live birth over complete cycles two to four. The model showed moderate discriminative ability (c-statistic: 0.65, 95% CI: 0.64 to 0.65) and evidence of overprediction (calibration-in-the-large = −0.08) and overfitting (calibration slope 0.85, 95% CI: 0.81 to 0.88) in the validation cohort. However, after recalibration the fit was much improved. The recalibrated model identified the following key predictors of live birth: female age (38 versus 32 years—adjusted odds ratio: 0.59, 95% CI: 0.57 to 0.62), number of eggs retrieved in the first complete cycle (12 versus 4 eggs; 1.34, 1.30 to 1.37) and outcome of the first complete cycle (live birth versus no pregnancy; 1.78, 1.66 to 1.91; live birth versus pregnancy loss; 1.29, 1.23 to 1.36). As an example, a 32-year-old with 2 years of non-tubal infertility who had 12 eggs retrieved from her first stimulation and had a live birth during her first complete cycle has a 46% chance of having a further live birth from the second complete cycle of IVF and an 81% chance over a further three cycles.LIMITATIONS, REASONS FOR CAUTIONThe developed model was updated using validation data that was 6 to 12 years old. IVF practice continues to evolve over time, which may affect the accuracy of predictions from the model. We were unable to adjust for some potentially important predictors, e.g. BMI, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. These were not available in the linked HFEA dataset.WIDER IMPLICATIONS OF THE FINDINGSBy appropriately adjusting for couples who discontinue treatment, our novel prediction model will provide more realistic chances of live birth in couples starting a second complete cycle of IVF. Clinicians can use these predictions to inform discussion with couples who wish to plan ahead. This prediction tool will enable couples to prepare emotionally, financially and logistically for IVF treatment.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. The authors have no conflict of interest.TRIAL REGISTRATION NUMBERN/A.

Tiotropium treatment for bronchiectasis: a randomised, placebo-controlled, crossover trial.

BackgroundTiotropium via the HandiHaler device is an established long-acting, anticholinergic bronchodilator that prevents exacerbations and improves lung function in patients with chronic obstructive pulmonary disease. We hypothesised that tiotropium would reduce pulmonary exacerbations and improve lung function in patients with stable bronchiectasis and airflow limitation, and assessed the effect of tiotropium on these outcomes.MethodsIn a randomised, double-blind, two-period crossover trial, we recruited adult patients from three hospitals in New Zealand. Patients were excluded if they had a smoking history of >20 pack-years. Patients were assigned to either the tiotropium–placebo or placebo–tiotropium sequence in a 1:1 ratio, using randomly permuted blocks stratified by centre. Participants and investigators were masked to treatment allocation. Eligible patients received tiotropium 18 μg via HandiHaler daily for 6 months followed by 6 months of placebo, or vice versa, with a washout period of 4 weeks. The primary end-point was rate of event-based exacerbations during the 6-month period. Primary analyses were carried out in an intention-to-treat set.Results90 patients were randomly assigned and 85 completed both treatment cycles. The rate of exacerbations was 2.17 per year under the tiotropium treatment and 2.27 per year under placebo (rate ratio 0.96, 95% CI 0.72–1.27; p=0.77). Tiotropium, compared with placebo, improved forced expiratory volume in 1 s by 58 mL (95% CI 23–92 mL; p=0.002). Adverse events were similar under both treatments.ConclusionsTiotropium via HandiHaler over 6 months significantly improved lung function but not frequency of exacerbations. Further research is required to understand the clinical context and significance of these findings.

P–652 Higher live birth rates with controlled ovarian stimulation vs. natural cycles in donor sperm IUI

Abstract Study question Are pregnancy rates after intra uterine insemination-donor sperm (IUI-D) in good prognosis patients with controlled ovarian stimulation (COS) different from those in natural cycles? Summary answer In good prognosis patients, IUI-D cycles with COS provided higher pregnancy outcomes compared to IUI-D in natural cycles. What is known already There is no consensus about the systematic use of COS for IUI-D in good prognosis patients, considering efficacy, safety, and efficiency. The objective of this study is to compare the clinical pregnancy rate in good prognosis patients undergoing an IUI-D cycle with COS versus natural cycle (NC). Study design, size, duration Retrospective cohort study of 5,369 first IUI-D performed between January 2012 and September 2019 in one fertility center. IUI-D with COS (n = 4,417) versus natural cycles (n = 952) were compared. Differences in pregnancy outcomes between study groups were evaluated using a Pearson’s Chi2 test. A p &amp;lt; 0.05 was considered statistically significant. Participants/materials, setting, methods Good prognosis patients were defined as women aged ≤38 years old, with a BMI ≤35 Kg/m2, and having regular menses. The indications for IUI-D were an absence of male partner or a sever partner male factor. COS consisted in a standard protocol of r-FSH or hMG-HP, in a dose between 25 IU to 75 IU, depending on the patient’s age and the acceptance of multiple pregnancy, to obtain between 1 to 2 follicles at ovulation. Main results and the role of chance Average age was slightly higher in COS patients (33.0±3.8 versus 31.6±4.1 years old in NC), as was BMI (23.7±3.6 in COS vs 23.08±4.1 in NC). Further, in the last follicular control, estradiol was higher (321±180 vs 244±108 pg/ml), LH was lower in (14 vs 28 UI/L), and the number of follicles &amp;gt; 16mm was higher (1.06±0.5 vs 0.96±0.4) in COS vs NC, respectively. Progesterone levels did not differ between groups. Stimulated cycles provided significantly better results for all pregnancy outcomes (p &amp;lt; 0.001): biochemical pregnancy rate was 27.8% in COS versus 23.0% in NC; clinical pregnancy rate was 20.5% versus 14.8%; ongoing pregnancy rate was 18.5% versus 13.3%; and live birth rate was 16.8% versus 12.3%. While the analysis was not adjusted for potential confounding factors, baseline characteristics between groups were very similar, so we could expect that the improved reproductive results were due to COS. Limitations, reasons for caution The main limitation of the study is its retrospective nature and the collection of data from one clinic. Differences found between study groups should be confirmed in a prospective controlled trial. Wider implications of the findings: In good prognosis patients undergoing their first IUI-D, controlled ovarian stimulation provides better reproductive outcomes; further analysis of cumulative pregnancy rate after 3 cycles would provide information for recommendations on the complete treatment cycle. Trial registration number non applicable

Cumulative live birth rate after IVF: trend over time and the impact of blastocyst culture and vitrification.

STUDY QUESTIONHas cumulative live birth rate (CLBR) improved over time and which factors are associated with such an improvement?SUMMARY ANSWERDuring an 11-year period, 2007–2017, CLBR per oocyte aspiration increased significantly, from 27.0% to 36.3%, in parallel with an increase in blastocyst transfer and cryopreservation by vitrification.WHAT IS KNOWN ALREADYWhile it has been shown that live birth rate (LBR) per embryo transfer (ET) is higher for fresh blastocyst than for fresh cleavage stage embryo transfer, CLBR per oocyte aspiration, including one fresh ET and all subsequent frozen embryo transfers (FET), does not seem to differ between the two culture strategies.STUDY DESIGN, SIZE, DURATIONA national register study including all oocyte aspirations performed in Sweden from 2007 to 2017 (n = 124 700 complete IVF treatment cycles) was carried out. Oocyte donation cycles were excluded.PARTICIPANTS/MATERIALS, SETTING, METHODSData were retrieved from the Swedish National Registry of Assisted Reproduction (Q-IVF) on all oocyte aspirations during the study period where autologous oocytes were used. CLBR was defined as the proportion of deliveries with at least one live birth per oocyte aspiration, including all fresh and/or frozen embryo transfers within 1 year, until one delivery with a live birth or until all embryos were used, whichever occurred first. The delivery of a singleton, twin, or other multiples was registered as one delivery. Cryopreservation of cleavage stage embryos was performed by slow freezing and of blastocyst by vitrification.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 124 700 oocyte aspirations were performed (in 61 313 women), with 65 304 aspirations in women <35 years and 59 396 in women ≥ 35 years, resulting in 38 403 deliveries with live born children. Overall, the CLBR per oocyte aspiration increased significantly during the study period, from 27.0% to 36.3% (odds ratio (OR) 1.039, 95% CI 1.035–1.043) and from 30.0% to 43.3% if at least one ET was performed (adjusted OR 1.055, 95% CI 1.050–1.059). The increase in CLBR was independent of maternal age, number of oocytes retrieved and number of previous IVF live births. The CLBR for women <35 and ≥35 years both increased significantly, following the same pattern. During the study period, a substantially increasing number of blastocyst transfers was performed, both in fresh and in FET cycles. Other important predicting factors for live birth, such as number of embryos transferred, could not explain the improvement. An increased single embryo transfer rate was observed with time.LIMITATIONS, REASONS FOR CAUTIONThe retrospective design implicates that other confounders of importance for CLBR cannot be ruled out. In addition, some FET cycles might be performed later than 1 year post oocyte aspiration for the last year (2017) and are, thus, not included in this study. In addition, no data on ‘dropouts’, i.e. patients that do not continue their treatment despite having cryopreserved embryos, are available, or if this drop-out rate has changed over time.WIDER IMPLICATIONS OF THE FINDINGSThe results suggest that blastocyst transfer, particularly when used in FET cycles and in combination with vitrification, is an important contributor to the improved live birth rates over time. This gives a possibility for a lower number of oocyte aspirations needed to achieve a live birth and a shortened time to live birth.STUDY FUNDING/COMPETING INTERESTSThe study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70940) and by Hjalmar Svensson’s research foundation. None of the authors declares any conflict of interest.

Effect of Azacitidine on CD4+CD25+Foxp3+ Regulatory T Cell on Immunity in Myelodysplastic Syndrome Survivors

Background: Immune editing is recognized as important in various pathogenic processes. We previously showed that regulatory T cell (Treg) levels were elevated in MDS with a poor prognosis and that Treg levels decreased with Azacitidine (AZA) treatment and became equivalent to that in the untreated group. In this study, we examined changes in the number of circulating Tregs, T cells, and NK cells in the peripheral blood of patients with MDS treated with AZA, and we evaluated the clinical significance of these findings with survival.Patients and Methods: Patients with MDS and with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) according to the WHO 2008 classification who were initially treated between January 2015 and December 2016 and followed up for more than 6 months were enrolled in the study. AZA was given intravenously at a dose of 75 mg/m2 daily for either 5 or 7 consecutive days every 4 weeks. The response was assessed using the IWG response criteria for MDS. A total of 50 patients with AML-MRC (n=11), refractory anemia with excess blasts (RAEB) (n=8), refractory cytopenia with multilineage dysplasia (RCMD) (n=28), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (n=12), and refractory anemia with ring sideroblastis (RARS) (n=1) were included in the study. The IPSS was classified as low (n=15) intermediate-1 (n=13), intermediate-2 (n=10), and high (n=13). Twenty-six patients did not require treatment, including a transfusion (untreated group). Twenty-two patients were treated with AZA (AZA group). The remaining patients received conventional chemotherapy. After obtaining informed consent, blood was drawn from all of the patients at initial diagnosis. In the 22 patients treated with AZA, blood was also drawn after 6 completed treatment cycles. CD4+CD25+Foxp3+ Treg cells, CD3+CD4+ T cells, CD3+CD8+ T cells, and CD3-CD56+ NK cells were analyzed using flow cytometry, and the absolute numbers of these cells were calculated. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared by the log-rank test for univariate analysis.Results: The median age was 74 years (range: 44-93 years), and 35 of the patients were male. The median period of observation was 391 days. In the AZA group, 10 patients died (AZA-ineffective group), and 12 had either a CR, PR, or HI (AZA-effective group). The 2-year OS of the AZA group was 43.7%. The absolute number of Tregs and Treg% values before treatment were not significantly different between the AZA group and the untreated group. The Treg levels in peripheral blood before treatment in the AZA-effective (0.80±0.39%) tended to be lower than that in the AZA-ineffective (1.29±0.82%) group (p=0.076). The CD8+ T cell counts before treatment were moderately higher in the AZA-effective group compared to that in the AZA-ineffective group (385.5 ± 129.0 vs. 195.5 ± 70.0 /μL, p<0.01). Similarly, the CD3-CD56+ NK cell counts before treatment differed significantly between the AZA-effective group (197.4 ± 138.8 /μL) and the AZA-ineffective group (82.3 ± 36.7 /μL) (p=0.015). In a univariate analysis, the MDS patients with elevated NK cells survived longer than the group with reduced NK cells (p=0.013). In a multivariate analysis, the lower percentage of Treg cells and the higher percentage of CD8+T cells before treatment were independent factors for OS (HR, 4.80; p=0.085, HR, 4.13; p=0.040, respectively). In the AZA group, the percentage of CD8+T cells before treatment associated with OS (HR, 39.24; p=0.018). After treatment, the AZA group had an increase in the NK cell counts, which tended to associate with survival (HR 4.29; p=0.067).Conclusions: The number of Tregs in MDS cases requiring treatment was higher than that in MDS cases for which treatment was unnecessary. The prognosis of the patients with high CD8+ T cells counts was better. In contrast, there was an increase in the number of NK cells after AZA treatment, which was found to be associated with an improved prognosis. These results suggest that an immunological mechanism associated with the prognosis of MDS may be enhanced by treatment with AZA. Further examination of this mechanism and of the influence of AZA on the immunological effect are required. DisclosuresNo relevant conflicts of interest to declare.

Pregnancy in Older Women: Analysis of Outcomes in Pregnancies from Donor oocyte In- vitro Fertilization.

Background:As the number of older women attempting to conceive through donor oocyte-in vitro fertilization (DO-IVF) rises, their safety in pregnancy needs to be judiciously considered.Aims:This study aims to review the obstetric and perinatal outcomes of pregnancies achieved by DO-IVF.Study Setting and Design:A retrospective study design conducted at a private health facility with services for assisted reproduction and gynecologic endoscopy.Methods:A retrospective comparative study of all pregnancies achieved using DO-IVF and that using Self oocyte In-vitro fertilization (SO-IVF) treatment over a 3 years' period was performed.Statistical Analysis:Comparative analysis of demographic variables, major obstetric, and perinatal complications was done with Chi-square test and Student's t-test as appropriate. Regression analysis was done to determine a significant predictor variable for pregnancy and delivery outcome. The significance level was set at P < 0.05.Results:A total of 343 completed IVF treatment cycles was reviewed; there were 238 DO-IVF and 105 SO-IVF cycles, with clinical pregnancy rate of 41.6% and 37.1%, respectively. The DO-IVF group was significantly older than the SO-IVF group (46.1 years vs. 34.1 years, P < 0.001). Major obstetric complications identified, were hypertensive disorders in pregnancy (23.9%), preterm labor (16.7%), antepartum hemorrhage (11.6%). There was no statistically significant difference between the two groups in terms of obstetric complications and adverse maternal or perinatal outcomes. There were 97 (77.6%) singleton and 28 (22.4%) multiple pregnancies. Pregnancy complications were significantly associated with fetal plurality, P < 0.001. Multiple pregnancy had higher odds of experiencing adverse perinatal 4.96 (1.95–12.58) and maternal 7.16 (2.05–25.03) outcomes compared to singleton pregnancies, P < 0.001.Conclusion:Key obstetric outcomes did not differ between DO or SO IVF achieved pregnancy. Even for older women, satisfactory outcomes can be expected for pregnancies achieved by DO-IVF. It is, however, instructive that for multiple pregnancies, obstetricians should institute appropriate surveillance strategies during pregnancy and delivery period and also to develop institutional capacity for quality neonatal care.

Does HPV infection have impact on results of photodynamic treatment of vulvar lichen sclerosus?

The association between lichen sclerosus (LS) and human papilloma virus (HPV) infections remains unclear. The co-occurrence of both pathologies may impact treatment and prognosis. This study aimed to assess the results of photodynamic therapy (PDT) for vulvar LS and the effect of incidence of HPV infection on the results of treatment and duration of remission. A total of 73 patients with LS were included in the study. In each patient, 14 types of HPV were detected. PDT was performed using the PhotoDyn 501, which emits light at 630 nm wavelength and power density of 204 mW/cm². Focal lesions were exposed for 10 min once weekly for a total of 10 weeks. The complete treatment cycle was repeated after 3 months, whenever required. The biopsy was repeated after completion of treatment. The number of treatment cycles for HPV-positive and HPV-negative patients were not statistically different (cases after one or two PDT cycles). An exception was a group of patients with LS requiring three PDT cycles. Analysis of remission period considering HPV results (positive vs. negative) did not reveal a significant statistical difference. Mean remission period among HPV-negative patients was longer in comparison to remission time for those with positive HPV results (14 ± 9 vs. 11 ± 9 months). PDT may be a promising, effective, and safe method for the treatment of LS regardless of HPV infection.

Investigation of the Effect of the Plasma Thin-Film Coating System Si−O−C−N on the Surface Hardening of High-Speed Steel

The results of studying changes in the strength properties of the surface of a tool product from high-speed steel (HSS) of the W6Mo5Cr4V2 type after its hardening by the application of the Si−O−C−N micron plasma coating system are presented. The study is conducted by comparing the properties of the surface, evaluated by the same methods before and after coating. In this case, the sample goes through a complete cycle of mechanical and heat treatment designed for the product before coating. The results of evaluation of the adhesive strength of the coating using the proposed method of recalculation are given, and the correspondence between the index of destruction of the coating of the VDI 3198: 1992-08 technique and the delamination coefficient is obtained. The study itself is carried out by indenting and scratching the surface with HV, HRC and HRB-type indenters in the load variation range of 0.1–200 N, which makes it possible to simulate different levels of contact pressure in the surface layer of the substrate and at the base–coating interface. It is shown that the application of a thin-film coating of the Si−O−C−N system by the plasma method makes it possible, in addition to standard heat treatment of HSS steel, to increase the surface resistance to penetration and scratching with harder bodies. The causes of the obtained positive effect are analyzed and the limits of the expediency of applying plasma hardening depending on the contact task are described. These results make it possible to consider the method of the additional plasma hardening of HSS steel as promising for implementation.

Study on practical methods for treatment of oil-contaminated and domestic wastewater

The implementation by small innovative enterprises of the LBR technology for household wastewater treatment, which is a complete cycle of urban wastewater treatment (WWTP), is one of the most perspective direction of strategic development of the regional economy, improving the parameters of its investment, environmental and social components. Each technological stage of technology is carried out on separate devices located indoors - a technological process of a closed hardware type. Such a process lends itself to automation, since each of the devices is technologically autonomous and can be replaced by another due to a malfunction or according to technological indications. In this way, high process stability and flexibility are achieved. All devices are of serial factory manufacturing, which ensures high quality, aesthetics and reasonable price parameters, as well as, if necessary, the ability to upgrade each unit individually. The hardware type of the technological process, being high-tech, energy-efficient and environmentally friendly, creates the prerequisites for a significant reduction in sanitary protection zones (2–6 times) and areas allocated directly to sewage treatment plants (7– 8 times). In addition, it becomes possible to flexibly change the capacity of WWTP (increase or decrease if necessary), as well as introduce purification stages necessary for specific conditions or remove unnecessary ones, without compromising the integrity of the technology and the efficiency of wastewater treatment. Implementation LBR technology by small innovative enterprises maximum environmental, social and economic efficiency and at prevent the waste of investment resources.

High Molecular Remission Rate in Pediatric Patients (pts) with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (r/r ALL) Treated with Blinatumomab: Rialto an Open-Label, Multicenter, Expanded Access Study

Introduction Despite a high cure rate for pediatric ALL, the prognosis for pts who suffer from r/r disease remains poor. Pediatric pts with r/r ALL face multiple lines of therapy, acute and long-term treatment toxicities, and have limited survival. New agents that are able to provide durable disease control and long-term survival with limited toxicity are needed. Blinatumomab (blin) is a bispecific T-cell engaging (BiTE®) antibody construct that redirects CD3+ cytotoxic T cells to lyse CD19+ B cells. We evaluated the safety and efficacy of blin in pediatric pts with B-cell precursor r/r ALL enrolled in an expanded access study initiated in 2014 (NCT02187354). Methods Eligible pts with r/r CD19+ ALL (≥ 2 relapses, relapse after allogeneic hematopoietic stem cell transplant [HSCT], or refractory to prior treatment) were > 28 days to 25% blasts. Subsequent therapy, including HSCT, was off protocol and per investigator preference. The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included morphologic complete response (CR; Results Of 98 treated pts (median age, 8.5 [range 0.4-17.0] years), 93% were enrolled in Europe, 54% had > 25% blasts at baseline, 41% had ≥ 50% blasts, and 48% had a cytogenetic abnormality. Prior treatments included HSCT (44%), radiotherapy (15%), and blin (4%); 56% of pts had ≥ 2 relapses, 41% had relapsed after HSCT, 14% were primary refractory and 20% were refractory to reinduction therapy. At data cutoff (March 9, 2018), 37 pts were on study. The median number of completed treatment cycles was 2 (range 1-5), with 4 pts completing 5 cycles of blin. Overall, 99% of pts experienced a TEAE, with a rate of 64% for grade ≥ 3. TRAEs were reported in 77% of pts (26% for grade ≥ 3); 21% were deemed serious. The most frequent TEAEs (any grade) included pyrexia (83%), vomiting (27%), headache (24%), and anemia (19%). Among TEAE categories of interest, rates of any grade/grade ≥ 3 were 67%/9% for infusion reactions, 44%/16% for infections, 43%/5% for neurologic events, 40%/31% for cytopenias, 18%/12% for elevated liver enzymes, 16%/2% for cytokine release syndrome, 8%/0% for decreased immunoglobulins, 4%/2% for tumor lysis syndrome, and 1%/0% for capillary leak syndrome. Dose interruption due to a TRAE was required by 19% of pts, and 4% discontinued blin due to a TRAE. There were 9 fatal AEs, all unrelated to blin. In the first 2 cycles of treatment, 60% of all 98 pts achieved CR, 40% achieved CR with full recovery of peripheral blood counts (PBC), and 48% achieved MRD response. Of 2 pts with t(17;19), both achieved CR with full PBC recovery and MRD response; of 4 pts with Down syndrome, 3 achieved CR (2 full PBC recovery) and MRD response; of 4 pts who had received prior blin treatment, 3 achieved CR (3 full PBC recovery) with blin retreatment and 2 achieved MRD response. Among 59 pts who achieved CR within 2 cycles, 27 (46%) proceeded to HSCT; 19 relapsed and 5 died after a median follow-up 5.3 (range, 0.3-13.2) months for a median RFS of 8.5 (95% CI, 2.9-NE) months from the time of CR. Among all 98 pts, median follow-up was 12.2 (range, 0.5-14.1) months; there were 38 deaths (32 disease related), and median OS was 13.0 (95% CI, 9.3-NE) months. Conclusions The safety profile of single-agent blin in this expanded access study was generally consistent with profiles reported in prior controlled trials of blin in pediatric and adult pts with r/r ALL. Blin was active in this pediatric r/r ALL population. Blin induced MRD response in almost half of the pts, including pts with t(17;19) or prior blin treatment. Pts with a lower leukemia burden ( Disclosures Locatelli:Bellicum: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Zugmaier:Amgen Inc.: Consultancy, Employment, Patents & Royalties: 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140227272, 20140228316, 20130323247, 20130287774, 20130287778, 20110262440, 20100112603, 7700299, 20070037228. Bader:Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Medac: Patents & Royalties, Research Funding; Novartis: Consultancy, Speakers Bureau. Bourquin:Amgen: Other: Travel Support. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding. Rossig:Genetech: Consultancy; Roche: Consultancy, Honoraria; MorphoSys: Honoraria; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Honoraria; EUSA Pharm: Consultancy.

Predicting the cumulative chance of live birth over multiple complete cycles of in vitro fertilization: an external validation study.

Are the published pre-treatment and post-treatment McLernon models, predicting cumulative live birth rates (LBR) over multiple complete IVF cycles, valid in a different context? With minor recalibration of the pre-treatment model, both McLernon models accurately predict cumulative LBR in a different geographical context and a more recent time period. Previous IVF prediction models have estimated the chance of a live birth after a single fresh embryo transfer, thereby excluding the important contribution of embryo cryopreservation and subsequent IVF cycles to cumulative LBR. In contrast, the recently developed McLernon models predict the cumulative chance of a live birth over multiple complete IVF cycles at two certain time points: (i) before initiating treatment using baseline characteristics (pre-treatment model) and (ii) after the first IVF cycle adding treatment related information to update predictions (post-treatment model). Before implementation of these models in clinical practice, their predictive performance needs to be validated in an independent cohort. External validation study in an independent prospective cohort of 1515 Dutch women who participated in the OPTIMIST study (NTR2657) and underwent their first IVF treatment between 2011 and 2014. Participants underwent a total of 2881 complete treatment cycles, with a complete cycle defined as all fresh and frozen thawed embryo transfers resulting from one episode of ovarian stimulation. The follow up duration was 18 months after inclusion, and the primary outcome was ongoing pregnancy leading to live birth. Model performance was externally validated up to three complete treatment cycles, using the linear predictor as described by McLernon et al. to calculate the probability of a live birth. Discrimination was expressed by the c-statistic and calibration was depicted graphically in a calibration plot. In contrast to the original model development cohort, anti-Müllerian hormone (AMH), antral follicle count (AFC) and body weight were available in the OPTIMIST cohort, and evaluated as potential additional predictors for model improvement. Applying the McLernon models to the OPTIMIST cohort, the c-statistic of the pre-treatment model was 0.62 (95% CI: 0.59-0.64) and of the post-treatment model 0.71 (95% CI: 0.69-0.74). The calibration plot of the pre-treatment model indicated a slight overestimation of the cumulative LBR. To improve calibration, the pre-treatment model was recalibrated by subtracting 0.35 from the intercept. The post-treatment model calibration plot revealed accurate cumulative LBR predictions. After addition of AMH, AFC and body weight to the McLernon models, the c-statistic of the updated pre-treatment model improved slightly to 0.66 (95% CI: 0.64-0.68), and of the updated post-treatment model remained at the previous level of 0.71 (95% CI: 0.69-0.73). Using the recalibrated pre-treatment model, a woman aged 30 years with 2 years of primary infertility who starts ICSI treatment for male factor infertility has a chance of 40% of a live birth from the first complete cycle, increasing to 72% over three complete cycles. If this woman weighs 70 kg, has an AMH of 1.5 ng/mL and an AFC of 10 measured at the beginning of her treatment, the updated pre-treatment model revises the estimated chance of a live birth to 30% in the first complete cycle and 59% over three complete cycles. If this woman then has five retrieved oocytes, no embryos cryopreserved and a single fresh cleavage stage embryo transfer in her first ICSI cycle, the post-treatment model estimates the chances of a live birth at 28 and 58%, respectively. Two randomized controlled trials (RCT) evaluating the effectiveness of gonadotropin dose individualization on basis of the AFC were nested within the OPTIMIST study. The strict dosing regimens, the RCT in- and exclusion criteria and the limited follow up time of 18 months might have influenced model performance in this independent cohort. Also, consistent with the original model development study, external validation was performed using the optimistic assumption that the cumulative LBR in couples who discontinue treatment without a live birth would have been equal to that of those who continue treatment. After national recalibration to account for geographical differences in IVF treatment, the McLernon prediction models can be introduced as new counselling tools in clinical practice to inform patients and to complement clinical reasoning. These models are the first to offer an objective and personalized estimate of the cumulative probability of a live birth over multiple complete IVF cycles. No external funds were obtained for this study. M.J.C.E., D.J.M. and S.B. have nothing to disclose. J.A.L, S.C.O, T.C.v.T. and H.LT. received an unrestricted personal grant from Merck BV. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Merck BV (the Netherlands) and Ferring pharmaceutics BV (the Netherlands), for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA). Not applicable.