Reduced human fecundity attributable to ambient fine particles in low- and middle-income countries.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) has been associated with reduced human fecundity. However, the attributable burden has not been estimated for low- and middle-income countries (LMICs), where the exposure-response function between PM2.5 and the infertility rate has been insufficiently studied. OBJECTIVE: This study examined the associations between long-term exposure to PM2.5 and human fecundity indicators, namely the expected time to pregnancy (TTP) and 12-month infertility rate (IR), and then estimated PM2.5-attributable burden of infertility in LMICs. METHODS: We analyzed 164,593 eligible women from 100 Demographic and Health Surveys conducted in 49 LMICs between 1999 and 2021. We assessed PM2.5 exposures during the 12 months before a pregnancy attempt using the global satellite-derived PM2.5 estimates produced by Atmospheric Composition Analysis Group (ACAG). First, we created a series of pseudo-populations with balanced covariates, given different levels of PM2.5 exposure, using a matching approach based on the generalized propensity score. For each pseudo-population, we used 2-stage generalized Gamma models to derive TTP or IR from the probability distribution of the questionnaire-based duration time for the pregnancy attempt before the interview. Second, we used spline regressions to generate nonlinear PM2.5 exposure-response functions for each of the two fecundity indicators. Finally, we applied the exposure-response functions to estimate number of infertile couples attributable to PM2.5 exposure in 118 LMICs. RESULTS: Based on the Gamma models, each 10 µg/m3 increment in PM2.5 exposure was associated with a TTP increase by 1.7 % (95 % confidence interval [CI]: -2.3 %-6.0 %) and an IR increase by 2.3 % (95 %CI: 0.6 %-3.9 %). The nonlinear exposure-response function suggested a robust effect of an increased IR for high-concentration PM2.5 exposure (>75 µg/m3). Based on the PM2.5-IR function, across the 118 LMICs, the number of infertile couples attributable to PM2.5 exposure exceeding 35 µg/m3 (the first-stage interim target recommended by the World Health Organization global air quality guidelines) was 0.66 million (95 %CI: 0.061-1.43), accounting for 2.25 % (95 %CI: 0.20 %-4.84 %) of all couples affected by infertility. Among the 0.66 million, 66.5 % were within the top 10 % high-exposure infertile couples, mainly from South Asia, East Asia, and West Africa. CONCLUSION: PM2.5 contributes significantly to human infertility in places with high levels of air pollution. PM2.5-pollution control is imperative to protect human fecundity in LMICs.

Preparation of Fe-BN-C catalysts derived from ZIF-8 and their performance in the oxygen reduction reaction.

Enhancing the oxygen reduction reaction (ORR) activity and stability of the fuel cell cathode electrocatalysts and reducing their costs are critical. In response to this need, Fe, B, and N co-doped hollow mesoporous carbon materials were prepared by a simple chemical doping one-step pyrolysis method using ZIF-8 as a precursor. The results showed that the optimized catalyst displayed a higher limiting current density (6.154 mA cm-2) and half-wave potential (0.859 V), which showed significant enhancement compared with the Pt/C catalyst (5.487 mA cm-2 and 0.853 V). Moreover, the optimized catalyst had outstanding long-term stability with a current density retention higher than 91% after 36 000 s of stability testing. This work provides a facile strategy for the design of outstanding ORR performance of non-precious metal oxygen reduction catalysts.

Estimating birthweight reduction attributable to maternal ozone exposure in low- and middle-income countries.

The effect of O3 on birthweight in low- and middle-income countries (LMICs) remains unknown. A multicenter epidemiological study was conducted to evaluate the association between maternal peak-season O3 exposure and birthweight, using 697,148 singleton newborns obtained in 54 LMICs between 2003 and 2019. We estimated the birthweight reduction attributable to peak-season O3 exposure in 123 LMICs based on a nonlinear exposure-response function (ERF). With every 10-part per billion increment in O3 concentration, we found a reduction in birthweight of 19.9 g [95% confidence interval (CI): 14.8 to 24.9 g]. The nonlinear ERF had a monotonic decreasing curve, and no safe O3 exposure threshold was identified. The mean reduction in birthweight reduction attributable to O3 across the 123 LMICs was 43.8 g (95% CI: 30.5 to 54.3 g) in 2019. The reduction in O3-related birthweight was greatest in countries in South Asia, the Middle East, and North Africa. Effective O3 pollution control policies have the potential to substantially improve infant health.

Association of classic and 11-oxygenated androgens with polycystic ovaries and menstrual cycle prolongation in infertile women with PCOS.

BACKGROUND AND AIMS: The etiology of polycystic ovary syndrome (PCOS) is unclear. This study aimed to evaluate the role of classic and 11-oxygenated (11oxyC19) androgens in two typical signs of PCOS, polycystic ovary morphology (PCOM) and menstrual cycle prolongation. MATERIALS AND METHODS: A total of 462 infertile women with diagnosed PCOS and/or commonly accompanied metabolic disorders were recruited. Classic and 11oxyC19 androgens were determined with a sensitive high-performance liquid chromatography-differential mobility spectrometry tandem mass spectrometry apparatus. Least absolute shrinkage and selection operator logistic regression with fivefold cross-validation was applied to construct prediction models. RESULTS: For PCOM, the most significant contributing androgen was testosterone (T), with the weight of 51.6%. The AUC of the prediction model was 0.824 in validation set. For menstrual cycle prolongation, androstenedione (A4) was the most significant contributing androgen with weights of 77.5%. The AUC the prediction model was less than 0.75. When including other variables, the most significant variable turned to be AMH both in PCOM and in menstrual cycle prolongation. CONCLUSION: Androgens had more contribution in PCOM than in menstrual cycle prolongation. The classic androgen T or A4 contributed more than 11oxyC19 androgens. However, their contributions were diminished when other factors were considered, especially AMH.

AMHconverter: an online tool for converting results between the different anti-Müllerian hormone assays of Roche Elecsys®, Beckman Access, and Kangrun.

Background: The anti-Müllerian hormone (AMH) is gaining attention as a key factor in determining ovarian reserve and polycystic ovarian syndrome, and its clinical applications are becoming more widespread worldwide. Objective: To identify the most accurate formula for converting AMH assay results between different platforms, so that the developed AMH converter can be used to reduce the need for multiple AMH tests at different hospitals. Methods: Assuming that the Beckman Access, Kangrun, and Roche Elecsys® AMH assays fit a linear relationship from the lowest to the highest concentration (a global relationship), we used Passing-Bablok regression to determine the conversion equation between each two assays. When the relationship between two AMH assays was a local one, spline regression was used. Bland-Altman plots were drawn to check systemic bias and heterogeneity of variance across different ranges of values. The fitting effects of the models were evaluated using the squared coefficient of determination (r2), adjusted r2, root mean square error (RMSE), Akaike information criterion (AIC), and corrected AIC. Results: The coefficient of variance for multiple controls in the Kangrun, Roche, and Beckman assays was lower than 5%, and the bias of multiple controls was lower than 7%. A global linear relationship was observed between the Kangrun and Roche assays, with the intercept being zero, for which Passing-Bablok regression was employed for data conversion between the two platforms. For the other two pairs of platforms, i.e., Roche and Kangrun or Beckman and Kangrun, spline regression was applied, with the intercepts not including zero. The six corresponding formulas were developed into an online AMH converter (http://121.43.113.123:8006/). Conclusion: This is the first time Passing-Bablok plus spline regression has been used to convert AMH concentrations from one assay to another. The formulas have been developed into an online tool, which makes them convenient to use in practical applications.

Factors influencing the sperm retrieval rate of microdissection testicular sperm extraction in patients with nonmosaic Klinefelter syndrome.

To investigate the factors affecting the sperm retrieval rate of microdissection testicular sperm extraction (micro-TESE) in patients with nonmosaic Klinefelter syndrome (KS), 64 patients with nonmosaic KS who underwent micro-TESE in the Center for Reproductive Medicine of Peking University Third Hospital (Beijing, China) between January 2016 and December 2017 were included in the study. Data on medical history, physical examination and laboratory examination results, and micro-TESE outcomes were collected. Patients were divided into two groups according to micro-TESE outcomes. The following factors were compared between the two groups by the Mann‒Whitney U test or Student's t-test based on the distribution (nonnormal or normal) of the factors: age, testicular size, follicle-stimulating hormone level, luteinizing hormone level, testosterone level, and anti-Müllerian hormone level. The overall success rate of sperm retrieval was 50.0%. Correlation analysis showed that testicular volume was positively correlated with testosterone level. Using a logistic regression model, age and anti-Müllerian hormone levels were found to be better predictors for the sperm retrieval rate than the other parameters.

An online tool for predicting ovarian responses in unselected patients using dynamic inhibin B and basal antimüllerian hormone levels.

Background: Reliable predictive models for predicting excessive and poor ovarian response in controlled ovarian stimulation (COS) is currently lacking. The dynamic (Δ) inhibin B, which refers to increment of inhibin B responding to exogenous gonadotropin, has been indicated as a potential predictor of ovarian response. Objective: To establish mathematical models to predict ovarian response at the early phase of COS using Δinhibin B and other biomarkers. Materials and methods: Prospective cohort study in a tertiary teaching hospital, including 669 cycles underwent standard gonadotropin releasing hormone (GnRH) antagonist ovarian stimulation between April 2020 and September 2020. Early Δinhibin B was defined as an increment in inhibin B from menstrual day 2 to day 6 through to the day of COS. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression with 5-fold cross-validation was applied to construct ovarian response prediction models. The area under the receiver operating characteristic curve (AUC), prevalence, sensitivity, and specificity were used for evaluating model performance. Results: Early Δinhibin B and basal antimüllerian hormone (AMH) levels were the best measures in building models for predicting ovarian hypo- or hyper-responses, with AUCs and ranges of 0.948 (0.887-0.976) and 0.904 (0.836-0.945) in the validation set, respectively. The contribution of the early Δinhibin B was 67.7% in the poor response prediction model and 56.4% in the excessive response prediction model. The basal AMH level contributed 16.0% in the poor response prediction model and 25.0% in the excessive response prediction model. An online website-based tool (http://121.43.113.123:8001/) has been developed to make these complex algorithms available in clinical practice. Conclusion: Early Δinhibin B might be a novel biomarker for predicting ovarian response in IVF cycles. Limiting the two prediction models to the high and the very-low risk groups would achieve satisfactory performances and clinical significance. These novel models might help in counseling patients on their estimated ovarian response and reduce iatrogenic poor or excessive ovarian responses.

High anti-Müllerian hormone (AMH) is associated with increased risks of ectopic pregnancy in women undergoing fresh embryo transfer cycle, a cohort study.

BACKGROUND: Ectopic pregnancy is more common amongst assisted reproduction cycles and is a cause of significant maternal morbidity. Few predictive markers exist to help identify and modify risk of ectopic pregnancy in preparing for embryo transfer. The relationship between serum and AMH and ectopic pregnancy rate is unknown. METHODS: This was a retrospective cohort study investigating women who underwent fresh embryo transfer cycles from January 2017 to December 2019 in Peking University Third Hospital. The primary outcome was ectopic pregnancy. Restricted cubic splines with four knots for AMH concentration (0-3, 3-6, 6-12, 12-max) were used to map out the non-linear relationship between the predicted ectopic pregnancy rate and the serum AMH concentration. Log binomial regression was used to test the crude risk ratio (cRR) and the adjusted risk ratio (aRR) after adjustment for confounders with 95% confidence intervals (CI) to determine the difference across various groups. RESULTS: A total of 13,718 cycles in women undergoing fresh embryo transfer were eligible for analysis. The ectopic pregnancy rate was 1.3% per embryo transfer cycle initiated and 3.3% per pregnancy. Serum AMH concentrations were higher amongst women with ectopic pregnancy than in women with a confirmed intrauterine pregnancy or heterotopic pregnancy or who did not become pregnant (Mean levels: 4.0 ng/ml vs 3.2 ng/ml, 1.7 ng/ml, and 2.8 ng/ml). An AMH concentration of 7 ng/ml represented the best cut-off value to predict ectopic pregnancy. The ectopic pregnancy rate was 3.4% per cycle and 7.5% per pregnancy in women with AMH levels ≥ 7 ng/ml; and 1.2% per cycle and 2.9% per pregnancy in women with AMH levels < 7 ng/ml. Serum AMH concentration ≥ 7 ng/ml was associated with an increased risk of ectopic pregnancy in all fresh embryo transfer cycles started (aRR = 2.35 (1.45, 3.58)) as well in women who became pregnant (aRR = 2.23 (1.49, 3.33). CONCLUSIONS: Baseline AMH concentration ≥ 7 ng/ml is associated with an increased risk of ectopic pregnancy in fresh embryo transfer cycles.

Development of a predictive model for increasing sperm retrieval success by microdissection testicular sperm extraction in patients with nonobstructive azoospermia.

Microdissection testicular sperm extraction (micro-TESE) is widely used to treat nonobstructive azoospermia. However, a good prediction model is required to anticipate a successful sperm retrieval rate before performing micro-TESE. This retrospective study analyzed the clinical records of 200 nonobstructive azoospermia patients between January 2021 and December 2021. The backward method was used to perform binary logistic regression analysis and identify factors that predicted a successful micro-TESE sperm retrieval. The prediction model was constructed using acquired regression coefficients, and its predictive performance was assessed using the receiver operating characteristic curve. In all, 67 patients (sperm retrieval rate: 33.5%) underwent successful micro-TESE. Follicle-stimulating hormone, anti-Müllerian hormone, and inhibin B levels varied significantly between patients who underwent successful and unsuccessful micro-TESE. Binary logistic regression analysis yielded the following six predictors: anti-Müllerian hormone (odds ratio [OR] = 0.902, 95% confidence interval [CI]: 0.821-0.990), inhibin B (OR = 1.012, 95% CI: 1.001-1.024), Klinefelter's syndrome (OR = 0.022, 95% CI: 0.002-0.243), Y chromosome microdeletion (OR = 0.050, 95% CI: 0.005-0.504), cryptorchidism with orchiopexy (OR = 0.085, 95% CI: 0.008-0.929), and idiopathic nonobstructive azoospermia (OR = 0.031, 95% CI: 0.003-0.277). The prediction model had an area under the curve of 0.720 (95% CI: 0.645-0.794), sensitivity of 65.7%, specificity of 72.2%, Youden index of 0.379, and cut-off value of 0.305 overall, indicating good predictive value and accuracy. This model can assist clinicians and nonobstructive azoospermia patients in decision-making and avoiding negative micro-TESE results.

GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis in doxorubicin-induced heart failure through inhibition of NADPH oxidase-derived oxidative stress.

Doxorubicin (DOX), which is widely used for the treatment of cancer, induces cardiomyopathy associated with NADPH oxidase-derived reactive oxygen species. GSK2795039 is a novel small molecular NADPH oxidase 2 (Nox2) inhibitor. In this study, we investigated whether GSK2795039 prevents receptor-interacting protein kinase 1 (RIP1)-RIP3-mixed lineage kinase domain-like protein (MLKL)-mediated cardiomyocyte necroptosis in DOX-induced heart failure through NADPH oxidase inhibition. Eight-week old mice were randomly divided into 4 groups: control, GSK2795039, DOX and DOX plus GSK2795039. H9C2 cardiomyocytes were treated with DOX and GSK2795039. In DOX-treated mice, the survival rate was reduced, left ventricular (LV) end-systolic dimension was increased and LV fractional shortening was decreased, and these alterations were attenuated by the GSK2795039 treatment. GSK2795039 inhibited not only myocardial NADPH oxidase subunit gp91phox (Nox2) protein, but also p22phox, p47phox and p67phox proteins and prevented oxidative stress 8-hydroxy-2'-deoxyguanosine levels in DOX-treated mice. RIP3 protein and phosphorylated RIP1 (p-RIP1), p-RIP3 and p-MLKL proteins, reflective of their respective kinase activities, markers of necroptosis, were markedly increased in DOX-treated mice, and the increases were prevented by GSK2795039. GSK2795039 prevented the increases in serum lactate dehydrogenase and myocardial fibrosis in DOX-treated mice. Similarly, in DOX-treated cardiomyocytes, GSK2795039 improved cell viability, attenuated apoptosis and necrosis and prevented the increases in p-RIP1, p-RIP3 and p-MLKL expression. In conclusion, GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis through inhibition of NADPH oxidase-derived oxidative stress, leading to the improvement of myocardial remodeling and function in DOX-induced heart failure. These findings suggest that GSK2795039 may have implications for the treatment of DOX-induced cardiomyopathy.

Inhibin B-to-Anti-Mullerian Hormone Ratio as Noninvasive Predictors of Positive Sperm Retrieval in Idiopathic Non-Obstructive Azoospermia.

Background: The lack of clinically useful biomarkers for predicting micro-TESE outcomes in males with idiopathic NOA. To find clinically reliable serum reproductive hormone markers to predict the outcome of sperm retrieval in men with idiopathic NOA undergoing micro-TESE. Methods: We analyzed the clinical data of 168 men with idiopathic NOA treated with micro-TESE. The clinical predictors of a successful sperm retrieval were put to the test using logistic regression analysis. The clinical net benefit was calculated using a decision-curve analysis, and the predictive power of each variable was assessed using the ROC-derived area under the curve. Result: Between positive group and negative group for sperm retrieval, there was a statistically significant difference in INHB, AMH, and INHB/AMH. AMH, INHB, and INHB/AMH were each independent predictors of successful sperm retrieval, with INHB (OR1.02, p = 0.03), AMH (OR0.85, p = 0.01), INHB/AMH (OR1.08, p < 0.01). The ROC curve determined the optimal cut-off values for serum INHB and INHB/AMH in positive sperm retrieval patients undergoing micro-TESE. 21.51 pg/mL was the cut-off value for INHB. The cut-off value for INHB/AMH was 3.19, which had a 86.3% sensitivity and a 53.8% specificity. Using INHB and INHB/AMH prior to micro-TESE sperm retrieval in idiopathic NOA patients improved the net benefit of positive sperm retrieval, and the net benefit score of INHB/AMH was better than that of INHB, according to decision analysis curves. Conclusion: Serum INHB have predictive value for sperm retrieval outcomes in idiopathic NOA patients undergoing micro-TESE. Combining INHB and AMH, INHB/AMH seems to be a better predictor.

NEDD4 attenuates oxidized low­density lipoprotein­induced inflammation and dysfunction in vascular endothelial cells via regulating APEX1 expression.

Atherosclerosis chiefly results from inflammation as well as vascular endothelial cell dysfunction. Methylation levels of neuronally expressed developmentally downregulated 4 (NEDD4) were found to be fortified in atherosclerosis patients and NEDD4 deficiency enhanced vascular calcification. However, the exact function of NEDD4 in inflammation and vascular endothelial dysfunction remains to be elucidated. In the present study, CCK-8 assay was used to estimate cell viability. Reverse transcription-quantitative PCR was adopted to examine the expression of NEDD4, inflammation-associated enzymes and apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1). Western blotting was used to test NEDD4, endothelial nitric oxide synthase, inducible nitric oxide synthase and APEX1 protein levels. Cytotoxicity was detected by a lactate dehydrogenase (LDH) kit. Reactive oxygen species level was tested by a corresponding kit. Vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 contents were examined with ELISA. Cell adhesion assays evaluated the adhesion of endothelial cells. Co-immunoprecipitation assay was used to test the relationship between NEDD4 and APEX1. The data revealed that NEDD4 expression rapidly declined in oxidized low density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs). Following NEDD4 overexpression, the active damage, inflammatory release and endothelial cell dysfunction in ox-LDL-induced HUVECs were attenuated. After co-transfection of APEX1 interference plasmids and NEDD4 overexpression plasmids, cell damage, inflammatory release and endothelial cell dysfunction in ox-LDL-induced HUVECs were improved again. Taken together, NEDD4 attenuated ox-LDL-induced inflammation and endothelial dysfunction by regulating APEX1 expression.

Effects of Greenness on Myopia Risk and School-Level Myopia Prevalence Among High School-Aged Adolescents: Cross-sectional Study.

BACKGROUND: Myopia is a serious public health issue. High school-aged adolescents in Beijing have an alarming prevalence of myopia. Therefore, determining myopia protective factors is essential. Green space has a certain association with myopia protective factors that can protect against myopia. OBJECTIVE: This study aims to examine the effects of green space around schools on individual myopia risk in high school-aged adolescents and the school-level myopia prevalence. METHODS: Green space was measured using the normalized difference vegetation index (NDVI). A total of 13,380 samples of 51 high schools were selected from a 2021 Beijing Municipal Health Commission survey. Adolescent myopia was defined as a spherical equivalent of ≤-1.00 diopters in the worse eye. Generalized linear mixed models with a binomial error structure were used to analyze the effects of the NDVI on personal myopia risk and adjust them by other factors, such as demographics, exposure time, and outdoor exercise. The effects of the NDVI on school-level myopia prevalence with adjusted demographics and the relative position factors of trees were analyzed through quasibinomial regression. RESULTS: The overall prevalence of myopia was 80.61% (10,785/13,380, 95% CI 79.93%-81.27%). Although with a 0.1 increase in the 500 and 1000 m buffer NDVIs adjusted by demographic and other factors, the high school-aged personal myopia risk significantly dropped by 16% (odds ratio [OR] 0.84, 95% CI 0.73-0.97) and 12% (OR 0.88, 95% CI 0.79-0.99), respectively. However, only the adjusted 500 m buffer NDVI (by demographics and the position of trees) with a 0.1 increase significantly reduced the school-level myopia prevalence by 15% (OR 0.85, 95% CI 0.74-0.98). Subgroup analysis showed that the adjusted effects of the 500 m buffer NDVI are significant in schoolgirls (OR 0.82, 95% CI 0.72-0.93), juniors (OR 0.82, 95% CI 0.72-0.94), the Han nationality (OR 0.84, 95% CI 0.72-0.97), 1-year exposure (OR 0.84, 95% CI 0.71-0.99) and 3-year exposure (OR 0.78, 95% CI 0.65-0.94). CONCLUSIONS: The greenness of a 500 m buffer around schools is associated with a lower personal myopia risk among adolescents and a lower prevalence of myopia in schools. With regard to prevention and control activities, green space within a 500 m buffer around schools is suggested as an independent protective factor for adolescent myopia.

Sensitive HPLC-DMS/MS/MS method coupled with dispersive magnetic solid phase extraction followed by in situ derivatization for the simultaneous determination of multiplexing androgens and 17-hydroxyprogesterone in human serum and its application to patients with polycystic ovarian syndrome.

BACKGROUND AND AIMS: Androgens play important roles in polycystic ovarian syndrome (PCOS). However, measures of androgens based on mass spectrometry (MS) remain complex due to endogenous inferences of isomers or compounds with similar structures. Lack of sensitivity can also affect the accurate quantification of androgens, especially for very low level of 11-oxygenated androgens. MATERIALS AND METHODS: We developed a fast and sensitive high-performance liquid chromatography-differential mobility spectrometry tandem mass spectrometry (HPLC-DMS/MS/MS) method for the simultaneous determination of seven androgens and 17-hydroxyprogesterone. Dispersive magnetic solid phase extraction (DMSPE) was conducted with core-shell structured nanoparticles of magnetic graphene oxide (Fe3O4@GO). In situ derivatization was performed using Girard's Reagent P. RESULTS: Linear ranges of the eight analytes were set in terms of clinical use. Intra- and inter-run precisions were < 16.7 % and 12.9 % for all the analytes and relative error was - 14.7-13.3 % and - 9.3-11.0 %, respectively. Extraction recoveries were 54.0-92.7 % for different analytes. The method was validated and was applied to assay 432 clinical samples. CONCLUSION: The developed method is green, fast, sensitive and accurate for the determination of endogenous androgens. It can be readily implemented in medical laboratories to provide superior analytical performance over the traditional electrochemiluminescence immunoassay method.

An online tool for predicting ovarian reserve based on AMH level and age: A retrospective cohort study.

Purpose: To establish a more convenient ovarian reserve model with anti-Müllerian hormone (AMH) level and age (the AA model), with blood samples taken at any time in the menstrual cycle. Methods: We have established this AA model for predicting ovarian reserve using the AMH level and age. The outcome variable was defined as poor ovarian response (POR) with <5 oocytes retrieved during assisted reproductive technology treatment cycles. Least Absolute Shrinkage and Selection Operator logistic regression with 5-fold cross validation methods was applied to construct the model, and that with the lowest scaled log-likelihood was selected as the final one. Results: The areas under the receiver operating characteristic curve for the training, inner, and external validation sets were 0.862, 0.843, and 0.854 respectively. The main effects of AMH level and age contributing to the prediction of POR were 95.3% and 1.8%, respectively. The incidences of POR increased with its predicted probability in both the model building and in external validation datasets, indicating its stability. An online website-based tool for assessing the score of ovarian reserve (http://121.43.113.123:9999) has been developed. Conclusions: Based on external validation data, the AA model performed well in predicting POR, and was more cost-effective and convenient than our previous published models.

Anti-Müllerian hormone in guiding the selection of a freeze-all versus a fresh embryo transfer strategy: a cohort study.

PURPOSE: To explore an interaction effect between serum anti-Müllerian hormone (AMH) levels and the relative treatment effect of a freeze-all versus a fresh embryo transfer strategy on live birth. METHODS: This was a retrospective cohort study investigating couples with infertility and eligible for both freeze-all and fresh embryo transfer between 2017 and 2019. Women with an absolute indication for a freeze-all strategy were excluded. Multivariable fractional polynomial interaction analysis within a logistic regression model was used to evaluate whether the treatment effect of a freeze-all versus a fresh transfer strategy varied at different AMH levels. Non-linear interactions were also considered. The primary outcome was the live birth after the first transfer. RESULTS: A total of 13,503 women underwent a fresh embryo transfer and 2247 women underwent a freeze-all strategy. Live birth rates were slightly higher in the freeze-all group compared to those in the fresh embryo transfer group (35% vs 33%). There was a non-linear interaction between baseline serum AMH levels and the relative treatment effect of a freeze-all strategy versus a fresh transfer strategy on live birth (P = 0.0161). The benefit on live birth from a freeze-all embryo transfer strategy was greatest in women with a high serum level (> 7 ng/ml). The interaction remained valid when different imputation methods were used. CONCLUSION: As serum AMH level increased, there was a nonlinear increase in relative treatment effect of a freeze-only transfer versus a fresh transfer strategy on live birth, and such an effect reaches its maximum in women with high AMH levels.

An Online Tool Using Basal or Activated Ovarian Reserve Markers to Predict the Number of Oocytes Retrieved Following Controlled Ovarian Stimulation: A Prospective Observational Cohort Study.

Background: Predicting the number of oocytes retrieved (NOR) following controlled ovarian stimulation (COS) is the only way to ensure effective and safe treatment in assisted reproductive technology (ART). To date, there have been limited studies about predicting specific NOR, which hinders the development of individualized treatment in ART. Objective: To establish an online tool for predicting NOR. Materials and Methods: In total, 621 prospective routine gonadotropin releasing hormone (GnRH) antagonist COS cycles were studied. Independent variables included age, body mass index, antral follicle counts, basal FSH, basal and increment of anti-mullerian hormone, Luteinizing hormon, estradiol, testosterone, androstenedione, and inhibin B. The outcome variable was NOR. The independent variables underwent appropriate transformation to achieve a better fit for a linear relationship with NOR. Pruned forward selection with holdback validation was then used to establish predictive models. Corrected Akaike's information criterion, Schwarz-Bayesian information criterion, scaled -log[likelihood], and the generalized coefficient of determination (R2) were used for model evaluation. Results: A multiple negative binomial regression model was used for predicting NOR because it fitted a negative binomial distribution. We established Model 1, using basal ovarian reserve markers, and Model 2, using both basal and early dynamic markers for predicting NOR following COS. The generalized R2 values were 0.54 and 0.51 for Model 1 and 0.64 and 0.62 for Model 2 in the training and validation sets, respectively. Conclusion: Models 1 and 2 could be applied to different scenarios. For directing the starting dose of recombinant follicle stimulation hormone (rFSH), Model 1 using basic predictors could be used prior to COS. Model 2 could be used for directing the adjustment of rFSH dosages during COS. An online tool (http://121.43.113.123:8002/) based on these two models is also developed. We anticipate that the clinical application of this tool could help the ART clinics to reduce iatrogenic ovarian under- or over-responses, and could reduce costs during COS for ART.