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BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets of FDA-approved cancer immunotherapies, but the biological and mechanistic consequences of their application are incompletely understood. We show here that the immune checkpoint molecule PD-L1 regulates homologous recombination in cancer cells by promoting BRCA1 nuclear foci formation and DNA end resection. Genetic depletion of tumor PD-L1 reduced homologous recombination, increased nonhomologous end joining, and elicited synthetic lethality to PARP inhibitors olaparib and talazoparib in vitro in some, but not all, BRCA1 wild-type tumor cells. In vivo, genetic depletion of tumor PD-L1 rendered olaparib-resistant tumors sensitive to olaparib. In contrast, anti-PD-L1 immune checkpoint blockade neither enhanced olaparib synthetic lethality nor improved its efficacy in vitro or in wild-type mice. Tumor PD-L1 did not alter expression of BRCA1 or its cofactor BARD1 but instead coimmunoprecipitated with BARD1 and increased BRCA1 nuclear accumulation. Tumor PD-L1 depletion enhanced tumor CCL5 expression and TANK-binding kinase 1 activation in vitro, similar to known immune-potentiating effects of PARP inhibitors. Collectively, these data define immune-dependent and immune-independent effects of PARP inhibitor treatment and genetic tumor PD-L1 depletion. Moreover, they implicate a tumor cell–intrinsic, immune checkpoint–independent function of PD-L1 in cancer cell BRCA1-mediated DNA damage repair with translational potential, including as a treatment response biomarker. Significance: PD-L1 upregulates BRCA1-mediated homologous recombination, and PD-L1–deficient tumors exhibit BRCAness by manifesting synthetic lethality in response to PARP inhibitors, revealing an exploitable therapeutic vulnerability and a candidate treatment response biomarker. See related commentary by Hanks, p. 2069

PURPOSE: To assess the association between maternal education level and live birth after in vitro fertilization (IVF). METHODS: We studied women who underwent the first cycle of fresh or frozen-thawed embryo transfer between 2014 and 2019. Women were divided into four educational categories according to the level of education received (elementary school graduate or less, middle school graduate, high school graduate, college graduate or higher). The live birth rate was compared between different education level groups. We used logistic regression to analyze the association between maternal education level and live birth after IVF. RESULTS: We studied 41,546 women, who were grouped by maternal educational level: elementary school graduate or less (n = 1590), middle school graduate (n = 10,996), high school graduate (n = 8354), and college graduate or higher (n = 20,606). In multivariable logistic regression analysis, we did not demonstrate a statistically significant relationship between educational level and live birth in middle school graduate (adjusted odds ratio [AOR] 0.96; 95% confidence interval [CI], 0.84–1.09), high school graduate (AOR 1.01; 95% CI, 0.87–1.14) or college graduate or higher (AOR 1.01; 95% CI, 0.88–1.14) patients, with elementary school graduate or less as the reference group. CONCLUSIONS: Maternal educational level was not associated with the likelihood of live birth in patients undergoing fresh or frozen embryo transfer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02345-4.

Up to 90% of patients who are under the active treatment suffer from cancer-related fatigue (CRF). CRF can persist about 10 years after diagnosis and/or treatment. Accumulating reports support that ginseng and ginseng injections are both potential drugs for the treatment of CRF but few studies put them together for analysis.Two reviewers independently extracted data in 3 databases (PubMed, Cochrane Library and China National Knowledge Infrastructure) from their inception to May 24, 2021. The primary outcome was the effect of ginseng in alleviating CRF. The secondary outcome was ginseng in alleviating emotional or cognitive fatigue. Standardized mean difference (SMD) was employed.Twelve studies were included to evaluate efficacy of ginseng oral administration and ginseng injections on CRF. The pooled SMD was 0.40 (95% confidence Interval [95% CI] [0.29-0.51], P .00001). Six studies were included to evaluate efficacy of ginseng oral administration on CRF and the SMD was 0.29 (95% CI [0.15-0.42], P .0001). The order was 2000 mg/d, 3000 mg/d, 1000 mg/d and placebo from high efficacy to low. Ten studies were included to evaluate efficacy of ginseng injections on CRF and the SMD was 0.74 (95% CI [0.59-0.90], P .00001). Emotional fatigue was reported in 4 studies, ginseng oral administration in 2 and ginseng injections in 2. The pooled SMD was 0.12 (95% CI [-0.04 to 0.29], P = .15). Cognitive fatigue was reported in 4 studies focusing on ginseng injections and the SMD was 0.72 (95% CI [0.48-0.96], P .00001).Ginseng can improve CRF. Intravenous injection might be better than oral administration. Ginseng injections may alleviate cognitive fatigue. No evidence was found to support that ginseng could alleviate emotional fatigue.

BackgroundA number of studies have compared the clinical outcomes between the two endometrial preparation methods: natural cycles (NCs) and hormone replacement treatment (HRT) before frozen embryo transfer, but the results were conflicting. In order to mitigate the potential effect of embryos per se, several researchers have worked on this subject for euploid blastocyst transfer, but the results were still inconsistent. Therefore, the present study was aimed to investigate the clinical outcomes between HRT and NC for autologous single vitrified–warmed euploid blastocyst transfer based on our data.MethodsA total of 598 frozen-thawed single euploid blastocyst transfer cycles in the assisted reproductive center of Northwest Women’s and Children’s Hospital from January 2014 to May 2021 were retrospectively analyzed. Women were stratified into the NC (n = 125) or HRT (n = 473) group according to the patient’s preference and the physician’s guidance. Multivariate regression models and subgroup analysis were constructed to analyze the association between endometrial preparation and live birth.ResultsWomen in the NC group had a higher live birth rate (68.80% versus 58.35%, P = 0.034) and a lower risk of total pregnancy loss (8.51% versus 21.14%, P = 0.005) when compared with women in the HRT group. The biochemical pregnancy rate (75.20% versus 74.00%, P = 0.784) and clinical pregnancy rate (74.40% versus 69.98%, P = 0.334) were similar between the two groups (NC versus HRT). NC was associated with an increased odds of live birth compared with HRT by different multivariable analysis models (Model 1: adjusted odds ratio [aOR], 95% confidence interval [CI]: 0.57, 0.36 - 0.90; Model 2: aOR, 95%CI: 0.57, 0.35 - 0.92). In addition, the increased chance of live birth in the NC group was found in all subgroups. No major obstetrical complications and two malformation livebirths were reported.ConclusionsIn women undergoing single euploid frozen blastocyst transfers, the NC group was associated with a lower pregnancy loss rate and an ultimately higher live birth rate than the HRT group. Although HRT is convenient for both clinicians and patients, the lower live birth rate should be taken into account and NC might be the first choice of endometrial preparation method.

We aimed to explore the effect of three pro-nuclei (3PN) incidence on laboratory and clinical outcomes after early rescue intracytoplasmic sperm injection (rescue-ICSI).This study included 509 early rescue-ICSI cycles from February 2014 to February 2019. The patients were divided into 3PN = 0% (394 cycles) and 3PN 0% (115 cycles) group. Main outcomes compared were good quality embryo, available embryo, implantation (IR), clinical pregnancy (CPR), abortion (AR) and live birth rates (LBR).There were no significant differences in the basal characteristics between two groups (3PN incidence made negative effects on the clinical outcomes after early rescue-ICSI.

PURPOSE: To investigate the relationship between different duration of estrogen administration and live birth rate (LBR) after autologous single frozen blastocyst transfer with hormone replacement therapy. METHODS: A total of 2026 frozen blastocyst transfer cycles in the assisted reproductive center of northwest women and children’s hospital from January, 2017, to August, 2020, were retrospectively analyzed. All the cycles were allocated into 3 groups according to the duration of estrogen administration: group A, 11–14 days (n = 346); group B, 15–18 days (n = 1191), and group C, ≥ 19 days (n = 489). Baseline data, clinical, and perinatal outcomes of the three groups were compared. A multivariate regression model was constructed to analyze the association between duration of estradiol administration and clinical outcomes. RESULTS: We did not observe a significant association between duration of estrogen supplementation and LBR in group B (adjusted odds ratio [aOR] 1.14; 95% confidence interval [CI], 0.89–1.45) or group C (aOR 1.16; 95% CI, 0.86–1.56) patients with group A as the reference group, through logistic regression analysis. No statistical differences were observed in perinatal outcomes among the three groups. CONCLUSION: The duration of estrogen administration was not associated with the likelihood of live birth in women undergoing frozen-thawed autologous single-blastocyst transfer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-022-02481-5.

IntroductionNatural cycle (NC) and hormone replacement treatment (HT) are frequently used endometrial preparation protocols prior to frozen-thawed embryo transfer in ovulatory women. It is not clear which protocol results in a higher live birth rate. It has been suggested that there is an increased risk in maternal and perinatal morbidity following HT protocol due to the lack of corpus luteum. The objective of this trial is to compare the clinical outcomes of NC and HT protocols in frozen embryo transfer.Methods and analysisCOMPETE is an open-label, single-centre, randomised controlled trial targeting to recruit 888 women, with 444 women each in two arms (1:1 treatment ratio). Women undergoing in vitro fertilisation scheduled for a frozen embryo transfer and have a regular menstrual cycle are eligible. Exclusion criteria include ovulation disorders and intrauterine adhesions. The primary outcome is live birth resulting from the first frozen embryo transfer after randomisation. Secondary outcomes include biochemical pregnancy, clinical pregnancy, multiple pregnancy, ongoing pregnancy, miscarriage, endometrial thickness, cycle cancellation, gestational diabetes mellitus, hypertensive disorders of pregnancy, antepartum haemorrhage, preterm birth, birth weight, large for gestational age, congenital anomaly and perinatal mortality. The data analysis will be following the intention-to-treat principle.Ethics and disseminationThis study has been approved by the Institutional Review Board of Northwest women’s and children’s hospital (2020008). Written informed consent will be obtained from each participant before randomisation. The results of the trial will be presented via publications.Trial registration numberChiCTR2000040640.

Background The ideal protocols of endometrial preparation for polycystic ovary syndrome (PCOS) patients are lacking and need further declaration. Our objective was to compare the clinical outcomes of frozen-thawed embryo transfer (FET) with and without pretreatment gonadotropin-releasing hormone agonist (GnRHa) in PCOS patients. Methods In this retrospective cohort study, we used propensity score matching (PSM) to compare the live birth rate between patients who underwent FET with hormone replacement treatment (HRT) and patients with GnRHa pretreatment (GnRHa + HRT). Patients using GnRHa + HRT (n = 514) were matched with 514 patients using HRT. Results The live birth rate was higher in the GnRHa + HRT group compared with the HRT group with no significant difference (60.12% vs 56.03%, p = 0.073). The clinical pregnancy rate (75.29% vs 70.62%), miscarriage rate (14.20% vs 13.81%) and ectopic pregnancy rate (0.39% vs 0.19%) were similar between the two groups. The preterm birth rate in GnRHa + HRT was higher than HRT (20.23% vs 13.04%). No difference was found in live birth between GnRHa +HRT and HRT before adjusting for covariates (crude OR 1.22, 95%CI, 0.99–1.51, p = 0.062) and after PSM (OR 1.47, 95%CI, 0.99–2.83, p = 0.068). In addition, there is a marginally difference after adjusting for covariates (aOR 1.56, 95%CI, 1.001–2.41, p = 0.048), this finding with p-value close to 0.05 represent insufficient empirical evidence. Similar results were obtained after propensity score matching in the entire cohort. Conclusions GnRHa pretreatment could not improve the live birth rate in women with PCOS.

To compare the clinical outcome of fresh embryo transfer with frozen-thawed embryo transfer in subsequent cycle of GnRH antagonist protocol. Totally, 1430 women were enrolled from the cases of our Assisted Reproduction Center from January 2015 to January 2019 for this retrospective cohort study. The inclusion criteria of the subjects included women with ages under 40 years, 3–10 oocytes retrieved, good embryo quality according to gardener score, GnRH antagonist protocol, underwent first cycle of fresh embryo transfer or freeze-all strategy and transferred in subsequent cycle. However, the patients with endometriosis, PGD/PGS cycles, history of recurrent pregnancy loss and uterine pathology were excluded. 495 women of group I underwent fresh embryo transfer in first cycle and 935 patients of group II received frozen-thawed transfer in subsequent cycle. The primary outcome was clinical pregnancy rate. A logistic regression analysis was performed to determine the variables that could be independently associated with clinical pregnancy rate. Models were adjusted for covariates including patients’ age, fertilization type, infertility type, infertility duration, the number of oocytes retrieved, the number of embryos transferred and type of embryo transferred. Clinical pregnancy rate was significantly higher in frozen-thawed embryo transfer than in fresh embryo transfer (63.70% vs. 54.50%, p

Spirituality has long served as a source of solace for many grievers following a loss. For other mourners, whose bereavement experience has been significantly challenged by struggles in their relationship with God and/or their faith community, the opposite is true. Complicated spiritual grief (CSG) is a spiritual crisis following the loss of a loved one. To assess CSG in samples of bereaved adults, a simple-to-use, multidimensional measure of spiritual crisis following loss called the Inventory of Complicated Spiritual Grief (ICSG) was previously developed and validated. However, subsequent research providing greater clarity about the construct of CSG supported the need to revise and update the ICSG. The goal of the present study was to establish the psychometric validity of a revised measure of CSG, called the Inventory of Complicated Spiritual Grief 2.0 (ICSG 2.0), with a large, diverse cohort of bereaved Christian adults (

Hydrogen sulfide (H

Objective To investigate ovarian sensitivity in subgroups of patients with a low prognosis, as defined by the POSEIDON criteria, undergoing in vitro fertilization treatment and measures to improve ovarian sensitivity in these patients. Design We conducted a retrospective cohort analysis. Setting The study was conducted at an IVF clinic in a public hospital. Patients A total of 32,128 fresh IVF cycles from January 2014 to October 2018 at a single IVF clinic were included in the analysis. Patients with a low prognosis were categorized into four groups based on the POSEIDON criteria. Interventions None. Main outcome measure The primary outcome measures were the follicular output rate (FORT) and the follicle-to-oocyte index (FOI). Results The FORTs in the order from the highest to the lowest were 1.18 in group 3, 0.98 in group 4, 0.76 in group 1, and 0.68 in group 2. The trend in the FOI values was consistent with that in the FORTs. Among patients with poor ovarian sensitivity, 58.41% of patients with FORTs ≥ 0.30 in the second cycle underwent an adjustment to the ovarian stimulation (OS) protocol and 41.59% underwent an adjustment to the gonadotropin (Gn) starting dose. Among patients with normal ovarian sensitivity, 43.56% of those with FORTs ≥ 0.80 in the second cycle underwent an adjustment to the OS protocol and 56.44% underwent an adjustment to the Gn starting dose. Conclusion Ovarian sensitivity was the highest in group 3 (young women with poor ovarian reserve), followed by groups 4 (women at advanced age with poor ovarian reserve) and 1 (young women with good ovarian reserve), and it was the lowest in group 2 (women at advanced age with good ovarian reserve). For patients with poor ovarian sensitivity, it is preferred to recommend an adjustment to the OS protocol, while for those with normal ovarian sensitivity, adjusting the Gn starting dose is preferred.

It is unknown whether seasonal variation influences the outcome of in vitro fertilization (IVF). Previous studies related to seasonal variation of IVF were all small sample size, and the results were conflicting. We performed a retrospective cohort study evaluating the relationship between seasonal variability and live birth rate in the year of 2014–2017. Patients were grouped into four seasons (Winter (December-February), Spring (March-May), Summer (June-August), and Autumn (September-November)) according to the day of oocyte pick-up (OPU). Multivariate logistic regression analysis was performed to evaluate association between seasonal variation and live birth. Models were adjusted for covariates including temperature, sunshine hour, infertility type, infertility duration, infertility factor and BMI. In total 38,476 women were enrolled, of which 25,097 underwent fresh cycles, 13,379 were frozen embryo transfer. Live birth rates of fresh embryo transfer were 50.36%, 53.14%, 51.94% and 51.33% for spring, summer, autumn and winter, respectively. Clinical pregnancy rate between the calendar months varied between 55.1% and 63.4% in fresh embryo transfer (ET) and between 58.8% and 65.1% in frozen embryo transfer (FET) (P-values 0.073 and 0.220). In the unadjusted model and adjust model, seasonal variation was not associated with live birth. In conclusion, there was no significant difference of seasonal variations in the outcome of IVF with fresh embryo transfer and frozen embryo transfer.

The authors present the development and validation of the Coping Assessment for Bereavement and Loss Experiences (CABLE), the first instrument designed to assess a range of potentially constructive...

To investigate the clinical efficacy of growth hormone (GH) in normal response patients with poor embryo quality in previous in vitro fertilization cycles. A total of 1562 infertile women w...

The ectopic pregnancy (EP) rate after in vitro fertilization-embryo transfer (IVF-ET) is higher than after spontaneous conception. The reason for the increased risk of EP is not clear. We aimed to determine the risk factors associated with EP in patients undergoing IVF-ET.This was a 1:4 matched case-control study that enrolled 225 EP patients and 900 matched intrauterine pregnancy patients from the ART center of Northwest Women's and Children's Hospital from January 2014 to April 2018. Conditional logistic regression was used to analyze the association between risk factors and EP, and a receiver-operating characteristic (ROC) curve was generated for the predictors of EP.Our findings showed that tubal factor (OR 1.61; 95% CI 1.12-2.31) and pelvic surgery other than cesarean section (OR 2.04; 95% CI 1.26-3.29) were associated with a higher risk of EP (p = 0.001). An endometrial thickness 12 mm prior to embryo transfer (OR 0.27; 95% CI 0.13-0.56) and the number of transferable embryos (OR 0.71; 95% CI 0.65-0.78) were protective factors against EP (p 0.001). The other factors did not have a significant effect on the probability of developing ectopic pregnancy. The area under the curve of the endometrial thickness and the number of transferable embryos for EP prediction were higher than those for tubal factor and pelvic surgery other than cesarean section.An endometrial thickness 12 mm is a strong protective factor against ectopic pregnancy. Attention should be paid to women with specific characteristics who have undergone IVF-ET.

Study question What factors does multivariate logistic regression show to be significantly associated with the likelihood of clinical pregnancy in vitrified-warmed embryo transfer (VET) cycles? Summary answer Assisted hatching (AH) and if the reason to freeze embryos was to avoid the risk of ovarian hyperstimulation syndrome (OHSS) were significantly positively associated with a greater likelihood of clinical pregnancy. What is known already Single factor analysis has shown AH, number of embryos transferred and the reason of freezing for OHSS to be positively and damaged blastomere to be negatively significantly associated with the chance of clinical pregnancy after VET. It remains unclear what factors would be significant after multivariate analysis. Study design, size, duration The study was a retrospective analysis of 2313 VET cycles from 1481 patients performed between January 2008 and April 2012. A multivariate logistic regression analysis was performed to identify the factors to affect clinical pregnancy outcome of VET. Participants/materials, setting, methods There were 22 candidate variables selected based on clinical experiences and the literature. With the thresholds of α entry = α removal= 0.05 for both variable entry and variable removal, eight variables were chosen to contribute the multivariable model by the bootstrap stepwise variable selection algorithm (n = 1000). Eight variables were age at controlled ovarian hyperstimulation (COH), reason for freezing, AH, endometrial thickness, damaged blastomere, number of embryos transferred, number of good-quality embryos, and blood presence on transfer catheter. A descriptive comparison of the relative importance was accomplished by the proportion of explained variation (PEV). Main results and the role of chance Among the reasons for freezing, the OHSS group showed a higher OR than the surplus embryo group when compared with other reasons for VET groups (OHSS versus Other, OR: 2.145; CI: 1.4-3.286; Surplus embryos versus Other, OR: 1.152; CI: 0.761-1.743) and high PEV (marginal 2.77%, P = 0.2911; partial 1.68%; CI of area under receptor operator characteristic curve (ROC): 0.5576-0.6000). AH also showed a high OR (OR: 2.105, CI: 1.554-2.85) and high PEV (marginal 1.97%; partial 1.02%; CI of area under ROC: 0.5344-0.5647). The number of good-quality embryos showed the highest marginal PEV and partial PEV (marginal 3.91%, partial 2.28%; CI of area under ROC: 0.5886-0.6343). Limitations, reasons for caution This was a retrospective multivariate analysis of the data obtained in 5 years from a single IVF center. Repeated cycles in the same woman were treated as independent observations, which could introduce bias. Results are based on clinical pregnancy and not live births. Prospective analysis of a larger data set from a multicenter study based on live births is necessary to confirm the findings. Wider implications of the findings Paying attention to the quality of embryos, the number of good embryos, AH and the reasons for freezing that are associated with clinical pregnancy after VET will assist the improvement of success rates.

The Drug Abuse Resistance Education (D.A.R.E.) program is a widespread but controversial school-based drug prevention program in the United States as well as in many other countries. The present multivariate meta-analysis reviewed 20 studies that assessed the effectiveness of the D.A.R.E. program in the United States. The results showed that the effects of the D.A.R.E. program on drug use did not vary across the studies with a less than small overall effect while the effects on psychosocial behavior varied with still a less than small overall effect. In addition, the characteristics of the studies significantly explained the variation of the heterogeneous effects on psychosocial behavior, which provides empirical evidence for improving the school-based drug prevention program.

Background Propensity score methods have become a popular tool for reducing selection bias in making causal inference from observational studies in medical research. Propensity score matching, a key component of propensity score methods, normally matches units based on the distance between point estimates of the propensity scores. The problem with this technique is that it is difficult to establish a sensible criterion to evaluate the closeness of matched units without knowing estimation errors of the propensity scores. Methods The present study introduces interval matching using bootstrap confidence intervals for accommodating estimation errors of propensity scores. In interval matching, if the confidence interval of a unit in the treatment group overlaps with that of one or more units in the comparison group, they are considered as matched units. Results The procedure of interval matching is illustrated in an empirical example using a real-life dataset from the Nursing Home Compare, a national survey conducted by the Centers for Medicare and Medicaid Services. The empirical example provided promising evidence that interval matching reduced more selection bias than did commonly used matching methods including the rival method, caliper matching. Interval matching’s approach methodologically sounds more meaningful than its competing matching methods because interval matching develop a more “scientific” criterion for matching units using confidence intervals. Conclusions Interval matching is a promisingly better alternative tool for reducing selection bias in making causal inference from observational studies, especially useful in secondary data analysis on national databases such as the Centers for Medicare and Medicaid Services data. Electronic supplementary material The online version of this article (doi:10.1186/s12874-015-0049-3) contains supplementary material, which is available to authorized users.