Does growth hormone supplementation of in vitro fertilization/intracytoplasmic sperm injection improve cumulative live birth rates in women with poor embryonic development in the previous cycle?

BACKGROUND: Growth hormone (GH) has been proposed as an adjunct in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles, especially in women with poor ovarian response. However, it is unclear whether GH supplementation is effective in women with poor embryonic development in the previous IVF cycle. The aim of this study was to evaluate the effectiveness of GH supplementation in IVF/ICSI cycles in women with poor embryonic development in the previous cycle. METHODS: This is a retrospective cohort study from a public fertility center in China, in which we performed propensity score-matching (PSM) for female age and AFC in a ratio of 1:1. We compared the cumulative live birth rate per started cycle, as well as a series of secondary outcomes. We included 3,043 women with poor embryonic development in the previous IVF/ICSI cycle, of which 1,326 had GH as adjuvant therapy and 1,717 had not. After PSM, there were 694 women in each group. RESULTS: After PSM, multivariate analyses showed the cumulative live birth rate to be significantly higher in the GH group than the control group [N = 694, 34.7% vs. N = 694, 27.5%, risk ratio (RR): 1.4 (95%CI: 1.1-1.8)]. Endometrial thickness, number of oocytes retrieved, number of embryos available, and number of good-quality embryos were significantly higher in the GH group compared to controls. Pregnancy outcomes in terms of birth weight, gestational age, fetal sex, preterm birth rate, and type of delivery were comparable. When we evaluated the impact of GH on different categories of female age, the observed benefit in the GH group did not appear to be significant. When we assessed the effect of GH in different AFC categories, the effect of GH was strongest in women with an AFC5-6 (32.2% versus 19.5%; RR 2.0; 95% CI 1.2-3.3). CONCLUSIONS: Women with poor embryonic quality in the previous IVF/ICSI cycles have higher rates of cumulative live birth with GH supplementation.

Optimizing timing for intrauterine insemination (IUI) in donor sperm cycles: pre- versus post-ovulation insemination in natural cycles.

PURPOSE: To investigate whether pregnancy outcomes of natural cycle intrauterine insemination (IUI) with donor sperm can be improved by performing insemination after confirmation of ovulation. METHODS: This retrospective cohort study evaluated 751 couples undergoing 1170 cycles of artificial insemination with donor sperm (AID) in natural cycles between January 2018 and January 2021. Patients underwent AID either within 6-12 h after spontaneous luteinizing hormone (LH) surge (pre-ovulation group) or after ovulation was confirmed by ultrasound (post-ovulation group). Propensity score matching was performed to account for differences in baseline characteristics between groups. The main outcome measures of this study were clinical pregnancy rate and live birth rate. RESULTS: After propensity score matching, each group comprised 216 cycles. No significant differences were observed between the pre-ovulation and post-ovulation groups in terms of clinical pregnancy rate (30.6% vs 27.3%, respectively, p = .458) and live birth rate (25.0% vs 22.7%, respectively, p = .651). However, upon excluding cases of luteinized unruptured follicle syndrome (LUFS) from the pre-ovulation group, the clinical pregnancy rate (33.5% vs 27.3%, respectively, p = .043) and live birth rate (27.4% vs 22.7%, respectively, p = .039) were significantly higher in the pre-ovulation group. CONCLUSIONS: For fertile women undergoing AID in natural cycles, pre-ovulation insemination timing yielded superior pregnancy outcomes compared to post-ovulation insemination when ovulation was achieved. However, due to the occurrence of LUFS, pre- and post-ovulation AID resulted in comparable overall pregnancy outcomes in natural cycles.

The natural cycle protocol of endometrial preparation for frozen embryo transfer decreases the miscarriage rate in women with recurrent pregnancy loss.

OBJECTIVE: To investigate whether different endometrial preparation methods lead to different results. DESIGN: Retrospective cohort study. PATIENTS: Women with recurrent pregnancy loss undergoing frozen embryo transfer (FET). INTERVENTIONS: Natural cycle (NC) protocol (n = 111) with no drug or human chorionic gonadotropin (HCG) used for endometrial preparation, vs. the hormone replacement therapy (HRT) protocol (n = 797) with estrogen or gonadotropin releasing hormone agonist (GnRH-a) plus estrogen used for endometrial preparation. MAIN OUTCOME MEASURES: Miscarriage rate and live birth rate (LBR). RESULTS: Compared to women in the HRT protocol, women undergoing NCs had fewer previous FET cycles, lower antral follicle counts (AFCs), fewer oocytes retrieved and a thicker endometrium on the day of progesterone administration. Women in the HRT group had a higher miscarriage rate (29.4% vs. 17.2%) and a lower LBR (37% vs. 46.9%) than the rates of women in the NC group. Univariate analysis showed that female age also had a negative association with the miscarriage rate. Logistic regression indicated that endometrial preparation using the NC protocol was linked to a decreased likelihood of miscarriage. CONCLUSIONS: The NC protocol decreased the miscarriage rate and increased the LBR for patients with recurrent pregnancy loss compared with the HRT protocol.

Increased versus standard gonadotrophin dosing in predicted poor responders of IVF: an open-label randomized controlled trial.

STUDY QUESTION: Does an increased dosing of FSH improve the live birth rate as compared to standard FSH dosing in expected poor responders who undergo IVF? SUMMARY ANSWER: In this trial, women with an expected poor response allocated to increased FSH dosing did not have a statistically significant increase in cumulative live births as compared to a standard FSH dose. WHAT IS KNOWN ALREADY: Poor ovarian reserve leads to worse IVF outcomes owing to the low number and quality of oocytes. Clinicians often individualize the FSH dose using ovarian reserve tests, including antral follicle count (AFC), and basal plasma FSH or anti-Müllerian hormone level. However, the evidence that increased FSH dosing improves fertility outcomes in women with an expected poor response is lacking. STUDY DESIGN, SIZE, DURATION: We performed a parallel, open-label randomized controlled trial between March 2019 and October 2021 in an assisted reproduction centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women <43 years of age with AFC <10 referred for their first IVF cycle were randomized for increased or standard FSH dosing. In participants allocated to increased FSH dosing, women with AFC 1-6 started with 300 IU/day, while women with AFC 7-9 started with 225 IU/day. In participants allocated to the standard care, women started with 150 IU/day. The primary outcome was cumulative live birth attributable to the first IVF cycle including fresh and subsequent frozen-thawed cycles within 18 months of randomization. Live birth was defined as the delivery of one or more living infants ≥24 weeks' gestation. This trial was powered to detect an 11% difference in live birth attributable to the first IVF cycle. Outcomes were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We randomized 661 women to start FSH at increased dosing (n = 328) or standard dosing (n = 333). The primary outcome cumulative live birth occurred in 162/328 (49.4%) women in the increased group versus 141/333 (42.3%) women in the standard group [risk ratio (RR) 1.17 (95% CI, 0.99-1.38), risk difference 0.07 (95% CI, -0.005, 0.15), P = 0.070]. The live birth rate after the first embryo transfer in the increased versus standard group was 125/328 (38.1%) versus 117/333 (35.1%), respectively [RR 1.08 (95% CI, 0.83-1.33), P = 0.428]. Cumulative clinical pregnancy rates were 59.1% versus 57.1% [RR 1.04 (95% CI, 0.91-1.18), P = 0.586] with miscarriage rates of 9.8% versus 14.4% [RR 0.68 (95% CI, 0.44-1.03), P = 0.069] in the increased versus standard group, respectively. Other secondary outcomes, including biochemical pregnancy, ongoing pregnancy, multiple pregnancy and ectopic pregnancy, were not significantly different between the two groups both from the first and cumulative embryo transfer. LIMITATIONS, REASONS FOR CAUTION: As this study is open-label, potential selective cancelling and small dose adjustments could have influenced the results. WIDER IMPLICATIONS OF THE FINDINGS: In women with predicted poor response, we did not find evidence that increased FSH dosing improves live birth rates. A standard dose of 150 IU/day is recommended at the start of IVF in these women to reduce potential adverse effects and costs. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the General Projects of Social Development in Shaanxi Province (No. 2022SF-565). B.W.M. is supported by NHMRC (GNT1176437). B.W.M. reports personal fees from ObsEva, and funding from Merck and Ferring outside the submitted work. TRIAL REGISTRATION NUMBER: Registered at Chinese clinical trial registry (www.chictr.org.cn). Registration number ChiCTR1900021944. TRIAL REGISTRATION DATE: 17 March 2019. DATE OF FIRST PATIENT'S ENROLMENT: 20 March 2019.

Gonadotropin-releasing hormone agonist downregulation combined with hormone replacement therapy improves the reproductive outcome in frozen-thawed embryo transfer cycles for patients of advanced reproductive age with idiopathic recurrent implantation failure.

BACKGROUND: To determine whether gonadotropin-releasing hormone (GnRH) agonist downregulation combined with hormone replacement therapy (HRT) can improve the reproductive outcomes in frozen-thawed embryo transfer cycles for older patients (aged 36-43 years) with idiopathic recurrent implantation failure (RIF). METHODS: This retrospective cohort study involved 549 older patients undergoing their third cleavage-stage embryo or blastocyst transfer over a 5-year period (January 2015-December 2020) at Northwest Women's and Children's Hospital after in vitro fertilization/intracytoplasmic sperm injection cycles. Patients with known endometriosis or adenomyosis were excluded from the study. The patients were divided into three groups according to the endometrial preparation protocol: the natural cycle (NC) group (n = 65), the HRT group (n = 194), and the GnRH agonist downregulation combined with HRT cycle (GnRH agonist-HRT) group (n = 290). The primary outcome was the live birth rate, and the secondary outcomes were the clinical pregnancy, miscarriage, and ongoing pregnancy rates. RESULTS: The live birth rate in the GnRH agonist-HRT group (36.55%) was higher than that in the HRT group (22.16%) and NC group (16.92%) (P < 0.0001). Similarly, a logistic regression model adjusting for potential confounders showed that the live birth rate was higher in the GnRH agonist-HRT group than in the HRT group (odds ratio, 0.594; 95% confidence interval, 0.381-0.926; P = 0.021) and NC group (odds ratio, 0.380; 95% confidence interval, 0.181-0.796; P = 0.010). CONCLUSIONS: The GnRH agonist-HRT protocol improves the live birth rate in frozen-thawed embryo transfer cycles for patients of advanced reproductive age with RIF. We hypothesize that the GnRH agonist-HRT protocol enhances implantation-related factors and promotes optimal endometrial receptivity, leading to an improved live birth rate. These findings are also useful for further investigating the underlying mechanism of the GnRH agonist-HRT protocol in improving the reproductive outcomes for patients of advanced reproductive age with RIF. TRIAL REGISTRATION: This research protocol was approved by the hospital institutional ethics committee (No. 2021002).

Exascale integrated modeling of low-order wavefront sensing and control for the Roman Coronagraph instrument.

Astronomical instruments to detect exoplanets require extreme wavefront stability. For these missions to succeed, comprehensive and precise modeling is required to design and analyze suitable coronagraphs and their wavefront control systems. In this paper, we describe techniques for integrated modeling at scale that is, to the best of our knowledge, 1000 times faster than previously published works. We show how this capability has been used to validate performance and perform uncertainty quantification for the Roman Coronagraph instrument. Finally, we show how this modeling capacity may be necessary to design and build the next generation of space-based coronagraph instruments.

Brain edema after oocyte retrieval: a case report.

BACKGROUND: Brain edema is a rare and serious complication of assisted reproductive technology (ART). The increased intracranial pressure and injured brain parenchyma are life-threatening and may even result in death. The pathogenesis may involve increased vascular permeability mediated by vascular endothelial growth factor and other vasoactive substances, including interleukin 6, interleukin 1ß, angiotensin II, insulin-like growth factor 1, transforming growth factor ß, and the renin-angiotensin system. CASE PRESENTATION: We presented a unique case report of a 29-year-old woman developed sudden irritability, blurred consciousness, and vomiting 8 h after oocyte retrieval. Blood examinations showed hyponatremia and cranial computed tomography showed swelling of the brain parenchyma. After therapeutic use of hypertonic saline and mannitol infusion, the patient's consciousness recovered and her neurological state improved. CONCLUSIONS: Brain edema is a rare and serious complication of ART. Quick infusion of hypertonic salt solution and mannitol is a key treatment. A good prognosis can be achieved after prompt treatment.

Notch-1 signaling promotes reattachment of suspended cancer cells by cdc42-dependent microtentacles formation.

Circulating tumor cells (CTCs) are associated with a higher risk of metastasis in tumor patients. The adhesion and arrest of CTCs at a secondary site is an essential prerequisite for the occurrence of tumor metastasis. CTC reattachment has shown to be dependent on microtentacle (McTN) formation in vivo. However, the specific molecular mechanism of McTN formation in suspended cancer cells remains largely unclear. Here, we demonstrated that the activation of Notch-1 signaling triggers McTN formation to facilitate cell reattachment in suspended cell culture conditions. Moreover, molecular mechanistic studies revealed that McTN formation is governed by the balance between microtubule-driven outgrowth and actomyosin-driven cell contractility. The activation of Notch-1 downregulates the acetylation level of microtubules via the Cdc42/HDAC6 pathway, which contributes to microtubule polymerization. Simultaneously, Notch-1 signaling-induced Cdc42 activation also reduced phosphorylation of myosin regulatory light chain, leading to cell contractility attenuation. Altogether, these results defined a novel mechanism by which Notch-1 signaling disturbs the balance between the expansion of microtubules and contraction of the cortical actin, which promotes McTN formation and cell reattachment. Our findings provide a new perspective on the effective therapeutic target to prevent CTC reattachment.

Predictive value of basal androgen levels on ongoing pregnancy rates during in vitro fertilization cycles.

We aimed to evaluate the impact of elevated basal androgen levels on the endometrial receptivity. This study retrospectively enrolled 5278 fresh in vitro fertilization (IVF) cycles and sought to determine whether increased basal androgen levels are associated with adverse outcomes in regard to ongoing pregnancy rates. The results showed that the average age of our sample was 29.31 years. Almost 61.6% of all embryo transfers were with Day 3 embryos and the remaining 38.4% were with Day 5 embryos. The ongoing pregnancy rate was 56.4%. The ongoing pregnancy rates according to the various ordinal serum androgen intervals (<10.00, 10.00-19.99, 20.00-29.99, 30.00-39.99, and ≥40.00 ng/dL) were 60.12, 56.62, 58.64, 55.48, and 50.17%, respectively. The ongoing pregnancy rates were significantly lower in patients with high basal androgen levels (e40 ng/dL) (p < .05). Multivariate regression analysis showed that age, BMI, and endometrial thickness were inversely associated with basal androgen levels (p < .0001 for all). In conclusion, elevated serum basal androgen levels on cycle Day 3 before IVF is associated with reduced ongoing pregnancy rates.

Optically coherent image formation and denoising using a plug and play inversion framework.

The performance of optically coherent imaging systems can be limited by measurement and speckle noise. In this paper, we develop an image formation framework for computing the maximum a posteriori estimate of an object's reflectivity when imaged using coherent illumination and detection. The proposed approach allows for the use of Gaussian denoising algorithms (GDAs), without modification, to mitigate the exponentially distributed and signal-dependent noise that occurs in coherent imaging. Several GDAs are compared using both simulated and experimental data. The proposed framework is shown to be robust to noise and significantly reduce reconstruction error compared to the standard inversion technique.

Hepatitis B virus infection reduces fertilization ability during in vitro fertilization and embryo transfer.

Whether hepatitis B virus (HBV) infection impairs human infertility is unclear. The present retrospective case-controlled study investigated the impact of HBV on sperm parameters, ovarian stimulation, and outcomes of in vitro fertilization (IVF) and embryo transfer. A total of 224 couples with at least one partner being HBsAg-seropositive undergoing their first IVF and embryo transfer cycle were identified, which included 77 couples with female partners being HBsAg-seropositive, 136 couples with male partners being HBsAg-seropositive, and 11 couples with both partners being HBsAg-seropositive. A total of 448 both HBsAg-seronegative couples served as controls. The percentage of normal sperm morphology was significantly lower in HBsAg-seropositive male partners than that in HBsAg-seronegative male partners (11.9 ± 9.4% vs. 19.0 ± 11.9%, P < 0.01). The duration of infertility was significantly prolonged in HBV-seropositive patients compared with HBV-seronegative patients (4.9 vs. 4.1 years, P < 0.01). Couples with female partners being HBsAg-seropositive had significantly lower top-quality embryo rate than control group (22.4% vs. 31.6%, P < 0.01). In addition, the fertilization rates in groups with male or female partners being HBsAg-seropositive were both significantly lower than the matched controls (80.2% vs. 82.8%, P < 0.05; 76.6% vs. 84.3%, P < 0.01, respectively). HBV infection was also found to be associated negatively with fertilization rate by logistic regression analysis (odds ratios: 0.410, 95% confidence interval: 0.186-0.906, P < 0.05). However, there was no significant difference in clinical pregnancy rates between HBsAg-seropositive and HBsAg-seronegative group. These results suggest that chronic HBV infection is likely to represent a significant cause of infertility.

No adverse effects were identified on the perinatal outcomes after laser-assisted hatching treatment.

The aim of this study was to evaluate the safety of laser-assisted hatching (LAH) by comparing obstetric and neonatal outcomes between assisted hatching and control groups in cryopreserved embryo transfer cycles. A retrospective cohort analysis was carried out. A total of 699 women with 392 infants delivered were included. Laser- assisted hatching was carried out on D-3 thawed and warmed embryos before transfer in 480 cryopreserved embryos transfer cycles. Obstetric outcomes, neonatal outcomes, and congenital birth defects were recorded. A total of 815 cryopreserved embryo transfer cycles (480 in LAH group and 335 in control group) in 699 patients were analysed. Statistically significantly higher implantation (31.85% versus 16.95%), clinical pregnancy (53.96% versus 33.43%) and live delivery (44.58% versus 23.88%) rates were observed in the LAH group (all P < 0.001). For either singleton or multiple gestations, no statistically significant differences were found in mean gestational age, mean birth weight and mean Apgar score. Four major malformations occurred in the assisted hatching group and three malformations (one major and two minor) in the control group. This study did not identify any harmful effect of LAH on neonates, which suggested that LAH may be a safe treatment in cryopreserved embryo transfer cycles.

Use of hCG for luteal support in natural frozen-thawed blastocyst transfer cycles: a cohort study.

Introduction: In the realm of natural frozen-thawed embryo transfer (FET) cycles, the application of luteal phase support (LPS) is a prevalent practice, primarily due to its beneficial impact on reproductive outcomes. Among the various LPS medications, human chorionic gonadotropin (hCG) is one that exerts its function on both the corpus luteum and the endometrium. Objective: To evaluate the effect of hCG administration as LPS on reproductive outcomes in natural FET cycles. Methods: This study was a retrospective cohort analysis conducted at a tertiary care hospital. It included women who underwent natural FET treatment from January 2018 to December 2022. Participants were divided into the hCG LPS group and the non-hCG LPS group on the basis of whether they used hCG as LPS after blastocyst transfer. The primary outcome was the clinical pregnancy and live birth rates. The secondary outcomes included the early miscarriage rate (before 12th gestational week) and total miscarriage rate. Results: A total of 4762 women were included in the analysis, and 1910 received hCG LPS and 2852 received no hCG LPS (control group). In the general cohort, the clinical pregnancy and live birth rates in the hCG LPS group were significantly lower than those in the control group (63.82% vs 66.41%, aOR 0.872, 95% CI 0.765-0.996, P=0.046; 53.98% vs 57.15%, aOR 0.873, 95% CI 0.766-0.991, P=0.035, respectively). The early miscarriage and total miscarriage rates were similar between the two groups. In a subgroup analysis, in women who received an hCG trigger, there was no significant difference in the clinical pregnancy rate or live birth rate between the two groups. However, in women who ovulated spontaneously, the clinical pregnancy and live birth rates in the hCG LPS group were significantly lower than those in the control group (60.99% vs 67.21%, aOR 0.786, 95% CI 0.652-0.946, P=0.011; 50.56% vs 57.63%, aOR 0.743, 95% CI 0.619-0.878, P=0.001, respectively). Conclusion: Among women undergoing natural cycle frozen-thawed blastocyst transfer, hCG LPS is associated with lower clinical pregnancy and live birth rates. Additionally, the adverse effect of hCG LPS is more pronounced in women who ovulate spontaneously.

Aligned fibrous scaffolds promote directional migration of breast cancer cells via caveolin-1/YAP-mediated mechanosensing.

Tumorigenesis and metastasis are highly dependent on the interactions between the tumor and the surrounding microenvironment. In 3D matrix, the fibrous structure of the extracellular matrix (ECM) undergoes dynamic remodeling during tumor progression. In particular, during the late stage of tumor development, the fibers become more aggregated and oriented. However, it remains unclear how cancer cells respond to the organizational change of ECM fibers and exhibit distinct morphology and behavior. Here, we used electrospinning technology to fabricate biomimetic ECM with distinct fiber arrangements, which mimic the structural characteristics of normal or tumor tissues and found that aligned and oriented nanofibers induce cytoskeletal rearrangement to promote directed migration of cancer cells. Mechanistically, caveolin-1(Cav-1)-expressing cancer cells grown on aligned fibers exhibit increased integrin ß1 internalization and actin polymerization, which promoted stress fiber formation, focal adhesion dynamics and YAP activity, thereby accelerating the directional cell migration. In general, the linear fibrous structure of the ECM provides convenient tracks on which tumor cells can invade and migrate. Moreover, histological data from both mice and patients with tumors indicates that tumor tissue exhibits a greater abundance of isotropic ECM fibers compared to normal tissue. And Cav-1 downregulation can suppress cancer cells muscle invasion through the inhibition of YAP-dependent mechanotransduction. Taken together, our findings revealed the Cav-1 is indispensable for the cellular response to topological change of ECM, and that the Cav-1/YAP axis is an attractive target for inhibiting cancer cell directional migration which induced by linearization of ECM fibers.

FGFR4 genetic polymorphisms determine the chemotherapy response of Chinese patients with non-small cell lung cancer.

AIM: To investigate the relationship of fibroblast growth factor receptor 4 (FGFR4) gene polymorphisms with the response of Chinese patients with non-small cell lung cancer (NSCLC) to chemotherapy. METHODS: A total of 629 patients with Stage III (A+B) or IV NSCLC, as well as 729 age- and gender-matched healthy controls were recruited. All the patients received platinum-based chemotherapy, and the therapeutic effects were evaluated. Three polymorphisms in the FGFR4 gene (rs351855G/A, rs145302848C/G, and rs147603016G/A) were genotyped, and the association between the 3 polymorphisms and the chemotherapy effect was analyzed using SPSS software, version 16.0. RESULTS: The genotype frequencies of rs145302848C/G and rs147603016G/A were not significantly different between NSCLC patients and healthy controls on one hand, and between the responders and non-responders to the chemotherapy on the other hand. The distribution of AA genotype and A-allele of rs351855G/A was significantly lower in NSCLC patients than in healthy controls. Using patients with the GG genotype as a reference, the AA carrier had a significantly reduced risk for the development of NSCLC after normalizing to age, sex and smoking habits. In NSCLC patients, this genotype occurred more frequently in the responders to the chemotherapy than in non-responders. The chance of being a responder was significantly increased with the AA genotype as compared to G genotype. The AA genotype of rs351855G/A had a better prognosis compared with GA and GG genotype carriers: the overall survival of patients with the AA genotype of rs351855G/A was significantly longer than those with the GG+GA genotype (21.1 vs 16.5 months). CONCLUSION: The rs351855G/A polymorphisms of FGFR4 gene can be used to predict the occurrence, chemotherapy response and prognosis of NSCLC.

Who may benefit from an increased gonadotropin dosing in predicted poor responders undergoing IVF/ICSI? A secondary analysis assessing treatment selection markers of a randomized trial.

OBJECTIVE: To evaluate whether we can identify patient characteristics that serve as treatment selection markers to distinguish which women with expected poor response benefit from increased dosing of follicle-stimulating hormone (FSH) in terms of improving the cumulative live birth rate compared to standard FSH dosing and which women. STUDY DESIGN: We performed a secondary analysis of an RCT performed between March 2019 and October 2021 comparing cumulative live birth after increased dosing (N = 328) who received 225 or 300 IU/day according to their antral follicle count (AFC) and standard dosing (N = 333) who received 150 IU/day of gonadotropin. RESULTS: The MFPI analysis showed the benefit of the increased dosing of FSH on cumulative live birth starts to emerge when women were older than 30 years (women > 30 years: 46.5 % vs. 34.2 %; adjusted relative risk (aRR) 1.32, 95 % confidence interval (95 %CI) 1.05-1.66; women ≤ 30 years: 54.7 % vs. 58.6 %; aRR 0.91, 95 % CI 0.72-1.14; p for interaction 0.019). Only those who had AFC between 1 and 3 benefited from the increased FSH dose (AFC 1-3: 38.5 % vs. 6.5 %; aRR 5.88, 95 % CI 1.50-23.15; AFC 4-9: 50.3 % vs. 46.0 %; aRR 1.08, 95 % CI 0.92-1.27; p for interaction 0.023). Expected poor responders defined by the Bologna criteria and POSEIDON criteria did not significantly benefit from the increased dosing of FSH. CONCLUSIONS: Women who are aged >30 years or have AFC 1-3 are likely to benefit from increased dosing of FSH by having a higher cumulative live birth rate.

Effect of increased gonadotropin dosing on maternal and neonatal outcomes in predicted poor responders undergoing IVF: follow-up of a randomized trial.

OBJECTIVE: To evaluate, in women scheduled for IVF with predicted poor ovarian response, the effect of increased dosing of gonadotropin on maternal and neonatal outcomes compared with standard dosing. STUDY DESIGN: We performed a follow-up study of an open-labelled randomized controlled trial comparing increased (225 or 300 IU/d) versus standard (150 IU/d) dose gonadotrophins on cumulative live birth rates. We randomized 661 women with a predicted poor ovarian response (based on their antral follicle count) scheduled for their first IVF/ICSI cycle. Here, we report on maternal and neonatal outcomes between increased and standard dosing groups. RESULTS: There was a trend of increased risk of gestational diabetes mellitus in the increased gonadotrophin dose group compared with the standard group in both cumulative live birth pregnancies (14.8% vs. 7.8%, relative risk (RR) 1.90, 95% confidence interval (CI) 0.96-3.74, P = 0.06) and live birth pregnancies in the first transfer (15.2% vs. 7.7%, RR 1.98, 95 %CI 0.93-4.19, P = 0.08), without reaching statistical significance. The occurrence of gestational diabetes mellitus was significantly higher in the increased gonadotrophin dose group (24/149, 16.1% vs. 8/128, 6.3%; risk ratio (RR) 2.58, 95 %CI 1.19 to 5.54, P = 0.02) in singleton pregnancies. In women with first embryo transfer cycle, maternal hypothyroidism occurred also more frequent in the increased gonadotrophin dose group than the standard group (16.0% vs. 6.8%, RR 2.34, 95 %CI:1.07-5.11, P = 0.03). CONCLUSIONS: In women with predicted poor ovarian response, increased dosing of gonadotropin may result in an increased risk of gestational diabetes mellitus and maternal hypothyroidism.

Live birth rate following frozen-thawed blastocyst transfer is higher in high-grade day 6 blastocysts than in low-grade day 5 blastocysts.

Background: Day 5 (D5) blastocysts are generally given priority to transfer than day 6 (D6) blastocysts; however, which one should be prioritized to transfer when only low-grade D5 and high-grade D6 blastocysts are available? Methods: A large retrospective cohort study was carried out to evaluate the live birth rate (LBR) following D5 and D6 blastocysts in single frozen-thawed blastocyst transfer (FBT) during January 2014 and December 2018. A multivariate logistic regression was conducted to evaluate the combined impact of expansion day (D5 and D6) and blastocyst quality (high grade/low grade) on LBR, accounting for the potential confounding factors. The biopsied blastocysts from a consecutive PGT-A case series during February 2013 to December 2021 were analyzed in a supplementary study. Results: The LBR achieved in high-grade D6 blastocyst transfer was significantly higher than that in low-grade D5 blastocyst transfer (50.43% vs. 40.70%, aOR 1.54, 95% CI 1.05-2.26, p = 0.027). There were no significant differences in preterm birth rate, very preterm birth rate, mean live birth weight, and birth weight <1,500 g and >4,000 g between the two cohorts. As for aneuploidy analysis in PGT, there were 54.55% of euploid blastocysts (30/55) among high-grade D6 blastocysts, significantly higher than the 41.39% of euploid blastocysts (565/1,365) among low-grade D5 blastocysts (p < 0.001). Conclusions: Our data suggest that D6 blastocysts with high morphology grading are preferred than D5 blastocysts with low morphology grading when selecting blastocyst transfer to shorten the time of conception.

Functions and clinical significance of mechanical tumor microenvironment: cancer cell sensing, mechanobiology and metastasis.

Dynamic and heterogeneous interaction between tumor cells and the surrounding microenvironment fuels the occurrence, progression, invasion, and metastasis of solid tumors. In this process, the tumor microenvironment (TME) fractures cellular and matrix architecture normality through biochemical and mechanical means, abetting tumorigenesis and treatment resistance. Tumor cells sense and respond to the strength, direction, and duration of mechanical cues in the TME by various mechanotransduction pathways. However, far less understood is the comprehensive perspective of the functions and mechanisms of mechanotransduction. Due to the great therapeutic difficulties brought by the mechanical changes in the TME, emerging studies have focused on targeting the adverse mechanical factors in the TME to attenuate disease rather than conventionally targeting tumor cells themselves, which has been proven to be a potential therapeutic approach. In this review, we discussed the origins and roles of mechanical factors in the TME, cell sensing, mechano-biological coupling and signal transduction, in vitro construction of the tumor mechanical microenvironment, applications and clinical significance in the TME.

Comparison of endometrial preparation protocols (natural cycle versus hormone replacement cycle) for frozen embryo transfer (COMPETE): a study protocol for a randomised controlled trial.

INTRODUCTION: Natural 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 ANALYSIS: COMPETE 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 DISSEMINATION: This 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 NUMBER: ChiCTR2000040640.