Effect of estradiol supplementation on luteal support following a significant reduction in serum estradiol levels after hCG triggering: a prospective randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the impact of adding 4 mg estradiol valerate to progesterone for luteal support on pregnancy rates in IVF cycles following a long protocol with reduced luteal serum estradiol levels post-hCG triggering. DESIGN, SETTING, AND PARTICIPANTS: The prospective randomized controlled trial was conducted at a public tertiary hospital reproductive center with 241 patients who experienced a significant decrease in serum estrogen levels post-oocyte retrieval. INTERVENTIONS: Participants received either a daily 4 mg dose of estradiol valerate in addition to standard progesterone or standard progesterone alone for luteal support. RESULTS: The ongoing pregnancy rate did not show a significant difference between the E2 group and the control group (56.6% vs. 52.2%, with an absolute rate difference (RD) of 4.4%, 95% CI -0.087 to 0.179, P = 0.262). Similarly, the live birth rate, implantation rate, clinical pregnancy rate, early abortion rate, and severe OHSS rate were comparable between the two groups. Notably, the E2 group had no biochemical miscarriages, contrasting significantly with the control group (0.0% vs. 10.7%, RD -10.7%, 95% CI -0.178 to -0.041, P = 0.000). In the blastocyst stage category, the clinical pregnancy rate was notably higher in the E2 group compared to the control group (75.6% vs. 60.8%, RD 14.9%, 95% CI 0.012 to 0.294, P = 0.016). CONCLUSION: Adding 4 mg estradiol valerate to progesterone for luteal support does not affect the ongoing pregnancy rate in embryo transfer cycles using a long protocol with a significant decrease in serum estradiol levels after hCG triggering. However, it may reduce biochemical miscarriages and positively impact clinical pregnancy rates in blastocyst embryo transfer cycles. TRIAL REGISTRATION: ChiCTR1800020342.

S-Allyl-L-cysteine (SAC) inhibits copper-induced apoptosis and cuproptosis to alleviate cardiomyocyte injury.

Cardiomyocyte injury is closely related to various myocardial diseases, and S-Allyl-L-cysteine (SAC) has been found to have myocardial protective effects, but its mechanism is currently unclear. Meanwhile, copper also has various physiological functions, and this study found that copper inhibited cell viability in a concentration and time-dependent manner, and was associated with multiple modes of death. Elesclomol plus CuCl2 (ES + Cu) significantly inhibited cell viability, and this effect could only be blocked by copper chelator TTM, indicating that "ES + Cu" induced cuproptosis in cardiomyocytes. SAC reduced the inhibitory effects of high concentration copper and "ES + Cu" on cell viability in a concentration and time-dependent manner, indicating that SAC plays a cardioprotective role under stress. Further mechanism study showed that high concentration of copper significantly induced cardiomyocyte apoptosis and increased the levels of LDH, MDA and ROS, while SAC inhibited the apoptosis and injury of cardiomyocytes induced by copper. "ES + Cu" significantly increased intracellular copper levels and decreased the expression of FDX1, LIAS, Lip-DLST and Lip-DLAT; FDX1 siRNA did not affect the expression of LIAS, but further reduced the expression of Lip-DLST and Lip-DLAT; SAC did not affect the expression of these genes, but enhanced the effect of "ES + Cu" in down-regulating these gene expression and restored intracellular copper levels. In addition, "ES + Cu" reduced ATP production, weakened the activity of mitochondrial complex I and III, inhibited cell viability, and increased the contents of injury markers LDH, MDA, CK-MB and cTnI, while SAC significantly improved mitochondrial function injury and cardiomyocyte injury induced by "ES + Cu". Therefore, SAC can inhibit apoptosis and cuproptosis to play a cardioprotective role.

Intermittent fasting and health outcomes: an umbrella review of systematic reviews and meta-analyses of randomised controlled trials.

Background: Benefits of Intermittent fasting (IF) on health-related outcomes have been found in a range of randomised controlled trials (RCTs). Our umbrella review aimed to systematically analyze and synthesize the available causal evidence on IF and its impact on specific health-related outcomes while evaluating its evidence quality. Methods: We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane databases (from inception up to 8 January 2024) to identify related systematic reviews and meta-analyses of RCTs investigating the association between IF and human health outcomes. We recalculated the effect sizes for each meta-analysis as mean difference (MD) or standardized mean difference (SMD) with corresponding 95% confidence intervals (CIs). Subgroup analyses were performed for populations based on three specific status: diabetes, overweight or obesity, and metabolic syndrome. The quality of systematic reviews was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system. This study is registered with PROSPERO (CRD42023382004). Findings: A total of 351 associations from 23 meta-analyses with 34 health outcomes were included in the study. A wide range of outcomes were investigated, including anthropometric measures (n = 155), lipid profiles (n = 83), glycemic profiles (n = 57), circulatory system index (n = 41), appetite (n = 9), and others (n = 6). Twenty-one (91%) meta-analyses with 346 associations were rated as high confidence according to the AMSTAR criteria. The summary effects estimates were significant at p < 0.05 in 103 associations, of which 10 (10%) were supported by high certainty of evidence according to GRADE. Specifically, compared with non-intervention diet in adults with overweight or obesity, IF reduced waist circumference (WC) (MD = -1.02 cm; 95% CI: -1.99 to -0.06; p = 0.038), fat mass (MD = -0.72 kg; 95% CI: -1.32 to -0.12; p = 0.019), fasting insulin (SMD = -0.21; 95% CI: -0.40 to -0.02; p = 0.030), low-density lipoprotein cholesterol (LDL-C) (SMD = -0.20; 95% CI: -0.38 to -0.02; p = 0.027), total cholesterol (TC) (SMD = -0.29; 95% CI: -0.48 to -0.10; p = 0.003), and triacylglycerols (TG) (SMD = -0.23; 95% CI: -0.39 to -0.06; p = 0.007), but increased fat free mass (FFM) (MD = 0.98 kg; 95% CI: 0.18-1.78; p = 0.016). Of note, compared with the non-intervention diet, modified alternate-day fasting (MADF) reduced fat mass (MD = -0.70 kg; 95% CI: -1.38 to -0.02; p = 0.044). In people with overweight or obesity, and type 2 diabetes, IF increases high-density lipoprotein cholesterol (HDL-C) levels compared to continuous energy restriction (CER) (MD = 0.03 mmol/L; 95% CI: 0.01-0.05; p = 0.010). However, IF was less effective at reducing systolic blood pressure (SBP) than a CER diet in adults with overweight or obesity (SMD = 0.21; 95% CI: 0.05-0.36; p = 0.008). Interpretation: Our findings suggest that IF may have beneficial effects on a range of health outcomes for adults with overweight or obesity, compared to CER or non-intervention diet. Specifically, IF may decreased WC, fat mass, LDL-C, TG, TC, fasting insulin, and SBP, while increasing HDL-C and FFM. Notably, it is worth noting that the SBP lowering effect of IF appears to be weaker than that of CER. Funding: This work was supported by the National Key Research and Development Program of China (Q-JW), the Natural Science Foundation of China (Q-JW and T-TG), Outstanding Scientific Fund of Shengjing Hospital of China Medical University (Q-JW), and 345 Talent Project of Shengjing Hospital of China Medical University (T-TG).

Intramuscular injection of human chorionic gonadotropin as luteal phase support in artificial cycle frozen-thawed embryo transfer does not improve clinical outcomes: a parallel, open-label randomized trial.

Background: Human chorionic gonadotropin (hCG) as one of the first signals secreted by the embryo to the mother may have a direct effect on the endometrium at implantation. The current study was aim to compare the clinical outcomes after frozen-thawed embryo transfer (FET) treated with artificial cycles (AC) between women who were administered intramuscular injection of human chorionic gonadotropin (hCG) as luteal phase support and the routine group. Methods: A randomized controlled trial of 245 women was conducted at the Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China from January 2019 to January 2020. Women <40 years of age undergoing their first FET treated with AC were included. Patients were randomly allocated into either: (1) the hCG treatment group, who received intramuscular injection of hCG since the third day of progesterone administration, at a dose of 2000 IU once every two days, for a total of four times, (2) the control group, receiving routine protocol without placebo on these four days. Clinical outcomes of the two groups were analyzed. Results: The primary outcome ongoing pregnancy rate in the hCG treatment group versus the control group was 73/124 (58.87%) versus 75/121 (61.98%), respectively (odds ratio [OR], 95% confidence interval [CI]:0.88, 0.53-1.47, P = 0.619). Secondary clinical outcomes including biochemical pregnancy, clinical pregnancy, early pregnancy loss, multiple pregnancy, live birth and preterm birth were also comparable between the two groups through the univariate analysis and multivariable regression analysis (P > 0.05). Conclusion: In women undergoing AC-FET, there was no significant difference in the clinical outcomes between the hCG treatment group and the control group. Clinicians should be cautious about adding IM-hCG as luteal phase support to improve the clinical outcome after AC-FET. Clinical trial registration: http://www.chictr.org.cn/showprojen.aspx?proj=32511, identifier ChiCTR1800020342.

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.

Increased risk of intracranial hemorrhage in preterm infants with OPRM1 gene A118G polymorphism.

BACKGROUND: To investigate the relationship between the OPRM1 gene A118G polymorphism and intracranial hemorrhage (ICH) in premature infants and identify the relevant genes in disease occurrence. METHODS: In the present case study analysis, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequencies of the OPRM1 gene All8G single nucleotide polymorphism (SNP) in a case group of premature infants with ICH (n=167) and a control group of premature infants (n=163) without ICH. RESULTS: In the case group, 73 (43.7%) wild type A118 homozygous (A/A), 82 (49.1%) mutant heterozygous (A/G), and 12 (7.2%) mutant G118 homozygous (G/G) individuals were observed. The frequencies of A and G alleles were 68.3% and 31.7% respectively. In the control group, 89 (54.6%) wild type A118 homozygous (A/A), 68 (41.7%) mutant heterozygous (A/G), and 6 (3.7%) mutant G118 homozygous (G/G) individuals were observed. The frequencies of A and G alleles were 75.5% and 24.5% respectively. There was no significant difference in the frequency distribution of the OPRM1 gene A118G polymorphism between the two groups (χ2=4.839, P=0.089). There was a significant difference in the positive rate of wild-type AA and mutant-type (A/G + G/G) between the two groups (χ2=3.913, P=0.048). Carrying the G allele of the individual was 1.5 times more frequent suffering from the risk of ICH than carrying the A allele [odds ratio (OR): 1.549; 95% confidence interval (CI): 1.003-2.391], indicating that the OPRM1 118G allele was positively correlated with ICH and can increase the risk of ICH occurrence. CONCLUSIONS: The OPRM1 gene A118G polymorphism is associated with ICH in premature infants. The OPRM1 gene A118G may play a critical role in the occurrence of ICH.

A novel solution configuration on liquid-based endometrial cytology.

OBJECTIVE: Early detection and diagnosis of endometrial carcinoma and precancerous change would undoubtedly become the most alluring part for researchers. With the emergence of endometrial brush samplers, a new upsurge in endometrial cytology is in the making. But endometrial specimens obtained by the endometrial brush samplers require special preservation solution. The objective of this study is to develop a new kind of endometrial-cell preservation solution and to test the availability compared with a patented liquid-based cell preservation solution. METHODS: In this controlled study, we had 5 endometrial cases collected with Li Brush from the First Affiliated Hospital of Xi'an Jiaotong University (09/2016 to 12/2016). The samples of each case were collected 2 times separately and perserved in different perservation solutions. One was a kind of novel endometrial cell preservation solution and the other was a kind of patented liquid-based cell (LBC) preservation solution. The endometrial cells were smeared on slides by using the ZP-C automated slide preparation system and stained with Papanicolaou stain. A semi-quantitative scoring system was used to analyze the quality of slides. Statistical analysis was performed using the Wilcoxon signed rank test on the SPSS program (SPSS 18.0). In all LBC preparations, endometrial cells from the novel endometrial cells preservation solution had more cell quantity, less red blood cell fragments, and the background was cleaner compared with control group. Although the novel endometrial-cell preservation solution showed cellularity and absence of blood and debris expressed by no statistically significant differences (p = 0.063 and 0.102 respectively). The preservation period of the two kinds of liquids was equivalent. CONCLUSIONS: The novel endometrial-cell preservation solution is superior to the liquid-base cell preservation solution for cervical cells, with clear background, diagnostic cells and low cost.

PBEF promotes the apoptosis of pulmonary microvascular endothelial cells and regulates the expression of inflammatory factors and AQP1 through the MAPK pathways.

Pre-B cell colony-enhancing factor (PBEF) has been shown to have a variety of biological functions. Studies have proven that PBEF plays a functional role in acute lung injury (ALI). Therefore, in this study, we aimed to confirm the importance of PBEF in ALI. The effects of PBEF overexpression on the apoptosis of human pulmonary microvascular endothelial cells (HPMECs) were analyzed by flow cytometry, and the results indicated that PBEF promoted the apoptosis of HPMECs, which aggravated the development of ALI. Comparative experiments involving increasing and decreasing PBEF expression demonstrated that PBEF promoted the expression of inflammatory factors, such as interleukin (IL)­1ß, IL­6 and IL­8 in the HPMECs , thus intensifying the inflammatory response. PBEF also inhibited the expression of aquaporin 1 (AQP1), which caused a dysfunction and imbalance in water transport. Moreover, we also found that tumor necrosis factor (TNF)­α promoted the expression of PBEF in the HPMECs. After blocking the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, we found that PBEF regulated the expression of inflammatory factors and AQP1, mainly through the MAPK pathways. Taken together, these results demonstrate that the increase in intracellular PBEF expression promoted the apoptosis of HPMECs and the expression of inflammatory factors and thus enhanced the inflammatory response and inhibited the expression of AQP1, which resulted in abnormal water transport, diminishing the regulatory effects of AQP1 on water transport.

Application of NT-proBNP in ventilator weaning for preterm infants with RDS.

OBJECTIVE: To evaluate the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels along with spontaneous breathing trial (SBT) in the prediction of ventilator weaning outcome among respiratory distress syndrome (RDS) preterm infants ready to wean. METHODS: NT-proBNP along with plasma albumin concentration, serum sodium, serum potassium, and hematocrit were measured immediately before SBT in preterm infants (≤32 weeks) mechanically ventilated due to RDS. Extubation was considered successful if infants remained extubated >48 hr. Either SBT failure or extubation failure was considered weaning failure. RESULTS: Sixty-three of 88 infants passed the SBT and were subsequently extubated. Of these, two (3.2%) cases rapidly developed laryngeal dyspnea imposing reintubation (excluded from analysis). Of the remaining 61 infants, 45 (73.8%) cases had successful extubation, and 16 (26.2%) cases were reintubated. Infants who failed weaning had lower gestational age, birth weight, and plasma albumin concentrations, higher NT-proBNP, doses of surfactant, occurrence of ventilator-associated pneumonia, and occurrence of pulmonary arterial hypertension than those who did not. NT-proBNP was the only independent factor that could predict weaning failure (OR = 1.872; P = 0.044). The ROC-AUC for NT-proBNP to predict weaning failure was 0.977 (95% CI 0.918-0.997; P < 0.001). The cut-off of NT-proBNP level 18,500 pg/ml to predict weaning failure had a positive likelihood ratio of 25.180. The addition of NT-proBNP to SBT in prediction of weaning failure significantly improved the net reclassification improvement (NRI = 0.224; P = 0.034). CONCLUSION: NT-proBNP is an independent factor that could predict weaning failure. Measurement of NT-proBNP prior to SBT may be helpful in promoting successful ventilator weaning along with SBT.

[Association between platelet-activating factor acetylhydrolase gene polymorphism and intracranial hemorrhage in preterm infants].

OBJECTIVE: To explore whether Val279Phe single nucleotide polymorphisms (SNPs) in the 9th exon of platelet-activating factor acetylhydrolase (PAF-AH) are associated with intracranial hemorrhage in preterm infants. METHODS: A case-control study was performed. Polymerase chain reaction (PCR) was used to test genotype and allele frequencies of the 9th exon Val279Phe SNPs of PAF-AH in 58 preterm infants with intracranial hemorrhage (hemorrhage group) and 65 preterm infants without intracranial hemorrhage (control group). RESULTS: There were significant differences in genotype frequency of Val279Phe SNPs in the 9th exon of PAF-AH between the hemorrhage and control groups (P<0.05). Frequency of normal genotype in the hemorrhage group (63.8%) was significantly lower than in the control group (81.5%). In contrast, frequency of heterozygous genotype (34.5%) in the hemorrhage group was significantly higher than in control group (16.9%). There were also significant differences in allele frequency of Val279Phe SNPs in the 9th exon of PAF-AH between the two groups (P<0.05). T allele frequency in the hemorrhage group (19.0%) was significantly higher than in the control group (10.0%). CONCLUSIONS: Val279Phe SNPs in the 9th exon of PAF-AH may be associated with intracranial hemorrhage in preterm infants.