Exposure of Reproductive-Aged Women to Multiple Metals and Its Associations with Unexplained Recurrent Miscarriage.

Exposure to heavy metals exerts toxic effects on female reproduction and embryo development. This study examined the exposure of patients with unexplained recurrent miscarriage (uRM) to multiple metals and the correlations among exposures to different metals. A total of 275 participants were enrolled, including 43 healthy women without previous miscarriage (the control group) and 232 uRM women (the case group); among these uRM women, 159 had two miscarriages (2M), 42 had three miscarriages (3M) and 31 had four or more miscarriages (≥4M). A total of 22 elements were measured in serum samples via inductively coupled plasma-mass spectrometry. The levels of calcium (104.37 mg/L vs. 92.65/93.02/92.61/92.47 mg/L) and selenium (131.85 µg/L vs. 117.80/118.04/115.88/124.35 µg/L) were higher in the controls than in the total uRM group and the 2M, 3M and ≥4M subgroups. The level of vanadium was significantly lower in the controls than in the total uRM group (0.15 µg/L vs. 0.23 µg/L), and the level of lead was lower in the controls than that in the total uRM group and the 2M, 3M and ≥4M subgroups (0.01 µg/L vs. 0.28/0.18/0.63/0.34 µg/L). After adjusting for age, body mass index and education level, calcium and selenium exposure were consistently negatively associated with miscarriage, while lead exposure was positively associated with miscarriage. In addition, the correlations among exposures to different metals slightly differed between the control and uRM groups. Therefore, changes in some metal elements in the blood might be related to the risk of uRM.

Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis.

Background: Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events. Methods: This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan-Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE). Findings: Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56 ± 11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were -4.26 ± 8.54 (3rd month), -4.72 ± 11.83 (6th month), -6.16 ± 15.41 (9th month), -6.07 ± 15.71 (12th month), and -7.96 ± 13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables. Interpretation: ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment. Funding: The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.

PGT-A improved singleton live birth rate among all age groups of women who underwent elective single blastocyst transfer: a single-centre retrospective study.

PURPOSE: This study assessed the difference in singleton live birth rate (SLBR) between preimplantation genetic testing for aneuploidy (PGT-A) and non-PGT in patients undergoing elective single frozen blastocyst transfer (eSFBT). METHODS: This retrospective cohort study evaluated 10,701 cycles of eSFBT, including PGT-A (n = 3125) and non-PGT (n = 7576). Cycles were further stratified according to age at retrieval. The main outcome was SLBR; secondary outcomes were clinical pregnancy, conception rates, and multiple live birth rate. Confounders were adjusted using multivariable logistic regression models, and the trend test was performed using the general linear model. RESULTS: SLBR was negatively correlated with age in the non-PGT group (p-trend < 0.001) but not in PGT-A group (p-trend = 0.974). Stratified by the age, SLBR were significantly different between two groups except for the 20-24-year-old group: PGT-A vs non-PGT group in 20-24, 25-29, 30-34, 35-39 and ≥ 40-year-old subgroups were, 53.5% vs 53.2%, 53.5% vs 48.0%, 53.5% vs 43.1%, 53.3% vs 32.5%, and 42.9% vs 17.6%, respectively. In addition, after adjusting for potential confounders, SLBR still remained significantly different in all age groups except in the youngest quartile (PGT-A vs non-PGT group, 20-24: adjusted odds ratio (aOR), 1.33, 95% CI, 0.92-1.92, p = 0.129; 25-29: aOR, 1.32, 95% CI, 1.14-1.52, p < 0.001; 30-34: aOR, 1.91, 95% CI, 1.65-2.20, p < 0.001; 35-39: aOR, 2.50, 95% CI, 1.97-3.17, p < 0.001; ≥ 40: aOR, 3.54, 95% CI, 1.66-7.55, p = 0.001). CONCLUSION: PGT-A might improve SLBR among all age groups and play an increasingly important role in SLBR in older patients who underwent eSFBT.

Decreased Ovarian Reserves With an Increasing Number of Previous Early Miscarriages: A Retrospective Analysis.

The fact of ovarian reserve (OR) decreased in women with recurrent miscarriage has been well known. However, Whether OR would decrease with increasing numbers of previous miscarriages (PMs) is still unclear. To address this, OR parameters of following four groups' patients were evaluated: 99 women with one previous miscarriage (PM1), 46 women with two previous miscarriages (PM2) and 35 women with three or more previous miscarriages (PM3). The control group included 213 women without a history of miscarriage (PM0). The correlation of OR parameters and the proportion of diminished ovarian reserve (DOR) patients between the four groups were analyzed using Kendall's Tau-B coefficients. The results showed the median anti-Müllerian hormone (AMH) levels were 4.04, 3.40, 3.14 and 2.55 respectively in the PM0, PM1, PM2 and PM3 groups, respectively (H=15.99, P = 0.001); the median antral follicle counts (AFCs) were 10, 8, 8 and 6, respectively (H=24.53, P < 0.001); and the proportions of DOR patients were 10.8%, 15.2%, 23.9% and 31.4% (χ2 = 13.01, P = 0.005). In addition, AMH level and AFC correlated negatively with the number of PMs (correlation coefficients -0.154, P < 0.001; -0.205, P < 0.001 respectively), the proportion of DOR patients correlated positively with the number of PMs (correlation coefficients 0.156, P = 0.001). After stratification by age, AMH and AFC levels were still significantly lower in the PM3 group than the PM0 group (P < 0.05). The proportion of DOR patients between the PM0 and PM3 groups was statistically significant (P < 0.001). This study showed that AMH levels and AFCs decreased as well as the proportion of DOR patients increased significantly as the number of PMs increased. In conclusion, our study indicates decreased AMH levels and AFCs might be one of the factors contributing to early miscarriage.

Differential transcriptional profiles of human cumulus granulosa cells in patients with diminished ovarian reserve.

PURPOSE: This study compared the gene expression profiles of cumulus granulosa cells in patients with diminished ovarian reserve and those with normal ovarian reserves to identify genes that may be involved in the pathogenesis of diminished ovarian reserve. METHODS: After retrieval of the cumulus-oocyte complex, the cumulus granulosa cells that surrounded the oocytes of 25 patients with diminished ovarian reserve and 25 patients with normal ovarian reserves were removed by mechanical stripping. Extraction of RNA from the cumulus granulosa cells was for RNA sequencing and analysis. RT-PCR was used to confirm the candidate genes. Statistical analysis was performed using student's t test. RESULTS: A total of 294 upregulated genes and 336 downregulated genes were identified in the POSEIDON patients relative to the normal ovarian reserve group. Bioinformatic analysis showed that the downregulated genes were highly enriched in the Wnt signaling pathway, negative regulation of stress fiber assembly, and cell chemotaxis, while the upregulated genes were highly enriched in functions associated with the regulation of interleukin-5 production and regulation of immune system processes. According to the differential expression levels and their potential functions, IL1RL1, IL33, SFRP4, and S1PR1 were validated by quantitative RT-PCR. The results of RT-PCR were consistent with those of RNA sequencing. CONCLUSION: Expression of IL1RL1, IL33, SFRP4, and S1PR1 in the cumulus granulosa cells may be involved in the pathogenesis of diminished ovarian reserve.

Comparison of Hysterosalpingography With Laparoscopy in the Diagnosis of Tubal Factor of Female Infertility.

Background: Laparoscopy is considered to be the gold standard in the evaluation of causes leading to infertility. Hysterosalpingography (HSG) permits indirect visualization of the cervical canal, uterine cavity, and tube patency, which is helpful for evaluating the causes of infertility. Objective: This study aimed to detect tubal abnormalities in infertile women by HSG or laparoscopy and determine the value of HSG in diagnosing fallopian tube status. Methods: The study group consisted of 1,276 patients. HSG was performed as a preliminary test for the evaluation of fallopian tube status. Women were subjected to laparoscopic examination on evidence of HSG abnormalities. Results: The negative predictive value of HSG for detecting patency or occlusion for the right/left tube was 92.08 and 95.44%, respectively. The kappa values for the consistent diagnosis in the right/left tube were 0.470 and 0.574, respectively. In cases of low patency of the right/left tube, there was a greater than a 40% chance for the tube to be patent, and the remaining high probability was pelvic adhesion. The positive predictive value of HSG for detecting patency or occlusion for both tubes was 87.2%. The kappa value was 0.898 [95% CI (0.838, 0.937), p < 0.001], which meant that the diagnostic accuracy of HSG for both tube patency/occlusion was explicit. The kappa value for the diagnosis of hydrosalpinx (especially for bilateral tube hydrosalpinx) was 0.838 [95% CI (0.754, 0.922), p < 0.001], and the diagnostic accuracy for HSG was 79.8, 67.9, and 72.4%, respectively. Conclusion: The current study concluded that HSG is a good diagnostic modality to detect tube abnormalities in infertile patients. HSG and laparoscopy are complementary to each other and whenever the patient is undertaken for diagnosis of infertility. Cost-effective HSG had good predictive value in identifying tubal factor infertility.

Effects of hormone replacement therapy on endometrial hormone concentrations and progesterone receptor expression in recurrent pregnancy loss: a self-controlled study.

AIM: To investigate the differential effects of endometrial preparation approaches, natural cycle (NC) and hormone replacement therapy (HRT), on the endometrial hormone conditions in patients with recurrent pregnancy loss (RPL). METHODS: 42 RPL patients were recruited, and a self-controlled trial was conducted to compare the effectiveness of NC to HRT on the same patient. The estradiol (E2) and progesterone (P) levels in both serum and endometrial tissue were measured in NC and HRT, respectively. Meanwhile, the expression levels of endometrial progesterone receptor A (PRA) and progesterone receptor B (PRB) were also compared between NC and HRT cycles during the window of receptivity. All statistical analyses were performed using GraphPad Prism 5, and data were averaged across subjects and tested for significance by pair-samples t-test. RESULTS: Hormone replacement slightly decreased serum E2 and P levels (0.9- and 0.8-fold in average, respectively), significantly elevated endometrial E2 and P (2.1- and 14.5-fold in average, respectively), and reduced endometrial E2/P ratio (0.34-fold in average) compared to the NC condition. However, no correlation was found between serum and endometrial hormone concentrations. Further, the PRA/PRB ratios of both stromal and glandular cells were comparable between HRT and NC conditions, even though stromal PRA expression was slightly elevated by HRT compared to NC (1.63±0.96 vs 1.18±0.99, p =.0173). CONCLUSION: The effects of HRT for endometrial preparation are similar or slightly superior to NC in RPL patients.

Association between long-chain non-coding RNA SRA1 gene single-nucleotide polymorphism and polycystic ovary syndrome susceptibility.

OBJECTIVE: To study the association between single-nucleotide polymorphism (SNP) of long-chain non-coding RNA steroid receptor RNA activator (lncRNA SRA1) gene and polycystic ovary syndrome (PCOS) susceptibility. METHODS: Sanger sequencing was used to analyze the genotypes of the lncRNA SRA1 gene rs801460, rs10463297, and rs250426 in 315 PCOS patients and 315 control groups. RESULTS: There was no correlation between lncRNA SRA1 gene rs801460, rs250426 SNP, and PCOS susceptibility (p > 0.05). The T allele at the rs10463297 locus of the SRA1 gene has a lower risk of PCOS than the C allele (OR = 0.63, 95%CI: 0.50-0.79, p < 0.01). Among people with a BMI ≥ 26.5 kg/m2, when carrying the TC genotype and CC genotype at rs801460, the risk of PCOS susceptibility was lower than the TT genotype (OR = 0.54, 95%CI: 0.33-0.89, p = 0.02). At different ages and BMI stratifications, there was a significant association between rs10463297 SNP and PCOS susceptibility (p < 0.05). Multi-factor dimensionality reduction (MDR) analysis results showed that age, BMI, rs801460, rs10463297, and rs250426 interactions constitute a "high-risk combination." PCOS susceptibility risk was 5.96 times that of a "low-risk combination" (95%CI: 4.14-8.56, p < 0.01). SRA1 gene rs801460, rs10463297, rs250426 constructed TCT haplotype was associated with increased risk of PCOS susceptibility (OR = 1.66, 95%CI: 1.20-2.30, p < 0.01); the CTT haplotype was associated with a decreased risk of PCOS susceptibility (OR = 0.56, 95%CI: 0.36-0.87, p = 0.01). LncRNA SRA1 gene rs10463297 SNP was correlated with the level of lncRNA SRA1 in the peripheral blood leukocytes (p < 0.01). CONCLUSION: From this study, we found that the lncRNA SRA1 gene rs10463297 SNP is associated with PCOS susceptibility.

The role of omentectomy in the surgical treatment of uterine serous carcinoma.

OBJECTIVE: The aims of this study were to assess the role of omentectomy in the staging of uterine serous carcinoma (USC) and to evaluate its impact on patient outcomes. STUDY DESIGN: Patients diagnosed with USC at the First Affiliated Hospital of Sun Yat-sen University of China were retrospectively reviewed. The clinicopathological characteristics and survival data of 187 patients were analyzed. Risk factors for omental metastasis were evaluated. Kaplan-Meier survival curves were used to compare survival status and the presence of omental metastasis. RESULTS: We found that 35 of 187 patients (18.7%) had omental metastases. Omental metastasis was significantly associated with adnexal involvement (40.0% vs 19.1%, P = 0.008, OR 2.828, 95% CI 1.286-6.218). Multivariate analysis showed that in addition to lymph node metastases and suboptimal surgery, omental metastasis in USC remained an independent predictor of decreased PFS and OS (PFS, HR 1.48, 95% CI 1.14-4.63, P = 0.024; OS, HR 1.39, 95% CI 1.04-3.60, P = 0.043). CONCLUSIONS: The incidence of omental metastasis is not low in patients with USC. Visual assessment and omental biopsy may be insufficient for recognizing occult metastases. Omentectomy should be part of the staging surgery in USC patients because it provides additional information about survival. Prospective studies are needed to confirm these results.