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Aggregation-induced emission (AIE) carbon dot (CDs) in solid state with tunable multicolor emissions have sparked significant interest in multidimensional anti-counterfeiting. However, the realization of solid-state fluorescence (SSF) by AIE effect and the regulation of fluorescence wavelength in solid state is a great challenge. In order to solve this dilemma, the AIE method to prepare multi-color solid-state CDs with fluorescence wavelengths ranging from bright blue to red emission is employed. Specifically, by using thiosalicylic acid and carbonyl hydrazine as precursors, the fluorescence wavelength can be accurately adjusted by varying the reaction temperature from 150 to 230 °C or changing the molar ratio of the precursors from 1:1 to 1:2. Structural analysis and theoretical calculations consistently indicate that increasing the sp 2 domains or doping with graphite nitrogen both cause a redshift in the fluorescence wavelength of CDs in the solid state. Moreover, with the multi-dimensional and adjustable fluorescence wavelength, the application of AIE CDs in the fields of multi-anti-counterfeiting encryption, ink printing, and screen printing is demonstrated. All in all, this work opens up a new way for preparing solid-state multi-color CDs using AIE effect, and further proposes an innovative strategy for controlling fluorescence wavelengths., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined., Methods: We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies., Results: We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i., Conclusions: Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers., (© 2024. The Author(s).)

The methyltransferase complex (MTC) deposits N6-adenosine (m 6 A) onto RNA, whereas the microprocessor produces microRNA. Whether and how these two distinct complexes cross-regulate each other has been poorly studied. Here we report that the MTC subunit B tends to form insoluble condensates with poor activity, with its level monitored by the 20S proteasome. Conversely, the microprocessor component SERRATE (SE) forms liquid-like condensates, which in turn promote the solubility and stability of the MTC subunit B, leading to increased MTC activity. Consistently, the hypomorphic lines expressing SE variants, defective in MTC interaction or liquid-like phase behaviour, exhibit reduced m 6 A levels. Reciprocally, MTC can recruit the microprocessor to the MIRNA loci, prompting co-transcriptional cleavage of primary miRNA substrates. Additionally, primary miRNA substrates carrying m 6 A modifications at their single-stranded basal regions are enriched by m 6 A readers, which retain the microprocessor in the nucleoplasm for continuing processing. This reveals an unappreciated mechanism of phase separation in RNA modification and processing through MTC and microprocessor coordination., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Zishen Yutai Pill exhibited clinical benefit to infertile women undergoing fresh embryo transfer cycles, improving their pregnancy outcomes. However, as the endometrial environment in frozen embryo transfer (FET) is different from fresh cycles, the effects of ZYP on fresh embryo transfer could not be generalized to FET., Objective: We aimed to explore the effects of ZYP on live birth rate in women's FET cycles., Methods: This multicentre, double-blind, placebo-controlled, randomized study was conducted at 11 reproductive medical centres in China. Women were recruited and randomly assigned to ZYP or placebo intervention (5 g once, 3 times per day) around the time of FET. The live birth rate was set as the primary outcome. Secondary outcomes included implantation rate, biochemical pregnancy rate, clinical pregnancy rate, pregnancy loss rates. Data was analyzed based on the intention-to-treat principle, with per protocol analysis as sensitivity analysis., Results: Between December 2017 and April 2019, 934 women were screened, of whom 880 met all eligibility criteria and were allocated to ZYP (n=441) or placebo (n=439). In ITT analysis, the live birth rates were 38.32% (169/441) in ZYP group and 32.57% (143/439) (absolute difference 5.75%, 95%CI [-0.57%, 12.00%], OR 1.29, 95%CI [0.98, 1.70], P=0.08). The intervention of ZYP did not result in significantly differences in all secondary outcomes compared with placebo (all P>0.05). Similar trends were observed in PP analysis. In post hoc analysis, ZYP resulted in higher rates of live birth than placebo among women in specific subgroups, i.e., with miscarriage history (39.23% vs. 26.45%, P=0.01) or advanced maternal age (33.93% vs. 21.85%, P=0.04)., Conclusion: In infertile women undergoing FET cycle, intervention with ZYP led to a trend of live birth rate increment compared with placebo, but without statistical significance. However, women with miscarriage history and advanced age could experience possible benefits from ZYP intervention., Registration: ChiCTR-INR-17010809 (http://www.chictr.org.cn)., Competing Interests: Declaration of competing interest This study was supported by the Guangdong Provincial Bureau of Traditional Chinese Medicine (Grant No. 20174002), Guangzhou International Science and Technology Cooperation Project (Grant No. 201807010044). Guangzhou Baiyunshan Zhongyi Pharmaceutical Co. Ltd. donated the study drugs, including Zishen Yutai Pill and the placebo for this research, but had no role in the data acquisition, statistical analysis and writing of this article. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Methyltransferase complex (MTC) deposits N 6-adenosine (m 6 A) onto RNA, whereas microprocessor produces miRNA. Whether and how these two distinct complexes cross-regulate each other has been poorly studied. Here we report that the MTC subunit B (MTB) tends to form insoluble condensates with poor activity, with its level monitored by 20S proteasome. Conversely, the microprocessor component SERRATE (SE) forms liquid-like condensates, which in turn promotes solubility and stability of MTB, leading to increased MTC activity. Consistently, the hypomorphic lines expressing SE variants, defective in MTC interaction or liquid-like phase behavior, exhibit reduced m 6 A level. Reciprocally, MTC can recruit microprocessor to MIRNA loci, prompting co-transcriptional cleavage of primary miRNA (pri-miRNAs) substrates. Additionally, pri-miRNAs carrying m 6 A modifications at their single-stranded basal regions are enriched by m 6 A readers, which retain microprocessor in the nucleoplasm for continuing processing. This reveals an unappreciated mechanism of phase separation in RNA modification and processing through MTC and microprocessor coordination.

In eukaryotes, RNA N 6 -methyladenosine (m 6 A) modification and microRNA (miRNA)-mediated RNA silencing represent two critical epigenetic regulatory mechanisms. The m 6 A methyltransferase complex (MTC) and the microprocessor complex both undergo liquid-liquid phase separation to form nuclear membraneless organelles. Although m 6 A methyltransferase has been shown to positively regulate miRNA biogenesis, a mechanism of reciprocal regulation between the MTC and the microprocessor complex has remained elusive. Here, we demonstrate that the MTC and the microprocessor complex associate with each other through the METHYLTRANSFERASE B (MTB)-SERRATE (SE) interacting module. Knockdown of MTB impaired miRNA biogenesis by diminishing microprocessor complex binding to primary miRNAs (pri-miRNAs) and their respective MIRNA loci. Additionally, loss of SE function led to disruptions in transcriptome-wide m 6 A modification. Further biochemical assays and fluorescence recovery after photobleaching (FRAP) assay indicated that SE enhances the liquid-liquid phase separation and solubility of the MTC. Moreover, the MTC exhibited enhanced retention on chromatin and diminished binding to its RNA substrates in the se mutant background. Collectively, our results reveal the substantial regulatory interplay between RNA m 6 A modification and miRNA biogenesis., (© 2024 The Author(s). Journal of Integrative Plant Biology published by John Wiley & Sons Australia, Ltd on behalf of Institute of Botany, Chinese Academy of Sciences.)

Inflammatory bowel disease (IBD) is characterized by an inflammatory response closely related to the immune system, but the relationship between inflammation and IBD remains unclear. We performed a comprehensive 2-sample Mendelian randomization (MR) analysis to determine the causal relationship between immune cell characteristics and IBD. Using publicly available genetic data, we explored the relationship between 731 immune cell characteristics and IBD risk. Inverse-variance weighting was the primary analytical method. To test the robustness of the results, we used the weighted median-based, MR-Egger, simple mode, and mode-based methods. Finally, we performed a reverse MR analysis to assess the possibility of reverse causality. We identified suggestive associations between 2 immune cell traits and IBD risk (P = 4.18 × 10-5 for human leukocyte antigen-DR on CD14+ monocytes, OR: 0.902; 95% CI: 0.859-0.947; for CD39+ CD4+ T cells, P = 6.24 × 10-5; OR: 1.042; 95% CI: 1.021-1.063). Sensitivity analysis results of these immune cell traits were consistent. In reverse MR analysis, we found no statistically significant association between IBD and these 2 cell traits. Our study demonstrates the close connection between immune cells and IBD using MR, providing guidance for future clinical and basic research., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Water content was an essential indicator in organic solvents, and it was necessary to develop a facile, cheap and readily available tool for the real-time, specifical and sensitive detection of water content. In this work, two novel D-π-A type near-infrared fluorescence sensors (DCM-1 and DCM-2) were designed and synthesized for the detection of trace water in organic solvents. DCM-1 and DCM-2 with solvent-dependent effects and large Stokes shift (>120 nm) showed good linear "intensity-to-content" relationships in four commonly-used organic solvents, and accomplished the ultra-fast and high-accuracy detection of the trace water in organic solvents. More importantly, a portable, fast, and accurate smartphone-assisted visual assay was designed for visual quantitative detection of the water content in organic solvents with a detection limit as low as 1.028 % v/v (e.g. in ethanol) and a wide detection range (0-60 % v/v). The smartphone-based visual assay was further applied to estimate the water content in disinfection alcohol and commercial liquor, which furnished a new strategy and broad prospects to achieve the accurate onsite detection of water content., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To evaluate the effect of age on the association between maternal body mass index (BMI) and cumulative live birth rates (CLBRs) following in vitro fertilization treatment., Method: We retrospectively analyzed the data of 26 567 women undergoing in vitro fertilization/intracytoplasmic sperm injection from 2016 to 2019. We conducted multivariate regression analysis of the association between CLBRs and maternal BMI and age category., Results: A total of 16 626 (62.58%) patients achieved a live birth. Women with obesity had significantly decreased CLBRs compared with women who had normal weight (odds ratio [OR] 0.73 [95% confidence interval (CI), 0.66-0.80]). The significant interaction between age and BMI suggested that the impact of BMI on CLBRs was moderated by women's age (P interaction <0.001). The association between obesity and CLBRs was inverse among women aged <30 years (OR, 0.63 [95% CI, 0.54-0.73]), 30 to 34 years (OR, 0.79 [95% CI, 0.67-0.93]), and 35 to 37 years (OR, 0.71 [95% CI, 0.52-0.98]); however, decreases in CLBRs with obesity were not observed in women aged 38 to 40 years (OR, 1.17 [95% CI, 0.70-1.94]) and ≥ 41 years (OR, 1.25 [95% CI, 0.53-2.96])., Conclusion: Maternal obesity was significantly associated with a lower likelihood of having a live birth, but the risk differed according to women's age. A higher BMI might have a less-pronounced detrimental effect with increasing age., (© 2023 International Federation of Gynecology and Obstetrics.)

Facile synthesis of Ultralong room-temperature phosphorescence (URTP) with super stability and long-afterglow are of great significance, but hard to achieve. Herein, a brilliant gram-scale and solvent-free pyrolysis treatment strategy has been developed to prepare high-performance URTP carbon dots (CDs) by regulating different temperature (250-500 °C). The optimized CDs (CD-400) showed room-temperature phosphorescence 1.99 s and lasting over 22 s to naked eyes, which is superior to most of the reported URTP CDs. Owing to the stabilization effects of the modified B 2 O 3 layer on the surface, the homogenous distribution of CD-400 with the narrow diameter of 1.44 nm was constructed, displaying a superb stability through hydrogen-bond network. In addition, the doping atoms (N, O) greatly enhanced the n-π* transitions and stabilized triplet excitons radiative transitions, facilitating the effective intersystem crossing (ISC) and the RTP emissions. More importantly, the B 2 O 3 -modified CDs were successfully applied in the multi-level information encryption (time-resolved RTP performance) and fingerprint identification (bifurcation, whorl and termination details)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tin (Sn) element plays a vital role in the human body, and its detection is a mandatory inspection item for canned food. The application of covalent organic frameworks (COFs) in fluorescence detection has received extensive attentions. In this work, we designed a kind of novel COFs (COF-ETTA-DMTA) with high specific surface area (353.13 m 2 /g) by solvothermal synthesis using 2,5-dimethoxy-1,4-dialdehyde and tetra (4-aminophenyl) ethylene as precursors. It shows fast response time (about 50 s), low detection limit (228 nM) and good linearity (R 2  = 0.9968) for the detection of Sn 2+ . Via coordination behavior, the recognition mechanism of COFs toward Sn 2+ was simulated and verified by the small molecule with the same functional unit. More importantly, this COFs was successfully applied to identify Sn 2+ in solid canned food (luncheon pork, canned fish, canned red kidney beans) with satisfactory results. This work provides a new approach for determining metal ions with COFs taking the advantage of their natural rich reaction set and specific surface area, improving the detection sensitivity and capacity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study assessed the psychometric properties of the culturally inclusive instructional design (CIID) scale with 31 items on a 7-point Likert scale. The data were collected from the training (N = 55) and validating samples (N = 80) of K-20 educators. Data analysis employed exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). EFA results revealed a clear five-factor structure, and the CFA results indicated good factor loadings. The reliability indices were .95 and .94 for the training and validation samples, respectively. The significant correlations among the factors indicated the five subscales measuring on the same CIID construct. In contrast, a non-perfect correlation presented a discriminating power for each subscale measuring the unique dimension of the construct. The study results established the validity and reliability of the instrument to measure culturally inclusive instructional design with implications for the design and development of online learning for cultural inclusivity., (© Association for Educational Communications and Technology 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: To compare the difference in the live birth rates (LBRs) between vaginal progesterone and intramuscular progesterone as luteal-phase support in programmed vitrified-warmed blastocyst transfer cycles and determine whether the association was moderated by overweight/obesity., Design: Retrospective cohort study., Setting: Tertiary reproductive medicine center., Patient(s): Patients who underwent transfer of single vitrified-warmed blastocyst in a programmed cycle between January 2018 and June 2021., Intervention(s): Vaginal or intramuscular progesterone as luteal-phase support. Analysis was performed using the generalized estimating equation framework and multivariate regression models. Interaction testing was used to determine whether overweight/obesity (body mass index of ≥25 kg/m 2 ) moderated the association between progesterone replacement and LBRs., Main Outcome Measure(s): The primary outcome was live birth. The secondary outcomes were biochemical pregnancy, clinical pregnancy, miscarriage, and total pregnancy loss., Result(s): A total of 6,905 programmed cycles (4,616 with vaginal progesterone and 2,289 with intramuscular progesterone) were included in the analysis. In the general cohort who underwent cryopreserved blastocyst transfer, the LBRs were 46.23% and 48.62% in the vaginal and intramuscular progesterone groups, respectively (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.82-1.01; adjusted OR [aOR], 0.89; 95% CI, 0.81-0.98), with a significantly increased rate of pregnancy losses in the vaginal progesterone group compared with that in the intramuscular progesterone group (22.22% vs. 18.90%; OR, 1.23; 95% CI, 1.08-1.39; aOR, 1.23; 95% CI, 1.08-1.40). Among normal-weight women, the LBR in the vaginal progesterone group was lower than that in the intramuscular progesterone group (aOR, 0.84; 95% CI, 0.75-0.95). On the other hand, among women with overweight/obesity, the LBRs were similar between the 2 groups of progesterone replacement (aOR, 1.06; 95% CI, 0.86-1.33). Interaction testing of the routes of progesterone administration and overweight/obesity was significant., Conclusion(s): Luteal-phase support with vaginal progesterone was associated with reduced LBRs compared with intramuscular progesterone for vitrified-warmed blastocyst transfer, and the association was modified by maternal overweight/obesity. Further research is needed to better understand the mechanisms behind the association., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Glaucoma is the leading cause of irreversible blindness, and its treatment is attracting widespread attention. Drug-loaded lacrimal suppositories can effectively treat xerophthalmia, but there is little research on the treatment of glaucoma with drug-loaded lacrimal suppositories. This article explored and expanded the non-pharmacological model of lacrimal suppository therapy for glaucoma by using a combination of lacrimal suppository and medication. The drug-loaded lacrimal suppository was rationally designed through the conjugation of gelatin with polyamide (PAM) via the formation of amide linkages, followed by Schiff base reaction grafting with latanoprost. In vitro drug release studies showed that latanoprost released from drug-loaded lacrimal embolus had sustained-release properties with a release time of 33 days and a drug release volume of 82.6%. The biological evaluation of drug-loaded lacrimal thrombus was carried out by IOP test, retinal potential test, and retinal H&E staining. The results showed that the IOP decreased to 27.125 ± 1.1254 mmHg, and the a and b waves of retinal potential increased to 4.39 ± 0.16 μV and 67.9 ± 2.17 μV, respectively. It indicated that latanoprost lacrimal suppository has a good therapeutic effect on glaucoma.

Objective: To identify whether the transfer of blastocysts that have been vitrified, thawed, biopsied, revitrified, and subsequently rethawed affects clinical outcome and neonatal outcome., Methods: A retrospective study was conducted in a single assisted reproduction technology center from September 2016 to March 2021. Women undergoing single frozen euploid blastocysts transfer were stratified into two groups based on number of vitrification-thawing cycles: single vitrification coupled with single biopsy (group A, n = 177) and double vitrification coupled with single biopsy (group B, n = 30). Pregnancy and perinatal outcomes of the two groups were compared., Results: Clinical pregnancy rates were similar between the two groups. Group B was associated with an increased likelihood of live birth when compared with group A by different multivariable analysis models (model 1: odds ratio, 0.42 [95% confidence interval, 0.18-0.97], P = 0.041; model 2: odds ratio, 0.38 [95% confidence interval, 0.16-0.92], P = 0.033). No major obstetrical complication was reported in the two groups and only one malformation live birth was reported in group A., Conclusion: The procedure of double vitrification-warming cycles, coupled with single biopsy, increases pregnancy loss and ultimately diminishes live birth but does not affect perinatal outcome. Future studies with a larger sample size would help to validate the results., (© 2022 International Federation of Gynecology and Obstetrics.)

Background: Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by αPDL1 immune checkpoint blockade antibodies., Methods: We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus αPDL1., Results: PDL1-expressing mouse and human ovarian cancer lines and mouse melanoma were more sensitive to chlorambucil-mediated proliferation inhibition in vitro versus corresponding genetically PDL1-depleted lines. Orthotopic peritoneal PDL1-expressing ID8agg ovarian cancer and subcutaneous B16 melanoma tumors were more chlorambucil-sensitive in vivo versus corresponding genetically PDL1-depleted tumors. Chlorambucil enhanced αPDL1 efficacy in tumors otherwise αPDL1-refractory, and improved antitumor immunity and treatment efficacy in a natural killer cell-dependent manner alone and plus αPDL1. Chlorambucil-mediated PDL1 depletion was relatively tumor-cell selective in vivo, and treatment efficacy was preserved in PDL1KO hosts, demonstrating tumor PDL1-specific treatment effects. Chlorambucil induced PDL1-dependent immunogenic tumor cell death which could help explain immune contributions. Chlorambucil-mediated PDL1 reduction mechanisms were tumor cell-type-specific and involved transcriptional or post-translational mechanisms, including promoting PDL1 ubiquitination through the GSK3β/β-TRCP pathway. Chlorambucil-mediated tumor cell PDL1 depletion also phenocopied genetic PDL1 depletion in reducing tumor cell mTORC1 activation and tumor initiating cell content, and in augmenting autophagy, suggesting additional treatment potential., Conclusions: Pharmacological tumor PDL1 depletion with chlorambucil targets tumor-intrinsic PDL1 signaling that mediates treatment resistance, especially in αPDL1-resistant tumors, generates PDL1-dependent tumor immunogenicity and inhibits tumor growth in immune-dependent and independent manners. It could improve treatment efficacy of selected agents in otherwise treatment-refractory, including αPDL1-refractory cancers, and is rapidly clinically translatable., Competing Interests: Competing interests: TC and ARK have filed a patent on PDL1 depletion drugs., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Late follicular phase progesterone elevation (LFPE) during ovarian stimulation is associated with reduced live birth rates (LBRs) after cleavage-stage embryo transfer. However, due to better synchronization with a stimulated endometrium, prior studies shown that LFPE had no effect on transferring embryos at blastocyst stage. The study aim to exam whether the developmental stage of embryos and serum progesterone levels on the day of human chorionic gonadotropin (hCG) administration jointly affect the odds of live birth in fresh fresh IVF/intracytoplasmic sperm injection (ICSI) cycles.  METHODS: The single-center retrospective cohort study included a total of 4,471 fresh embryo transfer cycles with 2,342 at cleavage stage versus 2,129 at blastocyst stage. Patients underwent IVF/ICSI with ovarian stimulation in gonadotropin-releasing hormone antagonist protocol. The serum progesterone level was examined both as a continuous variable and as a categorical variable by quartiles. Analysis was performed using the generalized estimating equations framework and multivariate regression models., Results: LBRs were inversely associated with progesterone as a continuous variable on the day of hCG in both the cleavage-stage (crude OR 0.87, 95%CI 0.73-1.03; adjusted OR 0.80, 95% CI 0.65-0.98) and the blastocyst-stage (crude OR 0.66, 95%CI 0.56-0,78; adjusted OR 0.61, 95%CI 0.50-0.73) groups. The interaction testing was highly significant (P = 0.018) indicating an effect modifying role of stage of embryos transferred on the association of pregesterone values with the LBRs in fresh cycles. A similar pattern for a greater reduction in ORs for live birth in cycles with blastocysts transfer was also observed when progesterone was analyzed by interquartile ranges. The findings remained unchanged in subgroup analysis stratified by types of ovarian response., Conclusions: In fresh cycles, detrimental effect of late follicular phase progesterone elevation on live birth was more prominent in blastocyst-stage group compared with that in clevaged-stage group., (© 2023. The Author(s).)

FYVE domain protein required for endosomal sorting 1 (FREE1), originally identified as a plant-specific component of the endosomal sorting complex required for transport (ESCRT) machinery, plays diverse roles either in endosomal sorting in the cytoplasm or in transcriptional regulation of abscisic acid signaling in the nucleus. However, to date, a role for FREE1 or other ESCRT components in the regulation of plant miRNA biology has not been discovered. Here, we demonstrate a nuclear function of FREE1 as a cofactor in miRNA biogenesis in plants. FREE1 directly interacts with the plant core microprocessor component CPL1 in nuclear bodies and disturbs the association between HYL1, SE and CPL1. Inactivation of FREE1 in the nucleus increases the binding affinity between HYL1, SE, and CPL1 and causes a transition of HYL1 from the inactive hyperphosphorylated version to the active hypophosphorylated form, thereby promoting miRNA biogenesis. Our results suggest that FREE1 has evolved as a negative regulator of miRNA biogenesis and provides evidence for a link between FYVE domain-containing proteins and miRNA biogenesis in plants., (© 2022 The Authors.)

Background: Ezetimibe is a widely used medication to reduce the plasma cholesterol level, particularly low-density lipoprotein level. However, its impact on cancer remains controversial. Here, its impacts on risks of various types of cancers were meta-analyzed., Methods: PubMed and Cochrane Library electronic databases were searched and randomized controlled trials with followed up for at least 24 weeks were selected and included. The experimental group was defined as those patients treated with ezetimibe alone or with other medications, and the control group was defined as those who received a placebo or the matched medication. The number of new cancer cases or cancer-related deaths was extracted. Statistical analysis was performed using Review Manager (version 5.3)., Results: Nine trials enrolling 35 222 patients were included in the analyses. Compared with the control group, ezetimibe increased the number of new intestine cancer patients [relative risk (RR), 1.30; 95% confidence interval (CI), 1.02-1.67; P  = 0.03] and had a trend to increase the number of new breast cancer patients (RR, 1.39; 95% CI, 0.98-1.98; P  = 0.07). There was no significant difference in new hepatobiliary cancer, prostate cancer, skin cancer or cancer of other sites. Ezetimibe did not significantly increase the risk of new cancer in total (RR, 1.03; 95% CI, 0.96-1.11; P  = 0.38), cancer-related death (RR, 1.11; 95% CI, 0.98-1.26; P  = 0.10) or cancer events (RR, 1.04; 95% CI, 0.97-1.12; P  = 0.30). In terms of lipid-lowering effect, ezetimibe significantly reduced total cholesterol and low-density lipoprotein cholesterol, increased high-density lipoprotein cholesterol., Conclusion: Ezetimibe may increase the risk of intestine cancer and has a trend of increasing the risk of breast cancer. There is no evidence to support that it increases or decreases the risk of other types., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Early Childhood Education (ECE) programs provide skills needed for successful kindergarten strides, especially for students from low socioeconomic backgrounds. While Florida's Voluntary Pre-Kindergarten (VPK) program currently serves most four-year-olds, some educators have questioned the program's quality. The purpose of this study was to investigate the direct and indirect effects of Florida's VPK program on kindergarten readiness and academic achievement for students attending the program in one county's VPK (CVPK) when compared to students who did not attend approved VPK programs in this county. The results suggest that, regardless of socioeconomic status, children who attended CVPK programs were just as prepared and performed equally as well in kindergarten as those who did not attend this program. Unfortunately, we cannot know how the CVPK program compared to specific pre-K alternatives without being able to distinguish program attendance across provider types (i.e., other ECE or no pre-K), which is something we recommend Florida begin tracking and make accessible., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: 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., Methods: 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., Results: 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)., Conclusion: 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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Autophagy is a highly conserved, self-digestion process that is essential for plant adaptations to various environmental stresses. Although the core components of autophagy in plants have been well established, the molecular basis for its transcriptional regulation remains to be fully characterized. In this study, we demonstrate that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1), a MADS-box family transcription factor that determines flowering transition in Arabidopsis, functions as a transcriptional repressor of autophagy. EMSAs, ChIP-qPCR assays, and dual-luciferase receptor assays showed that SOC1 can bind to the promoters of ATG4b, ATG7, and ATG18c via the conserved CArG box. qRT-PCR analysis showed that the three ATG genes ATG4b, ATG7, and ATG18c were up-regulated in the soc1-2 mutant. In line with this, the mutant also displayed enhanced autophagy activity, as revealed by increased autophagosome formation and elevated autophagic flux compared with the wild type. More importantly, SOC1 negatively affected the tolerance of plants to long-term carbon starvation, and this process requires a functional autophagy pathway. Finally, we found that SOC1 was repressed upon carbon starvation at both the transcriptional and protein levels. Overall, our study not only uncovers an important transcriptional mechanism that contributes to the regulation of plant autophagy in response to nutrient starvation, but also highlights novel cellular functions of the flowering integrator SOC1., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: A 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., Methods: A 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., Results: Women 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., Conclusions: In 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Gao, Shi, Shi and Bai.)

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., Competing Interests: Competing interests: BWM is supported by a NHMRC Investigatorgrant (GNT1176437). BWM reports consultancy for ObsEva. BMW has received research funding from Ferring and Merck. The other authors have none to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Research Question: How to prevent the transfer of a mutation causing osteogenesis imperfecta (OI) to offspring in a couple with recurrent adverse pregnancy outcomes, when the male partner is a gonosomal mosaic carrier. Design: High-throughput sequencing and first-generation DNA sequencing were performed using the tissues from an aborted fetus and its parents. Regions 2 Mb upstream and downstream of the COL1A1 gene were subjected to multiplex PCR to identify single nucleotide polymorphisms (SNPs) and family haplotypes associated with the disease-causing mutation. Single-cell whole-genome amplification and sequencing were performed on trophoblasts cultured in vitro for 5-6 days to construct embryonic SNP haplotypes, and first-generation sequencing was used for pathogenic locus verification and aneuploidy screening. Preimplantation genetic testing for monogenic disorders (PGT-M) was also performed. Results: The aborted fetus was heterozygous for the COL1A1 mutation c.1454G>A (chr17-48272089, p.Gly485Asp) suspected to cause OI. The variant was also detected in the peripheral blood cells and sperm of the male partner, who appeared to be a gonosomal mosaic carrier of the mutation. Three morphologically usable blastocysts were obtained in vitro and successfully expanded after a trophectoderm biopsy. Two blastocysts were unusable owing to aneuploidy; however, one was euploid and did not carry the paternal mutation. Post-transfer gestation was confirmed by systematic B-scan ultrasound, and amniocentesis findings were consistent with the PGT-M results. Conclusion: Parental gonadal mosaicism was the cause of recurrent terminated pregnancies due to fetal skeletal dysplasia. Using PGT-M to select embryos without the paternal pathogenic mutation prevented the vertical transmission of OI in this family, and a successful pregnancy was achieved., Competing Interests: Author RW was employed by Yikon Genomics Company, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bai, Li, Liu, Shi, He, Wei and Shi.)

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., (©2022 American Association for Cancer Research.)

The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can contribute to the resistance to targeted small molecules, cytotoxic chemotherapy, and αPD1 immunotherapy. As genetic PDL1 depletion is not currently clinically tractable, we screened FDA-approved drugs to identify those that significantly deplete tumor PDL1. Among the candidates, we identified the β-lactam cephalosporin antibiotic cefepime as a tumor PDL1-depleting drug (PDD) that increases tumor DNA damage and sensitivity to DNA-damaging agents in vitro in distinct aggressive mouse and human cancer lines, including glioblastoma multiforme, ovarian cancer, bladder cancer, and melanoma. Cefepime reduced tumor PDL1 post-translationally through ubiquitination, improved DNA-damaging-agent treatment efficacy in vivo in immune-deficient and -proficient mice, activated immunogenic tumor STING signals, and phenocopied specific genetic PDL1 depletion effects. The β-lactam ring and its antibiotic properties did not appear contributory to PDL1 depletion or to these treatment effects, and the related cephalosporin ceftazidime produced similar effects. Our findings highlight the rapidly translated potential for PDDs to inhibit tumor-intrinsic PDL1 signals and improve DNA-damaging agents and immunotherapy efficacy.

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors., Methods: Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon- γ KO mice and WT challenged with B16F10 melanoma and treated with α PD-1 or α PD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell-cell interactions., Results: α PD-1 ICI treated melanoma in young and aged hosts, whereas α PD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon- γ influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, α PD-1 versus α PD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes., Conclusion: Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain α PD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of α PD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon- γ also affect age-related IC expression and T cell function, meriting additional studies., Competing Interests: CONFLICT OF INTEREST The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Objective: To assess the efficacy of the Zishen Yutai Pill compared with placebo on live birth rates among women after fresh embryo transfer cycles., Methods: We conducted a double-blind, multicenter, placebo-controlled, randomized trial to investigate whether administration of the Zishen Yutai Pill would improve pregnancy outcomes among women undergoing fresh embryo transfer after in vitro fertilization or intracytoplasmic sperm injection. The primary outcome was live birth rate. Secondary outcomes were rates of implantation, biochemical pregnancy, clinical pregnancy, pregnancy loss, cycle cancellation, and maternal, fetal, and neonatal complications. A total sample size of 2,265 women (1:1 in two groups) was used to detect a live birth rate difference between the Zishen Yutai Pill and placebo. Participants were enrolled and randomized to receive 5 g of the Zishen Yutai Pill or placebo orally, three times per day during the study., Results: Recruitment was completed between April 2014 and June 2017, with 2,580 patients screened. Two thousand two hundred sixty-five patients were randomized: 1,131 to the Zishen Yutai Pill and 1,134 to placebo. Characteristics were similar between groups. In intention-to-treat analysis, the rates of live birth in the Zishen Yutai Pill (ZYP) group and placebo group were 26.8% and 23.0% (rate ratio [RR], 1.16; 95% CI 1.01-1.34; P=.038), respectively. The implantation rates were 36.8% and 32.6% in the ZYP and placebo groups, respectively (RR 1.13; 95% CI 1.01-1.25; P=.027). The biochemical pregnancy rate for the ZYP group was 35.5% compared with 31.1% in the placebo group (RR 1.14; 95% CI 1.02-1.28; P=.026). The rates of clinical pregnancy in the ZYP and placebo groups were 31.2% compared with 27.3%, respectively (RR 1.14; 95% CI 1.00-1.30; P=.043). There were no significant between-group differences in the rates of pregnancy loss, maternal, or neonatal complications (all P>.05)., Conclusion: The Zishen Yutai Pill increased the rate of live birth after fresh embryo transfer compared with placebo., Clinical Trial Registration: Chictr.org.cn, Chictr-TRC-14004494., Competing Interests: Financial Disclosure Dongzi Yang disclosed that the Zishen Yutai Pill is not approved by the U.S. Food and Drug Administration, but in China, the Zishen Yutai Pill is widely used in assisted reproductive technologies. The production process of Zishen Yutai Pill complies with the relevant requirements of law of China's Drug Administration and GMP, with approval from the China National Medical Products Administration (Permit No.Z44020008). The other authors did not report any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2021. The Author(s).)

Glutathione and 2-aminopyridine are used as carbon sources to prepare carbon dots (CDs) by a one-step hydrothermal reaction. The results show that the average particle diameter of CDs is 8.64 nm with uniform size distribution and the fluorescence quantum yield is 13.62%. We further demonstrate that novel CDs possess highly selective sensing of Fe 3+ from 0.2 to 200 μM with a low detection limit (0.194 μM). Meanwhile, the fluorescence of CDs can be repeated many times by the addition of S 2- . Moreover, the CDs are used for biological imaging of living cells with well cell penetrability and low toxicity. Furthermore, it is successfully applied for anti-counterfeiting and information encryption. More interestingly, it can be doped with hydrogel and filter paper to prepare solid-phase sensors exhibiting high sensitivity and fast response, demonstrating their tremendous potential for the simple, rapid, and low-cost monitoring of Fe 3+ and S 2- ., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fluorescent carbon dots (CDs) have attracted considerable interest due to their superior optical properties and facile preparation. In this work, O-phenylenediamine and melamine were used as precursors for the one-step hydrothermal synthesis of novel orange emissive CDs (O-CDs) in an aqueous solution. The fluorescence intensity (580 nm) of the O-CDs exhibited a good linear relationship with Ag + in the range of 0.0-50.0 μ M with the detection limit of 0.289 μ M. Moreover, the O-CDs were successfully used to determine Ag + in biological samples (Hela cells) because of their low cytotoxicity, and good biocompatibility. Besides, the O-CDs-doped solid-phase detection materials (test paper and hydrogel) were employed to monitor Ag + qualitatively and quantitatively, indicated that the O-CDs had a great capacity for the detection of Ag + in biological and environmental areas. Based on their extraordinary fluorescence property, the O-CDs could also be used as security ink. Overall, based on their excellent fluorescent performance, the CDs in this study have significant potential for practical application toward solid-phase sensing and security ink., (© 2021 IOP Publishing Ltd.)

Hydrogen sulfide (H 2 S) played crucial roles in biological processes and daily life, and the abnormal level of H 2 S was associated with many physiological processes. In this paper, we designed and developed a dicyanomethylene-4H-chromene (DCM)-based near-infrared (NIR) fluorescent probe DCM-NO guided by theoretical calculation. The probe displayed excellent selectivity towards H 2 S with a fast response time (3 min) and low detection limit (fluorescence 25.3 nM/absorption 6.61 nM) in Hela cells and real water samples. Furthermore, the probe-doped solid sensing materials (test strips and nanofibrous films) exhibited specific visualization of H 2 S under ambient light or hand-held UV lamp, providing great potential for on-site and real-time application in environmental and biological systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hemophilia A is an X-linked recessive bleeding disorder caused by various types of pathological defects in the factor VIII gene ( F8/ FVIII). Preimplantation genetic testing for monogenic disease (PGT-M) is a powerful tool to tackle the transmission of monogenic inherited disorders from generation to generation. In our case, a mutation in F8 had passed through female carriers in a hemophilia A family and resulted in two male patients with hemophilia A. To identify the etiological genetic variants of F8 , next-generation sequencing (NGS) was used for chromosome copy number variation detection, Sanger sequencing to verify mutation sites, single nucleotide polymorphism (SNP) for site amplification, and sequencing to validate the genetic linkage. Finally, a novel missense mutation, p. (Phe690Leu)/c.2070C > A, occurring in exon 13 of F8 , was screened out as a pathogenic mutation. Following this, an F8 normal euploid blastocyst was transferred. At the 18th week, the pregnant mother underwent amniocentesis, NGS, Sanger sequencing, and SNP typing that further confirmed that the fetus had a healthy genotype. After delivery, a neonatal blood sample was sent for FVIII concentration detection, and the result established that the FVIII protein was rescued to a nearly average level. We first identified a new type of pathogenic mutation in F8 , which has not been previously reported, selected a genetically healthy progeny for an affected family, and provided valuable knowledge of the diagnosis and treatment of hemophilia A., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bai, Xue, Tian, Liu and Li.)

Objectives: 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)., Methods: 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)., Results: There were no significant differences in the basal characteristics between two groups ( p  > .05). We observed that 3PN = 0% and 3PN > 0% groups had similar good quality embryo (47.02 versus 46.80%; p  = .917) and available embryo (83.28 versus 81.37%; p  = .247) rates. Our results showed that the IR (47.26 versus 51.05%; p  = .357), CPR (61.17 versus 66.08%; p  = .338) and LBR (52.80 versus 50.43%; p  = .656) were comparable between 3PN = 0% and 3PN > 0% groups. The 3PN = 0% group showed significantly lower AR than that in the 3PN > 0% group (11.20 versus 21.05%; p  = .029; OR 2.114; 95% CI 1.069-4.178)., Conclusions: 3PN incidence made negative effects on the clinical outcomes after early rescue-ICSI.

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 ( N  = 440). Analyses of the bifurcated sample supported a three-factor model measuring insecurity with God, estrangement from the spiritual community, and disruption in religious practices. Further analyses supported the convergent and incremental validity of a 28-item scale relative to other theoretically similar instruments and measures of poor bereavement outcome, indicating the instrument's research and clinical usefulness.

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 strategies for coping with grief following the death of a loved one. Exploratory and confirmatory factor analysis with an international sample of bereaved adults ( N  = 844) yielded a six-factor, 28-item structure. Use of this validated, clinically useful, self-report tool can inform clinicians and researchers in evaluating bereavement coping, and in developing interventions designed to increase the number and broaden the types of coping strategies used to facilitate healing following loss.

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., (Copyright © 2020 Chen, Wang, Zhou, Bai, Wang, Shi and Shi.)

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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.

Purpose: To compare the clinical outcome of fresh embryo transfer with frozen-thawed embryo transfer in subsequent cycle of GnRH antagonist protocol., Methods: 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., Results: Clinical pregnancy rate was significantly higher in frozen-thawed embryo transfer than in fresh embryo transfer (63.70% vs. 54.50%, p < 0.001). Miscarriage rate and ectopic pregnancy rate were comparable between two groups. Variables independently associated with clinical pregnancy rate were fresh/frozen embryo transfer, patients' age and the number of embryos transferred. After adjusting for variables, the frozen embryo transfer [adjusted odds ratio (aOR) 0.75; 95% CI, 0.59-0.95, p = 0.016] was a predictive factor of clinical pregnancy rate., Conclusion: Frozen embryo transfer is better than fresh embryo transfer in GnRH antagonist cycle in women with 3-10 oocytes retrieved.

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.

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 were enrolled in this matched case-control study: 781 women were treated with GH (study group), whereas 781 matched patients were treated without GH (control group). GH was administered by a daily subcutaneous injection of 2 or 4 IU started from either D2 of the previous cycle (6 weeks GH pretreatment) or the initial day of controlled ovarian stimulation (2 weeks GH pretreatment) until hCG trigger. The study group was further divided into four subgroups: 2 IU-6 weeks GH pretreatment, 4 IU-6 weeks GH pretreatment, 2 IU-2 weeks GH pretreatment, and 2 IU-4 weeks GH pretreatment. Patients receiving GH showed significantly lower Gn dosage. The total number of oocytes retrieved, embryos formed, endometrial thickness on hCG day were significantly higher with GH. 2PN rate and high-quality embryo rate were lower in the GH group. However, GH increased clinical pregnancy rate with significant difference. 4 IU-6 weeks GH pretreatment showed lowest duration of Gn and highest clinical pregnancy rate compared with other three groups. Number of transferred embryos was confounding factor both in univariate and multivariate analysis. Our study showed that co-treatment with GH in patients with normal ovarian response could increase pregnancy rate.

A new genus with a new species, Lasiopsychops impunctatus gen. et sp. nov., and a new species, Electropsychops oligophlebius sp. nov., of silky lacewings in Psychopsidae are described from mid-Cretaceous Burmese amber. Lasiopsychops gen. nov. has typical characters of the extant Psychopsidae, i.e., broad triangular forewing, broad costal space, presence of the vena triplica and the paired ectoprocts and gonocoxites 9 of female genitalia, implying its close affinity with the extant lineages of Psychopsidae. The new findings of the Cretaceous psychopsids enhance our knowledge on the diversity and evolution of Psychopsidae during the Mesozoic.

Background: Elective frozen-embryo transfer has been shown to result in a higher live-birth rate than fresh-embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen-embryo transfer increases live-birth rates among ovulatory women with infertility., Methods: In this multicenter, randomized trial, we randomly assigned 2157 women who were undergoing their first in vitro fertilization cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. Up to two cleavage-stage embryos were transferred in each participant. The primary outcome was a live birth after the first embryo transfer., Results: The live-birth rate did not differ significantly between the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.89 to 1.06; P=0.50). There were also no significant between-group differences in the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy. Frozen-embryo transfer resulted in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh-embryo transfer (0.6% vs. 2.0%; relative risk, 0.32; 95% CI, 0.14 to 0.74; P=0.005). The risks of obstetrical and neonatal complications and other adverse outcomes did not differ significantly between the two groups., Conclusions: The live-birth rate did not differ significantly between fresh-embryo transfer and frozen-embryo transfer among ovulatory women with infertility, but frozen-embryo transfer resulted in a lower risk of the ovarian hyperstimulation syndrome. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China; Chinese Clinical Trial Registry number, ChiCTR-IOR-14005406 .).

We provide the first report on the leaf-mining Tischeriidae genus Paratischeria Diškus & Stonis from Asia. We describe Paratischeria jingdongensis Xu & Dai, sp. nov., a new species discovered in Yunnan, China, feeding on Dalbergia assamica Benth., Fabaceae and redescribe P. hestias (Meyrick, 1915), comb. nov., a hitherto very little known species from India, which has been recently discovered in northern Vietnam, feeding on Helicteres viscida Blume, Malvaceae. We also report on the Fabaceae family as a novel host-plant family of Tischeriidae. The described and redescribed Paratischeria species are illustrated with photographs of the leaf-mines, adults, genitalia, and habitats. We also provide maps of new Paratischeria findings, and, along with a diagnostic scheme to the genus, present some data on global distribution of Paratischeria occurring in tropical and subtropical regions on both sides of the Equator. In addition, we designate a new Paratischeria neotropicana species group and provide two more new taxonomic combinations: Paratischeria heteroterae (Frey & Boll, 1878) comb. nov. and P. capnota (Meyrick, 1915) comb. nov.

The paper presents four Chinese species belonging to the genera Metriochroa Busck, Eumetriochroa Kumata, and Gibbovalva Kumata & Kuroko (Lepidoptera, Gracillariidae), including two new species: Metriochroa alboannulata Bai, sp. n. and Gibbovalva clavata Bai, sp. n. Eumetriochroa hiranoi Kumata, 1998, is newly recorded from China. Photographs of adults and figures of the genital structures are provided, along with keys to the Chinese species of Metriochroa, Eumetriochroa, and Gibbovalva.