Portable self-powered electrochemical aptasensing platform for ratiometric detection of mycotoxins based on multichannel photofuel cell.

Self-powered electrochemical sensors based on photofuel cells have attracted considerable research interest because their unique advantage of not requiring an external electric source, but their application in portable and multiplexed targets assay is limited by the inherent mechanism. In this work, a portable self-powered sensor constructed with multichannel photofuel cells was developed for the ratiometric detection of mycotoxins, namely ochratoxin A (OTA) and patulin (PAT). The spatially resolved CdS/Bi2S3-modified photoanodes and a shared Prussian Blue cathode were integrated on an etched indium-tin oxide slide to fabricate the multichannel photofuel cell. The aptamers of OTA and PAT were covalently bonded to individual photoanode regions to build sensitive interfaces, and the specific recognition of analytes impaired the output performance of constructed PFC. Accordingly, ratiometric sensing of OTA and PAT was achieved by utilizing the output performance of a control PFC as a reference signal. This approach effectively eliminates the impact of light intensity on the accuracy of the detection. Under the optimal conditions, the proposed sensing chip exhibited linear ranges of 2.0-1000 nM and 5.0-500 nM for OTA and PAT, respectively. The detection limits (3 S/N) were determined to be 0.25 nM for OTA and 0.27 nM for PAT. The developed ratiometric sensing method demonstrated good selectivity and stability in the simultaneous detection of OTA and PAT. It was successfully utilized for the analysis of OTA and PAT real samples. This work provides a new perspective for construction of portable and ratiometric self-powered sensing platform.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

Single-cell multi-omics profiling of human preimplantation embryos identifies cytoskeletal defects during embryonic arrest.

Human in vitro fertilized embryos exhibit low developmental capabilities, and the mechanisms that underlie embryonic arrest remain unclear. Here using a single-cell multi-omics sequencing approach, we simultaneously analysed alterations in the transcriptome, chromatin accessibility and the DNA methylome in human embryonic arrest due to unexplained reasons. Arrested embryos displayed transcriptome disorders, including a distorted microtubule cytoskeleton, increased genomic instability and impaired glycolysis, which were coordinated with multiple epigenetic reprogramming defects. We identified Aurora A kinase (AURKA) repression as a cause of embryonic arrest. Mechanistically, arrested embryos induced through AURKA inhibition resembled the reprogramming abnormalities of natural embryonic arrest in terms of the transcriptome, the DNA methylome, chromatin accessibility and H3K4me3 modifications. Mitosis-independent sequential activation of the zygotic genome in arrested embryos showed that YY1 contributed to human major zygotic genome activation. Collectively, our study decodes the reprogramming abnormalities and mechanisms of human embryonic arrest and the key regulators of zygotic genome activation.

Niobium Modification of CeO2 Tuning Electron Density of Nickel-Ceria Interfacial Sites for Enhanced CO2 Methanation.

CO2 methanation has attracted considerable attention as a promising strategy for recycling CO2 and generating valuable methane. This study presents a niobium-doped CeO2-supported Ni catalyst (Ni/NbCe), which demonstrates remarkable performance in terms of CO2 conversion and CH4 selectivity, even when operating at a low temperature of 250 °C. Structural analysis reveals the incorporation of Nb species into the CeO2 lattice, resulting in the formation of a Nb-Ce-O solid solution. Compared with the Ni/CeO2 catalyst, this solid solution demonstrates an improved spatial distribution. To comprehend the impact of the Nb-Ce-O solid solution on refining the electronic properties of the Ni-Ce interfacial sites, facilitating H2 activation, and accelerating the hydrogenation of CO2* into HCOO*, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis and density functional theory (DFT) calculations were conducted. These investigations shed light on the mechanism through which the activity of CO2 methanation is enhanced, which differs from the commonly observed CO* pathway triggered by oxygen vacancies (OV). Consequently, this study provides a comprehensive understanding of the intricate interplay between the electronic properties of the catalyst's active sites and the reaction pathway in CO2 methanation over Ni-based catalysts.

Effects of SARS-CoV-2 infection on embryological outcomes in assisted reproductive technology during the Omicron epidemic.

BACKGROUND: The influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on assisted reproductive technology (ART) has received increasing attention. It has been reported that the SARS-CoV-2 RiboNucleic Acid (RNA) cannot be detected in follicular fluid and granulosa cells. However, the detection rate of SARS-CoV-2 RNA in immature oocytes and blastocysts has still unknown. Moreover, the effect of SARS-CoV-2 infection on embryological outcomes in ART during the Omicron epidemic is limited. METHODS: A prospective study was performed to explore the detection rate of viral RNA in biological specimens from patients who tested positive for SARS-CoV-2 RNA and the effects of SARS-CoV-2 infection on embryological outcomes. A total of 211 patients underwent transvaginal oocyte retrieval at the Third Affiliated Hospital of Guangzhou Medical University between December 13, 2022 and December 30, 2022. Prior to transvaginal oocyte retrieval, 61 individuals tested positive for SARS-CoV-2 RNA within 24 h. Follicular fluid was preserved during oocyte retrieval. Granular cells were collected after degranulation (Intracytoplasmic sperm injection only). Immature oocytes were collected at the end of the ICSI. Unavailable blastocysts were collected on day 6 (D6). The TIANLONG SARS-CoV-2 RT-PCR-Kit was used to detect SARS-CoV-2 RNA in all samples. The COVID-19 and Non COVID-19 groups were contrasted in the following areas: fertilization rate, 2PN rate, Day 3 (D3) available embryos rate, D3 good-quality embryos rate, blastocyst formation rate, good-quality blastocyst formation rate. RESULTS: All samples were negative except for an immature oocytes sample that was positive for SARS-CoV-2 viral RNA with a detection rate of 6.67%. Whether in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), the rate of fertilization, 2PN, D3 available embryos, D3 good-quality embryos, blastocyst formation, good-quality blastocyst formation was not significantly negative different between the COVID-19 and the Non COVID-19 groups. Our findings were validated by an overview of the embryological outcome from the cycles before SARS- Cov-2 infection from the same patient. CONCLUSIONS: Except for immature oocytes, none of the follicular fluid, granulosa cells, or blastocysts samples contained viral RNA. In addition, SARS-CoV-2 infection had no detrimental effects on the embryological outcomes of ART.

Mendelian randomization study of thyroid function and anti-Müllerian hormone levels.

Objective: Although previous studies have reported an association between thyroid function and anti-Müllerian hormone (AMH) levels, which is considered a reliable marker of ovarian reserve, the causal relationship between them remains uncertain. This study aims to investigate whether thyrotropin (TSH), free thyroxine (fT4), hypo- and hyperthyroidism are causally linked to AMH levels. Methods: We obtained summary statistics from three sources: the ThyroidOmics Consortium (N = 54,288), HUNT + MGI + ThyroidOmics meta-analysis (N = 119,715), and the most recent AMH genome-wide association meta-analysis (N = 7,049). Two-sample MR analyses were conducted using instrumental variables representing TSH and fT4 levels within the normal range. Additionally, we conducted secondary analyses to explore the effects of hypo- and hyperthyroidism. Subgroup analyses for TSH were also performed. Results: MR analyses did not show any causality relationship between thyroid function and AMH levels, using normal range TSH, normal range fT4, subclinical hypothyroidism, subclinical hyperthyroidism and overt hypothyroidism as exposure, respectively. In addition, neither full range TSH nor TSH with individuals <50 years old was causally associated with AMH levels. MR sensitivity analyses guaranteed the robustness of all MR results, except for the association between fT4 and AMH in the no-DIO1+DIO2 group. Conclusion: Our findings suggest that there was no causal association between genetically predicted thyroid function and AMH levels in the European population.

Giant electrically tunable magnon transport anisotropy in a van der Waals antiferromagnetic insulator.

Anisotropy is a manifestation of lowered symmetry in material systems that have profound fundamental and technological implications. For van der Waals magnets, the two-dimensional (2D) nature greatly enhances the effect of in-plane anisotropy. However, electrical manipulation of such anisotropy as well as demonstration of possible applications remains elusive. In particular, in-situ electrical modulation of anisotropy in spin transport, vital for spintronics applications, has yet to be achieved. Here, we realized giant electrically tunable anisotropy in the transport of second harmonic thermal magnons (SHM) in van der Waals anti-ferromagnetic insulator CrPS4 with the application of modest gate current. Theoretical modeling found that 2D anisotropic spin Seebeck effect is the key to the electrical tunability. Making use of such large and tunable anisotropy, we demonstrated multi-bit read-only memories (ROMs) where information is inscribed by the anisotropy of magnon transport in CrPS4. Our result unveils the potential of anisotropic van der Waals magnons for information storage and processing.

miR-4433a-3p promotes granulosa cell apoptosis by targeting peroxisome proliferator-activated receptor alpha and inducing immune cell infiltration in polycystic ovarian syndrome.

BACKGROUND: Granulosa cell (GC) proliferation and apoptosis are critical events of the ovum energy supply, which lead to follicular growth retardation or atresia, and various ovulatory obstacles, eventually resulting in the development of ovarian disorders such as polycystic ovarian syndrome (PCOS). Apoptosis and dysregulated miRNA expression in GCs are manifestations of PCOS. miR-4433a-3p has been reported to be involved in apoptosis. However, there is no study reporting the roles of miR-4433a-3p in GC apoptosis and PCOS progression. METHODS: miR-4433a-3p and peroxisome proliferator-activated receptor alpha (PPAR-α) levels in GCs of PCOS patients or in tissues of a PCOS rat model were examined by quantitative polymerase chain reaction and immunohistochemistry. Bioinformatics analyses and luciferase assays were used to examine the association between miR-4433a-3p and PPAR-α, as well as PPAR-α and immune cell infiltration, in PCOS patients. RESULTS: miR-4433a-3p expression in GCs of PCOS patients was increased. miR-4433a-3p overexpression inhibited the growth of the human granulosa-like tumor cell line (KGN) and promoted apoptosis, while co-treatment with PPAR-α and miR-4433a-3p mimic rescued miR-4433a-3p-induced apoptosis. PPAR-α was a direct target of miR-4433a-3p and its expression was decreased in PCOS patients. PPAR-α expression was also positively correlated with the infiltration of activated CD4+ T cells, eosinophils, B cells, gamma delta T cells, macrophages, and mast cells, but negatively correlated with the infiltration of activated CD8+ T cells, CD56+ bright natural killer cells, immature dendritic cells, monocytes, plasmacytoid dendritic cells, neutrophils, and type 1 T helper cells in PCOS patients. CONCLUSION: The miR-4433a-3p/PPAR-α/immune cell infiltration axis may function as a novel cascade to alter GC apoptosis in PCOS.

Synchrotron X-ray powder diffraction under high pressures up to 33†MPa for mechanoresponsive materials.

Equipment for synchrotron X-ray diffraction at high pressures up to 33 MPa with an accuracy of ±0.1 MPa using a liquid as a pressure-transmitting medium has been developed. This equipment enables atomic-scale observation of the structural change of mechanoresponsive materials under applied pressures. The validity of the equipment is demonstrated by observation of the pressure dependence of the lattice parameters of copper. The observed bulk modulus of copper was found to be 139 (13) GPa which is a good agreement with the literature value. The developed equipment was subsequently applied to a repeatable mechanoluminescence material, Li0.12Na0.88NbO3:Pr3+. The bulk modulus and compressibility along the a and c axes were determined as 79 (9) GPa, 0.0048 (6) GPa-1 and 0.0030 (9) GPa-1, respectively, for the R3c phase. The advance of high-pressure X-ray diffraction will play an important role in understanding mechanoresponsive materials towards their atomic-scale design.

Pharmacological ascorbate potentiates combination nanomedicines and reduces cancer cell stemness to prevent post-surgery recurrence and systemic metastasis.

Conventional chemotherapy targets proliferative cancer cells to halt tumor progression or regress tumors. However, the plasticity of tumor cells enables their phenotypical changes to acquire chemo-resistance, leading to treatment failure or tumor recurrence after a successful treatment course. Here, we report the use of high-dose pharmacologic ascorbate to potentiate treatment efficacy of nanoscale coordination polymers (NCPs) delivering two clinical combinations of chemotherapeutics, carboplatin/docetaxel and oxaliplatin/SN38, and to target metabolic plasticity of tumor cells. Combination treatments of high-dose ascorbate and NCPs overcome multi-drug resistance by significantly reducing the abundance of cancer stem cells (CSCs) in solid tumors, as evidenced by reduced expression of tumor pluripotency factors. The clearance of CSCs inhibits post-surgery recurrence and systemic metastasis in multiple mouse models of cancer.

No advantage of single day 6 good-quality blastocyst transfer versus single day 5 poor-quality blastocyst transfer in frozen-thawed cycles stratified by age: a retrospective study.

BACKGROUND: Blastocyst developmental speed, morphological grading and patient age are associated with pregnancy outcomes of frozen-thawed cycles. This study aimed to compare the clinical and neonatal outcomes between poor-quality D5 blastocysts and good-quality D6 blastocysts stratified by patient age. METHODS: A total of 1,623 cycles were divided into two groups: group A (n = 723) received one D5 poor-quality blastocyst; group B (n = 900) received one D6 good-quality blastocyst. Pregnancy and neonatal outcomes were compared among the four groups stratified by 35 years of age. RESULTS: When patients were in the same age group, there was no significant difference in terms of age, body mass index, infertility duration, infertility type, fertilization method, proportion of endometrial preparation protocols, and endometrial thickness between D5 poor-quality and D6 high-quality blastocysts groups. Live birth rate of D5 poor-quality blastocysts was higher than that of D6 high-quality blastocysts for patients aged < 35 years (35.48% vs. 31.13%, p > 0.05), but there was no statistical difference. The same trend was showed for patients aged ≥ 35 years (29.09% vs. 21.28%, p > 0.05). Moreover, when patients were in the same age category, there was no significant difference in terms of gestational age, birth weight, birth height, and rates of preterm birth, low birth weight, and very low birth weight between groups A and B. CONCLUSIONS: The preferential selection of poor-quality D5 blastocysts for transfer compared to high-quality D6 blastocysts is recommended, especially for advanced age patients. Single good-quality D6 blastocyst transfer can be considered for the acceptable live birth rate.

Horseradish Peroxidase-Coupled Ag3 PO4 /BiVO4 Photoanode for Biophotoelectrocatalytic Degradation of Organic Contaminants.

Photoelectrocatalysis (PEC) is regarded as a promising and sustainable process for removal of organic contaminants from wastewater. Meanwhile, enzymatic catalysis also provides an effective way to carry out polluted environment remediation under mild conditions. In this study, a biophotoelectrocatalytic (BPEC) system is designed to remove 4-nitrophenol (4-NP) based on a combination of PEC and enzymatic catalysis. The developed BPEC system is constructed with a Ag3 PO4 /BiVO4 photoanode and a horseradish peroxidase (HRP)-loaded carbon cloth (CC) cathode. On the photoanode, the construction of a direct Z-scheme Ag3 PO4 /BiVO4 heterojunction enhanced the separation efficiency of photogenerated carriers, which promoted the PEC degradation of 4-NP under visible light irradiation. After HRP was immobilized on the cathode, the degradation efficiency of 4-NP reached 97.1 % after 60 min PEC treatment. The result could be ascribed to the HRP-catalyzed oxidation reaction via in situ-generated H2 O2 from the CC cathode during the PEC process. Moreover, the possible degradation pathways of 4-NP in such a BPEC system are also discussed.

A single-cell transcriptomic landscape of mouse testicular aging.

INTRODUCTION: Advanced paternal age of reproduction is an increasing trend, especially in developed countries and areas. This trend results in elevated risks of adverse reproductive outcomes such as reduced fertility rates, increased pregnancy loss, and poor childhood health. Yet, a systematic profiling of aging-associated molecular and cellular alterations in testicular tissue is still missing. OBJECTIVES: We aimed to dissect aging-associated molecular characteristics in testes of mice. METHODS: Single-cell transcriptomic sequencing and analysis were conducted in testes of young (2 months old) and old mice (24 months old). Immunofluorescences and immunochemistry were used to characterize aging-associated phenotypes and verify single cell sequence results. RESULTS: Here, we constructed the first single-cell transcriptomic atlases of testes of young and old mice. In-depth dissection of aging-dependent transcriptional alterations in specific cell types revealed multiple dysregulated biological processes such as increased 'senescence-associated secretory phenotype' and 'inflammation', which were major aging-associated characteristics. Further analysis of aging-related differentially expressed genes uncovered a disrupted balance of undifferentiated and differentiated spermatogonia stem cells in spermatogonia, indicative of a potential role of spermatogonia stem cells in aging-associated subfertility. Importantly, for the first time, our results identified an increased subtype of aging-specific macrophages, which may contribute to a hostile proinflammatory microenvironment during testicular aging. CONCLUSION: Taken together, our findings depict the distinct single-cell transcriptional features of the aged mouse testes and provide enormous resources for a comprehensive understanding of the cell-type-specific molecular mechanisms underlying mouse testicular aging, which may shed light on developing novel potential diagnostic biomarkers and therapeutic targets for age-associated male subfertility.

SRSF10 is essential for progenitor spermatogonia expansion by regulating alternative splicing.

Alternative splicing expands the transcriptome and proteome complexity and plays essential roles in tissue development and human diseases. However, how alternative splicing regulates spermatogenesis remains largely unknown. Here, using a germ cell-specific knockout mouse model, we demonstrated that the splicing factor Srsf10 is essential for spermatogenesis and male fertility. In the absence of SRSF10, spermatogonial stem cells can be formed, but the expansion of Promyelocytic Leukemia Zinc Finger (PLZF)-positive undifferentiated progenitors was impaired, followed by the failure of spermatogonia differentiation (marked by KIT expression) and meiosis initiation. This was further evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Notably, SRSF10 directly binds thousands of genes in isolated THY+ spermatogonia, and Srsf10 depletion disturbed the alternative splicing of genes that are preferentially associated with germ cell development, cell cycle, and chromosome segregation, including Nasp, Bclaf1, Rif1, Dazl, Kit, Ret, and Sycp1. These data suggest that SRSF10 is critical for the expansion of undifferentiated progenitors by regulating alternative splicing, expanding our understanding of the mechanism underlying spermatogenesis.

Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade.

Long-circulating nanomedicines efficiently deliver chemotherapies to tumors to reduce general toxicity. However, extended blood circulation of nanomedicines can increase drug exposure to leukocytes and lead to hematological toxicity. Here, we report a two-stage release strategy to enhance the drug deposition and antitumor efficacy of OxPt/SN38 core-shell nanoparticles with a hydrophilic oxaliplatin (OxPt) prodrug coordination polymer core and a lipid shell containing a hydrophobic cholesterol-conjugated SN38 prodrug (Chol-SN38). By conjugating cholesterol to the phenol group of SN38 via an acetal linkage and protecting the 20-hydroxy position with a trimethylsilyl (TMS) group, Chol-SN38 releases SN38 in two stages via esterase-catalyzed cleavage of the acetal linkage in the liver followed by acid-mediated hydrolysis of the TMS group to preferentially release SN38 in tumors. Compared to irinotecan, OxPt/SN38 reduces SN38 blood exposure by 9.0 times and increases SN38 tumor exposure by 4.7 times. As a result, OxPt/SN38 inhibits tumor growth on subcutaneous, spontaneous, and metastatic tumor models by causing apoptotic and immunogenic cell death. OxPt/SN38 exhibits strong synergy with the immune checkpoint blockade to regress subcutaneous colorectal and pancreatic tumors with 33-50% cure rates and greatly inhibits tumor growth and invasion in a spontaneous prostate cancer model and a liver metastasis model of colorectal cancer without causing side effects. Mechanistic studies revealed important roles of enhanced immunogenic cell death and upregulated PD-L1 expression by OxPt/SN38 in activating the tumor immune microenvironment to elicit potent antitumor immunity. This work highlights the potential of combining innovative prodrug design and nanomedicine formulation to address unmet needs in cancer therapy.

Inactivated Covid-19 vaccine did not undermine live birth and neonatal outcomes of women with frozen-thawed embryo transfer.

STUDY QUESTION: Does inoculation with inactivated vaccines against coronavirus disease 2019 (Covid-19) before frozen-thawed embryo transfer (FET) affect live birth and neonatal outcomes? SUMMARY ANSWER: Inactivated Covid-19 vaccines did not undermine live birth and neonatal outcomes of women planning for FET. WHAT IS KNOWN ALREADY: Accumulating reports are now available indicating the safe use of mRNA vaccines against Covid-19 in pregnant and lactating women, and a few reports indicate that they are not associated with adverse effects on ovarian stimulation or early pregnancy outcomes following IVF. Evidence about the safety of inactivated Covid-19 vaccines is very limited. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort analysis from Reproductive Medical Center of a tertiary teaching hospital. Clinical records and vaccination record of 2574 couples with embryos transferred between 1 March 2021 and 30 September 2021 were screened for eligibility of this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical and vaccination data of infertile couples planning for FET were screened for eligibility of the study. The reproductive and neonatal outcomes of FET women inoculated with inactivated Covid-19 vaccines or not were compared. The primary outcomes were live birth rate per embryo transfer cycle and newborns' birth height and weight. Secondary outcomes included rates of ongoing pregnancy, clinical pregnancy, biochemical pregnancy and spontaneous miscarriage. Multivariate logistical regression and propensity score matching (PSM) analyses were performed to minimize the influence of confounding factors. Subgroup analyses, including single dose versus double dose of the vaccines and the time intervals between the first vaccination and embryo transfer, were also performed. MAIN RESULTS AND THE ROLE OF CHANCE: Vaccinated women have comparable live birth rates (43.6% versus 45.0% before PSM, P = 0.590; and 42.9% versus 43.9% after PSM, P = 0.688), ongoing pregnancy rates (48.2% versus 48.1% before PSM, P = 0.980; and 52.2% versus 52.7% after PSM, P = 0.875) and clinical pregnancy rate (55.0% versus 54.8% before PSM, P = 0.928; and 54.7% versus 54.2% after PSM, P = 0.868) when compared with unvaccinated counterparts. The newborns' birth length (50.0 ± 1.6 versus 49.0 ± 2.9 cm before PSM, P = 0.116; and 49.9 ± 1.7 versus 49.3 ± 2.6 cm after PSM, P = 0.141) and birth weight (3111.2 ± 349.9 versus 3030.3 ± 588.5 g before PSM, P = 0.544; and 3053.8 ± 372.5 versus 3039.2 ± 496.8 g after PSM, P = 0.347) were all similar between the two groups. Neither single dose nor double dose of vaccines, as well as different intervals between vaccination and embryo transfer showed any significant impacts on reproductive and neonatal outcomes. LIMITATIONS, REASONS FOR CAUTION: The main findings might be limited by retrospective design. Besides, inoculations of triple dose of Covid-19 vaccines were not available by the time of data collection, thus the results cannot reflect the safe use of triple dose of inactivated Covid-19 vaccines. Finally, history of Covid-19 infection was based on patients' self-report rather than objective laboratory tests. WIDER IMPLICATIONS OF THE FINDINGS: Eligible individuals of inactivated vaccines against Covid-19 should not postpone vaccination plan because of their embryo transfer schedule, or vice versa. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Medical Key Discipline of Guangzhou (2021-2023). All authors had nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Comparative clinical outcome following individualized follitropin delta dosing in Chinese women undergoing ovarian stimulation for in vitro fertilization /intracytoplasmic sperm injection.

BACKGROUND: To compare the efficacy and safety of follitropin delta in its individualized fixed-dose regimen with follitropin alfa in a conventional adjustable dosing regimen in Chinese women.  METHODS: This was a subgroup analysis of the randomized, multi-center, assessor-blind, non-inferiority trial (GRAPE) including 759 Chinese women (aged 20-40 years) recruited in 16 reproductive medicine clinics in China. Women were randomized in a 1:1 ratio to be treated with either follitropin delta dose based on anti-Müllerian hormone (AMH) and body weight or conventional dosing with follitropin alfa following a gonadotropin-releasing hormone (GnRH) antagonist protocol. The primary outcome was ongoing pregnancy rate assessed 10-11 weeks after embryo transfer in the fresh cycle (non-inferiority margin -10.0%). RESULTS: 378 in the follitropin delta group and 381 in the follitropin alfa group were randomized and exposed. Non-inferiority was confirmed with respect to ongoing pregnancy with rates of 31.0% vs. 25.7% for follitropin delta compared to follitropin alfa, estimated mean difference of 5.1% (95% confidence interval (CI) -1.3% to 11.5%). The clinical pregnancy rate (35.4% vs. 31.5%, P = 0.239) and live birth rate (31.0% vs. 25.5%, P = 0.101) were comparable between the follitropin delta group and the follitropin alfa group. Overall, the individualized follitropin delta treatment resulted in fewer oocytes retrieved compared to follitropin alfa treatment (10.3 ± 6.2 vs. 12.5 ± 7.5, P < 0.001), which was mainly due to fewer oocytes (10.5 ± 6.4 vs. 13.9 ± 7.8) in women with AMH ≥ 15 pmol/L. Accordingly there was a lower incidence of early ovarian hyper-stimulation syndrome (OHSS) and/or preventive interventions (6.1% vs. 11.0%, P = 0.013). A daily follitropin delta dose of 10.2 µg (95% CI: 9.3-11.2 µg) was estimated to provide the same number of oocytes retrieved as a starting dose of 150 IU/d of follitropin alfa. CONCLUSION: Follitropin delta in its individualized fixed-dose regimen showed similar efficacy and improved safety compared with follitropin alfa in a conventional adjustable dosing regimen in Chinese women. CLINICAL TRIAL REGISTRATION NUMBER: NCT03296527.

Effect of inactivated COVID-19 vaccination on intrauterine insemination cycle success: A retrospective cohort study.

Background: Vaccine hesitancy was found in couples seeking artificial reproductive technology (ART) services. As the main vaccine used in China, investigations into the influence of inactivated coronavirus disease 2019 (COVID-19) vaccines on human fertility is needed. Methods: This retrospective cohort study included data on COVID-19 vaccination, clinical characteristics, and reproductive outcome of 1,000 intrauterine insemination (IUI) cycles in 653 couples from March 2021 to March 2022 in a single university hospital-based center for reproductive medicine. The IUI cycles were divided into two categories based on sperm source, including 725 cycles in 492 women undergoing artificial insemination with their husband's sperm (AIH) and 275 cycles in 161 women undergoing artificial insemination with donor sperm (AID). Women were then divided into two groups. The vaccine exposed group included women vaccinated prior to insemination and the unexposed group included women who were not vaccinated or vaccinated after insemination. Reproductive outcomes including ongoing pregnancy rate, clinical pregnancy rate, and miscarriage rate were assessed. Results: Inactivated COVID-19 vaccinated women prior to intrauterine insemination in AIH cycles have comparable ongoing pregnancy rate (11.1 vs. 10.3%, P = 0.73), clinical pregnancy rate (12.5 vs. 11.3%, P = 0.60) as compared with unvaccinated counterparts. Similarly, there were no significant differences in ongoing pregnancy rate (20.9 vs. 28.1%, P = 0.17), clinical pregnancy rate (21.7 vs. 28.8%, P = 0.19) between vaccine exposed and unexposed groups in AID cycles. Multivariable logistic regression analyses showed that inactivated COVID-19 vaccination status cannot independently influence the reproductive outcomes of AIH and AID cycles. Subgroup analysis of vaccine exposed cycles showed that doses of vaccination and Interval between the last dose of vaccination and insemination have no influence on the reproductive outcomes of AIH cycles. Conclusions: No negative effects were found on female fertility in IUI cycles following exposure to the inactivated COVID-19 vaccine. These findings indirectly reflect the safety of inactivated COVID-19 vaccine toward reproductive health and help to mitigate vaccine hesitancy among people planning to conceive.

A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy.

Despite potent preclinical antitumor activity, activation of stimulator of interferon genes (STING) has shown modest therapeutic effects in clinical studies. Many STING agonists, including 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), show poor pharmacokinetic properties for sustaining STING activation in tumors and achieving optimal antitumor efficacy. Improved delivery of STING agonists and their effective combination with other treatments are needed to enhance their therapeutic effects. Herein, a 2D nanoplatform, cGAMP/MOL, is reported via conjugating cGAMP to a nanoscale metal-organic layer (MOL) for simultaneous STING activation and radiosensitization. The MOL not only exhibits strong radiosensitization effects for enhanced cancer killing and induction of immunogenic cell death, but also retains cGAMP in tumors for sustained STING activation. Compared to free cGAMP, cGAMP/MOL elicits stronger STING activation and regresses local tumors upon X-ray irradiation. Further combination with an immune checkpoint inhibitor bridges innate and adaptive immune systems by activating the tumor microenvironment to elicit systemic antitumor responses.

Inactivated COVID-19 vaccination does not affect in vitro fertilization outcomes in women.

STUDY QUESTION: Do inactivated coronavirus disease-2019 (COVID-19) vaccines affect IVF outcomes among the vaccine recipients? SUMMARY ANSWER: The receipt of inactivated COVID-19 vaccines before ovarian stimulation has little effect on the outcomes of IVF, including ovarian stimulation outcomes, embryo development and pregnancy rates. WHAT IS KNOWN ALREADY: Limited studies have reported that COVID-19 vaccines do not affect ovarian function, embryo development or pregnancy outcomes. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study performed at the Third Affiliated Hospital of Guangzhou Medical University on 240 women vaccinated with either CoronaVac or Sinopharm COVID-19 before ovarian stimulation in the exposed group and 1343 unvaccinated women before ovarian stimulation in the unexposed group. All participants received fresh embryo transfers between 1 March 2021 and 15 September 2021. The included women were followed up until 12 weeks of gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Vaccination information of all subjects was followed up by a nurse, and the IVF data were obtained from the IVF data system. The following aspects were compared between the vaccinated and the unvaccinated groups: parameters of ovarian stimulation, embryo development and pregnancy rates. Regression analyses were performed to control for confounders of embryo development and pregnancy rates. Propensity score matching (PSM) was performed to balance the baseline parameters of the two groups. The primary outcome was the ongoing pregnancy rate. MAIN RESULTS AND THE ROLE OF CHANCE: Liner regression analysis revealed that the number of oocytes retrieved (regression coefficient (B) = -0.299, P = 0.264), embryos suitable for transfer (B = -0.203, P = 0.127) and blastocysts (B = -0.250, P = 0.105) were not associated with the status of vaccination before ovarian stimulation, after adjusting for the confounders. The ongoing pregnancy rate in the women of the vaccinated group was not significantly lower than that in the unvaccinated group (36.3% vs 40.7%, P = 0.199) (adjust odd ratio = 0.91, 95% CI = 0.68-1.22, P = 0.52). After PSM, the rates of ongoing pregnancy (36.0% vs 39.9%, P = 0.272), implantation (35.4% vs 38.3%, P = 0.325), biochemical pregnancy (47.3% vs 51.6%, P = 0.232), clinical pregnancy (44.4% vs 47.4%, P = 0.398) and early miscarriage (15.0% vs 12.1%, P = 0.399) were not significantly different between the vaccinated and the unvaccinated groups. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study of women with infertility. The results from the present study warrant confirmation by prospective studies with a larger cohort. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study with a large sample size on the effect of inactivated COVID-19 vaccines on ongoing pregnancy rates of women undergoing IVF. The present results showed that vaccination has no detrimental effect on IVF outcomes. Therefore, women are recommended to receive COVID-19 vaccines before undergoing their IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (No. 2018YFC1003803 to J.L.), the Guangzhou Science and Technology Plan Project (No. 202102010076 to H.L.) and the Medical Key Discipline of Guangzhou (2021-2023), as well as the Sino-German Center for Research Promotion Rapid Response Funding Call for Bilateral Collaborative Proposals between China and Germany in COVID-19 Related Research (No. C-0032 to Xingfei Pan). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.