This umbrella meta-analysis aimed to examine the effect of prenatal vitamin D supplementation on maternal and neonatal outcomes. Scopus and PubMed were searched up to September 2024 to include relevant studies. The outcomes included gestational diabetes mellitus (GDM), preeclampsia, cesarean section, preterm delivery (PTD), low birth weight (LBW), small for gestational age (SGA), stillbirth, neonatal mortality, birth weight, birth length, and head circumference at birth. Standardized mean difference (SMD) and relative risk (RR) with their 95

BACKGROUND:Inositol (ISL) refers to a group of simple carbohydrates known for their insulin-sensitizing effects, with Myo-inositol (MYO) and d-chiro-inositol (DCI) being the most prevalent isoforms. OBJECTIVE:This umbrella meta-analysis aimed to evaluate the impact of inositol supplementation on gestational diabetes (GDM) as well as maternal and neonatal outcomes in women with GDM. We performed a systematic search of the literature in the PubMed and Scopus databases up until September 2024 to identify relevant studies. METHOD:Publications with the following criteria were eligible: (i) the study design was a meta-analysis of RCTs, (ii) the population consisted of pregnant women with GDM, (iii) the intervention involved ISL supplementation, compared to a placebo, and (iv) the primary outcome was the incidence of GDM. The secondary outcomes included glycemic indices, preterm birth, pregnancy-induced hypertension, birth weight, neonatal hypoglycemia, gestational age at birth, cesarean delivery, shoulder dystocia, macrosomia, and neonatal intensive care unit admission. The pooled results were presented as standardized mean differences for continuous outcomes and relative risks (RR) with 95% confidence intervals (CI) for dichotomous outcomes, using a random effects model. RESULTS:A total of 19 studies involving 17 932 participants were included in the analysis. ISL supplementation was linked to a lower risk of GDM (RR: 0.42; 95% CI = 0.37-0.49), reduced need for insulin therapy (RR: 0.33; 95% CI = 0.19-0.58), decreased incidence of pregnancy-induced hypertension (RR: 0.34; 95% CI = 0.27-0.44), lower rates of preterm birth (RR: 0.38; 95% CI = 0.31-0.47), and a reduced rate of neonatal hypoglycemia. Additionally, ISL significantly lowered oral glucose tolerance test results, fasting blood sugar levels, and birth weight, while increasing fasting serum insulin levels and gestational age at birth. Subgroup analyses indicated that the effects varied based on the type of intervention and dosage of ISL used. CONCLUSION:Administering ISL during pregnancy might offer a promising approach to the prevention and management of GDM and its related health outcomes.

Background: We aimed to investigate the association between heatwave exposure and preterm birth, and to determine whether assignment to the Fetal Medicine Foundation-directed low-dose aspirin (FMF-LAD) intervention modified this association. Methods: In this post-hoc analysis of the Chinese Preeclampsia Prevention and Management (ChiPERM) randomised controlled trial, we included 20,890 pregnant individuals from 14 hospitals. Participants were allocated to FMF-LAD intervention (first-trimester screening + low dose aspirin) or control. Exposure to heatwave was defined using location-specific thresholds (exceeding 92.5th, 95th, or 97.5th) of daily mean/maximum/minimum temperature persisting for four or more consecutive days. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for preterm birth. Effect modification by FMF-LAD intervention assignment was assessed using multiplicative interaction terms. Findings: The cohort comprised 20,890 participants, of whom 12,845 (61.5%) were assigned to the FMF-LAD intervention group and 8,045 (38.5%) to the control group. Heatwave exposure defined by Tmax at the 97.5th percentile (Max_q97.5_d4) was significantly associated with increased risk of preterm birth across all gestational windows. Among participants in the control group, each additional day of Tmax heatwave exposure during the entire pregnancy was associated with a hazard ratio of 1.18 (95% CI 1.14 to 1.24) for preterm birth. This association was significantly attenuated in the FMF-LAD intervention group (HR 1.08, 95% CI 1.04 to 1.12; P for difference 0.002). A similar protective modification was observed for minimum temperature heatwave exposure, in which the association observed in the control group (HR 1.16, 95% CI 1.11 to 1.21) was substantially attenuated among those in the intervention group (HR 0.99, 95% CI 0.95 to 1.03; P for difference <0.001). Interpretation: Exposure to heatwave exposure during pregnancy was associated with a significant increase in the risk of preterm birth, with this association present across all gestational trimesters and consistent across multiple heatwave definitions and temperature thresholds. These findings indicate that the FMF-LAD first-trimester screen-and-prevent strategy did not substantially decreases the risk of heat-related preterm birth. These findings highlight the need to integrate climate considerations into antenatal care, and an optimal preventive strategy for enhance heat resilience in a warming world is required.

Background: This study aimed to compare the effectiveness of Fetal Medicine Foundation (FMF) based combined screening versus the American College of Obstetricians and Gynecologists (ACOG) based screening for preventing preterm preeclampsia in real-world clinical practice. Methods: This pragmatic, stepped-wedge cluster randomized trial was conducted across 14 hospitals in China from July 2021 to December 2023 (ChiCTR2100043520). The control phase used ACOG risk-factor screening, and the intervention phase used FMF combined screening. The primary outcome was preterm preeclampsia. Secondary outcomes included placental abruption, preterm birth, postpartum hemorrhage, neonatal asphyxia, and neonatal intensive care unit (NICU) admission. Findings: A total of 18,576 women with singleton pregnancies at 11-13+6 weeks’ gestation were included (6,606 in control phrase and 11,970 in intervention phrase). The incidence of preterm preeclampsia did not significantly differ (0.56% vs 0.48%; adjusted odds ratio [aOR] 1.07, 95% confidence interval [CI] 0.56-2.04; P = .808). FMF screening was associated with significant reductions in placental abruption (aOR 0.53, 95% CI 0.36-0.78; P = .001), neonatal asphyxia (aOR 0.23, 95% CI 0.10-0.54; P < .001), and NICU admission (aOR 0.62, 95% CI 0.47-0.83; P < .001), but with higher rates of postpartum hemorrhage (aOR 2.10, 95% CI 1.08-4.10; P = .029) and preterm birth (aOR 1.29, 95% CI 1.01-1.65; P = .043). Interpretation: The first-trimester screening strategy utilizing the FMF algorithm did not yield a significant reduction in the incidence of preterm preeclampsia comparing to ACOG based strategy, which should be accompanied by education on aspirin prophylaxis and strict adherence to the protocol in order to achieve a reduction in preterm preeclampsia. Evaluation of the complexities regarding aspirin administration and compliance within screening-to-prevention pathways is indicated.

Myelin sheath is essential for the maintenance of neural system functions. The mediator complex (MED) is associated with neurodegenerative diseases. Mutation of the MED subunit Med20 leads to abnormal brain development, but whether Med20 modulates myelination remains unknown. In this study, we report that Med20 is an important modulator of myelination in the peripheral nervous system. Loss of Med20 in Schwann cells (SCs) induces ferroptosis, thus impairing myelination. The functions of Med20 in SCs are mediated by its downstream target DDB1. DDB1 controls SC ferroptosis by regulating Hmox1 through a "DDB1-UHRF1-BACH1-Hmox1" transcription regulation axis and its direct interaction and subsequent simultaneous ubiquitination of the HO-1 protein. HO-1 inhibitor ZnPP or ferroptosis inhibitor Fer-1 is sufficient and efficient for antagonizing ferroptosis in SCs and restoring myelination in Med20-deficient mice. The results of our study reveal that Med20 is an important regulator in the network that controls myelination in the peripheral nervous system.

Oligodendrocyte maturation arrest in hypoxia-induced white matter injury (WMI) results in long-term neurofunctional disabilities of preterm infants. Although neurons are closely linked to myelination regulation, how neurons respond to the above process remains elusive. Here, we identify a compensatory role of neuronal Slit1-dependent signaling in protecting against hypoxia-induced hypomyelination and ameliorating motor and cognitive disabilities. Conditional ablation of Slit1 in neurons exacerbates hypoxia-induced hypomyelination but is negligible for developmental myelination. Secreted Slit1 from hypoxic neurons directly targets oligodendrocyte, acting through Robo2-srGAP1-RhoA signaling. Pharmacological inhibition of RhoA restores myelination and promotes neurofunctional recovery in adolescent mice. Notably, natural selection analysis and functional validation indicate an adaptive variant with higher Slit1 gene expression in the Tibetan population, which has low oxygen availability. Collectively, these findings show a neuronal Slit1-dependent program of OL differentiation and suggest that targeting the Slit1-Robo2 signaling axis may have therapeutic potential for treatment of preterm infants with hypoxic WMI.

O-linked N-acetylglucosamine transferase (OGT)-catalyzed O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation) is closely associated with diabetes progression. This study aims to investigate the mechanism of OGT in regulating endothelial dysfunction in gestational diabetes mellitus (GDM). Expressions of OGT, O-linked N-acetylglucosamine (O-GlcNAc), enhancer of zeste homolog 2 (EZH2), and HEK27me3 in human umbilical vein endothelial cells (HUVECs) and GDM-derived HUVECs (GDM-HUVECs) were assessed by western blot. RT-qPCR and western blot assays were used to test the OGT overexpression and EZH2 silencing levels. CCK-8, EdU, wound healing, and transwell invasion assays were used to analyze the cell proliferative, migratory, and invasive abilities. Tube formation assay was performed to evaluate angiogenesis ability of cells. Western blot assay was performed to estimate vascular endothelial growth factor (VEGF) and p-VEGFR2 levels in cells. The binding of O-GlcNAc and EZH2 after OGT overexpression was measured by Co-IP assay. The results showed that OGT, O-GlcNAc, EZH2, and HEK27me3 expressions were declined in GDM-HUVECs. OGT overexpression induced the proliferation, migration, and invasion of GDM-HUVECs, and also elevated angiogenesis and the expressions of VEGF and p-VEGFR2 in cells. O-GlcNAc, EZH2, and HEK27me3 expressions were upregulated after OGT overexpression. OGT upregulation induced the binding between O-GlcNAc and EZH2. EZH2 silencing attenuated the promotion of OGT overexpression on the proliferative, invasive, migratory, and angiogenic capacities of GDM-HUVECs. To be concluded, OGT overexpression stabilized EZH2 expression by promoting O-GlcNAcylation modification of EZH2, and further enhanced proliferation, migration, and invasion as well as angiogenesis of GDM-HUVECs. While these effects were decayed after EZH2 absenting. Overall, the modulation of OGT on endothelial dysfunction in GDM provides a novel perspective for the clinical treatment of GDM.

Mutations or dysregulation of nucleoporins (Nups) are strongly associated with neural developmental diseases, yet the underlying mechanisms remain poorly understood. Here, we show that depletion of Nup Seh1 in radial glial progenitors results in defective neural progenitor proliferation and differentiation that ultimately manifests in impaired neurogenesis and microcephaly. This loss of stem cell proliferation is not associated with defects in the nucleocytoplasmic transport. Rather, transcriptome analysis showed that ablation of Seh1 in neural stem cells derepresses the expression of p21, and knockdown of p21 partially restored self -renewal capacity. Mechanistically, Seh1 cooperates with the NuRD transcription repressor complex at the nuclear periphery to regulate p21 expression. Together, these findings identified that Nups regulate brain development by exerting a chromatin -associated role and affecting neural stem cell proliferation.

BACKGROUND:Preeclampsia, a severe pregnancy syndrome, is widely accepted divided into early- and late-onset preeclampsia (EOPE and LOPE) based on the onset time of preeclampsia, with distinct pathophysiological origins. However, the molecular mechanism especially immune-related mechanisms for EOPE and LOPE is currently obscure. In the present study, we focused on placental immune alterations between EOPE and LOPE and search for immune-related biomarkers that could potentially serve as potential therapeutic targets through bioinformatic analysis. METHODS:The gene expression profiling data was obtained from the Gene Expression Omnibus database. ESTIMATE algorithm and Gene Set Enrichment Analysis were employed to evaluate the immune status. The intersection of differentially expressed genes in GSE74341 series and immune-related genes set screened differentially expressed immune-related genes. Protein-protein interaction network and random forest were used to identify hub genes with a validation by a quantitative real-time PCR. Kyoto Encyclopedia of Genes and Genomes pathways, Gene Ontology and gene set variation analysis were utilized to conduct biological function and pathway enrichment analyses. Single-sample gene set enrichment analysis and CIBERSORTx tools were employed to calculate the immune cell infiltration score. Correlation analyses were evaluated by Pearson correlation analysis. Hub genes-miRNA network was performed by the NetworkAnalyst online tool. RESULTS:Immune score and stromal score were all lower in EOPE samples. The immune system-related gene set was significantly downregulated in EOPE compared to LOPE samples. Four hub differentially expressed immune-related genes (IL15, GZMB, IL1B and CXCL12) were identified based on a protein-protein interaction network and random forest. Quantitative real-time polymerase chain reaction validated the lower expression levels of four hub genes in EOPE compared to LOPE samples. Immune cell infiltration analysis found that innate and adaptive immune cells were apparent lacking in EOPE samples compared to LOPE samples. Cytokine-cytokine receptor, para-inflammation, major histocompatibility complex class I and T cell co-stimulation pathways were significantly deficient and highly correlated with hub genes. We constructed a hub genes-miRNA regulatory network, revealing the correlation between hub genes and hsa-miR-374a-5p, hsa-miR-203a-3p, hsa-miR-128-3p, hsa-miR-155-3p, hsa-miR-129-2-3p and hsa-miR-7-5p. CONCLUSIONS:The innate and adaptive immune systems were severely impaired in placentas of EOPE. Four immune-related genes (IL15, GZMB, IL1B and CXCL12) were closely correlated with immune-related pathogenesis of EOPE. The result of our study may provide a new basis for discriminating between EOPE and LOPE and acknowledging the role of the immune landscape in the eventual interference and tailored treatment of EOPE.

OBJECTIVE: In recent years, the ratio of soluble fms-like tyrosine kinase 1 to placental growth factor for use in predicting preeclampsia has been explored extensively. Despite extensive research, available data on its effectiveness in predicting preeclampsia in twin pregnancies are limited and conflicting. This meta-analysis aimed to assess the diagnostic accuracy of the soluble fms-like tyrosine kinase 1 to placental growth factor ratio in distinguishing cases with preeclampsia in twin pregnancies from healthy controls. DATA SOURCES: Studies that evaluated the use of the soluble fms-like tyrosine kinase 1 to placental growth factor ratio in predicting preeclampsia were searched in PubMed, Embase, and Cochrane databases from inception to August 6, 2023, without language restriction. STUDY ELIGIBILITY CRITERIA: The following population, exposure, comparators, outcomes, and study designs were included: women with twin pregnancies; an increased soluble fms-like tyrosine kinase 1 to placental growth factor ratio with preeclampsia as the outcome; women without preeclampsia; a 2 pound 2 diagnostic table, diagnostic accuracy data, and the incidence of preeclampsia; and prospective cohort studies and observational comparative studies, respectively. STUDY APPRAISAL AND SYNTHESIS METHODS: The quality of the included studies was evaluated. Key parameters, including the specificity, sensitivity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio, were calculated using the random- and fixedeffects models. In addition, the area under the receiver operating characteristic curve and the summary receiver operating characteristic curve were evaluated. RESULTS: A total of 7 studies were included, including 442 women with twin pregnancies (115 patients with preeclampsia and 327 controls without preeclampsia). The results highlighted the promising effectiveness of the soluble fms-like tyrosine kinase 1 to placental growth factor ratio in predicting preeclampsia in twin pregnancies with a pooled specificity of 0.89 (95% confidence interval, 0.80-0.95), a sensitivity of 0.84 (95% confidence interval, 0.73-0.93), a positive likelihood ratio of 32.76 (95% confidence interval, 12.82-83.74), and a negative likelihood ratio of 0.03 (95% confidence interval, 0.01-0.08). The combined diagnostic odds ratio was 35.72 (95% confidence interval, 12.92-98.76), and the area under the receiver operating characteristic curve was 0.92. CONCLUSION: These collective findings underscore the potential of the soluble fms-like tyrosine kinase 1 to placental growth factor ratio as an accurate marker for identifying preeclampsia among women with twin pregnancies.

BackgroundExisting literature indicates that Gestational diabetes mellitus (GDM) and maternal obesity disrupt the normal colonization of the neonatal gut microbiota alone. Still, the combined impact of GDM and excessive gestational weight gain (EGWG) on this process remains under explored. The association between gestational weight gain before/after GDM diagnosis and neonatal gut microbiota characteristics is also unclear.The purpose of this study is to conduct investigation and analysis on the above-mentioned issues, providing a basis for optimizing clinical management plans.MethodsThis study involved 98 mother-infant pairs categorized into GDM and non-GDM groups. The GDM group was further subdivided based on gestational weight gain (GWG) into normal (GDM+NGWG) and excessive (GDM+EGWG) weight gain groups. Neonatal stool samples were collected within 24 hours post-delivery for gut microbiota profiling through 16S rRNA gene sequencing. Statistical analyses explored correlations between total GWG/BMI gain and those before/after GDM diagnosis (t-GWG/GBG; b-GWG/GBG; a-GWG/GBG) with key bacterial taxa.ResultsNotable genus-level changes included enrichment of Escherichia and Klebsiella, and depletion of Bacteroides, Bifidobacterium, Coprococcus, Ruminococcus among GDM-Total and GDM+EGWG groups compared to non-GDM. Further,LEfSe analysis identified 30 differential bacteria taxa between GDM-Total and healthy control groups, which increased to 38 between GDM+EGWG and non-GDM groups, highlighting more pronounced microbial shifts associated with EGWG. Clostridium was negatively correlated with t-GWG and newborn birth weight; The Coriobacteriaceae showed a negative correlation with t-GWG, t-GBG, and a-GBG. Additionally,Collinsella exhibited negative correlations with t-GBG and a-GBG.ConclusionThis study has identified that the presence of EGWG in GDM mothers further exacerbated neonatal gut microbial perturbations. Total GWG/GBG and those after the diagnosis of GDM were negatively correlated with the abundance of neonatal gut Clostridium, Coriobacteriaceae, and Collinsella. These findings provide new insights for precise prevention and management of GDM.

Studying the effects of maternal iron deficiency anemia (IDA) is complex owing to its diverse causes, each independently impacting the placenta and fetus. Simple treatment with iron supplements does not always resolve the anemia. Therefore, delving into how IDA alters placental development at a molecular level is crucial to further optimize treatment. This review addresses the effects of IDA on placental structures and functions, including changes in oxygen levels, blood vessels, and the immune system. Profound understanding of physiological characteristics and regulatory mechanisms of placental development is key to explain the mechanisms of abnormal placental development in pregnancy-associated disorders. In turn, future strategies for the prevention and treatment of pregnancy complications involving the placenta can be devised. These studies are significant for improving human reproductive health, enhancing sociodemographic qualities, and even lifelong wellbeing, a focal point in future placental research.

Chemotherapy-induced alopecia (CIA) represents one of the most common side effects of cancer treatment. Currently, scalp cooling systems are utilized to treat CIA, but their safety and effectiveness remain limited. The objective of this study was to investigate the effect of fucoidan on CIA and to elucidate the possible mechanism of fucoidan in treating CIA. The results showed that when the dosage of fucoidan was 100 mg/kg·d, it could effectively alleviate CIA induced by cyclophosphamide and promote hair recovery. Altering the dosage affected the therapeutic effect. A lower dosage (50 mg/kg·d) could not effectively prevent the hair from falling off, and the regrown hair was sparse, while an increased dosage led to slow hair growth, although the hair regrown was thick and black. It was also found that with the increase in dosage, key CIA proteins P53 and Fas were down-regulated. However, the cyclin was decreased when the dose was too high. In addition, fucoidan proved beneficial to cyclophosphamide treatment, which further inhibited tumor growth, aggravated tumor necrosis, and reduced the side effects of cyclophosphamide, especially at high doses. These results demonstrate that fucoidan has a therapeutic effect on CIA and does not compromise the effect of chemotherapy.

Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth-restricted placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.

The United States Food and Drug Administration (FDA) has been warning about the psychiatric disorders associated with montelukast (MTK) for years. To study the characteristics of the presence of MTK-associated adverse events (AEs), we obtained data from the FDA Adverse Event Reporting System database and used a case (MTK) vs. non-case (all other drugs) analysis to investigate the safety signals in a disproportionality study. 27,507 reported AEs from January 2004 to December 2022 were analyzed. Disproportionality analysis shows that psychiatric, respiratory, thoracic, and mediastinal disorders as well as social circumstances are the most commonly reported AEs. In addition, our study found several unreported AEs, such as increased systolic blood pressure, diastolic dysfunction, hypothyroidism, obesity, bursitis, and polycystic ovaries. The timing of AE occurrence indicates that MTK-associated AEs are mainly acute effects. Most importantly, we found that 60.1% of patients reporting AEs in the category of psychiatric disorders were younger than 18 years. In summary, we revealed an age-preference pattern of psychiatric AEs in patients prescribed MTK. Our study is helpful for physicians and health professionals to better evaluate the value and risk of MTK and to achieve the goal of optimal patient care.

Background: Preterm birth (PTB) is the main cause of infant disease and death worldwide. Approximately 70% of neonatal deaths and 36% of infant deaths worldwide are caused by premature birth. Gestational weight gain (GWG) is associated with adverse pregnancy outcomes. This study explored the relationship between the rate of GWG and PTB among pregnant women at low risk of preterm birth. Methods: Our study used a cohort of mother-child pairs with a one-and-a-half-year follow-up from January 2020 to June 2021. We excluded pregnant women with undisputed high-risk factors for PTB and the remaining women were considered the low-risk group. The average rate of GWG was utilized in this research as the measure of GWG. Multivariate logistic regression was used to evaluate the relationship between GWG and PTB among pregnant women at low risk for preterm birth. Results: The final cohort study of mother-child pairs included 3480 pregnant women in the low-risk group. Women with low GWG had a higher possibility of PTB than those with adequate GWG. Comparing underweight women with an adequate GWG rate to underweight women with a low GWG rate, PTB risk increased by 2.52-fold with a low GWG rate. Compared to women with adequate GWG, underweight women with excessive GWG had significantly higher odds of PTB. No significant results were observed for pregnant women classified as overweight or obese. Conclusions: A reasonable GWG during pregnancy can effectively reduce the risk of PTB, especially for pregnant women with low pre-pregnancy body mass index. Low or excessive GWG may lead to an increased risk of PTB.

Dysregulation of factors in nucleocytoplasmic transport is closely linked to neural developmental diseases. Mutation in Hikeshi, encoding a nonconventional nuclear import carrier of heat shock protein 70 family (HSP70s), leads to inherited leukodystrophy; however, the pathological mechanisms remain elusive. Here, we showed that Hikeshi is essential for central nervous system (CNS) myelination. Deficiency of Hikeshi, which is observed in inherited leukodystrophy patients, resulted in murine oligodendrocyte maturation arrest. Hikeshi is required for nuclear translocation of HSP70s upon differentiation. Nuclear-localized HSP70 promotes murine oligodendrocyte differentiation and remyelination after white matter injury. Mechanistically, HSP70s interacted with SOX10 in the nucleus and protected it from E3 ligase FBXW7-mediated ubiquitination degradation. Importantly, we discovered that Hikeshi-dependent hyperthermia therapy, which induces nuclear import of HSP70s, promoted oligodendrocyte differentiation and remyelination following in vivo demyelinating injury. Overall, these findings demonstrate that Hikeshi-mediated nuclear translocation of HSP70s is essential for myelinogenesis and provide insights into pathological mechanisms of Hikeshi-related leukodystrophy.

Objective: To explore the key points for preventing and reducing severe pre-eclampsia (SPE) and its severe complications in the tertiary medical referral system of a second-tier city by analyzing the clinical characteristics of SPE. Methods: The clinical data of 341 patients with SPE who terminated pregnancy in Women and Children's Hospital, School of Medicine, Xiamen University, from January 1, 2020 to December 31, 2022 were retrospectively analyzed, and the pre-eclampsia (PE) risk factors, clinical characteristics and severe complications of SPE between the patients referred from primary hospitals (referral group) and the patients received regular prenatal care in the tertiary referral center (central group) were compared, as well as the influence of the referral timing on the maternal and perinatal outcomes. Results: Among the 341 cases of SPE, 92 cases were in the referral group and 249 cases were in the central group. (1) Analysis of PE risk factors: there was no statistical difference in the proportion of risk factors of PE between these two groups [75.0% (69/92) vs 71.9% (179/249); χ2=0.328, P=0.567]. (2) Analysis of clinical features: the gestational ages at the PE early warning factors onset, at the PE first symptom onset and at SPE diagnosed, pregnancy terminated and onset of SPE severe complications in the referral group were significantly earlier than those in the central group (all P<0.05), the proportions of terminating pregnancy before 32 weeks of gestation, between 32 and 34 weeks of gestation, intensive care unit (ICU), neonatal ICU hospitalization and fetal growth restriction in single pregnancies were higher than those in the central group, while the live birth rate was lower than that in the central group (all P<0.05). (3) Analysis of SPE severe complications: the rates of SPE severe complications in the referral group was higher than that in the central group [28.3% (26/92) vs 13.7% (34/249); χ2=9.885, P=0.002]. Among them, the rates of placental abruption [7.6% (7/92) vs 2.8% (7/249); χ2=3.927, P=0.048] and still birth [6.5% (6/92) vs 0.4% (1/249); χ2=9.656, P=0.002] in the referral group were significantly higher than those in the central group. (4) Analysis of referral timings: the timings included referral after onset of SPE severe complications (9.8%, 9/92), referral after SPE diagnosed (63.0%, 58/92), referral after detection of SPE early warning signs (20.7%, 19/92) and referral after detection of PE risk factors (6.5%, 6/92). The gestational ages at SPE diagnosed and pregnancy terminated in group of referral after onset of SPE severe complications and group of referral after SPE diagnosed were significantly earlier than those in group of referral after detection of PE early warning signs and group of referral after detection of PE risk factors (P<0.05). The earlier the referral, the higher the live birth rates (P<0.05). Conclusions: The tertiary referral center of the second-tier city plays an important role in reducing the maternal and perinatal damage of PE. The timing of referral in primary medical institutions is the key point of reducing the occurrence of SPE severe complications and maternal, perinatal damage of PE. It is necessary for medical institutions of all levels in all regions to improve the ability of early identification and early intervention for PE, to enhance the awareness of SPE and its severe complications prevention and control. Primary medical institutions should especially pay attention to raise the consciousness of PE risk factors and early warning signs, and to improve the ability of PE risk factors and early warning signs screening.

The dedifferentiation process of tumorigenesis and somatic cell reprogramming has some commonness and differences, which is the key question to cancer therapeutic strategy and stem cell applications. To further explore the commonalities and variance between carcinogenesis and induced pluripotent stem cell reprogramming, we investigated the role of stemness factors OSKM (OCT4, SOX2, KLF4, and MYC) in the pan-cancer process using public clinical data. Expression of OSKM in human pan-cancer was analyzed via the Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) database based on the RNA-seq data of tissues. The correlation of expression between OSKM genes was analyzed via the Tumor Immune Evaluation Resource (TIMER) database, while the STRING tool was used to construct the protein-protein interaction network for OSKM. Prognostic impact of OSKM in pan-cancer was analyzed by Cox proportional hazards regression model. The relationships between OSKM and tumor stemness, tumor microenvironment and immune checkpoint and were performed by Sangerbox platform using Pearson correlation analysis. Our results showed that OSKM were universally expressed and significantly altered in tumors compared with adjacent normal tissues in most tumor types. In addition, correlation analysis revealed the relevance of OSKM genes to patient prognosis, cancer cell stemness, tumor microenvironment or immune checkpoint. However, there is little similarity between these genes in terms of how they function in each cancer type. This study elucidates the different roles of core stemness factors OSKM in pan-cancer, offering potential therapeutic targets for novel anti-cancer strategies and knowledge to minimize the potential carcinogenic effects during stem cell transplantation.

Background:Evaluation of the therapeutic effects of cerclage on preterm birth (PTB) caused by cervical incompetence remains challenging. The vaginal microbiome is associated with preterm births. Thus, this study aimed to analyse the vaginal microbiota of patients with cervical incompetence, explore the relationship between the composition of the vaginal microbiota before cervical cerclage and at term delivery, and assess the effect of cervical cerclage on the vaginal microbiota.Methods:Patients (n = 30) underwent cerclage performed by the same surgical team. Vaginal swabs were obtained pre-surgery and seven days post-surgery. A gestational age-matched cohort of healthy pregnant women (n = 20) (no particular abnormality during pregnancy, delivery at term) was used as the control group and sampled during a comparable pregnancy. All collected vaginal swabs were analysed by 16S rRNA gene sequencing.Results:When comparing the healthy control and cervical cerclage groups, the enriched microorganism in the healthy controls was G. Scardovia, and the enriched microorganism of the cerclage was G. Streptococcus. α diversity was significantly increased in patients who received cerclage with preterm delivery compared with those with full-term delivery, and the enriched microorganism was F. Enterococcus. A comparison before and after nonemergency cerclage suggested that the enriched microorganisms were G. Lactobacillus and F. Lactobacillaceae before surgery. After nonemergency cerclage, the enriched microorganisms were F. Enterobacteriaceae and C. Gammaproteobacteria. Vaginal microbiota diversity significantly increased, and the proportion of women with Lactobacillus spp.-depleted microbiomes increased after emergency cerclage. Significant differences in β diversity were found between the groups. Before the emergency cerclage, the enriched microorganisms were G. Lactobacillus, O. Alteromonadales, and P. Firmicutes. After emergency cerclage, the enriched microorganisms were P. Actinobacteria, C. Actinobacteria, P. Proteobacteria, F. Bifidobacteriaceae, O. Bifidobacteriales, G. Gardnerella, and G. Veillonella.Conclusion:Cerclage (particularly emergency cerclage) may alter the vaginal microbiota by increasing microbiota diversity, decreasing vaginal Lactobacillus abundance, and increasing the abundance of pathogenic bacteria that are not conducive to pregnancy maintenance, thereby affecting surgical efficacy. Therefore, the role of the vaginal microbiome should be considered when developing treatment strategies for pregnant women with cervical incompetence.Clinical trial registration:https://www.chictr.org.cn, identifier ChiCTR2100046305.