Bayesian analysis of physiologically based toxicokinetic (PBTK) modeling for pentachlorophenol exposure in pregnant women.

Pentachlorophenol (PCP) is a persistent organic compound that is widely present in the environment. The estimation of internal exposure levels for a given external exposure using toxicokinetic models is key to the human health risk assessment of PCP. The present study developed a physiologically based multicompartmental pharmacokinetic (PBTK) model to describe and predict the behavior of pentachlorophenol (PCP) in an organism. The model consists of stomach, intestines, adipose tissue, kidneys and fast- and poorly perfused tissues that are interconnected via blood circulation. We constructed a PBTK model of PCP in rats and extrapolated it to human dietary PCP exposure. The toxicokinetic data of PCP in human tissues and excreta were obtained from the published literature. Based on the collected PCP dietary survey and internal exposure data of pregnant women in Shanghai, Bayesian statistical analysis was performed for the model using Markov chain Monte Carlo (MCMC) simulation. The posterior distributions of the sensitive parameters were estimated, and the model was parameter optimized and validated using the pregnant women's test dataset. The results showed that the root mean square error (RMSE) improved 37.3% compared to the original model, and a systematic literature search revealed that the optimized model achieved acceptable prediction results for other datasets in China. A PCP metabolism model based on the exposure characteristics of pregnant women in China was constructed in the present study. The model provides a theoretical basis for the study of PCP toxicity and risk assessment.

Efficacy and safety of a smartphone application-based treatment of ketogenic diet in pediatric refractory epilepsy.

OBJECTIVE: We aimed to find predictors for smartphone application-based ketogenic diet (KD) treatment effectiveness and safety. METHODS: The efficacy was evaluated according to the reduction in seizure frequency after the intervention of KD; safety was evaluated based on adverse effects. The ordinal logistic regression analysis was used to explore the influencing factors of efficacy. RESULTS: The study sample included 116 males and 65 females with a median age of 2.27 years. The baseline frequency of seizure was more than five times/day in 123 children, 50.83% of them received three or more antiepileptic drugs (AEDs). Seventy-two patients' KD initiation mode was outpatient, and 73 completed the 12-month follow-up. A total of 88 (48.62%) patients had reported a reduction in seizure ≥50%. Compared with 12 months, those who had received KD therapy for only 3 (P = 0.009) and 6 months (P = 0.005) were more likely to show negative outcomes. Outpatient initiation had better outcomes (P = 0.029) than inpatient initiation. For the number of AEDs applied, patients on two AEDs were more likely to achieve better outcomes (P = 0.001). Adverse events had been noted among 77 patients; BMI Z-score at KD initiation was associated with adverse effects (P = 0.003). SIGNIFICANCE: Our study suggested that outpatient initiation and long-term treatment of KD should be encouraged. PLAIN LANGUAGE SUMMARY: Our research shows that the KD is a helpful treatment for children with refractory epilepsy, reducing seizures by more than 50% in nearly half of the cases, with some experiencing complete seizure freedom. We used a smartphone app to improve communication between patients and their healthcare teams, resulting in a high retention, and app usage was linked to reduced adverse effects. We recommend early consideration of KD treatment for patients failing two AED, encourage outpatient initiation, and advocate for longer-term KD use.

Immune response and safety of inactivated SARS-CoV-2 vaccines during pregnancy: a real-world observational study.

BACKGROUND: As pregnant women are excluded from clinical trials of inactivated SARS-CoV-2 vaccines, it is important to assess the immune response in women receiving the vaccination while unknowingly pregnant. METHODS: In a multicenter cross-sectional study, we enrolled 873 pregnant women aged 18-45 years. Serum antibody levels induced by inactivated vaccines were determined. Adverse events were collected by self-reported survey after vaccination. Logistic regression model and restricted cubic spline model were used to investigate the association of factors with antibody positivity. RESULTS: As the doses of the vaccine increase, neutralizing antibody (NAb) positivity was 98.3%, 39.5%, and 9.5% in pregnant women, respectively. The dose of vaccine and duration since vaccination were associated with NAb positivity. The OR of two and three doses of vaccines were 7.20 and 458.33 (P < 0.05). NAb levels and duration since vaccination showed a linear relationship in pregnant women vaccinated two doses, with a decrease to a near seropositivity threshold at 22 weeks. Adverse events were mainly mild or moderate after vaccinated during pregnancy, with no increase in incidence compared with whom vaccinated during pre-pregnancy. CONCLUSIONS: The use of inactivated vaccines during pregnancy induced favorable immune persistence, and the incidence of adverse events did not increase.

Quantum battery based on dipole-dipole interaction and external driving field.

The Dicke model is a fundamental model in quantum optics, which describes the interaction between quantum cavity field and a large ensemble of two-level atoms. In this work, we propose an efficient charging quantum battery achieved by considering an extension Dicke model with dipole-dipole interaction and an external driving field. We focus on the influence of the atomic interaction and the driving field on the performance of the quantum battery during the charging process and find that the maximum stored energy exhibits a critical phenomenon. The maximum stored energy and maximum charging power are investigated by varying the number of atoms. When the coupling between atoms and cavity is not very strong, compared to the Dicke quantum battery, such quantum battery can achieve more stable and faster charging. In addition, the maximum charging power approximately satisfies a superlinear scaling relation P_{max}∝ßN^{α}, where the quantum advantage α=1.6 can be reached via optimizing the parameters.

Analysis of the efficacy and safety of inpatient and outpatient initiation of KD for the treatment of pediatric refractory epilepsy using generalized estimating equations.

Objective: To compare the efficacy and safety of inpatient and outpatient initiation ketogenic diet (KD) protocol of pediatric refractory epilepsy. Methods: Eligible children with refractory epilepsy were randomly assigned to receive KD with inpatient and outpatient initiation. The generalized estimation equation (GEE) model was used to analyze the longitudinal variables of seizure reduction, ketone body, weight, height, body mass index (BMI), and BMI Z-score at different follow-up times between the two groups. Results: Between January 2013 and December 2021, 78 and 112 patients were assigned to outpatient and inpatient KD initiation groups, respectively. There were no statistical differences between the two groups based on baseline demographics and clinical characteristics (all Ps > 0.05). The GEE model indicated that the rate of reduction of seizures≥50% in the outpatient initiation group was higher than that of the inpatient initiation group (p = 0.049). A negative correlation was observed between the seizure reduction and blood ketone body at 1, 6, and 12 months (all Ps < 0.05). There were no significant differences in height, weight, BMI, and BMI Z-score between the two groups over the 12-month period by the GEE models (all Ps > 0.05). Adverse events were reported by 31 patients (43.05%) in the outpatient KD initiation group and 46 patients (42.20%) in the inpatient KD initiation group, but these differences were not statistically significant (p = 0.909). Conclusion: Our study shows that outpatient KD initiation is a safe and effective treatment for children with refractory epilepsy.

The Association between Dietary Iron Intake, SNP of the MTNR1B rs10830963, and Glucose Metabolism in Chinese Population.

Type 2 diabetes is associated with both dietary iron intake and single-nucleotide polymorphism (SNP) of intronic rs10830963 in melatonin receptor 1B (MTNR1B); however, it is unclear whether they interact. The aim of this study was to examine the associations between dietary iron intake, SNP of rs10830963, and glucose metabolism. Data were obtained from the Shanghai Diet and Health Survey (SDHS) during 2012-2018. Standardized questionnaires were carried out through face-to-face interviews. A 3-day 24 h dietary recall was used to evaluate dietary iron intake. Anthropometric and laboratory measurements were applied. Logistic regression and general line models were used to evaluate the association between dietary iron intake, SNP of the MTNR1B rs10830963, and glucose metabolism. In total, 2951 participants were included in this study. After adjusting for age, sex, region, years of education, physical activity level, intentional physical exercise, smoking status, alcohol use, and total energy, among G allele carriers, dietary iron intake was associated with a risk of elevated fasting glucose, higher fasting glucose, and higher HbA1c, while no significant results were observed among G allele non-carriers. The G allele of intronic rs10830963 in MTNR1B potentially exacerbated unfavorable glucose metabolism with the increasing dietary iron intake, and it was possibly a risk for glucose metabolism homeostasis in the Chinese population.

Rapid determination of plasma vigabatrin by LC-ESI-MS/MS supporting therapeutic drug monitoring in children with infantile spasms.

Vigabatrin is one of the second-generation anti-seizure medications (ASMs) designated orphan drugs by the FDA for monotherapy for pediatric patients with infantile spasms from 1 month to 2 years of age. Vigabatrin is also indicated as the adjunctive therapy for adults and pediatric patients 10 years of age and older with refractory complex partial seizures. Ideally, the vigabatrin treatment entails achieving complete seizure freedom without significant adverse effects, and the therapeutic drug monitoring (TDM) will make a significant contribution to this aim, which provides a pragmatic approach to such epilepsy care in that the dose tailoring can be undertaken for uncontrollable seizures and in cases of clinical toxicity guided by the drug concentrations. Thus, reliable assays are mandatory for TDM to be valuable, and blood, plasma, or serum are the matrixes of choice. In this study, a simple, rapid, and sensitive LC-ESI-MS/MS method for the measurement of plasma vigabatrin was developed and validated. The sample clean-up was performed by an easy-to-use method, i.e., protein precipitation using acetonitrile (ACN). Chromatographic separation of vigabatrin and vigabatrin-13C,d2 (internal standard) was achieved on the Waters symmetry C18 column (4.6 mm × 50 mm, 3.5 µm) with isocratic elution at a flow rate of 0.35 mL min-1. The target analyte was completely separated by elution with a highly aqueous mobile phase for 5 min, without any endogenous interference. The method showed good linearity over the 0.010-50.0 µg mL-1 concentration range with a correlation coefficient r2 = 0.9982. The intra-batch and inter-batch precision and accuracy, recovery, and stability of the method were all within the acceptable parameters. Moreover, the method was successfully used in pediatric patients treated with vigabatrin and also provided valuable information for clinicians by monitoring plasma vigabatrin levels in our hospital.

Risk-benefit assessment of methylmercury and n-3 polyunsaturated fatty acids through fish intake by pregnant women in Shanghai, China: Findings from the Shanghai Diet and Health Survey.

BACKGROUND: Fish and shellfish contain nutrients essential for fetal health, especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The concern of mercury (Hg) pollution limits fish consumption among women in pregnancy, which could adversely affect child development. This study aimed to conduct risk-benefit assessment and provide recommendations for fish intake by pregnant women in Shanghai, China. METHODS: Secondary analysis was conducted using cross-sectional data from a representative sample of the Shanghai Diet and Health Survey (SDHS) (2016-2017), China. Dietary intakes of Hg and DHA + EPA were calculated from the food frequency questionnaire (FFQ) on fish items and 24hr recall record. Raw fish samples (59 common species of fish in Shanghai) were purchased in local markets and their concentrations of DHA, EPA and Hg were measured. Net IQ points gain was used to evaluate the health risk and benefit at a population level by FAO/WHO model. Recommended fish (i.e., high- DHA + EPA and low-level MeHg) were defined, and then the proportion of those hit 5.8 IQ points were simulated with their consumption frequency for 1, 2 and 3 times per week. RESULTS: The average consumption of fish and shellfish was 66.24 g/d among pregnant women in Shanghai. The mean concentrations of Hg and EPA + DHA in fish species most commonly consumed in Shanghai were 0.179 mg/kg and 0.374 g/100 g, respectively. Only 1.4% of the population exceeded the MeHg reference dose of 0.1 µg/kg·bw/d, whereas 81.3% of those who did not meet the recommended daily intakes of 250 mg EPA + DHA. In FAO/WHO model, the proportion of 28.4% reached the maximum IQ points gain. Along with the increase of "recommended fish" consumed, the simulated values of the proportion raised to 74.5, 87.3 and 91.9%, respectively. CONCLUSION: The pregnant women in Shanghai, China had an adequate fish consumption with low-level Hg exposure, but balancing the benefits of fish intake and risk of potential Hg exposure was still a challenge. It is necessary to define a local level of "recommended fish" consumption for developing dietary recommendations for pregnant women.

Vitamin D Supplementation for the Outcomes of Patients with Gestational Diabetes Mellitus and Neonates: A Meta-Analysis and Systematic Review.

Background: Prevention and timely treatment of gestational diabetes mellitus (GDM) are important to the prognosis of pregnant women and neonates. We aimed to conduct a meta-analysis to evaluate the effects and safety of vitamin D supplementation on GDM patients and neonates, to provide insights into clinical GDM treatment. Methods: Two authors searched the Medline, PubMed, Cochrane Library, Web of Science, Embase, CNKI, and Wanfang databases for randomized controlled trials (RCTs) on the effects and safety of vitamin D supplementation in GDM patients. The quality of the included RCTs was evaluated according to Cochrane handbook. RevMan 5.3 software was used for statistical analysis. Results: A total of 20 RCTs involving 1682 GDM patients were finally included, of whom 837 received vitamin D supplementation. Vitamin D supplementation in GDM patients increased the serum 25(OH)D level (SMD = 4.07, 95% CI: (2.73, 5.41)) and HDL level (SMD = 0.41, 95% CI: (0.23, 0.58)) and reduced serum LDL (SMD = -0.49, 95% CI: (-0.68, -0.29)), TG (SMD = -0.59, 95% CI: (-1.01, -0.17)), and TC (SMD = -0.67, 95% CI: (-1.19, -0.14)) levels in GDM patients (all P < 0.05). Besides, vitamin D supplementation reduced the risk of premature birth (OR = 0.37, 95% CI: (0.22, 0.62)), hyperbilirubinemia (OR = 0.38, 95% CI: (0.25, 0.58)), and neonatal hospitalization (OR = 0.38, 95% CI: (0.25, 0.58)) of neonates (all P < 0.05). No significant publication bias in synthesized results was found (all P > 0.05). Conclusions: Vitamin D supplementation improves the blood lipid level in GDM patients and reduces adverse neonatal outcomes. The dose and duration of vitamin D supplementation for safety need to be further investigated in future high-quality studies.

Blockage of TRPV4 Downregulates the Nuclear Factor-Kappa B Signaling Pathway to Inhibit Inflammatory Responses and Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus.

The blockage of transient receptor potential vanilloid 4 (TRPV4) inhibits inflammation and reduces hippocampal neuronal injury in a pilocarpine-induced mouse model of temporal lobe epilepsy. However, the underlying mechanisms remain largely unclear. NF-κB signaling pathway is responsible for the inflammation and neuronal injury during epilepsy. Here, we explored whether TRPV4 blockage could affect the NF-κB pathway in mice with pilocarpine-induced status epilepticus (PISE). Application of a TRPV4 antagonist markedly attenuated the PISE-induced increase in hippocampal HMGB1, TLR4, phospho (p)-IκK (p-IκK), and p-IκBα protein levels, as well as those of cytoplasmic p-NF-κB p65 (p-p65) and nuclear NF-κB p65 and p50; in contrast, the application of GSK1016790A, a TRPV4 agonist, showed similar changes to PISE mice. Administration of the TLR4 antagonist TAK-242 or the NF-κB pathway inhibitor BAY 11-7082 led to a noticeable reduction in the hippocampal protein levels of cleaved IL-1ß, IL-6 and TNF, as well as those of cytoplasmic p-p65 and nuclear p65 and p50 in GSK1016790A-injected mice. Finally, administration of either TAK-242 or BAY 11-7082 greatly increased neuronal survival in hippocampal CA1 and CA2/3 regions in GSK1016790A-injected mice. Therefore, TRPV4 activation increases HMGB1 and TLR4 expression, leading to IκK and IκBα phosphorylation and, consequently, NF-κB activation and nuclear translocation. The resulting increase in pro-inflammatory cytokine production is responsible for TRPV4 activation-induced neuronal injury. We conclude that blocking TRPV4 can downregulate HMGB1/TLR4/IκK/κBα/NF-κB signaling following PISE onset, an effect that may underlie the anti-inflammatory response and neuroprotective ability of TRPV4 blockage in mice with PISE.

Tumor-derived miRNAs as tumor microenvironment regulators for synergistic therapeutic options.

MicroRNAs (miRNAs) are a class of non-coding RNAs that perform post-transcriptional gene regulation. This review focuses on the role of tumor cell-derived miRNAs in the regulation of the tumor microenvironment (TME) via receptor cell recoding, including angiogenesis, expression of immunosuppressive molecules, formation of radiation resistance, and chemoresistance. Furthermore, we discuss the potential of these molecules as adjuvant therapies in combination with chemotherapy, radiotherapy, or immunotherapy, as well as their advantages as efficacy predictors for personalized therapy. MiRNA-based therapeutic agents for tumors are currently in clinical trials, and while challenges remain, additional research on tumor-derived miRNAs is warranted, which may provide significant clinical benefits to cancer patients.

Ligand-gated ion channel P2X7 regulates NLRP3/Caspase-1-mediated inflammatory pain caused by pulpitis in the trigeminal ganglion and medullary dorsal horn.

Emerging research has revealed that the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasomes contribute to the development of inflammatory and neuropathic pains. In addition, microglia are involved in the central nervous system (CNS) pain conduction. However, the relationship between NLRP3 inflammasome and dental inflammatory pain conduction is yet to be established. Therefore, this study aimed to investigate the roles of P2X7 and NLRP3/Caspase-1 (CASP1) in the inflammatory pain caused by pulpitis using a rat experimental pulpitis model. We discovered that the decreased pain threshold was inversely correlated with the increased expression of NLRP3, Caspase-1, P2X7, interleukin-1ß (IL-1ß), and IL-18 in the trigeminal ganglion and dorsal horn of the medulla after dental pulp exposure. Furthermore, the pain threshold of rats caused by pulpitis was increased by intraperitoneal injection of Brilliant Blue G (BBG), a P2X7 inhibitor, and the expression levels of NLRP3 and related inflammatory factors IL-1ß and IL-18 were decreased. Moreover, treatment with 130 nM KCl, a P2X7 inhibitor, significantly reduced the expression of NLRP3, IL-1ß, IL-18, Caspase-1, and P2X7 in microglia after lipopolysaccharide(LPS) stimulation. In conclusion, our findings suggest that NLRP3/ CASP1 plays a vital role in the conduction of dental pain; the P2X7regulates NLRP3 pathway in the context of dental inflammatory pain conduction, and inhibiting P2X7 may be a potential strategy for dental inflammatory pain relief.

Efficacy and safety of low-dose aspirin combined with low-molecular-weight heparin in treatment of preeclampsia: a meta-analysis and systematic review.

Introduction: The role of low-dose aspirin combined with low-molecular-weight heparin (LMWH) in the treatment of preeclampsia (PE) remains unclear. We aimed to assess the efficacy and safety of low-dose aspirin combined with LMWH in PE treatment, to provide evidence for clinical PE management. Material and methods: We searched PubMed and other databases for randomized controlled trials (RCTs) on the effects and safety of low-dose aspirin and LMWH in the treatment of PE up to January 31, 2021. Two researchers strictly followed the inclusion and exclusion criteria to independently conduct the literature screening, data extraction and quality evaluation. We used RevMan 5.3 statistical software for synthesized analysis. Results: A total of 8 RCTs involving 861 patients were included. The synthesized outcome indicated that the differences in systolic blood pressure (MD = -10.61, 95% CI: -13.19 - -8.02), diastolic blood pressure (MD = -9.24, 95% CI: -14.49- -4.00), 24-hour urinary protein (MD = -2.24, 95% CI: -3.97- -0.50), prothrombin time (MD = 1.42, 95% CI: 0.53-2.32), activated partial thromboplastin time (MD = 2.91, 95% CI: 2.06-3.75), FIB (MD = -1.24, 95% CI: -1.32- -1.15), and adverse perinatal outcomes (MD = 0.41, 95% CI: 0.20-0.85) between the two groups were statistically significant (all p < 0.05), while the difference in the adverse reactions of pregnant women (MD = 0.44, 95% CI: 0.18-1.10) between the two groups was not statistically significant (p = 0.08). No publication bias was detected in all the synthesized outcomes (all p > 0.05). Conclusions: Low-dose aspirin combined with LMWH treatment of PE may be advantageous to improve blood pressure, 24-hour proteinuria and coagulation function, and it may reduce the adverse reactions in pregnant women without increasing adverse perinatal outcomes.

Path Analysis Reveals the Direct Effect of PCB28 Exposure on Cognitive Dysfunction in Older Chinese Females.

Background: Research indicates that exposure to polychlorinated biphenyls (PCBs) can cause neurobehavioral impairments in neonates and adults, but the way specific PCBs' congeners impact cognition functions at a low exposure level in a real-life co-exposure system remains poorly understood. This study aimed to investigate the association of PCBs burden with cognition function among elderly adults. Methods: Based on the Weitang Geriatric Diseases study (2014−2015), the current study measured the plasma concentrations of six indicator-PCBs by GC-MS/MS and assessed the cognitive dysfunction (CoD) via an Abbreviated Mental Test in 266 participants (ages 61−90). Sequential logistic regression was used to analyze the effects of PCBs on cognition functions. Female participants aged less than or equal to 80 years were selected, and path analysis was used to determine the direct or indirect impacts of co-exposure PCBs on CoD by structural equation modeling. Results: After sequential adjustments to potential confounding factors and correction by the Bonferroni, no statistically significant correlation between PCBs exposure and CoD was found in participants (p > 0.05). However, in the co-exposure system, after controlling for co-exposures and confounders, exposure to PCB28 had a direct effect on CoD in females aged between 61 and 80, with a factor load of 0.670. Conclusions: After adjusting for the co-exposures and confounders, exposure to PCB28 can directly increase the risk of cognitive impairment in older Chinese females.

Thyroid-disrupting effects caused by exposure to alternative flame retardants from groundwater contamination in rural central China.

Accumulating evidence reveals that exposure to alternative flame retardants (AFRs) results in defective thyroid functions. AFRs are detectable in various environmental media in developed cities in China. However, few studies have reported the contamination levels of AFR in groundwater in rural areas, indicating an urgent need to investigate exposure of AFRs and perform health risk assessment for populations that use groundwater as the main source of drinking water. This study investigated the concentrations of AFRs in groundwater in rural areas of central China. Moreover, Nthy-ori-3-1 cells were used to determine the thyroid cytotoxicities and thyroid-interfering effects of a single AFR as well as the mixtures of AFRs based on the AFR contamination levels in real-world. The results revealed that all classes of AFRs were detectable in rural areas in central China. Dechlorane plus, hexabromocyclododecane, bromophenols (BPs), novel brominated flame retardants (NBFRs) and organophosphate flame retardants (OPFRs) exhibited spatial contamination patterns, with an average concentrations (median) of 157.89 ± 88.61 (185.47) pg/L, 0.09 ± 0.29 (not detectable) ng/L, 5.20 ± 5.92 (3.43) ng/L, 3338.11 ± 3758.78 (2836.72) pg/L, and 79.35 ± 97.19 (53.62) ng/L, respectively. The half maximal effective concentrations (EC50) of BPs, OPFRs, and NBFRs ranged 98.4-4012 µM, 42.0-2506 µM, and 10.1-203.7 µM, respectively. Several AFRs exhibited more cytotoxic effects than did traditional brominated flame retardants. It is intriguing that several single AFRs and mixtures at environmentally-relevant exposure levels promoted the viability of Nthy-ori-3-1 cells. Taken together, our study demonstrates that AFRs are present in the groundwater in rural areas in central China and AFRs exhibit thyroid disrupting effects.

Correlation between intestinal microbiotal imbalance and 5-HT metabolism, immune inflammation in chronic unpredictable mild stress male rats.

To explore the role of intestinal microbiota on the occurrence of depression-like behavior. Twenty male adult Wistar rats were randomly divided into control and experimental groups. Depression-like behavior of the rats was validated using sucrose preference test (SPT) and forced swimming test (FST) after chronic unpredictable mild stress (CUMS) for 3 weeks. Fecal microbiota was analyzed through 16S rRNA sequence analysis. The levels of 5-HT and inflammatory factors in the colon, brain and sera were measured using enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR) and western blotting analyses. The percentage of different types of immune cells in the peripheral blood was determined through flow cytometry. CUMS caused depression-like symptoms, including anhedonia and desperate behavior. Significant differences were found in the structure and abundance of intestinal microbiota. CUMS intervention significantly increased the levels of 5-HT and Tph1 in the colon and decreased the level of Scl6a4. The concentrations of 5-HT and Tph2 in the prefrontal and hippocampal tissues were lower, while IDO1 was higher. Certain cytokines, such as IL-6, IL-1 and TNF-ɑ, were significantly elevated in peripheral blood, while the percentage of CD3+ CD4+ double-positive cells and CD4+ /CD8+ ratio were downregulated in the CUMS group. Pearson correlation analysis showed that intestinal microbiota was significantly associated with not only the metabolism of 5-HT in intestinal and brain tissues, but also with the proportion of immune cells and certain cytokines. Stress can lead to disturbances in the intestinal microbial structure, which may contribute to depression by interfering with 5-HT metabolism and immune inflammatory responses.

Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient.

Background: O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant systemic disorder characterized by global developmental delay caused by mutations in the KMT2E gene. The aim of this study was to investigate the role of KMT2E mutations as a cause of ODLURO syndrome in a Chinese boy. Methods: We reported the clinical course of a Chinese boy who was diagnosed with ODLURO syndrome by the whole exome sequencing. We extracted genomic DNA of the proband and parents, gene variations were screened using whole-exome sequencing, followed by validation using direct Sanger sequencing. The effect of mRNA splicing variants were analyzed through a minigene splice assay and in vitro reverse transcription PCR (RT-PCR). Results: The proband presented with recurrent seizures and developmental delay. Using genetic analysis, we identified that the proband carried a de novo heterozygous splicing variant (c.1248+1G>T) in the KMT2E gene. In vivo transcript analysis showed that the proband did not carry any KMT2E mRNA transcript, while a specific exon11-exon13 (440 bp) transcript was detected in the unaffected parents. The in vitro minigene splice assay conducted in HEK293 cells confirmed that the c.1248+1G>T variant resulted in exon 12 skipping, which in turn caused an alteration in KMT2E mRNA splicing. The mutant transcript created a premature stop codon at the 378 amino acid position that could have been caused nonsense-mediated mRNA decay (NMD). Conclusion: We verified the pathogenic effect of the KMT2E c.1248+1G>T splicing variant, which disturbed normal mRNA splicing and caused mRNA decay. Our findings suggest that splice variants play an important role in the molecular basis of ODLURO, and that careful molecular profiling of these patients could play an essential role in tailoring of personalized treatment options soon.

Iodine nutrition status and thyroid autoimmunity during pregnancy: a cross-sectional study of 4635 pregnant women.

BACKGROUND: Pregnant women in Shanghai have long been at risk for mild iodine deficiency. Because thyroid autoimmunity in pregnant women can lead to premature birth and miscarriage as well as neurodevelopmental deficits in the fetus, the aim of this study was to explore the association of iodine nutrition status with thyroid antibodies during pregnancy. METHODS: A pregnancy-birth cohort was conducted including 4635 pregnant women in Shanghai, China. The eligible participants underwent a face-to-face interview and completed questionnaire surveys to collect baseline information and diet intake. Spot urine samples were collected to test urine iodine. Thyroid antibodies including thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyrotrophic antibodies (TRAb) were tested. Single-factor analysis and logistic regression were used to evaluate the association between iodine status and thyroid autoimmunity during pregnancy. RESULTS: The median urinary iodine excretion level in the sample was 138.14 µg/L (interquartile range [IQR] 80.90-219.00 µg/L). Among all the subjects, 25.9% consumed non-iodized salt, 54.5% had iodine deficiency, and 31.0% had thyroid autoimmunity. The proportion of patients with iodine deficiency was significantly higher among those who consumed non-iodized salt (36.9% vs. 33.1%; p = 0.04). After adjusting for age, educational status, former smoker status, former drinker status, first pregnancy, and previous thyroid disease, non-iodized salt (odds ratio [OR] = 1.394 [confidence interval, CI, 1.165-1.562]; p = 0.003), iodine-rich food (OR = 0.681 [CI 0.585-0.793]; p = 0.003), iodized nutritional supplements (OR = 0.427 [CI 0.347-0.526]; p = 0.003), were found to be individually associated with thyroid autoimmunity in all participants. The results of the multivariable restricted cubic spline regression analysis showed a non-linear relationship between the continuous change in iodine intake and thyroid autoimmunity (p = 0.019). Participants with iodine deficiency (urinary iodine concentration, UIC,< 100 µg/L) had an increased risk of testing positive for thyroid antibodies (TPOAb/TgAb/TRAb[+]; OR = 1.324 [CI 1.125-1.559]; p < 0.001). Moreover, this associated existed even after removing participants with previous thyroid disease. CONCLUSION: Inadequate iodine nutrition in pregnant women is an independent risk factor for thyroid autoimmunity in Shanghai. It's important to maintain the adequate iodine status in pregnant women.

Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer.

The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 µM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.

Rationale and Design of the ADIDAS Study: Association Between Dapagliflozin-Induced Improvement and Anemia in Heart Failure Patients.

BACKGROUND: Heart failure (HF) is one of the most serious health concerns worldwide. Anemia is a highly prevalent comorbidity and outcome predictor in HF patients. Sodium glucose co-transport 2 (SGLT2) inhibitors have been demonstrated to reduce the risk of cardiovascular death and HF hospitalization in HF patients. PURPOSE: This investigator-initiated, interventional, prospective, double-blind, multicenter study is designed to investigate whether anemia correction is one of the prerequisites and determinants related to the beneficial effects of dapagliflozin in HF patients. METHODS AND RESULTS: Up to 2030 HF participants receiving standard care will be randomly assigned to either oral dapagliflozin 10 mg once daily or placebo 10 mg once daily for 12 months. The primary outcome is the composite incidence of hospital admission for HF and all-cause death. Secondary outcomes include change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score and change in 6-min walk distance and hemoglobin level. Patients will be followed for 12 months after randomization. CONCLUSIONS: The ADIDAS trial offers an opportunity to assess the hemoglobin change and association between hemoglobin change and readmissions due to heart failure and all-cause death in patients with heart failure treated with dapagliflozin or placebo. This study could highlight if dynamic hemoglobin change is related to the outcome for HF patients. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04707261. Registration date, 2020/12/01, "retrospectively registered".