The impact of mindfulness therapy combined with mentalization-based family therapy on suicidal ideation in adolescents with depressive disorder: randomized intervention study.

BACKGROUND: Adolescents with depression who engage in non-suicidal self harming behaviors are more likely to adopt negative coping strategies when faced with negative events. Therefore, these patients should be introduced to positive coping strategies. Evidences have showed that mindfulness-based interventions can positively impact the psychology of patients with mental disorders. This study was to explore the impact of a combination of mindfulness therapy and mentalization-based family therapy (MBFT) on suicidal ideation in adolescents with depressive disorder. METHODS: Eighty adolescent patients with depression and suicidal ideation admitted to our hospital from September 2021 to February 2022 were selected as subjects. They were divided into a control group and a study group using the random number table method, with each group comprising 40 subjects. The control group received MBFT, whereas the study group received both mindfulness therapy and MBFT. The psychological status and suicidal ideations of the two groups were compared before and after the intervention. RESULTS: The psychological health scores of both groups of patients were lower after the intervention, with the scores of the study group being lower than those of the control group (P < 0.05). The scores on the suicidal ideation scales for both groups were lower after intervention, and the study group scored lower than the control group (P < 0.05). The absolute values of the differences in psychological health scale scores and suicidal ideation scale scores before and after the intervention were higher in the study group than in the control group (P < 0.05). CONCLUSION: The combination of mindfulness therapy and MBFT can improve the psychological condition of adolescents with depression, reduce their suicidal ideations, and help them develop a healthy and positive outlook toward life, making this method worthy of clinical recommendation.

Patterns and driving factors of functional traits of desert species with different elevational distributions in the Tibetan Plateau and adjacent areas.

Variations in functional traits serve as measures of plants' ability to adapt to environment. Exploring the patterns of functional traits of desert plants along elevational gradients is helpful to understand the responses and adaptation strategies of species to changing environments. However, it is unknown whether the relationship between functional traits and elevation is affected by differences in the species' elevational distributions (elevation preference and species' range). Importantly, most researches have concerned with differences in mean trait values and ignored intraspecific trait variation. Here, we measured functional traits of desert plants along a wide elevational gradient in the Tibetan Plateau and adjacent areas and explored functional trait patterns over elevation in species with different elevational distributions. We decomposed trait variation and further investigated characterizations of intraspecific variation. Ultimately, the main drivers of trait variation were identified using redundancy analysis. We found that species' elevational distributions significantly influenced the relationship of functional traits such as plant height, leaf dry matter content, leaf thickness, leaf nitrogen and carbon content with elevation. Species with a lower elevational preference showed greater trait variation than species with a higher elevational preference, suggesting that species that prefer high elevation are more conservative facing environmental changes. We provide evidence that interspecific trait variation in leaf thickness and leaf carbon content decreased with increasing species' range, indicating that increased variations in resistance traits within species make greater responsiveness to environmental changes, enabling species a wider range. Elevation, temperature and precipitation were the main drivers of trait variation in species with a low elevational preference, while the effect of precipitation on trait variation in species with a high elevational preference was not significant. This study sheds new insights on how plants with different elevational distributions regulate their ecological strategies to cope with changing environments.

Inhibition of esophageal cancer progression through HACE1-TRIP12 interaction and associated RAC1 ubiquitination and degradation.

Objective: This study investigated the significance of HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) in esophageal cancer (ESCA) and its underlying mechanism in ESCA regulation through the induction of RAC1 ubiquitination and degradation. Methods: Characterization studies of HACE1 in ESCA clinical tissues and cell lines were performed. Next, the effects of HACE1 on the biological behavior of ESCA cells were examined by silencing and overexpressing HACE1. Protein-protein interactions (PPIs) involving HACE1 were analyzed using data from the String website. The function of HACE1 in RAC1 protein ubiquitination was validated using the proteasome inhibitor MG132. The effects of HACE1 on ESCA cells through RAC1 were elucidated by applying the RAC1 inhibitor EHop-016 in a tumor-bearing nude mouse model. To establish the relationship between HACE1 and TRIP12, rescue experiments were conducted, mainly to evaluate the effect of TRIP12 silencing on HACE1-mediated RAC1 regulation in vitro and in vivo. The PPI between HACE1 and TRIP12 and their subcellular localization were further characterized through co-immunoprecipitation and immunofluorescence staining assays, respectively. Results: HACE1 protein expression was notably diminished in ESCA cells but upregulated in normal tissues. HACE1 overexpression inhibited the malignant biological behavior of ESCA cells, leading to restrained tumor growth in mice. This effect was coupled with the promotion of RAC1 protein ubiquitination and subsequent degradation. Conversely, silencing HACE1 exhibited contrasting results. PPI existed between HACE1 and TRIP12, compounded by their similar subcellular localization. Intriguingly, TRIP12 inhibition blocked HACE1-driven RAC1 ubiquitination and mitigated the inhibitory effects of HACE1 on ESCA cells, alleviating tumor growth in the tumor-bearing nude mouse model. Conclusion: HACE1 expression was downregulated in ESCA cells, suggesting that it curbs ESCA progression by inducing RAC1 protein degradation through TRIP12-mediated ubiquitination.

The impact of 5-aminosalicylates on the efficacy of mesenchymal stem cell therapy in a murine model of ulcerative colitis.

Inflammatory bowel disease (IBD) is distinguished by persistent immune-mediated inflammation of the gastrointestinal tract. Previous experimental investigations have shown encouraging outcomes for the use of mesenchymal stem cell (MSC)-based therapy in the treatment of IBD. However, as a primary medication for IBD patients, there is limited information regarding the potential interaction between 5-aminosalicylates (5-ASA) and MSCs. In this present study, we employed the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model to examine the influence of a combination of MSCs and 5-ASA on the development of UC. The mice were subjected to weight measurement, DAI scoring, assessment of calprotectin expression, and collection of colons for histological examination. The findings revealed that both 5-ASA and MSCs have demonstrated efficacy in the treatment of UC. However, it is noteworthy that 5-ASA exhibits a quicker onset of action, while MSCs demonstrate more advantageous and enduring therapeutic effects. Additionally, the combination of 5-ASA and MSC treatment shows a less favorable efficacy compared to the MSCs alone group. Moreover, our study conducted in vitro revealed that 5-ASA could promote MSC migration, but it could also inhibit MSC proliferation, induce apoptosis, overexpress inflammatory factors (IL-2, IL-12P70, and TNF-α), and reduce the expression of PD-L1 and PD-L2. Furthermore, a significant decrease in the viability of MSCs within the colon was observed as a result of 5-ASA induction. These findings collectively indicate that the use of 5-ASA has the potential to interfere with the therapeutic efficacy of MSC transplantation for the treatment of IBD.

Contrasting impacts of fertilization on topsoil and subsoil greenhouse gas fluxes in a thinned Chinese fir plantation.

Globally, forest soils are considered as important sources and sinks of greenhouse gases (GHGs). However, most studies on forest soil GHG fluxes are confined to the topsoils (above 20 cm soil depths), with only very limited information being available regarding these fluxes in the subsoils (below 20 cm soil depths), especially in managed forests. This limits deeper understanding of the relative contributions of different soil depths to GHG fluxes and global warming potential (GWP). Here, we used a concentration gradient-based method to comprehensively investigate the effects of thinning intensity (15% vs. 35%) and nutrient addition (no fertilizer vs. NPK fertilizers) on soil GHG fluxes from the 0-40 cm soil layers at 10 cm depth intervals in a Chinese fir (Cunninghamia lanceolata) plantation. Results showed that forest soils were the sources of CO2 and N2O, but the sinks of CH4. Soil GHG fluxes decreased with increasing soil depth, with the 0-20 cm soil layers identified as the dominant producers of CO2 and N2O and consumers of CH4. Thinning intensity did not significantly affect soil GHG fluxes. However, fertilization significantly increased CO2 and N2O emissions and CH4 uptake at 0-20 cm soil layers, but decreased them at 20-40 cm soil layers. This is because fertilization alleviated microbial N limitation and decreased water filled pore space (WFPS) in topsoils, while it increased WFPS in subsoils, ultimately suggesting that soil WFPS and N availability (especially NH4+-N) were the predominant regulators of GHG fluxes along soil profiles. Generally, there were positive interactive effects of thinning and fertilization on soil GHG fluxes. Moreover, the 35% thinning intensity without fertilization had the lowest GWP among all treatments. Overall, our results suggest that fertilization may not only cause depth-dependent effects on GHG fluxes within soil profiles, but also impede efforts to mitigate climate change by promoting GHG emissions in managed forest plantations.

Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

Neurosyphilis complicated by anti-γ-aminobutyric acid-B receptor encephalitis: A case report.

BACKGROUND: Syphilis is an infectious disease caused by Treponema pallidum that can invade the central nervous system, causing encephalitis. Few cases of anti-N-methyl-D-aspartate receptor autoimmune encephalitis (AE) secondary to neurosyphilis have been reported. We report a neurosyphilis patient with anti-γ-aminobutyric acid-B receptor (GABABR) AE. CASE SUMMARY: A young man in his 30s who presented with acute epileptic status was admitted to a local hospital. He was diagnosed with neurosyphilis, according to serum and cerebrospinal fluid (CSF) tests for syphilis. After 14 d of antiepileptic treatment and anti-Treponema pallidum therapy with penicillin, epilepsy was controlled but serious cognitive impairment, behavioral, and serious psychiatric symptoms were observed. He was then transferred to our hospital. The Mini-Mental State Examination (MMSE) crude test results showed only 2 points. Cranial magnetic resonance imaging revealed significant cerebral atrophy and multiple fluid-attenuated inversion recovery high signals in the white matter surrounding both lateral ventricles, left amygdala and bilateral thalami. Anti-GABABR antibodies were discovered in CSF (1:3.2) and serum (1:100). The patient was diagnosed with neurosyphilis complicated by anti-GABABR AE, and received methylprednisolone and penicillin. Following treatment, his mental symptoms were alleviated. Cognitive impairment was significantly improved, with a MMSE of 8 points. Serum anti-GABABR antibody titer decreased to 1:32. The patient received methylprednisolone and penicillin after discharge. Three months later, the patient's condition was stable, but the serum anti-GABABR antibody titer was 1:100. CONCLUSION: This patient with neurosyphilis combined with anti-GABABR encephalitis benefited from immunotherapy.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

[Chaihu Sanshen Capsules protect rats from myocardial ischemia reperfusion injury via PKCßâ ¡/NOX2/ROS signaling pathway].

This study aims to explore the pathogenesis of myocardial ischaemia reperfusion injury(MIRI) based on oxidative stress-mediated programmed cell death and the mechanism and targets of Chaihu Sanshen Capsules in treating MIRI via the protein kinase Cß(PKCßⅡ)/NADPH oxidase 2(NOX2)/reactive oxygen species(ROS) signaling pathway. The rat model of MIRI was established by the ligation of the left anterior descending branch. Rats were randomized into 6 groups: sham group, model group, clinically equivalent-, high-dose Chaihu Sanshen Capsules groups, N-acetylcysteine group, and CGP53353 group. After drug administration for 7 consecutive days, the area of myocardial infarction in each group was measured. The pathological morphology of the myocardial tissue was observed by hematoxylin-eosin(HE) staining. The apoptosis in the myocardial tissue was observed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL). Enzyme-linked immunosorbent assay(ELISA) was employed to measure the le-vels of indicators of myocardial injury and oxidative stress. The level of ROS was detected by flow cytometry. The protein and mRNA levels of the related proteins in the myocardial tissue were determined by Western blot and real-time quantitative PCR(RT-qPCR), respectively. Compared with the sham group, the model group showed obvious myocardial infarction, myocardial structural disorders, interstitial edema and hemorrhage, presence of a large number of vacuoles, elevated levels of myocardial injury markers, myocardial apoptosis, ROS, and malondialdehyde(MDA), lowered superoxide dismutase(SOD) level, and up-regulated protein and mRNA le-vels of PKCßⅡ, NOX2, cysteinyl aspartate specific proteinase-3(caspase-3), and acyl-CoA synthetase long-chain family member 4(ACSL4) in the myocardial tissue. Compared with the model group, Chaihu Sanshen Capsules reduced the area of myocardial infarction, alleviated the pathological changes in the myocardial tissue, lowered the levels of myocardial injury and oxidative stress indicators and apoptosis, and down-regulated the mRNA and protein levels of PKCßⅡ, NOX2, caspase-3, and ACSL4 in the myocardial tissue. Chaihu Sanshen Capsules can inhibit oxidative stress and programmed cell death(apoptosis, ferroptosis) by regulating the PKCßⅡ/NOX2/ROS signaling pathway, thus mitigating myocardial ischemia reperfusion injury.

Two new chemical constituents from the aerial parts of Tripterygium wilfordii.

Tripterygium wilfordii has been historically employed as a conventional botanical insecticide and a plant of medicinal significance. A new dihydroagarofuran sesquiterpene (1) and a new acyclic compound (2), along with seven known compounds (3-9), have been isolated from the aerial parts of Tripterygium wilfordii. The identification of the structures of novel compounds were accomplished through comprehensive spectroscopic analyses, encompassing HRESIMS, NMR, UV, IR, and a comparative analysis with spectroscopic data from compounds previously characterised. In in-vitro bioassay, compound 8 exhibited significant inhibitory activity for NO release in LPS-induced RAW 264.7 cells, with an IC50 value of 15.7 µM.

Low-molecular-weight heparin and preeclampsia - does the sword cut both ways? Three case reports and review of literature.

BACKGROUND: Low-molecular-weight heparins (LMWH) are the most commonly used anticoagulants during pregnancy. It is considered to be the drug of choice due to its safety in not crossing placenta. Considering the beneficial effect in the improvement of microcirculation, prophylactic application of LMWH in patients with preeclampsia became a trend. However, the bleeding risk related with LMWH in preeclampsia patients has seldomly been evaluated. This current study aimed to identify the potential risks regarding LMWH application in patients with preeclampsia. CASE SUMMARY: Herein we present a case series of three pregnant women diagnosed with preeclampsia on LMWH therapy during pregnancy. All the cases experienced catastrophic hemorrhagic events. After reviewing the twenty-one meta-analyses, the bleeding risk related with LMWH seems ignorable. Only one study analyzed the bleeding risk of LMWH and found a significantly higher risk of developing PPH in women receiving LMWH. Other studies reported minor bleeding risks, none of these were serious enough to stop LMWH treatment. Possibilities of bleeding either from uterus or from intrabdominal organs in preeclampsia patients on LMWH therapy should not be ignored. Intensive management of blood pressure even after delivery and homeostasis suture in surgery are crucial. CONCLUSION: Consideration should be given to the balance between benefits and risks of LMWH in patients with preeclampsia.

Effects of hypertension and use of antihypertensive drugs in pregnancy on the risks of childhood cancers in Taiwan.

BACKGROUND: Childhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks. OBJECTIVE: This population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring. METHODS: Data on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers. RESULTS: Offspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth. CONCLUSIONS: In this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

Role of phosphate in microalgal-bacterial symbiosis system treating wastewater containing heavy metals.

Phosphorus is one of the important factors to successfully establish the microalgal-bacterial symbiosis (MABS) system. The migration and transformation of phosphorus can occur in various ways, and the effects of phosphate on the MABS system facing environmental impacts like heavy metal stress are often ignored. This study investigated the roles of phosphate on the response of the MABS system to zinc ion (Zn2+). The results showed that the pollutant removal effect in the MABS system was significantly reduced, and microbial growth and activity were inhibited with the presence of Zn2+. When phosphate and Zn2+ coexisted, the inhibition effects of pollutants removal and microbial growth rate were mitigated compared to that of only with the presence of Zn2+, with the increasing rates of 28.3% for total nitrogen removal, 48.9% for chemical oxygen demand removal, 78.3% for chlorophyll-a concentration, and 13.3% for volatile suspended solids concentration. When phosphate was subsequently supplemented in the MABS system after adding Zn2+, both pollutants removal efficiency and microbial growth and activity were not recovered. Thus, the inhibition effect of Zn2+ on the MABS system was irreversible. Further analysis showed that Zn2+ preferentially combined with phosphate could form chemical precipitate, which reduced the fixation of MABS system for Zn2+ through extracellular adsorption and intracellular uptake. Under Zn2+ stress, the succession of microbial communities occurred, and Parachlorella was more tolerant to Zn2+. This study revealed the comprehensive response mechanism of the co-effects of phosphate and Zn2+ on the MABS system, and provided some insights for the MABS system treating wastewater containing heavy metals, as well as migration and transformation of heavy metals in aquatic ecosystems.

Triterpenoids and triterpenoid saponins from Vitex negundo and their anti-inflammatory activities.

Seven undescribed polyoxygenated ursane-type triterpenoids (vitnegundins A-G), three undescribed triterpenoid saponins (vitnegundins H-J), and 17 known ones were isolated from an EtOH extract of the aerial parts of Vitex negundo L. The structures of the undescribed compounds were established by extensive spectroscopic analysis. The absolute configurations of vitnegundins A, B, and E were determined by single-crystal X-ray diffraction data. Vitnegundins B-D are pentacyclic triterpenoids possessing rare cis-fused C/D rings and vitnegundins C-H represent undescribed ursane-type triterpenoids with 12,19-epoxy moiety. In the biological activity assay, vitnegundin A, vitnegundin E, and swinhoeic acid displayed inhibitory effects against LPS-induced NO release in BV-2 microglial cells, with IC50 values of 11.8, 44.2, and 19.6 µM, respectively.

Experimental study on the full cycle evolution of high-intensity atmospheric dc arc discharge from breakdown to extinguishment.

In this study, the spatiotemporal evolution of full cycle of high-intensity dc argon arc discharge at atmospheric pressure is investigated by using a transferred arc device, which is easy to be directly observed in the experiment. Combining the voltage and current waveforms with high-speed images, the full cycle evolution process of high-intensity atmospheric dc arc can be divided into five different stages: breakdown pulse stage, cathode heating stage, current climbing stage, stable arc discharge stage, and finally arc extinguishing stage. The characteristics of each different stage are analyzed in detail through the electrical properties, high-speed pictures, and spectroscopic measurements. The results show that the strong luminescence region develops from the vicinity of cathode and anode to the middle in the breakdown pulse stage, which is explained from the spatiotemporal evolution of distributions of excited argon atom and ions. The development velocity of emission intensity of argon ions is mainly determined by the dominant stepwise ionization process. Then the cathode heating stage appears with many bright and nonuniformly distributed light spots on the cathode surface, and the electron emission mechanism of cathode gradually changes to the thermionic emission as the surface temperature rises. With the increase of arc current, the discharge channel significantly expands, then becomes stable due to the increment of the Lorentz force. The characteristics of arc extinguishing stage are clarified in terms of the decay of charged particles density.

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together.

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children's Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

Prognostic Significance of KIF-12 Functioning as a Tumour Suppressor in Papillary Thyroid Carcinoma.

Objective: To explore the potential value of a novel marker, KIF-12, in the progression and prognosis of papillary thyroid carcinoma (PTC) through integrative bioinformatics analysis, and clinical sample validation of the prognostic value of KIF-12. Materials and Methods: We extracted the clinicopathological data of 502 PTC patients from The Cancer Genome Atlas-Thyroid Cancer (TCGA-THCA) dataset to identify reliable differentially expressed genes (DEGs) between high and low KIF12 expression groups. Functional enrichment analysis was performed on upregulated DEGs. Gene set enrichment analysis (GESA) was performed to identify the biological pathways. We further applied Cox analysis to determine independent risk factors associated with the PTC progression-free interval (PFI), and a nomogram was established to predict disease outcome. Finally, the prognostic value of KIF12 was validated by means of clinical samples from PTC patients with and without lateral lymph node metastasis. Results: On the basis of the TCGA-THCA database, we found that low KIF-12 expression was significantly related to a higher TNM stage (p<0.05), BRAF mutation status (p = 0.019), and extrathyroidal extension (p<0.001). KIF-12 was an independent prognostic factor of PTC (OR=0.319, 95% CI=0.130-0.784, P=0.013). The prognostic value of KIF12 was also successfully validated in clinical samples from twenty-nine PTC patients with lateral lymph node metastasis by comparison with twenty-two PTC patients without lymph node metastasis (P = 0.004). Conclusions: We report that KIF-12 has a tumor suppressive function in PTC and may be a useful prognostic tool to predict patient outcomes.

Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies.

Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

The effect of nitrogen input on N2O emission depends on precipitation in a temperate desert steppe.

Nitrous oxide (N2O) is the third most important greenhouse gas, and can damage the atmospheric ozone layer, with associated threats to terrestrial ecosystems. However, to date it is unclear how extreme precipitation and nitrogen (N) input will affect N2O emissions in temperate desert steppe ecosystems. Therefore, we conducted an in-situ in a temperate desert steppe in the northwest of Inner Mongolia, China between 2018 and 2021, in which N inputs were combined with natural extreme precipitation events, with the aim of better understanding the mechanism of any interactive effects on N2O emission. The study result showed that N2O emission in this desert steppe was relatively small and did not show significant seasonal change. The annual N2O emission increased in a non-linear trend with increasing N input, with a much greater effect of N input in a wet year (2019) than in a dry year (2021). This was mainly due to the fact that the boost effect of high N input (on June 17th 2019) on N2O emission was greatly amplified by nearly 17-46 times by an extreme precipitation event on June 24th 2019. In contrast, this greatly promoting effect of high N input on N2O emission was not observed on September 26th 2019 by a similar extreme precipitation event. Further analysis showed that soil NH4+-N content and the abundance of ammonia oxidizing bacteria (amoA (AOB)) were the most critical factors affecting N2O emission. Soil moisture played an important indirect role in regulating N2O emission, mainly by influencing the abundance of amoA (AOB) and de-nitrification functional microorganisms (nosZ gene). In conclusion, the effect of extreme precipitation events on N2O emission was greatly increased by high N input. Furthermore, in this desert steppe, annual N2O flux is co-managed through soil nitrification substrate concentration (NH4+-N), the abundance of soil N transformation functional microorganisms and soil moisture. Overall, it was worth noting that an increase in extreme precipitation coupled with increasing N input may significantly increase future N2O emissions from desert steppes.