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Abstract Background Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer’s disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets. Methods We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent. Results We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment. Conclusions Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.

Abstract Background Metastasis is the primary cause of recurrence and death in patients with papillary thyroid carcinoma (PTC). LncRNA ACTA2-AS1, a long non-coding RNA, acts as a tumor suppressor in multiple types of human malignancies, while the role of ACTA2-AS1 in PTC metastasis remains unclear. Methods The ACTA2-AS1 expression in PTC tissues was analyzed. The sponged roles of ACTA2-AS1 via miR-4428/KLF9 axis were identified using starBase tool. The function of ACTA2-AS1 in PTC was performed with in vitro and in vivo experiments. The correlation between DNA methylation and mRNA expressions of these gene in the TCGA dataset was explored. Results ACTA2-AS1 expression was downregulated in PTC tissues without metastasis and further decreased in PTC tissues with lymph node metastasis compared with that in normal tissues. Functionally, the overexpression of ACTA2-AS1 inhibited the growth, proliferation, and invasion of PTC cells, whereas its depletion exerted opposite effect. In vivo, ACTA2-AS1 expression inhibited PTC metastasis. Furthermore, ACTA2-AS1 acted as a competing endogenous RNA for miR-4428, thereby positively regulating the expression of miR-4428 target gene, KLF9. Finally, miR-4428 overexpression enhanced invasive potential of PTC cells and significantly weakened the effects of ACTA2-AS1 on promotion and inhibition of KLF9 expression as well as invasive ability of PTC cells, respectively. In the TCGA dataset, the methylation level of ACTA2-AS1 was significantly correlated with its mRNA expression (r = 0.21, p = 2.1 × e−6). Conclusions Our findings demonstrate that ACTA2-AS1 functions as a tumor suppressor in PTC progression at least partly by regulating the miR-4428-dependent expression of KLF9. Graphical abstract

Background and ObjectivePrevious research suggested a relationship between the Systemic Immune-Inflammation Index (SII) and multiple adverse health conditions. However, the role of SII in prediabetes and insulin resistance (IR) remains poorly understood. Therefore, this study aims to explore the potential relationship between SII and prediabetes and IR, providing data support for effective diabetes prevention by reducing systemic inflammation.MethodsLinear regression models were used to assess the correlation between continuous SII and risk markers for type 2 diabetes (T2D). Subsequently, multivariate logistic regression models and subgroup analyses were employed to evaluate the association between SII tertiles and prediabetes and IR, controlling for various confounding factors. Finally, restricted cubic spline graphs were used to analyze the nonlinear relationship between SII and IR and prediabetes.ResultsAfter controlling for multiple potential confounders, SII was positively correlated with fasting blood glucose (FBG) (β: 0.100; 95% CI: 0.040 to 0.160), fasting serum insulin (FSI) (β: 1.042; 95% CI: 0.200 to 1.885), and homeostasis model assessment of insulin resistance (HOMA-IR) (β: 0.273; 95% CI: 0.022 to 0.523). Compared to participants with lower SII, those in the highest tertile had increased odds of prediabetes (OR: 1.17; 95% CI: 1.02-1.34; p for trend < 0.05) and IR (OR: 1.35; 95% CI: 1.18 to 1.51; p for trend

Peer relationships play an indispensable role in the social, emotional, and cognitive development of children. However, children exhibiting social withdrawal, such as unsociability, may face challenges in social adjustment. In collectivistic cultures like China, unsociability may be perceived negatively, aligning poorly with collective norms. The objective of the present investigation was to examine the associations between unsociability, receptive vocabulary, and indicators of social adjustment in a cohort of young migrant children residing in urban regions of mainland China. The study mainly aimed to investigate the potential moderating influence of receptive language on these associations. The study involved 148 young children (82 boys, 66 girls, Mage = 62.32 months, SD = 6.76) enrolled in preschools or kindergartens in Shanghai, People’s Republic of China. Multiple sources of assessment were utilized, encompassing evaluations from mothers (about child unsociability), teacher (assessing social adjustment), and standardized tests (measuring receptive vocabulary). The results indicated that the relations between unsociability and peer exclusion were more positive among children with lower levels of receptive vocabulary but not significant for children with higher levels of receptive vocabulary. Similarly, the relations between unsociability and peer exclusion were more negative among children with lower levels of receptive vocabulary but not significant for children with higher levels of receptive vocabulary. Thus, this study informs us about how receptive vocabulary is jointly associated with unsociable children’s development. As well, the findings highlight the importance of considering the meaning and implication of unsociability in Chinese culture.

IntroductionConduct problems in children are related to callous-unemotional (CU) behaviors. However, results of the relationships between CU behaviors and conduct problems among preschoolers mainly focused on Western countries, no studies have examined whether CU behaviors predict conduct problem in Chinese preschoolers. The primary objective of the current study therefore was to examine the associations between CU behaviors and conduct problems as well as the moderating effects of surgency and child gender in Chinese preschool children.MethodsThe present study randomly selected 2,154 children (1,043 boys, Mage = 56 months, SD = 10.47) from six kindergartens in Shanghai, People’s Republic of China. Mothers rated children’s surgency and teachers reported children’s CU behaviors and conduct problems.ResultsResults demonstrated that CU behaviors were positively associated with conduct problems. Surgency and child gender significantly moderated these associations. Specifically, CU behaviors were positively associated with conduct problems, with a stronger effect found for high levels of surgency. CU behaviors had a positive association with conduct problems, with a stronger effect found for boys.DiscussionThis study indicate that temperament and gender characteristics influence conduct problems in preschoolers who exhibit high levels of CU behaviors. As well, the findings emphasize the significance of considering the meaning and implication of CU behaviors in Chinese culture.

Abstract Alzheimer disease (AD) is a common neurodegenerative disease with a late onset. It is critical to identify novel blood-based DNA methylation biomarkers to better understand the extent of the molecular pathways affected in AD. Two sets of blood DNA methylation genetic prediction models developed using different reference panels and modelling strategies were leveraged to evaluate associations of genetically predicted DNA methylation levels with AD risk in 111,326 (46,828 proxy) cases and 677,663 controls. A total of 1,168 cytosine-phosphate-guanine (CpG) sites showed a significant association with AD risk at a false discovery rate (FDR)

Abstract Background Promyelocytic leukemia protein (PML) is a primary component of PML nuclear bodies (PML-NBs). PML and PML-NBs play critical roles in processes like the cell cycle, DNA damage repair, apoptosis, and the antiviral immune response. Previously, we identified five porcine PML alternative splicing variants and observed an increase in the expression of these PML isoforms following Japanese encephalitis virus (JEV) infection. In this study, we examined the functional roles of these PML isoforms in JEV infection. Methods PML isoforms were either knocked down or overexpressed in PK15 cells, after which they were infected with JEV. Subsequently, we analyzed the gene expression of PML isoforms, JEV, and the interferon (IFN)-β signaling pathway using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Viral titers were determined through 50% tissue culture infectious dose (TCID50) assays. Results Our results demonstrated that the knockdown of endogenous PML promoted JEV replication, while the overexpression of PML isoforms 1, 3, 4, and 5 (PML1, PML3, PML4, and PML5) inhibited JEV replication. Further investigation revealed that PML1, PML3, PML4, and PML5 negatively regulated the expression of genes involved in the interferon (IFN)-β signaling pathway by inhibiting IFN regulatory factor 3 (IRF3) post-JEV infection. Conclusions These findings demonstrate that porcine PML isoforms PML1, PML3, PML4, and PML5 negatively regulate IFN-β and suppress viral replication during JEV infection. The results of this study provide insight into the functional roles of porcine PML isoforms in JEV infection and the regulation of the innate immune response.

High temperatures affect grape yield and quality. Grapes can develop thermotolerance under extreme temperature stress. However, little is known about the changes in transcription that occur because of high-temperature stress. The heat resistance indices and transcriptome data of five grape cultivars, ‘Xinyu’ (XY), ‘Miguang’ (MG), ‘Summer Black’ (XH), ‘Beihong’ (BH), and ‘Flame seedless’ (FL), were compared in this study to evaluate the similarities and differences between the regulatory genes and to understand the mechanisms of heat stress resistance differences. High temperatures caused varying degrees of damage in five grape cultivars, with substantial changes observed in gene expression patterns and enriched pathway responses between natural environmental conditions (35 °C ± 2 °C) and extreme high temperature stress (40 °C ± 2 °C). Genes belonging to the HSPs, HSFs, WRKYs, MYBs, and NACs transcription factor families, and those involved in auxin (IAA) signaling, abscisic acid (ABA) signaling, starch and sucrose pathways, and protein processing in the endoplasmic reticulum pathway, were found to be differentially regulated and may play important roles in the response of grape plants to high-temperature stress. In conclusion, the comparison of transcriptional changes among the five grape cultivars revealed a significant variability in the activation of key pathways that influence grape response to high temperatures. This enhances our understanding of the molecular mechanisms underlying grape response to high-temperature stress.

Abstract Skin wound healing often leads to scar formation, presenting physical and psychological challenges for patients. Advancements in messenger RNA (mRNA) modifications offer a potential solution for pulsatile cytokine delivery to create a favorable wound‐healing microenvironment, thereby preventing cutaneous fibrosis. This study aimed to investigate the effectiveness of human adipose‐derived stem cells (hADSCs) enriched with N1‐methylpseudouridine (m1ψ) modified transforming growth factor‐β3 (TGF‐β3) and interleukin‐10 (IL‐10) mRNA in promoting scar‐free healing in preclinical models. The results demonstrated that the modified mRNA (modRNA)‐loaded hADSCs efficiently and temporarily secreted TGF‐β3 and IL‐10 proteins. In a dorsal injury model, hADSCs loaded with modRNA TGF‐β3 and IL‐10 exhibited multidimensional therapeutic effects, including improved collagen deposition, extracellular matrix organization, and neovascularization. In vitro experiments confirmed the ability of these cells to markedly inhibit the proliferation and migration of keloid fibroblasts, and reverse the myofibroblast phenotype. Finally, collagen degradation mediated by matrix metalloproteinase upregulation was observed in an ex vivo keloid explant culture model. In conclusion, the synergistic effects of the modRNA TGF‐β3, IL‐10, and hADSCs hold promise for establishing a scar‐free wound‐healing microenvironment, representing a robust foundation for the management of wounds in populations susceptible to scar formation.

This paper presents a theoretical framework for the business decision-making process of the power generators as price takers when considering the participation of energy storage. The framework assesses rational valuation, optimal sales strategies, and hedging options for power plants with and without a gross sales constraint. The valuation and optimal sales strategy problems are analyzed using a risk-neutral pricing approach, dynamic programming principles, and the trinomial tree model suitable for the regime switching model. The formulation of a price risk hedging scheme flexible and widely used over-the-counter electricity derivative, the electricity contract for difference, as a tool for hedging electricity spot price risk. The minimum variance hedge ratio and its corresponding hedging efficiency formula are derived. In the section of numerical simulations, we first use the EM algorithm to calibrate the electricity spot model based on electricity spot price data of Nord Pool. Numerical simulations are then conducted on the operational decision-making of power generators under three different forms of energy storage. The results of the simulations provide a basis for power generators to evaluate the real-time value of power plants, to select optimal real-time power sales, and to determine the optimal timing of power plant transfer and storage methods.

Purpose: This study aims to revolutionize the treatment of aggressive triple-negative breast cancer (TNBC), notorious for its resistance to standard therapies. By ingeniously combining Tamoxifen (TMX) and Docetaxel (DTX) within a lipid-coated mesoporous silica nanoparticle (LP-MSN) delivery system, we intend to enhance therapeutic efficacy while circumventing DTX resistance mediated by CYP3A4 expression. Methods: We rigorously tested TNBC cell lines to confirm the responsiveness to Docetaxel (DTX) and Tamoxifen (TMX). We adeptly engineered LP-MSN nanoparticles and conducted a thorough examination of the optimal drug release strategy, evaluating the LP-MSN system's ability to mitigate the impact of CYP3A4 on DTX. Additionally, we comprehensively analyzed its pharmacological performance. Results: Our innovative approach utilizing TMX and DTX within LP-MSN showcased remarkable efficacy. Sequential drug release from the lipid layer and mesoporous core curbed CYP3A4-mediated metabolism, substantially enhancing cytotoxic effects on TNBC cells without harming normal cells. Conclusion: This pioneering research introduces a breakthrough strategy for tackling TNBC. By capitalizing on synergistic TMX and DTX effects via LP-MSN, we surmount drug resistance mediated by CYP3A4. This advancement holds immense potential for transforming TNBC treatment, warranting further clinical validation.

Objectives: Previous studies have suggested a potential link between glycan levels and pancreatic cancer. To better characterize this relationship, we performed a study to evaluate the association between genetically predicted N-glycan levels in plasma and pancreatic cancer risk. Methods: Using genetic variants identified to be associated with plasma N-glycan levels in large genome-wide association studies (GWAS) as instruments, we evaluated the associations between plasma N-glycans and pancreatic cancer risk by analyzing data from 8275 pancreatic cancer cases and 6723 controls. Results: We observed that lower predicted PGP110 levels were significantly associated with an increased risk of pancreatic cancer after adjusting for multiple comparisons. Conclusions: Our study did not support strong associations between human plasma N-glycans and the risk of pancreatic cancer, although the observed association with PGP110 warrants further investigation. Simple summary Objectives: Pancreatic cancer is a fatal malignancy. Therefore, there is an urgent need to better understand its risk factors and identify markers for better predicting individual risk of developing this cancer. Previous research has suggested that glycans may play a role in the development of pancreatic cancer. To better understand their relationship, we conducted a study to assess the associations between N-glycan levels predicted by genetic factors and pancreatic cancer risk. Methods: We used genetic factors related to blood N-glycan levels as instruments. We further evaluated the associations between plasma N-glycans and pancreatic cancer risk by analyzing data from 8275 pancreatic cancer patients and 6723 controls. Results: We only observed one association between predicted levels of PGP110 and pancreatic cancer risk. Conclusions: Our study did not support strong associations between N-glycan levels and pancreatic cancer risk, although the observed association with PGP110 can be further studied.

ABSTRACTObjective: To explore the prognostic value of red blood cell distribution width (RDW) in newly diagnosed aplastic anemia (AA) patients treated with cyclosporine A (CsA) plus androgen or CsA alone.Methods: We retrospectively analyzed the clinical outcome of 220 patients with AA. According to the baseline level of RDW before treatment, the patients were divided into the high-RDW group (RDW ≥ 15%) and the normal-RDW group (RDW

Abstract Introduction The Davos Assessment of Cognitive Biases Scale (DACOBS) is widely used to assess cognitive biases in patients who have schizophrenia. However, the lack of a modified Chinese‐language version of the DACOBS (MCL‐DACOBS) precludes Chinese schizophrenic patients from treatment aimed at normalizing cognitive biases, impacting their prognosis. Here, we aimed to produce a DACOBS for China and test the validity and reliability of the resultant MCL‐DACOBS. Methods Eighteen researchers collaborated to develop the MCL‐DACOBS: A total of 15 researchers modified and translated the English version of the DACOBS, 1 native‐English‐speaking researcher back‐translated the scale, and 2 Chinese sinologists localized and optimized the language of the MCL‐DACOBS. Forty‐two volunteers checked the scale items’ comprehensibility, and the two sinologists performed further localization and optimization based on their feedback. The final version of the MCL‐DACOBS used in this study was thus derived from the harmonized English‐language version of the scale. Confirmatory factor analyses (CFAs) were used to examine the best latent structure of the MCL‐DACOBS. Cronbach's α and intraclass correlation coefficients (ICCs) were used to check the reliability. The discriminative ability of the MCL‐DACOBS was assessed according to the area under the receiver operating characteristic curve. Results The CFA showed that all items loaded onto factors with loadings >0.400. A two‐factor structure showed a good model fit (root mean square error of approximation = .018, Tucker–Lewis index = .978, comparative fit index = .984). Promax rotation demonstrated that each item had a high factor load (0.432–0.774). Cronbach's α coefficient and ICC for the MCL‐DOCABS were .965 and .957, respectively, indicating that the scale has ideal reliability. Conclusion The MCL‐DACOBS has good validity and good reliability, and its psychometric properties indicate that it is a valid tool for measuring cognitive biases in Chinese patients with schizophrenia.

The single cell RNA sequencing technique has been particularly used during the last years, allowing major discoveries. However, the widespread application of this analysis has showed limitations. Indeed, the direct study of fresh tissues is not always feasible, notably in the case of genetically engineered mouse embryo or sensitive tissues whose integrity is affected by classical digestion methods. To overcome these limitations, single nucleus RNA sequencing offers the possibility to work with frozen samples. Thus, single nucleus RNA sequencing can be performed after genotyping-based selection on samples stocked in tissue bank and is applicable to retrospective studies. Therefore, this technique opens the field to a wide range of applications requiring adapted protocols for nucleus isolation according to the tissue considered. Here we developed a protocol of nucleus isolation from frozen murine placenta and pancreas. These two complex tissues were submitted to a combination of enzymatic and manual dissociation before undergoing different steps of washing and centrifugation. The entire protocol was performed with products usually present in a research lab. Before starting the sequencing process, nuclei were sorted by flow cytometry. The results obtained validate the efficiency of this protocol which is easy to set up and does not require the use of commercial kits. This specificity makes it adaptable to different organs and species. The association of this protocol with single nucleus RNA sequencing allows the study of complex samples that resist classical lysis methods due to the presence of fibrotic or fatty tissue, such as fibrotic kidney, tumors, embryonic tissues or fatty pancreas.

Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles in etiology of AD remain largely elusive. We performed a comprehensive splicing transcriptome-wide association study (spTWAS) using intronic excision expression genetic prediction models of 12 brain tissues developed through three modelling strategies, to identify candidate susceptibility splicing introns for AD risk. A total of 111,326 (46,828 proxy) cases and 677,663 controls of European ancestry were studied. We identified 343 associations of 233 splicing introns (143 genes) with AD risk after Bonferroni correction (0.05/136,884 = 3.65 × 10−7). Fine-mapping analyses supported 155 likely causal associations corresponding to 83 splicing introns of 55 genes. Eighteen causal splicing introns of 15 novel genes (EIF2D, WDR33, SAP130, BYSL, EPHB6, MRPL43, VEGFB, PPP1R13B, TLN2, CLUHP3, LRRC37A4P, CRHR1, LINC02210, ZNF45-AS1, and XPNPEP3) were identified for the first time to be related to AD susceptibility. Our study identified novel genes and splicing introns associated with AD risk, which can improve our understanding of the etiology of AD.

Abstract Voriconazole is a first‐line medicine for treating invasive fungal infections. We evaluated the pharmacokinetics (PK) and safety of single/multiple doses of voriconazole injection of Hailing Pharmaceutical Group (Test, T), an imitation of Vfend® (Reference, R). Healthy subjects (n = 36) randomly received a once‐daily dose of T or R 3 or 4 mg/kg on Day 1 (single dose), a once‐daily dose of T or R 6 mg/kg on Day 4, and then six consecutive days for twice‐daily doses of T or R 3 or 4 mg/kg (multiple doses). The plasma was collected up to 72 h at time points after dosing on Day 1/10. Samples were measured by the liquid chromatography tandem mass spectrometry method. PK parameters were confirmed according to a non‐compartmental model. The relationship between the PK profiles of T and R revealed the different behavior in 3‐ and 4‐mg/kg groups. After single/multiple doses in the 3‐mg/kg group, the mean value for the area under the plasma concentration–time curve (AUC0−t, AUC0−∞) of R is about twice T. However, there was a high degree of similarity in the 4‐mg/kg group. The maximum plasma concentration (Cmax) of T and R showed no noticeable difference in the two groups. The median Tmax of T and R were within 2.0–2.13 h in the 3‐mg/kg group and 2.0–2.17 h in the 4‐mg/kg group. Severe adverse events did not occur. No clinically significant differences were found in safety and tolerance between T and R. This clinical study indicated that voriconazole injection might provide a safer alternative medicine.

Background Acute myeloid leukemia (AML) with t(8;21) is generally associated with a favorable clinical course. Loss of sex chromosome (LOS) are frequently observed in t (8;21) AML, but the prognostic value of LOS remains uncertain.Methods A total of 73 patients with AML with t(8;21) were studied and divided into t(8;21) with LOS group (n = 36) and t(8;21) alone group (n = 37). The patients with t(8;21) AML with ACAs other than LOS were excluded. The clinical characteristics of these two groups were compared, and the prognostic value of LOS was evaluated based on disease-free survival (DFS) and overall survival (OS).Results The clinical characteristics (except for gender) were found to have no significant difference between these two groups, and the male patients tended to account for a larger proportion in the former group (P = .001). The OS of the t(8;21) AML with LOS group was significantly longer than that of the t(8;21) AML alone group (P = .005). While not obvious, the patients with LOS seemed to have longer DFS (P = .061). The multivariable analysis also showed LOS to be an independent favorable prognostic factor of t(8;21) AML (P = .022).Conclusions Our results suggested that LOS could be associated with a favorable prognosis in t(8;21) AML patients without other ACAs, and for this subtype of AML, longer DFS and a satisfactory and stable survival can be achieved with high-dose cytarabine (HDAC) consolidation treatment.

Background Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-dioxygenase (TDO) are enzymes catabolizing the essential amino acid tryptophan into kynurenine. Expression of these enzymes is frequently observed in advanced-stage cancers and is associated with poor disease prognosis and immune suppression. Mechanistically, the respective roles of tryptophan shortage and kynurenine production in suppressing immunity remain unclear. Kynurenine was proposed as an endogenous ligand for the aryl hydrocarbon receptor (AHR), which can regulate inflammation and immunity. However, controversy remains regarding the role of AHR in IDO1/TDO-mediated immune suppression, as well as the involvement of kynurenine. In this study, we aimed to clarify the link between IDO1/TDO expression, AHR pathway activation and immune suppression.Methods AHR expression and activation was analyzed by RT-qPCR and western blot analysis in cells engineered to express IDO1/TDO, or cultured in medium mimicking tryptophan catabolism by IDO1/TDO. In vitro differentiation of naïve CD4+ T cells into regulatory T cells (Tregs) was compared in T cells isolated from mice bearing different Ahr alleles or a knockout of Ahr, and cultured in medium with or without tryptophan and kynurenine.Results We confirmed that IDO1/TDO expression activated AHR in HEK-293-E cells, as measured by the induction of AHR target genes. Unexpectedly, AHR was also overexpressed on IDO1/TDO expression. AHR overexpression did not depend on kynurenine but was triggered by tryptophan deprivation. Multiple human tumor cell lines overexpressed AHR on tryptophan deprivation. AHR overexpression was not dependent on general control non-derepressible 2 (GCN2), and strongly sensitized the AHR pathway. As a result, kynurenine and other tryptophan catabolites, which are weak AHR agonists in normal conditions, strongly induced AHR target genes in tryptophan-depleted conditions. Tryptophan depletion also increased kynurenine uptake by increasing SLC7A5 (LAT1) expression in a GCN2-dependent manner. Tryptophan deprivation potentiated Treg differentiation from naïve CD4+ T cells isolated from mice bearing an AHR allele of weak affinity similar to the human AHR.Conclusions Tryptophan deprivation sensitizes the AHR pathway by inducing AHR overexpression and increasing cellular kynurenine uptake. As a result, tryptophan catabolites such as kynurenine more potently activate AHR, and Treg differentiation is promoted. Our results propose a molecular explanation for the combined roles of tryptophan deprivation and kynurenine production in mediating IDO1/TDO-induced immune suppression.

ObjectivesThis study aimed to explore the moderating role of teacher–child relationships in the relations between social avoidance and social adjustment (i.e., prosocial behavior, peer exclusion, and anxious-fearful behavior) in Chinese migrant preschoolers.MethodsParticipants were 148 migrant children aged 4–6 years (82 boys, Mage = 62.32, SD = 6.67) attending kindergartens in Shanghai, People's Republic of China. Mothers reported children's social avoidance, and teachers rated teacher–child relationships and children's social adjustment.ResultsResults indicated that social avoidance was positively related to peer exclusion and negatively related to prosocial behavior. Teacher–child relationships moderated those associations. Specifically, teacher–child closeness buffered the relationship between social avoidance and peer exclusion, whereas teacher–child conflict exacerbated the relations between social avoidance and peer exclusion and anxious-fearful behavior.ConclusionThe current finding informs us of the importance of improving teacher–child closeness and reducing teacher–child conflict to buffer the negative adjustment among socially avoidant young children who migrated from rural-to-urban China. The findings also highlight the importance of considering the meaning and implication of social avoidance for migrant preschoolers in Chinese culture.

BackgroundWork addiction (WA), which can impair personal relationships, engagement in recreational activities, and/or health, is a behavioral addiction. A tool for the early detection of WA in China is needed.ObjectiveThe aim of this study was to develop and determine the validity and reliability of a Chinese version of the Bergen Work Addiction Scale (C-BWAS).MethodsTwo hundred social workers who provided post-discharge services for adolescents with non-suicidal self-injury (NSSI) were enrolled in this study. The construct validity of the C-BWAS was assessed by confirmatory factor analysis (CFA). Criterion validity was assessed by conducting Pearson correlation analyses of C-CWAS scores with Hamilton Depression Scale (HAM-D) and Hamilton Anxiety Scale (HAM-A) scores. Cronbach’s α and the intra-class correlation coefficient (ICC) were used to evaluate the reliability of the C-BWAS.ResultsCFA confirmed a one-dimensional structure of the C-BWAS with good construct validity indices [comparative fit index (CFI) = 0.964, Tucker–Lewis index (TLI) = 0.951, root-mean-square error of approximation (RMSEA) = 0.079, and minimum discrepancy Ĉ/degrees of freedom (Cmin/DF) = 0.362]. The standardized regression weights ranged from 0.523 to 0.753. All C-BWAS items loaded on one major factor (loading weights, 0.646–0.943). Coefficients of correlation between C-BWAS scores and HAM-D and HAM-A scores were 0.889 and 0.933, respectively. The Cronbach’s α coefficient and ICC for the instrument was 0.837 and 0.905, respectively.ConclusionThe presently developed C-BWAS showed very good reliability and acceptably validity. It can be employed as a useful tool for assessing WA severity in social workers who provide post-discharge services for adolescents with NSSI.

Background: Waldenström macroglobulinemia (WM) is a rare subtype of B-cell lymphoma. Rituximab-based combination therapy and Bruton’s tyrosine kinase (BTK) inhibitors have greatly improved the prognosis of WM. Despite the high response rate and good tolerance of BTK inhibitors in treatment of WM, a proportion of patients still experience disease progression.Case presentation: We report a 55-year-old man with relapsed WM. The patient achieved partial remission after six courses of CHOP chemotherapy and multiple plasma exchanges in initial treatment. He was admitted to the hospital with abdominal distension, and was diagnosed with relapsed WM and subsequently started on zanubrutinib. Disease progression and histological transformation occurred during treatment. We performed liquid biopsies on transformed plasma, tumor tissue and ascites at the same time and found high consistency between ascites and tissues. Moreover, we detected resistance mutations of BTK inhibitors (BTK, PLCG2) in ascites that were not detected in plasma or tissue. Eventually, the patient died during the 15-month follow-up after relapse.Conclusion: We describe a rare case of WM transformation to DLCBCL treated with chemoimmunotherapy and BTK inhibition. We analyzed tumor DNA obtained at different anatomic sites and circulating tumor DNA (ctDNA) derived from plasma and ascites specimens, with apparent significant temporal and spatial heterogeneity. The case specifically highlights the clinical value of ctDNA of ascites supernatant from WM patients, which is a more convenient and relatively noninvasive method compared with traditional invasive tissue biopsy.

Abstract The negative symptoms of schizophrenia can be present at any clinical stage, but evaluating the negative symptoms always remains challenging. To screen the negative symptoms effectively, self‐evaluation should be introduced. To date, professional psychiatrists used almost all of the scales available to screen the negative symptoms but could not obtain an accurate outcome. At the same time, an advanced self‐assessment scale is needed to accompany the patients’ self‐feeling‐based treatment strategies to understand their feelings about their symptoms. Hence, Chinese self‐evaluation of negative symptoms (SNS) should be introduced in China. This study aims to examine the validity and reliability of the Chinese version of SNS. Two hundred patients with schizophrenia were included in this study and were evaluated entirely with the self‐assessed negative symptoms by the Chinese version. The correlation analysis was performed between SNS and the Scale for Assessment of Negative Symptoms (SANS) to assess the criterion validity of SNS for screening negative symptoms. Exploratory factor analysis was used to determine the constructive validity of the SNS. Two senior professional psychiatrists were involved in this assessment based on their clinical experience and capability to define the severity of the negative symptoms. Receiver operating characteristic curve (ROC) analysis was performed to assess the cutoff point of SNS. Cronbach's alpha coefficient and intraclass correlation (ICC) coefficient were used to determine the reliability of SNS. We have the following findings: The Chinese version of SNS demonstrated a significant correlation with the SANS (r = .774, p

Using the best path data set of tropical cyclones from the China Meteorological Administration, NCEP/NCAR (National Centers for Environmental Prediction–National Center for Atmospheric Research) reanalysis data, JMA (Japan Meteorological Agency) SST (surface sea temperature) data and NCEP subsurface sea temperature data, the sea temperature background of tropical cyclones affecting Hainan Province in the dry season was analyzed using typical cases from November to December. The results show that there was a significant positive correlation between the number of tropical cyclones affecting Hainan Province and the sea surface temperature in the South China Sea and the Western Pacific. The high SST in the South China Sea and Northwest Pacific were favorable for the occurrence and development of tropical cyclones. The circulation situation also had a significant impact on tropical cyclones during the concurrent period. The wind field convergence was conducive to the occurrence and development of tropical cyclones. The high subsurface sea temperature in the Western Pacific at the depth of 5–50 m was conducive to the strengthening of convection in the Pacific warm pool and the occurrence of the tropical cyclones. The typical cases of 1993 and 2017 have effectively verified the impact of the sea surface temperature background and circulation situation on tropical cyclones affecting the Hainan Province from November to December.

Background and Objectives: Peritoneal dialysis-associated peritonitis (PDAP) poses significant challenges in peritoneal dialysis (PD) patient management and outcomes. Total bilirubin has gained attention due to its antioxidant and immunomodulatory properties. However, its relationship with PDAP prognosis remains underexplored. Materials and Methods: We conducted a retrospective single-center study involving 243 PDAP patients stratified into tertile-based groups according to total bilirubin levels. The association between total bilirubin levels and treatment failure risk was investigated through statistical analyses and restricted cubic spline curve analysis. Results: Our analysis revealed a non-linear correlation between total bilirubin levels and PDAP treatment failure risk. At total bilirubin levels below 8.24 µmol/L, a protective effect was observed, while levels exceeding this threshold heightened the risk of treatment failure. Conclusions: This study unveils a dual role of total bilirubin in PDAP prognosis. Below a certain threshold, it confers protection, while higher levels exacerbate the risk of treatment failure. These findings emphasize the need for further investigation in larger, multicenter prospective studies to validate and elucidate the mechanisms behind bilirubin’s impact on PDAP, potentially guiding the development of targeted therapeutic strategies.

Abstract Background Previous studies have revealed that low frequency repeated transcranial magnetic stimulation (rTMS) on the contralesional primary motor cortex (cM1) is less effective in severe stroke patients with poor neural structural reserve than in patients with highly reserved descending motor pathway. This may be attributed to the fact that secondary motor cortex, especially contralesional dorsal premotor cortex (cPMd), might play an important compensatory role in the motor function recovery of severely affected upper extremity. The main purpose of this study is to compare the effectiveness of low frequency rTMS on cM1 and high frequency rTMS on cPMd in subcortical chronic stroke patients with severe hemiplegia. By longitudinal analysis of multimodal neuroimaging data, we hope to elucidate the possible mechanism of brain reorganization following different treatment regimens of rTMS therapy, and to determine the cut-off of stimulation strategy selection based on the degree of neural structural reserve. Methods/design The study will be a single-blinded randomized controlled trial involving a total of 60 subcortical chronic stroke patients with severe upper limb motor impairments. All patients will receive 3 weeks of conventional rehabilitation treatment, while they will be divided into three groups and receive different rTMS treatments: cM1 low frequency rTMS (n = 20), cPMd high frequency rTMS (n = 20), and sham stimulation group (n = 20). Clinical functional assessment, multimodal functional MRI (fMRI) scanning, and electrophysiological measurement will be performed before intervention, 3 weeks after intervention, and 4 weeks after the treatment, respectively. Discussion This will be the first study to compare the effects of low-frequency rTMS of cM1 and high-frequency rTMS of cPMd. The outcome of this study will provide a theoretical basis for clarifying the bimodal balance-recovery model of stroke, and provide a strategy for individualized rTMS treatment for stroke in future studies and clinical practice. Trial registration Chinese Clinical Trial Registry, ChiCTR1900027399. Registered on 12 Nov 2019, http://www.chictr.org.cn/showproj.aspx?proj=43686 .

ObjectivesThe present study examined the moderating effect of children’s resilience on the relations between unsociability and social adjustment (i.e., prosocial behaviors, peer exclusion, interpersonal skills, internalizing problems) in Chinese preschool migrant children.MethodsParticipants were N = 148 children (82 boys, Mage = 62.32 months, SD = 6.76) attending two public kindergartens in Shanghai, People’s Republic of China. Mothers provided ratings of children’s unsociability and resilience; teachers assessed children’s social adjustment outcomes, and children reported their receptive vocabulary.ResultsUnsociability was positively associated with peer exclusion and internalizing problems, and negatively associated with prosocial behaviors and interpersonal skills among Chinese preschool migrant children. Moreover, children’s resilience significantly moderated the relationship between unsociability and social adjustment. Specifically, among children with lower levels of resilience, unsociability was significantly and positively associated with peer exclusion and internalizing problems, while among children with higher levels of resilience, unsociability was not associated with social adjustment difficulties.ConclusionThe current findings inform us of the importance of improving children’s resilience to buffer the negative adjustment among Chinese migrant unsociable young children. The findings also highlight the importance of considering the meaning and implication of unsociability for preschool migrant children in Chinese culture.

The primary aim of the present study was to examine the potential moderating role of screen time in the links between shyness and indices of socio-emotional adjustment in young Chinese children. Participants were N = 211 children (112 boys, 99 girls) ages 43–66 months (M = 58.84 months, SD = 5.32) recruited from two public kindergartens in Shanghai, People’s Republic of China. Mothers completed assessments of children’s shyness and screen time, and both mothers and teachers completed measures of indices of children’s socio-emotional functioning (prosocial, internalizing problems, learning problems). Among the results, shyness was positively associated with internalizing problems and negatively associated with prosocial behavior, whereas screen time was positively associated with internalizing problems. However, several significant shyness × screen time interaction effects were observed. The pattern of these results consistently revealed that at higher levels of screen time, links between shyness and indices of socio-emotional difficulties were exacerbated. Results are discussed in terms of the implications of shyness and screen time in early childhood.

Abstract Brain pathological features during manic/hypomanic and depressive episodes in the same patients with bipolar disorder (BPD) have not been described precisely. The study aimed to investigate depressive and manic-phase-specific brain neural activity patterns of BPD in the same murine model to provide information guiding investigation of the mechanism of phase switching and tailored prevention and treatment for patients with BPD. In vivo two-photon imaging was used to observe brain activity alterations in the depressive and manic phases in the same murine model of BPD. Two-photon imaging showed significantly reduced Ca2+ activity in temporal cortex pyramidal neurons in the depression phase in mice exposed to chronic unpredictable mild stress (CUMS), but not in the manic phase in mice exposed to CUMS and ketamine. Total integrated calcium values correlated significantly with immobility times. Brain Ca2+ hypoactivity was observed in the depression and manic phases in the same mice exposed to CUMS and ketamine relative to naïve controls. The novel object recognition preference ratio correlated negatively with the immobility time in the depression phase and the total distance traveled in the manic phase. With recognition of its limitations, this study revealed brain neural activity impairment indicating that intrinsic emotional network disturbance is a mechanism of BPD and that brain neural activity is associated with cognitive impairment in the depressive and manic phases of this disorder. These findings are consistent with those from macro-imaging studies of patients with BPD. The observed correlation of brain neural activity with the severity of depressive, but not manic, symptoms need to be investigated further.

Abstract Background DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method. Methods Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single‐nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred‐funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls. Results Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history. Conclusions We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.

Base on daily observational precipitation at 18 stations in Hainan province and the daily weather system in Hainan province during 1966—2018, the characteristics of different types of summer precipitation and its influence on summer drought and flood are analyzed. The result shows: (1) Tropical cyclone precipitation (TCR) is the most important precipitation type in summer over Hainan Island, accounting for 35.6% of summer precipitation (SUMR), followed by tropical convergence zone precipitation (ITCZR) accounting for 29.4%, and southwest monsoon trough precipitation (SWTR) and subtropical high edge precipitation (STHR) account for 15.3% and 14.7%, respectively. (2) The spatial distribution of different types of SUMR and their contribution rate to SUMR have different characteristics. (3) In summer, the frequency of TCR is the smallest, but its intensity is the largest over Hainan Island. The frequency of ITCZR is the largest, but its intensity is the second largest. Heavy rain and above are mainly caused by TCR and ITCZR. (4) In recent 53 years, SUMR in Hainan Island showed a weak increasing trend, which was mainly due to the significant increase of ITCZR. Conversely, SWTR and STHR contributed negatively to its increasing trend. The frequency of SUMR has a weak increasing trend, in which the frequency of ITCZR is significantly increased, the frequency of SWTR and STHR is significantly reduced, and the frequency of TCR is slightly reduced. The frequency of torrential rain and above has a weak increasing trend, the corresponding frequency of ITCZR has a significant increasing trend, and the corresponding frequency of the other three types have weak decreasing trends. (5) TCR and ITCZR have an important influence on the summer drought and flood over Hainan Island. Summer drought often occurs in the years with less TCR and ITCZR, but their influence on the summer flood has inter-decadal change, which results in the occurrence of summer flooding. It also leads to more precipitation in summer flooding years in this period.

Abstract Peripheral T-cell lymphoma(PTCL) is a group of lymphoproliferative tumors originated from post-thymic T cells or mature natural killer (NK) cells. It shows highly aggressive clinical behaviour, resistance to conventional chemotherapy, and a poor prognosis. Although a few prognostic models of PTCL have been established in retrospective studies, some high-risk patients still can not be screened out. Therefor we retrospectively studied 347 newly diagnosed PTCL patients and assessed the prognostic role of lymphocyte-monocyte ratio (LMR) and platelet-monocyte ratio (PMR) in the complete response (CR) and survival of PTCL patients. Patients with LMR ≤ 1.68 and PMR ≤ 300 achieved a lower CR rate and a poor survival. In multivariate analysis, LMR ≤ 1.68 (HR = 1.751, 95% CI 1.158–2.647, p

Objectives: We tended to explore the association of indoor air pollution (IAP) and non-neoplastic digestive system diseases (NNDSD) among the Chinese middle-aged and older population.Methods: From 2011 to 2018, we included 7884 NNDSD-free adults from the China Health and Retirement Longitudinal Study (CHARLS). Physician-diagnosed NNDSD was obtained by self-reported information at baseline and updated across follow-up surveys. We investigated the associations between baseline exposure of solid fuel use for cooking and/or heating and NNDSD diagnosed during follow-up through Cox proportional hazard models. Furthermore, we examined the relationship between cooking fuel switching and NNDSD diagnosed during follow-up.Results: Solid fuel use for cooking and/or heating was positively associated with NNDSD after adjusting for potential confounders. The risk of NNDSD among subjects who always use solid fuel for cooking (adjusted hazard ratio [aHR]: 1.42; 95% confidence interval [CI]: 1.09, 1.84) was higher than those with always clean fuels. Moreover, we found a lower NNDSD risk among participants who switched from solid to clean cooking fuel (aHR: 0.65; 95% CI: 0.49, 0.87) than those with always solid fuels.Conclusion: Our present study shows that indoor solid fuel use is a dependent risk factor for NNDSD. Moreover, switching to clean fuel may contribute to the prevention of digestive system illnesses.

Social avoidance has been found to be related to negative social adjustment, yet evidence of the relationship between social avoidance and social adjustment is very limited in suburban preschoolers in China. Moreover, the underlying mechanisms that help to explain the associations between social avoidance and socio-emotional adjustment remain poorly considered. The goal of the present study was to examine the moderating effect of marital conflict in the link between social avoidance and indices of socio-emotional functioning among young children in mainland China. Participants were N = 256 children aged from 49 to 72 months (125 boys, 131 girls, Mage = 59.06 months, SD = 6.58) attending preschools/kindergartens in suburban areas of Shanghai, People’s Republic of China. Multi-source assessments were employed, with mothers reporting marital conflict as well as rating their children’s social withdrawal (i.e., social avoidance, shyness, unsociability), and teachers assessing indices of children’s socio-emotional functioning at school (i.e., anxious-fearful behavior, peer exclusion, and loneliness). Children were asked about their loneliness. Among the results, social avoidance was positively associated with anxious-fearful behavior, peer exclusion, and loneliness (marginal significance). Moreover, as hypothesized, marital conflict was found to exacerbate the relations between social avoidance and peer exclusion, and loneliness. Results are discussed in terms of the etiology and implications of social avoidance among young children in mainland China.

The occurrence of heavy menstrual bleeding (HMB) induced by pharmacological agents has been reported in young adult women. This study aimed to investigate a possible association between the occurrence rates of HMB and different treatment methods such as antidepressant agents alone and in combination with other pharmacological agents. The examined cohort included young women (age 18–35 years, n = 1,949) with bipolar disorder (BP) or major depressive disorder (MDD). Menstruation history for 24 months was recorded and evaluated according to pictorial blood loss assessment charts of HMB. Multivariate analyses were conducted to determine odds ratios (ORs) and 95% confidence intervals. The examined antidepressant agents had varying ORs for patients with BP vs. those with MDD. For example, the ORs of venlafaxine-induced HMB were 5.27 and 4.58 for patients with BP and MDD, respectively; duloxetine-induced HMB, 4.72 and 3.98; mirtazapine-induced HMB, 3.26 and 2.39; fluvoxamine-induced HMB, 3.11 and 2.08; fluoxetine-induced HMB, 2.45 and 1.13; citalopram-induced HMB, 2.03 and 1.25; escitalopram-induced HMB, 1.85 and 1.99; agomelatine-induced HMB, 1.45 and 2.97; paroxetine-induced HMB, 1.19 and 1.75; sertraline-induced HMB, 0.88 and 1.13; reboxetine-induced HMB, 0.45 and 0.45; and bupropion-induced HMB, 0.33 and 0.37, in each case. However, when antidepressant agents were combined with valproate, the OR of HMB greatly increased, with distinct profiles observed for patients with BP vs. those with MDD. For example, the ORs of HMB induced by venlafaxine combined with valproate were 8.48 and 6.70 for patients with BP and MDD, respectively; for duloxetine, 5.40 and 4.40; mirtazapine, 5.67 and 3.73; fluvoxamine, 5.27 and 3.37; fluoxetine, 3.69 and 4.30; citalopram, 5.88 and 3.46; escitalopram, 6.00 and 7.55; agomelatine, 4.26 and 5.65; paroxetine, 5.24 and 3.25; sertraline, 4.97 and 5.11; reboxetine, 3.54 and 2.19; and bupropion, 4.85 and 3.46, in each case. In conclusion, some antidepressant agents exhibited potential risks of inducing HMB. Therefore, a combined prescription of antidepressant agents and valproate should be carefully considered for young women with HMB.

Abstract Background Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. Methods We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry. Results We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10−6). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal. Conclusions Our study provides new insights into the etiology and underlying genetic architecture of AD.

Abstract Background Fatal hemorrhagic pneumonia is one of the most severe manifestations of Stenotrophomonas maltophilia (SM) infections. Here, we aimed to investigate the clinical characteristics of SM bacteremia and to identify the risk factors of hemorrhagic pneumonia caused by SM in patients with hematologic diseases. Methods The clinical records of 55 patients diagnosed with hematologic diseases and SM bacteremia were retrospectively reviewed. We compared patients’ clinical characteristics and outcomes between the hemorrhagic pneumonia group and non-hemorrhagic pneumonia group. Results Twenty-seven (49.1%) patients developed hemorrhagic pneumonia. The overall mortality rate of SM bacteremia was 67.3%. Hemorrhagic pneumonia (adjusted HR 2.316, 95% CI 1.140–4.705; P = 0.020) was an independent risk factor of 30-day mortality in hematological patients with SM bacteremia. Compared with the non-hemorrhagic pneumonia group, patients in the hemorrhagic pneumonia group were older and showed clinical manifestations as higher proportions of isolated SM in sputum culture, neutropenia and elevated procalcitonin (PCT). Multivariate analysis showed that neutropenia, high levels of PCT, prior tigecycline therapy within 1 month were independent risk factors associated with hemorrhagic pneumonia. Conclusions Neutropenia, high level of PCT and prior tigecycline therapy within 1 month were significant independent predictors of hemorrhagic pneumonia in hematologic patients with SM bacteremia. Due to no effective antibiotics to prevent hemorrhagic pneumonia, prophylaxis of SM infection and its progression to hemorrhagic pneumonia is particularly important.

BackgroundAlthough associations of physical activity and smoking with mortality have been well-established, the joint impact of physical activity and smoking on premature mortality among elderly hypertensive population was still unclear. This study aimed to assess association of physical activity, smoking, and their interaction with all-cause and cardiovascular disease (CVD) mortality risk in elderly hypertensive patients.MethodsWe included 125,978 Chinese hypertensive patients aged 60–85 years [mean (SD) age, 70.5 (6.9) years] who had records in electronic health information system of Minhang District of Shanghai, China in 2007–2015. Cox regression was used to estimate individual and joint association of smoking and physical activity on all-cause and CVD mortality. Interactions were measured both additively and multiplicatively. Additive interaction was evaluated by relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S).ResultsAmong 125,978 elderly hypertensive patients (median age 70.1), 28,250 deaths from all causes and 13,164 deaths from CVD were observed during the follow-up up to 11 years. There was an additive interaction between smoking and physical inactivity [RERI: all-cause 0.19 (95% CI: 0.04–0.34), CVD 0.28 (0.06–0.50); AP: all-cause 0.09 (0.02–0.16), CVD 0.14 (0.04–0.23); S: all-cause 1.21 (1.04–1.42), CVD 1.36 (1.06–1.75)], while the concurrence of both risk factors was associated with more than 2-fold risk of death [hazard ratio (HR): all-cause 2.10 (1.99–2.21), CVD 2.19 (2.02–2.38)].ConclusionOur study suggested that smoking and physical inactivity together may have amplified association on premature death compared to the sum of their individual associations, highlighting the importance of improving behavioral factors in combination and promoting a comprehensive healthy lifestyle in hypertensive elderly.

Metabolites/impurities (MIs) of penicillin are normally considered to be the main substances inducing immediate hypersensitivity reactions in penicillin treatment. Our previous research found that penicillin can cause non-allergic hypersensitivity reactions (NAHRs) by directly triggering vascular hyperpermeability and exudative inflammation. However, the chief culprits and underlying mechanisms involved in penicillin-induced NAHRs have not yet been fully elucidated. In this study, we used a combination of approaches including a mouse non-allergic hypersensitivity reaction model, UPLC-MS/MS analyses of arachidonic acid metabolites (AAMs), immunoblotting technique, and molecular docking, etc to investigate the culprits involved in penicillin-induced hypersensitivity reactions. We found penilloic acid, one of the main MIs of penicillin, could trigger NAHRs via inducing increased vascular permeability, while the other MIs did no exhibit similar effect. Penilloic acid-induced reactions were not IgE-dependent. Significantly increased arachidonic acids and cascade metabolites in lungs, and activation of RhoA/ROCK signaling pathway in the ears and lungs of mice were noticed after once administration of penilloic acid. This study revealed that penilloic acid was the chief culprit involved in penicillin-induced immediate NAHRs in mice, which mainly associated with direct stimulation of vascular hyperpermeability and exudative inflammation. The activations of AAMs and RhoA/ROCK signaling pathway played important roles in these reactions.

BackgroundCognitive performance improves clinical outcomes of patients with major psychiatric disorder (MPD), but is impaired by hyperglycemia. Psychotropic agents often induce metabolism syndrome (MetS). The identification of modifiable metabolic risk factors of cognitive impairment may enable targeted improvements of patient care.ObjectiveTo investigate the relationship between MetS and cognitive impairment in young women with MPD, and to explore risk factors.MethodsWe retrospectively studied women of 18–34 years of age receiving psychotropic medications for first-onset schizophrenia (SCH), bipolar disorder (BP), or major depressive disorder (MDD). Data were obtained at four time points: presentation but before psychotropic medication; 4–8 and 8–12 weeks of psychotropic therapy; and enrollment. MATRICS Consensus Cognitive Battery, (MCCB)—based Global Deficit Scores were used to assess cognitive impairment. Multiple logistic analysis was used to calculate risk factors. Multivariate models were used to investigate factors associated with cognitive impairment.ResultsWe evaluated 2,864 participants. Cognitive impairment was observed in 61.94% of study participants, and was most prevalent among patients with BP (69.38%). HbA1c within the 8–12 week-treatment interval was the most significant risk factor and highest in BP. Factors in SCH included pre-treatment waist circumference and elevated triglycerides during the 8–12 weeks treatment interval. Cumulative dosages of antipsychotics, antidepressants, and valproate were associated with cognitive impairment in all MPD subgroups, although lithium demonstrated a protect effect (all P < 0.001).ConclusionsCognitive impairment was associated with elevated HbA1c and cumulative medication dosages. Pre-treatment waist circumference and triglyceride level at 8–12 weeks were risk factors in SCH. Monitoring these indices may inform treatment revisions to improve clinical outcomes.

There has been limited studies examining treatment-induced heavy menstrual bleeding (HMB) in women with severe mental illnesses. The aim of this study was to examine HMB prevalence and HMB-associated factors in young women (18–34 years old) diagnosed with bipolar disorder (BP), major depressive disorder (MDD), or schizophrenia (SCZ) who have full insight and normal intelligence. Eighteen-month menstruation histories were recorded with pictorial blood loss assessment chart assessments of HMB. Multivariate analyses were conducted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Drug effects on cognition were assessed with the MATRICS Consensus Cognitive Battery (MCCB). HMB prevalence were: BP, 25.85%; MDD, 18.78%; and SCH, 13.7%. High glycosylated hemoglobin (HbA1c) level was a strong risk factor for HMB [BP OR, 19.39 (16.60–23.01); MDD OR, 2.69 (4.59–13.78); and SCZ OR, 9.59 (6.14–12.43)]. Additional risk factors included fasting blood sugar, 2-h postprandial blood glucose, and use of the medication valproate [BP: OR, 16.00 (95%CI 12.74–20.22); MDD: OR, 13.88 (95%CI 11.24–17.03); and SCZ OR, 11.35 (95%CI 8.84–19.20)]. Antipsychotic, antidepressant, and electroconvulsive therapy use were minor risk factors. Pharmacotherapy-induced visual learning impairment was associated with HMB [BP: OR, 9.01 (95%CI 3.15–13.44); MDD: OR, 5.99 (95%CI 3.11–9.00); and SCZ: OR, 7.09 (95%CI 2.99–9.20)]. Lithium emerged as a protective factor against HMB [BP: OR, 0.22 (95%CI 0.14–0.40); MDD: OR, 0.30 (95%CI 0.20–0.62); and SCZ: OR, 0.65 (95%CI 0.33–0.90)]. In SCZ patients, hyperlipidemia and high total cholesterol were HMB-associated factors (ORs, 1.87–2.22). Psychiatrist awareness of HMB risk is concerningly low (12/257, 2.28%). In conclusion, prescription of VPA should be cautioned for women with mental illness, especially BP, and lithium may be protective against HMB.

Abstract Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA. Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (N case = 14,361, N control = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions. Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98–1.15]; ORper-SD increment in ANM = 1.05 [0.98–1.11], OR per-SD increment in AFB = 0.85 [0.65–1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97–1.15], ORper-SD increment in ANM = 1.05 [0.98–1.13], ORper-SD increment in AFB = 0.81 [0.61–1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94–1.12], ORper-SD increment in ANM = 1.04 [0.95–1.14]). No outlying instrument was identified through the leave-one-out analysis. Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

Breast cancer is the most commonly diagnosed cancer (estimated 2.3 million new cases in 2020) and the leading cause of cancer death (estimated 685,000 deaths in 2020) in women globally. Breast cancers have been categorized into four major molecular subtypes based on the immunohistochemistry (IHC) expression of classic hormone and growth factor receptors including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as a proliferation marker Ki-67 protein expression. Triple-negative breast cancer (TNBC), a breast cancer subtype lacking ER, PR, and HER2 expression, is associated with a high metastatic potential and poor prognosis. TNBC accounts for approximately only 15%–20% of new breast cancer diagnoses; it is responsible for most breast cancer–related deaths due to the lack of targeted treatment options for this patient population, and currently, systemic chemotherapy, radiation, and surgical excision remain the major treatment modalities for these patients with TNBC. Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden and high tumor-infiltrating lymphocytes, resembling the features observed on melanoma or lung cancers, which can benefit from the treatment of immune checkpoint inhibitors (ICIs). Therefore, the immunogenic nature of this aggressive disease has presented an opportunity for the development of TNBC-targeting immunotherapies. The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment. In addition, immunotherapy becomes an active research area, both in the cancer biology field and in the oncology field. In this review, we will extend our coverage on recent discoveries in preclinical research and early results in clinical trials from immune molecule-based therapy including cytokines, monoclonal antibodies, antibody–drug conjugates, bi-specific or tri-specific antibodies, ICIs, and neoantigen cancer vaccines; oncolytic virus-based therapies and adoptive immune cell transfer–based therapies including TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, and T-cell receptor-T. In the end, we will list a series of the challenges and opportunities in immunotherapy prospectively and reveal novel technologies such as high-throughput single-cell sequencing and CRISPR gene editing-based screening to generate new knowledges of immunotherapy.

PurposeThis study aimed to characterize the clinical features of early-stage ovarian cancer (OC) survivors with second primary malignancies (SPMs) and provided a prediction tool for individualized risk of developing SPMs.MethodsData were obtained from the Surveillance, Epidemiology and End Results (SEER) database during 1998–2013. Considering non-SPM death as a competing event, the Fine and Gray model and the corresponding nomogram were used to identify the risk factors for SPMs and predict the SPM probabilities after the initial OC diagnosis. The decision curve analysis (DCA) was performed to evaluate the clinical utility of our proposed model.ResultsA total of 14,314 qualified patients were enrolled. The diagnosis rate and the cumulative incidence of SPMs were 7.9% and 13.6% [95% confidence interval (CI) = 13.5% to 13.6%], respectively, during the median follow-up of 8.6 years. The multivariable competing risk analysis suggested that older age at initial cancer diagnosis, white race, epithelial histologic subtypes of OC (serous, endometrioid, mucinous, and Brenner tumor), number of lymph nodes examined (

This study examined the psychometric properties of the Chinese version of the Social-Emotional Assessment Measure (SEAM) (33-66 months), which is designed to assess social-emotional difficulties and behavior disorders in young children. In this case, the SEAM was translated and back-translated. The sample included 2477 preschoolers (1256 boys; M[subscript age] = 57.57 months, SD = 10.93) residing in Shanghai, China. In summary, the results presented a 10-factor model that showed a good fit for the SEAM (33-66 months). Ultimately, the analyses demonstrated adequate internal consistency, reliability, and convergent validity. These findings indicate that the SEAM (33-36 months) is appropriate for use in Chinese preschool populations.