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Abstract Oxidative stress and neuroinflammation contribute to schizophrenia (SCZ) pathology and may influence treatment efficacy. Matrix metalloproteinase 9 (MMP9) is a critical molecular node mediating the interaction between oxidative stress and inflammation, and so may influence treatment efficacy. Here we examined the associations of plasma MMP9 concentration with antipsychotic drug responses, clinical symptoms, and brain structure. A total of 129 healthy controls and 124 patients with SCZ were included in this study. Patients were monitored clinically during 8 weeks of antipsychotic treatment and classified as poor responders (n = 49) or good responders (n = 75). We then compared plasma MMP9 concentrations in healthy controls at baseline and both SCZ responder groups at baseline and after the 8-week antipsychotic treatment regimen. Cognitive function was also examined using the MATRICS Consensus Cognitive Battery. In addition, we extracted regional white matter density from magnetic resonance images of patients. Compared to healthy controls, plasma MMP9 levels were significantly elevated in poor responders at baseline and negatively correlated with both white matter density in the right superior temporal gyrus and the change in cognitive symptoms after treatment. Conversely, there was no significant difference in plasma MMP9 between good responders and healthy controls, and no associations of plasma MMP9 with cognitive symptoms or regional white matter density among good responders. Elevated plasma MMP9 is associated with poor antipsychotic drug efficacy and white matter deficits in SCZ patients, and so may be a useful biomarker to guide personalized treatment.

Abstract The development and aging of the brain constitute a lifelong dynamic process, marked by structural and functional changes that entail highly coordinated cellular differentiation and epigenetic regulatory mechanisms. Chromatin accessibility serves as the foundational basis for genetic activity. However, the holistic and dynamic chromatin landscape that spans various brain regions throughout development and ageing remains predominantly unexplored. In this study, we employed single-nucleus ATAC-seq to generate comprehensive chromatin accessibility maps, incorporating data from 69,178 cells obtained from four distinct brain regions – namely, the olfactory bulb (OB), cerebellum (CB), prefrontal cortex (PFC), and hippocampus (HP) – across key developmental time points at 7 P, 3 M, 12 M, and 18 M. We delineated the distribution of cell types across different age stages and brain regions, providing insight into chromatin accessible regions and key transcription factors specific to different cell types. Our data contribute to understanding the epigenetic basis of the formation of different brain regions, providing a dynamic landscape and comprehensive resource for revealing gene regulatory programs during brain development and aging.

Abstract Background Dietary and gastrointestinal (GI) problems have been frequently reported in autism spectrum disorder (ASD). However, the relative contributions of autism-linked traits to dietary and GI problems in children with ASD are poorly understood. This study firstly compared the dietary intake and GI symptoms between children with ASD and typically developing children (TDC), and then quantified the relative contributions of autism-linked traits to dietary intake, and relative contributions of autism-linked traits and dietary intake to GI symptoms within the ASD group. Methods A sample of 121 children with ASD and 121 age-matched TDC were eligible for this study. The dietary intake indicators included food groups intakes, food variety, and diet quality. The autism-linked traits included ASD symptom severity, restricted repetitive behaviors (RRBs), sensory profiles, mealtime behaviors, and their subtypes. Linear mixed-effects models and mixed-effects logistic regression models were used to estimate the relative contributions. Results Children with ASD had poorer diets with fewer vegetables/fruits, less variety of food, a higher degree of inadequate/unbalanced dietary intake, and more severe constipation/total GI symptoms than age-matched TDC. Within the ASD group, compulsive behavior (a subtype of RRBs) and taste/smell sensitivity were the only traits associated with lower vegetables and fruit consumption, respectively. Self-injurious behavior (a subtype of RRBs) was the only contributing trait to less variety of food. Limited variety (a subtype of mealtime behavior problems) and ASD symptom severity were the primary and secondary contributors to inadequate dietary intake, respectively. ASD symptom severity and limited variety were the primary and secondary contributors to unbalanced dietary intake, respectively. Notably, unbalanced dietary intake was a significant independent factor associated with constipation/total GI symptoms, and autism-linked traits manifested no contributions. Conclusions ASD symptom severity and unbalanced diets were the most important contributors to unbalanced dietary intake and GI symptoms, respectively. Our findings highlight that ASD symptom severity and unbalanced diets could provide the largest benefits for the dietary and GI problems of ASD if they were targeted for early detection and optimal treatment.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. Its accurate pathogenic mechanisms are incompletely clarified, and effective therapeutic treatments are still inadequate. Autophagy is closely associated with AD and plays multiple roles in eliminating harmful aggregated proteins and maintaining cell homeostasis. This study identified 1191 differentially expressed genes (DEGs) based on the GSE5281 dataset from the GEO database, intersected them with 325 autophagy-related genes from GeneCards, and screened 26 differentially expressed autophagy-related genes (DEAGs). Subsequently, GO and KEGG enrichment analysis was performed and indicated that these DEAGs were primarily involved in autophagy–lysosomal biological process. Further, eight hub genes were determined by PPI construction, and experimental validation was performed by qRT-PCR on a SH-SY5Y cell model. Finally, three hub genes (TFEB, TOMM20, GABARAPL1) were confirmed to have potential application for biomarkers. A multigenic prediction model with good predictability (AUC = 0.871) was constructed in GSE5281 and validated in the GSE132903 dataset. Hub gene-targeted miRNAs closely associated with AD were also retrieved through the miRDB and HDMM database, predicting potential therapeutic agents for AD. This study provides new insights into autophagy-related genes in brain tissues of AD patients and offers more candidate biomarkers for AD mechanistic research as well as clinical diagnosis.

This study sought to explore potential roles of endothelial ferroptosis in radiation-associated atherosclerosis (RAA) and molecular mechanisms behind this phenomenon. Here, an in vivo RAA mouse model was used and treated with ferroptosis inhibitors. We found that the RAA group had a higher plaque burden and a reduction in endothelial cells with increased lipid peroxidation compared to the control group, while ameliorated by liproxstatin-1. In vitro experiments further confirmed that radiation induced the occurrence of ferroptosis in human artery endothelial cells (HAECs). Then, proteomics analysis of HAECs identified domain-containing protein 2 (DDHD2) as a co-differentially expressed protein, which was enriched in the lipid metabolism pathway. In addition, the level of lipid peroxidation was elevated in DDHD2-knockdown HAECs. Mechanistically, a significant decrease in the protein and mRNA expression of glutathione peroxidase 4 (GPX4) was observed in HAECs following DDHD2 knockdown. Co-immunoprecipitation assays indicated a potential interaction between DDHD2 and nuclear factor erythroid 2-related factor 2 (Nrf2). The downregulation of Nrf2 protein was also detected in DDHD2-knockdown HAECs. In conclusion, our findings suggest that radiation-induced endothelial ferroptosis accelerates atherosclerosis, and DDHD2 is a potential regulatory protein in radiation-induced endothelial ferroptosis through the Nrf2/GPX4 pathway.

BackgroundLeft bundle branch pacing (LBBP) can physiologically correct complete left bundle branch block (CLBBB), and has become the best alternative to biventricular pacing (BiVP).ObjectiveTo compare the efficacy of LBBP and BiVP in patients with heart failure (HF) complicated with CLBBB.MethodsThis was a single-center retrospective study. Patients with HF complicated with CLBBB who underwent successful cardiac resynchronization therapy (CRT) in Wuhan Asian Heart Hospital from June 2018 to June 2023 were enrolled and divided into LBBP group and BiVP group according to the pacing method. The primary endpoints were the absolute increase of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and echocardiographic response rate. Secondary endpoints were all-cause mortality, heart failure hospitalization (HFH), NT-proBNP, paced QRS duration, pacing threshold, and procedural duration.ResultsA total of 120 patients were enrolled in this study, including 60 patients in LBBP group and 60 patients in BiVP group. The median follow-up time was 37 ± 19 months. Compared with BiVP group, LBBP group had a more significant increase in absolute LVEF (ΔLVEF) (14.8 ± 9.9% vs. 10.7 ± 9.0%, P = 0.02), a more significant reduction in LVEDD (56.9 ± 10.9 mm vs. 61.1 ± 10.8 mm, P = 0.03), and a higher echocardiographic super response rate (65% vs. 45%, P = 0.02). There were no significant differences in all-cause mortality (1.7% vs. 10.0%, P = 0.11) and HFH (6.7% vs. 13.3%, P = 0.22). In terms of paced QRS duration (128.7 ± 14.1 ms vs. 137.5 ± 16.5 ms, P = 0.002), pacing threshold (0.72 ± 0.21 V/0.4 ms vs. 1.39 ± 0.51 V/0.4 ms, P

Antipsychotic drug treatment for schizophrenia (SZ) can alter brain structure and function, but it is unclear if specific regional changes are associated with treatment outcome. Therefore, we examined the effects of antipsychotic drug treatment on regional grey matter (GM) density, white matter (WM) density, and functional connectivity (FC) as well as associations between regional changes and treatment efficacy. SZ patients (n = 163) and health controls (HCs) (n = 131) were examined by structural magnetic resonance imaging (sMRI) at baseline, and a subset of SZ patients (n = 77) were re-examined after 8 weeks of second-generation antipsychotic treatment to assess changes in regional GM and WM density. In addition, 88 SZ patients and 81 HCs were examined by resting-state functional MRI (rs-fMRI) at baseline and the patients were re-examined post-treatment to examine FC changes. The Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) were applied to measure psychiatric symptoms and cognitive impairments in SZ. SZ patients were then stratified into response and non-response groups according to PANSS score change (≥50 % decrease or

Objective: We examined the relationships between infants’ growth trajectories and prenatal exposure to air pollution, which is still under-investigated. Methods: A birth cohort study was constructed using medical records of pregnant women and infants born between 2015 and 2019 in Foshan, China. Using satellite-based spatial-temporal models, prenatal exposure to air pollutants including particulate matter with an aerodynamic dimension of < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) was assessed at each woman's residence. Latent class growth modeling was used to identify trajectories of physical (body length and weight) growth and neurodevelopment, which were repeatedly measured within 1 year after birth. Logistic regression models were used to investigate the associations between prenatal exposure to air pollution and the risks of growth disorders, adjusting for an array of potential confounders. Results: We identified two growth trajectories for body length [normal: 3829 (93%); retardation: 288 (7%)], three for weight [normal: 2475 (59.6%); retardation: 390 (9.4%); overgrowth: 1287 (31%)], and two for neurodevelopment [normal: 956 (66.1%); retardation: 491 (33.9%)]. For exposure over whole pregnancy, SO2 was associated with an increased risk of body length retardation (OR for per 1 µg/m3 increment: 1.09, 95%CI: 1.01–1.17); PM2.5 (OR: 1.05, 95%CI: 1.03–1.07), SO2 (OR: 1.15, 95%CI: 1.08–1.22), and NO2 (OR: 1.05, 95%CI: 1.03–1.07) were positively associated with neurodevelopmental retardation. Such associations appeared stronger for exposures over the first and second trimesters. No significant associations were detected for weight growth. Conclusions: Maternal exposure to air pollution during pregnancy was associated with higher risks of impairments in both physical growth, particularly body length, and neurodevelopment.

BackgroundPrimary biliary cholangitis (PBC) is a chronic intrahepatic cholestatic autoimmune liver disease characterized by inflammatory injury of small and medium-sized bile ducts in the liver. The pathogenesis of PBC has yet to be entirely understood. CD47/signal-regulatory protein alpha (SIRPα) is closely related to developing autoimmune diseases by promoting inflammatory response. However, the effect of CD47/SIRPα on inflammatory response in PBC patients is still unclear.ObjectiveWe investigated the expression of CD47/SIRPα and the effect of inflammatory cytokines on the CD47 expression, analyzed potential autoantibodies against CD47 and the effect of anti-CD47 antibody on the inflammatory response in PBC, provided laboratory basis for the study of the pathogenesis and targets for non-invasive diagnosis and treatment on PBC.MethodsThe expression levels of CD47 and SIRPα on peripheral blood mononuclear cells (PBMC) were measured in 14 patients with PBC (the PBC group) and 13 healthy subjects (the Control group) by flow cytometry (FCM). The PBMC derived from healthy subjects were stimulated with healthy subjects’ serum, PBC patients’ serum, IFN-α or TNF-α, and the CD47 expression level on CD14+ monocytes was detected by FCM. The level of serum anti-CD47 antibody or IFN-α in PBC patients and healthy subjects was analyzed by ELISA. FCM was used to examine the TNF-α expression level in CD14+ monocytes of healthy subjects stimulated with isotype control antibody, anti-CD47 antibody, LPS or LPS combined with CD47 antibody.ResultsThe CD47 expression level on the CD14+ monocytes in PBC patients was statistically higher than that in the Control group (P0.05). The levels of serum anti-CD47 antibody and IFN-α in the PBC patients were higher than those in healthy subjects (P

Aortic stenosis (AS) complicated with acute ST-segment elevation myocardial infarction (STEMI) is a life-threatening emergency with high mortality. A 75-year-old male patient attended the emergency department of Wuhan Asia Heart Hospital in December 2021 with chest pain for 2 days and exacerbation for 1 h. The electrocardiogram (ECG) indicated atrial fibrillation with rapid ventricular response and ST-segment depression. Echocardiography showed severe AS and mild/moderate aortic insufficiency. The patient refused coronary angiography and further invasive procedures and then requested discharge, but he had recurrent chest pain on the third day. The ECG showed an extensive anterior wall STEMI. During preoperative preparation, he suffered from cardiogenic shock (CS). Concomitant percutaneous coronary intervention (PCI) and transcatheter aortic valve replacement (TAVR) was performed, but he died of CS and multiple organ failure 4 days after surgery. Patients with AS and STEMI might be susceptible to CS during perioperative period of concomitant PCI and TAVR, which requires proactive prevention.

Abstract Introduction Left atrial appendage closure (LAAC) is a novel treatment for stroke prevention in high-risk patients with non-valvular atrial fibrillation (NVAF). However, the long-term outcomes after LAAC in Chinese NVAF patients are still lacking. Methods This was a single-center, bidirectional, nonrandomized registered study. Patients who underwent LAAC implantation from May 2014 to April 2021 in a large Chinese center were enrolled. The primary endpoint was combined all-cause death and stroke. Results From May 2014 to April 2021, a total of 673 NVAF patients were enrolled. The overall successful implantation rate was 97.62% (657 of 673). The rate of perioperative adverse events was 1.19% (8 of 673), including 3 cardiac tamponades, 2 ischemic strokes, one device-related thrombus (DRT) and 2 device dislocations. 604 (92.24%) patients completed the follow-up, the median follow-up period was 36.9 months (IQR 24.8–56.5 months). 16 stroke events occurred in 15 patients (one patient suffered from both hemorrhagic and ischemic strokes). 13 patients (2.15%) had ischemic stroke, and the fatal rate was 0.33% (2 of 604). 3 patients (0.15%) suffered from hemorrhagic stroke, and the fatal rate was 0.17% (1 of 604). The overall stroke rate was 0.74% per-year. The combined death and stroke rate was 1.93% per-year. In the multivariate Cox regression analysis, age ≥ 75 (hazard ratio 2.264, 95% CI 1.074–4.772, P = 0.032) and ventricular cardiomyopathy (hazard ratio 2.738, 95% CI 1.060–7.071, P = 0.037) were independent predictors of combined mortality and stroke. Conclusion The overall successful implantation rate of LAAC was 97.62% and the rate of perioperative adverse events was 1.19% in this study, and the stroke rate was 0.74% per year during the long-term follow-up. Age ≥ 75 years and ventricular cardiomyopathy were independent predictors of the primary endpoint. Trial registration This study was retrospectively registered.

Abstract Backgrounds Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed. Methods Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively. Results We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone. Conclusions These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.

Objectives: This study was aimed at comparing the “late catch-up” phenomenon between the BuMA Supreme bioresorbable polymer sirolimus-eluting stent and the XIENCE stent through serial optical coherence tomography (OCT) at within 2 months and 2 year follow-ups. Methods: A total of 49 of 75 patients from the PIONEER-II study were enrolled in a 2 year OCT follow-up study; 44 patients with 50 lesions were included in the statistical analysis. The primary endpoints were neointimal thickness and late luminal loss (LLL) after stent implantation. Results: The stenosis diameter, and minimum in-stent or in-segment diameter, did not significantly differ between the BuMA Supreme and XIENCE arms at within 2 months and 2 year follow-ups. The strut neointimal coverage and thickness were greater in the BuMA group than the XIENCE group at the 1 and 2 month follow-ups (P = 0.044 and P = 0.010, respectively) but not at the 2 year OCT follow-up. Neither early luminal loss at the within 2 months follow-up (P = 0.849) nor LLL at the 2 year OCT follow-up (P = 0.613) showed differences between device arms. No significant differences in imaging and clinical endpoints were observed between device arms at follow-up. Conclusions: The BuMA Supreme stent’s faster re-endothelization with no “late catch-up” phenomenon has potential advantages over the XIECE stent for patients with coronary artery disease and high bleeding risk because it decreases the duration of dual antiplatelet therapy.

Abstract Background Spontaneous coronary artery dissection (SCAD) has emerged as an increasingly diagnosed cause of ST-segment elevation myocardial infarction (STEMI), which is easily missed or delayed. The effective use of coronary angiography (CAG) and advanced intracoronary imaging examinations in STEMI patients has led to increased detection of SCAD. Case presentation A 59-year-old woman with acute angina pectoris was diagnosed with STEMI detected by electrocardiography combined with measurement of myocardial enzymes. Due to the ongoing pandemic of coronavirus disease 2019 (COVID-19) in Wuhan, she was first given thrombolytic therapy after excluding contraindications according to the requirements of the current consensus statement; however, subsequently, both the symptoms of ongoing chest pain and the electrocardiographic results indicated the failure of thrombolytic therapy, so the intervention team administered rescue percutaneous coronary intervention treatment under third-grade protection. CAG confirmed total occlusion in the distal left anterior descending (LAD) artery, with thrombolysis in myocardial infarction (TIMI) 0 flow, whereas the left circumflex and right coronary arteries appeared normal, with TIMI 3 flow. Intravenous ultrasound (IVUS) was further performed to investigate the causes of occlusion, which verified the absence of atherosclerosis but detected SCAD with intramural haematoma. During the operation, the guidewire reached the distal end of the LAD artery smoothly, the balloon was dilated slightly, and the reflow of TIMI blood could be seen by repeated CAG. During the follow-up period of one and a half years, the patient complained of occasional, slight chest tightness. The repeated CAG showed that the spontaneous dissection in the LAD artery had healed well, with TIMI 3 flow. The repeated IVUS confirmed that the SCAD and intramural haematoma had been mostly resorbed and repaired. Conclusion This was a case of failed STEMI thrombolysis in our hospital during the outbreak of COVID-19. This case indicates that doctors need to consider the cause of the disease when treating STEMI patients, especially patients without traditional cardiovascular risk factors. Moreover, CAG and intracoronary imaging examinations should be actively performed to identify the aetiology and improve the treatment success rate.

Anomalous aortic origin of a coronary artery (AAOCA) is a congenital malformation of the coronary arteries that includes several subtypes. It is a leading cause of sudden cardiac death in young people, especially in competitive athletes. An accurate diagnosis and identification of high-risk patients with AAOCA for referral for surgical repair can help in the management of these patients. However, current diagnostic tools such as invasive angiography, echocardiography, and intravascular ultrasound have known limitations in visualizing coronary orifices and characterizing vessels. In this case report, we report on a 14-year-old adolescent who suffered from repeated incidents of syncope during exercise. Using the computed tomographic fractional flow reserve (CT-FFR) technique, we diagnosed AAOCA, which revealed that his left coronary artery (LCA) originated from the right sinus of Valsalva and ran between the aorta and the pulmonary artery with an intra-arterial wall course (∼20 mm in length), with an abnormal FFR of the LCA at rest. The patient was referred for undergoing unroofing surgery, and the results of repeat CT-FFR showed a significantly improved FFR of the LCA. The patient resumed his normal physical activities without the recurrence of syncope. In this report, we highlight the usefulness of CT-FFR as a non-invasive, feasible, and effective tool to guide whether a patient with AAOCA requires surgical revascularization and to evaluate the effectiveness of the procedure after surgery.

Objectives: To explore the rationale and value of consolidative cranial local therapy (CLT) in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). Methods: EGFR-mutant NSCLC patients with baseline BMs who received first-line EGFR-tyrosine kinase inhibitors (TKIs) at two academic centers from May 2015 to June 2020 were retrospectively enrolled. Patterns of tumor response and treatment failure were extensively analyzed in order to explore the rationale of CLT. Cranial lesions with number ⩽3 and largest tumor size ⩽3 cm at baseline and best response to EGFR-TKIs were defined as oligo-BMs and oligo-residual cranial disease (ORCD), respectively. To provide preliminary data supporting CLT, survival outcomes were compared in patients with ORCD, stratified by CLT status. Results: Of the 216 patients enrolled, 57.1% had oligo-BMs and 24.5% received first-line osimertinib. At best response to the first-line EGFR-TKIs, intracranial complete response, partial response, and stable disease occurred in 18.5, 31.9, and 44.4% of the whole population, respectively. For patients without CLT ( n = 193), ORCD was observed in 78.1% of the 105 patients with baseline oligo-BMs and 10.2% of the 88 patients with baseline multiple-BMs. With a median follow-up of 22.8 months, 107 patients had cranial first progressive disease (PD); more than 60% developed their first PD solely from the residual tumor sites at best response to EGFR-TKIs. Moreover, among patients with ORCD ( n = 108), patients who received CLT ( n = 17) achieved significantly longer progression-free survival (13.4 versus 8.5 months, p = 0.001) and overall survival (58.9 versus 28.8 months, p = 0.021) than those without CLT. Meanwhile, CLT remained as an independent prognostic factor associated with improved survival after Cox regression analyses. Conclusions: Cranial progressive disease developed mostly at the residual cranial lesions in EGFR-mutant NSCLC patients with baseline BMs who received first-line EGFR-TKIs. Consolidative cranial local therapy targeting the oligo-residual cranial tumor lesions may provide survival benefit, which warrants future validation.

BackgroundChildren with autism spectrum disorder (ASD) are at high risk of experiencing externalizing and internalizing problems. This study aimed to reveal how maternal parenting styles and autistic traits influence behavioral problems in children with ASD.MethodsThis study recruited 70 2–5 years children with ASD and 98 typically developing (TD) children. The Parental Behavior Inventory (PBI) and Autism Spectrum Quotient (AQ) were used to collect the maternal parenting styles and autistic traits, respectively. The children’s behavioral problems were reported by the mothers using the Strengths and Difficulties Questionnaire (SDQ). Hierarchical moderated regression analyses were used to determine whether maternal autistic traits moderated the association between parenting style and behavioral problems in the children.ResultsCompared to TD children, children with ASD exhibited more severe externalizing and internalizing problems (t = 4.85, p

Background and Hypothesis: Schizophrenia (SZ) patients display significant structural brain abnormalities; nevertheless, the genetic mechanisms regulating cortical anatomical variations and their correlation with the disease phenotype are still ambiguous. Study Design: We characterized anatomical variation using a surface-based method derived from structural magnetic resonance imaging of patients with SZ and age- and sex-matched healthy controls (HCs). Partial least-squares regression was performed across cortex regions between anatomical variation and average transcriptional profiles of SZ risk genes and all qualified genes from the Allen Human Brain Atlas. The morphological features of each brain region were correlated to symptomology variables in patients with SZ using partial correlation analysis. Study Results: A total of 203 SZ and 201 HCs were included in the final analysis. We observed significant variation of 55 regions of cortical thickness, 23 regions of volume, 7 regions of area, and 55 regions of local gyrification index (LGI) between SZ and HC groups. Expression profiles of 4 SZ risk genes and 96 genes from all qualified genes showed a correlation to anatomical variability, however, after multiple comparisons, the correlations were no longer significant. LGI variability in multiple frontal subregions was associated with specific symptoms of SZ, whereas cognitive function involving attention/vigilance was linked to LGI variability across nine brain regions. Conclusions: Cortical anatomical variation of patients with schizophrenia is associated with gene transcriptome profiles as well as clinical phenotypes.

A schematic model of SGSM2 suppressing the progression of RASWT thyroid cancer.

Abstract The indoleamine 2,3-dioxygenase (IDO) enzyme is the first rate-limiting enzyme of the tryptophan degradation pathway in which dysfunction of neuroactive metabolites has been implicated in the pathophysiology of schizophrenia. Inflammatory molecules such as pro-inflammatory cytokines could enhance the activity of IDO. There are few studies on the expression of IDO levels and its correlation with levels of inflammatory cytokines in first-episode drug-naive patients with schizophrenia. One hundred inpatients (female = 33, male = 67) with first-episode drug-naive schizophrenia entered a 6-week, double-blind, randomized, placebo-controlled clinical trial. All individuals were assigned celecoxib or placebo combined with risperidone. Serum levels of IDO and six inflammatory cytokines (IL-1β, IL-6, TNF-α IL-17, IL-4, and INF-γ) were measured. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychotic symptoms. Compared to healthy subjects, patients had significantly elevated levels of IDO and six cytokines at baseline. Over the 6-week treatment period, the decrease in the levels of IDO and TNF-α and the improvement in the PANSS total score, positive scores, and negative scores in the celecoxib group were significantly greater than in the placebo group. There was a significantly positive correlation between IDO levels and the PANSS negative scores and between IDO levels and TNF-α and IFN-γ levels in the celecoxib group. These findings showed abnormal expression of IDO levels which correlated with negative symptoms and pro-inflammatory cytokine levels in patients with first-episode drug-naive schizophrenia, suggesting the important role of IDO in the pathological mechanism of schizophrenia. Registration number: ChiCTR2000041403.

Summary: Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular emergency with high mortality, so identifying modifiable risk factors of AAD is of great public health significance. The associations of non-optimal temperature and temperature variability with AAD onset and the disease burden have not been fully understood. Methods: We conducted a time-stratified case-crossover study using a nationwide registry dataset from 1,868 hospitals in 313 Chinese cities. Conditional logistic regression and distributed lag models were used to investigate associations of temperature and temperature changes between neighboring days (TCN) with the hourly AAD onset and calculate the attributable fractions. We also evaluated the heterogeneity of the associations. Findings: A total of 40,270 eligible AAD cases were included. The exposure-response curves for temperature and TCN with AAD onset risk were both inverse and approximately linear. The risks were present on the concurrent hour (for temperature) or day (for TCN) and lasted for almost 1 day. The cumulative relative risks of AAD were 1.027 and 1.026 per 1°C lower temperature and temperature decline between neighboring days, respectively. The associations were significant during the non-heating period, but were not present during the heating period in cities with central heating. 23.13% of AAD cases nationwide were attributable to low temperature and 1.58% were attributable to temperature decline from the previous day. Interpretation: This is the largest nationwide study demonstrating robust associations of low temperature and temperature decline with AAD onset. We, for the first time, calculated the corresponding disease burden and further showed that central heating may be a modifier for temperature-related AAD risk and burden. Funding: This work was supported by the National Natural Science Foundation of China (92043301 and 92143301), Shanghai International Science and Technology Partnership Project (No. 21230780200), the Medical Research Council-UK (MR/R013349/1), and the Natural Environment Research Council UK (NE/R009384/1).

Background Nicorandil was reported to improve microvascular dysfunction and reduce reperfusion injury when administered before primary percutaneous coronary intervention. In this multicenter, prospective, randomized, double‐blind clinical trial (CHANGE [Effects of Nicorandil Administration on Infarct Size in Patients With ST‐Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention]), we investigated the effects of nicorandil administration on infarct size in patients with ST‐segment–elevation myocardial infarction treated with primary percutaneous coronary intervention. Methods and Results A total of 238 patients with ST‐segment–elevation myocardial infarction were randomized to receive intravenous nicorandil (n=120) or placebo (n=118) before reperfusion. Patients in the nicorandil group received a 6‐mg intravenous bolus of nicorandil followed by continuous infusion at a rate of 6 mg/h. Patients in the placebo group received the same dose of placebo. The predefined primary end point was infarct size on cardiac magnetic resonance (CMR) imaging performed at 5 to 7 days and 6 months after reperfusion. CMR imaging was performed in 201 patients (84%). Infarct size on CMR imaging at 5 to 7 days after reperfusion was significantly smaller in the nicorandil group compared with the placebo (control) group (26.5±17.1 g versus 32.4±19.3 g; P=0.022), and the effect remained significant on long‐term CMR imaging at 6 months after reperfusion (19.5±14.4 g versus 25.7±15.4 g; P=0.008). The incidence of no‐reflow/slow‐flow phenomenon during primary percutaneous coronary intervention was much lower in the nicorandil group (9.2% [11/120] versus 26.3% [31/118]; P=0.001), and thus, complete ST‐segment resolution was more frequently observed in the nicorandil group (90.8% [109/120] versus 78.0% [92/118]; P=0.006). Left ventricular ejection fraction on CMR imaging was significantly higher in the nicorandil group than in the placebo group at both 5 to 7 days (47.0±10.2% versus 43.3±10.0%; P=0.011) and 6 months (50.1±9.7% versus 46.4±8.5%; P=0.009) after reperfusion. Conclusions In the present trial, administration of nicorandil before primary percutaneous coronary intervention led to improved myocardial perfusion grade, increased left ventricular ejection fraction, and reduced myocardial infarct size in patients with ST‐segment–elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03445728.

Renal fibrosis commonly occurs in the process of chronic kidney diseases. Here, we explored the role of Jumonji domain containing 3 (Jmjd3)/interferon regulatory factor 4 (IRF4) axis in activation of myeloid fibroblasts and transition of M2 macrophages into myofibroblasts transition (M2MMT) in kidney fibrosis. In mice, Jmjd3 and IRF4 were highly induced in interstitial cells of kidneys with folic acid or obstructive injury. Jmjd3 deletion in myeloid cells or Jmjd3 inhibitor reduced the levels of IRF4 in injured kidneys. Myeloid Jmjd3 depletion impaired bone marrow-derived fibroblasts activation and M2MMT in folic acid or obstructive nephropathy, resulting in reduction of extracellular matrix (ECM) proteins expression, myofibroblasts formation and renal fibrosis progression. Pharmacological inhibition of Jmjd3 also prevented myeloid fibroblasts activation, M2MMT, and kidney fibrosis development in folic acid nephropathy. Furthermore, IRF4 disruption inhibited myeloid myofibroblasts accumulation, M2MMT, ECM proteins accumulation, and showed milder fibrotic response in obstructed kidneys. Bone marrow transplantation experiment showed that wild-type mice received IRF4-/- bone marrow cells presented less myeloid fibroblasts activation in injured kidneys and exhibited much less kidney fibrosis after unilateral ureteral obstruction. Myeloid Jmjd3 deletion or Jmjd3 inhibitor attenuated expressions of IRF4, α-smooth muscle actin and fibronectin and impeded M2MMT in cultured monocytes exposed to IL-4. Conversely, overexpression IRF4 abrogated the effect of myeloid Jmjd3 deletion on M2MMT. Thus, Jmjd3/IRF4 signaling has a crucial role in myeloid fibroblasts activation, M2 macrophages to myofibroblasts transition, extracellular matrix protein deposition, and kidney fibrosis progression.

Summary: Background: The associations of ambient temperature with acute myocardial infarction (AMI) have seldom been examined based on the time of symptom onset. Methods: We conducted a time-stratified case-crossover study among 1,046,773 eligible AMI patients from 2,093 hospitals in 324 Chinese cities from January 1, 2015 to June 30, 2021, after excluding those transferred from other hospitals or having not reported the time of symptom onset. Hourly exposure to ambient temperature was calculated as multiple moving 24-h averages (days) before hourly onset of AMI symptoms. Conditional logistic regression and distributed lag non-linear models with a duration of 0–21 days were used to estimate the cumulative associations of non-optimum temperature with AMI onset and the corresponding disease burden nationally. Subgroup analyses by region and period were conducted. Specifically, cities with and without centralized heating system were classified into heating and non-heating regions, respectively. The whole year in heating region was divided into heating and non-heating periods based on the duration of centralized heating in each city. Findings: Almost monotonically increasing risks were observed for both overall AMI and its two subtypes when ambient temperature declined. The effects of extremely low temperature occurred immediately on the concurrent day, and lasted up to almost 3 weeks. The excess risks of AMI onset associated with non-optimum ambient temperatures were observed during the whole year in the non-heating region and non-heating period in the heating region, but not during heating period. Specifically, odds ratios of AMI onset associated with extremely low temperature cumulated over 0–21 days were 1.24 (95% CI: 1.13–1.37), 1.46 (95% CI: 1.20–1.76), and 1.62 (95% CI: 1.46–1.81) in the heating region during non-heating period, in the non-heating region during winter and non-winter period, respectively. The heat effects on AMI onset were very modest and transient. Totally, 13.26% of AMI cases could be attributable to non-optimum temperatures nationally. The burden of AMI attributable to non-optimum temperature was much smaller in heating region than in non-heating region. Somewhat stronger effects were observed in females and patients aged older than 65. Interpretation: This nationwide study provided robust evidence that non-optimum ambient temperature may significantly trigger AMI onset, and for the first time estimated the disease burden after accounting for spatial and seasonal heterogeneity. Centralized heating might substantially mitigate AMI burden due to non-optimum temperature. Funding: Shanghai International Science and Technology Partnership Project, National Natural Science Foundation of China, Talent Training Program of Zhongshan Hospital, Fudan University.

Probiotics have been widely used in aquaculture and may serve as a potential alternative to antibiotics. Diverse sources of probiotics have different effects on the host, and the application of native probiotics isolated from target fish may play a better role. This study was conducted to evaluate the probiotic potential of the bacteria isolated from the gut of common carp (Cyprinus carpio L.). Based on morphological, 16 S rRNA sequencing and whole-genome sequencing analysis, an isolated strain that simultaneously produces protease, mannanase, amylase, and cellulose was identified as Bacillus velezensis R-71003. This strain showed antagonistic activity against various pathogens. Further studies showed that B. velezensis R-71003 was susceptible to ampicillin, gentamicin, penicillin G, erythromycin, chloramphenicol, amikacin, cefamezin, sulfamethoxazole, ciprofloxacin and norfloxacin. Additionally, B. velezensis R-71003 met the safety criteria based on safety evaluation results, such as haemolytic activity and biosafety tests in common carp. Moreover, B. velezensis R7–1003 was resistant to low pH (2) and higher bile salt concentration (0.3 %) and showed higher viability ability after high temperature exposure (60, 70, and 80 °C), as well as higher auto-aggregation and cell-surface hydrophobicity. In addition, the challenge test showed that B. velezensis R-71003 significantly increased the survival rate of common carp after challenged with Aeromonas hydrophila. Finally, the growth-promoting effects of sodium gluconate on B. velezensis R-71003 were evaluated. The results indicated that a low concentration of sodium gluconate could promote the growth of B. velezensis R-71003 and increase the expression levels of dnaA and yabD. Whole-genome analysis revealed that genome contains genes related to the biosynthesis of antibacterial substances, digestive enzymes, amino acids and vitamins, as well as stress resistance. The results collectively suggest that B. velezensis R-71003 exhibited good probiotic potential, and its combined application with sodium gluconate may be used to improve the health status of aquatic animals.

Renal fibrosis is an important pathological biomarker of chronic kidney disease (CKD). Stimulator of interferon genes/TANK binding kinase 1 (STING/TBK1) axis has been identified as the main regulator of innate immune response and closely related to fibrotic disorder. However, the role of STING/TBK1 signaling pathway in kidney fibrosis is still unknown. In this study, we investigated the effect of pharmacological inhibition of STING/TBK1 signaling on renal fibrosis induced by folic acid (FA). In mice, TBK1 was significantly activated in interstitial cells of FA-injured kidneys, which was markedly inhibited by H-151 (a STING inhibitor) treatment. Specifically, pharmacological inhibition of STING impaired bone marrow-derived fibroblasts activation and macrophage to myofibroblast transition in folic acid nephropathy, leading to reduction of extracellular matrix proteins expression, myofibroblasts formation and development of renal fibrosis. Furthermore, pharmacological inhibition of TBK1 by GSK8612 reduced myeloid myofibroblasts accumulation and impeded macrophage to myofibroblast differentiation, resulting in less deposition of extracellular matrix protein and less severe fibrotic lesion in FA-injured kidneys. In cultured mouse bone marrow-derived monocytes, TGF-β1 activated STING/TBK1 signaling. This was abolished by STING or TBK1 inhibitor administration. In addition, GSK8612 treatment decreased levels of α-smooth muscle actin and extracellular matrix proteins and prevents bone marrow-derived macrophages to myofibroblasts transition in vitro. Collectively, our results revealed that STING/TBK1 signaling has a critical role in bone marrow-derived fibroblast activation, macrophages to myofibroblasts transition, and kidney fibrosis progression.

Abstract Depression is the most prevalent mental disorder with substantial morbidity and mortality. Although genome-wide association studies (GWASs) have identified multiple risk variants for depression, due to the complicated gene regulatory mechanisms and complexity of linkage disequilibrium (LD), the biological mechanisms by which the risk variants exert their effects on depression remain largely unknown. Here, we perform a transcriptome-wide association study (TWAS) of depression by integrating GWAS summary statistics from 807,553 individuals (246,363 depression cases and 561,190 controls) and summary-level gene-expression data (from the dorsolateral prefrontal cortex (DLPFC) of 1003 individuals). We identified 53 transcriptome-wide significant (TWS) risk genes for depression, of which 23 genes were not implicated in risk loci of the original GWAS. Seven out of 53 risk genes (B3GALTL, FADS1, TCTEX1D1, XPNPEP3, ZMAT2, ZNF501 and ZNF502) showed TWS associations with depression in two independent brain expression quantitative loci (eQTL) datasets, suggesting that these genes may represent promising candidates. We further conducted conditional analyses and identified the potential risk genes that driven the TWAS association signal in each locus. Finally, pathway enrichment analysis revealed biologically pathways relevant to depression. Our study identified new depression risk genes whose expression dysregulation may play a role in depression. More importantly, we translated the GWAS associations into risk genes and relevant pathways. Further mechanistic study and functional characterization of the TWS depression risk genes will facilitate the diagnostics and therapeutics for depression.

IntroductionWomen are related to higher stroke risk and poorer outcome after stroke attack in patients with non-valvular atrial fibrillation (NVAF). The sex differences in efficacy and safety after left atrial appendage closure (LAAC) have remained elusive. This retrospective study aimed to investigate the safety, feasibility, and clinical outcomes of LAAC between women and men.MethodsFrom 2014 to 2018, 395 patients who underwent LAAC in our center were enrolled in this retrospective study. Baseline clinical characteristics, procedural parameters, and postoperative follow-up data were collected and compared between women and men.ResultsThe study included 154 women and 241 men. Compared with men, women were older (68.1 ± 7.9 vs. 64.6 ± 8.8, p < 0.01**), with higher CHA2DS2-VASc score (4.0 ± 1.7 vs. 3.0 ± 1.6, p < 0.01**). During the mean follow-up duration of 1,566 days (4.3 years), there were 39 major adverse cardiovascular events (MACE, including 19 cardiovascular or unexplained deaths, 15 ischemic strokes, and 5 major bleedings) recorded in 34 patients. The overall rate of ischemic stroke was 0.9 per 100 patient-years, and the overall rate of MACE was 2.1 per 100 patient-years. The cardiovascular or unexplained death and major bleeding were comparable between women and men. Compared with men, women had lower rates of ischemic stroke, fatal or disabling ischemic stroke, MACE, and fatal or disabling MACE, but none of them reached statistical differences (HR: 0.361, p = 0.099, HR: 0.429, p = 0.276, HR: 0.600, p = 0.170, and HR: 0.621, p = 0.254, respectively). In the adjusted analyses with multivariate Cox regression models, women had a lower fatal or disabling ischemic stroke rate compared with men (HR: 0.100, p = 0.041).ConclusionLeft atrial appendage closure was feasible and safe for patients of both genders. The ischemic stroke, cardiovascular or unexplained death, and major bleeding were comparable between women and men. However, women were the independent protective factors against fatal or disabling ischemic stroke after LAAC implantation.

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Abstract Periodical silver nanoparticle (NP) arrays were fabricated by magnetron sputtering method with anodic aluminum oxide templates to enhance the UV light emission from ZnO by the surface plasmon resonance effect. Theoretical simulations indicated that the surface plasmon resonance wavelength depended on the diameter and space of Ag NP arrays. By introducing Ag NP arrays with the diameter of 40 nm and space of 100 nm, the photoluminescence intensity of the near band-edge emission from ZnO was twofold enhanced. Time-resolved photoluminescence measurement and energy band analysis indicated that the UV light emission enhancement was attributed to the coupling between the surface plasmons in Ag NP arrays and the excitons in ZnO with the improved spontaneous emission rate and enhanced local electromagnetic fields.

Abstract Background BRAFV600E mutation is the most common mutation in thyroid cancer. It strongly activates MAPK/ERK pathway and indicates an invasive subtype of thyroid cancer. PLX4032 is a selective oral inhibitor of the BRAFV600 kinase although with limited effect in treating this panel of thyroid cancer, due to the feedback activation of MAPK/ERK as well as PI3K/AKT pathways. It was investigated that Vitamin C plays a positive role in inhibiting these pathways in thyroid cancer. However, whether Vitamin C could enhance the antitumor effect of PLX4032 remains largely unclear. Methods The antitumor efficacy of combination therapy with PLX4032 and Vitamin C on BRAFMT thyroid cancer cell was assessed by the MTT assay, EdU assay and colony formation, Chou-Talalay way was employed to analyze the synergistic effect. Flow cytometry were employed to assess cells’ apoptosis and cell cycle arrest in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity. Western blot and IHC were applied to investigate the mechanism underlying synergistic effect. Results PLX4032 or Vitamin C monotherapy was mildly effective in treating BRAFMT thyroid cancer cell and xenografts model. The combination therapy significantly inhibited cancer cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest compared to either monotherapy. PLX4032 monotherapy induced feedback activation of MAPK/ERK as well as PI3K/AKT pathway; while combination therapy significantly relieved this feedback. Conclusion Vitamin C promotes the antitumor effect of PLX4032 in BRAFMT thyroid cancer cell and xenografts model via relieving the feedback activation of MAPK/ERK as well as PI3K/AKT pathway. PLX4032/Vitamin C combination may be a potential therapeutic approach to treat BRAFMT thyroid cancer.

Background: The National Chest Pain Centers Program (NCPCP) is the largest nationwide, hospital-based, multifaceted, continuous quality improvement initiative, which aims to monitor and improve the quality of care for patients with acute chest pain. The accreditation of the standardized chest pain center is central to the project. The purpose of establishing chest pain centers is to develop a mechanism for “sending acute chest pain patients to a hospital with capabilities for the best treatment in the shortest time possible.” Objectives: This study aims to evaluate the effectiveness and implementation of the chest pain center accreditation and to identify factors that may influence its implementation in local settings. Study Design and Methods: Hospitals that have been accredited between January 2016 and September 2020 will be recruited in this study. We will conduct a self-controlled retrospective cohort study by comparing the care performance before, during, and after the accreditation. Measures for care performance will be selected based on the American College of Cardiology/American Heart Association clinical practice guidelines, which will be divided into prehospital processes, in-hospital processes, and in-hospital outcomes. For the implementation of the chest pain center accreditation, we will use a modified reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework to investigate the implementation process, and the consolidated framework for implementation research will be used to identify factors that emerge within the local context and influence the implementation fidelity and feasibility. Progress to Date: As of September 2020, there were 4,621 hospitals that registered the NCPCP, of which 1,507 hospitals were accredited. A total of 5,228,973 patients with a primary diagnosis on admission were enrolled from the registered hospitals, among which 34.6% were acute coronary syndromes. Conclusions: In this study, we proposed recommendations for improving the implementation of chest pain center accreditation, which will improve the quality of care for patients with acute chest pain and promote the sustainable development of chest pain center.

Epidemiological studies have shown that maternal hormone exposure is associated with autism spectrum disorders (ASD). The hormone oxytocin (OXT) is a central nervous neuropeptide that plays an important role in social behaviors as well as ASD etiology, although the detailed mechanism remains largely unknown. In this study, we aim to investigate the potential role and contribution of OXT to prenatal progestin exposure-mediated mouse offspring. Our in vitro study in the hypothalamic neurons that isolated from paraventricular nuclei area of mice showed that transient progestin exposure causes persistent epigenetic changes on the OXT promoter, resulting in dissociation of estrogen receptor β (ERβ) and retinoic acid-related orphan receptor α (RORA) from the OXT promoter with subsequent persistent OXT suppression. Our in vivo study showed that prenatal exposure of medroxyprogesterone acetate (MPA) triggers social deficits in mouse offspring; prenatal OXT deficiency in OXT knockdown mouse partly mimics, while postnatal ERβ expression or postnatal OXT peptide injection partly ameliorates, prenatal MPA exposure-mediated social deficits, which include impaired social interaction and social abilities. On the other hand, OXT had no effect on prenatal MPA exposure-mediated anxiety-like behaviors. We conclude that prenatal MPA exposure-mediated oxytocin suppression contributes to social deficits in mouse offspring.

ImportanceThe ongoing pandemic of COVID-19 is still affecting our life, but the effects of lockdown measures on gestational diabetes mellitus (GDM) in pregnant women remain unclear.AimTo investigate the association between COVID-19 lockdown and GDM.Subjects and MethodsMedical records of 140844 pregnant women during 2015-2020 were extracted from 5 hospitals in Guangdong Province, China. Pregnant women who underwent the COVID-19 Level I lockdown (1/23 - 2/24/2020) during pregnancy were defined as the exposed group (N=20472) and pregnant women who underwent the same calendar months during 2015-2019 (1/23 - 2/24) were defined as the unexposed group (N=120372). Subgroup analyses were used to explore the potential susceptible exposure window of COVID-19 lockdown on GDM. Cumulative exposure is quantitatively estimated by assigning different weights to response periods with different exposure intensities. A logistic regression model was used to estimate the association between COVID-19 lockdown exposure and GDM.ResultsThe rates of GDM in the exposed and unexposed groups were 15.2% and 12.4%, respectively. The overall analyses showed positive associations (odds ratio, OR=1.22, 95%CI: 1.17, 1.27) between lockdown exposure and GDM risk in all pregnant women. More pronounced associations were found in women who underwent the COVID-19 lockdown in their first four months of pregnancy, and the adjusted OR values ranged from 1.24 (95%CI: 1.10, 1.39) in women with 5-8 gestational weeks (GWs) to 1.35 (95%CI: 1.20, 1.52) with < 5 GWs. In addition, we found a positive exposure-response association of cumulative lockdown exposure with the risk of GDM.ConclusionsThe COVID-19 lockdown was associated with an increased risk of GDM, and the first four months of pregnancy may be the window for sensitive exposure.

Recurrence and new cases of cancer constitute a challenging human health problem. Aquaporins (AQPs) can be expressed in many types of tumours, including the brain, breast, pancreas, colon, skin, ovaries, and lungs, and the histological grade of cancer is positively correlated with AQP expression. Therefore, the identification of aquaporins is an area to explore. Computational tools play an important role in aquaporin identification. In this research, we propose reliable, accurate and automated sequence predictor iAQPs-RF to identify AQPs. In this study, the feature extraction method was 188D (global protein sequence descriptor, GPSD). Six common classifiers, including random forest (RF), NaiveBayes (NB), support vector machine (SVM), XGBoost, logistic regression (LR) and decision tree (DT), were used for AQP classification. The classification results show that the random forest (RF) algorithm is the most suitable machine learning algorithm, and the accuracy was 97.689%. Analysis of Variance (ANOVA) was used to analyse these characteristics. Feature rank based on the ANOVA method and IFS strategy was applied to search for the optimal features. The classification results suggest that the 26th feature (neutral/hydrophobic) and 21st feature (hydrophobic) are the two most powerful and informative features that distinguish AQPs from non-AQPs. Previous studies reported that plasma membrane proteins have hydrophobic characteristics. Aquaporin subcellular localization prediction showed that all aquaporins were plasma membrane proteins with highly conserved transmembrane structures. In addition, the 3D structure of aquaporins was consistent with the localization results. Therefore, these studies confirmed that aquaporins possess hydrophobic properties. Although aquaporins are highly conserved transmembrane structures, the phylogenetic tree shows the diversity of aquaporins during evolution. The PCA showed that positive and negative samples were well separated by 54D features, indicating that the 54D feature can effectively classify aquaporins. The online prediction server is accessible at http://lab.malab.cn/∼acy/iAQP.

Functional deficits in schizophrenia (SZ) are observed prior to the onset of psychosis and differ at different stages of SZ. However, there is a paucity of studies focused on adolescent first-episode SZ (AOS), adult first-episode SZ (AFES), and adult chronic SZ (CHSZ). In this study, we investigated regional activity and corresponding functional connectivity alterations that have aimed to compare the three disease stages simultaneously. The subjects comprised 49 patients with AOS, 57 patients with AFES, 51 patients with CHSZ, 41 adolescent healthy controls, and 138 adult healthy controls. We compared regional homogeneity (ReHo) between patients at each disease stage with matched healthy controls. We focused on the shared brain regions that showed significant differences between SZ patients at the three different disease stages and healthy controls. Further analysis was conducted to explore whether the patterns of the whole brain functional connectivity alterations were similar. The putamen and medial frontal gyrus (MFG) showed consistently abnormal patterns in AOS, AFES, and CHSZ. Commonly decreased ReHo values in the MFG and increased ReHo values in the bilateral putamen were found in AOS, AFES, and CHSZ. Functional connectivity of MFG remained common abnormality in different SZ stage. In conclusion, ReHo abnormalities in the MFG and the putamen may be common abnormal patterns of brain function in the three different stages of SZ. The vmPFC-dlPFC FC abnormality common occurs in adolescence and adulthood.. This study may provide a more comprehensive understanding of the neurodevelopmental abnormality across the AOS, AFES, and CHSZ.

Abstract Background Peripheral blood mononuclear cells (PBMCs) play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). However, the specific roles of PBMCs in the development and progression of idiopathic PAH (IPAH) have not been fully understood. Methods Here, differentially expressed genes (DEGs) of PBMCs or lung tissues between IPAH patients and healthy controls were identified via bioinformatics analysis of Gene Expression Omnibus (GEO) datasets GSE33463 and GSE48149, respectively. Subsequently, extensive target prediction and network analysis were performed to assess protein–protein interaction (PPI) networks, Gene Ontology (GO) terms, and pathway enrichment for DEGs. Co‐expressed DEGs between PBMCs and lung tissues coupled with corresponding predicted miRNAs involved in PAH were also assessed. We identified 251 DEGs in PBMCs and 151 DEGs in lung tissue samples from IPAH. PDK4, RBPMS2, and PDE5A expression were altered in both PBMCs and lung tissues from IPAH patients compared to healthy control. Results CXCL8, JUN, TLR8, IL1B, and TLR7 could be implicated as the hub genes in PBMCs, whereas ENO1, STAT1, CXCL10, GPI, and IRF1 in lung tissues. Finally, co‐expressed DEGs of PDK4, RBPMS2, and PDE5A coupled with corresponding predicted miRNAs, especially miR‐103a‐3p, miR‐185‐5p, and miR‐515‐5p, are significantly associated with IPAH. Conclusion Our findings collectively suggest that the expression levels of PDK4, RBPMS2, and PDE5A in PBMCs are associated with the expression of these genes in lung tissues. Thus, these molecules may serve as potential circulating biomarkers and/or possible therapeutic targets for IPAH.

BackgroundCatheter ablation target at the site with large His activation in the left ventricle poses a high risk of atrioventricular (AV) block. We aimed to identify far-field (FF) and near-field (NF) His activation at left upper septum (LUS).MethodsThree-D mapping of the aortic root and left ventricle was performed in 12 dogs. Two sites located at either the base or apex of the triangle interposed between the hinges of the the noncornary coronary cusp (NCC) - right coronary cusp (RCC) were chosen for a single radiofrequency (RF) application. Bipolar and unipolar pacing with different outputs at both sites was attempted to discern NF and FF His activation.ResultsThe sites chosen for NF and FF ablation were located at the base and apex of the triangle, which were 8.03 ± 1.18 mm (group 1) and 3.42 ± 0.61 mm (group 2) away from the RCC-NCC junction. Lower A/V ratios were found in group 1. Pacing could not differentiate NF from FF His activation. In group 1, ablation resulted in III degree AV block in all 6 dogs, whereas neither PR prolongation nor AV block occurred in group 2. Pathologic examination of group 1 showed complete/partial necrosis of the His bundle (HB) and left bundle branch in all 6 dogs. In group 2, no necrosis of the HB was seen in the 6/6 dogs.ConclusionAnatomical localization in the triangle of RCC-NCC junction can help differentiate NF from FF His activation.

Ionic liquids (ILs) are widely used for their physical and chemical properties. Toxicological assessments of ILs could help to avoid their threat to human health, but these are rarely reported, and no assessments of IL neurotoxicity in mammals have been performed. Here, we aimed to evaluate the neurotoxicity of chronic 1-octyl-3-methylimidazolium hexafluorophosphate ([C8mim][PF6]) (0, 1 mg/kg) exposure during development on rats. Our results indicated that chronic exposure to low-dose ([C8mim][PF6]) induces behavioural abnormalities, including cognitive deficits, social communication disorders, and sensory gating function impairment. Moreover, rats subjected to chronic ([C8mim][PF6]) exposure showed hypofunction of glutamatergic excitatory synapses, including increased expression of NMDA receptor subunits, increased density and immaturity of dendritic spines, and increased expression of PSD95. Additionally, ([C8mim][PF6]) exposure resulted in hippocampal-specific inflammatory activation, indicated by increased levels of proinflammatory factors, elevated nuclear localisation of NF-κB, and activation of microglia and astrocytes. In conclusion, chronic exposure to low-dose ([C8mim][PF6]) induced neurotoxicity, including damage to glutamatergic excitatory synapses and inflammatory activation, which may illuminate the associated behavioural abnormalities. The results presented here may be helpful for the safe use of ILs in the future.

Heavy metal cadmium (Cd) pollution is a serious problem affecting the sustainable development of aquaculture and the safety of aquatic foods. Research about the use of probiotics to attenuate toxic damage caused by Cd2+ in aquatic animals has received widespread attention. Bacillus coagulans (B. coagulans), a kind of probiotics commonly used in aquaculture, has been shown to adsorb Cd2+ both in vivo and vitro. Here, we aimed to determine the effects of B. coagulans on Cd2+ bioaccumulation, gut barrier function, oxidative stress and gut microbiota in common carp following Cd2+ exposure. The fish were exposure to Cd2+ at 0 and 0.5 mg/L and/or fed a B. coagulans-containing diet at 107, 108 and 109 CFU/g for 8 weeks. The results indicated that B. coagulans can maintain gut barrier function in Cd2+-exposed fish by reducing Cd2+ bioaccumulation, increasing the mRNA levels of tight junction protein genes (occludin, claudin-2 and zonula occludens-1), and decreasing the levels of diamine oxidase and D-lactic acid. In addition, B. coagulans could relieve oxidative stress in Cd2+-exposed fish by restoring the activities of glutathione peroxidase, catalase and superoxide dismutase. Moreover, Cd2+ exposure decreased the intestinal microbiota diversity and changed the intestinal microbiota compositions in common carp. However, supplementation with B. coagulans could reverse the altered intestinal microbiota diversity and composition after Cd2+ exposure, decrease the abundance of some pathogens (Shewanella and Vibrio), and increase the abundance of probiotics (Bacillus and Lactobacillus). These results indicate that B. coagulans may serve as a potential antidote for alleviating Cd2+ toxicity.

Background: Shared psychopathological features and mechanisms have been observed between schizophrenia (SZ) and bipolar disorder (BD), but their common risk genes and full genetic architectures remain to be fully characterized. The genome-wide association study (GWAS) datasets offer the opportunity to explore this scientific question using combined genetic data from enormous samples, ultimately allowing a better understanding of the onset and development of these illnesses.Methods: We have herein performed a genome-wide meta-analysis in two GWAS datasets of SZ and BD respectively (24,600 cases and 40,012 controls in total, discovery sample), followed by replication analyses in an independent sample of 4,918 SZ cases and 5,506 controls of Han Chinese origin (replication sample). The risk SNPs were then explored for their correlations with mRNA expression of nearby genes in multiple expression quantitative trait loci (eQTL) datasets.Results: The single nucleotide polymorphisms (SNPs) rs1637749 and rs3800908 at 7p22.3 region were significant in both discovery and replication samples, and exhibited genome-wide significant associations when combining all East Asian SZ and BD samples (29,518 cases and 45,518 controls). The risk SNPs were also significant in GWAS of SZ and BD among Europeans. Both risk SNPs significantly predicted lower expression of MRM2 in the whole blood and brain samples in multiple datasets, which was consistent with its reduced mRNA level in the brains of SZ patients compared with normal controls. The risk SNPs were also associated with MAD1L1 expression in the whole blood sample.Discussion: We have identified a novel genome-wide risk locus associated with SZ and BD in East Asians, adding further support for the putative common genetic risk of the two illnesses. Our study also highlights the necessity and importance of mining public datasets to explore risk genes for complex psychiatric diseases.

Background: Dyslipidemia is an important risk factor for myocardial infarction (MI). This study aimed to examine the health-related quality of life (HRQoL) and its predictors of patients with MI combined with dyslipidemia in China.Methods: Information on patients' sociological characteristics, lifestyle, clinical characteristics, and quality of life were collected by electronic medical records and questionnaires. Tobit regression model was used to investigate the predictors of quality of life.Results: There were 756 patients responded. The average EQ-5D score of all the patients was 0.95 (SD: 0.11). For all patients, factors such as age, high-fat and high-cholesterol diet, sports, family history of dyslipidemia, history of peripheral artery disease significantly affected HRQoL.Conclusions: Post-discharge care of the elderly group should be paid more attention to and suggestions on the healthy lifestyle (fat control) of the patients should be encouraged to improve the quality of life of these population.

Anxiety disorders are common mental disorders that often result in disability. Recently, large-scale genome-wide association studies (GWASs) have identified several novel risk variants and loci for anxiety disorders (or anxiety traits). Nevertheless, how the reported risk variants confer risk of anxiety remains unknown. To identify genes whose cis-regulated expression levels are associated with risk of anxiety traits, we conducted a transcriptome-wide association study (TWAS) by integrating genome-wide associations from a large-scale GWAS (N = 175,163) (which evaluated anxiety traits based on Generalized Anxiety Disorder 2-item scale (GAD-2) score) and brain expression quantitative trait loci (eQTL) data (from the PsychENCODE and GTEx). We identified 19 and 17 transcriptome-wide significant (TWS) genes in the PsychENCODE and GTEx, respectively. Intriguingly, 10 genes showed significant associations with anxiety in both datasets, strongly suggesting that genetic risk variants may confer risk of anxiety traits by regulating the expression of these genes. Top TWS genes included RNF123, KANSL1-AS1, GLYCTK, CRHR1, DND1P1, MAPT and ARHGAP27. Of note, 25 TWS genes were not implicated in the original GWAS. Our TWAS identified 26 risk genes whose cis-regulated expression were significantly associated with anxiety, providing important insights into the genetic component of gene expression in anxiety disorders/traits and new clues for future drug development.

ObjectivesSchizophrenia (SZ) is a complex psychiatric disorder with high heritability, and genetic components are thought to be pivotal risk factors for this illness. The glutamate decarboxylase 1 gene (GAD1) was hypothesized to be a candidate risk locus for SZ given its crucial role in the GABAergic neurotransmission system, and previous studies have examined the associations of single nucleotide polymorphisms (SNPs) spanning the GAD1 gene with SZ. However, inconsistent results were obtained. We hence examined the associations between GAD1 SNPs and SZ in two independent case-control samples of Han Chinese ancestry.Materials and MethodsTwo Han Chinese SZ case-control samples, referred as the discovery sample and the replication sample, respectively, were recruited for the current study. The discovery sample comprised of 528 paranoid SZ cases (with age of first onset ≥ 18) and 528 healthy controls; the independent replication sample contained 1,256 early onset SZ cases (with age of first onset < 18) and 2,661 healthy controls. Logistic regression analysis was performed to examine the associations between GAD1 SNPs and SZ.ResultsTen SNPs covering GAD1 gene were analyzed in the discovery sample, and two SNPs showed nominal associations with SZ (rs2241165, P = 0.0181, OR = 1.261; rs2241164, P = 0.0225, OR = 1.219). SNP rs2241164 was also nominally significant in the independent replication sample (P = 0.0462, OR = 1.110), and the significance became stronger in a subsequent meta-analysis combining both discovery and replication samples (P = 0.00398, OR = 1.138). Nevertheless, such association could not survive multiple corrections, although the effect size of rs2241164 was comparable with other SZ risk loci identified in genome-wide association studies (GWAS) in Han Chinese population. We also examined the associations between GAD1 SNPs and SZ in published datasets of SZ GWAS in East Asians and Europeans, and no significant associations were observed.ConclusionWe observed weak associations between GAD1 SNPs and risk of SZ in Han Chinese populations. Further analyses in larger Han Chinese samples with more detailed phenotyping are necessary to elucidate the genetic correlation between GAD1 SNPs and SZ.

Abstract Background Schizophrenia is characterized by several core behavioral features, in which the gastrointestinal symptoms are frequently reported. Maternal immune activation (MIA) has been developed in a rodent model to study neurodevelopmental disorders such as schizophrenia. However, the changes in the gut environment of MIA rats remain largely unknown. Methods 10 mg/kg of polyinosinic:polycytidylic acid (Poly I:C) on gestational day 9 was intravenously administered to rats to induce MIA in order to assess changes in behavior, the intestinal barrier and microbiota in offspring. Results Maternal immune activation offspring shown increased anxiety as indicated by reduced exploration of central area in open field test and decreased exploration of open arms in elevated plus test. Cognitive impairment of MIA offspring was confirmed by reduced exploration of novel arm in Y maze test and deficiency of PPI. Intestinal muscle thickness became thinner and some specific microbial anomalies previously identified clinically were observed in MIA offspring. In addition, an increase of inflammatory responses was found in the gut of MIA offspring. Conclusions Maternal immune activation alters behavior, intestinal integrity, gut microbiota and the gut inflammation in adult offspring.

Abstract Background Earlier vascular healing after drug-eluting stent (DES) implantation may reduce the incidence of late stent thrombosis and provide theoretical evidence to shorten dual antiplatelet therapy duration in patients with high bleeding risks. The BuMA supreme stent is a newly developed DES-coated with the sirolimus by using the international patent electronic grafted eG™ technology. Previous randomized trials showed that BuMA stents had better stent-strut coverage at 3-month follow-ups, which were evaluated by optical coherence tomography (OCT). However, there have been a limited number of studies that are directly evaluating the extent of neointima formation at the first and second months after stent implantation in high-bleeding-risk patients with coronary artery disease. This clinical trial is designed to demonstrate the non-inferiority of the BuMA supreme stent compared to the XIENCE stent in early neointimal formation. Methods/design This is a prospective, multicenter, randomized trial. Forty patients will be assigned into the first-month OCT group, and another 40 patients into the second-month OCT group. The patients in each cohort will be randomized again into two groups in a 1:1 ratio, either being implanted with the BuMA Supreme stent or the Xience V/Prime/Xpedition stent. The primary endpoint is stent-strut neointimal coverage rate (%) at the first and second months, respectively. Secondary endpoints include neointimal hyperplasia area/volume, neointimal hyperplasia thickness, stent-strut malapposition rate, late lumen loss (LLL), restenosis rate, device/lesion/clinical success rate, device-oriented composite endpoints at the first and second months, stent thrombosis and other serious adverse events and bleeding events at follow-up. Discussion The results will provide the first accurate imaging evidence on neointimal formation of the BuMA Supreme stent and the Xience stent at 1–2 months post PCI. The result should inspire further exploration and adjustment of DAPT treatments. Trial registration ClinicalTrials.gov, ID: NCT02747329. Registered on 21 April 2016. Last updated 17 May 2018.

Background: Dyslipidemia is a common comorbidity and an important risk factor for myocardial infarction (MI). This study aimed to examine the economic burden of MI combined with dyslipidemia in China.Methods: Patients who were hospitalized due to MI combined with dyslipidemia in 2016 were enrolled. Costs were measured based on electronic medical records and questionnaires. The annual costs were analyzed by conducting descriptive statistics, univariable, and multivariable analyses.Results: Data of 900 patients were analyzed, and 144 patients were dead during the follow-up. The majority of patients were aged 51–70 years (n = 563, 62.55%) and males (n = 706, 78.44%). For all-cause costs, the median annual direct medical costs, direct non-medical costs, indirect costs, and total costs were RMB 13,168 (5,212–29,369), RMB 600 (0–1,750), RMB 676 (0–1,787), RMB 15,361 (6,440–33,943), respectively; while for cardiovascular-related costs, the corresponding costs were RMB 12,233 (3,795–23,746), RMB 515 (0–1,680), RMB 587 (0–1,655), and RMB 14,223 (4,914–28,975), respectively. Lifestyle and complications significantly affected both all-cause costs and cardiovascular-related costs.Conclusions: Increasing attention should be paid to encourage healthy lifestyle, and evidence-based medicine should focus on optimal precautions and treatments for complications, to reduce the economic burden among MI patients with a comorbid dyslipidemia.

The level of CHB virus (HBV) core antibody (HBcAb) is different in four stages of chronic HBV infection and may be used for differential diagnosis of the natural history of chronic HBV infection. To address this question, we examined multiple blood biomarkers and assessed the efficacy to diagnose different stages of chronic HBV infection. The quantitative detection of HBcAb, hepatitis B surface antigen (HBsAg), HBV DNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet count (PLT) were determined in the serum of 73 cases of low-replicative phase (LR), 46 cases of immune-tolerant phase (IT), 44 cases of immune clearance phase (IC), and 57 cases of HBeAg-negative hepatitis (ENH). Differentiating performance of these serum protein levels was analyzed by receiver operating characteristic (ROC) curve analysis. Our results showed that the levels of HBcAb, ALT, and AST levels were significantly higher in IC and ENH than those in LR and IT (both P≤0.001). The levels of HBV DNA and HBsAg were higher in IC and IT than those in LR and ENH (both P≤0.001). Logistic regression models showed that HBcAb, HBsAg, HBV DNA, ALT, and AST were the independent variables, respectively, and when combined, they provided high diagnostic accuracy for the staging of CHB. To sum up, HBcAb quantification is a new index, which can reflect whether the liver is in the immune activation state of HBV infection, and is related to the inflammatory state of the host liver. The combined detection of HBcAb quantification and other indicators has showed promising efficiency for staging of IC and ENH and can assist the diagnosis and treatment of CHB.