Prognostic Impact of Left Atrial Appendage Patency After Device Closure.

BACKGROUND: The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post-LAA closure in patients with atrial fibrillation, remains elusive. METHODS: Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. RESULTS: Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post-LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787-1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17-8.83]; P=0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06-1.17]; P=0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29-10.42]; P=0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71-8.07]; P=0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28-10.09]; P=0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P=0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P=0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P=0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. CONCLUSIONS: LAA patency detected by cardiac computed tomography angiography at 3 months post-LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03788941.

Nomogram establishment for short-term survival prediction in ICU patients with aplastic anemia based on the MIMIC-IV database.

OBJECTIVE: To establish an efficient nomogram model to predict short-term survival in ICU patients with aplastic anemia (AA). METHODS: The data of AA patients in the MIMIC-IV database were obtained and randomly assigned to the training set and testing set in a ratio of 7:3. Independent prognosis factors were identified through univariate and multivariate Cox regression analyses. The variance inflation factor was calculated to detect the correlation between variables. A nomogram model was built based on independent prognostic factors and risk scores for factors were generated. Model performance was tested using C-index, receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and Kaplan-Meier curve. RESULTS: A total of 1,963 AA patients were included. A nomogram model with 7 variables was built, including SAPS II, chronic pulmonary obstructive disease, body temperature, red cell distribution width, saturation of peripheral oxygen, age and mechanical ventilation. The C-indexes in the training set and testing set were 0.642 and 0.643 respectively, indicating certain accuracy of the model. ROC curve showed favorable classification performance of nomogram. The calibration curve reflected that its probabilistic prediction was reliable. DCA revealed good clinical practicability of the model. Moreover, the Kaplan-Meier curve showed that receiving mechanical ventilation could improve the survival status of AA patients in the short term but did not in the later period. CONCLUSION: The nomogram model of the short-term survival rate of AA patients was built based on clinical characteristics, and early mechanical ventilation could help improve the short-term survival rate of patients.

Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients.

OBJECTIVES: Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. METHODS AND RESULTS: Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage (P < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications (P < 0.00001), VKORC1 did not demonstrate a similar association. CONCLUSION: The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.

Biosynthesis of Chryseno[2,1,c]oxepin-12-Carboxylic Acid from Glycyrrhizic Acid in Aspergillus terreus TMZ05-2, and Analysis of Its Anti-inflammatory Activity.

Glycyrrhizic acid, glycyrrhetinic acid, and their oxo, ester, lactone, and other derivatives, are known for their anti-inflammatory, anti-oxidant, and hypoglycemic pharmacological activities. In this study, chryseno[2,1-c]oxepin-12-carboxylic acid (MG) was first biosynthesized from glycyrrhizic acid through sequential hydrolysis, oxidation, and esterification using Aspergillus terreus TMZ05-2, providing a novel in vitro biosynthetic pathway for glycyrrhizic acid derivatives. Assessing the influence of fermentation conditions and variation of strains during culture under stress-induction strategies enhanced the final molar yield to 88.3% (5 g/L glycyrrhizic acid). CCK8 assays showed no cytotoxicity and good cell proliferation, and anti-inflammatory experiments demonstrated strong inhibition of NO release (36.3%, low-dose MG vs. model), transcriptional downregulation of classical effective cellular factors tumor necrosis factor-α (TNF-α; 72.2%, low-dose MG vs. model), interleukin-6 (IL-6; 58.3%, low-dose MG vs. model) and interleukin-1ß (IL-1ß; 76.4%, low-dose MG vs. model), and decreased abundance of P-IKK-α, P-IKB-α, and P-P65 proteins, thereby alleviating inflammatory responses through the NF-κB pathway in LPS-induced RAW264.7 cells. The findings provide a reference for the biosynthesis of lactone compounds from medicinal plants.

Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma.

Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106-4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

Decrease of lncRNA MEG3 in Acute Myeloid Leukemia Affected the Expression of p53 and MDM2.

BACKGROUND: The aim was to determine the clinical role of long non coding maternally expressed gene 3 (lncRNA MEG3) in adult acute myeloid leukemia (AML). METHODS: The expression levels of lncRNA MEG3 in bone marrow of AML patients and healthy donors were determined by qPCR. The correlation between expression levels of lncRNA MEG3 and clinical features was also analyzed. MTT assay and flow-cytometric assay were employed to determine the role of lncRNA MEG3 on the cell viability and apoptosis of AML cell lines. Expression levels of caspase-9, Bcl-2, MDM2, and p53 in those cells were determined by western blot. RESULTS: The expression levels of lncRNA MEG3 was significantly down-regulated in AML patients. Expression levels of lncRNA MEG3 were positively correlated with overall survival of patients. Up-regulation of lncRNA MEG3 could not only inhibit the cell growth and promoted apoptosis, but also increased the expression of caspase-9 and p53 and decreased the expression of Bcl-2 and MDM2. CONCLUSIONS: These results suggest that down-regulation of lncRNA MEG3 in AML patients might promote tumor progression and affect the p53-MDM2 pathway.

An integrated analysis identifies six molecular subtypes of pancreatic ductal adenocarcinoma revealing cellular and molecular landscape.

Pancreatic ductal adenocarcinoma (PDA) has been found to have a high mortality rate. Despite continuous efforts, current histopathological classification is insufficient to guide individualized therapies of PDA. We first define the molecular subtypes of PDA (MSOP) based on a meta-cohort of 845 samples from 11 PDA datasets. We then performed functional analyses involving immunity, fibrosis and metabolism. We recognized six molecular subtypes with different survival statistics and molecular composition. The squamous basal-like (SBL) subtype had a poor prognosis and high infiltration of ENO1+ (Enolase 1)/ADM+ (Adrenomedullin) cancer-associated fibroblasts (CAFs). The immune mesenchymal-like (IML) subtype and the normal mesenchymal-like (NML) subtype were characterized by genes associated with extracellular matrix (ECM) activities and immune responses, having favorable prognoses. IML was featured by elevated exhausted immune signaling and inflammatory CAFs infiltration, whereas NML was featured with myofibroblastic CAFs infiltration. The exocrine-like (EL) subtype was high in exocrine signals, while the pure classical-like (PCL) subtype lacked immunocytes infiltration. The quiescent-like (QL) subtype had diminished metabolic signaling and high infiltration of NK cells. SBL, IML and NML were enriched in innate anti-PD-1 resistance signatures. In sum, this MSOP depicts a vivid cell-to-molecular atlas of the tumor microenvironment of PDA and might facilitate to design a precise combination of therapies that target immunity, metabolism and stroma.

Tissue-resident innate lymphoid cells in asthma.

Asthma is a chronic airway inflammatory disease whose global incidence increases annually. The role of innate lymphoid cells (ILCs) is a crucial aspect of asthma research with respect to different endotypes of asthma. Based on its pathological and inflammatory features, asthma is divided into type 2 high and type 2 low endotypes. Type-2 high asthma is distinguished by the activation of type 2 immune cells, including T helper 2 (Th2) cells and ILC2s; the production of cytokines interleukin (IL)-4, IL-5 and IL-13; eosinophilic aggregation; and bronchial hyper-responsiveness. Type-2 low asthma represents a variety of endotypes other than type 2 high endotype such as the IL-1ß/ILC3/neutrophil endotype and a paucigranulocytic asthma, which may be insensitive to corticosteroid treatment and/or associated with obesity. The complexity of asthma is due to the involvement of multiple cell types, including tissue-resident ILCs and other innate immune cells including bronchial epithelial cells, dendritic cells, macrophages and eosinophils, which provide immediate defence against viruses, pathogens and allergens. On this basis, innate immune cells and adaptive immune cells combine to induce the pathological condition of asthma. In addition, the plasticity of ILCs increases the heterogeneity of asthma. This review focuses on the phenotypes of tissue-resident ILCs and their roles in the different endotypes of asthma, as well as the mechanisms of tissue-resident ILCs and other immune cells. Based on the phenotypes, roles and mechanisms of immune cells, the therapeutic strategies for asthma are reviewed.

A Seawater Salinity Sensor Based on Optimized Long Period Fiber Grating in the Dispersion Turning Point.

Variations of seawater salinity often cause ocean internal waves, water masses and stratification, which affect the stability of the ocean environment. Therefore, the study of seawater salinity is significant for the prediction of changes in the ocean environment. However, existing methods for measuring seawater salinity generally have the disadvantages of low sensitivity and low accuracy. In this work, we proposed a seawater salinity sensor based on long period fiber grating (LPFG) in the dispersion turning point (DTP), which has demonstrated the possibility to fabricate LPFG with a shorter grating period by CO2 laser in a thin single mode fiber (SMF) of 80 µm cladding diameter without etching. For obtaining higher sensitivity that could meet the measurement requirement in practice, the proposed sensor was optimized by combining etching cladding and DTP. After the LPFG working near DTP was fabricated by a CO2 laser, the cladding diameter was reduced to 57.14 µm for making cladding mode LP1,7 work near DTP by hydrofluoric acid (HF) solutions. The experimental results have demonstrated that a sensitivity of 0.571 nm/‱ can be achieved when the salinity increases from 5.001‱ to 39.996‱, and the sensor shows good repeatability and stability. Based on its excellent performance, the optimized LPFG is a prospective sensor to monitor seawater salinity in real time. Meanwhile, a low-cost way was provided to make LPFG work near DTP instead of ultraviolet exposure and femtosecond laser writing.

High psychological stress levels related to delivery can increase the occurrence of postpartum mental disorders.

Objective: The study sought to explore the relationship between high psychological stress levels related to delivery and postpartum mental disorders. Methods: A total of 284 parturients were included in the study from July 2021 to January 2022. The stress level at 1 month postpartum was assessed by the Impact of Event Scale-Revised (IES-R). Parturients with an IES-R score ≤ 9 were included in the low psychological stress level group, and those with an IES-R score > 9 were included in the high psychological stress level group. The Edinburgh Postnatal Depression Scale (EPDS), Union Physio-Psycho-Social Assessment Questionnaire (UPPSAQ-70), Symptom Checklist-90 (SCL-90) and Mini-International Neuropsychiatric Interview (M.I.N.I.) were conducted at 42 ± 7 days postpartum to assess the mental health of parturients.The parturients' mental health after birth was assessed by the EPDS, UPPSAQ-70, and SCL-90. Semi-structured diagnostic interviews were conducted at 42 ± 7 days postpartum by using the M.I.N.I. Results: The incidence rate of postpartum mental disorders was 20.42% (58/284), the incidence rates of postpartum depression, anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder were 17.96% (51/284), 11.97% (34/284), 4.58% (13/284) and 1.41% (4/284), respectively, and the comorbidity rate was 58.62% (34/58). A history of mental disorders and pregnancy complications were risk factors for postpartum depression (p = 0.028, p = 0.040, respectively); a history of mental disorders, a lack of physical exercise, partner violence and pregnancy complications were risk factors for postpartum anxiety disorders (p = 0.003, p = 0.007, p = 0.031, p = 0.048, respectively); and the delivery of female infants was a risk factor for postpartum obsessive-compulsive disorder (p = 0.022).The risk of postpartum depression, anxiety disorders and obsessive-compulsive disorder was 9.125 times (95% CI = 3.900 ~ 21.349, p < 0.01), 7.310 times (95% CI = 2.588 ~ 20.649, p < 0.01) and 6.259 times (95% CI = 1.347 ~ 29.093, p < 0.01) higher in postpartum women with high psychological stress levels related to delivery than in those with low psychological stress levels, respectively. Conclusion: The incidence of postpartum mental disorders is high and has a positive correlation with the level of psychological stress. This may lead to a new perspective of the effect of psychological stress on postpartum mental disorders and attract more attention to other mental disorders in addition to postpartum depression.

Analysis of sports behavior and the current situation of young students under the background of covid-19 / Análise do comportamento esportivo e da situação atual dos jovens estudantes sob o contexto da covid-19 / Análisis del comportamiento deportivo y de la situación actual de los jóvenes estudiantes en el contexto del covid-19

ABSTRACT Introduction With the repeated covid-19 epidemic, people have gradually realized the importance of physical exercise, so the sports enthusiasm of young students has also been improved to a certain extent. Objective Analyze the sports behavior and status in adolescent students under the background of covid-19. Methods A questionnaire survey was used in this paper. The questionnaire design is carried out from three aspects: current exercise status, changes of physical exercise, and sports behavior motivation of young students. Results Students and parents prefer exercises at home or in the open space of a relatively safe and single community, choosing non-contact sports that can be completed by a single person or are far away from each other. Improvement in both frequency and duration of exercise was observed in the young students, and most had a gain in psychological quality. Conclusion Physical education teachers must fully match the actual situation of the epidemic's current development by choosing effective teaching methods to promote the continuous development of young students' physical quality. Level of evidence II; Therapeutic studies - investigation of treatment results.

RESUMO Introdução Com a repetida epidemia da covid-19, as pessoas foram gradualmente percebendo a importância do exercício físico e um crescimento no engajamento esportivo entre os jovens estudantes foi observado. Objetivo Analisar o comportamento e o status esportivo dos estudantes adolescentes sob o contexto da covid-19. Métodos Este trabalho utilizou uma pesquisa por questionário com desenho realizado a partir de três aspectos: estado atual do exercício físico, alterações do exercício físico, e motivação do comportamento esportivo nos jovens estudantes. Resultados Os estudantes e seus pais preferem exercícios em casa ou em espaço aberto relativamente seguro e isolado, escolhendo esportes sem contato que podem ser realizados por uma única pessoa ou em que estejam longe um do outro. Observou-se uma melhora tanto na frequência quanto na duração dos exercícios físicos dos jovens estudantes e a maioria teve um ganho na qualidade psicológica. Conclusão Os professores de educação física devem combinar plenamente a situação real do atual desenvolvimento da epidemia escolhendo métodos de ensino eficazes que promovam o desenvolvimento contínuo da qualidade física dos jovens estudantes. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción Con la repetida epidemia del covid-19, la gente se fue dando cuenta de la importancia del ejercicio físico y se observó un aumento del interés por el deporte entre los jóvenes estudiantes. Objetivo Analizar el comportamiento y la situación deportiva de los estudiantes adolescentes en el contexto del covid-19. Métodos Este trabajo utilizó una encuesta con diseño de cuestionario realizada desde tres aspectos: estado actual del ejercicio, cambios de ejercicio y motivación del comportamiento deportivo en jóvenes estudiantes. Resultados Los estudiantes y sus padres prefieren hacer ejercicio en casa o en un espacio abierto relativamente seguro y aislado, eligiendo deportes sin contacto que puedan ser realizados por una sola persona o donde estén alejados unos de otros. Se observó una mejora tanto en la frecuencia como en la duración del ejercicio en los jóvenes estudiantes y la mayoría tuvo una ganancia en la calidad psicológica. Conclusión Los profesores de educación física deben ajustarse plenamente a la situación real del desarrollo actual de la epidemia eligiendo métodos de enseñanza eficaces que promuevan el desarrollo continuo de la calidad física de los jóvenes estudiantes. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

The Effect of Infectious Disease Threat on Malevolent Creativity.

The behavioral immune system (BIS), which evolved to protect humans from infectious disease threats, prompts people to be sensitive to disease-connoting cues. A common denominator of many disease-connoting cues is benign physical abnormalities, such as birthmarks and obesity. Previous studies found that among people whose BIS was activated (e.g., people who were exposed to situational disease prime or chronically concerned about disease threat), disease-connoting cues could make people feel threatened by infectious disease and induce their malevolence. Malevolence is a necessary feature of malevolent creativity (MC), which is defined as creativity that deliberately leads to harmful or immoral results. According to the motivated focus account of creativity, a threat could promote creativity when creativity is relevant to the threat. Thus, infectious disease threats might increase malevolent creativity. However, whether infectious disease threats could influence MC is unknown. Therefore, the current study aims to explore the effect of infectious disease threat on MC by two disease-connoting cues (birthmark, obesity). In Study 1 (n = 174), a 2 (threat prime: infectious disease, natural disaster) × 2 (disease-connoting cue: birthmarked face, normal face) between-subjects design was used. Participants were asked to complete a malevolent creativity task (MCT). In Study 2 (n = 131), we used a perceived vulnerability to disease scale (PVD) to assess people's dispositional tendencies of concerns about disease and selected high as well as low PVD participants. A 2 (PVD: high, low) × 2 (disease-connoting cue: obese, average-weight) between-subjects design was used. Participants were asked to complete the negotiation task to assess their MC. The results of Study 1 showed that, compared with participants in the normal face condition, participants in the birthmarked face condition showed higher MC fluency and total MC when they were exposed to situational disease prime. Compared with the natural disaster prime group, the infectious disease prime group showed higher MC fluency and total MC when they were provoked by a birthmark person. The results of Study 2 showed that, compared with the average-weight condition, the obese condition led to higher MC fluency and originality among high PVD participants. Compared with low PVD participants, high PVD participants showed higher MC fluency and originality when they negotiated with an obese person. Our studies suggest that among people whose BIS is situationally or chronically activated, birthmarks and obesity could increase MC, and people's malevolent creativity might be induced by disease-connoting cues during the pandemic.

[Association between Gestational Diabetes Mellitus and Postpartum Depressive Episode].

Objective To explore the association between gestational diabetes mellitus (GDM) and postpartum depressive (PPD) episode and the influencing factors of PPD episode. Methods The clinical data of pregnant women who filed in the Department of Obstetrics,Peking Union Medical College Hospital from March 1,2020 to February 28,2021 were collected.Oral glucose tolerance test (OGTT,75 g) and determination of glycosylated hemoglobin (HbA1c) were carried out in the second trimester,and fasting blood glucose and glycosylated albumin (GA) were determined in the third trimester.Mini-International Neuropsychiatric Interview (MINI,5.0 Chinese version) was used to diagnose depressive episode and anxiety disorder within (42±7) days after delivery.We analyzed the influencing factors of PPD episode by multiple Logistic regression to explore the relationship between GDM and PPD episode.Fasting glucose and GA in the third trimester,as well as the incidence of PPD episode,between women with and without GDM were compared. Results The GDM,75 g OGTT,and HbA1c in the second trimester,as well as fasting blood glucose and GA in the third trimester,showed no significant differences between the PPD group and the non-PPD group (all P>0.05).Postpartum generalized anxiety disorder (OR=4.656,95%CI=1.130-19.184, P=0.033),obsessive-compulsive disorder (OR=11.989,95%CI=1.004-143.113, P=0.049),and the history of mental disorder before pregnancy (OR=13.567,95%CI=2.191-83.991, P=0.005) were the risk factors of PPD episode.The fasting blood glucose and GA in the third trimester,the incidence of PPD episode,and the PPD episode comorbidities of generalized anxiety disorder and obsessive-compulsive disorder had no significant differences between pregnant women with and without GDM (all P>0.05).Conclusions There is no association between GDM and PPD episode under routine blood glucose management. Special attention should be paid to pregnant women with a history of mental disorder before pregnancy.

Different responses to risperidone treatment in Schizophrenia: a multicenter genome-wide association and whole exome sequencing joint study.

Risperidone is routinely used in the clinical management of schizophrenia, but the treatment response is highly variable among different patients. The genetic underpinnings of the treatment response are not well understood. We performed a pharmacogenomic study of the treatment response to risperidone in patients with schizophrenia by using a SNP microarray -based genome-wide association study (GWAS) and whole exome sequencing (WES)-based GWAS. DNA samples were collected from 189 patients for the GWAS and from 222 patients for the WES after quality control in multiple centers of China. Antipsychotic response phenotypes of patients who received eight weeks of risperidone treatment were quantified with percentage change on the Positive and Negative Syndrome Scale (PANSS). The GWAS revealed a significant association between several SNPs and treatment response, such as three GRM7 SNPs (rs141134664, rs57521140, and rs73809055). Gene-based analysis in WES revealed 13 genes that were associated with antipsychotic response, such as GPR12 and MAP2K3. We did not identify shared loci or genes between GWAS and WES, but association signals tended to cluster into the GPCR gene family and GPCR signaling pathway, which may play an important role in the treatment response etiology. This study may provide a research paradigm for pharmacogenomic research, and these data provide a promising illustration of our potential to identify genetic variants underlying antipsychotic responses and may ultimately facilitate precision medicine in schizophrenia.

Methylome-wide association study of different responses to risperidone in schizophrenia.

Background: Accumulating evidence shows that DNA methylation plays a role in antipsychotic response. However, the mechanisms by which DNA methylation changes are associated with antipsychotic responses remain largely unknown. Methods: We performed a methylome-wide association study (MWAS) to evaluate the association between DNA methylation and the response to risperidone in schizophrenia. Genomic DNA methylation patterns were assessed using the Agilent Human DNA Methylation Microarray. Results: We identified numerous differentially methylated positions (DMPs) and regions (DMRs) associated with antipsychotic response. CYP46A1, SPATS2, and ATP6V1E1 had the most significant DMPs, with p values of 2.50 × 10-6, 3.53 × 10-6, and 5.71 × 10-6, respectively. The top-ranked DMR was located on chromosome 7, corresponding to the PTPRN2 gene with a Sidák-corrected p-value of 9.04 × 10-13. Additionally, a significant enrichment of synaptic function and neurotransmitters was found in the differentially methylated genes after gene ontology and pathway analysis. Conclusion: The identified DMP- and DMR-overlapping genes associated with antipsychotic response are related to synaptic function and neurotransmitters. These findings may improve understanding of the mechanisms underlying antipsychotic response and guide the choice of antipsychotic in schizophrenia.

Secondary myeloid neoplasms after CD19 CAR T therapy in patients with refractory/relapsed B-cell lymphoma: Case series and review of literature.

Background: Several chimeric antigen receptor T cells (CAR T) targeting CD19 have induced profound and prolonged remission for refractory/relapsed (R/R) B-cell lymphoma. The risk of secondary malignancies, especially myeloid neoplasms, is of particular concern in the CAR T community, which still remains unclear. Methods: Four patients with R/R B-cell lymphoma after CD19 CAR T therapy diagnosed with secondary myeloid neoplasms (SMN) from 2 hospitals in eastern China were presented, including 3 with myelodysplastic syndrome (MDS) and 1 with acute myeloid leukemia (AML). Using single-cell RNA sequencing (scRNA-seq), we compared the cellular components of bone marrow (BM) samples obtained from one of these MDS patients and a health donor. We also provided a review of recently published literature concerning SMN risk of CAR T therapy. Results: Relevant demographic, clinical, laboratory, therapeutic and outcome data were collected and presented by chart review. In our case series, the male-female ratio was 3.0 and the median age at MDS onset was 61.25 years old (range, 50-78). Median number of previous systemic therapies was 4.5 (range, 4-5), including autologous hematopoietic stem cell transplantation (auto-HSCT) in one patient. BM assessments prior to CAR T therapy confirmed normal hematopoiesis without myeloid neoplasms. Moreover, for 3 patients with SMN in our series, cytogenetic analysis predicted a relatively adverse outcome. In our experience and in the literature, treatment choices for the patients with SMN included allogeneic hematopoietic stem cell transplantation (allo-HSCT), hypomethylating agent (HMA), period filgrastim, transfusions and other supportive care. Finally, treatment responses of lymphoma, together with SMN, directly correlated with the overall survival of this community. Of note, it appeared that pathogenesis of MDS wasn't associated with the CAR T toxicities, since all 4 patients experienced a pretty mild CRS of grade 1-2. Additionally, scRNA-seq analysis described the transcriptional alteration of CD34+ cells, identified 13 T/NK clusters, and also indicated increased cytotoxic T cells in MDS BM. Conclusion: Our study illustrated the onset and progression of SMN after CD19 CAR T therapy in patients with R/R B-cell lymphoma, which provides useful information of this uncommon later event.

Cytochrome P450 Enzymes and Drug Metabolism in Humans.

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

Gene × environment interaction in major depressive disorder.

Major depressive disorder (MDD) is a multifactorial disorder, where multiple susceptibility genes interact with environmental factors, predisposing individuals to the development of the illness. In this article, we reviewed different gene × environment interaction (G×E) studies shifting from a candidate gene to a genome-wide approach. Among environmental factors, childhood adversities and stressful life events have been suggested to exert crucial impacts on MDD. Importantly, the diathesis-stress conceptualization of G×E has been challenged by the differential susceptibility theory. Finally, we summarized several limitations of G×E studies and suggested how future G×E studies might reveal complex interactions between genes and environments in MDD.

Value of detecting peri-device leak and incomplete endothelialization by cardiac CT angiography in atrial fibrillation patients post Watchman LAAC combined with radiofrequency ablation.

OBJECTIVES: To explore the value of detecting the peri-device leak (PDL) and device endothelialization after left atrial appendage closure (LAAC) by cardiac computed tomography (CT) in patients with atrial fibrillation (AF), who underwent Watchman LAAC combined with radiofrequency ablation of atrial fibrillation (AFCA). METHODS: Patients with symptomatic drug-refractory atrial fibrillation at high risk of stroke (CHA2 DS2 -VASc Score ≥ 2), who underwent Watchman LAAC combined with AFCA in our center from March 2017 to December 2018 were enrolled. Maximum diameter of LAA orifice was determined by preoperative CCTA. A standardized view of Watchman device was obtained by postoperative CCTA multiplannar reconstruction to evaluate the PDL and device endothelialization. RESULTS: Approximately 84 patients post successful LAAC and AFCA were enrolled in this study. The satisfactory LAA occlusion rate was 100%. There was no death, bleeding, stroke, and device-related thrombus (DRT) events. At 6-month postprocedure, CCTA images evidenced complete endothelialization in 44 patients (no contrast enhancement in LAA); contrast enhancement in LAA and visible PDL in 33 patients; contrast enhancement in LAA but without PDL in seven patients (incomplete device endothelialization). Maximum diameter of LAA orifice could independently predict the occurrence of PDL (odds ratio, 1.31; 95% confidence interval, 1.11-1.55; p = .002), sensitivity was 69.7% and specificity was 80.4% with the cutoff value of maximum diameter of LAA orifice more than 28.2 mm on predicting PDL. CONCLUSIONS: CCTA is feasible to evaluate PDL and device endothelialization after LAAC. The maximum diameter of LAA orifice derived from CT can independently predict the occurrence of post-LAAC PDL.