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Hemophilia A (HA) is a monogenic disease characterized by plasma clotting factor 8 (F8) deficiency due to F8 mutation. We have been attempting to cure HA permanently using a CRISPR-Cas9 gene-editing strategy. Here, we induced targeted integration of BDDF8 (B-domain-deleted F8) gene into the albumin locus of HA mice by hydrodynamic tail vein injection of editing plasmid vectors. One week after treatment, a high F8 activity ranging from 70% to 280% of normal serum levels was observed in all treated HA mice but dropped to background levels 3-5 weeks later. We found that the humoral immune reaction targeting F8 is the predominant cause of the decreased F8 activity. We hypothesized that hydrodynamic injection-induced liver damage triggered the release of large quantities of inflammatory cytokines. However, co-injection of plasmids expressing a dozen immunomodulatory factors failed to curtail the immune reaction and stabilize F8 activity. The spCas9 plasmid carrying a miR-142-3p target sequence alleviated the cellular immune response but was unable to deliver therapeutic efficacy. Strikingly, immunosuppressant cyclo-phosphamide virtually abolished the immune response, leading to a year-long stable F8 level. Our findings should have important implications in developing therapies in mouse models using the hydrodynamic gene delivery approach, highlighting the ne-cessity of modulating the innate immune response triggered by liver damage.

Background Depression is a common and serious complication in new mothers. We investigated the hypothesis that neuraxial labor analgesia is associated with a decreased risk of postpartum depression. Methods In this multicenter prospective cohort study with propensity score matching, 599 nulliparous women with single term cephalic pregnancy who planned vaginal delivery were enrolled and self-selected neuraxial analgesia or not. The primary outcome was 6-week postpartum depression assessed with the Chinese version Edinburgh Postnatal Depression Scale; a score of ≥10 was set as the threshold of postpartum depression. Logistic regression models were established to assess the association between neuraxial labor analgesia and postpartum depression. Results Of the 577 parturients who completed the study, 417 (72.3%) received neuraxial analgesia and 160 (27.7%) did not. After propensity score matching, 433 parturients were included in the analysis; of whom, 279 (64.4%) received neuraxial analgesia and 154 (35.6%) did not. The incidence of postpartum depression was lower in parturients with neuraxial analgesia than in those without (14.9% [62/417] vs. 23.8% [38/160], P=0.012 before matching; 13.3% [37/279] vs. 23.4% [36/154], P=0.007 after matching). After adjustment for confounding factors, neuraxial analgesia was associated with decreased odds of postpartum depression (odds ratio [OR] 0.50, 95% CI 0.28-0.88, P=0.015 before matching; OR 0.40, 95% CI 0.21-0.77, P=0.006 after matching). Limitations As an observational study, unidentified confounders might influence the results. Conclusions In nulliparae with single term cephalic pregnancy preparing to give vaginal delivery neuraxial analgesia during labor was associated with a decreased risk of 6-week postpartum depression.

Background: The novel coronavirus 2019 (COVID-19) pandemic and related compulsory measures have triggered a wide range of psychological issues. However, the effect of COVID-19 on mental health in late-middle-aged adults remains unclear.Methods: This cross-sectional, web-based survey recruited 3,730 participants (≥ 50 years old) between February 28 and March 11 of 2020. The Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Insomnia Severity Index, and Acute Stress Disorder Scale were used to evaluate depression, anxiety, insomnia, and acute stress symptoms. Multivariate logistic regression analysis was fitted to explore risk factors that were associated with the selected outcomes.Results: The mean age of the participants was 54.44 ± 5.99 years, and 2,026 (54.3%) of the participants were female. The prevalence of depression, anxiety, insomnia, and acute stress symptoms among late-middle-aged adults in China during the COVID-19 pandemic was 20.4, 27.1, 27.5, and 21.2%, respectively. Multivariable logistic regression analyses showed that participants who were quarantined had increased odds ratios for the four mental health symptoms, and those with a good understanding of the COVID-19 pandemic displayed a decreased risk for all mental health symptoms among late-middle-aged adults. In addition, participants with a low income and with a risk of COVID-19 exposure at work had a remarkably high risk of depression, anxiety, and acute stress symptoms.Conclusions: Mental health symptoms in late-middle-aged adults in China during the COVID-19 pandemic are prevalent. Population-specific mental health interventions should be developed to improve mental health outcomes in late-middle-aged adults during this public health emergency.

Eight pairs of meroterpenoid enantiomers and four achiral meroterpenoids were isolated from Rhododendron anthopogonoides Maxim. Seventeen of them, named (+)-/(-)-anthoponoids A-G, (+)-daurichromene D, and anthoponoids H and I, are undescribed compounds with structural diversity. Their structures were characterized herein by a combined application of spectroscopic techniques, X-ray crystallographic analysis, ECD calculation, and the modified Mosher's method. (+)-/(-)-Anthoponoid A and anthoponoid I are the first Rhododendron meroterpenoids found to possess a hexahydroxanthene motif and a diterpene unit, respectively. Some isolates were identified as NF-κB pathway inhibitors, and (+)-anthoponoid E, (-)-anthoponoid G, and anthoponoid H showed suppressive effects on LPS-induced inflammatory responses in RAW 264.7 macrophages.

Background Accurate diagnosis of delirium is very important for prevention and treatment. Present study was designed to validate the 3-Minute Diagnostic Interview for CAM-defined Delirium Chinese version (3D-CAM-CN) in surgical ICU patients. Methods In this prospective diagnostic study, the 3D-CAM was translated into Chinese with culture adaption. Two interviewers (Roles A and B) independently administrated 3D-CAM-CN assessment in adult patients from postoperative days 1 to day 3. At the meantime, a panel of psychiatrists diagnosed delirium according to the Diagnostic and Statistical Manual of Mental Disorders-fifth edition as the reference standard. The sensitivity and specificity were calculated to analyze the diagnostic character of the 3D-CAM-CN. Kappa coefficient was used to evaluate interrater reliability. Results Two hundred forty-five adult patients were assessed for at least 2 days, resulting a total of 647 paired-assessments. When compared with the reference standard, the sensitivity and specificity of the 3D-CAM-CN assessment were 87.2 and 96.7%, respectively, by Role A and 84.6 and 97.4%, respectively, by Role B, with good interrater reliability (Kappa coefficient = 0.82, P Conclusion Our results showed that the 3D-CAM-CN can be used as a reliable and accurate instrument for delirium assessment in surgical patients. Trial registration This trail was approved by the Clinical Research Ethic Committee of Peking University First Hospital (No. 2017–1321) and registered on Chinese clinical trial registry on July 6, 2017 (ChiCTR-OOC-17011887).

Highlights • LLD patients present lower functional connectivity in the right FPN. • LLD patients present impaired white matter integrity in tracts to the right FPN. • FPN alterations were negatively correlated with anxiety severity in LLD patients. • The right IFG might be a crucial hub underlying the neuropathology of LLD., The present study investigated functional connectivity and white matter integrity of the fronto-parietal network (FPN) to reveal the neural mechanisms that underlie late-life depression (LLD). Fifty patients with LLD and 40 non-depressed controls were included in the study. A multi-parametric approach was used by applying independent component analysis (ICA) to estimate functional connectivity of the FPN and by applying tract­based spatial statistics to examine white-matter integrity in tracts to the FPN. Patients with LLD exhibited functional abnormalities in the right inferior frontal gyrus, middle frontal gyrus, and inferior parietal gyrus and lower white matter fractional anisotropy in the right inferior fronto-occipital fasciculus, anterior thalamic radiation, and uncinate fasciculus. Alterations of functional connectivity and white matter fractional anisotropy in these regions were negatively correlated with the severity of symptomatic anxiety in LLD patients. The right inferior frontal gyrus might be a crucial hub in transferring information between these abnormal regions. Significant correlations were found between anxiety symptoms and brain alterations, suggesting that impairments in the FPN network might be involved in symptomatic anxiety in elderly individuals with depression.

Seismic performance of RC beam-column joints under low cyclic loading with different cycle numbers was analyzed by FEA software, to study duration effect of long period ground motion. The loading with different cycle numbers was used to simulate the duration of the ground motion. Hysteretic curves and skeleton curves of the joints were obtained. The results indicate that as the cycle number increases, the capacity and ductility of the joint declines, and the stiffness of the joint attenuates faster.

Aims: To investigate the incidence of depression at different time points within the first year after stroke in mainland China and to identify risk factors related to a poor 1‐year prognosis in stroke patients. Methods: Subjects with acute cerebrovascular diseases were recruited and enrolled from 56 hospitals in mainland China between April 2008 and April 2010. Demographic data, previous disease history, and clinical data were collected. Four follow‐up visits were occurred within the first year after stroke. The modified Rankin Scale ≥2 represents an unfavorable prognosis. Depression was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition and was divided into persistent, recurrent and transient types. Results: The 1‐year cumulative incidence of depression in stroke patients was 41.8%. Logistic regression analysis showed that the 1‐year prognosis level was associated with age, disability before onset, neurological functional deficit level at admission, and a range of depression types. The odds ratio for persistent depression is the highest (OR = 7.615, P 40% of patients within the first year after stroke. Persistent depression is the first independent determinant of prognosis during the first year after stroke.

Summary Background Familial benign chronic pemphigus or Hailey–Hailey disease (HHD; OMIM 169600) is an autosomal dominant blistering disease. Pathogenic mutations in ATP2C1 encoding a novel Ca2+ pump have recently been identified. Objectives To identify mutations in ATP2C1 in Chinese patients with HHD. Methods Eleven unrelated Chinese patients with HHD were subjected to mutation detection in ATP2C1. Eight of them had a family history of HHD. The 27 coding exons and their flanking sequences were amplified and sequenced. Results Five of the 11 patients were identified to have heterozygous mutations including three nonsense mutations and two splicing mutations in ATP2C1. Conclusions Four novel mutations, nonsense mutations S887X and W795X and splicing mutations 118−1 ga and 1890+1del(gtgag)ins53, were found in this series of Chinese patients with HHD.

Background Studies show that poststroke depression (PSD) increases mortality risk at 1 year. However, whether PSD increases the risk of recurrent stroke at 1 year remains unclear. This study was to investigate whether PSD at 2 weeks following a stroke could increase risk of recurrent stroke at 1 year. Methods and Results This was a multi-centered prospective cohort study. A total of 2306 patients with acute stroke were enrolled in our study. PSD was diagnosed according to the criteria set by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The outcomes of recurrent stroke were followed up via face-to-face or phone interview. A total of 1713 patients had complete follow-up data, with 481 (28.1%) cases of PSD and 158 (9.2%) cases of cumulative recurrent stroke at 1 year. Multivariate logistic regression analysis showed a 49% increase of OR of recurrent stroke at 1 year in patients with PSD, compared to patients without PSD following a stroke (OR = 1.49, 95%CI: 1.03–2.15). There was no significant correlation between anti-depressant drugs and the risk of recurrent stroke at 1 year following a stroke (OR = 1.96, 95%: CI 0.95–4.04). Conclusions Based on the DSM-IV diagnostic criteria, nearly 3 out of 10 hospitalized stroke patients in China were diagnosed with PSD at 2 weeks following a stroke. PSD is associated with a higher risk of recurrent stroke at 1 year. Our study did not find benefit of anti-depressant drugs in reducing such risk.