Cytokine Response Patterns in Severe Pandemic 2009 H1N1 and Seasonal Influenza among Hospitalized Adults

BACKGROUND: Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis. METHODS: Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed. RESULTS: 63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2-15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2-27 times lower than seasonal influenza; P-values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3-4, 55% vs 85%; day 6-7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6-61.5, per log(10)unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their 'responsiveness' to stimuli was shown to change dynamically during the illness course. CONCLUSIONS: A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis

Examining Patterns of Adversity in Chinese Young Adults Using the Adverse Childhood Experiences – International Questionnaire (ACE-IQ)

Ample evidence supports significant and enduring associations between adverse childhood experiences (ACEs) and negative outcomes later in life. Subsets of ACEs (e.g. childhood maltreatment and household dysfunction) have been examined in Chinese populations, but no known study has comprehensively examined the full constellation of different types of ACEs or patterns of ACE exposure in Chinese samples. As a direct response to the call toestablish a global ACEs surveillance framework, this study provides the first translation and validation of the World Health Organization ACE – International Questionnaire (ACE-IQ).Further, patterns of ACE exposure were identified through latent class analysis. The 29-item ACE-IQ was translated and back-translated from English to traditional Chinese to measure exposure to 13 categories of ACEs. The Chinese ACE-IQ demonstrated good content validity; the ACE-IQ domain subscales also showed satisfactory test-retest reliability and semantic equivalence. In a sample of 433 Chinese young adults, three patterns of ACE exposure were uncovered: Low ACEs (65.82%), Household Violence (24.94%), and Multiple ACEs (9.24%).Concurrent exposure to physical abuse, domestic violence, and emotional abuse (i.e. Household Violence) was a novel pattern found in this study sample, and suggests there may be traditional Chinese norms that potentiate risks for violent household environments in the absence of other household risk factors. Findings underscore the importance of examining ACE exposure within local contexts, as children’s adverse experiences may be idiosyncratic to geographic, social, and cultural norms

Patterns of Exposure to Adverse Childhood Experiences and their Associations with Mental Health: A Survey of 1,346 University Students in East Asia

Adverse childhood experiences (ACEs) constitute a significant global mental health burden. Prior studies typically investigated the impact of ACEs on mental health using a cumulative risk approach; most ACEs studies were also conducted in Western settings. Purpose. This study aimed to examine ACEs using a pattern-based approach and assess their associations with mental health outcomes by early adulthood in East Asia. Methods. The present study included measures of exposure to 13 categories of ACEs, depression, anxiety, maladjustment, and posttraumatic stress in a sample of 1,346 university students from Hong Kong, China, Taiwan, and Japan. Results. Latent class analysis indicated three distinct patterns of ACE exposure: Class 1: Low ACEs (76.0%); Class 2: Household Violence (20.6%); and Class 3: Household Dysfunction (3.4%). Those representing Class 3 had significantly more ACEs compared with those in Classes 1 or 2. Controlling for age and sex, those in Class 2 reported significantly higher depression and maladjustment symptoms compared with those in Class 1; both Classes 2 and 3 had significantly higher anxiety symptoms and odds for meeting diagnostic criteria for posttraumatic stress disorders compared with those in Class 1. Conclusions. Study findings suggest young adults’ mental health, at least under certain contexts, are more closely linked with the nature and pattern of ACE co-occurrence, rather than the number of ACEs

Novel Nuclear Partnering Role of EPS8 With FOXM1 in Regulating Cell Proliferation

One hallmark of cancer cells is sustaining proliferative signaling that leads to uncontrolled cell proliferation. Both the Forkhead box (FOX) M1 transcription factor and the Epidermal Growth Factor (EGF) receptor Pathway Substrate 8 (EPS8) are known to be activated by mitogenic signaling and their levels upregulated in cancer. Well-known to regulate Rac-mediated actin remodeling at the cell cortex, EPS8 carries a nuclear localization signal but its possible nuclear role remains unclear. Here, we demonstrated interaction of FOXM1 with EPS8 in yeast two-hybrid and immunoprecipitation assays. Immunostaining revealed co-localization of the two proteins during G2/M phase of the cell cycle. EPS8 became nuclear localized when CRM1/Exportin 1-dependent nuclear export was inhibited by Leptomycin B, and a functional nuclear export signal could be identified within EPS8 using EGFP-tagging and site-directed mutagenesis. Downregulation of EPS8 using shRNAs suppressed expression of FOXM1 and the FOXM1-target CCNB1, and slowed down G2/M transition in cervical cancer cells. Chromatin immunoprecipitation analysis indicated recruitment of EPS8 to the CCNB1 and CDC25B promoters. Taken together, our findings support a novel partnering role of EPS8 with FOXM1 in the regulation of cancer cell proliferation and provides interesting insight into future design of therapeutic strategy to inhibit cancer cell proliferation

The validity of ICD-11 PTSD and Complex PTSD in East Asian cultures: findings with young adults from China, Hong Kong, Japan, and Taiwan

Background: The ICD-11 classifies posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD) as two distinct diagnoses. Few studies have tested the validity of ICD-11 CPTSD in non-Western settings, particularly in Asia.Objective: This study assessed the factorial, concurrent, and discriminant validity of CPTSD symptoms with four samples of young adults from mainland China, Hong Kong, Japan, and Taiwan.Method: Young adults aged 18–24 years were recruited by convenience sampling and provided their data anonymously online. Study measures included the International Trauma Questionnaire (ITQ) to measure PTSD and CPTSD, and measures of childhood adversity, depression, anxiety, age, and sex. Confirmatory factor analysis (CFA) was performed for each sample to evaluate the validity of two CPTSD measurement models. Structural equation modelling (SEM) was used to determine the multivariate associations between study variables for the full sample.Results: A total of 1,346 young adults completed the survey. CFA showed both models of CPTSD examined fit the data well across all four samples. SEM findings showed that number of childhood adversities significantly associated with both PTSD and CPTSD factors; depression significantly associated with CPTSD factors but not PTSD, whereas anxiety significantly associated with both.Conclusions: Study findings provide evidence for PTSD and CPTSD as separate and valid diagnoses in Asia. More cross-cultural comparisons are needed to understand whether risks for either condition differ by geographical or sociocultural norms

Translation and validation of the Chinese ICD-11 International Trauma Questionnaire (ITQ) for the Assessment of Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD)

Two stress related disorders have been proposed for inclusion in the revised ICD11: Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD). The International Trauma Questionnaire (ITQ) is a bespoke measure of PTSD and CPTSD, and has been widely used in English speaking countries. Objective. The primary aim of this study was to develop a Chinese version of the ITQ and assess its content, construct, and concurrent validity. Methods. Six mental health practitioners and experts rated the Chinese translated and back-translated items to assess content validity. A sample of 423 Chinese young adults completed the ITQ, the WHO Adverse Childhood Experiences International Questionnaire, and the Hospital Anxiety and Depression Scale. Among them, 31 participants also completed the English and Chinese versions of the ITQ administered in random order at retest. Four alternative confirmatory factor analysis models were tested using data from participants who reported at least one adverse childhood experience (ACE; N=314). Results. The Chinese ITQ received excellent ratings on relevance and appropriateness. Test-retest reliability and semantic equivalence across English and Chinese versions were acceptable. The correlated first-order six-factor model and a second-order twofactor (PTSD and DSO) both provided acceptable model fit. The six ITQ symptoms clusters were all significantly correlated with anxiety, depression, and number of ACEs. Conclusions. The Chinese ITQ generates scores with acceptable psychometric properties and provides evidence for including PTSD and CPTSD as separate diagnoses in ICD-11

Translation and psychometric evaluation of the Chinese Adjustment Disorder – New Module 20

The Adjustment Disorder – New Module 20 (ADNM-20) was developed for the assessment of adjustment disorder symptoms. The aim of the present study was to translate and conduct psychometric testing of the Chinese version of the ADNM-20. The English version was translated into traditional Chinese in an iterative process with an expert panel of mental health professionals. A total of 433 university students in Hong Kong between ages 18-24 completed the Chinese ADNM-20 and the Hospital Anxiety and Depression Scale via an online survey; 32 were retested after two weeks. The content validity indices were excellent for most of the items. Confirmatory factor analysis supported a unidimensional first-order structure with excellent composite reliability. The test-retest reliability of the Chinese version was below satisfactory for the individual items; the intra-class correlation for the overall scale was moderate. The Chinese version of the ADNM-20 also indicated a moderate positive correlation with anxiety and depression symptoms. Initial results support the content, factorial, and discriminant validity of the translated scale. More research is needed to assess its reliability in this cultural context. The ADNM-20 can be quickly employed for the assessment of adjustment disorder as proposed for ICD-11