Improving interprofessional communication: Conceptualizing, operationalizing and testing a healthcare improvisation communication workshop.

BACKGROUND: Communication errors are a leading cause of adverse events in the acute and ambulatory healthcare setting. We now understand that communication within and across professions and patients is a complex achievement with numerous barriers, including cultural, educational, and structural hurdles. Improvisation has been identified as an approach with great potential to develop communication skills for multi-disciplinary healthcare students. OBJECTIVE: We report on the interdisciplinary conceptualization, operationalization, and effectiveness testing of a novel educational healthcare improvisation communication workshop. DESIGN: Prospective pre-post test experimental. SETTING: University of California, Irvine. PARTICIPANTS: Total of 158 nursing, medicine, and population health students. METHODS: We conceptualized improvisation through the constructs of presence, trust, and acceptance to develop workshop activities, then used the Kirkpatrick Learning Framework to test the workshop's feasibility, learning outcomes, and preliminary behavior changes. RESULTS: Participants rated the feasibility of the workshop highly. Pre-post workshop effectiveness testing showed significant increases in communication and collaboration competencies. Qualitative data suggested workshop activities were powerful learning modality because they were premised by introducing their conceptual underpinning and providing tangible examples via the video and debrief. Qualitative data also suggested preliminary behavior changes post workshop. CONCLUSIONS: We have developed and tested a communication teaching modality with strong conceptual grounding and empirical evidence of its efficacy in engaging healthcare students in collaborative communication, with documented evidence of learning that health educators can use in their courses. Future research is needed (and currently underway) to generate the evidence that the workshop can be adopted and sustained within a multi-school curriculum, which includes testing the feasibility of cross-school curriculum logistics (i.e. cross-listing the course to meet different school registrar policies, teaching workload sharing across faculty, etc.), as well as continued effectiveness testing.

Tramadol versus codeine and the short-term risk of cardiovascular events in patients with non-cancer pain: A population-based cohort study.

AIMS: The effect of tramadol on the cardiovascular system is largely unknown. There is concern that, with its multimodal mechanism of action to increase serotonin and norepinephrine levels in the body, it could increase the risk of arterial ischaemia and cardiovascular events. We aimed to compare the short-term risk of cardiovascular events with the use of tramadol to that of codeine among patients with non-cancer pain. METHODS: We conducted a retrospective population-based cohort study using data from the Clinical Practice Research Datalink (CPRD) with new users of tramadol or codeine from April 1998 to March 2017. Exposure was defined using an approach analogous to an intention-to-treat, with a maximum follow-up of 30 days. The primary endpoint was myocardial infarction, and secondary endpoints were unstable angina, ischaemic stroke, coronary revascularization, cardiovascular death and all-cause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusted for high-dimensional propensity score. RESULTS: The final cohort included 123 394 tramadol users and 914 333 codeine users. When tramadol was compared to codeine, the adjusted hazard ratio (HR) of myocardial infarction was 1.00 (95% CI 0.81-1.24). There was also no evidence of elevated risks of unstable angina (0.92; 95% CI 0.67-1.27), ischaemic stroke (0.98; 95% CI 0.82-1.17), coronary revascularization (0.97; 95% CI 0.69-1.38), cardiovascular death (1.07; 95% CI 0.93-1.23) or all-cause mortality (1.03; 95% CI 0.94-1.14) when tramadol was compared to codeine. CONCLUSIONS: Short-term use of tramadol, compared with codeine, was not associated with an increased risk of cardiac events among patients with non-cancer pain.

Endoplasmic Reticulum Stress Induces CAP2 Expression Promoting Epithelial-Mesenchymal Transition in Liver Cancer Cells.

Cyclase-associated protein 2 (CAP2) has been addressed as a candidate biomarker in various cancer types. Previously, we have shown that CAP2 is expressed during multi-step hepatocarcinogenesis; however, its underlying mechanisms in liver cancer cells are not fully elucidated yet. Here, we demonstrated that endoplasmic reticulum (ER) stress induced CAP2 expression, and which promoted migration and invasion of liver cancer cells. We also found that the ER stress-induced CAP2 expression is mediated through activation of protein kinase C epsilon (PKCε) and the promotor binding of activating transcription factor 2 (ATF2). In addition, we further demonstrated that CAP2 expression promoted epithelial-mesenchymal transition (EMT) through activation of Rac1 and ERK. In conclusion, we suggest that ER stress induces CAP2 expression promoting EMT in liver cancers cells. Our results shed light on the novel functions of CAP2 in the metastatic process of liver cancer cells.

USO1 isoforms differentially promote liver cancer progression by dysregulating the ER-Golgi network.

Alternative splicing of RNA transcripts plays an important role in cancer development and progression. Recent advances in RNA-seq technology have made it possible to identify alternately spliced events in various types of cancer; however, research on hepatocellular carcinoma (HCC) is still limited. Here, by performing RNA-seq profiling of HCC transcripts at isoform level, we identified tumor-specific and molecular subtype-dependent expression of the USO1 isoforms, which we designated as a normal form USO1-N (XM_001290049) and a tumor form USO1-T (NM_003715). The expression of USO1-T, but not USO1-N, was associated with worse prognostic outcomes of HCC patients. We confirmed that the expression of USO1-T promoted an aggressive phenotype of HCC, both in vitro and in vivo. In addition, structural modeling analyses revealed that USO1-T lacks an ARM10 loop encoded by exon 15, which may weaken the dimerization of USO1 and its tethering to GM130. We demonstrated that USO1-T ensured unstacking of the Golgi and accelerated the vesicles trafficking from endoplasmic reticulum (ER) to Golgi and plasma membrane in multiple liver cancer cells. ERK and GRASP65 were found to be involved in the USO1-T-mediated Golgi dysfunction. Conclusively, we provide new mechanophysical insights into the USO1 isoforms that differentially regulate the ER-Golgi network, promoting the heterogeneous HCC progression.

TPRG1-AS1 induces RBM24 expression and inhibits liver cancer progression by sponging miR-4691-5p and miR-3659.

BACKGROUND & AIMS: Noncoding RNAs (ncRNAs) play critical roles in hepatocellular carcinoma (HCC) progression. Here, by performing RNA-sequencing (RNA-Seq) profiling, we sought to identify novel ncRNAs that potentially drive the heterogeneous progression of liver cancers. METHODS: RNA-Seq profiles were obtained from 68 HCC specimens and 10 samples of adjacent non-tumour liver tissues. The functional significance of the potential driver ncRNAs was evaluated by cell experiments. RESULTS: TPRG1-AS1 was identified as a potential driver noncoding RNA that promotes heterogeneous liver cancer progression. TPRG1-AS1 induced tumour suppressor RNA-binding motif protein 24 (RBM24), suppressing tumour growth by activating apoptotic tumour cell death. In addition, we report that TPRG1-AS1 acts as a competing endogenous RNA (ceRNA) for RBM24, sponging miR-4691-5p and miR-3659 to interfere with their binding to RBM24. CONCLUSIONS: We suggest that TPRG1-AS1 is a novel ceRNA sponging miR-4691-5p and miR-3659, resulting in RBM24 expression and suppression of liver cancer growth. Our results provide new insights into the functions of ncRNAs in heterogeneous HCC progression.

YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior.

The expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016-0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18-0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p < 0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1-expressing HCCs. By performing cell culture experiments, we validated that ERα expression enhanced YAP phosphorylation, attenuating its nuclear translocation, which in turn suppressed the downstream signaling pathways and cancer cell growth. In conclusion, we suggest that ERα expression is an indicator of more favorable prognosis in HCC and that this effect is mediated by inactivation of YAP signaling. Our results provide new clinical and pathobiological insights into ERα and YAP signaling in HCC.

"ACEing" the Evidence Within Physical Medicine and Rehabilitation (PM&R).

Introduction: While evidence-based medicine (EBM) is important in all fields of medicine, it can be specifically challenging for the field of physical medicine and rehabilitation (PM&R), a rapidly developing field where the standard hierarchy of evidence does not always apply and randomized controlled trials can be difficult to design. We developed an EBM curriculum for residents that improved EBM competency and was specific to the field of PM&R. Methods: We developed a blended learning longitudinal approach to EBM designed specifically for PM&R residents, with a pre- and postcourse assessment by the Evidence-Based Practice Questionnaire (EBPQ) and Assessing Competency in EBM (ACE) tool. Interactive presentations paired with structured presession assignments were held for five introductory sessions, followed by monthly EBM and journal club sessions over 1 academic year. Results: Fourteen residents of varying postgraduate years of training participated in the EBM curriculum from 2018 to 2019. EBPQ scores after completion of 1 academic year of this EBM curriculum were significantly improved compared to precurriculum EBPQ scores. Comparison of pre- and post-EBPQ and ACE tool scores stratified by postgraduate year did not show a significant correlation between resident levels and self-reported prior EBM education. Discussion: This longitudinal blended learning EBM curriculum resulted in an increase in residents' self-reported behaviors and knowledge/skills regarding EBM. The curriculum was also effective in advancing competency of the residents to an EBM Advanced level using the ACE tool. The curriculum can be easily replicated in other PM&R residency programs.

Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress-related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. SIGNIFICANCE: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.

EPHB6 mutation induces cell adhesion-mediated paclitaxel resistance via EPHA2 and CDH11 expression.

Mutations affect gene functions related to cancer behavior, including cell growth, metastasis, and drug responses. Genome-wide profiling of cancer mutations and drug responses has identified actionable targets that can be utilized for the management of cancer patients. Here, the recapitulation of pharmacogenomic data revealed that the mutation of EPHB6 is associated with paclitaxel resistance in cancer cells. Experimental data confirmed that the EPHB6 mutation induces paclitaxel resistance in various cancer types, including lung, skin, and liver cancers. EPHB6 mutation-induced paclitaxel resistance was mediated by an interaction with EPHA2, which promotes c-Jun N-terminal kinase (JNK)-mediated cadherin 11 (CDH11) expression. We demonstrated that EPHB6-mutated cells acquire cell adhesion-mediated drug resistance (CAM-DR) in association with CDH11 expression and RhoA/focal adhesion kinase (FAK) activation. Targeted inhibition of EPHA2 or CDH11 reversed the acquired paclitaxel resistance, suggesting its potential clinical utility. The present results suggest that the EPHB6 mutation and its downstream EPHA2/JNK/CDH11/RhoA/FAK signaling axis are novel diagnostic and therapeutic targets for overcoming paclitaxel resistance in cancer patients.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: There are no head-to-head randomized controlled trials comparing different direct oral anticoagulants (DOACs). Thus, we systematically reviewed and meta-analyzed observational studies assessing the comparative effectiveness and safety of DOACs for stroke prevention in patients with atrial fibrillation (AF). METHODS: We systematically searched MEDLINE and EMBASE up to February 2019 for observational studies comparing different DOACs head-to-head in patients with AF. Two independent reviewers identified studies, extracted data, and assessed the risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Random-effects models were used to meta-analyze data across higher-quality studies. RESULTS: We identified 25 cohort studies including 1,079,565 patients with AF treated with DOACs. Meta-analysis of the 19 studies at moderate risk of bias yielded a similar risk of ischemic stroke for rivaroxaban versus dabigatran (six studies; hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.83-1.04; I2: 0%), apixaban versus dabigatran (five studies; HR 0.94; 95% CI 0.82-1.09; I2: 0%), and apixaban versus rivaroxaban (four studies; HR 1.07; 95% CI 0.93-1.23; I2: 0%). Regarding major bleeding, there was an increased risk for rivaroxaban versus dabigatran (six studies; HR 1.33; 95% CI 1.20-1.47; I2: 22%) and decreased risks for apixaban versus either dabigatran (eight studies; HR 0.71; 95% CI 0.64-0.78; I2: 0%) or rivaroxaban (eight studies; HR 0.56; 95% CI 0.48-0.65; I2: 69%). CONCLUSIONS: As head-to-head trials comparing different DOACs do not exist, available evidence derives exclusively from observational studies. These data suggest that while dabigatran, rivaroxaban, and apixaban have a similar effect on the risk of ischemic stroke, apixaban may be associated with a decreased risk of major bleeding compared with either dabigatran or rivaroxaban.

Cardiovascular Disease-Related Morbidity and Mortality in Women With a History of Pregnancy Complications.

BACKGROUND: Women with a history of certain pregnancy complications are at higher risk for cardiovascular (CVD) disease. However, most clinical guidelines only recommend postpartum follow-up of those with a history of preeclampsia, gestational diabetes mellitus, or preterm birth. This systematic review was undertaken to determine if there is an association between a broader array of pregnancy complications and the future risk of CVD. METHODS: We systematically searched PubMed, MEDLINE and EMBASE (via Ovid), CINAHL, and the Cochrane Library from inception to September 22, 2017, for observational studies of the association between the hypertensive disorders of pregnancy, placental abruption, preterm birth, gestational diabetes mellitus, low birth weight, small-for-gestational-age birth, stillbirth, and miscarriage and subsequent CVD. Likelihood ratio meta-analyses were performed to generate pooled odds ratios (OR) and 95% intrinsic confidence intervals (ICI). RESULTS: Our systematic review included 84 studies (28 993 438 patients). Sample sizes varied from 250 to 2 000 000, with a median follow-up of 7.5 years postpartum. The risk of CVD was highest in women with gestational hypertension (OR 1.7; 95% ICI, 1.3-2.2), preeclampsia (OR 2.7; 95% ICI, 2.5-3.0), placental abruption (OR 1.8; 95% ICI, 1.4-2.3), preterm birth (OR 1.6; 95% ICI, 1.4-1.9), gestational diabetes mellitus (OR 1.7; 95% ICI, 1.1-2.5), and stillbirth (OR 1.5; 95% ICI, 1.1-2.1). A consistent trend was seen for low birth weight and small-for-gestational-age birth weight but not for miscarriage. CONCLUSIONS: Women with a broader array of pregnancy complications, including placental abruption and stillbirth, are at increased risk of future CVD. The findings support the need for assessment and risk factor management beyond the postpartum period.

Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer.

Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.

Integrative analysis of genomic and epigenomic regulation of the transcriptome in liver cancer.

Hepatocellular carcinoma harbors numerous genomic and epigenomic aberrations of DNA copy numbers and DNA methylation. Transcriptomic deregulation by these aberrations plays key driver roles in heterogeneous progression of cancers. Here, we profile DNA copy numbers, DNA methylation, and messenger RNA expression levels from 64 cases of hepatocellular carcinoma specimens. We find that the frequencies of the aberrancies of the DNA copy-number-correlated (CNVcor) expression genes and the methylation-correlated expression (METcor) genes are co-regulated significantly. Multi-omics integration of the CNVcor and METcor genes reveal three prognostic subtypes of hepatocellular carcinoma, which can be validated by an independent data. The most aggressive subtype expressing stemness genes has frequent BAP1 mutations, implying its pivotal role in the aggressive tumor progression. In conclusion, our integrative analysis of genomic and epigenomic regulation provides new insights on the multi-layered pathobiology of hepatocellular carcinoma, which might be helpful in developing precision management for hepatocellular carcinoma patients.Hepatocellular carcinoma is known to harbour numerous genomic and epigenomic aberrations, driving transcriptomic deregulation. Here, the authors integrate genomic, epigenomic, and expression data to reveal three prognostic subtypes, providing insight to the pathobiology of hepatocellular carcinoma.

Activated Rac1 regulates the degradation of IκBα and the nuclear translocation of STAT3-NFκB complexes in starved cancer cells.

In several human tumors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NFκB) are activated and interact; how these STAT3-NFκB complexes are transported to the nucleus is not fully understood. In this study, we found that Rac1 was activated in starved cancer cells and that activated Rac1 coexisted with STAT3 and NFκB. Rac1 knockdown and overexpression of the dominant-negative mutant Rac1N19 inhibited the degradation of IκBα, an inhibitor of NFκB. MG132, an inhibitor of the ubiquitin proteasome pathway, increased the amount of non-phosphorylated IκBα, but not serine-phosphorylated IκBα, indicating that IκBα degradation by Rac1 in starved cancer cells is independent of IκBα serine phosphorylation by IKK. Rac1 knockdown also inhibited the nuclear translocation of STAT3-NFκB complexes, indicating that this translocation requires activated Rac1. We also demonstrated that the mutant STAT3 Y705F could form complexes with NFκB, and these unphosphorylated STAT3-NFκB complexes translocated into the nucleus and upregulated the activity of NFκB in starved cancer cells, suggesting that phosphorylation of STAT3 is not essential for its translocation. To our knowledge, this is the first study demonstrating the crucial role of Rac1 in the function of STAT3-NFκB complexes in starved cancer cells and implies that targeting Rac1 may have future therapeutic significance in cancer therapy.

Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications.

Poly (ADP-ribose) polymerase1 (PARP1) has been reported as a possible target for chemotherapy in many cancer types. However, its action mechanisms and clinical implications for gastric cancer survival are not yet fully understood. Here, we investigated the effect of PARP1 inhibition in the growth of gastric cancer cells. PARP1 inhibition by Olaparib or PARP1 siRNA could significantly attenuate growth and colony formation of gastric cancer cells, and which were mediated through induction of G2/M cell cycle arrest but not apoptosis. FOXO3A expression was induced by PARP1 inhibition, suggesting that FOXO3A might be one of downstream target of the PARP1 effect on gastric cancer cell growth. In addition, by performing tissue microarrays on the 166 cases of gastric cancer patients, we could observe that the expression status of PARP1 and FOXO3A were significantly associated with overall survival (OS) and relapse-free survival (RFS). Strikingly, combined expression status of PARP1 and FOXO3A showed better prediction for patient's clinical outcomes. The patient group with PARP1+/FOXO3A- expression had the worst prognosis while the patient group with PARP1-/FOXO3A+ had the most favorable prognosis (OS: P = 6.0 × 10(-9), RFS: P = 2.2 × 10(-8)). In conclusion, we suggest that PARP1 and FOXO3A play critical roles in gastric cancer progression, and might have therapeutic and/or diagnostic potential in clinic.

Comparison of craniofacial growth of untreated Class I and Class II girls from ages 9 to 18 years: a longitudinal study.

INTRODUCTION: The purposes of this study were to examine and compare the craniofacial growth in girls with Class I or Class II occlusion from the ages of 9 to 18. METHODS: Twenty-five Class I (ANB, 1°-4°) and 21 Class II (ANB, >4°) untreated Caucasian girls were selected from the Burlington Growth Centre in Toronto, Ontario, Canada. Cephalograms of each subject at ages 9, 14, and 18 years were traced, and 29 parameters were measured. The growth changes in each parameter from ages 9 to 14, 14 to 18, and 9 to 18 were calculated, and comparisons of each parameter were made between the 2 groups. RESULTS: From ages 9 to 14, the Class I and Class II groups had similar skeletal growth patterns (increases of SNA and SNB angles, decreases of ANB, MP-SN, and gonial angles). Dentally, the Class II group showed less maxillary incisal proclination and more overbite than did the Class I group. From ages 14 to 18, the 2 groups also showed similar growth patterns, with little sagittal but continued vertical growth, and the MP-SN angle continued to decrease. From ages 9 to 18 (combined periods of 9-14 and 14-18), the 2 groups showed similar skeletal growth, with the exception of a slightly higher ANS-ME/N-Me in the Class I group. Dental changes were similar in the 2 groups, except that overbite increased slightly more in the Class II group. CONCLUSIONS: Overall, the craniofacial growth patterns of Class I and Class II girls were similar. With growth, the face became more flattened with a decrease of the ANB angle, and the mandible demonstrated forward rotation with decreases of the MP-SN and gonial angles, and an increase of PFH:AFH.

Hepatitis C virus attenuates interferon-induced major histocompatibility complex class I expression and decreases CD8+ T cell effector functions.

BACKGROUND & AIMS: Major histocompatibility complex (MHC) class I-restricted CD8(+) T cells are required for clearance of hepatitis C virus (HCV) infection. MHC class I expression is up-regulated by type I and II interferons (IFNs). However, little is known about the effects of HCV infection on IFN-induced expression of MHC class I. METHODS: We used the HCV cell culture system (HCVcc) with the genotype 2a Japanese fulminant hepatitis-1 strain to investigate IFN-induced expression of MHC class I and its regulatory mechanisms. HCVcc-infected Huh-7.5 cells were analyzed by flow cytometry, metabolic labeling, immunoprecipitation, and immunoblotting analyses. Protein kinase R (PKR) was knocked down with lentiviruses that express small hairpin RNAs. The functional effects of MHC class I regulation by HCV were demonstrated in co-culture studies, using HCV-specific CD8(+) T cells. RESULTS: Although the baseline level of MHC class I was not affected by HCV infection, IFN-induced expression of MHC class I was notably attenuated in HCV-infected cells. This was associated with replicating HCV RNA, not with viral protein. HCV infection reduced IFN-induced synthesis of MHC class I protein and induced phosphorylation of PKR and eIF2α. IFN-induced MHC class I expression was restored by small hairpin RNA-mediated knockdown of PKR in HCV-infected cells. Co-culture of HCV-specific CD8(+) T cells and HCV-infected cells that expressed HLA-A2 demonstrated that HCV infection reduced the effector functions of HCV-specific CD8(+) T cells; these functions were restored by small hairpin RNA-mediated knockdown of PKR. CONCLUSIONS: IFN-induced expression of MHC class I is attenuated in HCV-infected cells by activation of PKR, which reduces the effector functions of HCV-specific CD8(+) T cells. This appears to be an important mechanism by which HCV circumvents antiviral adaptive immune responses.

Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health And Nutrition Examination Survey, 2001 to 2010.

BACKGROUND: The monitoring of national trends in hypertension treatment and control can provide important insight into the effectiveness of primary prevention efforts for cardiovascular disease. The objective of this study was to examine recent trends in antihypertensive medication use and its impact on blood pressure control among US adults with hypertension. METHODS AND RESULTS: A total of 9320 hypertensive people aged ≥18 years from the National Health and Nutrition Examination Survey 2001 to 2010 were included in this study. The prevalence of antihypertensive medication use increased from 63.5% in 2001 to 2002 to 77.3% in 2009 to 2010 (P(trend)<0.01). Most notably, there was a large increase in the use of multiple antihypertensive agents (from 36.8% to 47.7%, P(trend)<0.01). Overall, the use of thiazide diuretics, ß-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers increased by 23%, 57%, 31%, and 100%, respectively. In comparison with monotherapy, single-pill combinations and multiple-pill combinations were associated with 55% and 26% increased likelihoods of blood pressure control, respectively. By the 2009 to 2010 time period, 47% of all hypertensive people and 60% of treated hypertensive people had blood pressure controlled. However, higher treated but uncontrolled hypertension rates continued to persist among older Americans, non-Hispanic blacks, diabetic people, and those with chronic kidney disease. Also, Mexican Americans with hypertension were still less likely to take antihypertensive medication than non-Hispanic whites with hypertension. CONCLUSIONS: Antihypertensive medication use and blood pressure control among US adults with hypertension significantly increased over the past 10 years. Combination therapy regimens can facilitate achievement of blood pressure goals.

Blood pressure randomized methodology study comparing automatic oscillometric and mercury sphygmomanometer devices: National Health and Nutrition Examination Survey, 2009-2010.

OBJECTIVES: The mercury sphygmomanometer has been the gold standard used for obtaining blood pressure (BP) for the National Health and Nutrition Examination Survey (NHANES) from 1960 to the present. However, due to environmental concerns and an increased use of automated oscillometric BP devices, NHANES has been exploring an alternative to using the standard mercury sphygmomanometer (mercury) to measure BP. METHODS: The accuracy of Omron HEM-907XL BP readings was compared with that of mercury BP device readings for gender, age group, race and ethnicity, and body mass index categories and cuff-size subgroups. Each person had three BP measurements per device recorded sequentially. The order of the devices and readers were randomly assigned. A total of 6,460 participants had three valid systolic readings, and 6,338 had three valid diastolic readings. RESULTS: Omron and mercury measurements were correlated (r = 0.92, systolic BP; r = 0.79, diastolic BP). Overall, the mean between-device differences (Omron and mercury) were -1.6 mm Hg for systolic and -0.6 mm Hg for diastolic (p < 0.05 for both). The mean between-device differences were less than or about 2 mm Hg for each subgroup: gender, age group, race and ethnicity, and body mass index categories, and cuff-size subgroups. The exceptions were mean systolic between-device differences for those using the extra-large BP cuff (-3.1 mm Hg) and obese individuals (-2.6 mm Hg), and the mean diastolic between-device differences for the underweight group (-3.5 mm Hg). Assuming mercury to be the gold standard, between-device agreements for the frequency of high BP (140/90 mm Hg or more) and stage II high BP (160/100 mm Hg or more) were above chance (kappa = 0.72 for both). Omron underestimated the high BP frequency by 2.28% and stage II high BP frequency by 0.77%. CONCLUSIONS: Lower estimates of high BP by the Omron device may require adjusting future national prevalence estimates accordingly to account for between-device differences.

Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor γ, controls hepatitis B virus replication.

In this study, HepG2-hepatitis B virus (HBV)-stable cells that did not overexpress HBx and HBx-deficient mutant-transfected cells were analyzed for their expression of HBV-induced, upregulated adipogenic and lipogenic genes. The mRNAs of CCAAT enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), adiponectin, liver X receptor α (LXRα), sterol regulatory element binding protein 1c (SREBP1c), and fatty acid synthase (FAS) were expressed at higher levels in HepG2-HBV and lamivudine-treated stable cells and HBx-deficient mutant-transfected cells than in the HepG2 cells. Lamivudine treatment reduced the mRNA levels of PPARγ and C/EBPα. Conversely, HBV replication was upregulated by adiponectin and PPARγ agonist rosiglitazone treatments and was downregulated by adiponectin siRNAs. Collectively, our results demonstrate that HBV replication and/or protein expression, even in the absence of HBx, upregulated adipogenic or lipogenic genes, and that the control of adiponectin might prove useful as a therapeutic modality for the treatment of chronic hepatitis B.