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Cortistatin (CST) is a small molecule bioactive peptide containing an FWKT tetramer. It is widely distributed in nervous, immune and endocrine systems. Many studies have shown that CST can exert many biological effects, for example: regulating sleep, learning and memory processes, inducing immune tolerance, inhibiting inflammatory responses, and regulating endocrine metabolism. Notably, it is found that CST and its receptors are also widely distributed in the cardiovascular system, such as the aorta, coronary arteries and heart. In recent years, increasing studies have shown that CST played an important role in the development of cardiovascular diseases, such as reducing myocardial damage, inhibiting autoimmune myocarditis, alleviating vascular smooth muscle cell (VSMC) proliferation and migration, reducing vascular calcification (VC), and inhibiting atherosclerosis and aneurysm formation. Therefore, we reviewed the cardiovascular effects of CST in the heart and blood vessels, which will help to understand the role of CST and its receptors in the pathogenesis of cardiovascular diseases, and highlight novel strategies and targets for the prevention and treatment of cardiovascular diseases.

Objectives To identify distinctive patterns of respiratory-related health services use (HSU) between birth and 3 years of age, and to examine associated symptom and risk profiles. Methods This study included 729 mother and child pairs enrolled in the Toronto site of the Canadian Healthy Infant Longitudinal Development study in 2009-2012; they were linked to Ontario health administrative databases (2009-2016). A model-based cluster analysis was performed to identify distinct groups of children who followed a similar pattern of respiratory-related HSU between birth and 3 years of age, regarding hospitalization, emergency department (ED) and physician office visits for respiratory conditions and total health care costs (2016 Canadian dollars). Results The majority (estimated cluster weight = 0.905) showed a pattern of low and stable respiratory care use (low HSU) while the remainder (weight = 0.095) showed a pattern of high use (high HSU). From 0 to 3 years of age, the low- and high-HSU groups differed in mean trajectories of total health care costs ($783 per 6 months decreased to $114, vs $1796 to $177, respectively). Compared to low-HSU, the high-HSU group was associated with a constant risk of hospitalizations, early high ED utilization and physician visits for respiratory problems. The two groups differed significantly in the timing of wheezing (late onset in low-HSU vs early in high-HSU) and future total costs (stable vs increased). Conclusions One in ten children had high respiratory care use in early life. Such information can help identify high-risk young children in a large population, monitor their long-term health, and inform resource allocation.

The physiological function of endothelial cells plays an important role in maintaining normal cardiovascular function. Endothelial dysfunction induced by AngII (angiotensin II) is the pathological mechanism of occurrence and development of cardiovascular diseases. Human recombinant relaxin-2 (H2 relaxin), which has protective effect on cardiovascular functions, ameliorates damage to endothelial cells induced by angiotensin II (AngII) treatment. However, the exact mechanisms remain unclear. In this study, we researched the mechanisms of H2 relaxin inhibiting AngII-induced endothelial dysfunction from the protective effect of H2 relaxin on endothelial function though inhibiting excessive mitochondrial fission. Here, we found that H2 relaxin increased eNOS, SOD1 expression, inhibited excessive mitochondrial fission and decreased ROS level in HUVECs treated with AngII. However, overexpression of fission protein 1 (Fis1) prevented H2 relaxin from protecting against AngII-induced low eNOS, SOD1 expression, excessive mitochondrial fission and increased ROS level in HUVECs. Our study indicated that excessive mitochondrial fission could be a target for H2 relaxin to treat endothelial dysfunction in angiocardiopathy.

BackgroundThe economic impact of multimorbidity in severe or difficult-to-treat asthma has not been comprehensively investigated.AimsTo estimate the incremental healthcare costs of coexisting chronic conditions (comorbidities) in patients with severe asthma, compared with non-severe asthma and no asthma.MethodsUsing health administrative data in British Columbia, Canada (1996–2016), we identified, based on the intensity of drug use and occurrence of exacerbations, individuals who experienced severe asthma in an incident year. We also constructed matched cohorts of individuals without an asthma diagnosis and those who had mild/dormant or moderate asthma (non-severe asthma) throughout their follow-up. Health service use records during follow-up were categorised into 16 major disease categories based on the International Classification of Diseases. Incremental costs (in 2016 Canadian Dollars, CAD$1=US$0.75=₤0.56=€0.68) were estimated as the adjusted difference in healthcare costs between individuals with severe asthma compared with those with non-severe asthma and non-asthma.ResultsRelative to no asthma, incremental costs of severe asthma were $2779 per person-year (95% CI 2514 to 3045), with 54% ($1508) being attributed to comorbidities. Relative to non-severe asthma, severe asthma was associated with incremental costs of $1922 per person-year (95% CI 1670 to 2174), with 52% ($1003) being attributed to comorbidities. In both cases, the most costly comorbidity was respiratory conditions other than asthma ($468 (17%) and $451 (23%), respectively).ConclusionsComorbidities accounted for more than half of the incremental medical costs in patients with severe asthma. This highlights the importance of considering the burden of multimorbidity in evidence-informed decision making for patients with severe asthma.

Increasing evidence suggests that the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome participates in cardiovascular diseases. However, its role and activation mechanism during hypertension remains unclear. In this study, we tested the role and mechanism of calcium-sensing receptor (CaSR) in NLRP3 inflammasome activation during hypertension. We observed that the expressions of CaSR and NLRP3 were increased in spontaneous hypertensive rats (SHRs) along with aortic fibrosis. In vascular smooth muscle cells (VSMCs), the activation of NLRP3 inflammasome associated with CaSR and collagen synthesis was induced by angiotensin II (Ang II). Furthermore, inhibition of CaSR and NLRP3 inflammasome attenuated proinflammatory cytokine release, suggesting that CaSR-mediated activation of the NLRP3 inflammasome may be a therapeutic target in aortic dysfunction and vascular inflammatory lesions.

Introduction There is little information on recent trends in the economic burden of asthma. Our objective was to estimate the excess costs of asthma and their trend in British Columbia, Canada, from 2002 to 2011. Methods A retrospective cohort of individuals aged 5–55 years was constructed from the provincial administrative health databases, consisting of patients with physician-diagnosed asthma and a propensity-score-matched comparison sample from the general population. Total direct medical costs were calculated as the sum of hospitalizations, outpatient visits and medication costs, adjusted to 2012 Canadian dollars ($). Excess costs were defined as the difference in costs between the asthma and comparison groups. Results A total of 341 457 individuals (mean age at entry 27.3, 54.1% female) were equally divided into the asthma and comparison groups. Excess costs in patients with asthma were $1028.0 (95% CI $982.7–$1073.4) per patient-year (PY). Medications contributed to the greatest share of excess costs ($471.7/PY), whereas hospitalization and outpatient costs were, respectively, $272.2/PY and $284.1/PY. Only $192.9/PY was attributable to asthma itself. There was a 2.9%/year increase in excess costs (P < 0.001), a combination of asthma-attributable costs declining by 0.8%/year while nonasthma excess costs increasing by 3.8%/year. The most dramatic trend was observed in asthma-related outpatient costs, which decreased by %6.6/year. Conclusions A significant share of excess costs in asthma is not attributable to the disease itself. The pattern of costs changed significantly during the study period. The burden of comorbid conditions should be considered in developing evidence-based policies for management of patients with asthma.

Accumulating evidence has indicated that vascular smooth muscular cells (VSMCs) play an important role in the development of vascular calcification (VC). Cortistatin (CST), a novel bio-active peptide, has been shown to exert multiple protective effects on the cardiovascular system. However, the role and possible mechanism of CST in VC remain unclear. Therefore, we used β-glycerophosphoric acid (β-GP) to induce calcification in rat and human VSMCs to determine the effects of CST on osteoblastic differentiation and VSMC mineralization in vitro. Compared with the control, β-GP significantly increased alkaline phosphatase (ALP) activity and calcium content in cultured rat and human VSMCs, as well as multicellular node formation and calcium deposition, as confirmed by von Kossa and Alizarin Red S staining assays. After incubating rat and human VSMCs with β-GP in the presence of different doses of CST (10−8 or 10−7 mol/L), CST clearly reversed the β-GP-induced increases in ALP activity and calcium content and formation of pathological calcified nodes of VSMCs in a dose-independent manner. Moreover, 10−8 and 10−7 mol/L CST inhibited the phenotypic transformation of VSMCs into osteoblastic cells by decreasing the osteocalcin protein levels, increasing the SM-α-actin protein levels, and reducing endoplasmic reticulum stress by decreasing the protein expression of glucose-regulated protein 94 and CCAAT/enhancer-binding protein homologous protein. In conclusion, CST directly inhibited β-GP-induced calcification of VSMCs in vitro, probably by suppressing ERS and phenotypic transformation of VSMCs into osteoblastic cells. These results indicate that CST represents a potential target for the prevention and treatment of VC.

Background Asthma control is increasingly used as an outcome measure in asthma trials. Economic evaluations of asthma interventions require converting the impact of interventions on control to impact on resource use. The purpose of this study was to estimate the savings in direct costs by achieving asthma symptom control as defined in the Global Initiative for Asthma (GINA) 2014 management strategy. Methods Adolescents and adults with asthma were recruited through random digit dialing. Asthma control per GINA and the use of healthcare resources were assessed at baseline and three-monthly visits up to 1 year. We used regression models to associate costs, measured in 2012 Canadian dollars ($), with symptom control, adjusting for potential confounding variables. Results The final sample included 517 individuals (average age 48.9, 65.8% female) with mostly mild–moderate asthma contributing 2033 follow-up visits. In 598 (29.4%), 809 (39.8%), and 626 (30.8%) of visits, asthma was symptomatically controlled, partially controlled, or uncontrolled, respectively. The average 3-month costs of asthma were $134.5. Of these, 20.5% were attributable to inpatient care, 47.8% to outpatient care, and 31.5% to medication. Compared to controlled asthma, partially controlled asthma was associated with a nonsignificant increase of $9.5 (95% CI -$13.6 – $32.6) in adjusted 3-month costs and uncontrolled asthma with a statistically significant increase of $81.7 (95% CI $48.5 – $114.9). Conclusion A substantial fraction of this population-based sample of largely mild–moderate asthmatics was symptomatically uncontrolled. Achieving symptom control was associated with a reduction in direct costs. The adjusted values from this study can be used to inform cost-effectiveness analyses of asthma treatments.

Background The recent Global Initiative for Asthma management strategy recommends achieving symptom control and minimizing the future risk of poor outcomes as priorities for asthma management. Objective The objective was to quantify the association between symptom control and health-related quality of life in asthma. Methods In a prospectively recruited random sample of adults with asthma, we ascertained symptom control and measured health-related quality of life using a generic (EuroQol five-dimensional questionnaire [EQ-5D]) and a disease-specific (Asthma Quality of Life Questionnaire) instrument, to estimate EQ-5D and five-dimensional Asthma Quality of Life Questionnaire (AQL-5D) utilities, respectively. We measured the adjusted difference in utilities across symptom control levels and calculated the loss of predictive efficiency due to aggregating multiple symptoms into one symptom control variable. Results The final sample included 958 observations from 494 individuals (mean age at baseline 52.2 ± 14.5 years; 67.0% women). Asthma was symptomatically controlled, partially controlled, and uncontrolled in 269 (28.1%), 367 (38.3%), and 322 (33.6%) observations, respectively. A person with symptomatically uncontrolled asthma would gain 0.0512 (95% CI 0.0339–0.0686) in EQ-5D or 0.0802 (95% CI 0.0693–0.0910) in AQL-5D utilities by achieving symptom control. The loss of predictive efficiency was 55.4% and 27.6% for EQ-5D and AQL-5D utilities, respectively. Conclusions Asthma symptom control status corresponds well with both generic and disease-specific quality-of-life measures. The trade-off, however, between ease of use and predictive power should be reconsidered in developing simplified measures of control. Our results have direct relevance in informing decision-analytic models of asthma and deducing the effect of interventions on quality of life through their impact on asthma control.

Introduction A key to prevent and control fires lies in the early and accurate detection of fire signatures. Over-heated or burned electrical cable with PVC (polyvinyl chloride) insulation or sheath is a frequent cause of fire. PVC cable insulation contains a large amount of various additives like plasticizers, which can be substantially emitted under overheating conditions. Our recent study showed that two widely-used plasticizers, Dioctyl phthalate (DOP) and 2-Ethylhexanol (2-EH), are ubiquitously present in the vapors of different overheated PVC cables, and can be used as a reliable signature of cable overheating [1]. These compounds, especially DOP, have low vapor pressure under normal conditions, and are usually measured through analytical methods like gas-chromatograph mass spectroscopy. These techniques are generally expensive and time-consuming, and thus not suitable for wide applications in fire detection. Metal oxide semiconductor (MOS) gas sensors offer a promising alternative for low-cost and real-time detection of plasticizers. Nevertheless, MOS sensors sensitive and selective to DOP and 2-EH are not yet available. MOS sensors with high gas sensing performance are often made of nanostructured materials based on SnO2, ZnO, etc. Modification of the materials surface by noble metals or metal oxides may efficiently further enhance the sensing performance. In this contribution, we report on the development of gas sensors targeting detection of the fire signature gases and cable overheating, with an emphasis on modified SnO2 hollow nanofibers [2] and ZnO flowers. Results and Conclusions SnO2 nanofibers obtained via electrospinning were porous and hollow, with a diameter of around 200 nm and length of 1-2 mm. They were loaded with various amounts of NiO, In2O3, and ZnO oxides via a facile impregnation-calcination route (Fig. 1). Samples loaded with 2.8 at.% In2O3 (SIn-0.1) and 5.0 at.% ZnO (SZn-0.5) exhibited excellent response to the fire signature gases, DOP and 2-EH, whilst NiO modification deteriorated the sensing performance. A maximum response of 44 and 27 to 100 ppm DOP and 2-EH, respectively, was achieved, ~5 or 9 times larger than that of a commercial TGS822 VOC sensor (Fig. 2). The nanofiber gas sensors exhibited very fast response speed with typical response time of 3-5 s at 260 °C. In contrast, the recovery was much slower, taking ~10 min for DOP. Moreover, low cross-sensitivity towards common interfering gases such as ethanol and H2 were observed. Large-scale simulation tests performed in a 182 L chamber showed that the modified sensors started to respond to the fire hazard earlier than a conventional smoke detector, particularly at lower cable temperatures (below 200 °C), whilst the TGS822 sensor exhibited almost no response (Fig. 3). ZnO flowers fabricated via a hydrothermal route were in a size of a few microns, assembled with nano-columns of ~200 nm diameter. Samples were decorated with various amounts of CuO, Cr2O3, and Au. The modification led to decrease of the operation temperature and enhanced response to the signature gases. The modified ZnO samples presented a maximum response of 48 and 28 to 100 ppm DOP and 2-EH, respectively (Fig. 4). Sensitive response to the cable overheating was also achieved. These results showed that MOS sensors based on modified SnO2 nanofibers and ZnO flowers can effectively detect the overheating of PVC cables, promising for early warning of electrical fires. References [1] J. Han,W. Chen, A. Yu, J. Yi, Detection of semi-volatile plasticizers as a signature of early electrical fire, Frontiers in Materials (2019) 6:250. doi: 10.3389/fmats.2019.00250. [2] J. Yi, W. Chen, J. Han, D. Chen, Sensitive and selective detection of plasticizer vapors with modified-SnO2 hollow nanofibers for electrical fire warning, Sensors & Actuators B. Chemical 287 (2019) 364–370. doi: 10.1016/j.snb.2019.02.025. Figure 1

Background The present study was designed to examine whether cortistatin (CORT) could protect rats from myocardial injury induced by subcutaneously injecting isoproterenol (ISO) and to clarify the possible mechanisms. Methods Male Sprague-Dawley (SD) rats were placed at random into four groups: the control group, the ISO group, the ISO + CORT 25 µg/(kg·d) group, and the ISO + CORT 50 µg/(kg·d) group. Rat models of myocardial injury were established with the subcutaneous (s.c.) injections of 85 mg/kg ISO for 2 days. In the ISO+ CORT 25 µg/(kg·d) group and ISO+ CORT 50 µg/(kg·d) group, rats were given s.c. injections of CORT 25 µg/(kg·d) and CORT 50 µg/(kg·d) on the day before ISO, 3 days, respectively. Serum malondialdehyde (MDA) content, lactate dehydrogenase (LDH) activity, and creatine kinase isoenzyme (CK-MB) activity were measured by corresponding test kits. Western blot was applied to evaluate the expression of endoplasmic reticulum stress-related protein glucose regulatory protein 78 (GRP78), enhancer-binding protein homologous protein (CHOP), cysteinyl aspartate specific proteinase-12 (caspase-12), LC3-II, Beclin-1, and p62 in the rat myocardium. Results CORT alleviated the increased enzyme activities of serum LDH and CK-MB, and content of MDA (a typical marker of lipid peroxidation) in rats induced by ISO. CORT also prevented pathological myocardial injury in rats induced by ISO. Moreover, CORT attenuated the increased protein levels of GRP78, CHOP, and caspase-12, and reduced the increase of LC3-II, LC3-II/I, Beclin-1, and p62 in rats induced by ISO. Conclusions These data demonstrate that CORT can attenuate ISO-induced acute myocardial injury in rats likely by reducing lipid peroxidation, and inhibiting endoplasmic reticulum stress and autophagy. This supports CORT as a potentially being a new target for preventing and treating myocardial injury and its related disease.

We assessed the association between long-term inhaled corticosteroid (ICS) use and bone mineral density (BMD) in older women with chronic respiratory disease. Women with > 50% adherence to ICS use had very slightly accelerated BMD loss at the total hip compared with those with lower or ICS use. This study evaluated the impact of long-term ICS therapy on bone loss in older women with asthma or chronic obstructive pulmonary disease (COPD). We used a population-based bone densitometry registry linked with administrative health data covering the province of Manitoba, Canada (1999–2013), to identify women aged > 40 years who had diagnosed asthma or COPD. ICS exposure was defined as cumulative dispensed days and medication possession ratio (MPR). Associations were examined both cross-sectionally and longitudinally, and results were covariate adjusted. Among 6561 women with asthma and/or COPD (mean age 65 years [SD = 11]), compared to no ICS treatment, those in the highest tertile of prior ICS use (≥ 720 days) had lower BMD at the femoral neck (− 0.09 T-score, 95% CI − 0.16, − 0.02) and total hip (− 0.14 T-score, 95% CI − 0.22, − 0.05), but not at the lumbar spine. Over a mean of 5 years of follow-up, the highest tertile of ICS exposure (MPR > 0.5) was associated with a − 0.02 SD/year (95% CI − 0.04, − 0.01) greater decline in total hip BMD relative to non-users, with no significant effect at the femoral neck or lumbar spine. Middle and lower tertiles of ICS use were not associated with baseline or longitudinal change in BMD. The highest tertile of ICS use was associated with a slightly lower hip BMD at baseline and slightly greater reduction in total hip BMD over time in older women with asthma or COPD. No adverse effects on BMD were seen from low to moderate ICS exposure.

BACKGROUND: Little is known about the impact of care provider’s specialty on the medical costs of COPD patients over time. OBJECTIVE: To compare the long-term medical costs between newly hospitalized COPD patients whose post-discharge care was initiated by a pulmonary specialist versus by a general practitioner. DESIGN: Retrospective matched cohort study. PARTICIPANTS: We identified patients with an incident COPD-related hospitalization from the administrative health database (January 1, 1996, to December 31, 2012) of British Columbia, Canada. MAIN MEASURES: Patients were categorized as receiving specialist care or primary care within the first 90 days after discharge from an incident COPD-related hospitalization. Using propensity scores, we matched each patient who initially received specialist care to a patient who received primary care based on demographics, COPD severity, comorbidity, and admission time. A survival-adjusted, multi-part generalized linear model was used to estimate direct medical costs (in 2015 Canadian dollars, [$], including inpatient, outpatient, pharmacy, and community care costs) as overall and as COPD-specific and comorbidity-related costs over the following 5 years. KEY RESULTS: The sample included 7710 patients under each group. The initial specialist-care recipients had a modestly higher 5-year survival than the generalist-care recipients (0.564 [95% CI 0.535, 0.634] vs 0.555 [95% CI 0.525, 0.625]; P

Unplanned reoperation, emergency department (ED) visits, and hospital readmission following thyroid operations usually arise due to complications and are a source of frustration for both surgeons and patients. With the aim of providing insight important for the development of patient quality care improvement initiatives, the primary objective of this review was to evaluate the available literature systematically in order to determine the contemporary rates of reoperation, readmission, and ED visits following thyroid operations. A secondary study objective was to determine if there were any practices that showed promise in reducing the occurrence of these undesirable postoperative events.This systematic review was conducted in accordance with the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses protocols. Twenty-two studies were included in the systematic review. Meta-analysis was performed to obtain the weighted-pooled summary estimates of rates of reoperations, ED visits, and unplanned hospital readmission. Jackknife sensitivity analyses were performed for each data set. Finally, in order to detect the risk of publication bias and the small-study effect, funnel plot analysis was performed.The pooled rate estimate for reoperation was very low (0.6% [confidence interval (CI) 0.3-1.1%]). This was subject to publication bias because smaller studies tended to report lower rates of reoperation. The pooled rate of ED visits was 8.1% [CI 6.5-9.8%], while the pooled rate of hospital readmission from 19 studies was 2.7% [CI 2.1-3.4%]. Neck hematoma was the most common reason for reoperation, while postoperative hypocalcemia was the most common reason for hospital readmission.ED visits and hospital readmission after thyroidectomy are common, and there are several practices that can reduce their occurrence. Routine postoperative calcium and vitamin D supplementation may reduce rates of postoperative hypocalcemia, and avoiding postoperative hypertension may decrease the risk of neck hematoma development and the need for reoperation. Older age, thyroid cancer, dependent functional status, higher ASA score, diabetes, chronic obstructive pulmonary disease, steroid use, hemodialysis, and recent weight loss increase the risk of hospital readmission after thyroid surgery. By further identifying risk factors for reoperation, ED visits, and readmission, this review may assist practitioners in optimizing perioperative care and therefore reducing patient morbidity and mortality after thyroid operations.

Additional file 1. The surface (a) and back (b) of fenjian in visible light (pictured by portable Dino-Lite digital microscope).

Immigration from regions with a high incidence of tuberculosis (TB) has slowed the decline of TB in low-incidence regions. Targeted screening of new immigrants and treatment for latent TB infection (LTBI) is needed to reinvigorate this decline. This meta-analysis compares LTBI diagnostic tests by positive test prevalence and proportion of positive tests by TB incidence. A systematic literature search was performed and data extracted based on tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA) use in immigrants. For the eight studies performing tests concurrently, data were compared by positive tests and concordance, while other studies comparing individual tests were analyzed based on demographic factors. Data were analyzed via meta-analysis. Forty-five studies with a combined sample size of 93,249 individuals were included in the analyses, 2206 of which were from the eight concurrent studies. Odds of a positive TST were significantly higher than an IGRA (odds ratio 1.46; 95 % confidence interval 1.07–2.01) and test agreement was moderate. Proportion of positive TST and IGRA tests increased with TB incidence, although not linearly. TST and IGRA data relating to immigrants are lacking, especially long-term follow-up and comparative data. Further data are urgently needed to determine TB risks after immigration, long-term TB development, and treatment outcomes.

Little is known about the potential synergistic effect of comorbid psychological distress (PD) and uncontrolled asthma (UA) on productivity loss. We estimated the productivity loss associated with the combination of these two potentially preventable conditions in employed adults with asthma.A population-based random sample of 300 adults with asthma in British Columbia, Canada, was prospectively recruited between Dec 2010 and Aug 2012. PD and productivity loss due to absenteeism and presenteeism was measured using validated instruments, and asthma control was ascertained using 2010 Global Initiative for Asthma management strategy. We used two-part regression models to study the contribution of UA and PD to productivity loss.Compared with reference group (controlled asthma (CA)+noPD), those with UA+noPD had CAD$286 (95%CI $276–297) weekly productivity loss, and those with CA+PD had CAD$465 ($445–485). Those with UA+PD had CAD$449 (437–462) in productivity loss. There was no significant interaction effect of PD with asthma control levels on productivity loss (p=0.22).In patients without PD, uncontrolled asthma was associated with a higher productivity loss than controlled asthma, but this was not the case in patients with PD. This finding can be explained by the fact that the contribution of PD to productivity loss is so large that there is no room for synergy with asthma control. Future studies should assess the impact of interventions that modify PD in patients with asthma.

High concentrations of glucose induce cardiomyocyte apoptosis, and contribute to diabetic cardiomyopathy. Relaxin-2 and relaxin-3 are two members of the relaxin peptide family that are cardioprotective. However, it remains unknown whether relaxin-2 or relaxin-3 can regulate apoptosis in high glucose treated-neonatal rat ventricular myocytes (NRVMs). In cultured NRVMs, 33 mmol/l high glucose (HG) increased apoptosis in a time-dependent manner. HG-increased the protein expression of cleaved caspase-8 and -9, two initiators of the extrinsic and intrinsic pathways of apoptosis, Caspase-3 was attenuated by human recombinant relaxin-2 (H2 relaxin) or relaxin-3 (H3 relaxin), indicating that H2 and H3 relaxin inhibited HG-induced apoptosis. Furthermore, endoplasmic reticulum stress (ERS) markers CHOP and caspase-12 were markedly increased in HG-treated NRVMs, leading to apoptosis; this effect was also effectively attenuated by H2 relaxin or H3 relaxin. Treatment of NRVMs with HG reduced autophagy which cannot be adjusted by H2 relaxin or H3 relaxin. In conclusion, HG-induced apoptosis in NRVMs was mediated, in part, by the activation of the extrinsic and intrinsic pathways of apoptosis and ERS, all inhibited by H2 relaxin or H3 relaxin.

Cyclosporin A (CsA) is an effective immunosuppressive agent, but its myocardial toxicity limits its widespread and long-term clinical application. In this study, CsA treatment led to damages in myocardial fiber structure, an increase in myocardial fibrosis, and changes in heart size and shape; moreover, the degree of damage was exacerbated with prolonged drug application and increases in dose. However, the mechanism is not clear; therefore, the purpose of this study was to reveal the mechanism of CsA-induced myocardial fibrosis and identify a new target for the prevention and treatment of CsA-induced myocardial injury. Cardiac fibroblasts were treated with CsA (5, 10, or 20 μg/mL) for 24 h. Autophagy was observed by electron microscopy and immunofluorescence. The expression of NRP-2/WDFY-1, autophagy-related proteins (Beclin1 and LC3B), fibrosis-related proteins (MMP2/9), and fibroblast phenotype conversion factor (α-SMA) was evaluated by Western blot. The expression of collagen I was determined by ELISA. Then, we used the gene interference technique to alter WDFY-1 expression with or without CsA or 3-MA treatment for 24 h, and the effects on autophagy and the expression of autophagy-related proteins, fibrosis-associated proteins, IFN-α, TNF-α, and IL-6 were determined. The results showed the following: (1) CsA induced fibrosis-related protein (MMP2/9), fibroblast phenotype conversion factor (α-SMA), and collagen I up-regulation in a dose-dependent manner. (2) CsA induced the formation of autophagosomes and up-regulated the expression of Beclin1, LC3B, and the ERK/MAPK pathway in cardiac fibroblasts. (3) CsA induced NRP-2 down-regulation and WDFY-1 up-regulation. (4) Depletion of WDFY-1 inhibited CsA-induced autophagy, TNF-α and IFN-α up-regulation, and fibrosis. (5) The autophagy inhibitor 3-MA inhibited CsA-induced TNF-α and IFN-α up-regulation and fibrosis. Overall, cyclosporin A induces autophagy in cardiac fibroblasts through the NRP-2/WDFY-1 axis, which promotes the progression of myocardial fibrosis.

BackgroundThe effect of long-term inhaled corticosteroid (ICS) therapy on the bone health of older adults remains unclear due to its possible impact on bone mineral density (BMD).ObjectiveTo evaluate, cross-sectionally and longitudinally, the impact of ICS use on BMD in postmenopausal women with asthma or chronic obstructive pulmonary disease (COPD).MethodsWe used a population-based bone densitometry registry linked with administrative health data of the province of Manitoba, Canada (1999–2013), to identify women with diagnosed asthma or COPD. ICS use was defined as cumulative dispensed days prior to baseline BMD (cross-sectional analysis), and medication possession ratio (MPR) between two BMD measurements (longitudinal analysis). Results were adjusted for multiple covariates including the underlying respiratory diagnosis and its severity.ResultsIn the cross sectional analysis, compared with non-users, women with the highest tertile of prior ICS exposure had lower baseline BMD at the femoral neck (-0.09 standard deviations [SD] below a healthy young adult, 95% CI: −0.16, −0.02) and total hip (-0.14 SD, 95% CI: −0.22, −0.05), but not at the lumbar spine. Longitudinally, the highest tertile of ICS exposure was associated with a slight decline in total hip BMD relative to non-users (-0.02 SD/year, 95% CI: −0.04, −0.01), with no significant effect at the femoral neck and lumbar spine. Middle and lower tertiles of ICS use had no significant effects.ConclusionHigh exposure to ICS was associated with a small adverse effect on baseline hip BMD and total hip BMD loss in post-menopausal women with asthma or COPD.

A better understanding of the true burden of chronic obstructive pulmonary disease (COPD) needs to consider the implications of comorbidities. This study comprehensively examined the impact of comorbidities on excess direct medical costs in COPD patients.From health administrative data in British Columbia, Canada (1996–2012), we created a propensity-score-matched cohort of incident COPD patients and individuals without COPD. Health services use records were compiled into 16 major disease categories based on International Classification of Diseases codes. Excess costs (in 2015 Canadian dollars and converted to 2015 Euros; CAD1.000=EUR 0.706) were estimated as the adjusted difference in direct medical costs between the two groups.The sample included 128 424 subjects in each group. COPD patients generated excess costs of CAD5196/EUR3668 per person-year (95% CI CAD3540–8529), of which 26% was attributable to COPD itself and 51% was attributable to comorbidities (the remaining 23% could not be attributed to any specific condition). The major cost driver was excess hospitalisation costs. The largest components of comorbidity costs were circulatory diseases, other respiratory disorders, digestive disorders and psychological disorders (CAD696/EUR491, CAD312/EUR220, CAD274/EUR193 and CAD249/EUR176 per person-year, respectively).These findings suggest that the prevention and appropriate management of comorbidities in COPD patients may effectively reduce the overall burden of COPD.

High glucose induces apoptosis of cardiomyocytes and fibrosis of cardiac fibroblasts, contributing to diabetic cardiomyopathy. In this work, we explore the production of relaxin alterations and the significance of their receptor system components in the hearts of experimental diabetic cardiomyopathy rats. We measured rat relaxin-1 (equivalent to human relaxin-2), relaxin-3, RXFP1 and RXFP3 mRNA expression in the hearts of experimental diabetic cardiomyopathy rats. Neonatal rat ventricular myocytes (NRVMs) and cardiac fibroblasts were treated with 5.5 mmol/l normal glucose (NG) and 33 mmol/l high glucose (HG) for 0, 6, 12, 24, 48 and 72 h. Rat relaxin-1, relaxin-3, RXFP1 and RXFP3 mRNA expression were determined by real-time PCR. In the present study, we offer the first evidence that Relaxin-1 mRNA significantly increased and Relaxin-3 mRNA expression decreased at 4 and 8 weeks after STZ in the hearts of diabetic rats. In addition, significant down regulation of the mRNA expression of RXFP1 and RXFP3 was observed at 4 w after STZ; however, the mRNA expression levels of RXFP1 and RXFP3 were increased at 8 weeks after STZ. Apoptotic NRVMs induced by high glucose generate a decreased level of relaxin-1 and RXFP1. In HG-administered cardiac fibroblasts, Relaxin-1 mRNA was significantly increased and relaxin-3 mRNA was significantly decreased. Additionally, the mRNA expression of RXFP1 was decreased, and the mRNA expression of RXFP3 was increased. This results showed that an important role of relaxin-2, relaxin-3 and their receptors system in the regulation of diabetic cardiomyopathy.

Setting In low-incidence regions, tuberculosis (TB) often affects vulnerable populations. Guidelines recommend active case finding (ACF) in homeless populations, but there is no consensus on a preferred screening method. Objective We performed a systematic review and meta-analysis to evaluate the use of chest X-ray (CXR) screening in ACF for TB in homeless populations. Design Articles were identified through EMBASE, Medline and the Cochrane Library. Studies using symptom screens, CXRs, sputum sweeps, tuberculin skin tests and/or interferon-gamma release assays to detect active TB in homeless populations were sought. Data were extracted using a standardised method by two reviewers and validated with an objective tool. Results Sixteen studies addressing CXR screening of homeless populations for active TB in low-incidence regions were analysed. The pooled prevalence of active TB in the 16 study cohorts was 931 per 100 000 population screened (95%CI 565-1534) and 782/100 000 CXR performed (95%CI 566-1079). Six of seven longitudinal screening programs reported a reduction in regional TB incidence after implementation of the CXR-based ACF programme. Conclusion Our data suggest that CXR screening is a good tool for ACF in homeless populations in low-incidence regions.

This article describes the implementation of the CLARK transformation, the PARK transformation, the inverse PARK transformation and the SVPWM in the MATLAB / SIMULINK environment. The control system is then implemented with tri-cyclic nested loops, i.e., the current loop, the speed loop and the position loop. Simulation results show that the system has fast response, with small overshoot and high accuracy.

Background Productivity loss is an overlooked aspect of the burden of chronic health conditions. While modern guidelines emphasize achieving clinical control in asthma management, few studies have reported on the relationship between asthma control and productivity loss. We calculated the productivity loss that can be avoided by achieving and maintaining clinical control in employed adults with asthma. Methods We prospectively recruited a population-based random sample of adults with asthma in British Columbia, Canada. We measured productivity loss due to absenteeism and presenteeism using validated instruments, and ascertained asthma control according to the GINA (Global Initiative for Asthma) classification. We estimated the average gain in productivity for each individual if the individual's asthma was controlled in the past week, by fitting two-part regression models associating asthma control and productivity loss, controlling for potential confounding variables. Results The final sample included 300 employed adults (mean age, 47.9 years [SD 12.0]; 67.3% women). Of these, 49 (16.3%) reported absenteeism, and 137 (45.7%) reported presenteeism. Productivity loss due to presenteeism, but not absenteeism, was associated with asthma control. A person with uncontrolled asthma would avoid $184.80 (Canadian dollars [CAD]) in productivity loss by achieving clinical control during a week, CAD$167.50 (90.6%) of which would be due to presenteeism. The corresponding value was CAD$34.20 for partially controlled asthma and was not statistically significant. Conclusions Our results indicate that substantial gain in productivity can be obtained by achieving asthma control. Presenteeism is more responsive than absenteeism to asthma control, and, thus, is a more important source of preventable burden.

Objective To determine the magnitude of risk from all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) compared to the general population through a meta-analysis of observational studies. Methods We searched the Medline and Embase databases from their inception to October 2011. Observational studies that met the following criteria were assessed: 1) a prespecified SLE definition; 2) overall and/or cause-specific deaths, including cardiovascular disease (CVD), infections, malignancy, and renal disease; and 3) reported standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs). We calculated weighted–pooled summary estimates of SMRs (meta-SMRs) for all-cause and cause-specific mortality using the random-effects model and tested for heterogeneity using the I2 statistic by using Stata/IC statistical software. Results We identified 12 studies comprising 27,123 patients with SLE (4,993 observed deaths) that met the inclusion criteria. Overall, there was a 3-fold increased risk of death in patients with SLE (meta-SMR 2.98, 95% CI 2.32–3.83) when compared with the general population. The risks of death due to CVD (meta-SMR 2.72, 95% CI 1.83–4.04), infection (meta-SMR 4.98, 95% CI 3.92–6.32), and renal disease (SMR 7.90, 95% CI 5.50–11.00) were significantly increased. Mortality due to malignancy was the only cause-specific entity not increased in SLE (meta-SMR 1.19, 95% CI 0.89–1.59). Conclusion The published data indicated a 3-fold increase in all-cause mortality in patients with SLE compared to the general population. Additionally, all cause-specific mortality rates were increased except for malignancy, with renal disease having the highest mortality risk.

Background: Vascular remodeling, that contributes to cardiovascular diseases such as hypertension develops by anomalous proliferation and migration of vascular smooth muscle cells (VSMCs). Cortistatin (CST), a newly discovered biological peptide, has been acknowledged for its protective effects against cardiovascular diseases. Whether CST has an inhibitory regulation role in angiotensin II (Ang II)-induced proliferation and migration of VSMCs and what molecular mechanisms may participate in the CST inhibition process are still unknown. Methods: VSMCs were divided into control group, Ang II (10 −7 M) group, Ang II + PD98059 (5×10 −5 M) group, Ang II + SB203580 (10 −5 M) group, Ang II + SP600125 (10 −5 M) group, Ang II + XMD17-109 (10 −6 M) group, Ang II + CST (10 −8 M) group and Ang II + CST (10 −7 M) group. Cell proliferation was detected by western blotting and cell counting kit-8 (CCK8) analysis. Migration of VSMCs was measured by Transwell assay. Results: Compared with control group, Ang II upregulated the expression levels of proliferating cell nuclear antigen (PCNA) and osteopontin (OPN) and downregulated that of α-smooth muscle actin (α-SMA), increased the proliferation rate as shown by CCK8 and VSMC migration as shown by Transwell assay in cultured VSMCs of the Ang II group. Meanwhile, in Ang II-cultured VSMCs, we found activation of extracellular signal-regulated kinase (ERK) 1/2, p38 MAP kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and ERK5 pathways by western blotting at different time points. However, the proliferation and migration stimulated by Ang II were partly reversed by drug inhibitors of the four pathways, namely, PD98059, SB203580, SP600125 and XMD17-109. When Ang II-stimulated VSMCs were cultured with CST pretreatment, we found that proliferation and migration were greatly suppressed as well as that the ERK1/2, p38 MAPK, JNK and ERK5 pathways were deactivated by CST. Conclusions: The accumulated data suggest that CST may play a protective role in Ang II-promoted proliferation and migration of VSMCs via inhibiting the mitogen-activated protein kinase (MAPK) family pathways, providing a new orientation of CST in protecting against cardiovascular diseases.

Objectives This study aims to describe the utilization patterns of atypical antipsychotics (AA) among insured patients with bipolar I disorder in the USA. Methods We studied patients with bipolar I disorder who newly initiated an oral AA between 2002 and 2008. Utilization measures included adherence [medication possession ratio (MPR) ≥80%], persistence (gaps ≤15 days between refills and an absence of ≥30 days of continuous concomitant non-index AA use), non-compliance (16–29 day gaps with no evidence of switch/augmentation), and discontinuation of the index AA (≥30 days without index AA, no evidence of switch/augmentation). Results The study included 16 807 patients: mean age 43.3 years, 67.7% female. Overall, adherence to the index AA was low (8.3%; mean MPR = 0.2). Only 10.5% of the patients were persistent to index AA, another 13.6% were non-compliant, and 63.4% discontinued index AA with an average time to discontinuation of 66 days. A majority (69.5%) of the discontinued patients did not resume any antipsychotic therapy. Results were similar across insurance types and index AA. Conclusion Adherence to and persistence with AA treatment were low in new users with bipolar I disorder. Most patients discontinued the index AA and did not restart any antipsychotic treatment. Future study should distinguish physician-directed discontinuation versus patient non-adherence. Copyright © 2013 John Wiley & Sons, Ltd.

Background: Cognitive impairments are common in patients with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). To date there are no meta- analyses that have investigated the prevalence of mild cognitive impairment (MCI) in patients with COPD and CHF. Aims: To examine the individual study data set using meta-analysis to estimate the prevalence of MCI in patients with COPD and CHF. Methods Data sources: We identified relevant studies for COPD and CHF by searching published literature from inception to February 2016 using the MEDLINE and Web of Science databases. Study selection: Studies were included if they documented the prevalence of MCI and CHF for patients without dementia and employed appropriate screening tool for cognitive impairment. Data extraction and synthesis: 17 studies of CHF patients (n= 29,456) and 14 studies of COPD patients (n= 23, 116) were included for the meta-analysis. Main outcome measures : Prevalence of MCI in patients with COPD and CHF. The pooled prevalence of MCI for patients with COPD was estimated at 24% (95% CI: 12%, 38%). The prevalence of MCI in patients with CHF was 35% (95% CI: 25%, 45%). In the jackknife sensitivity analysis, both pooled estimates did not substantially vary when the meta-analysis was repeated with each included study being excluded one at a time. Conclusions: Approximately, 24% COPD patients and 35% CHF patients respectively had MCI. Studies are needed to examine the efficacy of intervention on MCI.

Current therapies for hepatitis B virus (HBV) cannot completely eliminate the HBV genome because of the stable population of covalently closed circular DNA (cccDNA) and so on. FIT-039, which is a cyclin-dependent kinase (CDK) 9 inhibitor, is known to suppress the replication of several DNA viruses including HSV, HPV and human adenovirus. In this study, we investigated the antiviral effect of FIT-039 on HBV infection. HepG2 cells expressing human sodium taurocholate cotransporting polypeptide (HepG2/NTCP cells) were infected with HBV in the presence of FIT-039. FIT-039 dose-dependently reduced intracellular viral RNA, nucleocapsid-associated viral DNA, and supernatant viral antigens without cytotoxicity in the infected cells (IC50 = 0.33 μM, CC50 > 50 μM). The antiviral activity of FIT-039 was prominent at an early phase of viral infection, although the compound did not inhibit preS1-binding to HepG2/NTCP cells. FIT-039 reduced cccDNA in HBV-replicating or HBV-infected cells. Furthermore, the antiviral activity of entecavir was significantly enhanced by the combination with FIT-039 in the chimeric mice having human hepatocytes infected with HBV. None of the mice had significant drug-related body weight or serum human-albumin concentration changes. These data suggest that CDK9 inhibitor FIT-039 is a promising antiviral candidate for HBV infection.

Asthmatic patients frequently have comorbidities, but the role of comorbidities in the economic burden of asthma is unclear. We examined the excess direct medical costs, including asthma- and comorbidity-related costs, in patients with asthma.We created a propensity score-matched cohort of patients newly diagnosed with asthma and non-asthmatic comparison subjects, both aged 5–55 years, from health administrative data (1997–2012) in British Columbia, Canada. Health services use records were categorised into 16 major disease categories based on International Classification of Diseases codes. Excess costs (in 2013 Canadian dollars ($)) were estimated as the adjusted difference in direct medical costs between the two groups.Average overall excess costs were estimated at $1058/person-year (95% CI 1006–1110), of which $134 (95% CI 132–136) was attributable to asthma and $689 (95% CI 649–730) to major comorbidity classes. Psychiatric disorders were the largest component of excess comorbidity costs, followed by digestive disorders, diseases of the nervous system, and respiratory diseases other than asthma. Comorbidity-attributable excess costs greatly increased with age but did not increase over the time course of asthma.These findings suggest that both asthma and comorbidity-related outcomes should be considered in formulating evidence-based policies and guidelines for asthma management.

Despite Canada's provision of universal health coverage, socioeconomic barriers to good-quality health care remain. Asthma provides an appropriate case study given its high prevalence, availability of effective controller therapies, and known variations in care.The aim of this study is to examine the extent of differences in the economic burden of asthma and indicators of guideline-based care across socioeconomic status (SES) gradients.A total of 29,283 adults with moderate to severe asthma were identified from British Columbia's administrative health data for the year 1997-2013 and were matched to adults without asthma on the basis of sex and age. Direct medical costs (in 2013 Canadian dollars, $) included all-cause inpatient, outpatient, and pharmacy costs. SES was measured at individual (receiving social assistance) and aggregate (median neighborhood household income) levels. We assessed the impact of SES on excess direct costs of asthma (the difference in all-cause direct medical costs between an asthma patient and the matched individual), and on use of asthma controller versus reliever medications. Associations were evaluated using generalized linear models.Asthmatics receiving social assistance incurred $706 (95% confidence interval, $302-$1014) higher annual excess costs than the rest of the sample. Annual excess costs were $120 ($18-$168) higher in low-SES versus high-SES neighborhoods. Low SES, at both individual and aggregate levels, was consistently associated with lower expenses on controller medications and higher expenses on reliever medications, indicators of suboptimal asthma care and control.Even under universal health care, individuals in lower SES groups did not receive guideline-based asthma care, potentially explaining their higher costs.

Interleukin 15 (IL-15) has recently been proposed as a myokine involved in regulating lipid metabolism. We investigated the effect of exercise training on IL-15 content in skeletal muscle and expression of IL-15 receptor (IL-15R) in adipose tissue of obese rats. After 12 weeks of a high-fat diet, obese rats underwent treadmill running at 26 m/min (60 min each, 5 days/week for 8 weeks). High-fat diet induced obesity, with increased body weight, body fat, and lipid profile. The level of IL-15 immunoreactivity (IL-15-ir) in plasma and gastrocnemius muscle was lower in obese than control rats, and the mRNA level of IL-15 in gastrocnemius muscle was markedly decreased. The mRNA and protein levels of IL-15R in adipose tissue were markedly lower in obese rats. Compared with sedentary obese rats, treadmill running showed decreased body weight and elevated mRNA expression of IL-15 in muscle and elevated IL-15-ir level in plasma and muscle. The mRNA and protein level of IL-15R were increased in adipose tissue in treadmill running obese rats. Our results showed that exercise training improve obesity and reversed the downregulation of the IL-15 in muscle and IL-15R in adipose tissue induced by high-fat diet.

Most patients with asthma have mild disease. However, the clinical course of mild asthma and risk factors for progression are not well studied.To examine the long-term trajectories of mild asthma and the effects of early-stage risk factors on the subsequent disease course.From the administrative health data of British Columbia, Canada, we identified patients aged 14 to 45 years with newly diagnosed mild asthma between January 1997 and December 2012. For each follow-up year, we categorized a patient's asthma severity into mild/dormant, moderate, or severe on the basis of the intensity of asthma medications and occurrence of exacerbations. Ordinal logistic regression was used to estimate the probability of severity or all-cause death in the next year as a function of a patient's severity history in the past 3 years and selected baseline risk factors.The study included 70,829 patients with incident mild asthma (62% women; mean age, 31 years). Over 10 years, 8% of these patients transitioned to moderate or severe asthma. Inappropriate use of rescue medications and older age were the most influential determinants for progression from mild asthma (odds ratios, 1.79; 95% CI, 1.68-1.90; P.001; 1.24 per 10-year increase in age; 95% CI, 1.22-1.27; P.001), whereas the presence of allergic rhinitis had no significant effects (odds ratio, 0.95; 95% CI, 0.91-1.00; P = .063).Mild asthma remains largely stable over time. However, potentially modifiable factors such as inappropriate use of rescue medications are associated with a worsened prognosis.

Environmental temperature is an important factor exerting pervasive influence on neuronal morphology and synaptic physiology. In theDrosophilabrain, axonal arborization of mushroom body Kenyon cells was enhanced when flies were raised at high temperature (30°C rather than 22°C) for several days. Isolated embryonic neurons in culture that lacked cell–cell contacts also displayed a robust temperature-induced neurite outgrowth. This cell-autonomous effect was reflected by significantly increased high-order branching and enlarged growth cones. The temperature-induced morphological alterations were blocked by the Na+channel blocker tetrodotoxin and a Ca2+channel mutation but could be mimicked by raising cultures at room temperature with suppressed K+channel activity. Physiological analyses revealed increased inward Ca2+currents and decreased outward K+currents, in conjunction with a distal shift in the site of action potential initiation and increased prevalence of TTX-sensitive spontaneous Ca2+transients. Importantly, the overgrowth caused by both temperature and hyperexcitability K+channel mutations were sensitive to genetic perturbations of cAMP metabolism. Thus, temperature acts in a cell-autonomous manner to regulate neuronal excitability and spontaneous activity. Presumably, activity-dependent Ca2+accumulation triggers the cAMP cascade to confer the activity-dependent plasticity of neuronal excitability and growth.

Sodium taurocholate cotransporting polypeptide (NTCP) has been reported as a functional receptor for hepatitis B virus (HBV) infection. However, HBV could not efficiently infect HepG2 cells expressing NTCP (NTCP-HepG2 cells) under adherent monolayer-cell conditions. In this study, NTCP was mainly detected in the basolateral membrane region, but not the apical site, of monolayer NTCP-HepG2 cells. We hypothesized that non-adherent cell conditions of infection would enhance HBV infectivity. Non-adherent NTCP-HepG2 cells were prepared by treatment with trypsin and EDTA, which did not degrade NTCP in the membrane fraction. HBV successfully infected NTCP-HepG2 cells at a viral dose 10 times lower in non-adherent phase than in adherent phase. Efficient infection of non-adherent NTCP-HepG2 cells with blood-borne or cell-culture-derived HBV was observed and was remarkably impaired in the presence of the myristoylated preS1 peptide. HBV could also efficiently infect HepaRG cells under non-adherent cell conditions. We screened several compounds using our culture system and identified proscillaridin A as a potent anti-HBV agent with an IC50 value of 7.2 nM. In conclusion, non-adherent host cell conditions of infection augmented HBV infectivity in an NTCP-dependent manner, thus providing a novel strategy to identify anti-HBV drugs and investigate the mechanism of HBV infection.

Background Severe asthma is associated with disproportionately high morbidity, but little is known about its natural history and how risk factors at first year of diagnosis modify its subsequent development. Methods Using administrative health data, we retrospectively followed patients 14–55 years of age with newly diagnosed severe asthma in British Columbia, Canada. Based on intensity of resource use (drug therapy) and occurrence of exacerbations, each patient-year was classified into mild, moderate, or severe asthma. We estimated the probability of transition between severity levels or to death over the study period using a four-state Markov model, and used this to assess the 10-year trajectory of severe asthma and the influence of baseline risk factors. Results We followed 13 467 patients. Ten years after incident severe asthma, 83% had transitioned to a less severe level (mild: 43%, moderate: 40%). Low socioeconomic status, high comorbidity burden, and high adherence (proportion of days covered (PDC) by asthma controller therapy) in the first year were independently associated with, respectively, 10%, 24% and 35% more time in severe asthma over the next 10 years. Sex was not associated with the clinical course. Conclusions Most patients with incident severe asthma used fewer resources over time, indicating a long-term transition to milder asthma. Potentially modifiable risk factors for poor prognosis of severe asthma include low socioeconomic status and high comorbidity burden. The association between PDC and future asthma severity is likely due to residual confounding by disease severity.

To examine the effect of comorbidities on health-related quality of life (HRQoL) and their interaction with asthma control. In a random sample of adults with asthma, we measured generic (EQ5D) and disease-specific (AQ5D) utility scores. Asthma symptom control was determined using the 2014 Global Initiative for Asthma Management Strategy. Comorbidity scores were calculated using a validated questionnaire. We used two-part regression models to measure the adjusted difference in utility across levels of symptom control and comorbidity scores and to examine the relative role of symptom control and comorbidity in explaining the variation in HRQoL. A total of 2,299 observations from 460 adult patients (mean age 52 years, 67 % women) were included. Compared to controlled asthma, uncontrolled asthma was associated with −0.018 reduction (95 % CI −0.028, −0.009) in EQ5D and −0.076 reduction (95 % CI −0.115, −0.052) in AQ5D utilities. An increase by one standard deviation in comorbidity score relative to the mean was associated with a change of −0.029 (95 % CI −0.043, −0.016) in EQ5D and −0.010 (95 % CI −0.020, −0.004) in AQLQ utilities. The impact of comorbidity was greater than asthma symptom control in explaining EQ5D variance (12 vs. 1 %) but smaller in explaining AQ5D variance (3 vs. 12 %). Generic and disease-specific HRQoL instruments differentially capture the impact of symptom control and comorbidity in asthma. The selection of HRQoL instruments for asthma studies should depend on the prevalence of comorbidity in the target population and the impact of interventions on asthma control and comorbidity.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder associated with increased comorbid prevalence of cardiovascular diseases. We aimed to quantify the magnitudes of association between overall and specific types of cardiovascular disease, major cardiovascular risk factors, and COPD.We searched Cochrane, Medline, and Embase databases for studies published between Jan 1, 1980, and April 30, 2015, on the prevalence of cardiovascular disease and its risk factors in patients with COPD versus matched controls or random samples from the general public. We assessed associations with random-effects meta-analyses. We studied heterogeneity and biases with random-effects meta-regressions, jackknife sensitivity analyses, assessment of funnel plots, and Egger tests.We identified 18,176 unique references and included 29 datasets in the meta-analyses. Compared with the non-COPD population, patients with COPD were more likely to be diagnosed with cardiovascular disease (odds ratio [OR] 2·46; 95% CI 2·02-3·00; p0·0001), including a two to five times higher risk of ischaemic heart disease, cardiac dysrhythmia, heart failure, diseases of the pulmonary circulation, and diseases of the arteries. Additionally, patients with COPD reported hypertension more often (OR 1·33, 95% CI 1·13-1·56; p=0·0007), diabetes (1·36, 1·21-1·53; p0·0001], and ever smoking (4·25, 3·23-5·60; p0·0001). The associations between COPD and these cardiovascular disease types and cardiovascular disease risk factors were consistent and valid across studies. Enrolment period, age, quality of data, and COPD diagnosis partly explained the heterogeneity.The coexistence of COPD, cardiovascular disease, and major risk factors for cardiovascular disease highlights the crucial need for the development of strategies to screen for and reduce cardiovascular risks associated with COPD.Canadian Institutes of Health Research.

Background Achieving and maintaining symptom control is a primary goal of asthma management. Although factors associated with the likelihood of achieving symptom control have been studied, there are unanswered questions on the stability of symptom control, that is, the tendency of individuals to remain at a given symptom control level over time. Objective The objective of this study was to evaluate the stability of symptom control using a longitudinal cohort of mild-moderate asthmatics. Methods Participants reported symptom control using the Global Initiative for Asthma criteria at 5 assessments during the 1-year follow-up period. We described variability in the stability of symptom control between individuals, and used a random-effects logistic regression model to evaluate the impact of a suite of factors on the stability of symptom control. Results A total of 429 individuals (67% female, mean age 51.6) contributed 2141 study visits. Individuals varied from completely stable in symptom control (18% remained at the same control level in all 5 visits) to completely unstable (12% changed the control level between all subsequent visits). Only 4% of between-individual variation in the stability of symptom control was explained by the included exposures, and a secondary analysis indicated that the history of symptom control stability was the best predictor of current stability. Conclusions The tendency to remain at a given control level varies significantly among patients with asthma. Only a small fraction of this variability is explained by observable characteristics. In the absence of predictors, a previous history of symptom control stability is the best indicator of future stability and should be considered when monitoring symptom control.

WOS: 000404447400031, PubMed ID: 28663316, …, ThermoFisher; Research Council of Lithuania [MIP-049/2015]; Crossref Funder Registry, This study was funded by ThermoFisher. A. Mebazaa and J. Motiejunaite would like to acknowledge the support of the Research Council of Lithuania, grant number MIP-049/2015. Funding information for this article has been deposited with the Crossref Funder Registry.

Background Cognitive impairment is common in people living with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF); however, accurate estimates of prevalence are lacking. To date, there are no meta-analyses that have specifically investigated prevalence of mild cognitive impairment (MCI) in this particular population. Our aim was to undertake a systematic review and apply meta-analytic methods to estimate the prevalence of MCI and any cognitive impairment (ACI) in people with COPD and CHF. Methods We identified relevant studies for COPD and CHF by searching the published literature from inception to February 2016 using the MEDLINE and Web of Science databases. Studies were included if they documented the prevalence of MCI and/or cognitive impairment for COPD and CHF patients without dementia. Results Seventeen studies including people with CHF (n = 29,456) and 14 studies including people with COPD (n = 23,116) were included. The pooled mean age for COPD was 66.3 years and for CHF, 75.6 years. The pooled prevalence of MCI in the COPD was 25% (95% CI: 23%, 42%) and ACI, 32% (95% CI: 18%, 38%). Correspondingly, the pooled prevalence of MCI in those with CHF was 32% (95% CI: 22%, 43%) and ACI, 31% (95% CI: 23%, 40%). Conclusions One in 4 people with COPD and 1 in 3 people with CHF had MCI, respectively. The overall prevalence of ACI for COPD was 32% and for CHF, 31%. Future work should consider ways of detecting, managing, or improving cognitive function and other cognition-related outcomes in this group of people.

Background Bronchial thermoplasty (BT) is a recently developed treatment for patients with moderate-to-severe asthma. A few studies have suggested the clinical efficacy of this intervention. However, no study has evaluated the cost-effectiveness of BT compared to other alternative treatments for moderate-to-severe allergic asthma, which currently include omalizumab and standard therapy. Objective To evaluate the cost-effectiveness of standard therapy, BT, and omalizumab for moderate-to-severe allergic asthma in the USA. Methods A probabilistic Markov model with weekly cycles was developed to reflect the course of asthma progression over a 5-year time horizon. The study population was adults with moderate-to-severe allergic asthma whose asthma remained uncontrolled despite using high-dose inhaled corticosteroids (ICS, with or without long-acting beta-agonists [LABA]). A perspective of the health-care system was adopted with asthma-related costs as well as quality-adjusted life years (QALYs) and exacerbations as the outcomes. Results For standard therapy, BT, and omalizumab, the discounted 5-year costs and QALYs were $15,400 and 3.08, $28,100 and 3.24, and $117,000 and 3.26, respectively. The incremental cost-effectiveness ratio (ICER) of BT versus standard therapy and omalizumab versus BT was $78,700/QALY and $3.86 million/QALY, respectively. At the willingness-to-pay (WTP) of $50,000/QALY and $100,000/QALY, the probability of BT being cost-effective was 9%, and 67%, respectively. The corresponding expected value of perfect information (EVPI) was $155 and $1,530 per individual at these thresholds. In sensitivity analyses, increasing the costs of BT from $14,900 to $30,000 increased its ICER relative to standard therapy to $178,000/QALY, and decreased the ICER of omalizumab relative to BT to $3.06 million/QALY. Reducing the costs of omalizumab by 25% decreased its ICER relative to BT by 29%. Conclusions Based on the available evidence, our study suggests that there is more than 60% chance that BT becomes cost-effective relative to omalizumab and standard therapy at the WTP of $100,000/QALY in patients with moderate-to-severe allergic asthma. However, there is a substantial uncertainty in the underlying evidence, indicating the need for future research towards reducing such uncertainty.

Clinical studies have suggested that metformin, a widely used antidiabetic agent, exerts a direct cardioprotective effect on cardiovascular disease in addition to its blood glucose-lowering activity. This study was designed to identify the role of metformin in rats with isoproterenol (ISO)-induced myocardial injury and to investigate its underlying mechanism. A rat model of myocardial ischemic injury was established by the subcutaneous injection of a high dose of ISO, a beta-adrenergic agonist. The results showed that pretreatment of metformin significantly reduced rat mortality induced by ISO, attenuated the increased plasma lactate dehydrogenase activity and myocardium malondialdehyde level, alleviated the hemodynamic disturbance, inhibited the upregulated gene expression of myocardial probrain natriuretic peptide and alleviated the myocardial morphological injury and apoptosis induced by ISO. Furthermore, western blot analysis showed that metformin suppressed the overexpression of the endoplasmic reticulum stress (ERS) markers cleaved caspase-12 and CEBP-homologous protein induced by ISO and increased the phosphorylation of AMP-activated protein kinase (AMPK). In conclusion, these data suggest that metformin might protect the myocardium against acute ischemic injury in rats at least partially by activating AMPK and alleviating aberrant ERS. These findings might provide further experimental evidence for treating patients at risk of ischemic heart disease with metformin.

Background: There is increasing evidence that community-based treatment of drug resistant tuberculosis (DRTB) is a feasible and cost-effective alternative to centralized, hospital-based care. Although several large programs have reported favourable outcomes from community-based treatment, to date there has been no systematic assessment of community-based DRTB treatment program outcomes. The objective of this study was to synthesize available evidence on treatment outcomes from community based multi-drug resistant (MDRTB) and extensively drug resistant tuberculosis (XDRTB) treatment programs. Methods: We performed a systematic review and meta-analysis of the published literature to examine treatment outcomes from community-based MDRTB and XDRTB treatment programs. Studies reporting outcomes from programs using community-based treatment strategies and reporting outcomes consistent with WHO guidelines were included for analysis. Treatment outcomes, including treatment success, default, failure, and death were pooled for analysis. Meta-regression was performed to examine for associations between treatment outcomes and program or patient factors. Results: Overall 10 studies reporting outcomes on 1288 DRTB patients were included for analysis. Of this population, 65% [95% CI 59-71%] of patients had a successful outcome, 15% [95% CI 12-19%] defaulted, 13% [95% CI 9-18%] died, and 6% [95% CI 3-11%] failed treatment for a total of 35% [95% CI 29-41%] with unsuccessful treatment outcome. Meta-regression failed to identify any factors associated with treatment success, including study year, age of participants, HIV prevalence, XDRTB prevalence, treatment regimen, directly observed therapy (DOT) location or DOT provider. Conclusions: Outcomes of community-based MDRTB and XDRTB treatment outcomes appear similar to overall treatment outcomes published in three systematic reviews on MDRTB therapy. Work is needed to delineate program characteristics associated with improved treatment outcomes.

Productivity loss is an overlooked aspect of the burden of chronic health conditions. While modern guidelines emphasize achieving clinical control in asthma management, few studies have reported on the relationship between asthma control and productivity loss. We calculated the productivity loss that can be avoided by achieving and maintaining clinical control in employed adults with asthma.We prospectively recruited a population-based random sample of adults with asthma in British Columbia, Canada. We measured productivity loss due to absenteeism and presenteeism using validated instruments, and ascertained asthma control according to the GINA (Global Initiative for Asthma) classification. We estimated the average gain in productivity for each individual if the individual’s asthma was controlled in the past week, by fitting two-part regression models associating asthma control and productivity loss, controlling for potential confounding variables.The final sample included 300 employed adults (mean age, 47.9 years [SD 12.0]; 67.3% women). Of these, 49 (16.3%) reported absenteeism, and 137 (45.7%) reported presenteeism. Productivity loss due to presenteeism, but not absenteeism, was associated with asthma control. A person with uncontrolled asthma would avoid $184.80 (Canadian dollars [CAD]) in productivity loss by achieving clinical control during a week, CAD$167.50 (90.6%) of which would be due to presenteeism. The corresponding value was CAD$34.20 for partially controlled asthma and was not statistically significant.Our results indicate that substantial gain in productivity can be obtained by achieving asthma control. Presenteeism is more responsive than absenteeism to asthma control, and, thus, is a more important source of preventable burden.

Interleukin 15 (IL-15) has recently been proposed as a circulating myokine involved in glucose uptake and utilization in skeletal muscle. However, the role and mechanism of IL-15 in exercise improving insulin resistance (IR) is unclear. Here, we investigated the alteration in expression of IL-15 and IL-15 receptor α (IL-15Rα) in skeletal muscle during treadmill running in rats with IR induced by a high-fat diet (HFD) and elucidated the mechanism of the anti-IR effects of IL-15. At 20 weeks of HFD, rats showed severe IR, with increased levels of fasting blood sugar and plasma insulin, impaired glucose tolerance, and reduced glucose transport activity. IL-15 immunoreactivity and mRNA level in gastrocnemius muscle were decreased markedly as compared with controls. IL-15Rα protein and mRNA levels in both soleus and gastrocnemius muscle were significantly decreased, which might attenuate the signaling or secretion of IL-15 in muscle. Eight-week treadmill running completely ameliorated HFD-induced IR and reversed the downregulated level of IL-15 and IL-15Rα in skeletal muscle of HFD-fed rats. To investigate whether IL-15 exerts its anti-IR effects directly in muscle, we pre-incubated muscle strips with the endoplasmic reticulum stress (ERS) inducer dithiothreitol (DTT) or tunicamycin (Tm); IL-15 treatment markedly decreased the protein expression of the ERS markers 78-kDa glucose-regulated protein, 94-kDa glucose-regulated protein and C/EBP homologous protein and inhibited ERS induced by DTT or Tm. Therefore, treadmill running promoted skeletal IL-15 and IL-15Rα expression in HFD-induced IR in rats. The inhibitory effect of IL-15 on ERS may be involved in improved insulin sensitivity with exercise training.