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Background: Tufuling Qiwei Tangsan (TQTS) is a commonly used Mongolian medicine preparation against psoriasis in China. However, its mechanism of action and molecular targets for the treatment of psoriasis is still unclear. Network pharmacology can reveal the synergistic mechanism of drugs at the molecular, target, and pathway levels and is suitable for the complex study of traditional Chinese medicine formulations. However, it is rarely involved in the application of Mongolian medicine with the same holistic concept of traditional Chinese medicine. Method: In this paper, the active compounds of TQTS were collected, and their targets were identified. Psoriasis-related targets were obtained by analyzing the differential expressed genes between psoriasis patients and healthy individuals. Then, the network concerning the interactions of potential targets of TQTS with well-known psoriasis-related targets was built. The core targets were selected according to topological parameters. And the enrichment analysis was carried out to explore the mechanism of action of TQTS. Moreover, molecular docking was performed to study the interaction between the selected ligands and receptors related to psoriasis. Result and Conclusion: Eighty-five active compounds of TQTS were screened, with corresponding 270 targets, and 313 differentially expressed genes were identified. Additionally, enrichment analysis showed that the targets of TQTS for treating psoriasis were mainly involved in multiple biological processes, including apoptosis, growth factor response, etc., and related pathways including PI3K-Akt and MAPK signaling pathway, and so on. Genes such as NFKB1, TP53, and MAPK1 are the key genes in the gene pathway network of TQTS against psoriasis. The 4 main active components of TQTS have certain binding activity with 13 potential targets, and the stability of their interaction with AKT1 is found to be the most efficient, which indicates the potential mechanism of TQTS on psoriasis.

Purpose of the study: Macrolide therapy is effective in reducing chronic obstructive pulmonary disease (COPD) exacerbations. Our recent study has shown the effectiveness of taking azithromycin in C...

Background COPD increases susceptibility to sleep disturbances, which may in turn predispose to increased respiratory symptoms. The objective of this study was to evaluate, in a population-based sample, the relationship between subjective sleep quality and risk of COPD exacerbations. Methods Data were obtained from the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Participants with COPD who had completed 18 months of follow-up were included. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI) and a three-factor analysis. Symptom-based (dyspnea or sputum change ≥ 48 h) and event-based (symptoms plus medication or unscheduled health services use) exacerbations were assessed. Association of PSQI with exacerbation rate was assessed by using negative binomial regression. Exacerbation-free survival was also assessed. Results A total of 480 participants with COPD were studied, including 185 with one or more exacerbations during follow-up and 203 with poor baseline sleep quality (PSQI score > 5). Participants with subsequent symptom-based exacerbations had higher median baseline PSQI scores than those without (6.0 [interquartile range, 3.0-8.0] vs 5.0 [interquartile range, 2.0-7.0]; P = .01), and they were more likely to have baseline PSQI scores > 5 (50.3% vs 37.3%; P = .01). Higher PSQI scores were associated with increased symptom-based exacerbation risk (adjusted rate ratio, 1.09; 95% CI, 1.01-1.18; P = .02) and event-based exacerbation risk (adjusted rate ratio, 1.10; 95% CI, 1.00-1.21; P = .048). The association occurred mainly in those with undiagnosed COPD. Strongest associations were with Factor 3 (sleep disturbances and daytime dysfunction). Time to symptom-based exacerbation was shorter in participants with poor sleep quality (adjusted hazard ratio, 1.49; 95% CI, 1.09-2.03). Conclusions Higher baseline PSQI scores were associated with increased risk of COPD exacerbation over 18 months’ prospective follow-up.

Background: Chronic obstructive pulmonary disease (COPD) is a common and chronic lung condition characterized by sudden flare-ups known as acute exacerbations (AECOPD). Relative increases in air pollution concentration and ambient temperature may play a clinically relevant role in precipitating AECOPDs. Objectives: To estimate the association between short-term exposures to air pollution and exacerbations in patients with mild-moderate COPD, as well as the influence of temperature on this relationship. Methods: In this case-crossover study, AECOPD events were collected prospectively from COPD participants within the Canadian Cohort Obstructive Lung Disease (CanCOLD). Daily particulate matter Results: Consistent positive associations (P Measurements and Main Results: Exposure to ambient PM2.5 and NO2 was associated with an increased odds of AECOPD (particularly on lag Day -1 and during the Cool period), challenging the conventional understanding of the precipitants for AECOPD.

Facilitating the identification of extreme inactivity (EI) has the potential to improve morbidity and mortality in COPD patients. Apart from patients with obvious EI, the identification of a such behavior during a real-life consultation is unreliable. We therefore describe a machine learning algorithm to screen for EI, as actimetry measurements are difficult to implement. Complete datasets for 1409 COPD patients were obtained from COLIBRI-COPD, a database of clinicopathological data submitted by French pulmonologists. Patient- and pulmonologist-reported estimates of PA quantity (daily walking time) and intensity (domestic, recreational, or fitness-directed) were first used to assign patients to one of four PA groups (extremely inactive [EI], overtly active [OA], intermediate [INT], inconclusive [INC]). The algorithm was developed by (i) using data from 80% of patients in the EI and OA groups to identify ‘phenotype signatures’ of non-PA-related clinical variables most closely associated with EI or OA; (ii) testing its predictive validity using data from the remaining 20% of EI and OA patients; and (iii) applying the algorithm to identify EI patients in the INT and INC groups. The algorithm’s overall error for predicting EI status among EI and OA patients was 13.7%, with an area under the receiver operating characteristic curve of 0.84 (95% confidence intervals: 0.75–0.92). Of the 577 patients in the INT/INC groups, 306 (53%) were reclassified as EI by the algorithm. Patient- and physician- reported estimation may underestimate EI in a large proportion of COPD patients. This algorithm may assist physicians in identifying patients in urgent need of interventions to promote PA.

Introduction In this analysis of the PHYSACTO® study, we assessed the efficacy of a self-management behaviour modification (SMBM) programme to improve physical activity (PA) levels, and the extent to which effects were mediated by readiness to change, motivation and confidence. Methods PHYSACTO® was a randomised, partially double-blind, parallel-group, 12-week trial to evaluate the effects of treatment on exercise capacity and PA. COPD patients received placebo, tiotropium 5 µg or tiotropium/olodaterol 5/5 µg, with or without exercise training, all with an SMBM intervention (the Living Well with COPD programme). Changes were assessed in readiness to change (stage of change visual analogue scale [VAS]), motivation (Treatment Self-Regulation Questionnaire [TSRQ]) and confidence (Perceived Competence Scale [PCS]) to engage in PA. Results PA was increased in all patients with complete PA data at Week 12 (n=262; +6038 steps·week−1, p, Self-management improves motivation and confidence to engage in physical activity in COPD patients in PHYSACTO https://bit.ly/2MKoPSy

Refereed/Peer-reviewed This study compared the multidimensional breathlessness response to incremental cardiopulmonary cycle exercise testing (CPET) in people with chronic obstructive pulmonary disease (COPD; n = 14, aged 69 ± 9 years, forced expiratory volume in 1-sec = 54 ± 16 % predicted) and healthy older (OA) (n = 35, aged 68 ± 5 years) and younger (YA) (n = 19, aged 28 ± 8 years) adults. Participants performed CPET and successively rated overall breathlessness intensity, unsatisfied inspiration, breathing too shallow, work/effort of breathing, and breathlessness-related unpleasantness, fear, and anxiety using the 0−10 Borg scale. At any given percent predicted peak minute ventilation, people with COPD rated all breathlessness sensations higher than OA and YAs, who were similar. Most between group differences disappeared when examined in relation to inspiratory reserve volume, except people with COPD reported higher levels of unsatisfied inspiration and breathing too shallow (vs YA), and breathlessness-related fear and anxiety (vs OA and YAs). Multidimensional ratings of breathlessness sensations during CPET provides further insight into differences in exertional symptom perceptions among people with COPD and without COPD.

We studied whether fractional exhaled nitric oxide (F ENO) can differentiate chronic obstructive pulmonary disease (COPD) with concurrent diagnosis of asthma from COPD-only as well as its ability t...

Jonathan Lévesque,1 Anestis Antoniadis,2 Pei Zhi Li,3 Frédéric Herengt,4 Christophe Brosson,5 Jean-Marie Grosbois,6 Alain Bernady,7 Anthony Bender,8,9 Murielle Favre,10 Antoine Guerder,11 Pascale Surpas,12 Thomas Similowski,11,13 Bernard Aguilaniu141Department of Medicine, Pneumology Service, Hôpital Maisonneuve-Rosemont, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; 2Laboratoire Jean Kuntzmann UMR5224, Statistics Department, Université Grenoble-Alpes, Grenoble, France; 3Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, Quebec, Canada; 4Centre de Réadaptation Cardio-Respiratoire-Dieulefit Santé, Dieulefit, France; 5Private Physiotherapist, Cours Liberation, Grenoble, France; 6Pneumology Service, Centre Hospitalier de Béthune, Béthune, France; 7Toki-Eder Centre Médical Cardio-Respiratoire, Cambo-les-Bains, France; 8Private Physiotherapist, Boulevard de Metz Mont-Saint-Martin, France; 9LUNEX International University of Health, Exercise and Sports, Differdange, Luxembourg; 10Centre de Pneumologie Henri Bazire, Saint-Julien-de-Ratz, France; 11AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie, Médecine Intensive et Réanimation, Département R3S, Paris, France; 12Centre Médical de Bayère, Charnay, France; 13Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; 14Faculty of Medicine, Université Grenoble-Alpes, Grenoble, FranceBackground: The 3-minute chair rise test (3-minute CRT) and the Disability Related to COPD Tool (DIRECT) are two reproducible and valid short tests that can assess the benefit of pulmonary rehabilitation (PR) in terms of functional capacity and dyspnea in everyday activities.Methods: We determined the minimal clinically important difference (MCID) of the DIRECT questionnaire and 3-minute CRT using distribution methods and anchor encroaches with a panel of eight standard tests in a cohort of 116 COPD patients who completed a PR program in real-life settings.Results: The estimated MCID for the 3-minute CRT and DIRECT scores was five repetitions and two units, respectively, using separate and combined independent anchors. The all-patient (body mass index-obstruction-dyspnea-exercise [BODE] scores 0–7), BODE 0–2 (n=42), and BODE 3–4 (n=50) groups showed improvements greater than the MCID in most tests and questionnaires used. In contrast, the BODE 5–7 group (n=24) showed improvements greater than MCID in only the 3-minute CRT, 6-minute walk test, endurance exercise test, and DIRECT questionnaire.Discussion and conclusion: This study demonstrates that the short and simple DIRECT questionnaire and 3-minute CRT are responsive to capture the beneficial effects of a PR program in COPD patients, including those with severe disease.Trial registration number: NCT03286660. Keywords: MCID, chair tests, tools, COPD, pulmonary rehabilitation, outcomes assessment

Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an established mouse model of gut microbiota dysbiosis. Using chick embryos exposed to dysbacteriosis-derived LPS, we found restriction in the development of long bones as demonstrated by Alcian blue and alizarin red staining. Micro-CT and histological analysis exhibited decreased trabecular volume, bone mineral density, and collagen production, as well as suppressed osteoblastic gene expression (Ocn, Runx2, Osx, and Dlx5) in chick embryonic phalanges following LPS treatment. Atomic force microscopy manifested decreased roughness of MC3T3-E1 cells and poorly developed matrix vesicles (MVs) in presence of LPS. The expression of the aforementioned osteoblastic genes was suppressed in MC3T3-E1 cells as well. High-throughput RNA sequencing indicated that retinoic acid (RA) may play an important role in LPS-induced osteopenia. The addition of RA suppressed Dlx5 expression in MC3T3-E1 cells, as was also seen when exposed to LPS. Quantitative PCR, Western blot, and immunofluorescent staining showed that retinoic acid receptor &alpha, (RAR&alpha, ) was upregulated by LPS or RA treatment, while the expression of DLX5 was downregulated. CYP1B1 expression was increased by LPS treatment in MC3T3-E1 cells, which might be attributed to the increased inflammatory factors and subsequently activated NF-&kappa, B signaling. Eventually, blocking RA signals with AGN193109 successfully restored LPS-inhibited osteoblastic gene expression. Taken together, our data reveals that maternal gut microbiota dysbiosis can interfere with bone ossification, in which Dlx5 expression regulated by RA signaling plays an important role.

The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid.In this multicenter, open-label trial, we randomly assigned 844 children (18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis.Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14).Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

Background The COPD Assessment Test (CAT) is a valid disease-specific questionnaire measuring health status. However, knowledge concerning its use regarding patient and disease characteristics remains limited. Our main objective was to assess the degree to which the CAT score varies and can discriminate between specific patient population groups. Methods The Canadian Cohort Obstructive Lung Disease (CanCOLD) is a random-sampled, population-based, multicenter, prospective cohort that includes subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] classifications 1 to 3). The CAT questionnaire was administered at three visits (baseline, 1.5 years, and 3 years). The CAT total score was determined for sex, age groups, smoking status, GOLD classification, exacerbations, and comorbidities. Results A total of 716 subjects with COPD were included in the analysis. The majority of subjects (72.5%) were not previously diagnosed with COPD. The mean FEV 1 /FVC ratio was 61.1 ± 8.1%, with a mean FEV 1 % predicted of 82.3 ± 19.3%. The mean CAT scores were 5.8 ± 5.0, 9.6 ± 6.7, and 16.1 ± 10.0 for GOLD 1, 2, and 3+ classifications, respectively. Higher CAT scores were observed in women, current smokers, ever-smokers, and subjects with a previous diagnosis of COPD. The CAT was also able to distinguish between subjects who experience exacerbations vs those who had no exacerbation. Conclusions These results suggest that the CAT, originally designed for use in clinically symptomatic patients with COPD, can also be used in individuals with mild airflow obstruction and newly diagnosed COPD. In addition, the CAT was able to discriminate between sexes and subjects who experience frequent and infrequent exacerbations. Trial Registry ClinicalTrials.gov; No.: NCT00920348; Study ID No.: IRO-93326.

In this study, we aimed to compare and validate the prognostic abilities of preoperative systemic immune cells in hepatocellular carcinoma (HCC) after curative hepatectomy. We developed two nomograms to predict the postoperative recurrence‐free survival (RFS) and overall survival (OS) after comparisons of the systemic immune cell prognostic scores. The two nomograms were constructed based on 305 patients who underwent curative hepatectomy for HCC. The predictive accuracy and discriminative ability of the nomograms were compared with six commonly used staging systems for HCC. The results were validated using bootstrap resampling and an internal validation cohort of 142 patients and an external validation cohort of 169 patients. Necroinflammatory activity in peritumoral liver tissues in the primary cohort was evaluated by hematoxylin and eosin (H&E) staining. Neutrophil, monocyte, and lymphocyte ratio (NMLR) had a higher area under the receiver operating characteristic curves (AUROC) value at both RFS (AUC = 0.603) and OS (AUC = 0.726) compared to that of other systemic immune cell prognostic scores. The independent predictors of RFS or OS, including α‐fetoprotein (AFP), tumor size, tumor number, microvascular invasion, and NMLR, were incorporated into the two nomograms. In the primary cohort, the C‐indexes of the RFS and OS nomograms were 0.705 and 0.797, respectively. The ROC analyses showed that the two nomograms had larger AUC values (0.664 for RFS and 0.821 for OS) than those of the American Joint Commission on Cancer seventh edition, Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, Japan Integrated Staging Score, Okuda stage, and the Vauthey's system. These results were verified by internal and external validations. The nomogram‐predicted probability of RFS was associated with peritumoral necroinflammatory activity scores (r = 0.304, P

Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD).To determine if the total number of airways quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD.Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways.Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never-smokers (P 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P 0.0001) and thinner walls (P 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEVTAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression.

The objective of this study is to evaluate whether a chronic obstructive pulmonary disease (COPD) self-management education program with coaching of a case manager improves patient-related outcomes and leads to practice changes in primary care. COPD patients from six family medicine clinics (FMCs) participated in a 1-year educational program offered by trained case managers who focused on treatment adherence, inhaler techniques, smoking cessation, and the use of an action plan for exacerbations. Health-care utilization, health-related quality of life (HRQL), treatment adherence, inhaler technique, and COPD knowledge were assessed at each visit with validated questionnaires. We also evaluated whether the use of spirometry and the assessment of individual patient needs led to a more COPD-targeted treatment by primary care physicians, based on changes in prescriptions for COPD (medication, immunization, and written action plan). Fifty-four patients completed the follow-up visits and were included in the analysis. The number of unscheduled physician visits went from 40 the year before intervention to 17 after 1 year of educational intervention ( p = 0.033). Emergency room visits went from five to two and hospitalizations from two to three (NS). Significant improvements were observed in HRQL ( p = 0.0001), treatment adherence ( p = 0.025), adequate inhaler technique ( p < 0.0001), and COPD knowledge ( p < 0.001). Primary care physicians increased their prescriptions for long-acting bronchodilators with/without inhaled corticosteroid, flu immunizations, and COPD action plans in the event patient had an exacerbation. The COPD self-management educational intervention in FMCs reduced unscheduled visits to the clinic and improved patients’ quality of life, self-management skills, and knowledge. The program had a positive impact on COPD-related practices by primary care physicians in the FMCs.

Background The number of pharmacological agents and guidelines available for COPD has increased markedly but guidelines remain poorly followed. Understanding underlying clinical reasoning is challenging and could be informed by clinical characteristics associated with treatment prescriptions. Methods To determine whether COPD treatment choices by respiratory physicians correspond to specific patients’ features, this study was performed in 1171 patients who had complete treatment and clinical characterisation data. Multiple statistical models were applied to explain five treatment categories: A: no COPD treatment or short-acting bronchodilator(s) only; B: one long-acting bronchodilator (beta2 agonist, LABA or anticholinergic agent, LAMA); C: LABA+LAMA; D: a LABA or LAMA + inhaled corticosteroid (ICS); E: triple therapy (LABA+LAMA+ICS). Results Mean FEV1 was 60% predicted. Triple therapy was prescribed to 32.9% (treatment category E) of patients and 29.8% received a combination of two treatments (treatment categories C or D); ICS-containing regimen were present for 44% of patients altogether. Single or dual bronchodilation were less frequently used (treatment categories B and C: 19% each). While lung function was associated with all treatment decisions, exacerbation history, scores of clinical impact and gender were associated with the prescription of > 1 maintenance treatment. Statistical models could predict treatment decisions with a

This study explored the impact of a self-management behaviour modification (SMBM) programme with/without bronchodilators and with/without exercise training (ExT) to improve daily physical activity on psychological and cognitive outcomes in COPD patients as a secondary analysis of the PHYSACTO trial. A 12-week, four-group, randomised, partially double-blind, placebo-controlled, parallel-group trial of SMBM in addition to tiotropium 5 µg, tiotropium/olodaterol 5/5 µg, tiotropium/olodaterol 5/5 µg plus ExT, or placebo was conducted in 304 patients. Outcomes included anxiety (Hospital Anxiety and Depression Scale (HADS)-A), depression (HADS-D and Patient-Health Questionnaire (PHQ)-9) and cognitive function (Montreal Cognitive Assessment (MoCA)). All outcomes showed statistically and clinically significant improvements after 12 weeks independent of treatment group. However, greater improvements in HADS-A and MoCA were seen in patients who exhibited greater increases in physical activity and exercise capacity, respectively, whereas greater improvements in HADS-D and PHQ-9 were seen in patients who exhibited increases in either physical activity or exercise capacity. The results indicate that SMBM with/without bronchodilators or ExT was associated with improved psychological and cognitive functioning. Anxiety reduced with increased physical activity, cognitive function improved with increased exercise capacity, and depression reduced with increases in either physical activity or exercise capacity. Interventions that increase daily physical activity or exercise capacity may improve psychological and cognitive outcomes in COPD., Behavioural modification adjunct to bronchodilator therapy and exercise training to increase exercise capacity and physical activity can also be beneficial for improving anxiety, cognitive function and depression in patients with COPD http://bit.ly/33ZufNM

Introduction Over the last decade, new evidence and many guidelines have been published on COPD pharmacological treatments; prescriptions are often not in accordance with guidelines. Materials and methods Trends in physician treatment choices from February 2012 to November 2018 (Feb.2012/Nov.2018) were analyzed using data from COPD patients (spirometry-confirmed diagnosis) included in the COLIBRI-COPD cohort. Inhaled drug treatments (short- or long-acting β2-agonist [SABA or LABA], short- or long-acting anticholinergic [SAMA or LAMA], or corticosteroid [ICS]) were classified into 5 treatment categories: “No initial maintenance treatment (IMT)” (untreated, or only SAMA or SABA); “1 long-acting bronchodilator (LABD)” (LABA or LAMA); “2 LABDs” (LABA + LAMA); “1 LABD + ICS” (LABA or LAMA + ICS); “2 LABDs + ICS” (LABA + LAMA + ICS). For the purpose of the study, 4 periods were defined to achieve balanced samples (T1-T4). Results Data from 4537 patients were collected. Over time, 3 major changes were observed: (1) an increase in treatment category “No IMT”, mostly for GOLD 1 or GOLD A categories (GOLD A: from 19.1% at T1 to 41.2% at T4); (2) an increase in treatment category “2 LABDs” for GOLD 2 to 4 and GOLD A to D categories (GOLD B: from 15.4% to 29.7%); (3) a decrease in ICS use (“1 LABD + ICS” or “2 LABDs + ICS”), mostly for GOLD 1 to 3 and GOLD A categories (GOLD A, 2 LABDs + ICS: from 35.3% to 11.1%). Conclusion Changes over time in therapeutic profiles suggest that new evidence from scientific publications and recommendations may have had a rapid impact on clinical practice.

DNA sequencing of the SERPINA1 gene to detect α1-antitrypsin (AAT) deficiency (AATD) may provide a better appreciation of the individual and cumulative impact of genetic variants on AAT serum levels and COPD phenotypes.AAT serum level and DNA sequencing of the coding regions of SERPINA1 were performed in 1359 participants of the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Clinical assessment for COPD included questionnaires, pulmonary function testing and computed tomography (CT) imaging. Phenotypes were tested for association with SERPINA1 genotypes collated into four groups: normal (MM), mild (MS and MI), intermediate (heterozygote MZ, non-S/non-Z/non-I, compound IS, and homozygote SS) and severe (ZZ and SZ) deficiency. Smoking strata and MZ-only analyses were also performed.34 genetic variants were identified including 25 missense mutations. Overall, 8.1% of alleles in this Canadian cohort were deficient and 15.5% of 1359 individuals were carriers of at least one deficient allele. Four AATD subjects were identified and had statistically lower diffusion capacity and greater CT-based emphysema. No COPD phenotypes were associated with mild and intermediate AATD in the overall cohort or stratified by smoking status. MZ heterozygotes had similar CT-based emphysema, but lowered diffusion capacity compared with normal and mild deficiency.In this Canadian population-based cohort, comprehensive genetic testing for AATD reveals a variety of deficient alleles affecting 15.5% of subjects. COPD phenotype was demonstrated in severe deficiency and MZ heterozygotes. This study shows the feasibility of implementing a diagnostic test for AATD using DNA sequencing in a large cohort.

Objective. To compare the safety and efficacy of 2 transcutaneous stimulation techniques, transcutaneous pulsed radiofrequency (TPRF) versus transcutaneous electrical nerve stimulation (TENS), in chronic shoulder tendonitis. Design. A prospective, randomized, and double-blind clinical trial. Setting. Academic pain service of a city hospital. Subjects. Fifty patients with sonography-confirmed shoulder tendonitis. Methods. Fifty patients were randomly allocated into two groups for electrical stimulation treatment with 3-month follow-ups: Group 1 n=25, TENS and Group 2 n=25, TPRF. Both groups underwent either treatment for 15 minutes every other day, three times total. Our primary goals were to find any treatment comfort level, adverse event, and changes in Constant–Murley shoulder (CMS) scores. The secondary goals were finding the changes in pain, enjoyment of life, and general activity (PEG) scores. Results. For primary goals, no adverse events were noted throughout this study. No differences were found between groups for treatment tolerability (3.20 + 0.87 vs. 2.16 + 0.75). Statistically significant lower PEG scores were noticeable with the TPRF group after the course (12.73 + 5.79 vs. 24.53 + 10.21, p=0.013). Their statistical significance lasted for 3 months although the difference gap diminished after 1 month. CMS scores were significantly higher in the TPRF group (70.84 + 6.74 vs. 59.56 + 9.49, p=0.007) right after treatment course but the significance did not last. Conclusions. In treating chronic shoulder tendinitis using two transcutaneous stimulation techniques, both TPRF and TENS are safe and effective. TPRF is superior to TENS.

We tested the hypothesis that abdominal binding (AB) would reduce breathlessness and improve exercise tolerance by enhancing neuromuscular efficiency of the diaphragm during exercise in adults with chronic obstructive pulmonary disease (COPD). In a randomized, controlled, crossover trial, 20 adults with COPD (mean ± SD FEV1, 60 ± 16% predicted) completed a symptom-limited constant-load cycle endurance exercise test at 75% of their peak incremental power output with concomitant measures of the diaphragm electromyogram (EMGdi) and respiratory pressures without (CTRL) vs. with AB sufficient to increase end-expiratory gastric pressure (Pga,ee) by 6.7 ± 0.3 cmH2O at rest. Compared to CTRL, AB enhanced diaphragmatic neuromuscular efficiency during exercise (p < 0.05), as evidenced by a 25% increase in the quotient of EMGdi to tidal transdiaphragmatic pressure swing. By contrast, AB had no demonstrable effect on exertional breathlessness and exercise tolerance; spirometry and plethysmography-derived pulmonary function test parameters at rest; and cardiac, metabolic, breathing pattern, inspiratory reserve volume and EMGdi responses during exercise (all p > 0.05 vs. CTRL). In conclusion, enhanced neuromuscular efficiency of the diaphragm during exercise with AB was not associated with relief of exertional breathlessness and improved exercise tolerance in adults with COPD.Clinical Trial Registration:ClinicalTrials.gov Identifier: NCT01852006.

Item does not contain fulltext BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Oscillometry (OS) offers faster and easier objective measures of lung function than spirometry (SP). We wished to characterize OS parameters within the CanCOLD cohort. 126 subjects from the Montreal CanCOLD site completed PROs (mMRC, COPD Assessment Tests, SGRQ), and performed SP (Medisoft, Sorinnes, Belgium) and OS (tremoFlo C-100, Thorasys, Canada) at the same visit. Subjects were divided into subgroups of Normal, AtRisk, GOLD1 and GOLD2+ as previously reported. Between group differences were sought using ANOVA and post hoc t-tests and associations between SP, PROs and ln transformed OS parameters (R5, R5-19, X5, AX) using Bonferroni corrected pairwise correlations. All GOLD2+ OS parameters differed from other groups; AX the most (median, IRQ: 20, 9, 29 cmH20/L vs. GOLD1 5, 2, 10; AtRisk 5, 2, 10; Normal 3, 2, 6, p The mMRC demonstrated the strongest correlation between PROs and both SP (FEV1 r=-0.46, FEV1% r=-0.49, FEV1/FVC r=-0.46, p

In this study, we investigated the effect of caffeine overexposure on corneal innervation in the early chicken embryo. Caffeine administration restricted corneal innervation by affecting trigeminal nerve development. Immunohistochemistry for phospho-Histone3 (pHIS3) and C-caspase3 revealed that cell survival was repressed by caffeine administration. Whole-mount in situ hybridization against semaphorin 3A (Sema3A) and neuropilin-1 (Nrp1) showed that both caffeine and 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH, a free radical generator) administration upregulates the expression of both Sema3A and Nrp1. Next, we demonstrated that lens ablation in the developing chicken embryos significantly affected NF-labeled periocular nerve fascicles and innervation to the central eye region. Subsequently, we used a neuroblastoma cell line to investigate in vitro whether or not Sema3A-Nrp1 signaling exerts a key role on the caffeine-suppressed neuron survival. Knocking-down Sema3A through transfection with Sema3A-siRNA dramatically decreased the responsiveness of cells to caffeine administration, as well as cell apoptosis. We suggest that Sema3A-Nrp1 signaling regulates Trp53 and Cdkn1a through Slit2-Robo1 and Ephb2. Taken together, we speculate here that caffeine-enhanced reactive oxygen species upregulates Sema3A-Nrp1 expression in the lens and periocular tissues, resulting in corneal cell apoptosis, accompanied by its chemorepellent role on the invasion of the developing cornea by trigeminal sensory fibers.

Rationale A series of studies conducted approximately 40 years ago demonstrated an acute bronchodilator effect of smoked cannabis in healthy adults and adults with asthma. However, the acute effects of vaporized cannabis on airway function in adults with advanced chronic obstructive pulmonary disease (COPD) remain unknown. Objectives To test the hypothesis that inhaled vaporized cannabis would alleviate exertional breathlessness and improve exercise endurance by enhancing static and dynamic airway function in COPD. Methods In a randomized controlled trial of 16 adults with advanced COPD (forced expiratory volume in 1 second [FEV1], mean ± SD: 36 ± 11% predicted), we compared the acute effect of 35 mg of inhaled vaporized cannabis (18.2% Δ9-tetrahydrocannabinol, Results Compared with CTRL, cannabis had no effect on breathlessness intensity ratings during exercise at isotime (cannabis, 2.7 ± 1.2 Borg units vs. CTRL, 2.6 ± 1.3 Borg units); exercise endurance time (cannabis, 3.8 ± 1.9 min vs. CTRL, 4.2 ± 1.9 min); cardiac, metabolic, gas exchange, ventilatory, breathing pattern, and/or operating lung volume parameters at rest and during exercise; spirometry and impulse oscillometry-derived pulmonary function test parameters at rest; and cognitive function, psychoactivity, and mood. Conclusions Single-dose inhalation of vaporized cannabis had no clinically meaningful positive or negative effect on airway function, exertional breathlessness, and exercise endurance in adults with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT03060993).

Dexamethasone (Dex), a synthetic glucocorticoid (GC) with long-lasting treatment effects, has been proved to exert a modulatory effect on osteoblast proliferation and differentiation during embryonic osteogenesis. However, it is still controversial if Dex exposure influences endochondral ossification and the underlying mechanism. In this study, chick embryos in vivo and preosteoblast cell cultures in vitro were utilized to investigate the effects of Dex on osteoblast formation and differentiation during the skeletal development. We first demonstrated that Dex exposure could shorten the long bones of 17-day chick embryos in vivo, and also downregulated the expressions of osteogenesis-related genes. Next, we established that Dex exposure inhibited the proliferation and viability of preosteoblasts-MC3TC-E1 cells, and the addition of insulin-like growth factor 1 (IGF-1) could dramatically rescue these negative effects. On the basis of remarkable changes in the rescue experiments, we next verified the important role of angiogenesis in osteogenesis by culturing isolated embryonic phalanges in Dulbecco's modified Eagle's medium culture or on the chick chorioallantoic membrane (CAM). Then, we transplanted MC3T3-E1 cell masses onto the CAM. The data showed that Dex exposure reduced the vessel density within the developed cell mass, concomitantly with the downregulation of IGF-1 pathway. We verified that the inhibition of blood vessel formation caused by Dex could be rescued by IGF-1 treatment using the CAM angiogenesis model. Eventually, we demonstrated that the shortened length of the phalanges in the presence of Dex could be reversed by IGF-1 addition. In summary, these findings suggested that the inhibition of Igf-1 signal caused by Dex exposure exerts a detrimental impact on the formation of osteoblasts and angiogenesis, which consequently shortens long bones during osteogenesis.

Funding: World Health Organization and Canadian Institutes of Health Research. Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1–3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. Findings: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8–9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1–7·3), but no significant effect on mortality (aOR 0·7, 0·4–1·1) or acquired rifampicin resistance (aOR 0·1, 0·0–1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2–0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. Interpretation: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. Funding World Health Organization and Canadian Institutes of Health Research. Postprint

Damaged cartilage has very low regenerative potential which has led to the search for novel tissue-engineering approaches to help treat cartilage defects. While various approaches have been reported, there is no perfect treatment currently. In this study we evaluated the effects of a plant extract, chlorogenic acid (CGA), as part of chondrocyte transplantation on a model of knee joint injury in chicks. First, primary cultured chondrocytes used to evaluate the effects of CGA on chondrogenesis. Then using an articular cartilage injury model of chick knee we assessed the functional recovery after transplantation of the complexes containing chondrocytes and CGA in an alginate scaffold. Histological analysis, PCR, and western blot were further used to understand the underlying mechanisms. We showed that 60 μM CGA in alginate exhibited notable effects on stimulating chondrogenesis in vitro. Secondly, it was shown that the application of these complexes accelerated the recovery of injury-induced dysfunction by gait analysis when followed for 21 days. Histochemical analysis demonstrated that there was less abnormal vasculature formation, more chondrocyte proliferation and cartilage matrix synthesis in the presence of the complexes containing CGA. We discovered CGA treated transplantation up-regulated the expressions of Sox9 and Col2a1 which were responsible for the stimulation of chondrogenesis. Furthermore, the application of these complexes could suppress the abnormal angiogenesis and fibrosis at the injury site. Lastly, the elevated levels of inflammatory cytokines IL-1β, TNF-α, p-p65, and MMPs expression were decreased in the presence of CGA. This may be caused through adjusting cellular redox homeostasis associated with Nrf2. This study suggests that combining chondrocytes and CGA on an alginate scaffold can improve the recovery of damaged articular cartilage.

BACKGROUND Lymphangioleiomyomatosis (LAM) is a manifestation of tuberous sclerosis complex (TSC) that causes destruction of the lung and chronic respiratory failure. Population-based estimates of demographics, clinical outcomes, and health-care utilization are lacking for TSC and LAM. METHODS Data on demographics, clinical outcomes, and health-care utilization in the Quebec ministerial provincial health-care database were analyzed for their association with TSC and LAM. RESULTS A total of 1,004 subjects with TSC were identified using International Classification of Diseases, Ninth and 10th Revisions, codes for a prevalence of one in 7,872 people. There were 38 subjects with LAM, nine of whom also had TSC. Mean ages as well as the mean age at death were lower in the LAM and TSC group than in the control group. Mortality rates were higher in subjects with LAM than in those with TSC or in control subjects. Subjects with LAM experienced more medical visits and hospitalizations than did those with TSC and control subjects; these were associated with higher health-care costs. Frequently prescribed drugs in TSC or LAM included anticonvulsants, antidepressants, and sedatives; the use of mammalian target of rapamycin inhibitors was uncommon. CONCLUSIONS The prevalence of TSC in Quebec, Canada, is similar to estimates from previously published surveys. LAM is likely underreported, perhaps due to suboptimal case identification or referral. Health-care utilization and mortality for LAM are high, suggesting that timely diagnosis and therapy could be beneficial. Mental health disorders may be an unrecognized clinical feature of LAM. These results provide a population-based background for policymakers and researchers to better address the needs of patients with TSC and LAM.

The liver X receptor (LXR) isoform LXR‑α has a significant role in lipid metabolism and innate immunity. Overexpression of neuron‑derived orphan nuclear receptor‑1 (NOR‑1) in macrophages reduces the synthesis of inflammatory cytokines and chemokines. However, to date, the mechanisms via which NOR‑1 inhibits lipopolysaccharide (LPS)‑induced inflammation in Kupffer cells (KCs) via LXR‑α have not been elucidated. T0901317 is the most potent LXR‑α ligand, leading to its activation. In the present study, KCs were isolated from C57BL/6 mice and randomly divided into five groups: Control, T0901317, LPS, LPS + T0901317 and LPS + T0901317 + NOR‑1 small hairpin (sh)RNA groups. In order to investigate the role of NOR‑1 in inflammation, shRNA targeting NOR‑1 was used to specifically knock down NOR‑1 mRNA in KCs. The expression levels of LXR‑α and NOR‑1 in KCs were determined by reverse transcription quantitative polymerase chain reaction and western blot analyses. The protein levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 in the supernatant of KCs were evaluated by ELISA. The results revealed that LXR‑α expression in the T0901317 group was higher than that in the control group; furthermore, LXR‑α expression was higher in KCs treated with LPS + T0901317 compared with that in KCs treated with LPS only. The expression levels of NOR‑1 in each group showed a similar trend. shRNA targeting of NOR‑1 suppressed the mRNA expression of NOR‑1, but had no influence on LXR‑α mRNA expression. NOR‑1 protein expression was augmented in the LPS + T0901317 group compared with that in the LPS + T09 + shRNA group. In the supernatant of KCs, the TNF‑α levels in the LPS + T0901317 group were lower than those in the LPS group, whereas the IL‑10 levels were higher in the LPS + T0901317 group compared with those in the LPS group. The results of the present study suggested that ligand T0901317 promotes LXR‑α expression, which consequently suppresses LPS‑induced inflammation by elevating NOR‑1 expression in KCs.

Background/Aims: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. Methods: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. Results: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. Conclusion: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade. (C) 2018 The Author(s) Published by S. Karger AG, Basel

Introduction: PHYSACTO ® has demonstrated improvements in daily physical activity (PA) and PA-related symptoms in COPD patients (pts) receiving bronchodilators (BDs) ± exercise training (ExT) added to a self-management behaviour-modification programme (SMBM). Aim: To explore the impact of BDs ± ExT and SMBM on psychological and cognitive function. Methods: A 12-week (wk), randomised, partially double-blind, placebo-controlled, parallel-group trial (NCT02085161) of BDs ± ExT (tiotropium [T] 5 µg; T + olodaterol [O] 5/5 µg; T+O 5/5 µg + ExT), all with SMBM, was conducted in 304 COPD pts. Psychological outcomes included changes in levels of depression and anxiety (Hospital Anxiety and Depression Scale, HADS; Patient Health Questionnaire-9, PHQ-9) and cognitive function (Montreal Cognitive Assessment, MoCA) adjusting for age, sex, BMI, smoking, FEV 1 , and treatment group. Results: Anxiety (HADS-A -1.1), depression (HADS-D -.7, PHQ-9 -1.3) and cognitive function (MoCA +1.8) showed statistically (p Conclusions: In moderate-severe COPD, BD ± ExT with SMBM are associated with improvements in psychological and cognitive symptoms; greater improvements in depression and anxiety are associated with greater increases in PA variables. Interventions that increase daily PA may improve both physical and psychological/cognitive function in COPD pts.

According to clinical trials, azithromycin taken daily for 1 year, decreased exacerbations of chronic obstructive pulmonary disease (COPD).Effectiveness evaluation of long-term azithromycin to reduce exacerbations in severe COPD patient on optimal therapy in real-life practice.We conducted a retrospective observational study of severe COPD patients who were prescribed azithromycin (PA)(250 mg, at least 3 times weekly for at least 6 months). Comparison group included severe COPD patients not prescribed azithromycin (NPA). Data were extracted from clinical chart review.Study included 126 PA and 69 NPA patients. They had severe airflow obstruction, mostly emphysema and one-third bronchiectasis. A predominant feature in the PA group was respiratory tract colonization with Pseudomonas aeruginosa. The mean number of exacerbations per patient per year in the PA group was 3.2 ± 2.1 before initiating azithromycin, and 2.3 ± 1.6 during following year on therapy (p 0.001). Patients in the NPA group had 1.7 ± 1.3 and 2.5 ± 1.7 exacerbations during first and second follow-up year respectively (p 0.001). Exacerbation changes from pre to post differed between groups (p 0.001). Decrease in emergency visits and hospital admissions was significant in PA group. Exacerbation reductions and patient proportions having ≥2 exacerbations extended to the second year of treatment.These data showed that long-term azithromycin reduces exacerbation numbers in severe COPD patients, and benefits persist beyond one year. Desirable effects are more likely to outweigh the risks and adverse events in patients colonized with Pseudomonas aeruginosa.

Nonalcoholic steatohepatitis (NASH) is a major threat to health worldwide. Lipotoxicity and macrophage-mediated inflammation play key roles in the pathogenesis of NASH. In this study, we found that individuals with higher serum LDL-C levels have a higher prevalence of nonalcoholic fatty liver disease (NAFLD) and elevated levels of glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase and alkaline phosphatase. A logistic regression analysis revealed that serum LDL-C level is an independent risk factor for the prevalence and prognosis of NAFLD. In vitro, we used ox-LDL and MβCD-cholesterol to treat Huh7 cells and found that cholesterol loading reduced lysosomal quantity and impaired lysosomal acidification, reducing the number of multivesicular bodies (MVBs) colocalizing with lysosomes. The bafilomycin A1 inhibition of lysosomal function also inhibited lysosomal MVBs degradation, promoting the release of exosomes from the Huh7 cells. Next, we found that cholesterol loading promoted exosome release from the Huh7 cells. The exosomes from the cholesterol-loaded cells increased the ratio of the THP-1 cells positive for the M1 marker (iNOS-1) without affecting the ratio of the cells positive for the M2 marker (CD206). Moreover, an elevated level of miR-122-5p was observed in exosomes derived from the Huh7 cells loaded with cholesterol. While the miR-122-5p mimics promoted THP-1 M1 polarization, downregulating miR-122-5p in the Huh7 cells inhibited the exosome-induced activation of macrophages and macrophage-related inflammation. These findings suggest that cholesterol plays an important role in the development and progression of NASH. Cholesterol-induced lysosomal dysfunction increases exosome release from hepatocytes, resulting in M1 polarization and macrophage-induced inflammation in a miR-122-5p-dependent manner.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9–12 months (the “shorter regimen”) and individualised regimens of ≥20 months (“longer regimens”).We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD −0.15, 95% CI −0.17– −0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0–0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07–0.16), prothionamide/ethionamide (aRD 0.07, 95% CI −0.01–0.16) or ethambutol (aRD 0.09, 95% CI 0.04–0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

This is a proof of concept study that aims to establish feasibility and safety of a new strategy that includes an action plan for early treatment of acute exacerbations of COPD (AECOPD) with doubling dose of a combination of a long-acting beta2 agonist and an inhaled corticosteroid, and to explore its potential for avoiding the requirement of prednisone and its safety. Thirty-seven COPD outpatients with previous exacerbations were enrolled and followed-up for 12 months. The written action plan included a standing prescription to be used in the event of an AECOPD: Antibiotic, for 5 days (for purulent exacerbations) and doubling a combination of Salmeterol and Fluticasone Propionate for 10 days. The primary outcome was "treatment success" defined as "no need of prednisone within 30 days of the onset." Twenty-seven patients experienced an AECOPD and doubled their combination dose. Among the 27 patients, there were 21 patients (78%) who did not require prednisone, and none of those had cardiovascular events, pneumonia, ER and hospital admissions. We have assessed that an early treatment of AECOPD with doubling the dose of a combination of Salmeterol and Fluticasone Propionate appears to be safe, well-tolerated and adhered to, and results in no requirement of systemic corticosteroid in a large proportion of patients presenting with mild-to-moderate worsening of dyspnea. This trial has the potential to change the approach of treatment of AECOPD and reduce the use of oral corticosteroids.

Long-term physical activity self-monitoring in COPD patients requires the use of valid and user-friendly devices. We examined the validity and long-term usability of the Fitbit One Pedometer in COPD patients. In study A, COPD patients (n=11;FEV1%Pred 34.5 ±12;age, 69.6 ±6.5, 55% male) simultaneously wore the Fitbit one and the Actigraph GT3X activity monitor for 7 days. Study B, COPD patients (n=7;age, 63 ±6, FEV1%Pred 45±11) completed a usability questionnaire and participanted in qualitative interviews. Bland-Altman plots showed good agreement between daily step counts from the Fitbit One and the Actigraph, and intraclass correlations of 0.9 (CI: 07-0.9). Overall there was high usage, acceptability and satisfaction with the pedometer in terms of comfort and appearance and 60% of patients reported willingness to use it for longer than 12 months. Usability issues registered include replacement due to loss (n=02) and underestimation of daily stairs. Qualitative interviews revealed that COPD patients feel more empowered using a self-monitoring tool, but they have expectations to understand the accuracy of other physical activity outcomes including daily stairs, minutes active and calories. These results suggest that the Fitbit One is a valid device to count steps in COPD patients and feasible for long-term usability, but other activity outcomes from this pedometer requires further testing.

Chronic breathlessness is a multidimensional and aversive symptom, which is often poorly explained by underlying pathophysiology [1]. For many sufferers, breathlessness is refractory to maximal medical therapies that target disease processes [2]. However, opioids are thought to be a possible therapeutic avenue to treat symptomology independently of disease [3]. Importantly, research in chronic pain has demonstrated that qualities such as anxiety and depression (collectively termed negative affect here) can both exacerbate symptoms [4] and reduce opioid efficacy [5, 6]. Therefore, it may be pertinent to consider such behavioural factors when contemplating the use of opioids for breathlessness., Diminished opioid efficacy in the treatment of breathlessness is related to negative affect and anticipatory brain activity in the anterior cingulate and medial prefrontal cortex. http://bit.ly/2LXyyDo

Objective: To investigate anti-ulcerative drug ( AUD ) use in patients undergoing Arthroscopic operation against Stress ulcer (SU). Methods: A total of 297 patients undergoing Arthroscopic operation during Jan. to Aug. 2013 in our hospital were recruited and retrospectively analyzed with Excel spreadsheet. Results: Among 297 patients in the study, ninety-four patients (31.6%) used AUD before operation, most (94.9%) administered by intravenous, and drug utilization index(DUI) was 1.35. Ninety-eight point nine patients used proton pump inhibitors (PPIs) in which Lansoprazole was prescribed most. Conclusion: This study highlights the overuse of PPIs in patients undergoing Arthroscopic operation