Personalised multicomponent interventions for tobacco dependence management in low socioeconomic populations: a systematic review and meta-analysis.

BACKGROUND: There remains a disproportionally high tobacco smoking rate in low-income populations. Multicomponent tobacco dependence interventions in theory are effective. However, which intervention components are necessary to include for low socioeconomic status (SES) populations is still unknown. OBJECTIVE: To assess the effectiveness of multicomponent tobacco dependence interventions for low SES and create a checklist tool examining multicomponent interventions. METHODS: EMBASE and MEDLINE databases were searched to identify randomised controlled trials (RCTs) published with the primary outcome of tobacco smoking cessation measured at 6 months or post intervention. RCTs that evaluated tobacco dependence management interventions (for reduction or cessation) in low SES (experience of housing insecurity, poverty, low income, unemployment, mental health challenges, illicit substance use and/or food insecurity) were included. Two authors independently abstracted data. Random effects meta-analysis and post hoc sensitivity analysis were performed. RESULTS: Of the 33 included studies, the number of intervention components ranged from 1 to 6, with smoking quit rates varying between 1% and 36.6%. Meta-analysis revealed that both the 6-month and 12-month outcome timepoints, multicomponent interventions were successful in achieving higher smoking quit rates than the control (OR 1.64, 95% Cl 1.41 to 1.91; OR 1.74, 95% Cl 1.30 to 2.33). Evidence of low heterogeneity in the effect size was observed at 6-month (I2=26%) and moderate heterogeneity at 12-month (I2=56%) outcomes. CONCLUSION: Multicomponent tobacco dependence interventions should focus on inclusion of social support, frequency and duration of components. Employing community-based participatory-action research approach is essential to addressing underlying psychosocioeconomic-structural factors, in addition to the proven combination pharmacotherapies. PROSPERO REGISTRATION NUMBER: CRD42017076650.

Prevalence and burden of obstructive lung disease in the urban poor population of Ottawa, Canada: a community-based mixed-method, observational study.

BACKGROUND: Globally the burden of Obstructive Lung Diseases (OLD) is growing, however its effect on urban poor populations with the high prevalence of tobacco dependence is virtually unknown. The purpose of this project is to estimate the prevalence and burden of OLD in the urban, low-income populations of Ottawa, Canada. METHODS: The study presented in this paper was part of the PROMPT (Management and Point-of-Care for Tobacco Dependence) project; a prospective cohort study in a community-based setting (n = 80) with meaningful Patient Engagement from design to dissemination. Spirometry data, standardized questionnaires and semi-structured interviews from PROMPT were interpreted to understand the lung function, disease burden and social determinants (respectively) in this population. RESULTS: The prevalence of OLD among those who completed spirometry (N = 64) was 45-59%. Generic and disease-specific quality of life was generally poor in all PROMPT participants, even those without OLD, highlighting the higher disease burden this vulnerable population faces. Quality of life was impacted by two major themes, including i) socioeconomic status and stress and ii) social networks and related experiences of trauma. CONCLUSION: The prevalence and disease burden of OLD is significantly higher in Ottawa's urban poor population than what is observed in the general Canadian population who smoke, suggesting an etiological role of the social determinants of health. This urges the need for comprehensive care programs addressing up-stream factors leading to OLDs, including poor access and utilization of preventive healthcare addressing the social determinants of health. TRIAL REGISTRATION: ClinicalTrails.gov - NCT03626064 , Retrospective registered: August 2018.

The Safety and Efficacy of Marijuana in Persons Living with HIV.

The prevalence of the use of marijuana throughout the world is substantial. In light of ongoing increases in accessibility to marijuana, safety and efficacy must be established to guide recommendations for safe use. Of particular interest is at-risk populations such as persons living with HIV (PLWH) in whom there are higher rates of marijuana use and inherent risks of comorbid conditions. Databases and reference lists were searched for relevant studies investigating marijuana or cannabinoid use, HIV, and/or pulmonary diseases. The effect of marijuana on the human body is complex and not yet fully understood. The principal components, tetrahydrocannabinol, and cannabidiol interact with cannabinoid receptors. As some cannabinoid receptors are located in the immune system, many have investigated the effect of marijuana on the immune system. Although marijuana would appear to have anti-inflammatory properties, there are conflicting findings on its immune effect in PLWH. In the lung, marijuana smoke is thought to cause harm. Marijuana smokers have shown increased rates of respiratory symptoms, and a variety of changes on lung function has been reported. Limited data are available specific to the safety of marijuana on the lung, cognition, malignancy risk, and cardiovascular disease in PLWH who are already at increased risk of chronic diseases. Marijuana use is common in PLWH, but significant research gaps exist with regard to its safety and efficacy. Until further evidence on its safety is available, recommendations should be to avoid the use in PLWH.

Assessing community (peer) researcher's experiences with conducting spirometry and being engaged in the 'Participatory Research in Ottawa: Management and Point-of-care for Tobacco-dependence' (PROMPT) project.

PLAIN SUMMARY: This article examines the overall experiences of community researchers in their involvement with the 'PROMPT' project for smoking cessation, which targeted community members who were homeless or at-risk for homelessness. More specifically, four community members, representing the study population were involved in the project as researchers. They were asked to complete surveys at both the beginning and end of each research training session to better understand their learning as it related to using a key instrument for this project, a spirometer, to measure project participants' lung function. Spirometry is typically performed by trained healthcare providers. Community researchers were also interviewed to explore what their experiences were like working as a researcher with their own at-risk community. Although the researchers felt that the training was sufficient, more research is needed to evaluate training effectiveness among community researchers in delivering acceptable quality lung function testing using a spirometer. Upon analyzing the small group discussion and survey results, we found that the community researchers had an overall positive experience with both the project, and the training that was provided to equip them with the knowledge, tools, and resources they needed to successfully work in a research project of this kind. They also faced challenges that are common in such community-based projects, such as the power differential between the researchers with a healthcare background and themselves who have lived experience with the issue at hand. ABSTRACT: Background The Ottawa Citizen Engagement and Action Model (OCEAM) used a Community Based Participatory Action Research (CBPAR) approach by involving the most at-risk urban population. Community (peer) researchers participated in every step of the study despite the multiple challenges. Objective To assess the community researchers' training and experiences in a CBPAR project, PROMPT: Participatory Research in Ottawa: Management and Point-of-care for Tobacco Dependence. Method Four community researchers were recruited, representative of the PROMPT project's target population with current or past poly-substance use; smoking tobacco; and/or being homeless or at-risk for homelessness. The community researchers participated in all phases of PROMPT, including study design, development of questionnaires, participant recruitment, administering consent forms and questionnaires, as well as hand-held spirometry after rigorous training. To assess their knowledge and comfort level with spirometry testing after standardized training, questionnaires were administered pre- and post-training. In turn, to assess their overall experience, interviews were conducted at the end of study completion. Results All community researchers underwent small-group training sessions including presentations, discussions and hands-on practice adapted from standardized training material prepared for health care professionals. Spirometry training was included in all sessions. Self-perceived knowledge and confidence in administering spirometry, as well as skill-testing score averages improved between the pre- and post-training questionnaires. Overall, all the community researchers had a fulfilling experience participating in the project. Conclusion Despite challenges, involving community researchers with lived experience is feasible, satisfying and productive even in the most marginalized populations. Standardized spirometry training of community researchers' representative of the PROMPT target population, with no healthcare educational background, was feasible and effective in improving knowledge, confidence and readiness to administer spirometry.

Management and Point-of-Care for Tobacco Dependence (PROMPT): a feasibility mixed methods community-based participatory action research project in Ottawa, Canada.

OBJECTIVE: To determine the feasibility of a Community-Based Participatory Tobacco Dependence Strategy (PROMPT) in the inner city population of Ottawa (Canada). DESIGN: A feasibility mixed methods prospective cohort study following principles of community-based participatory action research. INTERVENTION: Recruited 80 people whouse drugs, followed them for 6 months while providing access to counselling, nicotine replacement therapy and peer-support in a community setting. SETTING: Community research office in downtown Ottawa, adjacent to low-income housing, shelter services and street-based drug consumption. PRIMARY OUTCOME: Retention rate at 6-month follow-up. SECONDARY OUTCOME: Biochemically validated 7-day point prevalence smoking abstinence at 26 weeks, self-reported abstinence in the past 7 days with exhaled carbon monoxide ≤10 ppm. RESULTS: The average age of participants was 43.8 years. The 6-month follow-up rate was 42.5%. The mean number of smoking years reported was 27.3 years. The participants were 70% male, 33.7% reported less than a high-school education, 21% identified as indigenous and 43.8% reported an income between US$1000 and US$1999 per month. The baseline mean daily cigarette use was 20.5 and 9.3 cigarettes at study end, with mean reduction of 11.2 cigarettes at 6 months (P=0.0001). There was a considerable reduction in self-reported illicit substance use (18.8%), including a reduction in the opioids heroin (6.3%), fentanyl (2.6%) and Oxycontin (3.8%). The study findings also reveal psycho-socioeconomic benefits such as improved health, return to work and greater community engagement. CONCLUSIONS: The PROMPT project describes socioeconomic variables associated with tobacco and polysubstance use. A programme focused on tobacco dependence, easily accessible in the community and led by community peers with lived experience is feasible to implement and has the potential to support positive life changes. PROMPT's patient engagement model is an effective harm-reduction strategy for the growing opioid use crisis and can improve the health outcomes of marginalised at-risk populations worldwide.

RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation.

Novel anti-inflammatory approaches targeting chronically activated kinase pathways in chronic obstructive pulmonary disease (COPD) are needed. We evaluated RV568, a p38 mitogen-activated protein kinase-α and -γ and SRC family kinase inhibitor, in cellular and in vivo models relevant to COPD and examined its safety and efficacy in COPD patients.The anti-inflammatory activities of RV568 were tested in primary cultured monocytes, macrophages and bronchial epithelial cells and in vivo in lipopolysaccharide and cigarette smoke-exposed murine models. RV568 was evaluated in a 14-day trial in COPD patients.RV568 showed potent anti-inflammatory effects in monocytes and macrophages, which were often greater than those of corticosteroids or the p38 inhibitor Birb796. RV568 combined with corticosteroid had anti-inflammatory effects suggestive of a synergistic interaction in poly I:C-stimulated BEAS-2B cells and in the cigarette smoke model. In COPD patients, inhaled RV568 (50 µg and 100 µg) improved pre-bronchodilator forced expiratory volume in 1 s (69 mL and 48 mL respectively) and significantly reduced sputum malondialdehyde (p<0.05) compared to placebo, although there were no changes in sputum cell counts. Adverse events during RV568 and placebo treatment were similar.RV568 shows potent anti-inflammatory effects on cell and animal models relevant to COPD. RV568 was well-tolerated and demonstrated a modest clinical benefit in a 14-day COPD clinical trial.

The role of airway hyperresponsiveness measured by methacholine challenge test in defining asthma severity in asthma-obesity syndrome.

PURPOSE OF REVIEW: Asthma is a complex disease defined by chronic inflammation of the airways. In research and clinical practice measures used for diagnosis, an assessment of control and severity of asthma are varied and there exists no gold standard. To date, several studies have explored the link between obesity and asthma although the exact mechanism is not yet fully understood. A study undertaken by our research group in 2015, on the effects of weight loss on asthma severity in obese asthmatics, demonstrated that an improvement in airway hyperresponsiveness could be achieved after significant weight reduction with a weight loss program. The objective of this article is to review the current literature for the primary and secondary outcomes studied to estimate the effects of weight loss on asthma severity in adults with obesity and asthma. RECENT FINDINGS: A review of the most recent research conducted since 2014 demonstrates that effects of weight loss on asthma severity in adults with obesity and asthma has not been the focus of majority of the studies. Apart from our study published in 2015, very few studies used airway hyperresponsiveness as the primary or secondary outcome measure. The literature reveals that significant weight loss does, however, lead to improvement in asthma severity and control in adults with obesity and asthma. SUMMARY: The current literature suggests that improvement in lung function requires moderate to significant (5-10%) weight loss in adults with obesity and asthma. However, with a few exceptions, the majority of these studies were small and used variable and questionable asthma severity outcome measures. There is an urgent need for standardization of diagnosis of asthma, study inclusion criteria, and outcome measures to assess asthma severity in research setting. Long-term effects of weight loss interventions on asthma severity and control, in adults with obesity and asthma, also remain unanswered.

Discovery of Narrow Spectrum Kinase Inhibitors: New Therapeutic Agents for the Treatment of COPD and Steroid-Resistant Asthma.

The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.

Atorvastatin in combination with inhaled beclometasone modulates inflammatory sputum mediators in smokers with asthma.

BACKGROUND: Statins have pleiotropic immunomodulatory effects that may be beneficial in the treatment of asthma. We previously reported that treatment with atorvastatin improved asthma symptoms in smokers with asthma in the absence of a change in the concentration of a selection of sputum inflammatory mediators. OBJECTIVE: To determine the effects of atorvastatin alone and in combination with inhaled corticosteroid on a range of sputum cytokines, chemokines and growth factors implicated in the pathogenesis of asthma, and their association with asthma control questionnaire (ACQ) and/or asthma quality of life questionnaire (AQLQ) scores. METHODS: Sputum samples were analysed from a sub-group of 39 smokers with mild to moderate asthma recruited to a randomised controlled trial comparing atorvastatin (40 mg/day) versus placebo for four weeks, followed by inhaled beclometasone (400 µg/day) for a further four weeks. Induced sputum supernatant fluid was analysed (Luminex or biochemical analyses) for concentrations of 35 mediators. RESULTS: Sputum mediator concentrations were not reduced by inhaled beclometasone alone. Atorvastatin significantly reduced sputum concentrations of CCL7, IL-12p70, sCD40L, FGF-2, CCL4, TGF-α and MMP-8 compared with placebo and, when combined with inhaled beclometasone, reduced sputum concentrations of MMP-8, IL-1ß, IL-10, MMP-9, sCD40L, FGF-2, IL-7, G-CSF and CCL7 compared to ICS alone. Improvements in ACQ and/or AQLQ scores with atorvastatin and ICS were associated with decreases in G-CSF, IL-7, CCL2 and CXCL8. CONCLUSION: Short-term treatment with atorvastatin alone or in combination with inhaled beclometasone reduces several sputum cytokines, chemokines and growth factors concentrations unresponsive to inhaled corticosteroids alone, in smokers with asthma.

Defect of adaptation to hypoxia in patients with COPD due to reduction of histone deacetylase 7.

BACKGROUND: Hypoxia inducible factor (HIF)-1 plays an important role in cellular adaptation to hypoxia by activating oxygen-regulated genes such as vascular endothelial growth factor (VEGF) and erythropoietin. Sputum VEGF levels are reported to be decreased in COPD, despite hypoxia. Here we show that patients with COPD fail to induce HIF-1α and VEGF under hypoxic condition because of a reduction in histone deacetylase (HDAC) 7. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with moderate to severe COPD (n = 21), smokers without COPD (n = 12), and nonsmokers (n = 15). PBMCs were exposed to hypoxia (1% oxygen, 5% CO(2), and 94% N(2)) for 24 h, and HIF-1α and HDAC7 protein expression in nuclear extracts were determined by sodium dodecyl sulfate poly acrylamide gel electrophoresis (SDS-PAGE)/Western blotting. RESULTS: HIF-1α was significantly induced by hypoxia in each group when compared with the normoxic condition (12-fold induction in nonsmokers, 24-fold induction in smokers without COPD, fourfold induction in COPD), but induction of HIF-1α under hypoxia was significantly lower in patients with COPD than in nonsmokers and smokers without COPD (P < .05 and P < .01, respectively). VEGF messenger RNA detected by quantitative real-time polymerase chain reaction was correlated with HIF-1α protein in nuclei (r = 0.79, P < .05), and HDAC7 protein expression was correlated with HIF-1α protein in nuclei (r = 0.46, P < .05). HDAC7 knockdown inhibited hypoxia-induced HIF-1α activity in U937 cells, and HIF-1α nuclear translocation and HIF-1α binding to the VEGF promoter in A549 cells. CONCLUSIONS: HDAC7 reduction in COPD causes a defect of HIF-1α induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD.

Hypoxia-inducible factor 1alpha induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription.

Corticosteroids are potent anti-inflammatory agents, but corticosteroid insensitivity is a major barrier for the treatment of some chronic inflammatory diseases. Here, we show that hypoxia induces corticosteroid-insensitive inflammation via reduced transcription of histone deacetylase-2 (HDAC2) in lung epithelial and macrophage cells. HDAC2 mRNA and protein expression was reduced under hypoxic conditions (1% O(2)). Hypoxia enhanced interleukin-1beta-induced interleukin-8 (CXCL8) production in A549 cells and decreased the ability of dexamethasone to suppress the CXCL8 production. Deletion or point mutation studies revealed that binding of the transcription factor hypoxia-inducible factor (HIF) 1alpha to a HIF response element at position -320, but not HIF-1beta or HIF-2alpha, results in reduced polymerase II binding at the site, leading to reduced promoter activity of HDAC2. Our results suggest that activation of HIF-1alpha by hypoxia decreases HDAC2 levels, resulting in amplified inflammation and corticosteroid resistance.

Impact of protein acetylation in inflammatory lung diseases.

Chronic inflammatory lung diseases are characterized by increased expression of multiple inflammatory genes following activation by proinflammatory transcription factors, such as nuclear factor kappaB (NF-kappaB) and AP-1. Gene expression is, at least in part, regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein (CBP), which have intrinsic histone acetyltransferase (HAT) activity. Conversely gene repression is mediated via a combination of histone deacetylases (HDAC) and other corepressors. In asthma, the level of HAT activity is elevated in bronchial biopsies, whereas HDAC activity levels are only partially reduced and inhaled corticosteroids are able to reduce the increased HAT activity back to those seen in normal subjects. In contrast, in chronic obstructive pulmonary disease (COPD), there is a greater reduction in HDAC activity and HDAC2 expression but no difference in HAT activity. HAT and HDAC are also reported to modify a large and expanding number of nonhistone proteins, including nuclear import proteins, chaperones, cytoskeletal proteins, and other transcriptional factors, such as NF-kappaB and signal transducer and activation of transcription (STAT). Acetylation regulates several aspects of protein function and stability leading to differing effects on inflammatory gene expression and cell recruitment involved in the pathogenesis of inflammatory diseases. This review will examine the impact of acetylation on the function of key proteins involved in airway inflammatory disease and the effects of current therapies on acetylation status of key proteins. Further appreciation of the role of these changes may lead to the development of novel therapeutic approaches to inflammatory lung diseases that are currently difficult to treat.

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah(enu2) mice.

Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah(enu2) mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah(enu2) mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah(enu2) mice and corresponded to rapid reduction of serum Phe levels.

Mode of glucocorticoid actions in airway disease.

Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5%) of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD) do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR), which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.