The Lung Microbiome Predicts Mortality and Response to Azithromycin in Lung Transplant Recipients with Chronic Rejection.

Rationale: Chronic lung allograft dysfunction (CLAD) is the leading cause of death after lung transplant, and azithromycin has variable efficacy in CLAD. The lung microbiome is a risk factor for developing CLAD, but the relationship between lung dysbiosis, pulmonary inflammation, and allograft dysfunction remains poorly understood. Whether lung microbiota predict outcomes or modify treatment response after CLAD is unknown. Objectives: To determine whether lung microbiota predict post-CLAD outcomes and clinical response to azithromycin. Methods: Retrospective cohort study using acellular BAL fluid prospectively collected from recipients of lung transplant within 90 days of CLAD onset. Lung microbiota were characterized using 16S rRNA gene sequencing and droplet digital PCR. In two additional cohorts, causal relationships of dysbiosis and inflammation were evaluated by comparing lung microbiota with CLAD-associated cytokines and measuring ex vivo P. aeruginosa growth in sterilized BAL fluid. Measurements and Main Results: Patients with higher bacterial burden had shorter post-CLAD survival, independent of CLAD phenotype, azithromycin treatment, and relevant covariates. Azithromycin treatment improved survival in patients with high bacterial burden but had negligible impact on patients with low or moderate burden. Lung bacterial burden was positively associated with CLAD-associated cytokines, and ex vivo growth of P. aeruginosa was augmented in BAL fluid from transplant recipients with CLAD. Conclusions: In recipients of lung transplants with chronic rejection, increased lung bacterial burden is an independent risk factor for mortality and predicts clinical response to azithromycin. Lung bacterial dysbiosis is associated with alveolar inflammation and may be promoted by underlying lung allograft dysfunction.

Genetic deficiency of the transcription factor NFAT1 confers protection against fibrogenic responses independent of immune influx.

Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple profibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor nuclear factor of activated T cells 1 (NFAT1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key profibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/--deficient mice subjected to bleomycin injury demonstrated improved survival and protection from lung fibrosis and collagen deposition as compared with bleomycin-injured wild-type (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WT→WT and Nfat1-/-→WT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibroprotection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/platelet-derived growth factor receptor alpha (PDGFRα)pos MCs demonstrated decreased MC numbers, proliferation [↓ cyclin D1 and 5-ethynyl-2'-deoxyuridine (EdU) incorporation], myofibroblast differentiation [↓ α-smooth muscle actin (α-SMA)], and survival (↓ Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed using pharmacological and genetic inhibition. Our findings identify NFAT1 as a critical mediator of profibrotic processes, contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.NEW & NOTEWORTHY Idiopathic pulmonary fibrosis (IPF) is a fatal disease with hallmarks of fibroblastic foci and exuberant matrix deposition, unknown etiology, and ineffective therapies. Several profibrotic/proinflammatory pathways are implicated in accelerating tissue remodeling toward a honeycombed end-stage disease. NFAT1 is a transcriptional factor activated in IPF tissues. Nfat1-deficient mice subjected to chronic injury are protected against fibrosis independent of immune influxes, with suppression of profibrotic mesenchymal phenotypes including proliferation, differentiation, resistance to apoptosis, and autotaxin-related migration.

Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis.

Histopathologic evidence of deployment-related constrictive bronchiolitis (DRCB) has been identified in soldiers deployed to Southwest Asia. While inhalational injury to the airway epithelium is suspected, relatively little is known about the pathogenesis underlying this disabling disorder. Club cells are local progenitors critical for repairing the airway epithelium after exposure to various airborne toxins, and a prior study using an inducible transgenic murine model reported that 10 days of sustained targeted club cell injury causes constrictive bronchiolitis. To further understand the mechanisms leading to small airway fibrosis, a murine model was employed to show that sustained club cell injury elicited acute weight loss, caused increased local production of proinflammatory cytokines, and promoted accumulation of numerous myeloid cell subsets in the lung. Transition to a chronic phase was characterized by up-regulated expression of oxidative stress-associated genes, increased activation of transforming growth factor-ß, accumulation of alternatively activated macrophages, and enhanced peribronchiolar collagen deposition. Comparative histopathologic analysis demonstrated that sustained club cell injury was sufficient to induce epithelial metaplasia, airway wall thickening, peribronchiolar infiltrates, and clusters of intraluminal airway macrophages that recapitulated key abnormalities observed in DRCB. Depletion of alveolar macrophages in mice decreased activation of transforming growth factor-ß and ameliorated constrictive bronchiolitis. Collectively, these findings implicate sustained club cell injury in the development of DRCB and delineate pathways that may yield biomarkers and treatment targets for this disorder.

Vitamin D supplementation in children and young adults with persistent proteinuria secondary to glomerular disease.

BACKGROUND: Vitamin D deficiency is common in glomerular disease. Supplementation may be ineffective due to ongoing urinary losses of vitamin D binding protein. We sought to determine if daily cholecalciferol supplementation would increase vitamin D concentrations in children with glomerular disease and persistent proteinuria, without adverse effects. METHODS: Eighteen participants at least 5 years of age with primary glomerular disease and urine protein:creatinine ratio ≥ 0.5 were enrolled from four pediatric nephrology practices to receive cholecalciferol supplementation: 4,000 IU or 2,000 IU per day for serum 25 hydroxyvitamin vitamin D (25OHD) concentrations < 20 ng/mL and 20 ng/mL to < 30 ng/mL, respectively. Measures of vitamin D and mineral metabolism were obtained at baseline and weeks 6 and 12. Multivariable generalized estimating equation (GEE) regression estimated mean percent changes in serum 25OHD concentration. RESULTS: Median baseline 25OHD was 12.8 ng/mL (IQR 9.3, 18.9) and increased to 27.8 ng/mL (20.5, 36.0) at week 6 (p < 0.001) without further significant increase at week 12. A total of 31% of participants had a level ≥ 30 ng/mL at week 12. Supplementation was stopped in two participants at week 6 for mildly elevated calcium and phosphorus, respectively, with subsequent declines in 25OHD of > 20 ng/mL. In the adjusted GEE model, 25OHD was 102% (95% CI: 64, 141) and 96% (95% CI: 51, 140) higher versus baseline at weeks 6 and 12, respectively (p < 0.001). CONCLUSION: Cholecalciferol supplementation in vitamin D deficient children with glomerular disease and persistent proteinuria safely increases 25OHD concentration. Ideal dosing to fully replete 25OHD concentrations in this population remains unknown. CLINICAL TRIAL: NCT01835639. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effectiveness of nicotine salt vapes, cytisine, and a combination of these products, for smoking cessation in New Zealand: protocol for a three-arm, pragmatic, community-based randomised controlled trial.

BACKGROUND: Combining short-acting nicotine replacement therapy with varenicline increases smoking cessation rates compared with varenicline alone, but not all people tolerate these medications or find them helpful. We aim to investigate the therapeutic potential of an analogous combination, by evaluating the effectiveness, safety, and acceptability of combining nicotine salt e-cigarettes with cytisine, compared to nicotine salt e-cigarettes or cytisine only, on smoking abstinence at six months. METHODS: A pragmatic, community-based, investigator-blinded, randomised superiority trial design will be utilised. Eligible participants will be people who smoke daily (N = 800, 90% power) from throughout New Zealand, who are: aged ≥ 18 years, motivated to quit in the next two weeks, able to provide online consent, willing to use e-cigarettes and/or cytisine, and have daily access to a mobile phone. Recruitment will utilise multi-media advertising. Participants will be randomised (3:3:2 ratio) to 12 weeks of: 1) e-cigarettes (closed pod system, 3% nicotine salt, tobacco flavour) plus cytisine; 2) e-cigarettes alone, or 3) cytisine alone. All groups will receive a six-month, text-message-based behavioural support programme. The primary outcome is self-reported, biochemically verified, continuous abstinence at six months post-quit date. Secondary outcomes, measured at quit date, then one, three, six, and 12 months post-quit date, include self-reported continuous abstinence, 7-day point prevalence abstinence, cigarettes smoked per day, withdrawal and urge to smoke, time to (re)lapse, treatment use and compliance, treatment crossover, dual-use, use of other cessation products, change in e-cigarette products, continuation of product use, acceptability, change in health state, health-related quality of life, change in body mass index, adverse events, and cost per quitter. DISCUSSION: Pragmatic trials are of particular value as they reflect the 'real world' impact of interventions. The trial will provide some of the first evidence on the effectiveness of combining nicotine salt e-cigarettes with cytisine for smoking cessation, in a country with strong tobacco control policy. Findings will be incorporated into relevant systematic reviews, informing practice and policy. TRIAL REGISTRATION: NCT05311085 ClinicalTrials.gov. Registered 5th April, 2022.

A Pragmatic Randomized Comparative Trial of e-Cigarettes and Other Nicotine Products for Quitting or Long-Term Substitution in Smokers.

INTRODUCTION: Tobacco harm reduction has potential to improve individual and population health. However, little research exists on low-intensity interventions, such as encouraging longer-term NRT or e-cigarette use. We aimed to determine whether: (1) encouraging use of nicotine products as long-term tobacco substitutes is more effective for smoking abstinence than standard treatment, and (2) offering e-cigarettes is more effective than NRT. METHODS: An open-label, parallel-group randomized trial was conducted in Australia between 2014 and 2015, with 1563 adult daily smokers, randomized to: (A) standard cessation advice and NRT: advice to use NRT short-term, (B) quit or substitute advice and NRT: advice to use NRT as a longer-term substitute for smoking if required to maintain smoking cessation, or (C) Quit or substitute advice and NRT and/or e-cigarettes. Participants were offered an initial supply of products they could then purchase for up to 7 months. The primary outcome was self-reported continuous smoking abstinence at 7 months. Point prevalence, dual use, and cigarette reduction were secondary outcomes. RESULTS: At 7 months, 2.8% (N = 9) of group A (N = 324) were abstinent, compared with 1.8% (N = 11) in B (N = 620) and 1.3% (N = 8) in C (N = 619) (adjusted odds ratio [ORs]: B vs. A 0.66, 95% confidence interval [CI]: 0.27-1.63; C vs. A 0.46, 95% CI: 0.17-1.21; C vs. B 0.69, 95% CI 0.27-1.73). There were no suspected unexpected serious adverse reactions associated with trial products. CONCLUSION: A free trial of NRT and first generation e-cigarettes and advice on long-term substitution was no better for smoking abstinence than usual care. CLINICAL TRIAL REGISTRATION: The trial was registered with the Australian Therapeutic Goods Administration under their Clinical Trials Notification scheme and the Australian and New Zealand Clinical Trials Registry (ACTRN12612001210864). IMPLICATIONS: This pragmatic trial allowed the comparison of existing and alternative policy options under semi-realistic conditions, such as product choice and financial cost. All trial arms had low rates of smoking cessation. The findings suggest that providing unflavored cigalike e-cigarettes without additional support may not increase quitting compared with advice to use standard NRT in a general population of Australians who smoke. More intensive support and education, and/or opportunity to try a range of e-cigarette products, may be required to motivate quit attempts using e-cigarettes.

Closing the gaps in tobacco endgame evidence: a scoping review.

OBJECTIVE: Tobacco endgame policies aim to rapidly and permanently reduce smoking to minimal levels. We reviewed evidence syntheses for: (1) endgame policies, (2) evidence gaps, and (3) future research priorities. DATA SOURCES: Guided by JBI scoping review methodology, we searched five databases (PubMed, CINAHL, Scopus, Embase and Web of Science) for evidence syntheses published in English since 1990 on 12 policies, and Google for publications from key national and international organisations. Reference lists of included publications were hand searched. STUDY SELECTION: Two reviewers independently screened titles and abstracts. Inclusion criteria were broad to capture policy impacts (including unintended), feasibility, public and stakeholder acceptability and other aspects of policy implementation. DATA EXTRACTION: We report the results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. DATA SYNTHESIS: Eight policies have progressed to evidence synthesis stage (49 publications): mandatory very low nicotine content (VLNC) standard (n=26); product standards to substantially reduce consumer appeal or remove the most toxic products from the market (n=1); moving consumers to reduced risk products (n=8); tobacco-free generation (n=4); ending sales (n=2); sinking lid (n=2); tax increases (n=7); and restrictions on tobacco retailers (n=10). Based on published evidence syntheses, the evidence base was most developed for a VLNC standard, with a wide range of evidence synthesised. CONCLUSIONS: VLNC cigarettes have attracted the most attention, in terms of synthesised evidence. Additional focus on policies that reduce the availability of tobacco is warranted given these measures are being implemented in some jurisdictions.

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.

Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy. Objective: To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation. Design, Setting, and Participants: This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome. Interventions: Treatments were provided in accordance with the manufacturers' recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support. Main Outcomes and Measures: The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025. Results: Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, -1.62% [1-sided 97.5% CI, -5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002). Conclusions and Relevance: Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation. Trial Registration: anzctr.org.au Identifier: ACTRN12616001654448.

Betel Nut Use in Vanuatu: Investigating Opportunities to Reduce Harms to Health.

Background: Betel nut chewing is a public health concern in the Asia-Pacific region and is an emerging issue in Vanuatu. Despite the significant health risks associated with betel nut chewing, few interventions have been undertaken to reduce its harm. Objectives: To investigate betel nut use in Vanuatu and to identify opportunities to reduce its harm and possible interventions, framing the responses using the World Health Organization's MPOWER tobacco control model. Method: Qualitative research design, in the form of semi-structured interviews with ten participants with expertise in health, agriculture, education or non-communicable disease in Port Vila, Vanuatu during June 2017. Recorded interviews were transcribed verbatim, and a general inductive approach was used to identify key themes. Results: Participants reported a recent increase in betel nut use in Vanuatu due to the influence from Papua New Guinea and the Solomon Islands. To reduce the harm of betel nut use in Vanuatu, participants suggested policies and strategies that aligned with the MPOWER framework that could be adopted for betel nut control, including restricting cultivation and sale of betel nut in Vanuatu and using radio and existing community networks to reach people with messages about the dangers of betel nut use. Conclusion: Betel nut use may be growing in popularity in Vanuatu, where there are potential policy options to minimize harm. The MPOWER model for tobacco control may be a useful framework to help the Vanuatu government to deliver a comprehensive approach to reducing harm from betel nut use.

c-Jun N-terminal kinase (JNK)-mediated induction of mSin1 expression and mTORC2 activation in mesenchymal cells during fibrosis.

Mammalian target of rapamycin complex 2 (mTORC2) has been shown to regulate mTORC1/4E-BP1/eIF4E signaling and collagen I expression in mesenchymal cells (MCs) during fibrotic activation. Here we investigated the regulation of the mTORC2 binding partner mammalian stress-activated protein kinase-interacting protein 1 (mSin1) in MCs derived from human lung allografts and identified a novel role for mSin1 during fibrosis. mSin1 was identified as a common downstream target of key fibrotic pathways, and its expression was increased in MCs in response to pro-fibrotic mediators: lysophosphatidic acid (LPA), transforming growth factor ß, and interleukin 13. Fibrotic MCs had higher mSin1 protein levels than nonfibrotic MCs, and siRNA-mediated silencing of mSIN1 inhibited collagen I expression and mTORC1/2 activity in these cells. Autocrine LPA signaling contributed to constitutive up-regulation of mSin1 in fibrotic MCs, and mSin1 was decreased because of LPA receptor 1 siRNA treatment. We identified c-Jun N-terminal kinase (JNK) as a key intermediary in mSin1 up-regulation by the pro-fibrotic mediators, as pharmacological and siRNA-mediated inhibition of JNK prevented the LPA-induced mSin1 increase. Proteasomal inhibition rescued mSin1 levels after JNK inhibition in LPA-treated MCs, and the decrease in mSin1 ubiquitination in response to LPA was counteracted by JNK inhibitors. Constitutive JNK1 overexpression induced mSin1 expression and could drive mTORC2 and mTORC1 activation and collagen I expression in nonfibrotic MCs, effects that were reversed by siRNA-mediated mSIN1 silencing. These results indicate that LPA stabilizes mSin1 protein expression via JNK signaling by blocking its proteasomal degradation and identify the LPA/JNK/mSin1/mTORC/collagen I pathway as critical for fibrotic activation of MCs.

Behavioral and Subjective Effects of Reducing Nicotine in Cigarettes: A Cessation Commentary.

This commentary addresses critical questions regarding the impact of the reduction of nicotine on changes in smoking behavior. There appears to be moderate evidence that use of reduced nicotine cigarettes (RNC) increases the likelihood of making a quit attempt among smokers unmotivated to quit and among smokers motivated to quit who also used nicotine replacement therapy (NRT). There was limited evidence that RNC combined with NRT increased smoking abstinence, regardless of motivation to quit. Several plausible mechanisms via which RNC may influence smoking behavior, including reducing dependence, are reviewed. The moderate evidence that abrupt reduction in nicotine reduces self-reported dependence as well as smoking behavior and likelihood of relapse is also reviewed. The data reviewed here suggest that abrupt switching to, and extended use of, RNC can reduce cigarette dependence and several related constructs, including the ability to quit smoking. The data reviewed in this commentary suggest that abrupt reduction in the level of nicotine in combustible cigarettes could reduce smoking behavior, nicotine dependence, and other related constructs and increase quit attempts and eventual smoking cessation.

Hypnotherapy for smoking cessation.

BACKGROUND: Hypnotherapy is widely promoted as a method for aiding smoking cessation. It is intended to act on underlying impulses to weaken the desire to smoke, or strengthen the will to stop. OBJECTIVES: To evaluate the effect and safety of hypnotherapy for smoking cessation. SEARCH METHODS: For this update we searched the Cochrane Tobacco Addiction Group Specialized Register, and trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform), using the terms "smoking cessation" and "hypnotherapy" or "hypnosis", with no restrictions on language or publication date. The most recent search was performed on 18 July 2018. SELECTION CRITERIA: We considered randomized controlled trials that recruited people who smoked and implemented a hypnotherapy intervention for smoking cessation compared with no treatment, or with any other therapeutic interventions. Trials were required to report smoking cessation rates at least six months after the beginning of treatment. Study eligibility was determined by at least two review authors, independently. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data on participant characteristics, the type and duration of hypnotherapy, the nature of the control group, smoking status, method of randomization, and completeness of follow-up. These authors also independently assessed the quality of the included studies. In undertaking this work, we used standard methodological procedures expected by Cochrane.The main outcome measure was abstinence from smoking after at least six months' follow-up. We used the most rigorous definition of abstinence in each trial, and biochemically validated abstinence rates where available. Those lost to follow-up were considered to still be smoking. We summarized effects as risk ratios (RRs) and 95% confidence intervals (CIs). Where possible, we performed meta-analysis using a fixed-effect model. We also noted any adverse events reported. MAIN RESULTS: We included three new trials in this update, which brings the total to 14 included studies that compared hypnotherapy with 22 different control interventions. The studies included a total of 1926 participants. Studies were diverse and a single meta-analysis was not possible. We judged only one study to be at low risk of bias overall; we judged 10 studies to be at high risk of bias and three at unclear risk. Studies did not provide reliable evidence of a greater benefit from hypnotherapy compared with other interventions or no treatment for smoking cessation. Most individual studies did not find statistically significant differences in quit rates after six months or longer, and studies that did detect differences typically had methodological limitations.Pooling small groups of relatively comparable studies did not provide reliable evidence for a specific effect of hypnotherapy relative to controls. There was low certainty evidence, limited by imprecision and risk of bias, that showed no statistically significant difference between hypnotherapy and attention-matched behavioural treatments (RR 1.21, 95% CI 0.91 to 1.61; I2 = 36%; 6 studies, 957 participants). Results were similarly imprecise, and also limited by risk of bias, when comparing hypnotherapy to intensive behavioural interventions (not matched for contact time) (RR 0.93, 95% CI 0.47 to 1.82; I2 = 0%; 2 studies, 211 participants; very low certainty evidence). Results from one small study (40 participants) detected a statistically significant benefit of hypnotherapy compared to no intervention (RR 19.00, 95% CI 1.18 to 305.88), but this evidence was judged to be of very low certainty due to high risk of bias and imprecision. No significant differences were detected in comparisons of hypnotherapy with brief behavioural interventions (RR 0.98, 95% CI 0.57 to 1.69; I² = 0%; 2 studies, 269 participants), rapid/focused smoking (RR 1.00, 95% CI 0.43 to 2.33; I2 = 65%; 2 studies, 54 participants), and pharmacotherapies (RR 1.68, 95% CI 0.88 to 3.20; I2 = 5%; 2 studies, 197 participants). When hypnotherapy was evaluated as an adjunct to other treatments, the pooled result from five studies showed a statistically significant benefit in favour of hypnotherapy (RR 2.10, 95% CI 1.31 to 3.35; I² = 62%; 224 participants); however, this result should be interpreted with caution due to the high risk of bias across studies (four had a high risk or bias, one had an unclear risk), and substantial statistical heterogeneity.Most studies did not provide information on whether data specifically relating to adverse events were collected, and whether or not any adverse events occurred. One study that did collect such data did not find a statistically significant difference in the adverse event 'index' between hypnotherapy and relaxation. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether hypnotherapy is more effective for smoking cessation than other forms of behavioural support or unassisted quitting. If a benefit is present, current evidence suggests the benefit is small at most. There is very little evidence on whether hypnotherapy causes adverse effects, but the existing data show no evidence that it does. Further large, high-quality randomized controlled trials, and more comprehensive assessments of safety, are needed on this topic.

Ascending single dose pharmacokinetics of cytisine in healthy adult smokers.

1. Cytisine, a partial agonist for the α4ß2-nAChR, is used as a smoking cessation medication. Cytisine's current dosing is complex and involves taking 1.5 mg several times a day. The aim of this study was to explore the effect of dose on the pharmacokinetics and safety of cytisine after a single dose in healthy adult smokers. 2. Participants were assigned to one of three groups (n = 6 in each group) to receive a single oral dose of 1.5, 3 or 4.5 mg of cytisine. Blood samples were collected up to 24 h post dose. Pulse, blood pressure and respiratory rate were measured. Adverse effects were recorded. 3. Cytisine reached peak plasma concentration 1-2 h post dose in all participants irrespective of dose, with no dose-dependent changes in the elimination phase. Mean (SD) cytisine exposure (AUC0-24h) were 81.9 (15.8), 181.9 (40.8) and 254.5 (48.1) ng.h/mL following 1.5, 3 and 4.5 mg, respectively. 4. Cytisine appears to have predictable pharmacokinetics following a single dose of up to 4.5 mg and may be safe given as a single 4.5 mg dose, which is threefold greater than the recommended dose taken at one time. This study is registered in ClinicalTrials.gov (ID:NCT02585024).

Disgust but not Health Anxiety Graphic Warning Labels Reduce Motivated Attention in Smokers: A Study of P300 and Late Positive Potential Responses.

Background: Graphic health warning labels (GHWLs) on tobacco products attempt to leverage avoidance-promoting emotions, such as anxiety and disgust, to encourage cessation. Prior studies have relied on self-report or attentional metrics that may not accurately illuminate GHWLs' ability to motivate change. This report evaluates the impact of disgust- and anxiety-based GHWLs on electroencephalograph (EEG) measures of motivated attention among two groups of smokers-those that report higher versus lower cigarette dependence. We hypothesized that both anxiety and disgust GHWLs would reduce appetitive attention, as indexed by lowered P300 (P3) and late positive potential (LPP) activations. Methods: Sixty-one smokers provided demographic and smoking history before completing an oddball paradigm consisting of three counterbalanced stimuli blocks. Each block (100 trials) contained a neutral, GHWL-anxiety, or GHWL-disgust frequent image and a smoking cue as the oddball image (20%). Oddball trials for each block were averaged, P3 and LPP were identified at midline electrode positions (Fz, Cz, and Pz), and mean amplitude was analyzed. Results: Separate mixed-model ANOVAs of P3 and LPP reactivity revealed disgust-focused GHWLs reduced motivated attentional processing. Conversely, the anxiety-focused GHWL appeared to increase the salience of the smoking cue (Fz only). Less-dependent smokers showed lower P3 reactivity than those with higher dependence at Fz, but greater P3 reactivity at Cz and Pz. Conclusion: These results extend prior work in demonstrating that disgust, but not anxiety-based GHWLs, may reduce EEG-assessed motivated attention to smoking cues. Disgust may thus represent a more fruitful target for public health cessation efforts. Implications: Most GHWL evaluations have focused on fear (or anxiety) elicitation rather than disgust, an emotion that may have a unique link to smoking, having evolved specifically to facilitate the avoidance of contaminants via oral incorporation. Analyses of P300 and LPP responses to GHWLs suggest that disgust-focused images interfere with the EEG-indexed attentional processing of smoking cues and do so better than health anxiety-focused messages. However, interaction effects at different electrode sites indicated that GHWLs have complex effects in more versus less-dependent smokers and that an understanding of how smoking cues and anti-smoking imagery become associated over time is needed to identify relevant targets for public health efforts.

Burden of atrial fibrillation in Maori and Pacific people in New Zealand: a cohort study.

BACKGROUND: Atrial fibrillation (AF) is a major risk factor for ischaemic stroke and cardiovascular events. In New Zealand (NZ), Maori (indigenous New Zealanders) and Pacific people experience higher rates of AF compared with non-Maori/non-Pacific people. AIM: To describe a primary care population with AF in NZ. Stroke risk and medication adherence according to ethnicity are also detailed. METHODS: Electronic medical records for adults (≥20 years, n = 135 840, including 19 918 Maori and 43 634 Pacific people) enrolled at 37 NZ general practices were analysed for AF diagnosis and associated medication prescription information. RESULTS: The overall prevalence of non-valvular AF (NVAF) in this population was 1.3% (1769), and increased with age (4.4% in people ≥55 years). Maori aged ≥55 years were more likely to be diagnosed with NVAF (7.3%) than Pacific (4.0%) and non-Maori/non-Pacific people (4.1%, P < 0.001). Maori and Pacific NVAF patients were diagnosed with AF 10 years earlier than non-Maori/non-Pacific patients (median age of diagnosis: Maori = 60 years, Pacific = 61 years, non-Maori/non-Pacific = 71 years, P < 0.001). Overall, 67% of NVAF patients were at high risk for stroke (CHA2 DS2 -VASc ≥ 2) at the time of AF diagnosis. Almost half (48%) of Maori and Pacific NVAF patients aged <65 years were at high risk for stroke, compared with 22% of non-Maori/non-Pacific (P < 0.001). Irrespective of ethnic group, adherence to AF medication was suboptimal in those NVAF patients with a high risk of stroke or with stroke history. CONCLUSION: AF screening and stroke thromboprophylaxis in Maori and Pacific people could start below the age of 65 years in NZ.

The effectiveness and safety of combining varenicline with nicotine e-cigarettes for smoking cessation in people with mental illnesses and addictions: study protocol for a randomised-controlled trial.

BACKGROUND: Smoking rates are higher in New Zealand (NZ) adults with mental illnesses and alcohol and other drug (AOD) addictions, compared to the overall population. Quit attempts using "gold standard" smoking cessation treatments often fail in people with these conditions, so more flexible treatment regimens that adapt to a person's responsiveness to treatment are worth investigating. The STATUS trial aims to evaluate the effectiveness and safety of combining varenicline with nicotine e-cigarettes for smoking cessation among varenicline non-responders in treatment for mental health illnesses and/or AOD addictions. METHODS: This is a pragmatic two-arm, open-label, randomised trial. Participants will be daily smokers using mental health and/or addiction services in Auckland, aged ≥18 years, motivated to quit smoking, and eligible to access varenicline through the NZ special authority process. After 2 weeks of using varenicline plus behavioural support, participants who have not reduced their daily smoking by ≥50% will be randomised (1:1) to either 10 weeks of continued varenicline use or 10 weeks of varenicline plus an 18 mg/mL nicotine e-cigarette. All participants will receive weekly withdrawal-orientated behavioural support calls for 6 weeks post-randomisation. The primary outcome is self-reported biochemically-verified (exhaled carbon monoxide) continuous abstinence at 24 weeks post-randomisation. Secondary outcomes, measured at six, 12 and 24 weeks post-randomisation include: self-reported continuous abstinence, 7-day point prevalence abstinence, smoking reduction, time to relapse, cross-over, use of other smoking cessation support, serious adverse events, treatment adherence, compliance, acceptability, dual use, continuation of treatment use, mental illness symptoms and AOD use, health-related quality of life, and cost-analysis. A sample size of 338 will confer 80% power (p = 0.05) to detect a 15% absolute difference between the varenicline alone and varenicline plus e-cigarette groups. DISCUSSION: People with mental illness and/or AOD addictions are just as motivated as others to quit smoking, but are less likely to succeed. Adapting smoking cessation medication after a lack of responsiveness in the first 2 weeks of initial treatment in this priority population by adding a nicotine e-cigarette may be one way to increase long-term quit rates. TRIAL REGISTRATION: Australian NZ Clinical Trial Registry: ACTRN12616001355460 (29 September 2016).

Optical treatment of amblyopia in older children and adults is essential prior to enrolment in a clinical trial.

PURPOSE: Optical treatment alone can improve visual acuity (VA) in children with amblyopia, thus clinical trials investigating additional amblyopia therapies (such as patching or videogames) for children require a preceding optical treatment phase. Emerging therapies for adult patients are entering clinical trials. It is unknown whether optical treatment is effective for adults with amblyopia and whether an optical correction phase is required for trials involving adults. METHODS: We examined participants who underwent optical treatment in the Binocular Treatment for Amblyopia using Videogames (BRAVO) clinical trial (ANZCTR ID: ACTRN12613001004752). Participants were recruited in three age groups (7 to 12, 13 to 17, or ≥18 years), and had unilateral amblyopia due to anisometropia and/or strabismus, with amblyopic eye VA of 0.30-1.00 logMAR (6/12 to 6/60, 20/40 to 20/200). Corrective lenses were prescribed based on cycloplegic refraction to fully correct any anisometropia. VA was assessed using the electronic visual acuity testing algorithm (e-ETDRS) test and near stereoacuity was assessed using the Randot Preschool Test. Participants were assessed every four weeks up to 16 weeks, until either VA was stable or until amblyopic eye VA improved to better than 0.30 logMAR, rendering the participant ineligible for the trial. RESULTS: Eighty participants (mean age 24.6 years, range 7.6-55.5 years) completed four to 16 weeks of optical treatment. A small but statistically significant mean improvement in amblyopic eye VA of 0.05 logMAR was observed (S.D. 0.08 logMAR; paired t-test p < 0.0001). Twenty-five participants (31%) improved by ≥1 logMAR line and of these, seven (9%) improved by ≥2 logMAR lines. Stereoacuity improved in 15 participants (19%). Visual improvements were not associated with age, presence of strabismus, or prior occlusion treatment. Two adult participants withdrew due to intolerance to anisometropic correction. Sixteen out of 80 participants (20%) achieved better than 0.30 logMAR VA in the amblyopic eye after optical treatment. Nine of these participants attended additional follow-up and four (44%) showed further VA improvements. CONCLUSIONS: Improvements from optical treatment resulted in one-fifth of participants becoming ineligible for the main clinical trial. Studies investigating additional amblyopia therapies must include an appropriate optical treatment only phase and/or parallel treatment group regardless of patient age. Optical treatment of amblyopia in adult patients warrants further investigation.

Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling Intermediates in Mesenchymal Cell Activation.

Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen. Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E-BP1 pathway was identified as an important driver of collagen I expression in Fib-MCs in experiments utilizing raptor gene silencing and overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states.

Cytisine versus nicotine for smoking cessation.

BACKGROUND: Placebo-controlled trials indicate that cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months. We investigated whether cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit. METHODS: We conducted a pragmatic, open-label, noninferiority trial in New Zealand in which 1310 adult daily smokers who were motivated to quit and called the national quitline were randomly assigned in a 1:1 ratio to receive cytisine for 25 days or nicotine-replacement therapy for 8 weeks. Cytisine was provided by mail, free of charge, and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges. Low-intensity, telephone-delivered behavioral support was provided to both groups through the quitline. The primary outcome was self-reported continuous abstinence at 1 month. RESULTS: At 1 month, continuous abstinence from smoking was reported for 40% of participants receiving cytisine (264 of 655) and 31% of participants receiving nicotine-replacement therapy (203 of 655), for a difference of 9.3 percentage points (95% confidence interval, 4.2 to 14.5). The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men. Self-reported adverse events over 6 months occurred more frequently in the cytisine group (288 events among 204 participants) than in the group receiving nicotine-replacement therapy (174 events among 134 participants); adverse events were primarily nausea and vomiting and sleep disorders. CONCLUSIONS: When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12610000590066.).