Varenicline and Nicotine Replacement Therapy for Smokers Admitted to Hospitals: A Randomized Clinical Trial.

Importance: Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated. Objective: To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone. Design, Setting, and Participants: A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023. Interventions: A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants. Main Outcomes and Measures: The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events. Results: A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group). Conclusions and Relevance: In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence. Trial Registration: anzctr.org.au Identifier: ACTRN12618001792213.

The treatable traits of asthma in pregnancy: a clinical audit.

Rationale: Poor asthma control in pregnancy is associated with adverse perinatal outcomes. Treatable traits improve patient outcomes but the pattern and prevalence of treatable traits in pregnant women with asthma is unknown. Whether treatable traits in pregnant women with asthma can be identified via a virtual care consult is also unknown. The objective of the present study was to assess the prevalence of treatable traits in pregnant women with asthma using a virtual model of care. Methods: Pregnant women with asthma (n=196) underwent an assessment by an asthma nurse educator and a respiratory physician via telehealth. In this clinical audit, 16 treatable traits were assessed including two traits in the pulmonary domain, five traits in the behavioural/risk factors domain and nine traits in the extrapulmonary domain. Results: Pregnant women with asthma had a mean±sd of 7.5±2.0 treatable traits per person including 1.0±0.7 treatable traits per person in the pulmonary domain, 3.5±1.56 in the extrapulmonary domain and 2±0.9 in the risk factor/behavioural domain. Treatable traits in the behavioural/risk factor domain were most prevalent and these included limited asthma knowledge (96%), inadequate inhaler technique (84%) and no written asthma action plan (80%). On average 3.8±1.24 interventions per person were delivered for a mean±sd of 7.5±2.0 treatable traits per person. Conclusion: Virtual antenatal asthma care is a feasible approach for assessing treatable traits in pregnant women with mild asthma. Pregnant women with asthma exhibit multiple management issues. Virtual models of care might increase asthma in pregnancy service uptake and acceptability.

2D 1H sLASER Long-TE and 3D 31P Chemical Shift Imaging at 3 T for Monitoring Fasting-Induced Changes in Brain Tumor Tissue.

BACKGROUND: Emerging evidence suggests that fasting could play a key role in cancer treatment. Its metabolic effects on gliomas require further investigation. PURPOSE: To design a multi-voxel 1H/31P MR-spectroscopic imaging (MRSI) protocol for noninvasive metabolic monitoring of cerebral, fasting-induced changes on an individual patient/tumor level, and to assess its technical reliability/reproducibility. STUDY TYPE: Prospective. POPULATION: MRS phantom. Twenty-two patients (mean age = 61, 6 female) with suspected WHO grade II-IV glioma examined before and after 72-hour-fasting prior to biopsy/resection. FIELD STRENGTH/SEQUENCE: 3-T, 1H decoupled 3D 31P MRSI, 2D 1H sLASER MRSI at an echo time of 144 msec, 2D 1H MRSI (as water reference), T1-weighted, T1-weighted contrast-enhanced, T2-weighted, and FLAIR. sLASER and PRESS sequences were used for phantom measurements. ASSESSMENT: Phantom measurements and spectral simulations were performed with various echo-times for protocol optimization. In vivo spectral analyses were conducted using LCModel and AMARES, obtaining quality/fitting parameters (linewidth, signal-to-noise-ratio, and uncertainty measures of fitting) and metabolite intensities. The volume of glioma sub-regions was calculated and correlated with MRS findings. Ex-vivo spectra of necrotic tumor tissues were obtained using high-resolution magic-angle spinning (HR-MAS) technique. STATISTICAL TESTS: Wilcoxon signed-rank test, Bland-Altman plots, and coefficient of variation were used for repeatability analysis of quality/fitting parameters and metabolite concentrations. Spearman ρ correlation for the concentration of ketone bodies with volumes of glioma sub-regions was determined. A P-value <0.05 was considered statistically significant. RESULTS: 1H and 31P repeatability measures were highly consistent between the two sessions. ß-hydroxybutyrate and acetoacetate were detectable (fitting-uncertainty <50%) in glioma sub-regions of all patients who completed the 72-hour-fasting cycle. ß-hydroxybutyrate accumulation was significantly correlated with the necrotic/non-enhancing tumor core volume (ρ = 0.81) and validated using ex-vivo 1H HR-MAS. DATA CONCLUSION: We propose a comprehensive MRS protocol that may be used for monitoring cerebral, fasting-induced changes in patients with glioma. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

Effect of Azithromycin on Asthma Remission in Adults With Persistent Uncontrolled Asthma: A Secondary Analysis of a Randomized, Double-Anonymized, Placebo-Controlled Trial.

BACKGROUND: Asthma remission is a potential treatment goal. RESEARCH QUESTION: Does adding azithromycin to standard therapy in patients with persistent uncontrolled asthma induce remission compared with placebo? STUDY DESIGN AND METHODS: This secondary analysis used data from the Asthma and Macrolides: the Azithromycin Efficacy and Safety (AMAZES) clinical trial-a double-anonymized placebo-controlled trial that evaluated the safety and efficacy of azithromycin on asthma exacerbations. The primary remission definition (referred to as clinical remission) was zero exacerbations and zero oral corticosteroids during the previous 6 months evaluated at 12 months and a 5-item Asthma Control Questionnaire score ≤ 1 at 12 months. Secondary remission definitions included clinical remission plus lung function criteria (postbronchodilator FEV1 ≥ 80% or postbronchodilator FEV1 ≤ 5% decline from baseline) and complete remission (sputum eosinophil count < 3% plus the aforementioned criteria). Sensitivity analyses explored the robustness of primary and secondary remission definitions. The predictors of clinical remission were identified. RESULTS: A total of 335 participants (41.5% male; median age, 61.01 years; quartile 1-3, 51.03-68.73) who completed the 12-month treatment period were included in the analysis. Twelve months of treatment with azithromycin induced asthma remission in a subgroup of patients, and a significantly higher proportion in the azithromycin arm achieved both clinical remission (50.6% vs 38.9%; P = .032) and clinical remission plus lung function criteria (50.8% vs 37.1%; P = .029) compared with placebo, respectively. In addition, a higher proportion of the azithromycin group achieved complete remission (23% vs 13.7%; P = .058). Sensitivity analyses supported these findings. Baseline factors (eg, better asthma-related quality of life, absence of oral corticosteroid burst in the previous year) predicted the odds of achieving clinical remission. Azithromycin induced remission in both eosinophilic and noneosinophilic asthma. INTERPRETATION: In this study, adults with persistent symptomatic asthma achieved a higher remission rate when treated with azithromycin. Remission on treatment may be an achievable treatment target in moderate/severe asthma, and future studies should consider remission as an outcome measure.

Biologics (mepolizumab and omalizumab) induced remission in severe asthma patients.

BACKGROUND: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. METHODS: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real-world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5-item Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post-bronchodilator FEV1 ≥80%) or stabilization (post-bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut-offs of ACQ-5/FEV1 scores. The predictors of clinical remission were identified. RESULTS: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. CONCLUSION: Biologic treatment with mepolizumab or omalizumab for severe asthma-induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure.

A novel, multidomain, primary care nurse-led and mHealth-assisted intervention for dementia risk reduction in middle-aged adults (HAPPI MIND): study protocol for a cluster randomised controlled trial.

INTRODUCTION: Middle-aged multidomain risk reduction interventions targeting modifiable risk factors for dementia may delay or prevent a third of dementia cases in later life. We describe the protocol of a cluster randomised controlled trial (cRCT), HAPPI MIND (Holistic Approach in Primary care for PreventIng Memory Impairment aNd Dementia). HAPPI MIND will evaluate the efficacy of a multidomain, nurse-led, mHealth supported intervention for assessing dementia risk and reducing associated risk factors in middle-aged adults in the Australian primary care setting. METHODS AND ANALYSIS: General practice clinics (n≥26) across Victoria and New South Wales, Australia, will be recruited and randomised. Practice nurses will be trained to implement the HAPPI MIND intervention or a brief intervention. Patients of participating practices aged 45-65 years with ≥2 potential dementia risk factors will be identified and recruited (approximately 15 patients/clinic). Brief intervention participants receive a personalised report outlining their risk factors for dementia based on Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) scores, education booklet and referral to their general practitioner as appropriate. HAPPI MIND participants receive the brief intervention as well as six individualised dementia risk reduction sessions with a nurse trained in motivational interviewing and principles of behaviour change, a personalised risk reduction action plan and access to the purpose-built HAPPI MIND smartphone app for risk factor self-management. Follow-up data collection will occur at 12, 24 and 36 months. Primary outcome is ANU-ADRI score change at 12 months from baseline. Secondary outcomes include change in cognition, quality of life and individual risk factors of dementia. ETHICS AND DISSEMINATION: Project approved by Monash University Human Research Ethics Committee (ID: 28273). Results will be disseminated in peer-reviewed journals and at healthcare conferences. If effective in reducing dementia risk, the HAPPI MIND intervention could be integrated into primary care, scaled up nationally and sustained over time. TRIAL REGISTRATION NUMBER: ACTRN12621001168842.

In Vivo Measurement of Rat Brain Water Content at 9.4 T MR Using Super-Resolution Reconstruction: Validation With Ex Vivo Experiments.

BACKGROUND: Given that changes in brain water content are often correlated with disease, investigating water content non-invasively and in vivo could lead to a better understanding of the pathogenesis of several neurologic diseases. PURPOSE: To adapt a super-resolution-based technique, previously developed for humans, to the rat brain and report in vivo high-resolution (HR) water content maps in comparison with ex vivo wet/dry methods. STUDY TYPE: Prospective. ANIMAL MODEL: Eight healthy male Wistar rats. FIELD STRENGTH/SEQUENCE: 9.4-T, multi-echo gradient-echo (mGRE) sequence. ASSESSMENT: Using super-resolution reconstruction (SRR), a HR mGRE image (200 µm isotropic) was reconstructed from three low-resolution (LR) orthogonal whole-brain images in each animal, which was followed by water content mapping in vivo. The animals were subsequently sacrificed, the brains excised and divided into five regions (front left, front right, middle left, middle right, and cerebellum-brainstem regions), and the water content was measured ex vivo using wet/dry measurements as the reference standard. The water content values of the in vivo and ex vivo methods were then compared for the whole brain and also for the different regions separately. STATISTICAL TESTS: Friedman's non-parametric test was used to test difference between the five regions, and Pearson's correlation coefficient was used for correlation between in vivo and ex vivo measurements. A P-value <0.05 was considered statistically significant. RESULTS: Water content values derived from in vivo MR measurements showed strong correlations with water content measured ex vivo at a regional level (r = 0.902). Different brain regions showed significantly different water content values. Water content values were highest in the frontal brain, followed by the midbrain, and lowest in the cerebellum and brainstem regions. DATA CONCLUSION: An in vivo technique to achieve HR isotropic water content maps in the rat brain using SRR was adopted in this study. The MRI-derived water content values obtained using the technique showed strong correlations with water content values obtained using ex vivo wet/dry methods. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Treatable traits, combination inhaler therapy and the future of asthma management.

The landscape of asthma has considerably changed in the last decade. Effective medications and inhaler devices have been developed and integrated into the asthma pharmacopoeia, but unfortunately, the proportion of uncontrolled patients remains unacceptably high. This is now recognized to be mainly due to the inappropriate use of medications or inhaler devices, heterogeneity of the disease or other factors contributing to the disease. Currently, inhaled corticosteroids (ICS), with or without long-acting beta agonists (LABA), are the cornerstone of asthma management, and recently international guidelines recognized the importance of combination inhaler therapy (ICS/LABA) even in mild asthma. In future, ultra-long-acting personalized medications and smart inhalers will complement combination inhaler therapy in order to effectively addresses issues such as adherence, inhaler technique and polypharmacy (both of drugs and devices). Asthma is now acknowledged as a multifaceted cluster of disorders and the treatment model has evolved from one-size-fits-all to precision medicine approaches such as treatable traits (TTs, defined as measurable and treatable clinically important factors) which encourages the quality use of medications and identification and management of all underlying behavioural and biological treatable risk factors. TT requires research and validation in a clinical context and the implementation strategies and efficacy in various settings (primary/secondary/tertiary care, low-middle income countries) and populations (mild/moderate/severe asthma) are currently evolving. Combination inhaler therapy and the TTs approach are complementary treatment approaches. This review examines the current status of personalized medicine and combination inhaler therapy, and describes futuristic views for these two strategies.

The Superfund Research Program Analytics Portal: linking environmental chemical exposure to biological phenotypes.

The OSU/PNNL Superfund Research Program (SRP) represents a longstanding collaboration to quantify Polycyclic Aromatic Hydrocarbons (PAHs) at various superfund sites in the Pacific Northwest and assess their potential impact on human health. To link the chemical measurements to biological activity, we describe the use of the zebrafish as a high-throughput developmental toxicity model that provides quantitative measurements of the exposure to chemicals. Toward this end, we have linked over 150 PAHs found at Superfund sites to the effect of these same chemicals in zebrafish, creating a rich dataset that links environmental exposure to biological response. To quantify this response, we have implemented a dose-response modelling pipeline to calculate benchmark dose parameters which enable potency comparison across over 500 chemicals and 12 of the phenotypes measured in zebrafish. We provide a rich dataset for download and analysis as well as a web portal that provides public access to this dataset via an interactive web site designed to support exploration and re-use of these data by the scientific community at http://srp.pnnl.gov .

A shape-shifting nuclease unravels structured RNA.

RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts. Dis3-like 2 (Dis3L2) is a 3'-5' exoribonuclease that plays a critical role in human development. Dis3L2 independently degrades structured substrates, including coding and noncoding 3' uridylated RNAs. While the basis for Dis3L2's substrate recognition has been well characterized, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining cryogenic electron microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for RNA processing. We discovered a dramatic conformational change that is triggered by double-stranded RNA (dsRNA), repositioning two cold shock domains by 70 Å. This movement exposes a trihelix linker region, which acts as a wedge to separate the two RNA strands. Furthermore, we show that the trihelix linker is critical for dsRNA, but not single-stranded RNA, degradation. These findings reveal the conformational plasticity of Dis3L2 and detail a mechanism of structured RNA degradation.

Comorbidities Modify the Phenotype but Not the Treatment Effectiveness to Mepolizumab in Severe Eosinophilic Asthma.

BACKGROUND: Comorbidities in severe asthma are common and contribute to disease burden. The severe asthma phenotype and treatment response can be impacted by comorbid conditions. Real-world data on the use of mepolizumab in severe eosinophilic asthma (SEA) in the presence of comorbidities are needed to inform clinical practice. OBJECTIVE: To investigate the impact of comorbid conditions on baseline phenotype in patients with SEA and assess the mepolizumab treatment effect by comorbidity status in SEA. METHODS: Patients enrolled in the Australian Mepolizumab Registry (n = 309) were classified into subgroups defined by the presence or absence of comorbidities, including nasal polyps, aspirin-exacerbated airway disease, asthma-chronic obstructive pulmonary disease overlap (ACO), fungal sensitization, and obesity. Patient baseline characteristics were compared, and the impacts of comorbidity on phenotype, identified by differences in patient age and/or baseline biomarker levels and/or asthma severity, were assessed. The mepolizumab treatment effects on clinical and biological outcomes at 12 months were assessed. RESULTS: Across comorbidity subgroups, mepolizumab reduced the rate of clinically significant exacerbations (range: 47%-77%), maintenance oral corticosteroid use (dose reduction: 4.2-13.3 mg/d), and improved symptom control (Asthma Control Questionnaire-5 score: 1.9-2.4 point reduction) and lung function (mean: 3.4-9.3 post-bronchodilator percent predicted forced expiratory volume in 1 second). Peripheral blood eosinophils were reduced (mean: 480-780 cells/µL). Comorbidities (nasal polyps, obesity, ACO, and fungal sensitization) modified the baseline phenotype. CONCLUSIONS: Mepolizumab treatment is associated with comparable clinical improvements in patients with SEA and comorbidities. Mepolizumab effectively minimizes the disease impact and corticosteroid burden in patients with SEA.

Which smokers enroll in a hospital based smoking cessation trial? Survey of smoking related behaviors, quit attempts, and motivation to quit.

BACKGROUND: Understanding smoking behaviors in hospital patients who smoke may improve inpatient cessation treatments. This study aimed to describe smoking-related behaviors, past-quit attempts, and self-reported difficulties experienced in quitting among those who enrolled in a smoking cessation trial of varenicline. METHODS: Baseline data were obtained from adult hospitalized smokers (average ≥ 10 cigarettes/day in 4-weeks prior to hospitalization) who enrolled in a randomized, placebo-controlled trial of varenicline ± nicotine lozenges at five Australian public hospitals. A logistic regression model tested the association between participant characteristics and quitting in the previous 12 months. RESULTS: Participants' (n = 320; 57% male, 52.5 ± 12.1 years old) motivation and confidence in quitting were high. A total of 120 participants (37.5%) had attempted quitting in the previous 12-months. Prior hospitalization (P = .008) and employment status (P = .015) were significantly associated with past quit attempts. No statistically significant differences were noted in the reason for hospitalization or the level of nicotine dependence between participants who attempted quitting in the previous 12 months and their counterparts. Smoking cessation pharmacotherapy was used by 55% of those attempting to quit; nicotine replacement therapy (65.2%) and varenicline (16.7%) most common. Stress or anxiety, urges to smoke and a lack of motivation were the difficulties experienced in past quit attempts. CONCLUSIONS: Those who had a prior hospitalization and were unemployed had significantly greater odds of reporting past quit attempts. Further research is needed to investigate the degree of adherence among inpatient smokers with the smoke-free hospital policies and the frequency of NRT provision and uptake on admission.

Whole-Brain Water Content Mapping Using Super-Resolution Reconstruction with MRI Acquisition in 3 Orthogonal Orientations.

PURPOSE: Brain water content provides rich tissue contrast comparable to that of longitudinal relaxation time T1 , but mapping is usually performed at modest resolution. In particular, the slice thickness in 2D mapping methods is limited. Here, we combine super-resolution reconstruction techniques with a fast water content mapping method to acquire high and isotropic resolution (0.75 mm) water content maps at 3 Tesla. METHODS: A high-resolution multi-echo gradient echo image is super-resolution-reconstructed from 3 low-resolution, orthogonal multi-echo gradient echo image acquisitions, followed by water content mapping. The mapping accuracy and SNR of the proposed method are assessed using numerical simulations, phantom studies, and in vivo data acquired from 6 healthy volunteers at 3 Tesla. A high-resolution acquisition with an established mapping method is used as a reference. RESULTS: Whole-brain water content maps with 0.75 mm isotropic resolution are demonstrated. No bias in the water content values was seen following super-resolution reconstruction. In the in vivo experiments, a lower SD of the mean water content values was observed with the proposed method compared to the reference method. CONCLUSIONS: Super-resolution reconstruction of multi-echo gradient echo data is demonstrated, enabling whole-brain water content mapping with high and isotropic resolution. The accuracy of the proposed method is shown using phantoms and 6 healthy volunteers and was found to be unchanged compared to the conventional acquisition. The proposed method could increase the sensitivity of water content mapping sufficiently to enable the detection of very small lesions, such as cortical lesions in multiple sclerosis.

Educational interventions for health professionals managing chronic obstructive pulmonary disease in primary care.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable health condition. COPD is associated with substantial burden on morbidity, mortality and healthcare resources. OBJECTIVES: To review existing evidence for educational interventions delivered to health professionals managing COPD in the primary care setting. SEARCH METHODS: We searched the Cochrane Airways Trials Register from inception to May 2021. The Register includes records from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED) and PsycINFO. We also searched online trial registries and reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs. Eligible studies tested educational interventions aimed at any health professionals involved in the management of COPD in primary care. Educational interventions were defined as interventions aimed at upskilling, improving or refreshing existing knowledge of health professionals in the diagnosis and management of COPD. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed abstracts and full texts of eligible studies, extracted data and assessed the risk of bias of included studies. We conducted meta-analyses where possible and used random-effects models to yield summary estimates of effect (mean differences (MDs) with 95% confidence intervals (CIs)). We performed narrative synthesis when meta-analysis was not possible. We assessed the overall certainty of evidence for each outcome using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Primary outcomes were: 1) proportion of COPD diagnoses confirmed with spirometry; 2) proportion of patients with COPD referred to, participating in or completing pulmonary rehabilitation; and 3) proportion of patients with COPD prescribed respiratory medication consistent with guideline recommendations. MAIN RESULTS: We identified 38 studies(22 cluster-RCTs and 16 RCTs) involving 4936 health professionals (reported in 19/38 studies) and 71,085 patient participants (reported in 25/38 studies). Thirty-six included studies evaluated interventions versus usual care; seven studies also reported a comparison between two or more interventions as part of a three- to five-arm RCT design. A range of simple to complex interventions were used across the studies, with common intervention features including education provided to health professionals via training sessions, workshops or online modules (31 studies), provision of practice support tools, tool kits and/or algorithms (10 studies), provision of guidelines (nine studies) and training on spirometry (five studies). Health professionals targeted by the interventions were most commonly general practitioners alone (20 studies) or in combination with nurses or allied health professionals (eight studies), and the majority of studies were conducted in general practice clinics. We identified performance bias as high risk for 33 studies. We also noted risk of selection, detection, attrition and reporting biases, although to a varying extent across studies. The evidence of efficacy was equivocal for all the three primary endpoints evaluated: 1) proportion of COPD diagnoses confirmed with spirometry (of the four studies that reported this outcome, two supported the intervention); 2) proportion of patients with COPD who are referred to, participate in or complete pulmonary rehabilitation (of the four studies that reported this outcome, two supported the intervention); and 3) proportion of patients with COPD prescribed respiratory medications consistent with guideline recommendations (12 studies reported this outcome, the majority evaluated multiple drug classes and reported a mixed effect). Additionally, the low quality of evidence and potential risk of bias make the interpretation more difficult. Moderate-quality evidence (downgraded due to risk of bias concerns) suggests that educational interventions for health professionals probably improve the proportion of patients with COPD vaccinated against influenza (three studies) and probably have little impact on the proportion of patients vaccinated against pneumococcal infection (two studies). Low-quality evidence suggests that educational interventions for health professionals may have little or no impact on the frequency of COPD exacerbations (10 studies). There was a high degree of heterogeneity in the reporting of health-related quality of life (HRQoL). Low-quality evidence suggests that educational interventions for health professionals may have little or no impact on HRQoL overall, and when using the COPD-specific HRQoL instrument, the St George's Respiratory Questionnaire (at six months MD 0.87, 95% CI -2.51 to 4.26; 2 studies, 406 participants, and at 12 months MD -0.43, 95% CI -1.52 to 0.67, 4 studies, 1646 participants; reduction in score indicates better health). Moderate-quality evidence suggests that educational interventions for health professionals may improve patient satisfaction with care (one study). We identified no studies that reported adverse outcomes. AUTHORS' CONCLUSIONS: The evidence of efficacy was equivocal for educational interventions for health professionals in primary care on the proportion of COPD diagnoses confirmed with spirometry, the proportion of patients with COPD who participate in pulmonary rehabilitation, and the proportion of patients prescribed guideline-recommended COPD respiratory medications. Educational interventions for health professionals may improve influenza vaccination rates among patients with COPD and patient satisfaction with care. The quality of evidence for most outcomes was low or very low due to heterogeneity and methodological limitations of the studies included in the review, which means that there is uncertainty about the benefits of any currently published educational interventions for healthcare professionals to improve COPD management in primary care. Further well-designed RCTs are needed to investigate the effects of educational interventions delivered to health professionals managing COPD in the primary care setting.

Asthma remission: what is it and how can it be achieved?

Asthma treatment goals currently focus on symptom and exacerbation control rather than remission. Remission is not identical to cure, but is a step closer. This review considers the current definitions of remission in asthma, the prevalence and predictors, the pathophysiology of remission, the possibility of achieving it using the available treatment options, and the future research directions. Asthma remission is characterised by a high level of disease control, including the absence of symptoms and exacerbations, and normalisation or optimisation of lung function with or without ongoing treatment. Even in those who develop a symptomatic remission of asthma, persistent pathological abnormalities are common, leading to a risk of subsequent relapse at any time. Complete remission requires normalisation or stabilisation of any underlying pathology in addition to symptomatic remission. Remission is possible as part of the natural history of asthma, and the prevalence of remission in the adult asthma population varies between 2% and 52%. The factors associated with remission include mild asthma, better lung function, better asthma control, younger age, early-onset asthma, shorter duration of asthma, milder bronchial hyperresponsiveness, fewer comorbidities and smoking cessation or never smoking. Although previous studies have not targeted treatment-induced remission, there is some evidence to show that the current long-term add-on therapies such as biologics and azithromycin can achieve some criteria for asthma remission on treatment, at least in a subgroup of patients. However, more research is required. Long-term remission could be included as a therapeutic goal in studies of asthma treatments.

Patterns of azithromycin use in obstructive airway diseases: a real-world observational study.

BACKGROUND: Low-dose long-term azithromycin is recommended in clinical practice guidelines for obstructive airway diseases (OAD); however, an optimal therapeutic regimen is not yet established. AIM: To understand the patterns of azithromycin use in OAD, characterise the patients who received it and evaluate its safety and efficacy using real-world data. METHODS: We audited 91 patients who had received azithromycin for at least 4 weeks for the management of asthma, chronic obstructive pulmonary disease (COPD) or non-cystic fibrosis bronchiectasis. RESULTS: The mean age was 65 ± 18 years, 60% were female and 48% were ex-smokers. The majority had asthma (75%), either alone (50%) or in combination with COPD (12%) or bronchiectasis (13%). Most (64%) reported cough or sputum at baseline. The most common treatment regimen was azithromycin 250 mg daily (73%) for more than 1 year (57%), with only seven adverse events. There was a significant reduction in the proportions of patients requiring emergency department visits (48% vs 32%; P < 0.001) and hospital admissions (35% vs 31%; P < 0.001) after starting azithromycin. In 88% of cases, physicians favoured the use of azithromycin. CONCLUSION: Physicians are currently using low-dose azithromycin for a long duration of more than 1 year for the management of OAD. The typical case definition is an older non-smoking adult with persistent asthma, often in combination with another OAD and presenting with bothersome cough or sputum. Azithromycin was well tolerated and led to reduced healthcare utilisation. Further research is required to establish an optimal dosage regimen of azithromycin in OAD.

De novo sequencing and native mass spectrometry revealed hetero-association of dirigent protein homologs and potential interacting proteins in Forsythia × intermedia.

The discovery of dirigent proteins (DPs) and their functions in plant phenol biochemistry was made over two decades ago with Forsythia × intermedia. Stereo-selective, DP-guided, monolignol-derived radical coupling in vitro was then reported to afford the optically active lignan, (+)-pinoresinol from coniferyl alcohol, provided one-electron oxidase/oxidant capacity was present. It later became evident that DPs have several distinct sub-families, presumably with different functions. Some known DPs require other essential enzymes/proteins (e.g. oxidases) for their functions. However, the lack of a fully sequenced genome for Forsythia × intermedia made it difficult to profile other components co-purified with the (+)-pinoresinol forming DP. Herein, we used an integrated bottom-up, top-down, and native mass spectrometry (MS) approach to de novo sequence the extracted proteins via adaptation of our initial report of DP solubilization and purification. Using publicly available transcriptome and genomic data from closely related species, we identified 14 proteins that were putatively associated with either DP function or the cell wall. Although their co-occurrence after extraction and chromatographic separation is suggestive for potential protein-protein interactions, none were found to form stable protein complexes with DPs in native MS under the specific experimental conditions we have explored. Interestingly, two new DP homologs were found and they formed hetero-trimers. Molecular dynamics simulations suggested that similar hetero-trimers were possible between Arabidopsis DP homologs with comparable sequence similarities. Nevertheless, our integrated mass spectrometry method development helped prepare for future investigations directed to the discovery of novel proteins and protein-protein interactions. These advantages can be highly beneficial for plant and microbial research where fully sequenced genomes may not be readily available.