Understanding breathlessness burden and psychophysiological correlates in asthma.

BACKGROUND: Breathlessness is a disabling symptom, with complexity that is often under recognised and under treated in asthma. OBJECTIVE: To highlight the burden of breathlessness in people with severe compared with mild-to-moderate asthma and identify psychophysiological correlates of breathlessness. METHODS: This was a cross-sectional study of people with mild-to-severe asthma, who attended two in-person visits to complete a multidimensional assessment. The proportion of people with mild-to-moderate versus severe asthma who reported physically limiting breathlessness (modified Medical Research Council [mMRC] dyspnoea score ≥2) was compared. Psychophysiological factors associated with breathlessness in people with asthma were identified via a directed acyclic graph and explored with multivariate logistic regression to predict breathlessness. RESULTS: 144 participants were included, of which, 74 (51%) had mild-to-moderate asthma and 70 (49%) severe asthma. Participants were predominantly female (n=103, 72%) with a median (quartile 1, quartile 3) age of 63.4 (50.5,69.5) years and body mass index (BMI) of 31.3 (26.2, 36.0) kg/m2. The proportion of people reporting mMRC ≥2 was significantly higher in those with severe- (n=37, 53%) compared with mild-to-moderate (n=21, 31%) asthma (p=0.013). Dyspnoea-12 Total (8.00 [4.75, 17.00] versus 5.00 [2.00, 11.00], p=0.037) score was also significantly higher in the severe asthma group. Significant predictors of physically limiting breathlessness were: BMI, asthma control, exercise capacity, and hyperventilation symptoms. Airflow limitation and type-2 inflammation were poor breathlessness predictors. CONCLUSION: Over half of people with severe asthma experience physically limiting breathlessness despite treatment. Targeting psychophysiological factors, or traits, associated with breathlessness may help relieve this distressing symptom, which is of high priority to people with asthma.

Unhealthy lifestyle impacts on biological systems involved in stress response: hypothalamic-pituitary-adrenal axis, inflammation and autonomous nervous system.

An unhealthy lifestyle has a critical role in the pathogenesis and course of several chronic disorders. It has been hypothesized that lifestyle may also impact biological systems involved in stress response. A global index of unhealthy lifestyle was calculated based on the cumulative presence of five self-reported lifestyle habits (smoking, excessive alcohol use, drug use, low physical activity and short sleep) in 2783 participants (18-65 years) from the Netherlands Study of Depression and Anxiety. The functioning of biological stress systems was based on multiple physiological measures of cortisol, inflammatory cytokines and autonomic cardiac activity. The unhealthy lifestyle index was associated with hyperactivity of hypothalamus-pituitary-adrenal axis and increased inflammation, indicating that with increasing unhealthy habits, the level of biological stress increases. No association with the autonomic nervous system activity was observed; however, the use of drugs increased parasympathetic cardiac activity and significantly impacted on ANS. Results were not impacted by a recent episode of depression or anxiety disorder. An unhealthy lifestyle may unfavorably impact on biological systems involved in stress response, which may underlie progression of several psychiatric as well as somatic chronic disorders.

TMEM67, TMEM237, and Embigin in Complex With Monocarboxylate Transporter MCT1 Are Unique Components of the Photoreceptor Outer Segment Plasma Membrane.

The outer segment (OS) organelle of vertebrate photoreceptors is a highly specialized cilium evolved to capture light and initiate light response. The plasma membrane which envelopes the OS plays vital and diverse roles in supporting photoreceptor function and health. However, little is known about the identity of its protein constituents, as this membrane cannot be purified to homogeneity. In this study, we used the technique of protein correlation profiling to identify unique OS plasma membrane proteins. To achieve this, we used label-free quantitative MS to compare relative protein abundances in an enriched preparation of the OS plasma membrane with a preparation of total OS membranes. We have found that only five proteins were enriched at the same level as previously validated OS plasma membrane markers. Two of these proteins, TMEM67 and TMEM237, had not been previously assigned to this membrane, and one, embigin, had not been identified in photoreceptors. We further showed that embigin associates with monocarboxylate transporter MCT1 in the OS plasma membrane, facilitating lactate transport through this cellular compartment.

Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD. OBJECTIVE: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD. METHODS: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis. RESULTS: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13). CONCLUSION: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

A feasibility randomised controlled trial of Novel Activity Management in severe ASthma-Tailored Exercise (NAMASTE): yoga and mindfulness.

BACKGROUND: Physical inactivity is common in severe asthma and associated with poor health outcomes. New approaches are needed to address physical inactivity in this group. OBJECTIVE: To examine whether yoga and mindfulness improves health-related quality of life (HRQoL) compared with a minimal active control group and collect feasibility data to inform future studies. METHODS: Over 12-weeks, adults with severe asthma were recruited. Participants were randomised 2:1 to parallel yoga or control groups. All participants received an activity tracker. The yoga group received tailored group classes twice a week for 16-weeks with a qualified yoga instructor. The control group set activity goals with a research officer and received eight progress calls. Outcomes were assessed at 16-weeks. Primary outcome was St George's Respiratory Questionnaire (SGRQ). Secondary outcomes included asthma control, physical activity, breathlessness, and inflammation. Face-to-face qualitative interviews were conducted to determine acceptability. RESULTS: There were 15 participants randomised to yoga (mean 67 years; 60% female) and 9 to control (68 years; 56% female). Planned comparisons indicated the yoga group had greater SGRQ improvement than the control group. There was little change in secondary outcomes. Moderate-vigorous activity increased substantially in the control group. Participants found the intervention acceptable; key barriers and facilitators were social connection, the setting, addressing breathing and asthma symptoms, changing their mindset, and the intersection of different elements. CONCLUSION: A yoga and mindfulness intervention was feasible, acceptable to patients and improved HRQoL. The findings will inform design of much needed future research into physical activity interventions for severe asthma. World Health Organization International Clinical Trials Registry Platform The study was registered under the Australian New Zealand Clinical Trials Registry (ANZCTR) on the 26th of November 2018, Trial ID ACTRN12618001914257.

Disease burden of eosinophilic airway disease: Comparing severe asthma, COPD and asthma-COPD overlap.

BACKGROUND AND OBJECTIVE: There is less understanding of phenotypes and disease burden in asthma-COPD overlap (ACO) than either disease alone. Blood eosinophils may help identify the patients in the clinic with eosinophilic airway inflammation. The potential value of this approach requires an understanding of the illness burden associated with eosinophilic ACO, eosinophilic severe asthma and eosinophilic COPD, defined by blood eosinophils. METHODS: Participants from studies of multidimensional assessment in airway disease were pooled to identify patients with ACO (n = 106), severe asthma (n = 64) and COPD alone (n = 153). Patients were assessed cross-sectionally for demographic and clinical characteristics, including disease burden indicators such as health-related quality of life (HRQoL) and past-year exacerbation. Eosinophilic patients were identified using different thresholds of blood eosinophil count. RESULTS: Using a blood eosinophil count ≥0.3 × 109 /L, 41% had eosinophilic airway disease: 55% in ACO, 44% in severe asthma and 29% in COPD. Blood and sputum eosinophils were moderately correlated (rs = 0.51, n = 257, P < 0.001). Burden of disease was similar between eosinophilic and non-eosinophilic airway diseases, with poor HRQoL and high number of past-year exacerbations. Burden of disease was similar across eosinophilic severe asthma, COPD and ACO. Eosinophilic COPD tended to have poorer health status than eosinophilic ACO and severe asthma; however, in context of a high prevalence of eosinophilic ACO, cumulative population-level burden of eosinophilic disease was greater in ACO. CONCLUSION: Disease burden across eosinophilic ACO, eosinophilic severe asthma and eosinophilic COPD was high, particularly cumulative population-level burden in ACO. Factors beyond airway inflammation may drive disease burden in severe patients.

Treatable Traits That Predict Health Status and Treatment Response in Airway Disease.

BACKGROUND: A strategy based on the assessment and management of treatable traits (TTs) has been proposed as a new paradigm in airway disease. There is a potentially long list of TTs with likely different clinical impact. OBJECTIVE: To identify TTs most strongly associated with poorer health-related quality of life (HRQOL) and treatments that most substantially improved HRQOL. METHODS: We pooled data from 2 parallel-group clinical trials of multidimensional assessment and individualized management targeted to TTs versus usual care in patients with chronic obstructive pulmonary disease or severe asthma (intervention N = 45; control N = 46). Following multidimensional assessment, 22 TTs were identified and the intervention group received treatments tailored to their identified TT. We used Bayesian Model Averaging to examine associations between TTs and HRQOL (St George's Respiratory Questionnaire) at baseline, as well as between each TT treatment and the observed change in HRQOL postintervention. RESULTS: TTs most substantially associated with poorer baseline HRQOL were frequent chest infections, breathing pattern disorder, inadequate inhaler technique, systemic inflammation (C-reactive protein >3 mg/L), and depression. In both trials, TT treatment led to a large, significant improvement in HRQOL compared with usual care (Cohen's d = 1.19; P < .001). Receiving a statin for systemic inflammation and oral corticosteroid for eosinophilic airway inflammation was associated with the largest HRQOL improvements. Treatments for exercise intolerance, anxiety, and obesity were associated with smaller improvements in HRQOL. CONCLUSIONS: This study contributes to identifying clinically impactful TTs by showing that TTs across pulmonary, extrapulmonary, and behavioral domains were associated with HRQOL impairment and treatment response.

Understanding Clinicians' Perceived Barriers and Facilitators to Optimal Use of Acute Oxygen Therapy in Adults.

Background: Supplemental oxygen is commonly administered to patients in acute care. It may cause harm when used inappropriately. Guidelines recommend prescription of acute oxygen, yet adherence is poor. We aimed to identify barriers and facilitators to practicing in accordance with the evidence-based Thoracic Society of Australia and New Zealand (TSANZ) oxygen guideline, and to determine the beliefs and attitudes relating to acute oxygen therapy. Methods: A national cross-sectional survey was conducted. The survey consisted of 3 sections: (1) introduction and participant characteristics; (2) opinion/beliefs, knowledge and actions about oxygen therapy and other drugs; and (3) barriers and facilitators to use of the TSANZ guideline. Convenience sampling was employed. A paper-based survey was distributed at the TSANZ Annual Scientific Meeting. An online survey was emailed to the TSANZ membership and to John Hunter Hospital's clinical staff. Results: Responses were received from 133 clinicians: 52.6% nurses, 30.1% doctors, and 17.3% other clinicians. Over a third (37.7%) were unaware/unsure of the oxygen guideline's existence. Most (79.8%) believe that oxygen is a drug and should be treated as one. Most (92.4%) stated they only administered it based on clinical need. For four hypothetical cases, there was only one where the majority of participants identified the optimal oxygen saturation. A number of barriers and facilitators were identified when asked about practicing in accordance with the TSANZ guideline. Lack of oxygen equipment, getting doctors to prescribe oxygen and oxygen being treated differently to other drugs were seen as barriers. The guideline itself and multiple clinician characteristics were considered facilitators. Conclusion: There is discordance between clinicians' beliefs and actions regarding the administration of oxygen therapy and knowledge gaps about optimal oxygen therapy in acute care. Identified barriers and facilitators should be considered when developing evidence-based guidelines to improve dissemination and knowledge exchange.

Management of acute COPD exacerbations in Australia: do we follow the guidelines?

OBJECTIVE: We aimed to assess adherence to the Australian national guideline (COPD-X) against audited practice, and to document the outcomes of patients hospitalised with an acute exacerbation of chronic obstructive pulmonary disease (COPD) at discharge and 28 days after. METHODS: A prospective clinical audit of COPD hospital admission from five tertiary care hospitals in five states of Australia was conducted. Post-discharge follow-up was conducted via telephone to assess for readmission and health status. RESULTS: There were 207 admissions for acute exacerbation (171 patients; mean 70.2 years old; 50.3% males). Readmission rates at 28 days were 25.4%, with one (0.6%) death during admission and eight (6.1%) post-discharge within 28 days. Concordance to the COPD-X guidance was variable; 22.7% performed spirometry, 81.1% had blood gases collected when forced expiratory volume in 1 s was <1 L, 99.5% had chest radiography performed, 95.1% were prescribed systemic corticosteroids and 95% were prescribed antibiotic therapy. There were 89.1% given oxygen therapy and 92.6% when arterial oxygen tension was <80 mmHg; 65.6% were given ventilatory assistance when pH was <7.35. Only 32.4% were referred to pulmonary rehabilitation but 76.8% had general practitioner follow-up arranged. CONCLUSION: When compared against clinical practice guidelines, we found important gaps in management of patients admitted with COPD throughout tertiary care centres in Australia. Strategies to improve guideline uptake are needed to optimise care.

Does maintenance azithromycin reduce asthma exacerbations? An individual participant data meta-analysis.

BACKGROUND: Preventing exacerbations is an important goal of asthma treatment. Long-term treatment with azithromycin may help achieve this. Our aim was to conduct a systematic review and individual participant data (IPD) meta-analysis to examine the efficacy of azithromycin in reducing exacerbations in asthma, and in the subphenotypes of noneosinophilic asthma, eosinophilic asthma and severe asthma. METHOD: We completed a systematic search of Embase, MEDLINE, PubMed, Cochrane Library, ClinicalTrials.gov and reference lists of previous systematic reviews in February 2019. We included parallel-group, double-blind, randomised controlled trials in adults comparing at least 8 weeks of azithromycin treatment with placebo, where the outcome of exacerbations was assessed over at least 6 months. Data were extracted from published sources, Cochrane Risk of Bias Tool was applied and IPD were sought from authors. Reviews were undertaken in duplicate. We conducted an IPD meta-analysis on the primary outcome of exacerbations and a random effects meta-analysis for secondary outcomes. RESULTS: Three studies were identified (n=604). In the IPD meta-analysis, treatment with azithromycin was associated with a reduced rate of exacerbations (oral corticosteroid course due to worsening asthma, antibiotic use for lower respiratory tract infection, hospitalisation and/or emergency department visits) in asthma as well as in the noneosinophilic, eosinophilic and severe asthma subgroups. Examining each exacerbation type separately, patients with eosinophilic asthma reported fewer oral corticosteroid courses, and patients with noneosinophilic and severe asthma reported fewer antibiotic courses. Azithromycin was well tolerated. DISCUSSION: Maintenance use of azithromycin reduces exacerbations in patients with eosinophilic, noneosinophilic and severe asthma.

Extrapulmonary associations of health status in severe asthma and bronchiectasis: Comorbidities and functional outcomes.

BACKGROUND: Severe asthma and bronchiectasis are heterogeneous diseases that contribute to disability beyond the pulmonary system. The magnitude of the impact that these extrapulmonary features has on health-related quality of life (HRQoL) is unknown. METHODS: We analysed the cross-sectional relationships between HRQoL (St. George's Respiratory Questionnaire; SGRQ) and extrapulmonary characteristics, including physical activity (steps/day), anxiety and depression, isometric leg strength, systemic inflammation, and several comorbidities in adults with severe asthma (n = 70) and bronchiectasis (n = 61). RESULTS: Participants with severe asthma and bronchiectasis had similar SGRQ total scores (mean scores 43.7 and 37.8 for severe asthma and bronchiectasis; p > 0.05), and similar pulmonary and extrapulmonary characteristics. The associations between extrapulmonary variables and HRQoL did not differ according to diagnosis (all interactions p > 0.05). Greater anxiety and depressive symptoms, fewer steps/day and greater systemic inflammation were statistically associated with poorer HRQoL in both diseases (p < 0.05). Lower isometric leg strength in severe asthma, and greater Charlson Comorbidity Index in bronchiectasis were also associated with poorer HRQoL (p < 0.05). In the multivariable regression model performed in the combined disease groups, anxiety and depression, steps/day, systemic inflammation and isometric leg strength remained independently associated with HRQoL. Associations between extrapulmonary characteristics and SGRQ domains were stronger for the activity and impact domains, than symptoms. CONCLUSION: In severe asthma and bronchiectasis, extrapulmonary features including physical activity and leg strength have a significant impact on HRQoL, especially within the activity and impact domains. These features should be considered as part of the assessment of these conditions, and they may represent additional treatment targets to improve HRQoL.

Physical activity protects from incident anxiety: A meta-analysis of prospective cohort studies.

BACKGROUND: Prospective cohorts have suggested that physical activity (PA) can decrease the risk of incident anxiety. However, no meta-analysis has been conducted. AIMS: To examine the prospective relationship between PA and incident anxiety and explore potential moderators. METHODS: Searches were conducted on major databases from inception to October 10, 2018 for prospective studies (at least 1 year of follow-up) that calculated the odds ratio (OR) of incident anxiety in people with high PA against people with low PA. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). A random-effects meta-analysis was conducted and heterogeneity was explored using subgroup and meta-regression analysis. RESULTS: Across 14 cohorts of 13 unique prospective studies (N = 75,831, median males = 50.1%) followed for 357,424 person-years, people with high self-reported PA (versus low PA) were at reduced odds of developing anxiety (adjusted odds ratio [AOR] = 0.74; 95% confidence level [95% CI] = 0.62, 0.88; crude OR = 0.80; 95% CI = 0.69, 0.92). High self-reported PA was protective against the emergence of agoraphobia (AOR = 0.42; 95% CI = 0.18, 0.98) and posttraumatic stress disorder (AOR = 0.57; 95% CI = 0.39, 0.85). The protective effects for anxiety were evident in Asia (AOR = 0.31; 95% CI = 0.10, 0.96) and Europe (AOR = 0.82; 95% CI = 0.69, 0.97); for children/adolescents (AOR = 0.52; 95% CI = 0.29, 0.90) and adults (AOR = 0.81; 95% CI = 0.69, 0.95). Results remained robust when adjusting for confounding factors. Overall study quality was moderate to high (mean NOS = 6.7 out of 9). CONCLUSION: Evidence supports the notion that self-reported PA can confer protection against the emergence of anxiety regardless of demographic factors. In particular, higher PA levels protects from agoraphobia and posttraumatic disorder.

Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report.

"Treatable traits" have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.

Treatable traits can be identified in a severe asthma registry and predict future exacerbations.

BACKGROUND AND OBJECTIVE: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. METHODS: The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. RESULTS: In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. CONCLUSION: Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.

Is the reported increase in young female hospital-treated intentional self-harm real or artefactual?

BACKGROUND: The Australian Institute of Health and Welfare has reported an increased rate of hospital-treated intentional self-harm in young females (2000-2012) in Australia. These reported increases arise from institutional data that are acknowledged to underestimate the true rate, although the degree of underestimation is not known. OBJECTIVE: To consider whether the reported increase in young females' hospital-treated intentional self-harm is real or artefactual and specify the degree of institutional underestimation. METHODS: Averages for age- and gender-standardised event rates for hospital-treated intentional self-harm (national: Australian Institute of Health and Welfare; state: New South Wales Ministry of Health) were compared with sentinel hospital event rates for intentional self-poisoning (Hunter Area Toxicology Service, Calvary Mater Newcastle) in young people (15-24 years) for the period 2000-2012. A time series analysis of the event rates for the sentinel hospital was conducted. RESULTS: The sentinel hospital event rates for young females of 444 per 100,000 were higher than the state (378 per 100,000) and national (331 per 100,000) rates. There was little difference in young male event rates - sentinel unit: 166; state: 166 and national: 153 per 100,000. The sentinel hospital rates showed no change over time for either gender. CONCLUSION: There was no indication from the sentinel unit data of any increase in rates of intentional self-poisoning for young females. The sentinel and state rates were higher than the national rates, demonstrating the possible magnitude of underestimation of the national data. The reported increases in national rates of hospital-treated self-harm among young females might be due to artefactual factors, such as changes in clinical practice (greater proportion admitted), improved administrative coding of suicidal behaviours or possibly increased hospital presentations of community self-injury cases, but not intentional self-poisoning. A national system of sentinel units is needed for the accurate and timely monitoring of all hospital-treated self-harm.

Health-related quality of life burden in severe asthma.

It is largely unrecognised that the impacts of asthma are different in patients with severe disease compared with patients with mild to moderate disease. Severe asthma is associated with a significant health-related quality of life (HRQoL) burden due to excessive symptoms, frequent and life-threatening attacks, increased comorbidity burden, and high pharmacological treatment requirements. Interventions aimed at improving HRQoL need to be specifically tested in populations with severe asthma, including multicomponent interventions targeting the many clinical characteristics associated with the disease. It is necessary to have patient-reported outcome measures developed specifically for severe asthma. Public health messages recognising the significant burden of severe asthma on quality of life are needed.

Multidimensional assessment of severe asthma: A systematic review and meta-analysis.

The management of severe asthma is complex. Multidimensional assessment (MDA) of specific traits has been proposed as an effective strategy to manage severe asthma, although it is supported by few prospective studies. We aimed to systematically review the literature published on MDA in severe asthma, to identify the traits included in MDA and to determine the effect of MDA on asthma-related outcomes. We identified 26 studies and classified these based on study type (cohort/cross-sectional studies; experimental/outcome studies; and severe asthma disease registries). Study type determined the comprehensiveness of the assessment. Assessed traits were classified into three domains (airways, co-morbidities and risk factors). The airway domain had the largest number of traits assessed (mean ± SD = 4.2 ± 1.7) compared with co-morbidities (3.6 ± 2.2) and risk factors (3.9 ± 2.1). Bronchodilator reversibility and airflow limitation were assessed in 92% of studies, whereas airway inflammation was only assessed in 50%. Commonly assessed co-morbidities were psychological dysfunction, sinusitis (both 73%) and gastro-oesophageal reflux disease (GORD; 69%). Atopic and smoking statuses were the most commonly assessed risk factors (85% and 86%, respectively). There were six outcome studies, of which five concluded that MDA is effective at improving asthma-related outcomes. Among these studies, significantly more traits were assessed than treated. MDA studies have assessed a variety of different traits and have shown evidence of improved outcomes. This promising model of care requires more research to inform which traits should be assessed, which traits should be treated and what effect MDA has on patient outcomes.

Basal autonomic activity, stress reactivity, and increases in metabolic syndrome components over time.

CONTEXT: Basal autonomic nervous system (ANS) functioning has been linked to the metabolic syndrome (MetS), but the role of ANS reactivity in response to stress remains unclear. OBJECTIVE: To examine cross-sectionally and longitudinally to what extent ANS basal level and stress reactivity are related to MetS. DESIGN: 2-year and 6-year data from a prospective cohort: the Netherlands Study of Depression and Anxiety. SETTING: Participants were recruited from the general community, primary care, and mental health care organizations. PARTICIPANTS: 1922 respondents (mean age=43.7years). MAIN OUTCOME MEASURES: Indicators of ANS functioning were heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP). ANS stress reactivity was measured during a cognitively challenging stressor and a personal-emotional stressor. MetS components included triglycerides, high-density lipoprotein cholesterol, blood pressure, glucose and waist circumference. RESULTS: Cross-sectional analyses indicated that higher basal HR, lower basal values of RSA and PEP, and higher RSA reactivity during cognitive challenge were related to less favorable values of almost all individual MetS components. Longitudinal analyses showed that higher basal HR and shorter basal PEP predicted 4-year increase in many MetS abnormalities. Higher RSA stress reactivity during cognitive challenge predicted 4-year increase in number of MetS components. CONCLUSION: Higher basal sympathetic, lower basal parasympathetic activity, and increased parasympathetic withdrawal during stress are associated with multiple MetS components, and higher basal sympathetic activity predicts an increase in metabolic abnormalities over time. These findings support a role for ANS dysregulation in the risk for MetS and, consequently, the development of cardiovascular disease.

BIDIRECTIONAL PROSPECTIVE ASSOCIATIONS OF METABOLIC SYNDROME COMPONENTS WITH DEPRESSION, ANXIETY, AND ANTIDEPRESSANT USE.

BACKGROUND: Metabolic syndrome components-waist circumference, high-density lipoprotein cholesterol (HDL-C), triglycerides, systolic blood pressure and fasting glucose-are cross-sectionally associated with depression and anxiety with differing strength. Few studies examine the relationships over time or whether antidepressants have independent effects. METHODS: Participants were from the Netherlands Study of Depression and Anxiety (NESDA; N = 2,776; 18-65 years; 66% female). At baseline, 2- and 6-year follow-up, participants completed diagnostic interviews, depression and anxiety symptom inventories, antidepressant use assessment, and measurements of the five metabolic syndrome components. Data were analyzed for the consistency of associations between psychopathology indicators and metabolic syndrome components across the three assessment waves, and whether psychopathology or antidepressant use at one assessment predicts metabolic dysregulation at the next and vice versa. RESULTS: Consistently across waves, psychopathology was associated with generally poorer values of metabolic syndrome components, particularly waist circumference and triglycerides. Stronger associations were observed for psychopathology symptom severity than diagnosis. Antidepressant use was independently associated with higher waist circumference, triglycerides and number of metabolic syndrome abnormalities, and lower HDL-C. Symptom severity and antidepressant use were associated with subsequently increased number of abnormalities, waist circumference, and glucose after 2 but not 4 years. Conversely, there was little evidence that metabolic syndrome components were associated with subsequent psychopathology outcomes. CONCLUSIONS: Symptom severity and antidepressant use were independently associated with metabolic dysregulation consistently over time and also had negative consequences for short-term metabolic health. This is of concern given the chronicity of depression and anxiety and prevalence of antidepressant treatment.

Inflammation mediates the association between fatty acid intake and depression in older men and women.

Antioxidants and fatty acids are associated with depression and inflammation, and inflammation appears to predict depression risk; hence, the associations between these nutrients and depression may be mediated by inflammation. We hypothesized that inflammatory markers interleukin (IL)-6 and C-reactive protein (CRP) mediate the associations between antioxidant and fatty acid intakes, and depression. Participants were from the Hunter Community Study, a longitudinal cohort of adults aged 55-85 years. Dietary intake was assessed using the Older Australian's Food Frequency Questionnaire. Fasting blood samples were drawn for analysis of nutrient and inflammatory biomarkers. Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies-Depression scale at baseline and at 5-year follow-up. Linear mixed models were used to investigate longitudinal associations between dietary intakes and depression, and mediation analyses were carried out to determine if IL-6 and/or CRP were the mediators. Analyses were conducted on men and women separately and adjusted for potential confounders. Fruit and monounsaturated fat intakes were negatively associated with depression, whereas total fat and saturated fat intakes were positively associated with depression in both sexes. Omega-3 polyunsaturated fat was inversely associated with depression in men only. IL-6 was a significant mediator of the association between fruits with low carotenoid content and depression in women. CRP significantly mediated the relationship between total fat, saturated fat, and monounsaturated fat intakes and depression in women, and saturated fat intake and depression in men. Our findings raise the possibility that the association between fatty acid intake and depression is partially mediated by inflammatory markers.