Increasing physical activity in severe asthma: a systematic review and meta-analysis.

INTRODUCTION: Physical inactivity is common in asthma and is recognised as an important modifiable risk for poor clinical outcomes such as impaired asthma control and health-related quality of life (HRQoL). Despite evidence supporting the role of physical activity in reducing the risk of these outcomes, little is known about optimal interventions for increasing physical activity in those with severe disease. This systematic review and meta-analysis evaluates the effectiveness of interventions in increasing physical activity in severe asthma. METHODS: MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, Informit, SPORTDiscus and Cochrane databases were searched up to September 2021 for physical activity-based intervention studies that assessed physical activity outcomes (e.g. steps per day, time spent undertaking physical activity) in adults with severe asthma. Data on asthma-related (e.g. asthma control) and health-related outcomes (e.g. HRQoL) were assessed as secondary outcomes. The revised Cochrane Risk of Bias tool was used to assess risk of bias. Random-effects meta-analyses synthesised data where possible. RESULTS: Four randomised controlled trials (all 12 weeks in duration) including 176 adults with moderate-to-severe asthma were included. An increase in physical activity was reported with a moderate-vigorous intensity aerobic and resistance training intervention (steps per day and time spent undertaking physical activity), and an unsupervised pedometer-based intervention (steps per day). Meta-analyses showed that physical activity interventions had an overall positive effect on steps per day (mean difference (MD) 1588, 95% CI 399-2778; p=0.009, I2=23), asthma control (MD -0.65, 95% CI -0.95--0.35; p<0.0001, I2=0%) and HRQoL (MD 0.56, 95% CI 0.10-1.01; p=0.02, I2=16%) compared to control. CONCLUSION: While there is some evidence supporting the effectiveness of interventions in improving physical activity in adults with severe asthma, higher-quality, large-scale studies of longer duration are needed to determine the optimal intervention.

Associations of symptoms of anxiety and depression with health-status, asthma control, dyspnoea, dysfunction breathing and obesity in people with severe asthma.

BACKGROUND: Anxiety and depression are comorbidities of severe asthma. However, clinical characteristics associated with coexisting severe asthma and anxiety/depression are poorly understood. The study objective is to determine clinical characteristics associated with anxiety and depressive symptoms in severe asthma. METHODS: Severe asthma participants (N = 140) underwent a multidimensional assessment. Categorization of symptoms of anxiety and depression were based on HADS scale sub-scores and divided into four groups (< 8 on both subscales; ≥ 8 on one subscale; ≥ 8 on both subscales). Clinical characteristics were compared between subgroups. Multivariate logistic regression determined associations of clinical characteristics and anxiety and/or depressive symptoms in people with severe asthma. RESULTS: Participants were (mean ± SD) 59.3 ± 14.7 years old, and 62% female. There were 74 (53%) severe asthma participants without symptoms of anxiety/depression, 11 (7%) with symptoms of anxiety, 37 (26%) with symptoms of depression and 18 (13%) with symptoms of anxiety and depression. Quality of life impairment was greater in participants with symptoms of depression (4.4 ± 1.2) and combined symptoms of anxiety and depression (4.4 ± 1.1). Asthma control was worse in those with symptoms of depression (2.9 ± 1.1) and combined anxiety and depression (2.6 ± 1.0). In multivariate models, dysfunctional breathing was associated with symptoms of anxiety (OR = 1.24 [1.01, 1.53]). Dyspnoea was associated with symptoms of depression (OR = 1.90 [1.10, 3.25]). Dysfunctional breathing (OR 1.16 [1.04, 1.23]) and obesity (OR 1.17 [1.00, 1.35]) were associated with combined symptoms of anxiety and depression. CONCLUSION: People with severe asthma and anxiety and/or depressive symptoms have poorer QoL and asthma control. Dyspnoea, dysfunctional breathing and obesity are associated with these symptoms. These key clinical characteristics should be targeted in severe asthma management.

Factors associated with 6-min walk distance in severe asthma: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Exercise capacity is associated with health-related quality of life and symptom control in severe asthma. Thus, interventions targeting exercise capacity are likely to be beneficial. However, clinical and biological factors impacting exercise capacity in severe asthma are sparsely investigated. We aimed to describe the association of selected clinical and biological factors with 6-min walk distance (6MWD) in adults with severe asthma and investigate the impact of sex on these outcomes. METHODS: A cross-sectional study in adults with severe asthma was conducted. Exercise capacity was measured by 6-min walk test, and association between 6MWD and predictors were evaluated using multiple linear regression. RESULTS: A total of 137 patients (females, 85; median age, 59 years) were recruited. Overall, asthma control (-15.2 m, 95% CI -22.6 to -7.7; p = 0.0001) and BMI (-3.2 m, 95% CI -5.1 to -1.3; p = 0.001) were significantly associated with exercise capacity (adjusted variance, adj. R2  = 0.425). In females, 5-item Asthma Control Questionnaire (ACQ-5; p = 0.005) and BMI (p < 0.001) were significantly associated with 6MWD (adj. R2  = 0.423). In males, a 0.5-point increase in ACQ-5 was associated with a decrease in 6MWD by 10.2 m (95% CI -22.8 to 2.4; p = 0.11), but no clinical nor biological factors reached statistical significance (adj. R2  = 0.393). CONCLUSION: Asthma symptoms and BMI were associated with exercise capacity in the overall population. Optimizing these factors may enhance the ability of patients to improve their exercise capacity and gain the associated positive health outcomes, but further studies are warranted.

The needs and well-being of severe asthma and COPD carers: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Caring for people with severe asthma and chronic obstructive pulmonary disease (COPD) can impair the quality of life (QoL) of the carer. We aimed to describe the QoL and needs of severe asthma and COPD carers. METHODS: Carers of severe asthma (n = 89) and COPD (n = 48) completed an online cross-sectional survey assessing QoL and carer support needs using the Short Form Health Survey 12v2 (SF-12), the Hospital Anxiety and Depression Scale (HADS) and Carers Support Needs Assessment Tool (CSNAT) questionnaires. RESULTS: Carers of people with severe asthma and COPD were similar in age (mean ± SD 57.78 ± 14.09 vs. 56.93 ± 12.91) and gender (65% female vs. 66%); however, they differed in caring duration (proportion caring for >10 years: 65% vs. 33%, p < 0.002). QoL was impaired in both groups, but there were no significant differences between severe asthma and COPD carers in either of the SF-12 component scores. The HADS scores revealed no difference between groups. Compared to severe asthma carers, COPD carers had significantly greater needs for: 'having time for self' (33% vs. 13%, p = 0.006), 'equipment to help care for relative' (33% vs. 13%, p = 0.006), 'practical help in the home' (35% vs. 18%, p = 0.006) and 'getting a break from caring overnight' (21% vs. 6%, p = 0.023). CONCLUSION: QoL is impaired in carers of people with severe asthma to a similar degree of COPD carers and other debilitating diseases like cancer. These novel data highlight the support needs of severe asthma carers and identifies areas where tailored support is needed to reduce their substantial carer burden.

Targeting treatable traits in severe asthma: a randomised controlled trial.

RATIONALE: Treatable traits have been proposed as a new paradigm for airway disease management. OBJECTIVES: To characterise treatable traits in a severe asthma population and to determine the efficacy of targeting treatments to these treatable traits in severe asthma. METHODS: Participants (n=140) with severe asthma were recruited to a cross-sectional study and underwent a multidimensional assessment to characterise treatable traits. Eligible participants with severe asthma (n=55) participated in a 16-week parallel-group randomised controlled trial to determine the feasibility and efficacy of management targeted to predefined treatable traits, compared to usual care in a severe asthma clinic. The patient-reported outcome of health-related quality of life was the trial's primary end-point. MAIN RESULTS: Participants with severe asthma had a mean±sd of 10.44±3.03 traits per person, comprising 3.01±1.54 pulmonary and 4.85±1.86 extrapulmonary traits and 2.58±1.31 behavioural/risk factors. Individualised treatment that targeted the traits was feasible and led to significantly improved health-related quality of life (0.86 units, p<0.001) and asthma control (0.73, p=0.01). CONCLUSIONS: Multidimensional assessment enables detection of treatable traits and identifies a significant trait burden in severe asthma. Targeting these treatable traits using a personalised-medicine approach in severe asthma leads to improvements in health-related quality of life, asthma control and reduced primary care acute visits. Treatable traits may be an effective way to address the complexity of severe asthma.

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.

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.

Randomised controlled trial of a healthy lifestyle intervention among smokers with psychotic disorders: Outcomes to 36 months.

OBJECTIVE: People living with psychotic disorders (schizophrenia spectrum and bipolar disorders) have high rates of cardiovascular disease risk behaviours, including smoking, physical inactivity and poor diet. We report cardiovascular disease risk, smoking cessation and other risk behaviour outcomes over 36 months following recruitment into a two-arm randomised controlled trial among smokers with psychotic disorders. METHODS: Participants ( N = 235) drawn from three sites were randomised to receive nicotine replacement therapy plus (1) a Healthy Lifestyles intervention delivered over approximately 9 months or (2) a largely telephone-delivered intervention (designed to control for nicotine replacement therapy provision, session frequency and other monitoring). The primary outcome variables were 10-year cardiovascular disease risk and smoking status, while the secondary outcomes included weekly physical activity, unhealthy eating, waist circumference, psychiatric symptomatology, depression and global functioning. RESULTS: Significant reductions in cardiovascular disease risk and smoking were detected across the 36-month follow-up period in both intervention conditions, with no significant differences between conditions. One-quarter (25.5%) of participants reported reducing cigarettes per day by 50% or more at multiple post-treatment assessments; however, few (8.9%) managed to sustain this across the majority of time points. Changes in other health behaviours or lifestyle factors were modest; however, significant improvements in depression and global functioning were detected over time in both conditions. Participants experiencing worse 'social discomfort' at baseline (e.g. anxiety, mania, poor self-esteem and social disability) had on average significantly worse global functioning, lower scores on the 12-Item Short Form Health Survey physical scale and significantly greater waist circumference. CONCLUSION: Although the telephone-delivered intervention was designed as a comparison condition, it achieved excellent retention and comparable outcomes. Telephone-delivered smoking cessation support may potentially help to reduce smoking rates among people with psychotic disorders. Discomfort in social situations may also be a useful target for future health interventions, addressing confidence and social skills, and promoting social networks that reduce inactivity.

Addiction Vulnerability: Exploring Relationships Among Cigarette Smoking, Substance Misuse, and Early Psychosis.

OBJECTIVE: Smoking rates in adolescents at risk for psychosis are significantly greater than in those who are not at risk. Recent research suggests that cigarette smoking in adolescence may be a potential marker of transition to psychosis, although the exact relationship between the two remains unclear. Our aim was to examine whether tobacco smoking is a potential marker of transition to psychosis or subsequent episodes of psychosis, independently of other substance use, or alternatively whether smoking is essentially a general marker of later mental illness episodes. METHODS: This substudy was conducted as part of an audit of a specialized early psychosis community mental health service, the Psychological Assistance Service (PAS). A multilayered audit over 10 years (January 1997 to December 2007) of PAS presentations was conducted (N = 1997), which documented baseline sociodemographic and clinical characteristics and subsequent illness episodes and service usage. Among clients with baseline smoking status information (n = 421, mean age = 18.3 years), this study examined predictors of transition to or subsequent episodes of psychosis, substance misuse, and affective disorder. RESULTS: A recent psychosis episode at baseline and receiving ongoing treatment from PAS predicted transition to or subsequent psychosis episodes; however, baseline ultra-high-risk status was not predictive. In addition, baseline smoking/substance misuse status was a significant predictor, with smokers being twice as likely to experience a subsequent episode of psychosis, even after controlling for other baseline comorbidity. Baseline smoking status also independently predicted subsequent substance misuse episodes, but not subsequent affective disorder. Among clients experiencing post-PAS comorbid substance misuse and psychosis, the majority (80.3%) reported smoking at baseline. CONCLUSIONS: Smoking status at service presentation appeared to function as a general proxy for addiction vulnerability among young help seekers and thereby as a potential marker for the development of severe mental illness (including psychosis) and associated health problems. Routine evaluations of presenting problems need to incorporate comprehensive assessments of early substance misuse and tobacco smoking. Adjunctive lifestyle interventions promoting smoking cessation, physical health, and well-being need to be offered in conjunction with conventional mental health interventions tailored to key presenting problems, recovery, and psychological strengthening.

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.

Self-Reported Reasons for Smoking: Predicting Abstinence and Implications for Smoking Cessation Treatments Among Those With a Psychotic Disorder.

OBJECTIVES: People living with a psychotic illness have higher rates of cigarette smoking and face unique barriers to quitting compared to the general population. We examined whether self-reported reasons for smoking are useful predictors of successful quit attempts among people with psychosis. METHODS: As part of a randomized controlled trial addressing smoking and cardiovascular disease risk behaviors among people with psychosis, self-reported reasons for smoking were assessed at baseline (n = 235), 15 weeks (n = 151), and 12 months (n = 139). Three factors from the Reasons for Smoking Questionnaire (Coping, Physiological, and Stimulation/Activation) were entered into a model to predict short- and long-term abstinence. The relationship between these factors and mental health symptoms were also assessed. RESULTS: Participants scoring higher on the Stimulation/Activation factor (control of weight, enjoyment, concentration, and "peps me up") at baseline were just less than half as likely to be abstinent at 15 weeks. Female participants were five times more likely to abstinent at 15 weeks, and those with a higher global functioning at baseline were 5% more likely to be abstinent. There was a positive correlation between changes over time in the Stimulation/Activation factor from baseline to 12-month follow-up and the Brief Psychiatric Rating Scale total score at 12-month follow-up. This indicates that increasingly higher endorsement of the factor was associated with more psychological symptoms. There was also a negative correlation between the change over time in the Stimulation/Activation factor and global functioning at 12 months, indicating that increasingly higher endorsement of the factor led to lower global assessment of functioning. CONCLUSIONS: The Stimulation/Activation factor may be particularly important to assess and address among smokers with psychosis. It is recommended that further research use the Reasons for Smoking Questionnaire among smokers with psychosis as a clinical tool to identify specific quit barriers. Further research into why females have higher smoking cessation rates in the short term and relapse prevention interventions seem worthy of further investigation.

Early Therapeutic Alliance, Treatment Retention, and 12-Month Outcomes in a Healthy Lifestyles Intervention for People with Psychotic Disorders.

Engaging and retaining individuals with psychotic disorders in psychosocial treatments is difficult. Early therapeutic alliance, treatment retention, and 12-month outcomes were examined in a subsample of smokers with a psychotic disorder (N = 178) participating in a healthy lifestyles study comparing a telephone versus face-to-face delivered intervention. Therapeutic alliance was assessed using the Agnew Relationship Measure; primary outcomes were treatment retention and changes in symptoms and health behaviors. Contrary to expectations, early alliance did not predict treatment retention. However, elements of both client- and therapist-rated alliance predicted some clinical outcomes (e.g., higher confidence in the therapeutic alliance at session 1 predicted improvements in 12-month depression). Some modest interactions between early alliance and intervention condition were also identified (e.g., clients initially with lower self-perceived initiative, or higher therapist-perceived bonding benefited preferentially from the telephone-delivered intervention), highlighting the need to further examine the interplay between therapeutic alliance and treatment modality.

Randomized Controlled Trial of a Healthy Lifestyle Intervention Among Smokers With Psychotic Disorders.

INTRODUCTION: People with severe mental disorders typically experience a range of health problems; consequently, interventions addressing multiple health behaviors may provide an efficient way to tackle this major public health issue. This two-arm randomized controlled trial among people with psychotic disorders examined the efficacy of nicotine replacement therapy (NRT) plus either a face-to-face or predominantly telephone delivered intervention for smoking cessation and cardiovascular disease (CVD) risk reduction. METHODS: Following baseline assessment and completion of a common, individually delivered 90-minute face-to-face intervention, participants (n = 235) were randomized to receive NRT plus: (1) a "Healthy Lifestyles" intervention for smoking cessation and CVD risk behaviors or (2) a predominantly telephone-based intervention (designed to control for NRT provision, session frequency, and other monitoring activities). Research assistants blind to treatment allocation performed assessments at 15 weeks (mid-intervention) and 12 months after baseline. RESULTS: There were no significant differences between intervention conditions in CVD risk or smoking outcomes at 15 weeks or 12 months, with improvements in both conditions (eg, 12 months: 6.4% confirmed point prevalence abstinence rate; 17% experiencing a 50% or greater smoking reduction; mean reduction of 8.6 cigarettes per day; mean improvement in functioning of 9.8 points). CONCLUSIONS: The health disparity experienced by people with psychotic disorders is high. Face-to-face Healthy Lifestyle interventions appear to be feasible and somewhat effective. However, given the accessibility of telephone delivered interventions, potentially combined with lower cost, further studies are needed to evaluate telephone delivered smoking cessation and lifestyle interventions for people with psychotic disorders.

Core Function in Adults With Severe Asthma and Its Relationship With Breathing Symptoms.

BACKGROUND: People with asthma may have skeletal muscle dysfunction but data describing core function in severe asthma are limited. OBJECTIVE: To compare core function between people with severe asthma and healthy controls and to determine the difference between males and females. Furthermore, we aimed to investigate the association between core function and breathing symptoms. METHOD: Adults with a diagnosis of severe asthma and healthy controls undertook an assessment that included 3 core function tests: partial sit-up, Biering-Sorensen, and side bridge. Breathing symptoms were assessed by the modified Medical Research Council dyspnea scale, modified Borg scale, and Nijmegen questionnaire. RESULTS: People with severe asthma (n = 136) (38% male, age median [Q1-Q3] 59 y [45-68], body mass index 30 kg/m2 [26-37]) were compared with 66 people without respiratory disease (47% male, age 55 y [34-65], body mass index 25 kg/m2 [22-28]). There was no difference between groups in the partial sit-up (P = .09). However, participants with severe asthma performed worse with the Biering-Sorensen (P < .001), and the left and right side bridge test (P < .001 for both) than the healthy comparison group. Similar results were found when comparing males and females separately. Males with severe asthma had increased function compared with their female counterparts in the left side bridge test. Core function tests correlated with the breathing symptom measures, the modified Medical Research Council, modified Borg scale, and Nijmegen questionnaire (-0.51 > r > -0.19; P ≤ .03). CONCLUSIONS: Adults with severe asthma have worse core function than their control counterparts, independent of sex. Furthermore, as core function decreases, breathing symptoms increase.

Living With Asthma and Vocal Cord Dysfunction/Inducible Laryngeal Obstruction: "I Just Can't Get Air In".

BACKGROUND: Asthma and vocal cord dysfunction (VCD), also known as inducible laryngeal obstruction (ILO), may coexist, resulting in worse outcomes for patients. The experience of people with VCD/ILO and coexisting asthma is unknown. OBJECTIVE: We sought to determine whether coexistent VCD/ILO and asthma have deleterious impacts on quality of life. METHODS: We undertook a descriptive qualitative study using one-to-one semistructured interviews with 30 purposively recruited adult participants with a prior confirmed doctor asthma diagnosis and laryngoscopy-confirmed VCD/ILO. A thematic and content analysis was conducted to explore the data. RESULTS: Participants were mostly female (63%), mean ± SD age 63 ± 12 years. Four themes were identified: trapped voice, altered life, knowledge about VCD/ILO, and looking for solutions. Participants reported their voice being trapped in their throat or the voice being suddenly cut off when talking or singing. Self-reported VCD/ILO symptoms including throat tightness and breathlessness were highlighted by participants. The second theme described how patients struggle to communicate or tended to shorten conversations. Insufficient knowledge and existing confusion regarding whether asthma was causing the breathlessness was described in the third theme. Looking for solutions depicted participants' diagnostic journey and how they sought an explanation for the symptoms. CONCLUSIONS: People with asthma and coexisting VCD/ILO experience a substantial burden affecting the quality of life. These data describe the impact on patients with coexisting conditions and should be used to increase clinician awareness of the experience of VCD/ILO from patients' perspectives to support a personalized approach to care.

The illness burden of severe asthma contrasted to people with mild-to-moderate asthma: a qualitative study.

Background: Disabling symptoms of asthma including breathlessness, cough, wheeze and chest tightness largely impact quality of life; however, how these symptoms impact people with asthma of different severity levels remains unknown. This study aimed to compare and characterise patients' symptom experience and the burden caused, their quality of life, and the medication preferences of people with severe asthma against those of people with mild-to-moderate asthma. Methods: This was a multisite qualitative study involving two focus groups and semistructured interviews of adults with severe asthma undertaken in Australia and UK. Interviews were also undertaken in people with mild-to-moderate asthma. Audio recordings were transcribed and analysed thematically. Results: Participants in both severe asthma and mild-to-moderate asthma groups had a mean±sd age of 57±12 years. Between the severe asthma and mild-to-moderate asthma groups, 62% of participants were female and 86% lived with family. Themes were identified: 1) what is asthma and most bothersome symptoms: both groups reported breathlessness as the most bothersome symptom; 2) impacts on life: disease-related impact differed as people with severe asthma reported significant burden in their quality of life, which encompassed emotional, physical, social and financial wellbeing; and 3) personalised and responsive care: severe asthma interviewees preferred injectable biological therapy as a mode of treatment administration. Conclusions: People with asthma are burdened by breathlessness and cough and other disabling symptoms resulting in impaired quality of life. Understanding the experiences of people with asthma of different severities can improve the patient-clinician partnership.

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.

Natural selection and functional genetic variation in the p53 pathway.

The allele frequencies of two functional single-nucleotide polymorphisms (SNPs) in the p53 pathway, the MDM2 SNP309 and TP53 Arg72Pro, vary dramatically among populations. That the frequencies of the TP53 SNP follow a clinal distribution may suggest that selective pressure from environmental variables correlated with latitude contributed to these observed population differences. Recently, winter temperature and UV radiation were found to be significantly correlated with the TP53 and the MDM2 SNPs, respectively, in East Asians; whether these correlations are more extreme than expected based upon nonselective factors such as patterns of human migration remains unclear. Here, we genotyped these two SNPs in 971 unrelated individuals from 52 unique populations worldwide and tested for correlations with both latitude and a number of climate-related environmental variables on a global scale, controlling for these neutral processes. The TP53 SNP was associated with a significant selection signal for a few climate variables, such as short-wave radiation flux in the winter, but these signals were no longer significant after correction for multiple tests. The MDM2 SNP did not exhibit a significant signal with any climate variable. Therefore, these SNPs are unlikely to be under selective pressure driven by these variables. Thus, these data underscore the need to incorporate population history when assessing signatures of selection.

Cardiovascular outcomes of cancer patients in rural Australia.

Background: Cancer and heart disease are the two most common health conditions in the world, associated with high morbidity and mortality, with even worse outcomes in regional areas. Cardiovascular disease is the leading cause of death in cancer survivors. We aimed to evaluate the cardiovascular outcomes of patients receiving cancer treatment (CT) in a regional hospital. Methods: This was an observational retrospective cohort study in a single rural hospital over a ten-year period (17th February 2010 to 19th March 2019). Outcomes of all patients receiving CT during this period were compared to those who were admitted to the hospital without a cancer diagnosis. Results: 268 patients received CT during the study period. High rates of cardiovascular risk factors: hypertension (52.2%), smoking (54.9%), and dyslipidaemia (38.4%) were observed in the CT group. Patients who had CT were more likely to be readmitted with ACS (5.9% vs. 2.8% p = 0.005) and AF (8.2% vs. 4.5% p = 0.006) when compared to the general admission cohort. There was a statistically significant difference observed for all cause cardiac readmission, with a higher rate observed in the CT group (17.1% vs. 13.2% p = 0.042). Patients undergoing CT had a higher rate of mortality (49.5% vs. 10.2%, p ≤ 0.001) and shorter time (days) from first admission to death (401.06 vs. 994.91, p ≤ 0.001) when compared to the general admission cohort, acknowledging this reduction in survival may be driven at least in part by the cancer itself. Conclusion: There is an increased incidence of adverse cardiovascular outcomes, including higher readmission rate, higher mortality rate and shorter survival in people undergoing cancer treatment in rural environments. Rural cancer patients demonstrated a high burden of cardiovascular risk factors.

Population genetic analysis of the uncoupling proteins supports a role for UCP3 in human cold resistance.

Production of heat via nonshivering thermogenesis (NST) is critical for temperature homeostasis in mammals. Uncoupling protein UCP1 plays a central role in NST by uncoupling the proton gradients produced in the inner membranes of mitochondria to produce heat; however, the extent to which UCP1 homologues, UCP2 and UCP3, are involved in NST is the subject of an ongoing debate. We used an evolutionary approach to test the hypotheses that variants that are associated with increased expression of these genes (UCP1 -3826A, UCP2 -866A, and UCP3 -55T) show evidence of adaptation with winter climate. To that end, we calculated correlations between allele frequencies and winter climate variables for these single-nucleotide polymorphisms (SNPs), which we genotyped in a panel of 52 worldwide populations. We found significant correlations with winter climate for UCP1 -3826G/A and UCP3 -55C/T. Further, by analyzing previously published genotype data for these SNPs, we found that the peak of the correlation for the UCP1 region occurred at the disease-associated -3826A/G variant and that the UCP3 region has a striking signal overall, with several individual SNPs showing interesting patterns, including the -55C/T variant. Resequencing of the regions in a set of three diverse population samples helped to clarify the signals that we found with the genotype data. At UCP1, the resequencing data revealed modest evidence that the haplotype carrying the -3826A variant was driven to high frequency by selection. In the UCP3 region, combining results from the climate analysis and resequencing survey suggest a more complex model in which variants on multiple haplotypes may independently be correlated with temperature. This is further supported by an excess of intermediate frequency variants in the UCP3 region in the Han Chinese population. Taken together, our results suggest that adaptation to climate influenced the global distribution of allele frequencies in UCP1 and UCP3 and provide an independent source of evidence for a role in cold resistance for UCP3.