Dr Sarah Hiles

Background: Many patients drop out of guideline-recommended treatments for posttraumatic stress disorder (PTSD), yet there has been little systematic investigation of this issue. We aimed to examine dropout proportions from randomized controlled trials (RCTs) of guideline-recommended treatments for PTSD and whether proportions differed by type of treatment or trauma, PTSD severity or chronicity, or medication being permitted. Methods: Systematic review and meta-analysis of RCTs of guideline-recommended treatments for PTSD. Results: Eighty-five trials, with data for 6804 participants were included in the meta-analyses. The mean dropout proportion for guideline-recommended treatment was 20.9% (95%CI 17.2, 24.9) with evidence of high heterogeneity across studies. Military trauma was associated with higher dropout than civilian trauma. The civilian trauma group had similar dropout rates from guideline-recommended treatments, and active, waitlist or treatment as usual controls. In the military trauma group, dropout was higher from guideline-recommended treatments compared to active, waitlist or treatment as usual controls. Within this group, dropout from trauma-focused treatment was significantly higher than from non-trauma focused treatments overall, with the greatest difference in dropout rates occurring between randomization and treatment initiation. Limitations: Most RCTs exclude participants who have comorbid substance use disorder, suicidal behaviour, or history of psychosis, which limits the generalizability of findings. Conclusion: Dropout from guideline-recommended treatment for PTSD is higher in populations who have experienced military trauma and this population dropout from treatment in higher proportions when it is trauma-focused. The reasons for disparate rates of dropouts from recommended PTSD treatments require further investigation.

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.

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.

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.

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.

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.

Background: The level of physical activity (PA) and the prevalence of depression both change across the lifespan. We examined whether the association between PA and depression is moderated by age. As sense of mastery and functional limitations have been previously associated with low PA and depression in older adults, we also examined whether these are determinants of the differential effect of age on PA and depression. Methods: 1079 patients with major depressive disorder (aged 18¿88 years) were followed-up after two-years; depression diagnosis and severity as well as PA were re-assessed. Linear and logistic regression analyses were used to test reciprocal prospective associations between PA and depression outcomes. In all models the interaction with age was tested. Results: PA at baseline predicted remission of depressive disorder at follow-up (OR = 1.43 [95% CI: 1.07¿1.93], p =.018). This effect was not moderated by age. PA predicted improvement of depression symptom severity in younger (B = -2.03; SE =.88; p =.022), but not in older adults (B = 2.24; SE = 1.48; p =.128) (p =.015 for the interaction PA by age in the whole sample). The level of PA was relatively stable over time. Depression, sense of mastery and functional limitation were for all ages not associated with PA at follow-up. Conclusions: Age did not moderate the impact of PA on depressive disorder remission. Only in younger adults, sufficient PA independently predicts improvement of depressive symptom severity after two-year follow-up. Level of PA rarely changed over time, and none of the determinants tested predicted change in PA, independent of age.

Background Physical inactivity has been identified as a risk factor for depression and, less often, as a long-term consequence of depression. Underexplored is whether similar bi-directional longitudinal relationships are observed for anxiety disorders, particularly in relation to three distinct indicators of activity levels - sports participation, general physical activity and sedentary behavior. Method Participants were from the Netherlands Study of Depression and Anxiety (NESDA; N = 2932, 18-65 years old; 57% current anxiety or depressive disorder, 21% remitted disorder, 22% healthy controls). At baseline, 2, 4, and 6 years, participants completed a diagnostic interview and self-report questionnaires assessing psychopathology symptom severity, physical activity indicators, and sociodemographic and health covariates. Results Consistently across assessment waves, people with anxiety and/or depressive disorders had lower sports participation and general physical activity compared to healthy controls. Greater anxiety or depressive symptoms were associated with lower activity according to all three indicators. Over time, a diagnosis or greater symptom severity at one assessment was associated with poorer sports participation and general physical activity 2 years later. In the opposite direction, only low sports participation was associated with greater symptom severity and increased odds of disorder onset 2 years later. Stronger effects were observed for chronicity, with lower activity according to all indicators increasing the odds of disorder chronicity after 2 years. Conclusions Over time, there seems to a mutually reinforcing, bidirectional relationship between psychopathology and lower physical activity, particularly low sports participation. People with anxiety are as adversely affected as those with depression.

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.

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 = 43.7 years). 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.

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.

Depression and inflammatory markers have a reliable cross-sectional association although less is known about the prospective relationship. The current study investigated whether pro-inflammatory markers are prospectively associated with depression, and whether indicators of unhealthy lifestyle, physical health and psychosocial functioning may drive this association. Participants were drawn from the Hunter Community Study, a community-dwelling cohort of individuals aged 55-85 years (N=1410). Participants completed baseline physiological assessment, health-related questionnaires, and blood sampling for the analysis of inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6. Participants completed the same depressive symptom questionnaire again after 3.5-5.5 years. Depression outcomes at follow-up were analysed dichotomously using established scale cut-off scores and continuously as a "residual score", representing the variation in follow-up depressive symptoms not explained by baseline symptoms and age. Analyses were conducted on males and females separately. At baseline, indicators of unhealthy lifestyle, physical health and psychosocial functioning were associated with depressive symptoms and inflammatory markers. For males, there were no relationships between inflammatory markers and follow-up depression outcomes. In females, IL-6 was significantly associated with depression outcomes in univariate, but not multivariate analyses. However, IL-6 significantly mediated the association between the predictors of waist-to-hip ratio, smoking and psychological coping at baseline, and follow-up depression outcomes. The results support the inflammatory hypothesis of depression, although females may be more vulnerable to effects. The findings raise the possibility that unhealthy lifestyle and psychosocial stress may drive inflammation and subsequent depressive symptoms.

Objective: Hospital-treated deliberate self-poisoning (DSP) is common and the existing national monitoring systems are often deficient. Clinical Practice Guidelines (UK and Australia) recommend universal psychosocial assessment within the general hospital as standard care. We compared presentation rates, patient characteristics, psychosocial assessment and aftercare in UK and Australia. Methods: We used a cross sectional design, for a ten year study of all DSP presentations identified through sentinel units in Oxford, UK (n. = 3042) and Newcastle, Australia (n. = 3492). Results: Oxford had higher presentation rates for females (standardised rate ratio 2.4: CI 99% 1.9, 3.2) and males (SRR 2.5: CI 99% 1.7, 3.5). Female to male ratio was 1.6:1, 70% presented after-hours, 95% were admitted to a general hospital and co-ingestion of alcohol occurred in a substantial minority (Oxford 24%, Newcastle 32%). Paracetamol, minor tranquilisers and antidepressants were the commonest drug groups ingested, although the overall pattern differed. Psychosocial assessment rates were high (Oxford 80%, Newcastle 93%). Discharge referral for psychiatric inpatient admission (Oxford 8%, Newcastle 28%), discharge to home (Oxford 80%, Newcastle 70%) and absconding (Oxford 11%, Newcastle 2%) differed between the two units. Conclusions: Oxford has higher age-standardised rates of DSP than Newcastle, although many other characteristics of patients are similar. Services can provide a high level of assessment as recommended in clinical guidelines. There is some variation in after-care. Sentinel service monitoring routine care of DSP patients can provide valuable comparisons between countries.

This study investigated whether inflammation may explain the relationship between depression and incident cardiovascular hospitalisations. Participants (55¿85¿years) completed baseline depression and physical assessment. Those without self-reported cardiovascular events were followed prospectively for hospital admissions for angina, myocardial infarction and cerebral infarction (median 937¿days). Across 5140 person-years of risk (N¿=¿1692), there were 47 incident cardiovascular hospitalisations (2.8¿%). Controlling for age and gender, interleukin (IL)-6, C-reactive protein (CRP), body mass index (BMI) and waist-to-hip ratio were associated with future cardiovascular events. Mediation analysis showed that CRP accounted for 8.1¿% and IL-6 10.9¿% of the effect of depression on cardiovascular events, and including the indirect effect in the model substantially reduced the direct relationship between depression and cardiovascular hospitalisations. BMI and waist-to-hip ratio accounted for indirect effects of 7.7 and 10.4¿%, respectively. Inflammatory markers partly explain the association between depression and cardiovascular events, although other shared factors also likely contribute.