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INTRODUCTION: Several psychiatric disorders and medications used to treat them appear to be independently associated with skeletal deficits. As there is increasing evidence that lithium possesses skeletal protective properties, we aimed to investigate the association between lithium use and bone health in a group of women with bipolar disorder. METHOD: Women with bipolar disorder (n = 117, 20+ years) were recruited from south-eastern Australia. Bipolar disorder was confirmed using a clinical interview (SCID-I/NP). Bone mineral density (BMD; g/cm2 ) was measured at the spine, hip and total body using dual-energy x-ray absorptiometry and low bone mass determined by BMD T-score of <-1.0. Weight and height were measured, socioeconomic status (SES) determined and information on medication use and lifestyle factors self-reported. Linear and logistic regression were used to test associations between lithium and (i) BMD and (ii) low bone mass, respectively. RESULTS: Thirty-five (29.9%) women reported current lithium use. Lithium users and non-users differed in regard to SES and BMD; otherwise, groups were similar. After adjustments, mean BMD among lithium users was 5.1% greater at the spine (1.275 [95% CI 1.229-1.321] vs. 1.214 [1.183-1.244] g/cm2 , p = 0.03), 4.2% greater at the total hip (0.979 [0.942-1.016] vs. 0.938 [0.910-0.966] g/cm2 , p = 0.03) and 2.2% greater at the total body (1.176 [1.148-1.205] vs. 1.150 [1.129-1.171] g/cm2 , p = 0.08) compared to participants not receiving lithium. Lithium users were also less likely to have low bone mass (22.9% vs. 43.9%, p = 0.031). Associations persisted after adjustment for confounders. CONCLUSION: These data suggest lithium is associated with greater BMD and reduced risk of low bone mass in women with bipolar disorder. Research into the underlying mechanisms is warranted.

INTRODUCTION: Mood disorders are a major cause of disability, and current treatment options are inadequate for reducing the burden on a global scale. The aim of this project was to identify drugs suitable for repurposing to treat mood disorders. METHODS: This mixed-method study utilized gene expression signature technology and pharmacoepidemiology to investigate drugs that may be suitable for repurposing to treat mood disorders. RESULTS: The transcriptional effects of a combination of drugs commonly used to treat mood disorders included regulation of the steroid and terpenoid backbone biosynthesis pathways, suggesting a mechanism involving cholesterol biosynthesis, and effects on the thyroid hormone signaling pathway. Connectivity Map analysis highlighted metformin, an FDA-approved treatment for type 2 diabetes, as a drug having global transcriptional effects similar to the mood disorder drug combination investigated. In a retrospective cohort study, we found evidence that metformin is protective against the onset of mood disorders. DISCUSSION: These results provide proof-of-principle of combining gene expression signature technology with pharmacoepidemiology to identify potential novel drugs for treating mood disorders. Importantly, metformin may have utility in the treatment of mood disorders, warranting future randomized controlled trials to test its efficacy.

OBJECTIVES: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. METHODS: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. RESULTS: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. CONCLUSIONS: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

BACKGROUND: Falls are a common occurrence in psychiatric hospital settings, however population-based research among individuals with psychiatric disorders, in particular bipolar disorder (BD) is scant. Thus, we aimed to investigate falls risk in community-dwelling women diagnosed with BD. METHODS: Women with BD (cases, n = 119) were recruited from health care settings located in southeast Victoria, Australia. Age-matched controls (n = 357, ratio 3:1) without BD were participants in the Geelong Osteoporosis Study drawn from the same geographical region. Lifetime history of BD was identified by semi-structured clinical interview (SCID-IV/NP). Previous 12-month falls data were obtained via questionnaire. Information on mobility, alcohol use, general health, medication use, blood pressure, body mass index, socioeconomic status and use of a walking aid was collected. Generalised Estimating Equations, binary and ordinal logistic regression were used to determine the odds ratio (OR) and 95% confidence interval (CI) for falls following adjustment for confounders. RESULTS: During the 12-month period, 34 (28.6%, median age 48.4 yr) cases and 70 (19.6%, median age 49.1 yr) controls reported one fall; 22 (18.5%) cases and 18 (5.0%) controls reported ≥ two falls (p < 0.001). Cases had 2.5-fold increased odds of at least one fall and 2.9-fold increased likelihood of increasing falls categories (0 vs. 1 vs. 2 +), compared to controls [adjOR 2.5, 95%CI (1.8, 3.4), adjOR OR 2.9, 95%CI (2.0, 4.1)]. CONCLUSION: Risk of falls was greater among women with BD. Balance training could be a research and clinical focus for falls prevention programs among women with bipolar disorder to prevent the detrimental outcomes associated with falling.

BACKGROUND: Bipolar disorder (BD) is associated with significant psychological and physical comorbidity. Yet little is known about the bone health of individuals with BD. Thus, we aimed to investigate the association between BD and bone health in a population-based sample of women. METHODS: Women with a history of BD (cases; n = 117) were recruited from public and private health care settings and controls, without BD, were drawn from the Geelong Osteoporosis Study (n = 909). BD was identified using a semi-structured clinical interview (SCID-I/NP). Bone mineral density (BMD) was measured at the spine, femoral neck and total body using dual energy x-ray absorptiometry, and bone quality by quantitative heel ultrasound and included the following parameters: Speed of Sound (SOS), Broadband Ultrasound Attenuation (BUA) and Stiffness Index (SI). Weight and height were measured and information on medication use and lifestyle was obtained. RESULTS: Adjusted mean BMD among the cases was 4.3% lower at the hip and 1.6% lower at the total body compared to controls. Age was an effect modifier at the spine. Among women <50 years, mean spine BMD for cases was 3.5% lower than controls. No differences in spine BMD for those ≥50 years were detected. Cases also had a 1.0%, 3.2% and 7.8% lower adjusted mean SOS, BUA and SI compared to controls, respectively. LIMITATIONS: Course, chronicity and recovery of BD were not explored in relation to bone health. CONCLUSION: These data suggest BD is associated with low bone quantity and quality in women. Replication and research into underlying mechanisms is warranted.

Background Originally, sarcopenia meant ‘poverty of flesh’, but recent operational definitions have brought poor muscle function to the fore. None has considered psychological well‐being. We compared muscle function components of the European Working Group on Sarcopenia in Older People Version 2 (EWGSOP2), the Foundation for the National Institutes of Health (FNIH), and the Sarcopenia Definitions and Outcomes Consortium (SDOC) algorithms for individuals with and without depressive and anxiety symptoms. Methods This cross‐sectional study involved 348 women and 343 men (ages 60–96 years) from the Geelong Osteoporosis Study. Hospital Anxiety and Depression Scale scores for depression and anxiety ≥8 indicated depressive and anxiety symptoms. Measures included handgrip strength (HGS) and Timed Up and Go (TUG). Chi‐squared test identified inter‐group differences, and multivariable logistic regression identified poor muscle function in association with depressive or anxiety symptoms. Results Twenty‐nine (8.3%) women and 28 (8.2%) men had depressive symptoms, and 83 (23.9%) women and 41 (12.0%) men had anxiety symptoms. For women, proportions with low HGS were greater for those with vs. without depressive symptoms according to EWGSOP2 and FNIH (37.9% vs. 10.7%) and SDOC (51.7% vs. 26.7%); low HGS/body mass index (44.8% vs. 15.7%); and slow TUG (12.5% vs. 1.4%) (all P ≤ 0.011). In age‐adjusted models, women with depressive symptoms were two‐fold to five‐fold more likely to have low HGS by EWGSOP2 and FNIH {odds ratio [OR] 4.77 [95% confidence interval (CI) 1.83–12.45]} and SDOC [OR 2.59 (95% CI 1.10–6.07)], low HGS/body mass index [OR 3.92 (95% CI 1.69–9.07)], and 11‐fold more likely to have a slow TUG [OR 10.99 (95% CI 2.03–59.7)]. For men, a difference for low HGS for those with depressive symptoms was detected only for SDOC (64.3% vs. 40.0%, P = 0.013), but this was explained by age [OR 1.99 (95% CI 0.84–4.71)]. No differences were detected for anxiety symptoms.

BACKGROUND: Anticonvulsant use has been linked to bone deficits in specific patient populations. We studied the association between anticonvulsant use and bone health in a population-based sample of men and women. METHODS: Data from 926 men (24-73 yr) and 1070 women (21-94 yr) participating in the Geelong Osteoporosis Study were included. Bone mineral density (BMD, g/cm2) of the PA-spine and total hip was measured using dual-energy X-ray absorptiometry (Lunar). Bone quality was determined using quantitative heel ultrasound (QUS). Anthropometry was conducted and socioeconomic status was determined. Medication and lifestyle information was obtained via questionnaire. Linear regression was used to test associations between anticonvulsant use and bone health before and after adjustment for potential confounders. RESULTS: Seventeen (1.8%) men and 20 (1.9%) women reported anticonvulsant use. In men, anticonvulsant users had 9.1% lower adjusted mean BMD at the spine and hip compared to non-users. Body mass index was an effect modifier at the spine. Anticonvulsant users also had 1.8% lower speed of sound (SOS), 10.6% lower broadband ultrasound attenuation (BUA) and 13.7% lower stiffness index (SI) compared to non-users. In women, BMD tended to be lower at the hip compared to non-users as with the bone quality measure, BUA. No significant associations were observed at the spine or the other bone quality measures, SOS and SI. CONCLUSION: Our data suggest that bone quantity and quality, assessed using BMD and QUS, are lower for men and possibly women who use anticonvulsants. While further exploration into potential mechanisms is needed, our findings suggest that monitoring bone health among users of anticonvulsants is warranted.

OBJECTIVE: The role of mood disorders in cancer onset is unclear. The aim of this study was to investigate the association between mood disorder and incident cancer in a population-based sample of women. METHODS: Data were derived from women aged 28-94 years participating in the Geelong Osteoporosis Study. Mood disorder was identified via Clinical Interview (SCID-I/NP). Cancer data was obtained following linkage with the Victorian Cancer Registry. Demographic and lifestyle factors were self-reported. Nested case-control and retrospective study designs were utilized. RESULTS: In the case-control study (n=807), mood disorder was documented for 18 of the 75 (9.3%) cancer cases and among 288 controls (24.0% vs. 39.3%, p = 0.009). Prior exposure to mood disorder was associated with reduced cancer incidence (OR 0.49, 95%CI 0.28-0.84); this was sustained following adjustment for confounders (ORadj 0.52, 95%CI 0.30-0.90). In the retrospective cohort study (n=655), among 154 women with a history of mood disorder at baseline, 13 (8.5%) developed incident cancer during follow-up, whereas among 501 women with no history of mood disorder, 54 (10.8%) developed incident cancer. Exposure to mood disorder was not associated with incident cancer over the follow-up period (HR 0.58, 95%CI 0.31-1.08, p = 0.09). CONCLUSION: Mood disorder was associated with reduced odds of cancer onset. However, this finding was not supported in the retrospective cohort study. Larger studies able to investigate specific cancers and mood disorders as well as underlying mechanisms in both men and women are warranted.

Dynapenia is a key contributor to physical frailty. Cognitive impairment and dementia accompany frailty, yet links between skeletal muscle and neurocognition are poorly understood. We examined the cross-sectional relationship between lower limb muscle strength and global cognitive function. Participants were 127 women aged 51-87 years, from the Geelong Osteoporosis Study. Peak eccentric strength of the hip-flexors and hip abductors was determined using a hand-held dynamometer, and dynapenia identified as muscle strength t-scores < -1. Cognition was assessed using the Mini-Mental State Examination (MMSE), and MMSE scores below the median were rated as low. Associations between dynapenia and low cognition were examined using logistic regression models. Hip-flexor dynapenia was detected in 38 (71.7%) women with low cognition and 36 (48.7%) with good cognition (p = 0.009); for hip abductor dynapenia, the pattern was similar (21 (39.6%) vs. 9 (12.2%); p < 0.001). While the observed difference for hip-flexor strength was attenuated after adjusting for age and height (adjusted Odds Ratio (OR) 1.95, 95%CI 0.86-4.41), low cognition was nearly 4-fold more likely in association with hip abductor dynapenia (adjusted OR 3.76, 95%CI 1.44-9.83). No other confounders were identified. Our data suggest that low strength of the hip abductors and low cognition are associated and this could be a consequence of poor muscle function contributing to cognitive decline or vice versa. As muscle weakness is responsive to physical interventions, this warrants further investigation.

OBJECTIVES: We aimed to investigate fracture risk associated with anticonvulsant use in a population-based sample of men and women. METHODS: Data from 1,458 participants (51.8% women) with a radiologically confirmed incident fracture (cases) were compared to 1,796 participants (46.5% women) without fracture (controls). Lifestyle factors, medication use and medical history were self-reported. Associations between anticonvulsant use and fracture were explored using binary logistic regression following adjustment for confounders. RESULTS: In men, fracture cases and controls differed in age, smoking history, education, alcohol use, and gonadal hormone supplementation. In women, fracture cases and controls differed by previous fracture history, alcohol use, physical activity levels and use of anti-fracture agents. After adjustment for age, pooled anticonvulsant use was associated with a 3.4-fold higher risk of fracture in men and a 1.8-fold higher risk in women. Following further adjustments for confounders these patterns persisted; a 2.8-fold higher fracture risk in men and a 1.8-fold higher fracture risk in women. CONCLUSIONS: Anticonvulsant use was associated with increased fracture risk, independent of demographic, lifestyle, medical and medication related factors. While further studies exploring potential underlying mechanisms are warranted, regular monitoring of bone health in anticonvulsant users with risk factors may be useful.

We examined whether personality disorders (PDs) (any, cluster A/B/C) were associated with bone mineral density (BMD) in a population-based sample of Australian women (n = 696). Personality and mood disorders were assessed using semi-structured diagnostic interviews. BMD was measured at the spine, hip, and total body using dual-energy x-ray absorptiometry (GE-Lunar Prodigy). Anthropometrics, medication use, physical conditions, and lifestyle factors were documented. The association between PDs (any, cluster A/B/C) and BMD (spine/hip/total body) was examined with multiple linear regression models. The best models were identified by backward elimination including age, weight, physical activity, smoking status, alcohol consumption, dietary calcium intake, mood disorders, physical multimorbidity, socioeconomic status, and medications affecting bone. The variables were retained in the model if p < 0.05. All potential interactions in final models were tested. Those with cluster A PD, compared to those without, had 6.7% lower hip BMD [age, weight adjusted mean 0.853 (95% CI 0.803-0.903) vs. 0.910 (95% CI 0.901-0.919) g/cm2, p = 0.027] and 3.4% lower total body BMD [age, weight, smoking, alcohol, calcium adjusted mean 1.102 (95% CI 1.064-1.140) vs. 1.139 (95% CI 1.128-1.150) g/cm2, p = 0.056]. No associations were observed between cluster B/C PDs and hip/total body BMD or between any of the PD clusters and spine BMD. To our knowledge, this study is the first to investigate the bone health of women with PD in a population-based sample. Given the paucity of literature, replication and longitudinal research including the examination of underlying mechanisms and sex differences are warranted.

BACKGROUND: The extent of muscle deterioration associated with ageing or disease can be quantified by comparison with appropriate reference data. The objective of this study is to present normative data for lower-limb muscle strength and quality for 573 males and 923 females aged 20-97 yr participating in the Geelong Osteoporosis Study in southeastern Australia. METHODS: In this cross-sectional study, measures of muscle strength for hip flexors and hip abductors were obtained using a Nicholas manual muscle tester, a hand-held dynamometer (HHD; kg). Leg lean mass was measured by dual energy x-ray absorptiometry (DXA; kg), and muscle quality calculated as strength/mass (N/kg). RESULTS: For both sexes, muscle strength and quality decreased with advancing age. Age explained 12.9-25.3% of the variance in muscle strength in males, and 20.8-24.6% in females; age explained less of the variance in muscle quality. Means and standard deviations for muscle strength and quality for each muscle group are reported by age-decade for each sex, and cutpoints equivalent to T-scores of - 2.0 and - 1.0 were derived using data from young males (n = 89) and females (n = 148) aged 20-39 years. CONCLUSIONS: These data will be useful for quantifying the extent of dynapenia and poor muscle quality among adults in the general population in the face of frailty, sarcopenia and other age-related muscle dysfunction.

INTRODUCTION: Individuals with schizophrenia are known to be at higher risk of comorbid conditions, both physical and psychological. Osteoporosis is possibly one of these, leading to public health concerns due to higher rates of associated mortality and morbidity. We aim to systematically search all available evidence across electronic databases regarding the relationship between schizophrenia and bone fragility. METHODS AND ANALYSIS: A systematic search of the research databases CINAHL, MEDLINE Complete, Embase and PsycINFO will be conducted and identified papers reviewed for eligibility, with a second reviewer confirming inclusions. Searches will be run from database inception to 1 October 2020 and supplemented by the hand checking of references of identified articles. A previously published scoring system will be used for assessing the methodological quality and risk of bias. A meta-analysis is planned. ETHICS AND DISSEMINATION: Due to including published literature only, ethical permission will not be necessary. Results of this study will be published in a relevant scientific journal and presented at a conference in the field of interest. PROSPERO REGISTRATION NUMBER: CRD42020171959.

INTRODUCTION: Little is known about the bone health of adults with bipolar disorder, aside from evidence purporting bone deficits among individuals with other mental illnesses, or those taking medications commonly used in bipolar disorder. In this paper, we present the methodology of a case-control study which aims to examine the role of bipolar disorder as a risk factor for bone fragility. METHODS AND ANALYSIS: Men and women with bipolar disorder (~200 cases) will be recruited and compared with participants with no history of bipolar disorder (~1500 controls) from the Geelong Osteoporosis Study. Both cases and controls will be drawn from the Barwon Statistical Division, south-eastern Australia. The Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition is the primary diagnostic instrument, and psychiatric symptomatology will be assessed using validated rating scales. Demographic information and detailed lifestyle data and medical history will be collected via comprehensive questionnaires. Participants will undergo dual energy X-ray absorptiometry scans and other clinical measures to determine bone and body composition. Blood samples will be provided after an overnight fast and stored for batch analysis. ETHICS AND DISSEMINATION: Ethics approval has been granted from Barwon Health Research Ethics Committee. Participation in the study is voluntary. The study findings will be disseminated via peer-reviewed publications, conference presentations and reports to the funding body.

Background. Fragility fractures, associated with osteoporosis, are an escalating public health problem. We aim to describe sample selection, recruitment methods and reasons for non-participation in The PRedictors and Outcomes of incident FRACtures (PROFRAC) study. Design and Methods. Barwon Statistical Division residents aged 20+ years, with a radiologically-confirmed fracture between June 1st 2012 and May 31st 2013, were eligible. Individuals identified as fracture cases were invited by mail to complete a questionnaire. Reasons for non-participation were documented. Logistic regression techniques were used to determine odds ratios for participation and non-participation reasons. Results. A total of 1,458 of 2,155 (67.7%) adults with fracture (48.7% men) participated. Individuals were excluded due to inability to give informed consent, death, no knowledge of fracture, or inability to be contacted. The odds of participation decreased with age (OR 0.99, 95%CI 0.99-0.99, P=0.011) and increased among specific fracture groups [clavicle/scapula (OR 2.50, 1.30-4.68, P=0.006), forearm/humerus (OR 2.00, 1.22-3.27, P=0.006), wrist (OR 2.08, 1.31-3.32, P=0.002), hip (OR 2.12, 1.20-3.75, P=0.009), ankle (OR 1.85, 1.20-2.87, P=0.001), compared to face/skull fractures]. The odds of reporting disinterest, time constraints or personal reasons as the reason for non-participation decreased with age, whereas the odds of reporting frailty, language-related issues or illness as the reason for non-participation increased with of age [disinterest (OR 0.98, 0.97-0.98, P<0.001), time constraints (OR 0.97, 0.96-0.98, P<0.001), personal reasons (OR 0.98, 0.97-0.99, P=0.007), frailty (OR 1.12, 1.09-1.15, P<0.001), language-related issues (OR 1.02, 1.01-1.04, P<0.001), illness (OR 1.03, 1.02-1.05, P<0.001)]. Conclusions. Understanding drivers of research participation can inform study design to achieve optimal participation in health research.

UNLABELLED: This study aimed to compare fracture incidence in the elderly pre- and post-revision of bone density scan reimbursement guidelines, which changed in 2007. Fracture incidence by age group was calculated using population-specific data. Guideline changes did not appear to reduce fracture incidence in the study region located in south-eastern Australia. PURPOSE: In 2007, Medicare Australia revised reimbursement guidelines whereby individuals aged 70 years and over received reduced out-of-pocket expenses for dual energy X-ray absorptiometry (DXA) scans. The current study aims to determine whether fracture incidence in the elderly has changed since the revision of reimbursement guidelines. METHOD: Keyword searches of the two major radiological centres servicing the Barwon Statistical Division (BSD) were used to identify incident fractures for residents aged 75 years and over for 2006 and 2012. Pathological fractures were excluded. Fracture incidence by age strata (75-79 years, 80-84 years and 85+ years) were calculated using population-specific data from the Australian Bureau of Statistics (2006 and 2012). Standardised fracture ratios were calculated for men and women. RESULTS: In total, 996 fracture events were identified for BSD residents during 2006 and 1260 identified in 2012. The standardised fracture ratios between 2006 and 2012 were 1.12 (95%CI 1.11, 1.25) for men and 1.08 (95%CI 1.11, 1.16) for women. CONCLUSION: The change in reimbursement guidelines appears to have had little impact on reducing fracture incidence during this time frame for elderly men and women, in fact, fracture rates increased. Future research should investigate osteoporosis management following DXA over a longer time frame.

BACKGROUND: There is a growing understanding that depression is associated with systemic inflammation. Statins and aspirin have anti-inflammatory properties. Given these agents have been shown to reduce the risk of a number of diseases characterized by inflammation, we aimed to determine whether a similar relationship exists for mood disorders (MD). METHODS: This study examined data collected from 961 men (24-98 years) participating in the Geelong Osteoporosis Study. MD were identified using a semistructured clinical interview (SCID-I/NP). Anthropometry was measured and information on medication use and lifestyle factors was obtained via questionnaire. Two study designs were utilized: a nested case-control and a retrospective cohort study. RESULTS: In the nested case-control study, exposure to statin and aspirin was documented for 9 of 142 (6.3%) cases and 234 of 795 (29.4%) controls (P < .001); after adjustment for age, exposure to these anti-inflammatory agents was associated with reduced likelihood of MD (OR 0.2, 95%CI 0.1-0.5). No effect modifiers or other confounders were identified. In the retrospective cohort study of 836 men, among the 210 exposed to statins or aspirin, 6 (2.9%) developed de novo MD during 1000 person-years of observation, whereas among 626 nonexposed, 34 (5.4%) developed de novo MD during 3071 person-years of observation. The hazard ratio for de novo MD associated with exposure to anti-inflammatory agents was 0.55 (95%CI 0.23-1.32). CONCLUSIONS: This study provides both cross-sectional and longitudinal evidence consistent with the hypothesis that statin and aspirin use is associated with a reduced risk of MD.

BACKGROUND: According to a recent position paper by the American Heart Association, it remains unclear whether depression is a risk factor for incident Coronary Heart Disease (CHD). We assessed whether a depressive disorder independently predicts 18-year incident CHD in women. METHOD: A prospective longitudinal study of 860 women enrolled in the Geelong Osteoporosis Study (1993-2011) was conducted. Participants were derived from an age-stratified, representative sample of women (20-94 years) randomly selected from electoral rolls in South-Eastern Australia. The exposure was a diagnosis of a depressive disorder using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Outcomes data were collected from hospital medical records: (1) PRIMARY OUTCOME: a composite measure of cardiac death, non-fatal Myocardial Infarction or coronary intervention. (2) Secondary outcome: any cardiac event (un/stable angina, cardiac event not otherwise defined) occurring over the study period. RESULTS: Seven participants were excluded based on CHD history. Eighty-three participants (9.6%) recorded ≥1 cardiac event over the study period; 47 had a diagnosis that met criteria for inclusion in the primary analysis. Baseline depression predicted 18-year incidence, adjusting for (1) anxiety (adj. OR:2.39; 95% CIs:1.19-4.82), plus (2) typical risk factors (adj. OR:3.22; 95% CIs:1.45-6.93), plus (3) atypical risk factors (adj. OR:3.28; 95% CIs:1.36-7.90). This relationship held when including all cardiac events. No relationship was observed between depression and recurrent cardiac events. CONCLUSION: The results of this study support the contention that depression is an independent risk factor for CHD incidence in women. Moreover, the strength of association between depression and CHD incidence was of a greater magnitude than any typical and atypical risk factor.

We investigated change in health-related quality of life due to fracture in Australian adults aged over 50 years. Fractures reduce quality of life with the loss sustained at least over 12 months. At a population level, the loss was equivalent to 65 days in full health per fracture.

OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.

Objectives. To compare 12-month falls recall with falls reported prospectively on daily falls calendars in a clinical trial of women aged ≥70 years. Methods. 2,096 community-dwelling women at high risk of falls and/or fracture completed a daily falls calendar and standardised interviews when falls were recorded, for 12 months. Data were compared to a 12-month falls recall question that categorised falls status as "no falls," "a few times," "several," and "regular" falls. Results. 898 (43%) participants reported a fall on daily falls calendars of whom 692 (77%) recalled fall(s) at 12 months. Participants who did not recall a fall were older (median 79.3 years versus 77.8 years, P = 0.028). Smaller proportions of fallers who sustained an injury or accessed health care failed to recall a fall (all P < 0.04). Among participants who recalled "no fall," 85% reported zero falls on daily calendars. Few women selected falls categories of "several times" or "regular" (4.1% and 0.4%, resp.) and the sensitivity of these categories was low (30% to 33%). Simply categorising participants into fallers or nonfallers had 77% sensitivity and 94% specificity. Conclusion. For studies where intensive ascertainment of falls is not feasible, 12-month falls recall questions with fewer responses may be an acceptable alternative.

BACKGROUND: The social gradient of health and mortality is well-documented. However, data are scarce regarding whether differences in mortality are observed across socio-economic status (SES) measured at the small area-level. We investigated associations between area-level SES and all-cause mortality in Australian women aged ≥ 20 years. METHODS: We examined SES, obesity, hypertension, lifestyle behaviors and all-cause mortality within 10 years post-baseline (1994), for 1494 randomly-selected women. Participants' residential addresses were matched to Australian Bureau of Statistics Census data to identify area-level SES, and deaths were ascertained from the Australian National Deaths Index. Logistic regression models were adjusted for age, and subsequent adjustments made for measures of weight status and lifestyle behaviors. RESULTS: We observed 243 (16.3%) deaths within 10 years post-baseline. Females in SES quintiles 2-4 (less disadvantaged) had lower odds of mortality (0.49-0.59) compared to SES quintile 1 (most disadvantaged) under the best model, after adjusting for age, smoking status and low mobility. CONCLUSIONS: Compared to the lowest SES quintile (most disadvantaged), females in quintiles 2 to 5 (less disadvantaged) had significantly lower odds ratio of all-cause mortality within 10 years. Associations between extreme social disadvantage and mortality warrant further attention from research, public health and policy arenas.

UNLABELLED: We investigated change in health-related quality of life due to fracture in Australian adults aged over 50 years. Fractures reduce quality of life with the loss sustained at least over 12 months. At a population level, the loss was equivalent to 65 days in full health per fracture. PURPOSE: We aimed to quantify the change in health-related quality of life (HRQoL) that occurred as a consequence of a fracture using the EQ-5D-3 L questionnaire. METHODS: Adults aged ≥50 years with a low to moderate energy fracture were recruited from eight study centres across Australia. This prospective study included an 18-month follow-up of participants recruited within 2 weeks of a fracture (hip, wrist, humerus, vertebral and ankle). Information collected at baseline and 4, 12 and 18 months included characteristics of participants such as income level, education and prior fracture status. At 12 months post-fracture, the cumulative loss of quality of life was estimated using multivariate regression analysis to identify the predictors of HRQoL loss. RESULTS: Mean HRQoL for all participants before fracture was 0.86, with wrist fracture having the highest pre-fracture HRQoL (0.90), while vertebral fracture had the lowest (0.80). HRQoL declined to 0.42 in the immediate post-fracture period. Only participants with a wrist, humerus or ankle fracture returned to their pre-fracture HRQoL after 18 months. An increased loss of HRQoL over 12 months was associated with HRQoL prior to the fracture, hospitalisation, education and fracture site. The multiple regression explained 30 % of the variation in the cumulative HRQoL loss at 12 months post-fracture for all fractures. CONCLUSION: Low to moderate energy fractures reduce HRQoL, and this loss is sustained for at least 12 months or, in the case of hip and spine fractures, at least 18 months. At a population level, this represents an average loss of 65 days in full health per fragility fracture. This significant burden reinforces the n

BACKGROUND: Psychotropic agents known to cause sedation are associated with an increased risk of falls, but the role of psychiatric illness as an independent risk factor for falls is not clear. Thus, this study aimed to investigate the association between psychiatric disorders, psychotropic medication use and falls risk. METHODS: This study examined data collected from 1062 women aged 20-93 yr (median 50 yr) participating in the Geelong Osteoporosis Study, a large, ongoing, population-based study. Depressive and anxiety disorders for the preceding 12-month period were ascertained by clinical interview. Current medication use and falls history were self-reported. Participants were classified as fallers if they had fallen to the ground at least twice during the same 12-month period. Anthropometry, demographic, medical and lifestyle factors were determined. Logistic regression was used to test the associations, after adjusting for potential confounders. RESULTS: Fifty-six women (5.3%) were classified as fallers. Those meeting criteria for depression within the past 12 months had a 2.4-fold increased odds of falling (unadjusted OR = 2.4, 95% CI 1.2-4.5). Adjustment for age and mobility strengthened the relationship (adjusted OR = 2.7, 95% CI 1.4-5.2) between depression and falling, with results remaining unchanged following further adjustment for psychotropic medication use (adjusted OR = 2.7, 95% CI 1.3-5.6). In contrast, past (prior to 12-month) depression were not associated with falls. No association was observed between anxiety and falls risk. Falling was associated with psychotropic medication use (unadjusted OR = 2.8, 95% CI 1.5-5.2), as well as antidepressant (unadjusted OR = 2.4, 95% CI 1.2-4.8) and benzodiazepine use (unadjusted OR = 3.4, 95% CI 1.6-7.3); associations remained unchanged following adjustment for potential confounders. CONCLUSION: The likelihood of falls was increased among those with depression within the past 12 months, independent of psychotr

OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.

BACKGROUND: A self-report method seeking a binary response for assessing depression is a cost-effective and time-efficient way to obtain a psychiatric history, yet the reliability of this method is largely unknown. The aim of the study was to compare and assess the validity of two methods for identifying a past history of depression in a population-based study. METHODS: This study examined data collected from 891 men and 1086 women participating in the Geelong Osteoporosis Study. Self-reports of depression were compared with results obtained using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). RESULTS: Using the SCID-I/NP, 146 (16.4%) men and 285 (26.2%) women met criteria for a lifetime depression. Of those participants, 61.0% (n=263) self-reported a history of depression. The level of agreement between self-reporting depression and the SCID-I/NP depression module was reasonably high; 61% sensitivity, 89.5% specificity and the overall level of agreement (kappa) was 0.5. LIMITATIONS: Results may not be generalizable to other self-report instruments or be suitable for use in clinical samples. CONCLUSION: The SCID-I/NP remains the gold standard for identifying depression; however, given the moderate level of agreement between the self-report questionnaire and SCID-I/NP in our current study, we conclude that simple self-report methods can be used to identify depression with some degree of confidence.

OBJECTIVES: High levels of disability, functional impairment and mortality are independently associated with fracture and depression, however the relationship between fracture and depression is uncertain. The aim of this study was to investigate whether fracture is associated with subsequent depressive symptoms in a population-based sample of women. DESIGN: A study of age-matched fracture versus non-fracture cohorts of women. SETTING: Barwon Statistical Division, southeastern Australia. PARTICIPANTS: Two samples of women aged ≥35 years were drawn from the Geelong Osteoporosis Study (GOS). The fracture cohort included women with incident fracture identified from radiology reports and the non-fracture cohort were randomly selected from the electoral roll during 1994-1996. OUTCOME MEASURE: Symptoms of depression for women with and without fracture during the 12-month period 2000-2001 were identified by self-report questionnaire based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. RESULTS: A total of 296 women with fracture (12 hip, 48 vertebral, 91 wrist/forearm, 17 upper arm, 7 pelvis, 11 rib, 62 lower leg and 48 other fractures) and 590 women without fracture were included. Associations between fracture and depression differed between younger (≤65 years) and older (>65 years) women. Age and weight-adjusted odds ratio for depression following fracture among younger women was 0.62 (0.35 to 1.11, p=0.12) and 3.33 (1.24 to 8.98, p=0.02) for older women. Further adjustment for lifestyle factors did not affect the results. CONCLUSIONS: This study demonstrated that differences in mood status exist between older and younger women following fracture and that fracture is associated with increased depression in older women. Assessment of mood status in both the short and long term following fracture in the elderly seems justified, with early detection and treatment likely to result in improved outcomes.

BACKGROUND: Atopy, a common disorder characterized by a sensitivity to allergic reactions, affects a large proportion of the adult population and, as with depression, is associated with immune-inflammatory pathway changes. We sought to determine the role of atopic disorders in depression using data from a randomly-selected, population-based study of men and women. METHODS: Cross-sectional data derived from the Geelong Osteoporosis Study for 942 males and 1085 females were analyzed. Depression [major depressive disorder (MDD), minor depression and dysthymia] was assessed using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition. Data on medical conditions, including atopic disorders (asthma, hay fever and eczema), smoking status, alcohol consumption, socioeconomic status, and physical activity were documented by self-report. Logistic regression modeling was used to explore the associations between atopic disorders and depression. RESULTS: Atopic disorders were associated with a 59% increased likelihood of depression [gender and smoking-adjusted odds ratio (OR) 1:50, 95% CI 1.20-1.97]. Sub-group analyses revealed a similar pattern for those with MDD [gender and smoking-adjusted OR 1:54, 95% CI 1.22-1.94]. These associations were independent of socio-demographic characteristics, clinical and lifestyle factors. LIMITATIONS: Reliance on self-report for allergic symptoms and cross-sectional nature of study. CONCLUSION: This population-based study provides evidence of the potential contribution of allergic disorders to depression. Further research is required to elucidate the direction of this association and to further explicate its underlying physiology, including immune-inflammation markers.

OBJECTIVE: Medical illness is a risk factor for suicidality; however, disorder-specific risks are not well-known and these relationships are often explained by major depressive disorder (MDD). We aimed to investigate the relationship between suicidal ideation, MDD and medical illnesses in an age-stratified, population-based sample of men participating in the Geelong Osteoporosis Study. METHODS: Suicidal ideation and medical conditions were self-reported. Medical conditions were confirmed by medical records, medication use or clinical data where possible. MDD was determined using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition. RESULTS: Of the 907 men, 8.5% reported suicidal ideation. Thyroid disorders (OR 3.85, 95%CI 1.2-12.1), syncope and seizures (OR 1.96, 95%CI 1.1-3.5), liver disorders (OR 3.53, 95%CI 1.1-11.8; younger men only) and alcoholism (OR 2.15, 95%CI 1.1-4.4) were associated with increased odds of suicidal ideation, independent of age and MDD. Major vascular events doubled the odds of suicidal ideation but this was explained by MDD. No association was evident with high medical burden, musculoskeletal disease, metabolic factors, gastrointestinal disorders, headaches, cardiovascular disease, COPD, cancer and psoriasis. CONCLUSION: Health care professionals should focus on identification, assessment and management of suicidal ideation in the medically ill in patients both with and without MDD.

Gait speed is a recommended geriatric assessment of physical performance, but may not be regularly examined in clinical settings. We aimed to investigate whether quadriceps strength tests demonstrate similar predictive ability for incident falls as gait speed in older women. We investigated 135 female volunteers aged mean±SD 76.7±5.0 years (range 70-92) at high risk of fracture. Participants completed gait speed assessments using the GAITRite Electronic Walkway System, and quadriceps strength assessments using a hand-held dynamometer (HHD). Participants reported incident falls monthly for 3.7±1.2 years. N=99 (73%) participants fell 355 times during the follow-up period (mean fall rate 83 per 100 person years). We observed a reduced odds ratio for multiple falls (0.83, 95% CI 0.70-0.98) and a reduced hazard ratio for time to first fall (0.90, 95% CI 0.83-0.98), according to quadriceps strength. There was also a significantly shorter time to first fall for those with low quadriceps strength (<7.0 kg; lowest tertile) compared with those with normal quadriceps strength (estimated means [95% CI] 1.54 [1.02, 2.06] vs. 2.23 [1.82, 2.64] years; P=0.019), but not for those with low (<1.0 m/s) vs. normal gait speed (P=0.15). Quadriceps strength is a significant predictor of incident falls over three years amongst community-dwelling older women at high risk of fracture. Quadriceps strength tests may be an acceptable alternative to gait speed for geriatric assessments of falls risk.

BACKGROUND: The mind-body nexus has been a topic of growing interest. Further data are however required to understand the specific relationship between mood and anxiety disorders and individual physical health conditions, and to verify whether these psychiatric disorders are linked to overall medical burden. METHODS: This study examined data collected from 942 men, 20 to 97 years old, participating in the Geelong Osteoporosis Study. A lifetime history of mood and anxiety disorders was identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). The presence of medical conditions (lifetime) was self-reported and confirmed by medical records, medication use or clinical data. Anthropometric measurements and socioeconomic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Logistic regression models were used to test the associations. RESULTS: After adjustment for age, socioeconomic status, and health risk factors (body mass index, physical activity and smoking), mood disorders were associated with gastro oesophageal reflux disease (GORD), recurrent headaches, blackouts and/or epilepsy, liver disorders and pulmonary disease in older people, whilst anxiety disorders were significantly associated with thyroid, GORD and other gastrointestinal disorders, and psoriasis. Increased odds of high medical burden were associated with both mood and anxiety disorders. CONCLUSIONS: Our study provides further population-based evidence supporting the link between mental and physical illness in men. Understanding these associations is not only necessary for individual management, but also to inform the delivery of health promotion messages and health care.

BACKGROUND: Psychopathology seems to play a role in reflux pathogenesis and vice versa, yet few population-based studies have systematically investigated the association between gastro-oesophageal reflux disease (GORD) and psychopathology. We thus aimed to investigate the relationship between GORD-related symptoms and psychological symptomatology, as well as clinically diagnosed mood and anxiety disorders in a randomly selected, population-based sample of adult women. METHODS: This study examined data collected from 1084 women aged 20-93 yr participating in the Geelong Osteoporosis Study. Mood and anxiety disorders were identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP), and psychological symptomatology was assessed using the General Health Questionnaire (GHQ-12). GORD-related symptoms were self-reported and confirmed by medication use where possible and lifestyle factors were documented. RESULTS: Current psychological symptomatology and mood disorder were associated with increased odds of concurrent GORD-related symptoms (adjusted OR 2.1, 95% CI 1.3-3.5, and OR 3.0, 95% CI 1.7-5.6, respectively). Current anxiety disorder also tended to be associated with increased odds of current GORD-related symptoms (p = 0.1). Lifetime mood disorder was associated with a 1.6-fold increased odds of lifetime GORD-related symptoms (adjusted OR 1.6, 95% CI 1.1-2.4) and lifetime anxiety disorder was associated with a 4-fold increased odds of lifetime GORD-related symptoms in obese but not non-obese participants (obese, age-adjusted OR 4.0, 95% CI 1.8-9.0). CONCLUSIONS: These results indicate that psychological symptomatology, mood and anxiety disorders are positively associated with GORD-related symptoms. Acknowledging this common comorbidity may facilitate recognition and treatment, and opens new questions as to the pathways and mechanisms of the association.

BACKGROUND: We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is 'what is the source of this chronic low-grade inflammation?' DISCUSSION: This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency. SUMMARY: The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.

We aimed to optimize calcium intake among the 2,000+ older women taking part in the Vital D study. Calcium supplementation was not included in the study protocol. Our hypothesis was that annual feedback of calcium intake and informing women of strategies to improve calcium intake can lead to a sustained increase in the proportion of women who consume adequate levels of the mineral. Calcium intake was assessed on an annual basis using a validated short food frequency questionnaire (FFQ). Supplemental calcium intake was added to the dietary estimate. Participants and their nominated doctor were sent a letter that the participant's estimated daily calcium intake was adequate or inadequate based on a cutoff threshold of 800 mg/day. General brief statements outlining the importance of an adequate calcium intake and bone health were included in all letters. At baseline, the median daily consumption of calcium was 980 mg/day and 67 percent of 1,951 participants had calcium intake of at least 800 mg per day. Of the 644 older women advised of an inadequate calcium intake at baseline (<800 mg/day), 386 (60%) had increased their intake by at least 100 mg/day when re-assessed twelve months later. This desirable change was sustained at 24 months after baseline with almost half of these women (303/644) consuming over 800 mg calcium per day. This study devised an efficient method to provide feedback on calcium intake to over 2,000 older women. The improvements were modest but significant and most apparent in those with a low intake at baseline. The decreased proportion of these women with an inadequate intake of calcium 12- and 24-months later, suggests this might be a practical, low cost strategy to maintain an adequate calcium intake among older women.

BACKGROUND: Randomised, placebo-controlled trials are needed to provide evidence demonstrating safe, effective interventions that reduce falls and fractures in the elderly. The quality of a clinical trial is dependent on successful recruitment of the target participant group. This paper documents the successes and failures of recruiting over 2,000 women aged at least 70 years and at higher risk of falls or fractures onto a placebo-controlled trial of six years duration. The characteristics of study participants at baseline are also described for this study. METHODS: The Vital D Study recruited older women identified at high risk of fracture through the use of an eligibility algorithm, adapted from identified risk factors for hip fracture. Participants were randomised to orally receive either 500,000 IU vitamin D3 (cholecalciferol) or placebo every autumn for five consecutive years. A variety of recruitment strategies were employed to attract potential participants. RESULTS: Of the 2,317 participants randomised onto the study, 74% (n = 1716/2317) were consented onto the study in the last five months of recruiting. This was largely due to the success of a targeted mail-out. Prior to this only 541 women were consented in the 18 months of recruiting. A total of 70% of all participants were recruited as a result of targeted mail-out. The response rate from the letters increased from 2 to 7% following revision of the material by a public relations company. Participant demographic or risk factor profile did not differ between those recruited by targeted mail-outs compared with other methods. CONCLUSION: The most successful recruitment strategy was the targeted mail-out and the response rate was no higher in the local region where the study had extensive exposure through other recruiting strategies. The strategies that were labour-intensive and did not result in successful recruitment include the activities directed towards the GP medical centres. Comprehensive recruitment

BACKGROUND: Studies in adult intensive care have highlighted the importance of insulin and improved glucose control on survival, with 32% reduction in mortality, 22% reduction in intensive care stay and halving of the incidence of bacteraemia. Very low birth weight infants requiring intensive care also have relative insulin deficiency often leading to hyperglycaemia during the first week of life. The physiological influences on insulin secretion and sensitivity, and the potential importance of glucose control at this time are not well established. However there is increasing evidence that the early postnatal period is critical for pancreatic development. At this time a complex set of signals appears to influence pancreatic development and beta cell survival. This has implications both in terms of acute glucose control but also relative insulin deficiency is likely to play a role in poor postnatal growth, which has been associated with later motor and cognitive impairment, and fewer beta cells are linked to risk of type 2 diabetes later in life. METHODS: A multi-centre, randomised controlled trial of early insulin replacement in very low birth weight babies (VLBW, birth weight < 1500 g). 500 infants will be recruited from 10 centres in the UK and Europe. Babies will be randomised to receive a continuous insulin infusion (0.05 units/kg/h) or to receive standard neonatal care from the first day of life and for the next 7 days. If blood glucose (BG) levels fall infants will receive 20% dextrose titrated to maintain normoglycaemia (4-8 mmol/l). If BG is consistently above 10 mmol/l babies will receive standard treatment with additional insulin infusion. The primary end point will be mortality on or before expected date of delivery, secondary end points will be markers of morbidity and include episodes of sepsis, severity of retinopathy, chronic lung disease and growth.