Publications by authors named "Robert J Adams"

287 Publications

Prevalence of Probable Shift Work Disorder in Non-Standard Work Schedules and Associations with Sleep, Health and Safety Outcomes: A Cross-Sectional Analysis.

Nat Sci Sleep 2021 31;13:683-693. Epub 2021 May 31.

Flinders Health and Medical Research Institute (Sleep Health)/Adelaide Institute for Sleep Health, Flinders University, Bedford Park, SA, Australia.

Purpose: We aimed to estimate the prevalence of probable shift work disorder (pSWD) in a representative sample of Australian workers and identify sleep, health and safety correlates.

Patients And Methods: In 2019, data were collected from working respondents as part of a cross-sectional national sleep health survey conducted online (n=964 total; n=448 individuals on non-standard work schedules). We established the prevalence of pSWD according to International Classification of Sleep Disorders criteria (ICSD-R, ICSD-2 and ICSD-3). Poisson regression was used to determine crude and adjusted prevalence association (prevalence ratio, PR) of pSWD with sleep, health and safety outcomes.

Results: Overall prevalence of pSWD in workers on non-standard work schedules was 10.5%, ranging from 9.6% in early morning workers to 12.7% in rotating shift workers. In adjusted models, workers who met the criteria for pSWD were 1.8 times more likely to report both depression/bipolar disorder, and anxiety/panic disorder, and 1.7 times more likely to report work errors due to a sleep problem.

Conclusion: The prevalence of pSWD in employees engaged in non-standard work schedules is influenced by selection of factors used to quantify pSWD, including sleep/wake patterns. Higher likelihoods of mental health problems and workplace errors in those with pSWD highlight the importance of intervention and management of this under-recognised sleep disorder.
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http://dx.doi.org/10.2147/NSS.S301493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178694PMC
May 2021

Protecting the health and safety of the paramedic workforce in Australia: The role of cohort studies with new recruits.

Emerg Med Australas 2021 May 31. Epub 2021 May 31.

Flinders Health and Medical Research Institute (Sleep Health), College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.

Research related to the paramedic workforce is increasing, particularly given the associations with physical and mental health outcomes. However, it is clear that the evidence base to support future paramedic workforce initiatives lacks longitudinal data in cohorts of paramedics. We identify gaps in the epidemiological evidence base for this workforce, and provide insight into the role that prospective cohorts can, and should, play in future research in the paramedic workforce in order to identify health and safety changes over time, and the associations with job requirements, particularly shift work.
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http://dx.doi.org/10.1111/1742-6723.13808DOI Listing
May 2021

Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute SIV Infection in a Pigtailed Macaque Model of HIV.

J Infect Dis 2021 May 10. Epub 2021 May 10.

Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: While social distancing is a key public health response during viral pandemics, psychosocial stressors, such as social isolation, have been implicated in adverse health outcomes in general (1) and in the context of infectious disease, such as HIV (2,3). A comprehensive understanding of the direct pathophysiologic effects of psychosocial stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection.

Methods: To determine the effect of psychosocial stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly (n=35) and socially (n=41) housed SIV-infected pigtailed macaques (Macaca nemestrina).

Results: Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T cell declines and more CD4 and CD8 T cell activation compared to socially housed macaques throughout acute SIV infection.

Conclusions: These data demonstrate that psychosocial stress directly impacts the pathogenesis of acute SIV infection and imply that it may act as an integral variable in the progression of HIV infection and potentially of other viral infections.
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http://dx.doi.org/10.1093/infdis/jiab252DOI Listing
May 2021

Sleep macroarchitecture but not obstructive sleep apnea is independently associated with cognitive function in only older men of a population-based cohort.

J Sleep Res 2021 Apr 22:e13370. Epub 2021 Apr 22.

Flinders Health and Medical Research Institute - Sleep Health, Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

Evidence linking obstructive sleep apnea with cognitive dysfunction predominantly comes from clinical or select community samples. We investigated the independent cross-sectional association of obstructive sleep apnea and sleep macroarchitecture parameters with cognitive function in unselected community-dwelling middle-aged and older men. Four hundred and seventy-seven Florey Adelaide Male Ageing Study participants underwent successful home-based polysomnography. They also completed cognitive testing, including the inspection time task, Fuld object memory evaluation, trail-making test A and B, and mini-mental state examination. Multivariable regression models examined independent cross-sectional associations of obstructive sleep apnea and sleep macroarchitecture parameters with cognitive function. In univariable analyses, a higher apnea-hypopnea index and percentage of total sleep time with oxygen saturation <90% were associated with worse trail-making test A performance (both p < .05). A higher apnea-hypopnea index was also associated with worse trail-making test B performance and slower inspection time (both p < .05). In adjusted analyses, obstructive sleep apnea and sleep macroarchitecture parameters were not associated with cognitive function (all p > .05). In age-stratified analysis in men ≥65 years, greater stage 1 sleep was independently associated with worse trail-making test A performance, whereas greater stage 3 sleep was independently associated with better trail-making test A performance (both p < .05). Our findings suggest that obstructive sleep apnea is not independently associated with cognitive function. In older, but not younger, men, light sleep was associated with worse attention, whereas deep sleep was associated with better attention. Longitudinal population-based cohort studies are needed to determine if obstructive sleep apnea and disrupted sleep macroarchitecture independently predict prospective cognitive dysfunction and decline.
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http://dx.doi.org/10.1111/jsr.13370DOI Listing
April 2021

Economic evaluation of diagnostic sleep studies for obstructive sleep apnoea: a systematic review protocol.

Syst Rev 2021 Apr 9;10(1):104. Epub 2021 Apr 9.

Department of Health Economics, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia.

Background: Obstructive sleep apnoea (OSA) is a significant public health problem affecting a large proportion of the population and is associated with adverse health consequences and a substantial economic burden. Despite the existence of effective treatment, undiagnosed OSA remains a challenge. The gold standard diagnostic tool is polysomnography (PSG), yet the test is expensive, labour intensive and time-consuming. Home-based, limited channel sleep study testing (levels 3 and 4) can advance and widen access to diagnostic services. This systematic review aims to summarise available evidence regarding the cost-effectiveness of limited channel tests compared to laboratory and home PSG in diagnosing OSA.

Methods: Eligible studies will be identified using a comprehensive strategy across the following databases from inception onwards: MEDLINE, PsychINFO, SCOPUS, CINAHL, Cochrane Library, Emcare and Web of Science Core Collection and ProQuest databases. The search will include a full economic evaluation (i.e. cost-effectiveness, cost-utility, cost-benefit, cost-consequences and cost-minimisation analysis) that assesses limited channel tests and PSG. Two reviewers will screen, extract data for included studies and critically appraise the articles for bias and quality. Meta-analyses will be conducted if aggregation of outcomes can be performed. Qualitative synthesis using a dominance ranking matrix will be performed for heterogeneous data.

Discussion: This systematic review protocol uses a rigorous, reproducible and transparent methodology and eligibility criteria to provide the current evidence relating to the clinical and economic impact of limited channel and full PSG OSA diagnostic tests. Evidence will be examined using standardised tools specific for economic evaluation studies.

Trial Registration: PROSPERO (CRD42020150130).
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http://dx.doi.org/10.1186/s13643-021-01651-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035771PMC
April 2021

Effect of depression on health service utilisation in men: a prospective cohort study of Australian men aged 35 to 80 years.

BMJ Open 2021 03 17;11(3):e044893. Epub 2021 Mar 17.

Freemasons Centre for Male Health and Wellbeing, The University of Adelaide, Adelaide, South Australia, Australia.

Objectives: To examine the relationship between depression burden, health service utilisation and depression diagnosis in community-based men.

Design: Prospective cohort study.

Setting: Community-based.

Participants: Men aged 35-80 years at recruitment (2002-2005), randomly selected from the northern and western suburbs of Adelaide, Australia, without depression at baseline, who attended follow-up visits (2007-2010) (n=1464).

Primary And Secondary Outcome Measures: Depression symptoms were categorised into high burden (total score of ≥13 for the Beck Depression Inventory (BDI) or ≥10 for the Centre for Epidemiologic Studies Depression Scale (CES-D) or low burden (<13 for the BDI or <10 for the CES-D). Diagnosed depression was determined by patient-reported physician diagnosis. Frequent general practitioner (GP) visits were those occurring 5+ times over the preceding year. Use of national medical and prescription services (Medicare Benefit Schedule and Pharmaceutical Benefit Scheme; MBS and PBS) was assessed through data linkage.

Results: Frequent attendance and depression diagnosis was more common in men with a high than low burden of depression symptoms (45.9% vs 29.3%-18.7% vs 1.9%, p<0.001). Depression diagnoses were also more common in frequent GP attenders compared with low-average attenders (5.1% vs 2.2%, p<0.001). Among men with high burden of symptoms, there was no age-adjusted or multi-adjusted difference for likelihood of depression diagnosis between non-regular and frequent GP attenders. Annualised MBS and PBS expenditure was highest for men with undiagnosed depression.

Conclusions: Men with a high burden of depression symptoms have commensurate use of health services when compared with those with a low burden, but only half report a physician diagnosis of depression. Undiagnosed depression led to a higher usage of medical and prescription services.
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http://dx.doi.org/10.1136/bmjopen-2020-044893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978072PMC
March 2021

Transcranial Doppler Screening in a Current Cohort of Children With Sickle Cell Anemia: Results From the DISPLACE Study.

J Pediatr Hematol Oncol 2021 Mar 31. Epub 2021 Mar 31.

Division of Hematology and Oncology, University of Alabama Birmingham, Birmingham, AL College of Nursing Departments of Public Health Sciences Neurology and Neurosurgery, Medical University of South Carolina, Charleston, SC Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Divison of Hematology-Oncology, Children's National Medical Center, Washington, DC Aflac Cancer and Blood Disorder Center, Emory University, Atlanta, GA.

Stroke prevention guidelines for sickle cell anemia (SCA) recommend transcranial Doppler (TCD) screening to identify children at stroke risk; however, TCD screening implementation remains poor. This report describes results from Part 1 of the 28-site DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study, a baseline assessment of TCD implementation rates. This report describes TCD implementation by consortium site characteristics; characteristics of TCDs completed; and TCD results based on age. The cohort included 5247 children with SCA, of whom 5116 were eligible for TCD implementation assessment for at least 1 study year. The majority of children were African American or Black, non-Hispanic and received Medicaid. Mean age at first recorded TCD was 5.9 and 10.5 years at study end. Observed TCD screening rates were unsatisfactory across geographic regions (mean 49.9%; range: 30.9% to 74.7%) independent of size, institution type, or previous stroke prevention trial participation. The abnormal TCD rate was 2.9%, with a median age of 6.3 years for first abnormal TCD result. Findings highlight real-world TCD screening practices and results from the largest SCA cohort to date. Data informed the part 3 implementation study for improving stroke screening and findings may inform clinical practice improvements.
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http://dx.doi.org/10.1097/MPH.0000000000002103DOI Listing
March 2021

Dietary inflammatory index (DII®) and the risk of depression symptoms in adults.

Clin Nutr 2021 May 29;40(5):3631-3642. Epub 2020 Dec 29.

Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address:

Background & Aims: Findings from observational studies investigating the association between Dietary Inflammatory Index (DII®) scores and depression symptoms (DepS) are inconsistent. This study aims to assess the association between energy-adjusted DII (E-DII™) and DepS using the North West Adelaide Health Study (NWAHS) cohort as well as update a previous meta-analysis.

Methods: A total of 1743 (mean ± SD age: 56.6 ± 13.6 years, 51% female) study participants from NWAHS were included in the cross-sectional study and 859 (mean ± SD age: 58.4 ± 12.1 years, 52.6% female) in the longitudinal analyses. The Center for Epidemiological Studies Depression Scale (CES-D) was used for the measurement of DepS. E-DII scores were calculated from the dietary data collected using a validated food frequency questionnaire (FFQ). Data from two stages [Stage 3 (2008-10) and North West 15 (NW15) (2015)] were used. Log- and negative binomial regression were used to assess the association between quartiles of E-DII and DepS. A recent meta-analysis was updated by including 12 publications (six cross-sectional and six cohort studies) on the association between DII and DepS.

Results: In the cross-sectional analysis, a higher E-DII score (i.e., more pro-inflammatory diet) was associated with a 79% increase in odds of reporting DepS [OR: 1.79; 95% CI: 1.14-2.81; p = 0.01; p for trend (p) = 0.03]. Males with higher E-DII had a more than two-fold higher odds of DepS (OR: 2.27; 95% CI: 1.02-5.06; p = 0.045; p = 0.09). Females with higher E-DII had an 81% increase in odds of DepS (OR: 1.81; 95% CI: 1.01-3.26; p = 0.046; p = 0.07). These associations were consistent in the longitudinal analysis. Comparing highest to lowest quintiles of E-DII, the updated meta-analysis showed that a pro-inflammatory diet is associated with a 45% increase in odds of having DepS (OR: 1.45; 95% CI: 1.20-1.74; p < 0.01) with higher odds in females (OR: 1.53; 95% CI: 1.16-2.01; p = 0.01) compared to their male counterparts (OR: 1.29; 95% CI: 0.98-1.69; p = 0.15).

Conclusion: The data from the NWAHS and the updated meta-analysis of observational studies provide further evidence that a pro-inflammatory diet is positively associated with increased risk of DepS. These findings support the current recommendation on consuming a less inflammatory diet to improve DepS.
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http://dx.doi.org/10.1016/j.clnu.2020.12.031DOI Listing
May 2021

Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.

JAMA Netw Open 2021 01 4;4(1):e2030435. Epub 2021 Jan 4.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).

Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.

Design, Setting, And Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.

Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.

Main Outcomes And Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).

Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).

Conclusions And Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786247PMC
January 2021

Frailty and sarcopenia in combination are more predictive of mortality than either condition alone.

Maturitas 2021 Feb 1;144:102-107. Epub 2020 Dec 1.

National Health and Medical Research Council (NHMRC), Centre of Research Excellence: Frailty and Healthy Ageing, University of Adelaide, South Australia, Australia; Adelaide Geriatrics Training & Research with Aged Care (G-TRAC) Centre, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, South Australia, Australia; Aged and Extended Care Services, Central Adelaide Local Health Network, South Australia, Australia.

Background: Frailty and sarcopenia are age-related conditions with shared features and are both associated with adverse health outcomes. Relatively little is known about outcomes of these conditions in combination. The aim of this study was to examine the predictive ability of combined frailty and sarcopenia classification on mortality.

Methods: Frailty was measured in 716 community-dwelling adults aged ≥65 years from the North West Adelaide Health Study (mean age 74.1(6.1) years, 55.5 % female) using the frailty phenotype (FP) and sarcopenia using the revised consensus definition from the European Working Group on Sarcopenia. Participants were classified as: neither frail nor sarcopenic, frail-only, sarcopenic-only, or both frail and sarcopenic. All participants had a minimum of 10 years of mortality follow-up.

Results: We identified 2.8 % of participants as both frail and sarcopenic, 15.5 % as frail-only, and 3.5 % as sarcopenic-only. Classification as both frail and sarcopenic, in a multivariable model, resulted in significantly elevated mortality risk (HR = 3.52, p < .001), which was over three times that of those neither frail nor sarcopenic. Frail-only was also a significant mortality predictor (HR = 2.03, p = .001), while classification as sarcopenic-only was not a significant predictor of mortality (HR = 1.65, p = .141). There was no significant difference in severity of frailty (mean number of characteristics) or grip strength between frail-only and those with both conditions when stratified by sex.

Conclusions: Individuals identified as frail would benefit from screening and assessment for sarcopenia, and vice versa for those identified as sarcopenic, as the mortality risk for individuals with these conditions in combination is nearly double that of each separately.
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http://dx.doi.org/10.1016/j.maturitas.2020.11.009DOI Listing
February 2021

Frequency, trends and institutional variation in 30-day all-cause mortality and unplanned readmissions following hospitalisation for heart failure in Australia and New Zealand.

Eur J Heart Fail 2021 Jan 9;23(1):31-40. Epub 2020 Nov 9.

Department of Cardiology, The Prince Charles Hospital, Brisbane, Australia.

Aims: National 30-day mortality and readmission rates after heart failure (HF) hospitalisations are a focus of US policy intervention and yet have rarely been assessed in other comparable countries. We examined the frequency, trends and institutional variation in 30-day mortality and unplanned readmission rates after HF hospitalisations in Australia and New Zealand.

Methods And Results: We included patients >18 years hospitalised with HF at all public and most private hospitals from 2010-15. The primary outcomes were the frequencies of 30-day mortality and unplanned readmissions, and the institutional risk-standardised mortality rate (RSMR) and readmission rate (RSRR) evaluated using separate cohorts. The mortality cohort included 153 592 patients (mean age 78.9 ± 11.8 years, 51.5% male) with 16 442 (10.7%) deaths within 30 days. The readmission cohort included 148 704 patients (mean age 78.6 ± 11.9 years, 51.7% male) with 33 158 (22.3%) unplanned readmission within 30 days. In 392 hospitals with at least 25 HF hospitalisations, the median RSMR was 10.7% (range 6.1-17.3%) with 59 hospitals significantly different from the national average. Similarly, in 391 hospitals with at least 25 HF hospitalisations, the median RSRR was 22.3% (range 17.7-27.1%) with 24 hospitals significantly different from the average. From 2010-15, the adjusted 30-day mortality [odds ratio (OR) 0.991/month, 95% confidence interval (CI) 0.990-0.992, P < 0.01] and unplanned readmission (OR 0.998/month, 95% CI 0.998-0.999, P < 0.01) rates declined.

Conclusion: Within 30 days of a HF hospitalisation, one in 10 patients died and almost a quarter of those surviving experienced an unplanned readmission. The risk of these outcomes varied widely among hospitals suggesting disparities in HF care quality. Nevertheless, a substantial decline in 30-day mortality and a modest decline in readmissions occurred over the study period.
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http://dx.doi.org/10.1002/ejhf.2030DOI Listing
January 2021

The Association between Sleep Duration and Quality with Readmissions: An Exploratory Pilot-Study among Cardiology Inpatients.

Clocks Sleep 2020 Jun 2;2(2):120-142. Epub 2020 Apr 2.

Basil Hetzel Institute for Translational Health Research, Adelaide, SA 5011, Australia;

Readmissions within 30 days of discharge are prominent among patients with cardiovascular disease. Post hospital syndrome hypothesizes that sleep disturbance during the index admission contributes to an acquired transient vulnerability, leading to increased risk of readmission. This study evaluated the association of in-hospital sleep (a) duration and (b) quality with 30-day all-cause unplanned readmission. This prospective observational cohort study included patients admitted to the coronary care unit of a South Australian hospital between 2016-2018. Study participants were invited to wear an ActiGraph GT3X+ for the duration of their admission and for two weeks post-discharge. Validated sleep and quality of life questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), were administered. Readmission status and questionnaires were assessed at 30 days post-discharge via patient telephone interview and a review of hospital records. The final cohort consisted of 75 patients (readmitted: = 15, non-readmitted: = 60), of which 72% were male with a mean age 66.9 ± 13.1 years. Total sleep time (TST), both in hospital (6.9 ± 1.3 vs. 6.8 ± 2.9 h, = 0.96) and post-discharge (7.4 ± 1.3 h vs. 8.9 ± 12.6 h, = 0.76), was similar in all patients. Patient's perception of sleep, reflected by PSQI scores, was poorer in readmitted patients (9.13 ± 3.6 vs. 6.4 ± 4.1, = 0.02). Although an association between total sleep time and 30-day readmission was not found, patients who reported poorer sleep quality were more likely to be readmitted within 30 days. This study also highlighted the importance of improving sleep, both in and out of the hospital, to improve the outcomes of cardiology inpatients.
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http://dx.doi.org/10.3390/clockssleep2020011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445848PMC
June 2020

The Effect of Multimorbidity Patterns and the Impact of Comorbid Anxiety and Depression on Primary Health Service Use: The Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) Study.

Am J Mens Health 2020 Sep-Oct;14(5):1557988320959993

Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, Australia.

This study sought to determine patterns of multimorbidity and quantify their impact on use of primary health services in the presence and absence of anxiety and depression among a cohort of urban community-dwelling men in Australia. The analytic sample consisted of men ( = 2039; age 38-85) from the follow-up wave of a prospective cohort study of all participants of the Florey Adelaide Male Ageing Study (FAMAS; Stage 2 [2007-2010]) and age-matched men from the North-West Adelaide Health Study (NWAHS; Stage 3 [2008-2010]). Self-reported data and linkage with a national universal health coverage scheme (Medicare) provided information on the prevalence of eight chronic conditions and health service utilization information (including annual GP visits). Obesity and cardiovascular disease (CVD) were associated with the highest number of comorbid conditions. Two nonrandom multimorbidity "clusters" emerged: "CVD, Obesity, Diabetes" and "CVD, Obesity, Osteoarthritis." Participants with conditions comorbid with CVD were more likely to have 10 or more annual GP visits, compared to multimorbidity involving other conditions. In comparison to participants without CVD, the presence of CVD increased the chance of having 10 or more annual GP visits (adjusted risk ratio: 3.7; 95% CI [2.8, 4.8]). When CVD was comorbid with anxiety and depression, having 10 or more annual GP visits was more common (adjusted risk ratio: 1.8; 95% CI [1.2, 2.5]). Multimorbidity patterns involving CVD, especially for multimorbidity that includes CVD with comorbid anxiety and depression, should be considered in developing clinical trials to better inform medical decision-making and care for patients with CVD and comorbid conditions.
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http://dx.doi.org/10.1177/1557988320959993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873770PMC
October 2020

Association of metabolic phenotypes, grip strength and diabetes risk: The 15-year follow-up of The North West Adelaide Health Study, Australia.

Obes Res Clin Pract 2020 Nov - Dec;14(6):536-541. Epub 2020 Oct 9.

The Health Observatory, Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, 5001, South Australia, Australia; Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Sturt Road, Bedford Park, Adelaide, 5042, South Australia, Australia; Freemasons Centre for Men's Health, Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, 5001, South Australia, Australia. Electronic address:

Background: The association of diabetes risk in the long-term, metabolic phenotypes (MP) and muscle strength is unclear. We aimed to investigate the association between strictly defined MP, grip strength (GS) and diabetes.

Material And Methods: MP were defined according to BMI and presence of any individual metabolic abnormality for ≥18 years, in participants of the North West Adelaide Health Study (Australia) free of diabetes at baseline. The association of MP and dominant hand GS with incident diabetes over 15-years follow-up and the moderation effect of GS on the association between diabetes and MP were investigated by logistic regression models.

Results: Of 3039 participants followed over 13.3 years (SD 2.6), 236 (7.8%) developed diabetes. Compared to the metabolically healthy (MH) normal weight phenotype, the metabolically unhealthy (MU) overweight (OR 6.15, 95%CI 2.43-15.59) and obese (OR 12.32, 95%CI 4.97-30.52) phenotypes were associated with a high risk of diabetes, but not the MU normal weight (OR 1.73, 95%CI 0.57-5.25), MH overweight (OR 1.15, 95%CI 0.31-4.31) or MH obese phenotypes (OR 0.77, 0.07-8.89). GS was inversely associated with diabetes (OR 0.97, 95% CI 0.95-0.99) and attenuated the risk associated with MU overweight (beta = -0.296, p = 0.039) and MU normal weight (beta = -0.773; p for interaction = 0.009).

Conclusion: Strictly defined MP (rather than based on metabolic syndrome criteria) and GS, a proxy of muscle strength, might be useful for stratifying the risk of diabetes in the long-term. Improving muscle strength might be an important strategy to reduce diabetes risk.
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http://dx.doi.org/10.1016/j.orcp.2020.09.006DOI Listing
October 2020

Frailty state utility and minimally important difference: findings from the North West Adelaide Health Study.

Age Ageing 2021 02;50(2):565-569

National Health and Medical Research Council (NHMRC) Centre of Research Excellence: Frailty and Healthy Ageing, University of Adelaide, Adelaide, SA, Australia.

Background: frailty is a dynamic condition for which a range of interventions are available. Health state utilities are values that represent the strength of an individual's preference for specific health states, and are used in economic evaluation. This is a topic yet to be examined in detail for frailty. Likewise, little has been reported on minimally important difference (MID), the extent of change in frailty status that individuals consider to be important.

Objectives: to examine the relationship between frailty status, for both the frailty phenotype (FP) and frailty index (FI), and utility (preference-based health state), and to determine a MID for both frailty measures.

Design And Setting: population-based cohort of community-dwelling Australians.

Participant: in total, 874 adults aged ≥65 years (54% female), mean age 74.4 (6.2) years.

Measurements: frailty was measured using the FP and FI. Utilities were calculated using the short-form 6D health survey, with Australian and UK weighting applied. MID was calculated cross-sectionally.

Results: for both the FP and FI, frailty was significantly statistically associated (P < 0.001) with lower utility in an adjusted analysis using both Australian and UK weighting. Between-person MID for the FP was identified as 0.59 [standard deviation (SD) 0.31] (anchor-based) and 0.59 (distribution-based), whereas for the FI, MID was 0.11 (SD 0.05) (anchor-based) and 0.07 (distribution-based).

Conclusions: frailty is significantly associated with lower preference-based health state utility. Frailty MID can be used to inform design of clinical trials and economic evaluations, as well as providing useful clinical information on frailty differences that patients consider important.
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http://dx.doi.org/10.1093/ageing/afaa166DOI Listing
February 2021

Australia can use population level mobility data to fight COVID-19.

Med J Aust 2020 10 14;213(7):296-297.e1. Epub 2020 Sep 14.

Flinders University, Adelaide, SA.

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http://dx.doi.org/10.5694/mja2.50773DOI Listing
October 2020

Practice patterns for neuroimaging and transfusion therapy for management of neurologic complications in sickle cell anemia: DISPLACE consortium.

Pediatr Blood Cancer 2020 11 7;67(11):e28569. Epub 2020 Sep 7.

Division of Hematology & Oncology, University of Alabama, Birmingham, Alabama.

Background: Children with sickle cell anemia (SCA) are at risk for neurologic complications (stroke and silent cerebral infarct). The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines for sickle cell disease include recommendations for initiation and maintenance of chronic red cell transfusion (CRCT) therapy for children with SCA at risk for or with ischemic stroke. The guidelines do not include well-delineated recommendations for cerebral imaging for stroke screening. The purpose of this study was to evaluate current stroke risk screening, prevention, and intervention practices amongst the Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) study sites.

Procedure: A survey was administered to DISPLACE site principal investigators to identify current stroke prevention practices relative to the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study protocols and the 2014 NHLBI guidelines. Data were analyzed using descriptive statistics and line-by-line analysis of comments.

Results: Sites consistently applied NHLBI recommendations to initiate CRCT for ischemic stroke and abnormal transcranial Doppler ultrasound (TCD) results. Similarly, nearly all sites reported obtaining an magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) following an abnormal TCD result. There was wide variation for other indications for MRI/MRA, frequency of MRI/MRA, and other neurological indications for initiating CRCT.

Conclusions: Guideline-based practices for preventing ischemic stroke through TCD and CRCT initiation were evident in nearly all sites. Wide variation in practices pertaining to MRI/MRA exists, potentially influenced by more recent stroke prevention trials. New guidelines from the American Society of Hematology were published in April 2020, which may reduce practice variation.
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http://dx.doi.org/10.1002/pbc.28569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722116PMC
November 2020

FRAIL scale: Predictive validity and diagnostic test accuracy.

Australas J Ageing 2020 Dec 4;39(4):e529-e536. Epub 2020 Aug 4.

National Health and Medical Research Council (NHMRC) Centre of Research Excellence: Frailty and Healthy Ageing, University of Adelaide, Adelaide, South Australia, Australia.

Objective: To examine the predictive validity of the FRAIL scale for mortality, and diagnostic test accuracy (DTA) against the frailty phenotype (FP).

Measurement: Frailty was measured in 846 community-dwelling adults (mean age 74.3 [SD 6.3] years, 54.8% female) using a modified FRAIL scale and modified FP. Mortality was matched to death records.

Results: The FRAIL scale demonstrated significant predictive validity for mortality up to 10 years (Frail adjHR: 2.60, P < .001). DTA findings were acceptable for specificity (86.8%) and Youden index (0.50), but not sensitivity (63.6%), or area under the receiver operator curve (auROC) (0.75). DTA estimates were more acceptable when a cut-point of ≥2 characteristics was used rather than ≥3 in the primary DTA analysis.

Conclusion: The FRAIL scale is a valid predictor of mortality. DTA estimates depend on FRAIL scale cut-point used. This instrument is a potentially useful frailty screening tool.
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http://dx.doi.org/10.1111/ajag.12829DOI Listing
December 2020

Economic evaluation of cognitive behavioural therapy for insomnia (CBT-I) for improving health outcomes in adult populations: A systematic review.

Sleep Med Rev 2020 12 9;54:101351. Epub 2020 Jul 9.

Health Economics, Flinders University, College of Medicine and Public Health, Bedford Park, SA, Australia; National Centre for Sleep Health Services Research: A NHMRC Centre of Research Excellence, Flinders University, Bedford Park, SA, Australia.

Cognitive behavioural therapy for insomnia (CBT-I) is a promising intervention with established efficacy, yet evidence of its cost-effectiveness remains unclear. Systematic searches were conducted in Medline, Psychinfo, ProQuest, Cochrane, Scopus, CINAHL, Web of Science and Emcare. Titles and abstracts were screened against eligibility criteria, and studies reporting full economic evaluations of CBT-I in adult populations were included and examined in detail. Study characteristics were extracted using a standardised template. Quantitative measures and relevant findings were summarised using a qualitative approach following recommended reporting standards. 1,168 non-duplicate articles were identified, of which 44 were selected for full-text review. Seven full economic evaluations of CBT-I in adult populations met the inclusion criteria and were incorporated in the final synthesis. Using the dominance ranking framework to compare cost and outcomes, CBT-I was cost-effective compared to pharmacotherapy or no treatment. The limited number of studies included in this review implies that caution should be exercised when interpreting these results. Future studies are encouraged to employ longer time-horizons and larger sample sizes to enable better determination of sustained cost and outcomes changes. Prospero registration number: CRD42019133554.
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http://dx.doi.org/10.1016/j.smrv.2020.101351DOI Listing
December 2020

Androgens In Men Study (AIMS): protocol for meta-analyses of individual participant data investigating associations of androgens with health outcomes in men.

BMJ Open 2020 05 11;10(5):e034777. Epub 2020 May 11.

School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.

Introduction: This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men.

Methods And Analysis: Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.

Ethics And Dissemination: Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.

Prospero Registration Number: CRD42019139668.
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http://dx.doi.org/10.1136/bmjopen-2019-034777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239545PMC
May 2020

A durable protective immune response to wild-type measles virus infection of macaques is due to viral replication and spread in lymphoid tissues.

Sci Transl Med 2020 04;12(537)

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.

Infection with wild-type (WT) measles virus (MeV) is an important cause of childhood mortality that leads to lifelong protective immunity in survivors. WT MeV and the live-attenuated MeV used in the measles vaccine (LAMV) are antigenically similar, but the determinants of attenuation are unknown, and protective immunity induced by LAMV is less robust than that induced by WT MeV. To identify factors that contribute to these differences, we compared virologic and immunologic responses after respiratory infection of rhesus macaques with WT MeV or LAMV. In infected macaques, WT MeV replicated efficiently in B and T lymphocytes with spreading throughout lymphoid tissues resulting in prolonged persistence of viral RNA. In contrast, LAMV replicated efficiently in the respiratory tract but displayed limited spread to lymphoid tissue or peripheral blood mononuclear cells. In vitro, WT MeV and LAMV replicated similarly in macaque primary respiratory epithelial cells and human lymphocytes, but LAMV-infected lymphocytes produced little virus. Plasma concentrations of interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), CCL2, CCL11, CXCL9, and CXCL11 increased in macaques after WT MeV but not LAMV infection. WT MeV infection induced more protective neutralizing, hemagglutinin-specific antibodies and bone marrow plasma cells than did LAMV infection, although numbers of MeV-specific IFN-γ- and IL-4-producing T cells were comparable. Therefore, MeV attenuation may involve altered viral replication in lymphoid tissue that limited spread and decreased the host antibody response, suggesting a link between lifelong protective immunity and the ability of WT MeV, but not LAMV, to spread in lymphocytes.
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http://dx.doi.org/10.1126/scitranslmed.aax7799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895323PMC
April 2020

Sleep Duration Moderates the Relationship Between Perceived Work-Life Interference and Depressive Symptoms in Australian Men and Women from the North West Adelaide Health Study.

Int J Behav Med 2021 Feb;28(1):29-38

Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia.

Background: Mental health disorders are prevalent and costly to workplaces and individuals in Australia. Work-life interference is thought to contribute negatively. The interplay between work-life interference, depressive symptoms and sleep has not been explored to date in population data. The aims of this study were to establish whether sleep duration moderates the relationship between work-life interference and depressive symptoms, and whether this is expressed differentially in male and female respondents.

Methods: Data were drawn from the North West Adelaide Health Study (NWAHS) longitudinal, representative population-based cohort study. Working members of the cohort were invited to participate in a telephone survey about their work conditions, with an 86.7% response rate achieved. Data from 823 respondents were analysed after employing purposeful selection of covariates, using multivariable regression analysis.

Results: Sleep duration was found to moderate the relationship between work-life interference and depressive symptoms (F = 26.60, p < 0.001), and accounted for 19% of the variance observed in depressive symptoms. The strongest effect of work-life interference on depressive symptoms was observed in habitual short sleepers, with the effect weakening as sleep duration increased. The relationship was observed in male and female respondents, but was stronger in females.

Conclusions: Supporting and educating workers about the benefits of sleep for managing the relationship between work-life interference and depressive symptoms may offer a novel strategy for improving worker well-being, particularly when negative facets of work-life interference are not easily remedied or 'reduced'. There is a need for education and support strategies around sleep in Australian workplaces.
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http://dx.doi.org/10.1007/s12529-020-09866-9DOI Listing
February 2021

Association of persistent wild-type measles virus RNA with long-term humoral immunity in rhesus macaques.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Recovery from measles results in life-long protective immunity. To understand induction of long-term immunity, rhesus macaques were studied for 6 months after infection with wild-type measles virus (MeV). Infection caused viremia and rash, with clearance of infectious virus by day 14. MeV RNA persisted in PBMCs for 30-90 days and in lymphoid tissue for 6 months most often in B cells but was rarely detected in BM. Antibody with neutralizing activity and binding specificity for MeV nucleocapsid (N), hemagglutinin (H), and fusion proteins appeared with the rash and avidity matured over 3-4 months. Lymph nodes had increasing numbers of MeV-specific antibody-secreting cells (ASCs) and germinal centers with late hyalinization. ASCs appeared in circulation with the rash and continued to appear along with peripheral T follicular helper cells for the study duration. ASCs in lymph nodes and PBMCs produced antibody against both H and N, with more H-specific ASCs in BM. During days 14-21, 20- to 100-fold more total ASCs than MeV-specific ASCs appeared in circulation, suggesting mobilization of preexisting ASCs. Therefore, persistence of MeV RNA in lymphoid tissue was accompanied by continued germinal center formation, ASC production, avidity maturation, and accumulation of H-specific ASCs in BM to sustain neutralizing antibody and protective immunity.
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http://dx.doi.org/10.1172/jci.insight.134992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098782PMC
February 2020

Practice patterns for stroke prevention using transcranial Doppler in sickle cell anemia: DISPLACE Consortium.

Pediatr Blood Cancer 2020 04 11;67(4):e28172. Epub 2020 Jan 11.

Division of Hematology & Oncology, University of Alabama Birmingham, Birmingham, Alabama.

Background: Children with sickle cell anemia (SCA) are at increased risk for stroke. In 2014, the National Heart, Lung, and Blood Institute (NHLBI) developed guidelines for stroke prevention in SCA informed by the Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP II) trials. The guidelines specify the use of transcranial Doppler (TCD) screening and intervention with chronic red cell transfusions (CRCT) in children with SCA who have TCD indication of high stroke risk. The purpose of this study was to describe real-world practice patterns of stroke risk screening and intervention in sites that participated in the Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) Consortium.

Procedure: Site investigators completed a survey during the formative stages of the study to evaluate their TCD practices relative to the STOP studies. Descriptive statistics and analysis of free-text comments for more complex practices were evaluated.

Results: Results suggested universal acceptance of annual TCD screening and initiation of CRCT following an abnormal result among the DISPLACE Consortium, consistent with NHLBI recommendations. However, there was wide variation in methods for conducting TCD screenings (eg, dedicated Doppler vs TCD imaging), classifying TCD results, and actions taken for conditional and inadequate results.

Conclusions: Annual TCD screening and initiation of CRCT are critical stroke prevention practices that were universally embraced in the consortium. Additional research would be beneficial for informing clinical practices for areas in which guidelines are absent or unclear.
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http://dx.doi.org/10.1002/pbc.28172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036320PMC
April 2020

Systematic review of the efficacy of commonly prescribed pharmacological treatments for primary treatment of sleep disturbance in patients with diagnosed autoimmune disease.

Sleep Med Rev 2020 02 14;49:101232. Epub 2019 Nov 14.

Adelaide Institute for Sleep Health: A Flinders Centre of Research Excellence, Flinders University, Bedford Park, SA, Australia; Respiratory and Sleep Service, Southern Adelaide Local Health Network, Bedford Park, SA, Australia.

Sleep disturbances are commonly reported by patients with autoimmune disease, and are negatively related to both disease activity and quality of life. Despite the potential for sleep disturbance to exacerbate inflammatory pathways, acute management of sleep disturbance with pharmacological aids is not well understood in this patient group. The objective of this review was to determine the efficacy of pharmacological treatments for sleep disturbance to improve sleep outcomes in adult patients with diagnosed autoimmune disease. Four databases and grey literature were searched for randomized controlled trials which used a pharmacological treatment specifically to treat sleep disturbance in patients with diagnosed autoimmune disease, both in hospitalized and non-hospitalized settings. A sleep outcome was required to be the primary endpoint of the study. Of the 409 studies identified, a total of six were included in the systematic review. Risk of bias across the studies was largely unclear, making an assessment challenging; meta-analysis was not undertaken due to clinical and methodological heterogeneity between studies. While there appeared to be perceived improvement in self-reported sleep quantity and quality in existing studies with pharmacological treatment, there was also evidence of placebo effect on some measures. Relatively small numbers of patients have undergone gold-standard polysomnographic (PSG) recording of sleep which limits our knowledge of objectively determined sleep quantity and quality in patients with autoimmune disease receiving pharmacological treatment for sleep disturbance. Presently there is insufficient evidence to determine whether pharmacological treatment of sleep disturbance is beneficial for improving sleep quantity and quality in this patient group beyond rheumatoid arthritis.
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http://dx.doi.org/10.1016/j.smrv.2019.101232DOI Listing
February 2020

End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain.

Blood Adv 2019 12;3(23):3982-4001

Department of Pediatrics, Connecticut Children's/School of Medicine, University of Connecticut, Hartford, CT.

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.
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http://dx.doi.org/10.1182/bloodadvances.2019000882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963237PMC
December 2019

Serum Amyloid A-Mediated Inflammasome Activation of Microglial Cells in Cerebral Ischemia.

J Neurosci 2019 11 14;39(47):9465-9476. Epub 2019 Oct 14.

Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida 33612,

Serum amyloid A (SAA) proteins are acute-phase reactant associated with high-density lipoprotein (HDL) particles and increase in the plasma 1000-fold during inflammation. Recent studies have implicated SAAs in innate immunity and various disorders; however, the precise mechanism eludes us. Previous studies have shown SAAs are elevated following stroke and cerebral ischemia, and our studies demonstrated that SAA-deficient mice reduce inflammation and infarct volumes in a mouse stroke model. Our studies demonstrate that SAA increases the cytokine interleukin-1β (IL-1β), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B, and caspase-1 and may play a role in the pathogenesis of neurological disorders. SAA induced the expression of NLRP3, which mediated IL-1β induction in murine BV-2 cells and both sex primary mouse microglial cells, in a dose- and time-dependent fashion. Inhibition or KO of the NLRP3 in microglia prevented the increase in IL-1β. -acetyl-l-cysteine and mito-TEMPO blocked the induction of IL-1β by inhibiting ROS with SAA treatment. In addition, inhibition of cathepsin B with different drugs or microglia from CatB-deficient mice attenuated inflammasome activation. Our studies suggest that the impact of SAA on inflammasome stimulation is mediated in part by the receptor for advanced glycation endproducts and Toll-like receptor proteins 2 and 4. SAA induced inflammatory cytokines and an M1 phenotype in the microglial cells while downregulating anti-inflammation M2 phenotype. These studies suggest that brain injury to can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes. In the present study, serum amyloid A can induce that activation of the inflammasome in microglial cells and give rise to IL-1β release, which can further inflammation in the brain following neurological diseases. The also presents a novel target for therapeutic approaches in stroke.
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http://dx.doi.org/10.1523/JNEUROSCI.0801-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867810PMC
November 2019

Ischemic stroke in children and young adults with sickle cell disease in the post-STOP era.

Am J Hematol 2019 12 1;94(12):1335-1343. Epub 2019 Nov 1.

Department of Neurology, Medical University of South Carolina, Charleston, South Carolina.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trials established routine transcranial Doppler ultrasound (TCD) screening, with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. Implementation failures and limitations to the STOP protocol may contribute to continued ischemic stroke occurrence. In the "Post-STOP" study, we sought to assess the impact of the STOP protocol on the incidence of ischemic stroke in a multicenter cohort of former STOP and/or STOP 2 trial participants. A central team abstracted data for 2851 (74%) of the 3835 children who took part in STOP and/or STOP 2. Data included TCD and neuroimaging results, treatment, laboratory data, and detailed clinical information pertaining to the stroke. Two stroke neurologists independently confirmed each stroke using pre-specified imaging and clinical criteria and came to consensus. Among the 2808 patients who were stroke-free at the start of Post-STOP with available follow-up, the incidence of first ischemic stroke was 0.24 per 100 patient-years (95% CI, 0.18, 0.31), with a mean (SD) duration of follow-up of 9.1 (3.4) [median 10.3, range (0-15.4)] years. Most (63%) strokes occurred in patients in whom the STOP protocol had not been properly implemented, either failure to screen appropriately with TCD (38%) or failure to transfuse adequately patients with abnormal TCD (25%). This study shows that substantial opportunities for ischemic stroke prevention remain by more complete implementation of the STOP Protocol.
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http://dx.doi.org/10.1002/ajh.25635DOI Listing
December 2019

Sociodemographic, lifestyle and metabolic predictors of all-cause mortality in a cohort of community-dwelling population: an 18-year follow-up of the North West Adelaide Health Study.

BMJ Open 2019 08 24;9(8):e030079. Epub 2019 Aug 24.

Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.

Introduction: Studies examining potential factors of all-cause mortality comprehensively at community level are rare. Using long-term community-based follow-up study, we examined the association of sociodemographic and behavioural characteristics, metabolic and chronic conditions, and medication and health service utilisation with all-cause mortality.

Methods: We followed 4056 participants, aged 18-90 years, for 18 years in the North West Adelaide Health Study (NWAHS). Mortality data were obtained from South Australian (SA) public hospitals and registries including SA births, deaths and marriages, the National Death Index and the NWAHS follow-up. Predictors of all-cause mortality were explored using Cox proportional hazard model, adjusting for potential confounders. We performed subgroup analyses by sex and age.

Results: Mean (SD) age at baseline was 50.4 (16.4) years. Less than half (47.8%) of the participants were men. A total of 64 689.7 person-years from 4033 participants with 18.7 years of follow-up were generated. The median follow-up time was 17.7 years; 614 deaths were recorded. The overall crude death rate was 9.6 (95% CI 8.9 to 10.4) per 1000 person-years. After adjusting for potential confounders, a reduced risk of mortality was significantly associated with being separated or divorced, being in the highest Socioeconomic Indexes for Areas quintile, engaging in moderate exercise, being overweight (body mass index: 25.0-29.9 kg/m) and per 10% increase in per cent predicted forced expiratory volume in 1 s. We found that the most important predictors of all-cause mortality were sociodemographic and behavioural characteristics. Sociodemographic factors were more important predictors of all-cause mortality in young age bracket compared with older people.

Conclusions: Socioeconomic factors were found to be the most important predictors of all-cause mortality. The study highlights the need to address the social inequalities and strengthen behavioural interventions for different subgroups of population to prevent premature deaths.
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http://dx.doi.org/10.1136/bmjopen-2019-030079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720239PMC
August 2019

Higher Serum Sex Hormone-Binding Globulin Levels Are Associated With Incident Cardiovascular Disease in Men.

J Clin Endocrinol Metab 2019 12;104(12):6301-6315

Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.

Context: Sex hormone-binding globulin (SHBG) levels are associated with cardiovascular disease (CVD) risk factors. However, prospective data on the association between SHBG levels and CVD events are sparse, with conflicting results.

Objectives: To examine associations between serum SHBG, total testosterone (TT), and incident CVD and CVD-related mortality in middle-aged to elderly men.

Design And Methods: Data on 2563 community-dwelling men (35 to 80 years) were obtained from participants in the Men Androgen Inflammation Lifestyle Environment and Stress cohort. The analytic sample included 1492 men without baseline (2002 to 2007) CVD and with fasted morning serum SHBG and TT available at both baseline and follow-up (2007 to 2010) and without medications affecting TT or SHBG. Associations of baseline SHBG and TT, with incident CVD and CVD mortality, were analyzed using logistic regression for incident CVD and Cox proportional hazard regression for CVD mortality, adjusting for established CVD risk factors.

Results: In multivariable models, elevated baseline SHBG and lower baseline TT were independently associated with incident CVD (SHBG: OR, 1.54; 95% CI, 1.15 to 2.06 per SD increase in SHBG, P = 0.003; TT: OR, 0.71; 95% CI, 0.52 to 0.97 per SD decrease in TT; P = 0.03). A decrease in TT between time points was associated with incident CVD (OR, 0.72; 95% CI, 0.56 to 0.92; P = 0.01). Neither SHBG nor TT was significantly associated with all-age CVD mortality [hazard ratio (HR), 0.69; 95% CI, 0.29 to 1.63; P = 0.40; and HR, 0.60; 95% CI, 0.28 to 1.26; P = 0.18, respectively].

Conclusions: Among all men and men >65 years, elevated SHBG and lower TT were independently associated with both a greater risk of CVD and an increased CVD mortality risk.
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http://dx.doi.org/10.1210/jc.2019-01317DOI Listing
December 2019