Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-ß0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Effects of the antipsychotic quetiapine on sleep and breathing: a review of clinical findings and potential mechanisms.

Quetiapine is an antipsychotic medication indicated for schizophrenia and bipolar disorder. However, quetiapine also has hypnotic properties and as such is increasingly being prescribed at low doses 'off-label' in people with insomnia symptoms. Pharmacologically, in addition to its dopaminergic properties, quetiapine also modulates multiple other transmitter systems involved in sleep/wake modulation and potentially breathing. However, very little is known about the impact of quetiapine on obstructive sleep apnoea (OSA), OSA endotypes including chemosensitivity, and control of breathing. Given that many people with insomnia also have undiagnosed OSA, it is important to understand the effects of quetiapine on OSA and its mechanisms. Accordingly, this concise review covers the existing knowledge on the effects of quetiapine on sleep and breathing. Further, we highlight the pharmacodynamics of quetiapine and its potential to alter key OSA endotypes to provide potential mechanistic insight. Finally, an agenda for future research priorities is proposed to fill the current key knowledge gaps.

Associations of baseline obstructive sleep apnea and sleep macroarchitecture with cognitive function after 8 years in middle-aged and older men from a community-based cohort study.

Previous prospective studies examining associations of obstructive sleep apnea and sleep macroarchitecture with future cognitive function recruited older participants, many demonstrating baseline cognitive impairment. This study examined obstructive sleep apnea and sleep macroarchitecture predictors of visual attention, processing speed, and executive function after 8 years among younger community-dwelling men. Florey Adelaide Male Ageing Study participants (n = 477) underwent home-based polysomnography, with 157 completing Trail-Making Tests A and B and the Mini-Mental State Examination. Associations of obstructive sleep apnea (apnea-hypopnea index, oxygen desaturation index, and hypoxic burden index) and sleep macroarchitecture (sleep stage percentages and total sleep time) parameters with future cognitive function were examined using regression models adjusted for baseline demographic, biomedical, and behavioural factors, and cognitive task performance. The mean (standard deviation) age of the men at baseline was 58.9 (8.9) years, with severe obstructive sleep apnea (apnea-hypopnea index ≥30 events/h) in 9.6%. The median (interquartile range) follow-up was 8.3 (7.9-8.6) years. A minority of men (14.6%) were cognitively impaired at baseline (Mini-Mental State Examination score <28/30). A higher percentage of light sleep was associated with better Trail-Making Test A performance (B = -0.04, 95% confidence interval [CI] -0.06, -0.01; p = 0.003), whereas higher mean oxygen saturation was associated with worse performance (B = 0.11, 95% CI 0.02, 0.19; p = 0.012). While obstructive sleep apnea and sleep macroarchitecture might predict cognitive decline, future studies should consider arousal events and non-routine hypoxaemia measures, which may show associations with cognitive decline.

Insomnia and workplace productivity loss among young working adults: a prospective observational study of clinical sleep disorders in a community cohort.

OBJECTIVE: To examine associations between three clinically significant sleep disorders (chronic insomnia, obstructive sleep apnoea, restless legs syndrome) and workplace productivity losses among young Australian adults. DESIGN, SETTING: Prospective, observational study; 22-year follow-up of participants in the longitudinal birth cohort Raine Study (Perth, Western Australia). PARTICIPANTS: Currently employed 22-year-old Raine Study participants who underwent in-laboratory sleep disorder screening for moderate to severe obstructive sleep apnoea (apnoea-hypopnea index of more than fifteen events/hour or obstructive sleep apnoea syndrome) and were assessed for insomnia and restless legs syndrome using validated measures. MAIN OUTCOME MEASURES: Total workplace productivity loss over twelve months, assessed with the World Health Organization Health and Work Performance Questionnaire. RESULTS: Of 1235 contactable 22-year-old Raine Study cohort members, 554 people (44.9%; 294 women [53%]) underwent overnight polysomnography, completed the baseline sleep questionnaire, and completed at least three quarterly workplace productivity assessments. One or more clinically significant sleep disorders were identified in 120 participants (21.7%); 90 participants had insomnia (17%), thirty clinically significant obstructive sleep apnoea (5.4%), and two restless legs syndrome (0.4%). Seventeen people (14% of those with sleep disorders) had previously been diagnosed with a sleep disturbance by a health professional, including fourteen with insomnia. Median total workplace productivity loss was greater for participants with sleep disorders (164 hours/year; interquartile range [IQR], 0-411 hours/year) than for those without sleep disorders (30 hours/year; IQR, 0-202 hours/year); total workplace productivity loss was 40% greater for participants with sleep disorders (adjusted incidence rate ratio, 1.40; bias-corrected and accelerated 95% confidence interval, 1.10-1.76). The estimated population total productivity loss (weighted for disorder prevalence) was 28 644 hours per 1000 young workers per year, primarily attributable to insomnia (28 730 hours/1000 workers/year). CONCLUSION: Insomnia is a risk factor for workplace productivity loss in young workers. Tailored interventions are needed to identify and manage sleep disorders, particularly as most of the sleep disorders detected in the Raine Study had not previously been diagnosed.

Multinight Prevalence, Variability, and Diagnostic Misclassification of Obstructive Sleep Apnea.

Rationale: Recent studies suggest that obstructive sleep apnea (OSA) severity can vary markedly from night to night, which may have important implications for diagnosis and management. Objectives: This study aimed to assess OSA prevalence from multinight in-home recordings and the impact of night-to-night variability in OSA severity on diagnostic classification in a large, global, nonrandomly selected community sample from a consumer database of people that purchased a novel, validated, under-mattress sleep analyzer. Methods: A total of 67,278 individuals aged between 18 and 90 years underwent in-home nightly monitoring over an average of approximately 170 nights per participant between July 2020 and March 2021. OSA was defined as a nightly mean apnea-hypopnea index (AHI) of more than 15 events/h. Outcomes were multinight global prevalence and likelihood of OSA misclassification from a single night's AHI value. Measurements and Main Results: More than 11.6 million nights of data were collected and analyzed. OSA global prevalence was 22.6% (95% confidence interval, 20.9-24.3%). The likelihood of misdiagnosis in people with OSA based on a single night ranged between approximately 20% and 50%. Misdiagnosis error rates decreased with increased monitoring nights (e.g., 1-night F1-score = 0.77 vs. 0.94 for 14 nights) and remained stable after 14 nights of monitoring. Conclusions: Multinight in-home monitoring using novel, noninvasive under-mattress sensor technology indicates a global prevalence of moderate to severe OSA of approximately 20%, and that approximately 20% of people diagnosed with a single-night study may be misclassified. These findings highlight the need to consider night-to-night variation in OSA diagnosis and management.

Hemorrhagic Stroke in Children and Adults With Sickle Cell Anemia: The Post-STOP Cohort.

BACKGROUND: Hemorrhagic stroke in young patients with sickle cell anemia remains poorly characterized. METHODS: The Post-STOP (Stroke Prevention Trial in Sickle Cell Anemia) retrospective study collected follow-up data on STOP and STOP II clinical trial cohorts. From January 2012 to May 2014, a team of analysts abstracted data from medical records of prior participants (all with sickle cell anemia). Two vascular neurologists reviewed data to confirm hemorrhagic strokes defined as spontaneous intracerebral, subarachnoid, or intraventricular hemorrhage. Incidence rates were calculated using survival analysis techniques Results: Follow-up data were collected from 2850 of 3835 STOP or STOP II participants. Patients (51% male) were a median of 19.1 (interquartile range, 16.6-22.6) years old at the time of last known status. The overall hemorrhagic stroke incidence rate was 63 per 100 000 person-years (95% CI, 45-87). Stratified by age, the incidence rate per 100 000 person-years was 50 (95% CI, 34-75) for children and 134 (95% CI, 74-243) for adults >18 years. Vascular abnormalities (moyamoya arteriopathy, aneurysm or cavernous malformation) were identified in 18 of 35 patients with hemorrhagic stroke. CONCLUSIONS: The incidence rate of hemorrhagic stroke in patients with sickle cell anemia increases with age. Structural vascular abnormalities such as moyamoya arteriopathy and aneurysms are common etiologies for hemorrhage and screening may be warranted.

Effect of Single Housing on Innate Immune Activation in Immunodeficiency Virus-Infected Pigtail Macaques ( Macaca nemestrina ) as a Model of Psychosocial Stress in Acute HIV Infection.

OBJECTIVE: Simian immunodeficiency virus (SIV) infection of macaques recapitulates many aspects of HIV pathogenesis and is similarly affected by both genetic and environmental factors. Psychosocial stress is associated with immune system dysregulation and worse clinical outcomes in people with HIV. This study assessed the impact of single housing, as a model of psychosocial stress, on innate immune responses of pigtailed macaques ( Macaca nemestrina ) during acute SIV infection. METHODS: A retrospective analysis of acute SIV infection of 2- to si6-year-old male pigtailed macaques was performed to compare the innate immune responses of socially ( n = 41) and singly ( n = 35) housed animals. Measures included absolute monocyte count and subsets, and in a subset ( n ≤ 18) platelet counts and activation data. RESULTS: SIV infection resulted in the expected innate immune parameter changes with a modulating effect from housing condition. Monocyte number increased after infection for both groups, driven by classical monocytes (CD14 + CD16 - ), with a greater increase in socially housed animals (227%, p < .001, by day 14 compared with preinoculation time points). Platelet numbers recovered more quickly in the socially housed animals. Platelet activation (P-selectin) increased by 65% ( p = .004) and major histocompatibility complex class I surface expression by 40% ( p = .009) from preinoculation only in socially housed animals, whereas no change in these measures occurred in singly housed animals. CONCLUSIONS: Chronic psychosocial stress produced by single housing may play an immunomodulatory role in the innate immune response to acute retroviral infection. Dysregulated innate immunity could be one of the pathways by which psychosocial stress contributes to immune suppression and increased disease severity in people with HIV.

Multidimensional sleep health is associated with mental well-being in Australian adults.

The few studies assessing the relationship between mental health and a multidimensional measure of sleep have been conducted in samples of almost exclusively women. In the present study, we therefore assessed associations of multidimensional sleep health with mental well-being in Australian adults. A cross-sectional, national online survey of sleep health was conducted in 2019 in 2,044 community dwelling adults aged 18-90 years. Composite scores of self-reported healthy sleep were based on Ru-SATED (R-SATED) dimensions of satisfaction, alertness, timing, efficiency and duration scored 0 (never/rarely), 1 (sometimes) or 2 (usually/always), and regularity (social jet lag) was scored 0 (≥1 hr) or 1 (<1 hr). Mental well-being was identified by a report of no problem on the EuroQol (European quality of life) five dimension five level scale (EQ-5D-5L) anxiety/depression scale, as well as absence of six chronic depressive symptoms. Ordinal logistic regression analyses determined associations of mental well-being with sleep dimensions, and total R-SATED (range 0-11) and SATED scores (0-10), adjusted for sociodemographic and health factors. In males and females, healthy categories of SATED dimensions (but not regularity) were associated with mental well-being. A 1 unit increase in the total SATED score (mean [SD] 6.6 [2.1]) was associated with less problems on the EQ-5D-5L (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.08-1.14) and fewer chronic depressive symptoms (OR 1.20, 95% CI 1.17-1.23). These estimates did not differ when the total R-SATED score was considered. Sleep health promotion focussing solely on traditional messaging around healthy sleep duration may limit mental health gains. Rather, a more holistic approach to public health messaging to improve sleep health literacy may be beneficial for mental well-being.

Assessing the Clinical Utility of a Wearable Device for Physiological Monitoring of Heart Rate Variability in Military Service Members with Traumatic Brain Injury.

Introduction: Autonomic dysfunction has been implicated as a consequence of traumatic brain injury (TBI). Heart rate variability (HRV) may be a viable measure of autonomic dysfunction that could enhance rehabilitative interventions for individuals with TBI. This pilot study sought to assess the feasibility and validity of using the Zeriscope™ platform system in a real-world clinical setting to measure HRV in active-duty service members with TBI who were participating in an intensive outpatient program. Methods: Twenty-five service members with a history of mild, moderate, or severe TBI were recruited from a military treatment facility. A baseline assessment was conducted in the cardiology clinic where point validity data were obtained by comparing a 5-min recording of a standard 12-lead electrocardiogram (ECG) output against the Zeriscope platform data. Results: Compared with the ECG device, the Zeriscope device had a concordance coefficient (rc) of 0.16, falling below the standard deemed to represent acceptable accuracy in HR measurement (i.e., 0.80). Follow-up analyses excluding outliers did not significantly improve the concordance coefficient to an acceptable standard for the total participant sample. System Usability Survey responses showed that participants rated the Zeriscope system as easy to use and something that most people would learn to use quickly. Conclusions: This study demonstrated promise in ambulatory HRV measurement in a representative military TBI sample. Future research should include further refinement of such ambulatory devices to meet the specifications required for use in a military active-duty TBI population.

Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute Simian Immunodeficiency Virus Infection in a Pigtailed Macaque Model of Human Immunodeficiency Virus.

BACKGROUND: Although 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 human immunodeficiency virus (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 simian immunodeficiency virus (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 with 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.

Racial Differences in Blood Pressure Control Following Stroke: The REGARDS Study.

BACKGROUND AND PURPOSE: In the general population, Black adults are less likely than White adults to have controlled blood pressure (BP), and when not controlled, they are at greater risk for stroke compared with White adults. High BP is a major modifiable risk factor for recurrent stroke, but few studies have examined racial differences in BP control among stroke survivors. METHODS: We used data from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) to examine disparities in BP control between Black and White adults, with and without a history of stroke. We studied participants taking antihypertensive medication who did and did not experience an adjudicated stroke (n=306 and 7693 participants, respectively) between baseline (2003-2007) and a second study visit (2013-2016). BP control at the second study visit was defined as systolic BP <130 mm Hg and diastolic BP <80 mm Hg except for low-risk adults ≥65 years of age (ie, those without diabetes, chronic kidney disease, history of cardiovascular disease, and with a 10-year predicted atherosclerotic cardiovascular disease risk <10%) for whom BP control was defined as systolic BP <130 mm Hg. RESULTS: Among participants with a history of stroke, 50.3% of White compared with 39.3% of Black participants had controlled BP. Among participants without a history of stroke, 56.0% of White compared with 50.2% of Black participants had controlled BP. After multivariable adjustment, there was a tendency for Black participants to be less likely than White participants to have controlled BP (prevalence ratio, 0.77 [95% CI, 0.59-1.02] for those with a history of stroke and 0.92 [95% CI, 0.88-0.97] for those without a history of stroke). CONCLUSIONS: There was a lower proportion of controlled BP among Black compared with White adults with or without stroke, with no statistically significant differences after multivariable adjustment.

Hydroxycarbamide treatment reduces transcranial Doppler velocity in the absence of transfusion support in children with sickle cell anaemia, elevated transcranial Doppler velocity, and cerebral vasculopathy: the EXTEND trial.

EXpanding Treatment for Existing Neurological Disease (EXTEND) investigated whether hydroxycarbamide lowers transcranial Doppler (TCD) velocities in Jamaican children with sickle cell anaemia (SCA) and elevated TCD velocity with or without previous stroke. Forty-three children (age 2-17 years) with baseline maximum time-averaged mean velocity (TAMV) ≥ 170 cm/s were stratified into three risk categories based on treatment status and stroke history: Group 1 (no history of stroke, on hydroxycarbamide, n = 12); and Groups 2 (no stroke, no hydroxycarbamide, n = 21) and 3 (previous stroke, no hydroxycarbamide, n = 10). Open-label hydroxycarbamide at 20 mg/kg/day was commenced, with escalation to maximum tolerated dose (MTD) based on mild marrow suppression (average dose 25·4 ± 4·5 mg/kg/day). TCD was performed every six months with brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) at baseline and after 18-months of hydroxycarbamide. The maximum TAMV decreased significantly compared to baseline (24 ± 30 cm/s, P < 0·0001), with similar declines in all groups. Clinical stroke occurred in five children, one in Group 1, none in Group 2, and four in Group 3, P = 0·0032, comparing group incidence rates. Brain MRI/MRA was stable in children without clinical stroke. EXTEND documents the feasibility and benefits of hydroxycarbamide at MTD to lower TCD velocities and reduce stroke risk in children with SCA and no history of primary stroke in low-resource settings without transfusion management.

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

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.

Co-occurring depression and insomnia in Australian primary care: recent scientific evidence.

Depression and insomnia commonly co-occur, resulting in greater morbidity for patients, and difficult diagnostic and treatment decisions for clinicians. When patients report symptoms of both depression and insomnia, it is common for medical practitioners to conceptualise the insomnia as a secondary symptom of depression. This implies that there is little purpose in treating insomnia directly, and that management of depression will improve both the depression and insomnia symptoms. In this review, we present an overview of research investigating the comorbidity and treatment approaches for patients presenting with depression and insomnia in primary care. Evidence shows that clinicians should avoid routinely conceptualising insomnia as a secondary symptom of depression. This is because insomnia symptoms: (i) often occur before mood decline and are independently associated with increased risk of future depression; (ii) commonly remain unchanged following depression treatment; and (iii) predict relapse of depression after treatment for depression only. Furthermore, compared with control, cognitive behaviour therapy for insomnia improves symptoms of both depression and insomnia. It is critical that primary care clinicians dedicate specific diagnostic and treatment attention to the management of both depression (eg, psychotherapy, antidepressants) and insomnia (eg, cognitive behaviour therapy for insomnia administered by trained therapists or psychologists through a mental health treatment plan referral, by online programs, or by a general practitioner or nurse) when they co-occur. These treatments may be offered concurrently or sequentially (eg, insomnia treatment followed by depression treatment, or vice versa), depending on presenting symptoms, history, lifestyle factors and other comorbidities.

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

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.

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

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.

Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial.

BACKGROUND AND OBJECTIVE: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). METHODS: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. RESULTS: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. CONCLUSION: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

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.

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 (F7,815 = 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.