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For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10−16) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. National Heart, Lung, and Blood Institute, National Institutes of Health.

Mental health conditions confer considerable global disease burden in young adults, who are also the highest demographic to work shifts, and of whom 20% meet criteria for a sleep disorder. We aimed to establish the relationship between the combined effect of shift work and sleep disorders, and mental health. The Raine Study is the only longitudinal, population-based birth cohort in the world with gold-standard, Level 1 measurement of sleep (polysomnography, PSG) collected in early adulthood. Participants (aged 22y) underwent in-laboratory PSG and completed detailed sleep questionnaires. Multivariable adjusted robust linear regression models were conducted to explore associations with anxiety (GAD7) and depression (PHQ9), adjusted for sex, health comorbidities, and work hours/week. Data were from 660 employed young adults (27.3% shift workers). At least one clinically significant sleep disorder was present in 18% of shift workers (day, evening and night shifts) and 21% of non-shift workers ( p  = 0.51); 80% were undiagnosed. Scores for anxiety and depression were not different between shift and non-shift workers ( p  = 0.29 and p  = 0.82); but were higher in those with a sleep disorder than those without ( Md(IQR) anxiety: 7.0(4.0–10.0) vs 4.0(1.0–6.0)), and depression: (9.0(5.0–13.0) vs 4.0(2.0–6.0)). Considering evening and night shift workers only (i.e. excluding day shift workers) revealed an interaction between shift work and sleep disorder status for anxiety ( p  = 0.021), but not depression ( p  = 0.96), with anxiety scores being highest in those shift workers with a sleep disorder ( Md(IQR) 8.5(4.0–12.2). We have shown that clinical sleep disorders are common in young workers and are largely undiagnosed. Measures of mental health do not appear be different between shift and non-shift workers. These findings indicate that the identification and treatment of clinical sleep disorders should be prioritised for young workers as these sleep disorders, rather than shift work per se , are associated with poorer mental health. These negative mental health effects appear to be greatest in those who work evening and/or night shift and have a sleep disorder.

High ambient temperatures are associated with reduced sleep duration and quality, but effects on obstructive sleep apnea (OSA) severity are unknown. Here we quantify the effect of 24 h ambient temperature on nightly OSA severity in 116,620 users of a Food and Drug Administration-cleared nearable over 3.5 years. Wellbeing and productivity OSA burden for different levels of global warming were estimated. Globally, higher temperatures (99 th vs. 25 th ; 27.3 vs. 6.4 °C) were associated with a 45% higher probability of having OSA on a given night (mean [95% confidence interval]; 1.45 [1.44, 1.47]). Warming-related increase in OSA prevalence in 2023 was estimated to be associated with a loss of 788,198 (489,226, 1,087,170) healthy life years (in 29 countries), and a workplace productivity loss of 30 (21 to 40) billion United States dollars. Scenarios with projected temperatures ≥1.8 °C above pre-industrial levels would incur a further 1.2 to 3-fold increase in OSA burden by 2100. High ambient temperatures are associated with reduced sleep duration and quality, and increased obstructive sleep apnoea (OSA). Here the authors quantify the effect of 24 h ambient temperature on nightly OSA severity and report projected in losses of healthy life years and workplace productivity due to OSA in scenarios of projected temperatures ≥1.8° C above pre-industrial levels by 2100.

Despite its widespread clinical use, there is little data available from population-based studies on the determinants of serum sex hormone binding globulin (SHBG). We aimed to examine multifactorial determinants of circulating SHBG levels in community-dwelling men. Study participants comprised randomly selected 35-80 y.o. men (n = 2563) prospectively-followed for 5 years (n = 2038) in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. After excluding men with illness or medications known to affect SHBG (n = 172), data from 1786 men were available at baseline, and 1476 at follow-up. The relationship between baseline body composition (DXA), serum glucose, insulin, triglycerides, thyroxine (fT4), sex steroids (total testosterone (TT), oestradiol (E2)), and pro-inflammatory cytokines and serum SHBG level at both baseline & follow-up was determined by linear and penalized logistic regression models adjusting for age, lifestyle & demographic, body composition, metabolic, and hormonal factors. Restricted cubic spline analyses was also conducted to capture possible non-linear relationships. At baseline there were positive cross-sectional associations between age (β = 0.409, p<0.001), TT (β = 0.560, p<0.001), fT4 (β = 0.067, p = 0.019) and SHBG, and negative associations between triglycerides (β = -0.112, p<0.001), abdominal fat mass (β = -0.068, p = 0.032) and E2 (β = -0.058, p = 0.050) and SHBG. In longitudinal analysis the positive determinants of SHBG at 4.9 years were age (β = 0.406, p = <0.001), TT (β = 0.461, p = <0.001), and fT4 (β = 0.040, p = 0.034) and negative determinants were triglycerides (β = -0.065, p = 0.027) and abdominal fat mass (β = -0.078, p = 0.032). Taken together these data suggest low SHBG is a marker of abdominal obesity and increased serum triglycerides, conditions which are known to have been associated with low testosterone and low T4.

Sleep disorders are common, and largely undiagnosed in early-career workers. The combination of sleep disorders and shift work has implications for mental health, workplace safety, and productivity. Early identification and management of sleep disorders is likely to be beneficial to workers, employers and the community more broadly. We assessed the feasibility and acceptability of a tailored sleep disorder screening and management pathway for individuals with future shift work requirements. Paramedic students were invited to complete an online sleep health survey, which included validated sleep disorder screening questionnaires for insomnia, obstructive sleep apnea and restless legs syndrome. Participants were able to express interest in participating in a sleep monitoring and management study. Participants at risk for a sleep disorder were identified, contacted by the study physician (RJA), notified of their sleep disorder screening results and provided with information regarding management options. Feasibility of the screening and management pathways were determined by completion of the 12 week follow-up, and ability to engage with health services for diagnostic testing or treatment. Acceptability of these pathways was assessed with a semi-structured interview on completion of the study at 12 weeks. Screening was completed in thirty participants (mean age 22.5 ± 6.7, 63% female), 17 of whom were ‘at-risk’ for a sleep disorder and offered a management pathway. All participants engaged with the study physician (RJA), with 16 completing the study (94% completion rate). Three participants with excessive daytime sleepiness received feedback from the study physician (RJA) and no further care required. Of the remaining 14 participants, 11 (78%) engaged with health services after speaking with the study physician (RJA). Those who engaged with diagnostic and management services reported that a structured pathway with online screening was convenient and easy to follow. Facilitating screening and management of sleep disorders in students with future shift work requirements is both feasible and acceptable. These findings can inform the development of a preventive strategy for sleep disorders and ideally, a health services feasibility trial for future shift workers.

The rail industry in Australia screens workers for probable obstructive sleep apnea (OSA) due to known safety risks. However, existing criteria to trigger screening only identify a small proportion of workers with OSA. The current study sought to examine the relationship between OSA risk and rail incidents in real-world data from Australian train drivers, and conducted a proof of concept analysis to determine whether more conservative screening criteria are justified. Health assessment (2016–2018) and subsequent rail incident data (2016–2020) were collected from two passenger rail service providers. Predictors included OSA status (confirmed no OSA with a sleep study, controlled OSA, unknown OSA [no recorded sleep assessment data] and confirmed OSA with no indication of treatment); OSA risk according to the current Standard, and OSA risk according to more conservative clinical markers (BMI threshold and cardiometabolic burden). Coded rail safety incidents involving the train driver were included. Data were analysed using zero-inflated negative binomial models to account for over-dispersion with high 0 counts, and rail safety incidents are reported using Incidence Risk Ratios (IRRs). A total of 751 train drivers, typically middle-aged, overweight to obese and mostly men, were included in analyses. There were 43 (5.7%) drivers with confirmed OSA, 62 (8.2%) with controlled OSA, 13 (1.7%) with confirmed no OSA and 633 (84.4%) drivers with unknown OSA. Of the 633 train drivers with unknown OSA status, 21 (3.3%) met ‘at risk’ criteria for OSA according to the Standard, and incidents were 61% greater (IRR: 1.61, 95% Confidence Interval (CI) 1.02–2.56) in the years following their health assessment compared to drivers who did not meet ‘at risk’ criteria. A more conservative OSA risk status using lower BMI threshold and cardiometabolic burden identified an additional 30 ‘at risk’ train drivers who had 46% greater incidents compared to drivers who did not meet risk criteria (IRR (95% CI) 1.46 (1.00–2.13)). Our more conservative OSA risk criteria identified more workers, with greater prospective incidents. These findings suggest that existing validated tools could be considered in future iterations of the Standard in order to more sensitively screen for OSA.

Paramedics are routinely exposed to shift work. Existing research shows that shift work exposure is associated with adverse mental and physical health outcomes. However, the current understanding of the impact of commencing shift work in a paramedic role on health is limited. This can be addressed by recruiting new paramedics before they commence shift work, and conducting regular follow-ups of potential biological, psychological and social changes. The present study aimed to examine changes in biological, psychological and social factors relative to pre-shift work baseline in a cohort of paramedics commencing intern employment with an Australian ambulance service. This observational, mixed-methods, longitudinal study aims to recruit 40 interns from one Australian ambulance service. Data collection will occur at baseline (standard day schedule for initial training), and subsequently at three months, six months, nine months and twelve months, to measure biological, psychological and social changes relative to baseline measurements. Changes in cardiometabolic markers (cholesterol, triglycerides, fasting glucose), microbiome (self-collected stool samples), sleep and physical activity (actigraphy) will be measured. Interns will also complete a battery of self-report questionnaires, sleep diaries and qualitative interviews to explore various psychological and social variables over time. Statistical analyses will be conducted using mixed effects regression, specifying a random effect of subject on the intercept, allowing participants to vary according to individual baseline levels, as well as tracking progress over time, appropriately accounting for serial correlation. Qualitative study components will be analysed via coding and thematic analysis procedures. The present study protocol is a comprehensive outline of the observational study planned. The study will allow for greater knowledge of any changes in biological, psychological and social factors during a 12-month transition to shift work. The findings from the proposed study will have implications for the development of strategies to support early-career shift workers.