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Background: 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. Method and analysis: 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. Discussion: 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. [ABSTRACT FROM AUTHOR]

Background: On-call research and guidance materials typically focus on 'traditional' on-call work (e.g., emergency services, healthcare). However, given the increasing prevalence of non-standard employment arrangements (e.g., gig work and casualisation), it is likely that a proportion of individuals who describe themselves as being on-call are not included in current on-call literature. This study therefore aimed to describe the current sociodemographic and work characteristics of Australian on-call workers. Methods: A survey of 2044 adults assessed sociodemographic and work arrangements. Of this population, 1057 individuals were workforce participants, who were asked to provide information regarding any on-call work they performed over the last three months, occupation type, weekly work hours, and the presence or absence of non-standard work conditions. Results: Of respondents who were working, 45.5% reported working at least one day on-call in the previous month. There was a high prevalence of on-call work in younger respondents (63.1% of participants aged 18–24 years), and those who worked multiple jobs and more weekly work hours. Additionally, high prevalence rates of on-call work were reported by machinery operators, drivers, community and personal service workers, sales workers, and high-level managers. Conclusions: These data suggest that on-call work is more prevalent than previously recorded and is likely to refer to a broad set of employment arrangements. Current classification systems may therefore be inadequate for population-level research. A taxonomy for the classification of on-call work is proposed, incorporating traditional on-call work, gig economy work, relief, or unscheduled work, and out of hours work. [ABSTRACT FROM AUTHOR]

Background: Population-wide reductions in cardiovascular disease (CVD) have not been equally shared in the African American community due to a higher burden of CVD risk factors such as metabolic disorders and obesity. Differential concentrations of sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P) has been associated with the development of CVD, metabolic disorders (MetD), and obesity. Whether African Americans have disparate expression levels of sphingolipids that explain higher burdens of CVD remains unknown. Methods: A cross sectional analysis of plasma concentrations of ceramides, sphingosine, and S1P were measured from 8 whites and 7 African Americans without metabolic disorders and 7 whites and 8 African Americans with metabolic disorders using high performance liquid chromatography/tandem mass spectrometry methodology (HPLC/MS-MS). Subjects were stratified by both race and metabolic status. Subjects with one or more of the following physician confirmed diagnosis: diabetes, hypertension, hypercholesterolemia, or dyslipidemia were classified as having metabolic disease (MetD). Data was analyzed using a Two-Way ANOVA and Tukey’s post hoc test. Results: Total ceramide levels were increased in African Americans compared to African Americans with MetD. Ceramide C16 levels were higher in whites with MetD compared to African Americans with MetD (p<0.05). Ceramide C20 levels were higher in whites with MetD compared to whites. Ceramide C20 levels were higher in African Americans compared to African Americans with MetD. Furthermore, whites with MetD had higher levels of C20 compared to African Americans with MetD (p<0.0001). Ceramide C24:0 and C24:1 in African Americans was higher compared to African Americans with MetD (p<0.05). The plasma concentration of Sph-1P ceramide was higher in African Americans vs whites (p = 0.01). Lastly, ceramide C20 negatively correlated with hemoglobin A1c (HbA1c) levels in our study cohort. Conclusions: Plasma ceramide concentration patterns are distinct in African Americans with MetD. Further research with larger samples sizes are needed to confirm these findings and to understand whether racial disparities in sphingolipid concentrations have potential therapeutic implications for CVD-related health outcomes. [ABSTRACT FROM AUTHOR]

Elevated levels of FGF23 in individuals with chronic kidney disease (CKD) are associated with adverse health outcomes, such as increased mortality, large vessel disease, and reduced white matter volume, cardiovascular and cerebrovascular events. Apart from the well-known link between cardiovascular (CV) risk factors, especially diabetes and hypertension, and cerebrovascular damage, elevated FGF23 is also postulated to be associated with cerebrovascular damage independently of CKD. Elevated FGF23 predisposes to vascular calcification and is associated with vascular stiffness and endothelial dysfunction in the general population with normal renal function. These factors may lead to microangiopathic changes in the brain, cumulative ischemia, and eventually to the loss of white matter fibers. The relationship between FGF23 and brain integrity in individuals without CKD has hitherto not been investigated. In this study, we aimed to determine the association between FGF23, and white matter integrity in a cohort of 50 participants with varying degrees of CV risk burden, using high resolution structural human brain connectomes constructed from MRI diffusion images. We observed that increased FGF23 was associated with axonal loss in the frontal lobe, leading to a fragmentation of white matter network organization. This study provides the first description of the relationship between elevated levels of FGF23, white matter integrity, and brain health. We suggest a synergistic interaction of CV risk factors and FGF23 as a potentially novel determinant of brain health. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated the relationship between physical activity (PA) of low intensity and duration with quality of life (QoL) among individuals at risk or with cardiovascular disease (CVD). Objectives: To investigate whether PA of different intensity and duration moderates the relationship between CVD and its risk factors (obesity, hypertension, diabetes, dyslipidaemia) and QoL in adults. Methods: Population-based cross-sectional studies using data from the EpiFloripa Cohort Study (Southern Brazil; n = 1,220, 38.8±12.0 years, 48.2% males) and the North West Adelaide Health Study (NWAHS, South Australia; n = 1,661, 43.7±11.1 years, 49.7% males). The physical and psychological domains of QoL were assessed using the WHOQOL-Bref (EpiFloripa) or the SF-36 (NWAHS) questionnaires. The diagnosis of CVD and its risk factors were self-reported. PA was self-reported and quantified by its intensity [“walking” or moderate/vigorous (MVPA)] and duration (none, 1–150, ≥150 min/week). Both studies were analysed separately, and results were adjusted for sociodemographic variables. Results: Participants at risk or with CVD from both studies showed a lower QoL than ‘healthy’ individuals with a stronger relationship for the physical domain. PA duration showed a direct-trend relationship with QoL, but the associations were stronger for MVPA in both studies. However, when stratified by health status, the magnitude of the association between “walking” duration and a higher physical QoL was greater among those at risk or with CVD compared to ‘healthy’ individuals. Conversely, among Australians with CVD, MVPA was associated with a better physical QoL only when its duration was ≥150 min/week. All associations were stronger in the NWAHS than in the Brazilian study. Conclusions: “Walking” was more prevalent than MVPA and was consistently associated with a better physical QoL among those at risk or with CVD. These findings should be considered in the design of public health interventions designed to increase PA and improve QoL. [ABSTRACT FROM AUTHOR]

Functional RNAi based screening is affected by large numbers of false positive and negative hits due to prevalent sequence based off-target effects. We performed a druggable genome targeting siRNA screen intended to identify novel regulators of E-cadherin (CDH1) expression, a known key player in epithelial mesenchymal transition (EMT). Analysis of primary screening results indicated a large number of false-positive hits. To address these crucial difficulties we developed an analysis method, SENSORS, which, similar to published methods, is a seed enrichment strategy for analyzing siRNA off-targets in RNAi screens. Using our approach, we were able to demonstrate that accounting for seed based off-target effects stratifies primary screening results and enables the discovery of additional screening hits. While traditional hit detection methods are prone to false positive results which are undetected, we were able to identify false positive hits robustly. Transcription factor MYBL1 was identified as a putative novel target required for CDH1 expression and verified experimentally. No siRNA pool targeting MYBL1 was present in the used siRNA library. Instead, MYBL1 was identified as a putative CDH1 regulating target solely based on the SENSORS off-target score, i.e. as a gene that is a cause for off-target effects down regulating E-cadherin expression. [ABSTRACT FROM AUTHOR]

Hypercoagulability in sickle cell disease (SCD) is associated with multiple SCD phenotypes, association with stroke risk has not been well described. We hypothesized that serum levels of biomarkers of coagulation activation correlate with high transcranial Doppler ultrasound velocity and decreases with blood transfusion therapy in SCD patients. Stored serum samples from subjects in the Stroke Prevention in Sickle Cell Anemia (STOP) trial were analyzed using ELISA and protein multiplexing techniques. 40 subjects from each treatment arm (Standard Care [SC] and Transfusion [Tx]) at three time points—baseline, study exit and one year post-trial and 10 each of age matched children with SCD but normal TCD (SNTCD) and with normal hemoglobin (HbAA) were analyzed. At baseline, median vWF, TAT and D-dimer levels were significantly higher among STOP subjects than either HbAA or SNTCD. At study exit, median hemoglobin level was significantly higher while median TCD velocity was significantly lower in Tx compared to SC subjects. Median vWF (409.6 vs. 542.9 μg/ml), TAT (24.8 vs. 40.0 ng/ml) and D-dimer (9.2 vs. 19.1 μg/ml) levels were also significantly lower in the Tx compared to the SC group at study exit. Blood levels of biomarkers coagulation activation/thrombin generation correlated positively with TCD velocity and negatively with number of blood transfusions. Biomarkers of coagulation activation/thrombin generation were significantly elevated in children with SCD, at high risk for stroke. Reduction in levels of these biomarkers correlated with reduction in stroke risk (lower TCD velocity), indicating a possible role for hypercoagulation in SCD associated stroke. [ABSTRACT FROM AUTHOR]