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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]

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]

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]

Purpose: A number of previous studies have shown inconsistencies between sub-scale scores and component summary scores using traditional scoring methods of the SF-36 version 1. This study addresses the issue in Version 2 and asks if the previous problems of disagreement between the eight SF-36 Version 1 sub-scale scores and the Physical and Mental Component Summary persist in version 2. A second study objective is to review the recommended scoring methods for the creation of factor scoring weights and the effect on producing summary scale scores Methods: The 2004 South Australian Health Omnibus Survey dataset was used for the production of coefficients. There were 3,014 observations with full data for the SF-36. Data were analysed in LISREL V8.71. Confirmatory factor analysis models were fit to the data producing diagonally weighted least squares estimates. Scoring coefficients were validated on an independent dataset, the 2008 South Australian Health Omnibus Survey. Results: Problems of agreement were observed with the recommended orthogonal scoring methods which were corrected using confirmatory factor analysis. Conclusions: Confirmatory factor analysis is the preferred method to analyse SF-36 data, allowing for the correlation between physical and mental health. [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: 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]

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]

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]

Objective: The aim of this study is to describe the evolution of multimorbidity. Study Design and Setting: Data from 1854 South Australians who participated in the North West Adelaide longitudinal Health Study(NWAHS) was collected between baseline (2000–2002) and follow-up (2008–2010). Status for eight chronic diseases (CDs) was determined by biomedical measurement or self-report. Chronic disease (CD) mean age of occurrence and order of appearance was investigated. Results: The prevalence of multimorbidity increased from 32% to 64% during the 7.8±1.1 years of follow-up. The estimated mean age of onset of a new CD was significantly older for hypertension, cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) and younger for hypercholesterolemia, asthma and other mental problem. Hypercholesterolemia was more likely to develop as a first than as a subsequent CD (39%vs.16%, p<0.0001) while CVD (1%vs.5%, p<0.0001), diabetes (5%vs.11%, p<0.001) and COPD (6%vs.16%, p<0.0001) were less likely. The presence of mood disorders at baseline was associated with an increased risk of developing other mental disorders (36%vs.12%, p<0.0001), diabetes (18%vs.9%, p<0.01) and asthma (30%vs.21%, p<0.05). Conclusion: Longitudinal data could be used to study the evolution of multimorbidity and could provide information on CDs mean age of occurrence, order of appearance and impact on the development of future CDs. [ABSTRACT FROM AUTHOR]

The increasing use of the common marmoset (Callithrix jacchus) in research makes it important to diagnose spontaneous disease that may confound experimental studies. Bone disease and gastrointestinal disease are two major causes of morbidity and mortality in captive marmosets, but currently no effective antemortem tests are available to identify affected animals prior to the terminal stage of disease. In this study we propose that bone disease and gastrointestinal disease are associated disease entities in marmosets and aim to establish the efficacy of several economical antemortem tests in identifying and predicting disease. Tissues from marmosets were examined to define affected animals and unaffected controls. Complete blood count, serum chemistry values, body weight, quantitative radiographs, and tissue-specific biochemical markers were evaluated as candidate biomarkers for disease. Bone and gastrointestinal disease were associated, with marmosets being over seven times more likely to have either concurrent bone and gastrointestinal disease or neither disease as opposed to lesions in only one organ system. When used in tandem, serum albumin <3.5 g/dL and body weight <325 g identified 100% of the marmosets affected with concurrent bone and gastrointestinal disease. Progressive body weight loss of 0.05% of peak body weight per day predicted which marmosets would develop disease prior to the terminal stage. Bone tissue-specific tests, such as quantitative analysis of radiographs and serum parathyroid hormone levels, were effective for distinguishing between marmosets with bone disease and those without. These results provide an avenue for making informed decisions regarding the removal of affected marmosets from studies in a timely manner, preserving the integrity of research results. [ABSTRACT FROM AUTHOR]

Objectives: Emerging evidence shows that diet is related to asthma. The aim of this analysis was to investigate the association between monosodium glutamate (MSG) intake, overall dietary patterns and asthma. Methods: Data from 1486 Chinese men and women who participated in the Jiangsu Nutrition Study (JIN) were analyzed. In this study, MSG intake and dietary patterns were quantitatively assessed in 2002. Information on asthma history was collected during followed-up in 2007. Results: Of the sample, 1.4% reported ever having asthma. MSG intake was not positively associated with asthma. There was a significant positive association between 'traditional' (high loadings on rice, wheat flour, and vegetable) food pattern and asthma. No association between 'macho' (rich in meat and alcohol), 'sweet tooth' (high loadings on cake, milk, and yoghurt) 'vegetable rich' (high loadings on whole grain, fruit, and vegetable) food patterns and asthma was found. Smoking and overweight were not associated with asthma in the sample. Conclusion: While a 'Traditional' food pattern was positively associated with asthma among Chinese adults, there was no significant association between MSG intake and asthma. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS) have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS) disease using a well-characterized simian immunodeficiency (SIV)/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis) was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5). Animals expressing the Mane- A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P,0.001). Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease. [ABSTRACT FROM AUTHOR]