Serum amyloid A (SAA) is a family of acute-phase reactants. Plasma levels of human SAA1/SAA2 (mouse SAA1.1/2.1) can increase ≥1,000-fold during an acute-phase response. Mice, but not humans, express ...a third relatively understudied SAA isoform, SAA3. We investigated whether mouse SAA3 is an HDL-associated acute-phase SAA. Quantitative RT-PCR with isoform-specific primers indicated that SAA3 and SAA1.1/2.1 are induced similarly in livers (∼2,500-fold vs. ∼6,000-fold, respectively) and fat (∼400-fold vs. ∼100-fold, respectively) of lipopolysaccharide (LPS)-injected mice. In situ hybridization demonstrated that all three SAAs are produced by hepatocytes. All three SAA isoforms were detected in plasma of LPS-injected mice, although SAA3 levels were ∼20% of SAA1.1/2.1 levels. Fast protein LC analyses indicated that virtually all of SAA1.1/2.1 eluted with HDL, whereas ∼15% of SAA3 was lipid poor/free. After density gradient ultracentrifugation, isoelectric focusing demonstrated that ∼100% of plasma SAA1.1 was recovered in HDL compared with only ∼50% of SAA2.1 and ∼10% of SAA3. Thus, SAA3 appears to be more loosely associated with HDL, resulting in lipid-poor/free SAA3. We conclude that SAA3 is a major hepatic acute-phase SAA in mice that may produce systemic effects during inflammation.
Youth peer support workers (YPSWs) are young adults with lived experience of mental illness during childhood or adolescence who support young people receiving treatment in mental health services. The ...contributions made by YPSWs are a promising development to facilitate consumer-centered and recovery-oriented care. Although the youth peer support workforce is expanding rapidly, structurally embedding YPSWs in practice is challenging. To overcome these challenges and thereby improve care for young people, insight into YPSW roles, barriers and facilitators for implementing and pursuing youth peer support (YPS) is a necessity. This systematic review examined the published literature to identify existing knowledge on YPSW roles in treatment settings, and the barriers and facilitators for implementing and pursuing YPS in practice. A total of 24 studies from a variety of youth serving contexts were included in this review. Thematic synthesis resulted in six YPSW roles and five themes with barriers and facilitators. The roles included the: engagement role, emotional support role, navigating and planning role, advocacy role, research role and the educational role. The themes explored the needs of YPSWs, experiences of YPSWs, relationships between service users and YPSWs, the collaboration process between YPSWs and non-peer staff, and organizational readiness. This review underlines that YPSWs likely are a valuable addition to numerous youth treatment contexts. Overall, the implementation of YPSWs is a multifaceted operation that requires careful planning. We recommend services to set clear and realistic expectations for YPSWs, to consider potential power imbalances between YPSWs and non-peer staff, to provide adequate resources to pursue YPS, and to approach the implementation of YPSWs with a growth mindset.
While aggregation of neuroimaging datasets from multiple sites and scanners can yield increased statistical power, it also presents challenges due to systematic scanner effects. This unwanted ...technical variability can introduce noise and bias into estimation of biological variability of interest. We propose a method for harmonizing longitudinal multi-scanner imaging data based on ComBat, a method originally developed for genomics and later adapted to cross-sectional neuroimaging data. Using longitudinal cortical thickness measurements from 663 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, we demonstrate the presence of additive and multiplicative scanner effects in various brain regions. We compare estimates of the association between diagnosis and change in cortical thickness over time using three versions of the ADNI data: unharmonized data, data harmonized using cross-sectional ComBat, and data harmonized using longitudinal ComBat. In simulation studies, we show that longitudinal ComBat is more powerful for detecting longitudinal change than cross-sectional ComBat and controls the type I error rate better than unharmonized data with scanner included as a covariate. The proposed method would be useful for other types of longitudinal data requiring harmonization, such as genomic data, or neuroimaging studies of neurodevelopment, psychiatric disorders, or other neurological diseases.
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Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. ...Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral vector. Alternatively, we incubated primary hepatocytes from SAA-deficient mice with purified SAA. We analyzed conditioned media to determine the lipidation status of endogenously produced and exogenously added SAA. Examining the migration of lipidated species, we found that SAA is lipidated and forms nascent particles that are distinct from apoA-I-containing particles and that apoA-I lipidation is unaltered when SAA is overexpressed or added to the cells, indicating that SAA is not incorporated into apoA-I-containing HDL during HDL biogenesis. Like apoA-I formation, generation of SAA-containing particles was dependent on ABCA1, but not on scavenger receptor class B type I. Hepatocytes degraded significantly more SAA than apoA-I. Taken together, our results indicate that SAA's lipidation and metabolism by the liver is independent of apoA-I and that SAA is not incorporated into HDL during HDL biogenesis.
Abstract
Background
Older adults are at high risk of medication-related hospitalizations. Frailty is a phenotype commonly observed in older people due to declining physiological functions.
Aim
To ...examine the association of frailty with medication-related hospitalization among community dwelling older men.
Methods
A prospective observational cohort study was conducted among community dwelling older men (mean age 75.6 years SD 5.9) from Western Australia (4324) who participated in the Health in Men Study. Participants were followed-up at 12 and 24 months to determine adverse drug event-related hospitalization, hospitalizations for other causes and mortality.
Results and Discussion
The prevalence of frailty was 13.2%. At baseline, frailty was associated with exposure to polypharmacy, potentially inappropriate medication use and potential adverse drug–drug interactions with unadjusted odds ratios; 4.13 (3.48–4.89) P < 0.001, 2.46 (1.91–3.17) P < 0.001, 3.85 (3.03–4.90) P < 0.001, respectively. In unadjusted models, frail men were more likely to have non-accidental falls OR 3.16 (2.51–3.99) P < 0.001, acute kidney injury OR 3.37 (2.35–4.82) P < 0.001, ADE-related hospitalizations at 12 months OR 6.83 (4.91–9.51) and non-ADE-related hospitalizations OR 2.63 (2.01–3.45), or to be dead at 12 months OR 2.97 (1.79–4.92) and at 24 months OR 3.14 (2.28–4.33) when compared with non-frail men. After adjusting for age, living alone, cognitive decline, smoking status and comorbidity, frailty remained associated with ADE-related hospitalization OR 3.60 (2.41–5.37), non-ADE-related hospitalizations OR 1.74 (1.29–2.36) and death OR 1.67 (1.15–2.41).
Conclusion
The study suggests that frailty is a predictor of medication-related harm with poorer clinical outcomes including mortality.
ABSTRACT We report on the results of a recent blind search survey for gamma-ray pulsars in Fermi Large Area Telescope (LAT) data being carried out on the distributed volunteer computing system, ...Einstein@Home. The survey has searched for pulsations in 118 unidentified pulsar-like sources, requiring about 10,000 years of CPU core time. In total, this survey has resulted in the discovery of 17 new gamma-ray pulsars, of which 13 are newly reported in this work, and an accompanying paper. These pulsars are all young, isolated pulsars with characteristic ages between 12 kyr and 2 Myr, and spin-down powers between 1034 and 4 × 1036 erg s−1. Two of these are the slowest spinning gamma-ray pulsars yet known. One pulsar experienced a very large glitch during the Fermi mission. In this, the first of two associated papers, we describe the search scheme used in this survey, and estimate the sensitivity of our search to pulsations in unidentified Fermi-LAT sources. One such estimate results in an upper limit of 57% for the fraction of pulsed emission from the gamma-ray source associated with the Cas A supernova remnant, constraining the pulsed gamma-ray photon flux that can be produced by the neutron star at its center. We also present the results of precise timing analyses for each of the newly detected pulsars.
HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. ...Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface-associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane.
Objective
Although a significant number of professionals who provide eating disorder (ED) treatment have lived experience with an ED in the past, there is no consensus on whether these professionals ...should use these experiences in treatment. This review aims to evaluate current literature on recovered professionals with an ED past treating ED patients, unravelling advantages and disadvantages in treatment, the impact on professionals and their surroundings, and implications for practice.
Method
A systematic literature search was conducted which included 10 articles. We analysed qualitative data through a systematic synthesis. Strength of evidence was calculated for each subtheme.
Results
Three themes and 14 subthemes were divided into categories. The category ‘treatment (patient‐professional interaction)’ was divided into: advantages, disadvantages and other implications for treatment. Additionally, the category ‘professionals themselves’ included subthemes that directly impact or relate to ED professionals: recovery as a non‐linear process, the significant role of self‐care and adverse feelings of professionals. Finally, the category ‘work settings’ included: company culture and training, supervision and professional development.
Discussion
Recovered ED professionals are a promising addition to ED treatment due to the enhanced expertise of the professional. However, attention should be paid to the risk of distorted boundaries between patient and professional.
Highlights
This review aims to evaluate current literature about recovered professionals with an eating disorder past treating eating disorder patients.
Advantages we found were patients feeling recognised and understood with improved perspectives, and enhanced expertise of professionals.
Disadvantages were distorted boundaries, the vulnerability and risk of relapse of professionals.
To work as an eating disorder professional, it is important to focus on self‐care, stimulate a safe work setting and organising supervision among colleagues.
It has been hypothesized that predecessors of today's bryophytes significantly increased global chemical weathering in the Late Ordovician, thus reducing atmospheric CO2 concentration and ...contributing to climate cooling and an interval of glaciations. Studies that try to quantify the enhancement of weathering by non-vascular vegetation, however, are usually limited to small areas and low numbers of species, which hampers extrapolating to the global scale and to past climatic conditions. Here we present a spatially explicit modelling approach to simulate global weathering by non-vascular vegetation in the Late Ordovician. We estimate a potential global weathering flux of 2.8 (km(3) rock) yr(-1), defined here as volume of primary minerals affected by chemical transformation. This is around three times larger than today's global chemical weathering flux. Moreover, we find that simulated weathering is highly sensitive to atmospheric CO2 concentration. This implies a strong negative feedback between weathering by non-vascular vegetation and Ordovician climate.
The liver is the most common site of metastatic disease
. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at ...least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver
. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.
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