| 121. |
- Gustafsson, Johan, 1976, et al.
(författare)
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DSAVE: Detection of misclassified cells in single-cell RNA-Seq data
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 15:12 December
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell RNA sequencing has become a valuable tool for investigating cell types in complex tissues, where clustering of cells enables the identification and comparison of cell populations. Although many studies have sought to develop and compare different clustering approaches, a deeper investigation into the properties of the resulting populations is lacking. Specifically, the presence of misclassified cells can influence downstream analyses, highlighting the need to assess subpopulation purity and to detect such cells. We developed DSAVE (Down-SAmpling based Variation Estimation), a method to evaluate the purity of single-cell transcriptome clusters and to identify misclassified cells. The method utilizes down-sampling to eliminate differences in sampling noise and uses a log-likelihood based metric to help identify misclassified cells. In addition, DSAVE estimates the number of cells needed in a population to achieve a stable average gene expression profile within a certain gene expression range. We show that DSAVE can be used to find potentially misclassified cells that are not detectable by similar tools and reveal the cause of their divergence from the other cells, such as differing cell state or cell type. With the growing use of single-cell RNA-seq, we foresee that DSAVE will be an increasingly useful tool for comparing and purifying subpopulations in single-cell RNA-Seq datasets.
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| 122. |
- Gustafsson, Johan, 1976, et al.
(författare)
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Sources of variation in cell-type RNA-Seq profiles
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- Cell-type specific gene expression profiles are needed for many computational methods operating on bulk RNA-Seq samples, such as deconvolution of cell-type fractions and digital cytometry. However, the gene expression profile of a cell type can vary substantially due to both technical factors and biological differences in cell state and surroundings, reducing the efficacy of such methods. Here, we investigated which factors contribute most to this variation. We evaluated different normalization methods, quantified the variance explained by different factors, evaluated the effect on deconvolution of cell type fractions, and examined the differences between UMI-based single-cell RNA-Seq and bulk RNA-Seq. We investigated a collection of publicly available bulk and single-cell RNA-Seq datasets containing B and T cells, and found that the technical variation across laboratories is substantial, even for genes specifically selected for deconvolution, and this variation has a confounding effect on deconvolution. Tissue of origin is also a substantial factor, highlighting the challenge of using cell type profiles derived from blood with mixtures from other tissues. We also show that much of the differences between UMI-based single-cell and bulk RNA-Seq methods can be explained by the number of read duplicates per mRNA molecule in the single-cell sample. Our work shows the importance of either matching or correcting for technical factors when creating cell-type specific gene expression profiles that are to be used together with bulk samples.
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| 123. |
- Gyllensten, Kristina, 1977, et al.
(författare)
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A sustainable working life in the car manufacturing industry: The role of psychosocial factors, gender and occupation.
- 2020
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- In order to add to the existing knowledge about factors associated with retirement timing, in the car industry, it is useful to consider the psychosocial working conditions prior to retirement. This case-control study aimed to investigate relationships between psychosocial job factors and extended work after the age of 62 years among workers in the car industry in Sweden.A study invitation with a survey was sent to workers in one of Sweden's largest car manufacturing company, who were employed 2005-2015 and either retired at the age 55-62 years or working at 63 years or older. Psychosocial variables such as job demand-control (JDC) and effort-reward imbalance (ERI) were recorded through the survey. Multiple logistic regression models were used to investigate associations between psychosocial variables and retirement in 572 cases that had continued to work ≥ 63 years, and 771 controls who had retired at 62 or earlier.No associations were found between JDC-variables and retirement in the total sample or gender stratified analyses, but high demands-low control (high strain) was related to retirement before the age of 63 years in blue-collar workers. In contrast, high strain was related to continuing to work after 62 years for white-collar men and, high ERI was associated with extended work for the total sample of white-collar workers, and white-collar men, however these effects became non-significant in fully adjusted models.The relationships between psychosocial factors and extended work after 62 years were inconsistent, with high strain being related to retiring earlier for blue-collar workers.
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| 124. |
- Hadgu, Endale, et al.
(författare)
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Distribution and characteristics of androgen receptor (AR) in breast cancer among women in Addis Ababa, Ethiopia : A cross sectional study
- 2020
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Evaluation of the role of androgen receptor (AR) in the biology of breast cancer is an emerging area of research. There are compelling evidences that AR expression may be used to further refine breast cancer molecular subtyping with prognostic and therapeutic implications. Many studies indicated co-expression of AR with the hormonal receptors in breast cancer has a favorable prognosis. AR is also investigated by many researchers as a potential therapeutic target in treatment of breast cancer. Studies on the frequency and distribution of AR in breast cancer among Africans is barely available. Given the heightened interest to understand its role in breast cancer, we determined AR expression and assessed its association with clinicopathological parameters among Ethiopian women. In this study, 112 newly diagnosed patient with invasive breast cancer at Tikur Anbessa Specialized Hospital were enrolled. Immunohistochemical assessment of AR, ER, PR, Ki67 and HER2 were performed using tissue microarrays (TMA) constructed from their primary tumor block. Out of the 112 participants, 91 (81%) were positive for AR expression and the remaining 21 participants (19%) were negative for AR expression. Expression of AR in ER+, HER2+ and TNBC cases were 93%, 83% and 48% respectively. Our study reveals AR is expressed in a significant number of breast cancers patients and this may indicate that breast cancers cases in Ethiopia have favorable prognosis and could benefit from progresses in AR targeted treatments. Since AR expression has important consequences on the prognosis and treatment of breast cancer, further studies with an increased number of participants is necessary to confirm our reports.
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| 125. |
- Hadzibajramovic, Emina, 1977, et al.
(författare)
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A Rasch analysis of the Burnout Assessment Tool (BAT)
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:11
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Tidskriftsartikel (refereegranskat)abstract
- Burnout as a concept indicative of a work-related state of mental exhaustion is recognized around the globe. Numerous studies showed that burnout has negative consequences for both individuals and organizations but also for society at large, especially in welfare states where sickness absence and work incapacitation are covered by social funds. This underlines the importance of a valid and reliable tool that can be used to assess employee burnout levels. Although the Maslach Burnout Inventory is by far the most frequently used questionnaire for assessing burnout, it is associated with several shortcomings and has been criticized on theoretical as well as empirical grounds. Thus, there is a need for an alternative questionnaire with a strong conceptual basis and proper psychometric qualities. This challenge has been taken up by introducing the Burnout Assessment Tool (BAT), according to which burnout is conceived as a work-related state of exhaustion among employees, characterized by extreme tiredness, reduced ability to regulate cognitive and emotional processes, and mental distancing. Given that the BAT is a new measure of burnout, its psychometric properties need to be evaluated. This paper focuses on an evaluation of the internal construct validity of the BAT using Rasch analysis in two random samples (n = 800, each) drawn from larger representative samples of the working population of the Netherlands and Flanders (Belgium). The BAT has sound psychometric properties and fulfils the measurement criteria according to the Rasch model. The BAT score reflects the scoring structure indicated by the developers of the scale and the BAT's four subscales can be summarized into a single burnout score. The BAT score also works invariantly for women and men, younger and older respondents, and across both countries. Hence, the BAT can be used in organizations for screening and identifying employees who are at risk of burnout.
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| 126. |
- Hagberg, Lars, 1951, et al.
(författare)
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Herpes zoster in HIV-1 infection: The role of CSF pleocytosis in secondary CSF escape and discordance.
- 2020
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- HIV cerebrospinal fluid (CSF) escape is defined by a concentration of HIV-1 RNA in CSF above the lower limit of quantification of the employed assay and equal to or greater than the plasma HIV-1 RNA level in the presence of treatment-related plasma viral suppression, while CSF discordance is similarly defined by equal or higher CSF than plasma HIV-1 RNA in untreated individuals. During secondary CSF escape or discordance, disproportionate CSF HIV-1 RNA develops in relation to another infection in addition to HIV-1. We performed a retrospective review of people living with HIV receiving clinical care at Sahlgrenska Infectious Diseases Clinic in Gothenburg, Sweden who developed uncomplicated herpes zoster (HZ) and underwent a research lumbar puncture (LP) within the ensuing 150 days. Based on treatment status and the relationship between CSF and plasma HIV-1 RNA concentrations, they were divided into 4 groups: i) antiretroviral treated with CSF escape (N = 4), ii) treated without CSF escape (N = 5), iii) untreated with CSF discordance (N = 8), and iv) untreated without CSF discordance (N = 8). We augmented these with two additional cases of secondary CSF escape related to neuroborreliosis and HSV-2 encephalitis and analyzed these two non-HZ cases for factors contributing to CSF HIV-1 RNA concentrations. HIV-1 CSF escape and discordance were associated with higher CSF white blood cell (WBC) counts than their non-escape (P = 0.0087) and non-discordant (P = 0.0017) counterparts, and the CSF WBC counts correlated with the CSF HIV-1 RNA levels in both the treated (P = 0.0047) and untreated (P = 0.002) group pairs. Moreover, the CSF WBC counts correlated with the CSF:plasma HIV-1 RNA ratios of the entire group of 27 subjects (P = <0.0001) indicating a strong effect of the CSF WBC count on the relation of the CSF to plasma HIV-1 RNA concentrations across the entire sample set. The inflammatory response to HZ and its augmenting effect on CSF HIV-1 RNA was found up to 5 months after the HZ outbreak in the cross-sectional sample and, was present for one year after HZ in one individual followed longitudinally. We suggest that HZ provides a 'model' of secondary CSF escape and discordance. Likely, the inflammatory response to HZ pathology provoked local HIV-1 production by enhanced trafficking or activation of HIV-1-infected CD4+ T lymphocytes. Whereas treatment and other systemic factors determined the plasma HIV-1 RNA concentrations, in this setting the CSF WBC counts established the relation of the CSF HIV-1 RNA levels to this plasma set-point.
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| 127. |
- Hagg, David, et al.
(författare)
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A register-based approach to identifying treatment-resistant depression : Comparison with clinical definitions
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- Background Several definitions of treatment-resistant depression (TRD) are used for clinical research, but no verified model for use in register data exists. We aimed to compare a novel model created for use in register data-the Karolinska Institutet Model (KIM)-to the clinical definitions regarding the proportion of patients identified with TRD, their characteristics and clinical outcomes. Methods All patients in Sweden initiating antidepressant treatment with a diagnosis of depression in specialized healthcare 2006-2014 were identified and followed in national registers. In KIM, patients who initiated a third sequential, >28-day antidepressant treatment trial were defined as having TRD. Proportion of TRD and patient characteristics were compared with register adaptations of the European Staging Model (ESM), Massachusetts General Hospital Staging Method (MGH-s), and Maudsley Staging Model (MSM). Differences in patient characteristics were assessed with Chi-square tests and one-way ANOVAs. Hazard ratios for psychiatric hospitalization and for death from external causes were estimated by Cox proportional hazard regressions. Results Out of 127,108 antidepressant initiators with depression, the highest proportion of TRD was found using the MGH-s (19.0%), followed by MSM (15.3%), KIM (12.9%), and ESM (9.5%). Clinical characteristics were similar across the models. Compared with TRD patients identified by KIM, those identified by ESM had a marginally higher risk for psychiatric hospitalization (adjusted hazard ratio [aHR] 1.03, 95%CI 1.00-1.05), whereas those identified by MGH-s (aHR 0.92; 0.90-0.94) and MSM (aHR 0.95; 0.94-0.97) had a slightly reduced risk. Patients identified by MGH-s showed a reduced mortality compared with KIM (aHR 0.84; 0.72-0.98). Conclusions This study provides insight into the differing characteristics of patients captured by various TRD models when used for register research. Models yielding lower proportions of TRD seemed to identify patients with greater morbidity. The KIM may be useful for register based research in TRD.
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| 128. |
- Hagman, Emilia, et al.
(författare)
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Oral intake of mesoporous silica is safe and well tolerated in male humans
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Background Precisely engineered mesoporous silica has been shown to induce weight loss in mice, but whether it is safe to use in humans have not investigated.Objective The aim was to determine whether oral dosing, up to 9 grams/day, of precisely engineered mesoporous silica as a food additive can be used safely in male humans.Design This single blinded safety study consisted of two study arms including 10 males each (18-35 years). One arm consisted of participants with normal weight and one with obesity. After a placebo run-in period, all subjects were given porous silica three times daily, with increasing dose up to 9 grams/day (Phase 1). Subjects with obesity continued the study with highest dose for additional 10 weeks (Phase 2).Results All participants completed Phase 1 and 90% completed Phase 2, with approximately 1% missed doses. Participants reported no abdominal discomfort, and changes in bowel habits were minor and inconsistent. The side effects observed were mild and tolerable, biomarkers did not give any safety concern, and no severe adverse events occurred.Conclusion Mesoporous silica intake of up to 9 grams/day can be consumed by males without any major adverse events or safety concerns.
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| 129. |
- Hallingström, Maria, et al.
(författare)
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Mid-trimester amniotic fluid proteome’s association with spontaneous preterm delivery and gestational duration
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Background Amniotic fluid is clinically accessible via amniocentesis and its protein composition may correspond to birth timing. Early changes in the amniotic fluid proteome could therefore be associated with the subsequent development of spontaneous preterm delivery. Objective The main objective of this study was to perform unbiased proteomics analysis of the association between mid-trimester amniotic fluid proteome and spontaneous preterm delivery and gestational duration, respectively. A secondary objective was to validate and replicate the findings by enzyme-linked immunosorbent assay using a second independent cohort. Methods Women undergoing a mid-trimester genetic amniocentesis at Sahlgrenska University Hospital/Östra between September 2008 and September 2011 were enrolled in this study, designed in three analytical stages; 1) an unbiased proteomic discovery phase using LC-MS analysis of 22 women with subsequent spontaneous preterm delivery (cases) and 37 women who delivered at term (controls), 2) a validation phase of proteins of interest identified in stage 1, and 3) a replication phase of the proteins that passed validation using a second independent cohort consisting of 20 cases and 40 matched controls. Results Nine proteins were nominally significantly associated with both spontaneous preterm delivery and gestational duration, after adjustment for gestational age at sampling, but none of the proteins were significant after correction for multiple testing. Several of these proteins have previously been described as being associated with spontaneous PTD etiology and six of them were thus validated using enzyme linked immunosorbent assay. Two of the proteins passed validation; Neutrophil gelatinase-associated lipocalin and plasminogen activator inhibitor 1, but the results could not be replicated in a second cohort. Conclusions Neutrophil gelatinase-associated lipocalin and Plasminogen activator inhibitor 1 are potential biomarkers of spontaneous preterm delivery and gestational duration but the findings could not be replicated. The negative findings are supported by the fact that none of the nine proteins from the exploratory phase were significant after correction for multiple testing.
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| 130. |
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