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| 2. |
- Shungin, Dmitry, et al.
(author)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Journal article (peer-reviewed)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 3. |
- Danielsson, Bengt, et al.
(author)
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Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults - a Swedish nationwide study
- 2016
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In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 81:4, s. 773-783
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Journal article (peer-reviewed)abstract
- AimThe aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. MethodsA matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n=286092) and matched controls (n=1430460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds () and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. ResultsUse of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. ConclusionThe CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.
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| 4. |
- Gaulton, Kyle J, et al.
(author)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Journal article (peer-reviewed)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 6. |
- Johnell, Kristina, et al.
(author)
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Psychotropic drugs and the risk of fall injuries, hospitalisations and mortality among older adults
- 2017
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In: International Journal of Geriatric Psychiatry. - : Wiley. - 0885-6230 .- 1099-1166. ; 32:4, s. 414-420
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Journal article (peer-reviewed)abstract
- ObjectiveTo investigate whether psychotropics are associated with an increased risk of fall injuries, hospitalizations, and mortality in a large general population of older adults.MethodsWe performed a nationwide matched (age, sex, and case event day) case–control study between 1 January and 31 December 2011 based on several Swedish registers (n = 1,288,875 persons aged ≥65 years). We used multivariate conditional logistic regression adjusted for education, number of inpatient days, Charlson co-morbidity index, dementia and number of other drugs.ResultsAntidepressants were the psychotropic most strongly related to fall injuries (ORadjusted: 1.42; 95% CI: 1.38–1.45) and antipsychotics to hospitalizations (ORadjusted: 1.22; 95% CI: 1.19–1.24) and death (ORadjusted: 2.10; 95% CI: 2.02–2.17). Number of psychotropics was associated with increased the risk of fall injuries, (4 psychotropics vs 0: ORadjusted: 1.53; 95% CI: 1.39–1.68), hospitalization (4 psychotropics vs 0: ORadjusted: 1.27; 95% CI: 1.22–1.33) and death (4 psychotropics vs 0: ORadjusted: 2.50; 95% CI: 2.33–2.69) in a dose–response manner. Among persons with dementia (n = 58,984), a dose–response relationship was found between number of psychotropics and mortality risk (4 psychotropics vs 0: ORadjusted: 1.99; 95% CI: 1.76–2.25).ConclusionsOur findings support a cautious prescribing of multiple psychotropic drugs to older patients. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons, Ltd.
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| 7. |
- Karlsson, Anna, et al.
(author)
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A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer
- 2019
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In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Journal article (peer-reviewed)abstract
- Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.
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| 8. |
- Lilja, Johan
(author)
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The Realization of Attractive Quality : Conceptual and practical perspectives within the TQM system
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Within the quality community, quality management is often pictured as and referred to as rapidly evolving and continuously learning by interaction with the surrounding world. In general, an ability to evolve and transform is also seen as most desirable and the only choice for long term survival. In line with this picture, quality scholars, consultants, and practitioners strongly accentuate the necessity and great benefits from continuous improvement as well as systematic collection and usage of facts about what customers really value, to guide such improvement. This is reflected in the exhortations “improve continuously”, “focus on the customer” and “base decisions on facts”, found with minor variations in most modern quality literature. Strong exhortations mainly directed outwards, towards the many leaders and organizations out there. Towards leaders and organizations that still have not grasped the necessity and great winnings from continuous improvement, that are still not fully applying modern quality initiatives like Total Quality Management (TQM). However, while seemingly being busy exhorting others, doubts have been increasingly raised concerning whether TQM, as currently applied, actually lives up to these exhortations. Does TQM itself continuously improve and evolve? Is the current application of TQM really taking into account facts in the surrounding world about what customers value? When viewing TQM as a system, as now is commonly done, the problem implied is a lack of system goal fulfillment, questioning if the current TQM system’s structure and processes are really purposeful. More specifically the critics highlight the inadequacy of the current reactive one-sided defect avoidance focus, stressing that defects do not matter much if you are making a product no one wants to buy. What can be referred to as “an obsession with error avoidance” is in fact shown to stifle both innovation and value creation. As for what the TQM system currently is missing, the shortcoming is often referred to as a lack of focus on Attractive Quality. That is, a lack of focus on a different kind of quality elements, often described as being unrelated to the dissatisfaction expressed, but strongly contributing to the customer’s positive emotions, such as delight. The inclusion and realization of Attractive Quality has been widely emphasized as important and urgent for more than 20 years. However, a more systematic inclusion and realization within the TQM system has remained no more than merely “a vision”. A situation seemingly supporting the argument that TQM really has failed in terms of continuously evolving and improving. An inability to learn and adapt that in the long term will jeopardize the survival of the entire TQM system. This thesis then aims to move “from a vision to reality” both in terms of exploring the realization of Aattractive Qquality within TQM, and in a wider sense towards realizing the desired state of TQM as truly evolving and alive. In doing so the thesis addresses the three questions of what, why and how the vision of a more systematic creation of Aattractive Qquality creation actually should and could be realized within the system of TQM. Among the results presented in this thesis are a new two-dimensional perspective on Attractive Quality and a re-understanding of the TQM system. The thesis also introduces a new methodology called Attraction Detection Study (ADS) as part of the concluding suggestions about how Attractive Quality could be more systematically created within the system of TQM.
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| 9. |
- Liljedahl, Helena, et al.
(author)
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A gene expression-based single sample predictor of lung adenocarcinoma molecular subtype and prognosis
- 2021
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:1, s. 238-251
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Journal article (peer-reviewed)abstract
- Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer.
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| 10. |
- Mattsson, Johanna Sofia Margareta, 1985-, et al.
(author)
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Prognostic impact of COX-2 in non-small cell lung cancer : a comprehensive compartment-specific evaluation of tumor and stromal cell expression
- 2015
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In: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 356:2, s. 837-845
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Journal article (peer-reviewed)abstract
- Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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