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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)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. |
- Albert, Christian, et al.
(författare)
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Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy : A Systematic Review and Meta-analysis
- 2020
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Ingår i: American Journal of Kidney Diseases. - : Elsevier BV. - 0272-6386 .- 1523-6838. ; 76:6, s. 826-
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Forskningsöversikt (refereegranskat)abstract
- Rationale & Objective: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction.Study Design: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines.Setting & Study Populations: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms.Selection Criteria for Studies: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI.Data Extraction: Individual-study-data meta analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis.Analytical Approach: Individual-study-data meta analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses.Results: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.790.81) and 0.86 (95% CI, 0.84-0.8 6). Cutoff concentrations at 95% specificity for urinary NGAL were >580 ng/mL with 27% sensitivity for severe AKI and >589 ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were >364 ng/mL with 44% sensitivity and >546 ng/mL with 26% sensitivity, respectively.Limitations: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. Conclusions: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.
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| 4. |
- Aswad, Amr, et al.
(författare)
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Evolutionary history of endogenous Human Herpesvirus 6 reflects human migration out of Africa
- 2021
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Ingår i: Molecular biology and evolution. - : Oxford University Press. - 0737-4038 .- 1537-1719. ; 38:1, s. 96-107
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Tidskriftsartikel (refereegranskat)abstract
- Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result about 70 million people harbour the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if i) these integrations are ancient, ii) if they still occur, and iii) whether circulating virus strains differ from integrated ones. Here we used next generation sequencing and mining of public human genome datasets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly-related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or "reactivation" of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa.
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| 5. |
- Bornholdt, Dorothea, et al.
(författare)
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Genotype-Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:4, s. 587-594
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Tidskriftsartikel (refereegranskat)abstract
- Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotypephenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.
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| 6. |
- Crnkovic, Ivica, et al.
(författare)
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Guest Editorial
- 2007
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Ingår i: Journal of Systems and Software. - : Elsevier BV. - 0164-1212 .- 1873-1228. ; 80:5, s. 641-642
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Demichev, Vadim, et al.
(författare)
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A time-resolved proteomic and prognostic map of COVID-19
- 2021
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Ingår i: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
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| 8. |
- Haiman, Christopher A., et al.
(författare)
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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| 9. |
- Heinz, Judith, et al.
(författare)
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Strategies to reduce antibiotic use in women with uncomplicated urinary tract infection in primary care : protocol of a systematic review and meta-analysis including individual patient data
- 2020
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 10:10
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Uncomplicated urinary tract infection (UTI) in women is a common reason to present in general practice and is usually treated with antibiotics to reduce symptom severity and duration. Results of recent clinical trials indicate that non-antibiotic treatment approaches can also be effective. However, it remains unclear which patients would benefit from antibiotic treatment and which can effectively and safely be treated without antibiotics. This systematic review and meta-analysis aims to estimate the effect of treatment strategies to reduce antibiotic use in comparison with immediate antibiotic treatment and to identify prognostic factors and moderators of treatment effects. A further aim is to identify subgroups of patients benefiting from a specific therapy.Methods and analysis: A systematic literature search will be performed to identify randomised controlled trials which investigated the effect of treatment strategies to reduce antibiotic use in female adults with uncomplicated UTI compared with immediate antibiotic treatment. Therefore, the primary outcome of the meta-analysis is incomplete recovery. Anonymised individual patient data (IPD) will be collected. Aggregate data will be used for pairwise comparisons of treatment strategies using meta-analysis models with random effects accounting for potential between-study heterogeneity. Potential effect moderators will be explored in meta-regressions. For IPD, generalised linear mixed models will be used, which may be adjusted for baseline characteristics. Interactions of baseline variables with treatment effects will be explored. These models will be used to assess direct comparisons of treatment, but might be extended to networks.Ethics and dissemination: The local institutional review and ethics board judged the project a secondary analysis of existing anonymous data which meet the criteria for waiver of ethics review. Dissemination of the results will be via published scientific papers and presentations. Key messages will be promoted for example, via social media or press releases.
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| 10. |
- Kaußner, Yvonne, et al.
(författare)
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Reducing antibiotic use in uncomplicated urinary tract infections in adult women : a systematic review and individual participant data meta-analysis
- 2022
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Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 28:12, s. 1558-1566
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Forskningsöversikt (refereegranskat)abstract
- Background: Randomised controlled trials (RCTs) investigated analgesics, herbal formulations, delayed prescription of antibiotics, and placebo to prevent overprescription of antibiotics in women with uncomplicated urinary tract infections (uUTI).Objectives: To estimate the effect of these strategies and to identify symptoms, signs, or other factors that indicate a benefit from these strategies.Data sources: MEDLINE, EMBASE, Web of Science, LILACS, Cochrane Database of Systematic Reviews and of Controlled Trials, and ClinicalTrials.Study eligibility criteria, participants and interventions: RCTs investigating any strategies to reduce antibiotics vs. immediate antibiotics in adult women with uUTI in primary care.Methods: We extracted individual participant data (IPD) if available, otherwise aggregate data (AD). Bayesian random-effects meta-analysis of the AD was used for pairwise comparisons. Candidate moderators and prognostic indicators of treatment effects were investigated using generalised linear mixed models based on IPD.Results: We analysed IPD of 3524 patients from eight RCTs and AD of 78 patients. Non-antibiotic strategies increased the rates of incomplete recovery (OR 3.0; 95% credible interval (CrI), 1.7–5.5; Bayesian p-value (pB) = 0.0017; τ = 0.6), subsequent antibiotic treatment (OR 3.5; 95% CrI, 2.1–5.8; pB = 0.0003) and pyelonephritis (OR 5.6; 95% CrI, 2.3–13.9; pB = 0.0003). Conversely, they decreased overall antibiotic use by 63%.Patients positive for urinary erythrocytes and urine culture were at increased risk for incomplete recovery (OR 4.7; 95% CrI, 2.1–10.8; pB = 0.0010), but no difference was apparent where both were negative (OR 0.8; 95% CrI, 0.3–2.0; pB = 0.667). In patients treated using non-antibiotic strategies, urinary erythrocytes and positive urine culture were independent prognostic indicators for subsequent antibiotic treatment and pyelonephritis.Conclusions: Compared to immediate antibiotics, non-antibiotic strategies reduce overall antibiotic use but result in poorer clinical outcomes. The presence of erythrocytes and tests to confirm bacteria in urine could be used to target antibiotic prescribing.
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