| 1. |
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| 2. |
- Adamson, Carly, et al.
(författare)
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Efficacy of Dapagliflozin in Heart Failure with Reduced Ejection Fraction According to Body Mass Index.
- 2021
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:10, s. 1662-1672
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In heart failure with reduced ejection fraction (HFrEF), there is an ’obesity paradox’, where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a sodium-glucose co-transporter 2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse- outcomes in Heart Failure trial (DAPA-HF). METHODS AND RESULTS: Body mass index was examined using standard categories, i.e. underweight ($<$18.5 kg/m(2) ); normal weight (18.5-24.9 kg/m(2) ); overweight (25.0-29.9 kg/m(2) ); obesity class I (30.0-34.9 kg/m(2) ); obesity class II (35.0-39.9 kg/m(2) ); and obesity class III ($>$/=40 kg/m(2) ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal- weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% confidence interval) for the primary outcome with obesity class 1, the lowest risk group, as reference was: under/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI, e.g. hazard ratio for primary outcome: under/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00) (P-value for interaction = 0.79). The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) kg (P $<$ 0.001). CONCLUSION: We confirmed an ’obesity survival paradox’ in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03036124.
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| 3. |
- Belibasakis, Georgios N, et al.
(författare)
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Virulence and Pathogenicity Properties of Aggregatibacter actinomycetemcomitans
- 2019
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Ingår i: Pathogens. - Basel : MDPI. - 2076-0817. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Aggregatibacter actinomycetemcomitans is a periodontal pathogen colonizing the oral cavity of a large proportion of the human population. It is equipped with several potent virulence factors that can cause cell death and induce or evade inflammation. Because of the large genetic diversity within the species, both harmless and highly virulent genotypes of the bacterium have emerged. The oral condition and age, as well as the geographic origin of the individual, influence the risk to be colonized by a virulent genotype of the bacterium. In the present review, the virulence and pathogenicity properties of A. actinomycetemcomitans will be addressed.
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| 4. |
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| 5. |
- Butt, Jawad H., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide : Insights From the DAPA-HF Trial.
- 2021
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Ingår i: Circulation. Heart failure. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT- proBNP. METHODS: We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction $<$/=40% and a NT-proBNP level $>$/=600 pg/mL ($>$/=600 ng/L; $>$/=400 pg/mL if hospitalized for HF within the previous 12 months or $>$/=900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. RESULTS: Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857-2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, -303 pg/mL [95% CI, -457 to -150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88-0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27-0.67), 0.77 (0.56-1.04), 0.78 (0.60-1.01), and 0.78 (0.64-0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement ($>$/=5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (P for interaction=0.99) and decreased the proportion with a deterioration $>$/=5 points (P for interaction=0.87) across baseline NT-proBNP quartiles. CONCLUSIONS: In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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| 6. |
- Butt, Jawad H., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction : A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.
- 2021
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 6:6, s. 678-689
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men. Objective: To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Design, Setting, and Participants: Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B- type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Results: A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of $>$/=5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of $>$/=5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women. Conclusions and Relevance: Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.
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| 7. |
- Chapman, Mark A., et al.
(författare)
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Skeletal Muscle Transcriptomic Comparison between Long-Term Trained and Untrained Men and Women
- 2020
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 31:12
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Tidskriftsartikel (refereegranskat)abstract
- To better understand the health benefits of lifelong exercise in humans, we conduct global skeletal muscle transcriptomic analyses of long-term endurance- (9 men, 9 women) and strength-trained (7 men) humans compared with age-matched untrained controls (7 men, 8 women). Transcriptomic analysis, Gene Ontology, and genome-scale metabolic modeling demonstrate changes in pathways related to the prevention of metabolic diseases, particularly with endurance training. Our data also show prominent sex differences between controls and that these differences are reduced with endurance training. Additionally, we compare our data with studies examining muscle gene expression before and after a months-long training period in individuals with metabolic diseases, This analysis reveals that training shifts gene expression in individuals with impaired metabolism to become more similar to our endurance-trained group. Overall, our data provide an extensive examination of the accumulated transcriptional changes that occur with decades-long training and identify important "exercise-responsive" genes that could attenuate metabolic disease.
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| 8. |
- Claesson, Rolf, et al.
(författare)
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Characterization of Aggregatibacter actinomycetemcomitans Serotype b Strains with Five Different, Including Two Novel, Leukotoxin Promoter Structures
- 2020
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Ingår i: Vaccines. - Basel, Switzerland : MDPI. - 2076-393X. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- The JP2 genotype of A. actinomycetemcomitans, serotype b has attracted much interest during the past three decades due to its close association with periodontitis in young individuals and the enhanced expression of a leukotoxin (LtxA). A typical feature of this genotype is a 530-base pair (bp) deletion in the ltxCABD promoter region controlling leukotoxin expression. In the present work, we have characterized serotype b strains with four additional promoter types. Two novel types have been recognized, that is, one with a 230-bp deletion and one with a 172-bp duplication. Moreover, a strain with a 640-bp deletion and three strains with a full-length promoter, including the type strain Y4, were included in the present study. The seven strains were characterized by multi locus sequence typing (MLST) and arbitrarily primed polymerase chain reaction (PCR) and assessed for LtxA production. MLST showed that the strains with the non-JP2-like deletions represented distinct monophyletic groups, whereas the JP2 strain, HK1651, represented a separate branch. LtxA production was high in all three strains with a promoter deletion, whereas the other four strains showed significantly lower levels. It can be concluded that the genetic characterization and determination of LtxA production of A. actinomycetemcomitans isolates from individuals with periodontitis can contribute to the identification of novel virulent genotypes of this bacterium.
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| 9. |
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| 10. |
- Dewan, Pooja, et al.
(författare)
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Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease : An Analysis of DAPA-HF.
- 2021
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:4, s. 632-643
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Chronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure (HF) with reduced ejection fraction (HFrEF), associated with worse outcomes and often suboptimal treatment because of under-prescription of beta-blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. The aim of this study was to examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial. METHODS AND RESULTS: We examined whether the effects of dapagliflozin in DAPA-HF were modified by COPD status. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Overall, 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline N-terminal pro B-type natriuretic peptide, and less likely to be treated with a beta-blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without [18.9 (95% confidence interval 16.0-22.2) vs. 13.0 (12.1-14.0) per 100 person-years; hazard ratio (HR) for COPD vs. no COPD 1.44 (1.21-1.72); P $<$ 0.001]. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with [HR 0.67 (95% confidence interval 0.48-0.93)] and without COPD [0.76 (0.65-0.87); interaction P-value 0.47]. CONCLUSIONS: In DAPA-HF, one in eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all pre-specified outcomes was consistent in patients with and without COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03036124.
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| 11. |
- Emanuelsson, Eric B., et al.
(författare)
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Remodeling of the human skeletal muscle proteome found after long-term endurance training but not after strength training
- 2024
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 27:1
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Tidskriftsartikel (refereegranskat)abstract
- Exercise training has tremendous systemic tissue-specific health benefits, but the molecular adaptations to long-term exercise training are not completely understood. We investigated the skeletal muscle proteome of highly endurance-trained, strength-trained, and untrained individuals and performed exercise- and sex-specific analyses. Of the 6,000+ proteins identified, >650 were differentially expressed in endurance-trained individuals compared with controls. Strikingly, 92% of the shared proteins with higher expression in both the male and female endurance groups were known mitochondrial. In contrast to the findings in endurance-trained individuals, minimal differences were found in strength-trained individuals and between females and males. Lastly, a co-expression network and comparative literature analysis revealed key proteins and pathways related to the health benefits of exercise, which were primarily related to differences in mitochondrial proteins. This network is available as an interactive database resource where investigators can correlate clinical data with global gene and protein expression data for hypothesis generation.
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| 12. |
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| 13. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)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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| 14. |
- Haubek, Dorte, et al.
(författare)
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Prevalence of JP2 and Non-JP2 Genotypes of Aggregatibacter actinomycetemcomitans and Oral Hygiene Practice of Kenyan Adolescents in Maasai Mara
- 2021
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Ingår i: Pathogens. - : MDPI. - 2076-0817. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Aggregatibacter actinomycetemcomitans is implicated in the etiology of periodontitis that affects adolescents. The monitoring and mapping of the geographic dissemination pattern of JP2 and non-JP2 genotypes of A. actinomycetemcomitans are of interest. In Africa, the highly leukotoxic JP2 genotype is known to be prevalent, particularly in north-west Africa. The aims of this study were to determine the prevalence of JP2 and non-JP2 genotypes and investigate the oral hygiene practices among adolescents living in Maasai Mara, Kenya. A total of 284 adolescents (mean age: 15.0 yrs; SD 1.1) were interviewed regarding their age, gender, medical history, and oral hygiene practice, and the number of teeth present was recorded. One subgingival pooled plaque sample from all the first molars of each participant was analyzed by conventional PCR. The mean number of permanent teeth present was 27.9 (SD: 2.0; range: 22-32; 95% CI: 27.7-28.1). Sixteen (5.6%) and two (0.7%) adolescents were positive for non-JP2 and JP2 genotypes, respectively. For the vast majority of the adolescents, the use of a toothbrush (99.3%) and toothpaste (80.1%), as well as some kind of toothpick (>60.2%), were part of their oral hygiene practice, with dental floss (0.4%) and/or mouth rinses (0.4%) rarely being used. We have, for the first time, identified Kenyan adolescents colonized with the JP2 genotype. The prevalence of the JP2 genotype of A. actinomycetemcomitans is low, a possible indicator that it spreading through human migration from North and West Africa to East Africa is a rare occasion.
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| 15. |
- Johansson, Anders, 1955-, et al.
(författare)
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Genetic Profiling of Aggregatibacter actinomycetemcomitans Serotype B Isolated from Periodontitis Patients Living in Sweden
- 2019
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Ingår i: Pathogens. - Basel, Switzerland : MDPI. - 2076-0817. ; 8:3, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- The bacterium Aggregatibacter actinomycetemcomitans is associated with aggressive forms of periodontitis and with systemic diseases, such as endocarditis. By assessing a Ghanaian longitudinal adolescent cohort, we earlier recognized the cagE gene as a possible diagnostic marker for a subgroup of JP2 and non-JP2 genotype serotype b A. actinomycetemcomitans strains, associated with high leukotoxicity as determined in a semi-quantitative cell assay. This group of A. actinomycetemcomitans is associated with the progression of attachment loss. In the present work, we used conventional polymerase chain reaction (PCR) and quantitative PCR to perform the cagE genotyping of our collection of 116 selected serotype b A. actinomycetemcomitans strains, collected over a period of 15 years from periodontitis patients living in Sweden. The A. actinomycetemcomitans strains carrying cagE (referred to as cagE+; n = 49) were compared to the cagE-negative strains (n = 67), present at larger proportions in the subgingival plaque samples, and were also much more prevalent in the young (≤35 years) compared to in the old (>35 years) group of patients. Our present results underline the potential use of cagE genotyping in the risk assessment of the development of periodontal attachment loss in Swedish adolescents.
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| 16. |
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| 17. |
- Katus, Hugo, et al.
(författare)
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Early diagnosis of acute coronary syndrome
- 2017
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 38:41, s. 3049-3055
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Forskningsöversikt (refereegranskat)abstract
- The diagnostic evaluation of acute chest pain has been augmented in recent years by advances in the sensitivity and precision of cardiac troponin assays, new biomarkers, improvements in imaging modalities, and release of new clinical decision algorithms. This progress has enabled physicians to diagnose or rule-out acute myocardial infarction earlier after the initial patient presentation, usually in emergency department settings, which may facilitate prompt initiation of evidence-based treatments, investigation of alternative diagnoses for chest pain, or discharge, and permit better utilization of healthcare resources. A non-trivial proportion of patients fall in an indeterminate category according to rule-out algorithms, and minimal evidence-based guidance exists for the optimal evaluation, monitoring, and treatment of these patients. The Cardiovascular Round Table of the ESC proposes approaches for the optimal application of early strategies in clinical practice to improve patient care following the review of recent advances in the early diagnosis of acute coronary syndrome. The following specific 'indeterminate' patient categories were considered: (i) patients with symptoms and high-sensitivity cardiac troponin <99th percentile; (ii) patients with symptoms and high-sensitivity troponin <99th percentile but above the limit of detection; (iii) patients with symptoms and high-sensitivity troponin >99th percentile but without dynamic change; and (iv) patients with symptoms and high-sensitivity troponin >99th percentile and dynamic change but without coronary plaque rupture/erosion/dissection. Definitive evidence is currently lacking to manage these patients whose early diagnosis is 'indeterminate' and these areas of uncertainty should be assigned a high priority for research.
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| 18. |
- Kemoli, Arthur, et al.
(författare)
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Cultural and traditional oral practices : implications on oral health of a kenyan cohort of maasai adolescents
- 2022
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Ingår i: East African Medical Journal. - : African Journal Online (AJOL). - 0012-835X. ; 99:8, s. 5122-5128
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Tidskriftsartikel (refereegranskat)abstract
- Background: This is a review of a study carried out in Maasai Mara schools in January 2016. The project formed a part of “The Maasai Mara Science and Development Initiative” (MMSDI). We examined school children in the Maasai Mara North Conservancy for extraction of permanent mandibular incisors and primary canines, which form part of a long-held tradition in the Maasai community in Kenya.Objective: Review information on oral hygiene habits and examination of study participants, their oral hygiene procedures, and the presence of Aggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus in their oral cavities.Data sources: Three publications in 2018 and 2021 on traditional dental practices, the prevalence of JP2/Non-JP2 Genotypes of Aggregatibacter actinomycetemcomitans and A. aphrophilus, and inhibition of leukotoxic activity by herbal plants used in oral hygiene procedures by children from Maasai Mara.Results and conclusions: The results obtained indicated that of the 284 participants used in the three studies, 61% of them had had their primary canines extracted, among whom a majority (95%) had two mandibular central incisors missing. The microbiological findings in saliva and plaque samples harvested from the participants revealed that 72% of the oral samples had A. actinomycetemcomitans, with three of them being positive for the highly leukotoxic JP2 genotype of this bacterium. The prevalence of A. aphrophilus was even higher, which may affect the virulence potential of A. actinomycetemcomitans. Most of the adolescents used commercial toothbrushes and toothpaste for their oral hygiene practice, but also plant-derived chewing sticks for daily teeth cleaning. Interestingly, all the participants used Warburgia ugandensis as the material for chewing stick, and in vitro tests showed that its extract efficiently neutralized the leukotoxin that is expressed by A. actinomycetemcomitans.
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| 19. |
- Kemoli, Arthur, et al.
(författare)
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Prevalence and impact of infant oral mutilation on dental occlusion and oral health-related quality of life among Kenyan adolescents from Maasai Mara
- 2018
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Ingår i: BMC Oral Health. - : Springer Science and Business Media LLC. - 1472-6831. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Infant Oral Mutilation (IOM) includes germectomy and early extraction of primary and permanent incisors and canines, primarily in the lower jaw. The aim of the present study was to examine the prevalence and impact of IOM, involving the removal of mandibular permanent incisors and/or canines, on dental occlusion and Oral Health-Related Quality of Life (OHRQoL) among Kenyan adolescents from Maasai Mara.METHODS: In a cross-sectional study, 284 adolescents (14-18 yrs. of age) participated in an oral examination and an interview, using a structured questionnaire on age, gender, medical history, and IOM practice. For the analysis of the dental occlusion, participants with IOM, in terms of absence of two or more permanent teeth in the mandibular incisor and/or canine tooth segments (IOM group), were compared to participants who had all six incisors and canines present in the oral cavity (control group). OHRQoL was assessed using child perception questionnaire (CPQ11-14).RESULTS: The majority of the participants (61%) had been exposed to IOM, among whom 164 (95%) had absence of two mandibular central incisors. More individuals in the IOM group had maxillary overjet exceeding 5 mm than in the control group (50.9% vs. 20%, p < 0.001). Nineteen (11%) subjects in the IOM group had mesial occlusion in contrast to none in the control group (p < 0.001). The mean and median total CPQ scores and the mean and median CPQ domain scores were low in both groups with no significant differences between the groups.CONCLUSIONS: Approximately two-thirds of the study population presented with IOM, with the majority of them missing two mandibular permanent central incisors. Although some participants with IOM had substantial maxillary overjet and mesial occlusion, only few of them showed substantial effect on their OHRQoL.
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| 20. |
- Kosiborod, Mikhail N., et al.
(författare)
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Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients With Heart Failure and Reduced Ejection Fraction : Results From the DAPA-HF Trial.
- 2020
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Ingår i: Circulation. ; 141:2, s. 90-99
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse- Outcomes in Heart Failure), sodium-glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months. RESULTS: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3-91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57-0.86]; hazard ratio, 0.77 [95% CI, 0.61-0.98]; hazard ratio, 0.62 [95% CI, 0.46-0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P$<$0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78-0.90]; P$<$0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08-1.23]; odds ratio, 1.15 [95% CI, 1.08-1.22]; odds ratio, 1.14 [95% CI, 1.07-1.22]; number needed to treat=14, 15, and 18, respectively; P$<$0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score). CONCLUSIONS: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.
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| 21. |
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| 22. |
- Lindholm, Mark, et al.
(författare)
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Aggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus in a Kenyan Maasai Adolescent Population and Inhibition of Leukotoxic Activity by Herbal Plants Used as Part of Oral Hygiene Procedures
- 2021
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Ingår i: Journal of Clinical Medicine. - Basel : MDPI. - 2077-0383. ; 10:22
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A virulent genotype (JP2) of the periodonto-pathogen, Aggregatibacter actinomycetemcomitans (Aa), is widespread in North and West Africa, while its presence in East Africa has not been thoroughly investigated. This JP2 genotype is associated with periodontitis in adolescents and has a high leukotoxicity. The aim of the study was to examine the prevalence of Aa and its JP2 genotype, the prevalence of the oral, commensal Aggregatibacter aphrophilus in a Maasai adolescent population, and the effect of herbal plants for inhibition of leukotoxicity.METHODS: A total of 284 adolescents from Maasai Mara, Kenya, underwent an oral examination and microbial sampling. The presence of Aa and A. aphrophilus was analyzed by quantitative PCR and cultivation (the 58 samples collected at the last day of field study). The collected Aa strains were characterized and leukotoxin promoter typed. Additionally, herbal plants commonly used for oral hygiene were assessed for the inhibition of leukotoxicity.RESULTS AND CONCLUSIONS: The prevalence of Aa in stimulated whole saliva was high (71.8%), with the JP2 genotype detected in one individual, and A. aphrophilus in 99% of the sampled individuals. The commonly used herbal plant, Warburgia ugandensis, inactivated Aa leukotoxicity. The Aa virulence might be reduced through use of W. ugandensis and the high levels of A. aphrophilus.
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| 23. |
- Lindholm, Mark, et al.
(författare)
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Outer membrane vesicle-mediated serum protection in Aggregatibacter actinomycetemcomitans
- 2020
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Ingår i: Journal of Oral Microbiology. - : Taylor & Francis. - 2000-2297. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Aggregatibacter actinomycetemcomitans belongs to the HACEK group of fastidious Gram-negative organisms, a recognized cause of infective endocarditis. A. actinomycetemcomitans is also implicated in periodontitis, with rapid progress in adolescents. We recently demonstrated that the major outer membrane protein, OmpA1 was critical for serum survival of the A. actinomycetemcomitans serotype a model strain, D7SS, and that the paralogue, OmpA2 could operate as a functional homologue to OmpA1 in mediating serum resistance. In the present work, an essentially serum-sensitive ompA1 ompA2 double mutant A. actinomycetemcomitans strain derivative was exploited to elucidate if A. actinomycetemcomitans OMVs can contribute to bacterial serum resistance. Indeed, supplementation of OMVs resulted in a dose-dependent increase of the survival of the serum-sensitive strain in incubations in 50% normal human serum (NHS). Whereas neither OmpA1 nor OmpA2 was required for the OMV-mediated serum protection, OMVs and LPS from an A. actinomycetemcomitans strain lacking the LPS O-antigen polysaccharide part were significantly impaired in protecting D7SS ompA1 ompA2. Our results using a complement system screen assay support a model where A. actinomycetemcomitans OMVs can act as a decoy, which can trigger complement activation in an LPS-dependent manner, and consume complement components to protect serum-susceptible bacterial cells.
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| 24. |
- Lindholm, Mark, 1990-
(författare)
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Periodontitis in adolescents : presence of Aggregatibacter species and interactions with the host
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus are closely related gram-negative bacteria mainly found in the oral cavity. Periodontitis in adolescents is associated with the presence of A. actinomycetemcomitans, but not with the presence of A. aphrophilus. However, both can cause extra-oral infections such as endocarditis and brain abscesses. Several unknown virulence and environmental factors could influence their prevalence in different populations. A shift in the microbiological and demographical characteristics could also influence the prevalence of periodontitis in adolescents residing in Sweden.The aims of this PhD thesis were to study mechanisms that might influence serum resistance in A. actinomycetemcomitans and A. aphrophilus. In relation to this we wanted to study the presence of these bacterial species in two different adolescent populations (Västerbotten, Sweden and Kenya), factors influencing their prevalence, and the prevalence of periodontitis in adolescents in Sweden.In paper I, serum resistance was detected in all tested strains of A. actinomycetemcomitans and A. aphrophilus. The OmpA paralogues, OmpA1 and OmpA2 were important for serum resistance in both species, i.e., inactivation of their genes, respectively resulted in significantly reduced serum resistance. In A. actinomycetemcomitans, ompA1 mutant derivatives were fortuitously found with regained serum resistance as a result of increased expression of OmpA2. OmpA1 and OmpA2 from A. actinomycetemcomitans, and OmpA1 from A. aphrophilus were able to bind C4bp, an inhibitor of parts of the activating paths of the complement system, suggesting this to be one mechanism to mediate bacterial serum resistance.In paper II, we investigated the effects of outer membrane vesicles (OMV) on the serum resistance of A. actinomycetemcomitans. The survival rate of an almost totally serum sensitive A. actinomycetemcomitans ompA1 and ompA2 double mutant increased 100-fold when OMVs from a wildtype strain were supplemented. This effect was similar when OMVs from the ompA1 ompA2 double mutant were used, suggesting an OmpA-independent effect. On the other hand, OMVs from an LPS-deficient A. actinomycetemcomitans strain did not contribute to serum survival, consistent with an LPS-dependent serum resistance carried out by the vesicles. This appeared to be due to a substantial consumption of serum complement components by LPS in the OMVs.In paper III, the salivary prevalence of A. actinomycetemcomitans and A. aphrophilus was high (71.8% and 99% respectively) in the adolescent population from Maasai Mara, Kenya. A. aphrophilus was found in higher amounts compared to A. actinomycetemcomitans. Cultivation from subgingival samples of a subset of the population yielded a lower prevalence of A. actinomycetemcomitans (22.1%). The highly leukotoxic genotype, JP2, was discovered in one salivary sample, indicating the first JP2-genotype identified in East Africa.In paper IV, screening of dental radiographs from an adolescent population born in 2001 and residing in Västerbotten County, Sweden (n=1656) was performed. This resulted in 24 individuals (1.45%) positive for marginal bone loss (>2 mm). The dropout-rate was rather high and, eventually, thirteen of these individuals (cases) were periodontally examined, as well as 26 controls who did not display any marginal bone loss. Twelve of the cases were diagnosed with periodontitis, indicating an increase in the prevalence of periodontitis in adolescents. Moreover, this emphasized the potential of radiographs to identify small changes on marginal bone levels to diagnose periodontitis in adolescents. The cases had significantly higher values of clinical attachment loss, pocket probing depth and bleeding on probing. Significantly higher loads and prevalence of A. actinomycetemcomitans, Porphyromonas gingivalis and Filifactor alocis were generally detected in the saliva and subgingival plaque samples from the cases. In contrast, A. aphrophilus was more prevalent in the controls.In conclusion, outer membrane proteins OmpA1 and OmpA2, and outer membrane vesicles display protective effects contributing to serum resistance in A. actinomycetemcomitans and A. aphrophilus. The prevalence of these bacteria varies in different populations, and they are also affected by environmental factors. Finally, the prevalence of periodontitis in adolescents in Västerbotten is suggested to have increased and is associated with distinct microbiological characteristics and geographic origin.
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| 25. |
- Lindholm, Mark, et al.
(författare)
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Radiographic and clinical signs of periodontitis and associated bacterial species in a Swedish adolescent population
- 2023
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Ingår i: Journal of Periodontology. - : John Wiley & Sons. - 0022-3492 .- 1943-3670. ; 94:5, s. 630-640
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Tidskriftsartikel (refereegranskat)abstract
- Background: Periodontitis in adolescents has historically been rare in the Nordic countries but could be expected to increase due to changes in demographics. The primary aim was to cross-sectionally examine the presence of radiographic bone loss in adolescents in Västerbotten County, Sweden. The secondary aim was to compare periodontal and microbial parameters, as well as demographic patterns, in controls without bone loss with cases with bone loss.Methods: Adolescents born 2001 and who had a dental examination 2016 (n = 1656) were screened for proximal bone loss using bitewing radiographs taken during dental examinations (2014-2016). Individuals that exhibited proximal bone loss (> 2 mm) were invited to participate in a complete periodontal examination. Subgingival plaque and saliva were also sampled. For each adolescent with bone loss, two healthy individuals as controls were examined. Selected bacterial species in saliva and subgingival plaque were quantitatively examined by quantitative PCR. The subgingival plaque samples were also analysed with cultivation technique.Results: Proximal bone loss was identified in 24 individuals (1.45%) based on all the radiographs. Thirteen of these cases were periodontally examined and matched with 26 controls. Most cases were diagnosed with periodontitis (12/13 [92%]), whereas none of the controls had periodontitis. Higher concentrations and higher prevalence of the bacteria Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Filifactor alocis were generally found in the cases.Conclusion:The results suggest that periodontitis among adolescents, because of demographic differences (an increasingly heterogenous population), in Sweden is increasing and emphasizes the importance of radiographs for early detection of this disease.
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| 26. |
- Lindholm, Mark, et al.
(författare)
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Role of OmpA1 and OmpA2 in Aggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus serum resistance
- 2019
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Ingår i: Journal of Oral Microbiology. - : Taylor & Francis. - 2000-2297. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Aggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus belong to the HACEK group of fastidious Gram-negative organisms, a recognized cause of infective endocarditis. A. actinomycetemcomitans is also implicated in aggressive forms of periodontitis. We demonstrated that A. aphrophilus strains, as A. actinomycetemcomitans are ubiquitously serum resistant. Both species encode two Outer membrane protein A paralogues, here denoted OmpA1 and OmpA2. As their respective pangenomes contain several OmpA1 and OmpA2 alleles, they represent potential genotypic markers. A naturally competent strain of A. actinomycetemcomitans and A. aphrophilus, respectively were used to elucidate if OmpA1 and OmpA2 contribute to serum resistance. Whereas OmpA1 was critical for survival of A. actinomycetemcomitans D7SS in 50% normal human serum (NHS), serum resistant ompA1 mutants were fortuitously obtained, expressing enhanced levels of OmpA2. Similarly, OmpA1 rather than OmpA2 was a major contributor to serum resistance of A. aphrophilus HK83. Far-Western blot revealed that OmpA1AA, OmpA2AA, and OmpA1AP can bind to C4-binding protein, an inhibitor of classical and mannose-binding lectin (MBL) complement activation. Indeed, ompA1 mutants were susceptible to these pathways, but also to alternative complement activation. This may at least partly reflect a compromised outer membrane integrity but is also consistent with alternative mechanisms involved in OmpA-mediated serum resistance.
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| 27. |
- Orho-Melander, Marju, et al.
(författare)
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Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:11, s. 3112-3121
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCYR locus in samples of non-European ancestry and to fine-map across the associated genomic interval. RESEARCH DESIGN AND METHODS-We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the similar to 417-kb region of linkage disequilibrium. spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS-We provide comprehensive evidence that GCYR rs780094 is associated with opposite effects on fasting plasma triglyceride (P-meta = 3 x 10(-56)) and glucose (P-meta = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS-These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism. Diabetes 57:3112-3121, 2008
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| 28. |
- Oscarsson, Jan, et al.
(författare)
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Bacterial symbionts in oral niche use type VI secretion nanomachinery for fitness increase against pathobionts
- 2024
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Ingår i: iScience. - : Elsevier. - 2589-0042.
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Tidskriftsartikel (refereegranskat)abstract
- Microbial ecosystems experience spatial and nutrient restrictions, leading to the coevolution of cooperation and competition among cohabiting species. To increase their fitness for survival, bacteria exploit machinery to antagonizing rival species upon close contact. As such, the bacterial type VI secretion system (T6SS) nanomachinery, typically expressed by pathobionts, can transport proteins directly into eukaryotic or prokaryotic cells, consequently killing cohabiting competitors. Here we demonstrate first time that oral symbiont Aggregatibacter aphrophilus possesses a T6SS and can eliminate its close relative oral pathobiont Aggregatibacter actinomycetemcomitans using its T6SS. These findings bring newer the anti-bacterial prospects of symbionts against cohabiting pathobionts while introducing presence of an active T6SS in the oral cavity.
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| 29. |
- Oscarsson, Jan, et al.
(författare)
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Tools of Aggregatibacter actinomycetemcomitans to Evade the Host Response
- 2019
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Ingår i: Journal of Clinical Medicine. - Basel : MDPI. - 2077-0383. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Periodontitis is an infection-induced inflammatory disease that affects the tooth supporting tissues, i.e., bone and connective tissues. The initiation and progression of this disease depend on dysbiotic ecological changes in the oral microbiome, thereby affecting the severity of disease through multiple immune-inflammatory responses. Aggregatibacter actinomycetemcomitans is a facultative anaerobic Gram-negative bacterium associated with such cellular and molecular mechanisms associated with the pathogenesis of periodontitis. In the present review, we outline virulence mechanisms that help the bacterium to escape the host response. These properties include invasiveness, secretion of exotoxins, serum resistance, and release of outer membrane vesicles. Virulence properties of A. actinomycetemcomitans that can contribute to treatment resistance in the infected individuals and upon translocation to the circulation, also induce pathogenic mechanisms associated with several systemic diseases.
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| 30. |
- Patel, Riyaz S., et al.
(författare)
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Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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| 31. |
- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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| 32. |
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| 33. |
- Seyfried, Hans, et al.
(författare)
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Optical investigations of the combustion characteristics of a gas turbine pilot burner
- 2007
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Ingår i: Collection of Technical Papers - 45th AIAA Aerospace Sciences Meeting. ; 8, s. 5630-5641
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Konferensbidrag (refereegranskat)abstract
- This paper presents the application of several optical measurement techniques for the characterization of the combustion behavior of the pilot burner of a gas turbine combustor developed according to the lean premixed prevaporized (LPP) concept. The vaporization of the kerosene fuel (Jet-A) and its consequent mixing with air has been visualized using combined Laser-Induced Fluorescence (LIF) and Mie scattering measurements. In addition the feasibility of using Laser-Induced Incandescence (LII) for soot characterization has also been investigated. Furthermore, spontaneous flame emission (i.e. chemiluminescence and thermal radiation) have been measured providing information on the overall characteristics of the combustion. The LIF/Mie measurements can also be used to estimate the length and time scales for evaporation and mixing with air of Kerosene (Jet-A) for the LP(P)4 pilot burner.
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| 34. |
- Shen, Li, et al.
(författare)
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Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists : An Analysis of DAPA-HF.
- 2021
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Ingår i: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 9:4, s. 254-264
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial. BACKGROUND: MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination. METHODS: A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10 mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes. RESULTS: A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m(2)), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction = 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo. CONCLUSIONS: Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).
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| 35. |
- Teo, Koon K., et al.
(författare)
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Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals The ARB Trialists Collaboration
- 2011
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 29:4, s. 623-635
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Forskningsöversikt (refereegranskat)abstract
- Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) reduce cardiovascular disease (CVD) events, but a recent meta-analysis of selected studies suggested that ARBs may increase cancer risks.Objective Candesartan, irbesartan, telmisartan, valsartan, and losartan were assessed for incident cancers in 15 large parallel long-term multicenter double-blind clinical trials of these agents involving 138 769 participants.Patients and methods Individuals at high CVD risk were randomized to telmisartan (three trials, n=51 878), irbesartan (three trials, n=14 859), valsartan (four trials, n=44 264), candesartan (four trials, n=18 566), and losartan (one trial, n=9193) and followed for 23-60 months. Incident cancer cases were compared in patients randomized to ARBs versus controls. In five trials (n=42 403), the ARBs were compared to ACEi and in 11 trials (n=63 313) to controls without ACEi. In addition, in seven trials (n=47 020), the effect of ARBs with ACEi was compared to ACEi alone and in two trials ARBs with ACEi versus ARB alone (n=25 712).Results Overall, there was no excess of cancer incidence with ARB therapy compared to controls in the 15 trials [ 4549 (6.16%) cases of 73 808 allocated to ARB versus 3856 (6.31%) of 61 106 assigned to non-ARB controls; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.95-1.04] overall or when individual ARBs were examined. ORs comparing combination therapy with ARB along with ACEi versus ACEi was 1.01 (95% CI 0.94-1.10), combination versus ARB alone 1.02 (95% CI 0.91-1.13), ARB alone versus ACEi alone 1.06 (95% CI 0.97-1.16) and ARB versus placebo/control without ACEi 0.97 (95% CI 0.91-1.04). There was no excess of lung, prostate or breast cancer, or overall cancer deaths associated with ARB treatment.Conclusion There was no significant increase in the overall or site-specific cancer risk from ARBs compared to controls.
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| 36. |
- van Zuydam, Natalie, et al.
(författare)
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Genome-Wide Association Study of Peripheral Artery Disease
- 2021
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 2574-8300. ; 14:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (P-association <= 5x10(-8)) associations with PAD in 449 548 (N-cases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], P-diabetes=2.5x10(-9), P-interactionwithdiabetes=5.3x10(-7)). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], P-smokers=9.3x10(-10), P-interactionwithsmoking=3.9x10(-5)). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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