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1.	Lumbers, R. T., et al. (author) The genomics of heart failure: design and rationale of the HERMES consortium 2021 In: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541 Journal article (peer-reviewed)abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
2.	Dima, Danai, et al. (author) Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years. 2022 In: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469 Journal article (peer-reviewed)abstract Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
3.	Frangou, Sophia, et al. (author) Cortical thickness across the lifespan : Data from 17,075 healthy individuals aged 3-90 years 2022 In: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 431-451 Journal article (peer-reviewed)abstract Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
4.	Sønderby, Ida E., et al. (author) 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans 2021 In: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1 Journal article (peer-reviewed)abstract Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
5.	van der Meer, Dennis, et al. (author) Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition 2020 In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430 Journal article (peer-reviewed)abstract Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
6.	Sonderby, Ida E., et al. (author) Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia 2020 In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602 Journal article (peer-reviewed)abstract Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
7.	Shah, S, et al. (author) Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure 2020 In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163- Journal article (peer-reviewed)abstract Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
8.	Roswall, N., et al. (author) Long-Term Exposure to Transportation Noise and Risk of Incident Stroke: A Pooled Study of Nine Scandinavian Cohorts 2021 In: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 129:10 Journal article (peer-reviewed)abstract BACKGROUND: Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse. OBJECTIVE: We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population. METHODS: We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through linkage to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle confounders, and air pollution. RESULTS: During follow-up (median = 19.5 y), 11,056 stroke cases were identified. Road traffic noise (Lden) was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for individual- and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of <= 2.5 mu m (PM2.5) and NO2]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40-50 vs. <= 40 dB) (HR = 1.12; 95% CI: 0.99, 1.27), but not with higher exposure (>= 50 dB, HR = 0.94; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke. DISCUSSION: In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise.
9.	Boen, Rune, et al. (author) Beyond the global brain differences : intraindividual variability differences in 1q21.1 distal and 15q11.2 bp1-bp2 deletion carriers 2024 In: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 95:2, s. 147-160 Journal article (peer-reviewed)abstract Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
10.	Wimalarathna, A. A. A. K., et al. (author) Introduction of an interactive tool (the Dental Trauma Guide) in the undergraduate dental teaching to manage traumatic dental injuries 2021 In: Dental Traumatology. - : John Wiley & Sons. - 1600-4469 .- 1600-9657. ; 37:5, s. 717-724 Journal article (peer-reviewed)abstract Background/Aims Traumatic dental injuries (TDI) are complex problems where lack of proper care may result in serious complications. The need to improve the management of TDI is a frequently addressed concern. Methods of improvement in their diagnosis and management are continuously evolving. The interactive Internet tool, the Dental Trauma Guide (DTG), helps to simplify diagnostic and management dilemmas. However, it is not a freely available tool. The aim of the current study was to assess the knowledge and diagnostic skills of undergraduate dental students with access to the DTG compared with students without such access, in order to validate and promote this tool in dental education. Materials and Methods Two groups of students were randomly selected where one group of final year dental undergraduate students were exposed to lectures, demonstrations, discussions and tutorials on the management of TDI according to the standard undergraduate curriculum in Sri Lanka. Another test group of 21 students were provided with access to DTG during their training in paediatric dentistry. At the end of the study period, students were assessed on their knowledge of TDI using MCQs (Multiple Choice Questions) and OSCEs (Objective Structured Clinical Examination), based on the DTG. Results The students with access to the DTG were more knowledgeable in providing the correct answers to three out of the seven OSCE questions. Evaluation based on the MCQs did not reveal a significant difference (p = .913). However, users of the DTG showed a statistically significant difference with better overall knowledge based on their answers (p = .028). Following this period of evaluation, all of the students were provided with access to the DTG to supplement their learning experience. Conclusion The Dental Trauma Guide is a useful supplementary tool for undergraduate students to arrive at a correct diagnosis and treatment plan for TDI.
11.	Nyberg, Lars, 1966-, et al. (author) Individual differences in brain aging : heterogeneity in cortico-hippocampal but not caudate atrophy rates 2023 In: Cerebral Cortex. - : Oxford University Press. - 1047-3211 .- 1460-2199. ; 33:9, s. 5075-5081 Journal article (peer-reviewed)abstract It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.
12.	Andrikopoulos, Petros, et al. (author) Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide 2023 In: Nature Communications. - 2041-1723 .- 2041-1723. ; 14:1 Journal article (peer-reviewed)abstract The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.
13.	Olén, Ola, et al. (author) Increasing Risk of Lymphoma Over Time in Crohn's Disease but Not in Ulcerative Colitis : A Scandinavian Cohort Study 2023 In: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 21:12, s. 3132-3142 Journal article (peer-reviewed)abstract Background & Aims: Earlier studies have provided varying risk estimates for lymphoma in patients with inflammatory bowel disease (IBD), but often have been limited by detection biases (especially during the first year of follow-up evaluation), misclassification, and small sample size; and rarely reflect modern-day management of IBD.Methods: We performed a binational register-based cohort study (Sweden and Denmark) from 1969 to 2019. We compared 164,716 patients with IBD with 1,639,027 matched general population reference individuals. Cox regression estimated hazard ratios (HRs) for incident lymphoma by lymphoma subtype, excluding the first year of follow-up evaluation.Results: From 1969 to 2019, 258 patients with Crohn's disease (CD), 479 patients with ulcerative colitis (UC), and 6675 matched reference individuals developed lymphoma. This corresponded to incidence rates of 35 (CD) and 34 (UC) per 100,000 person-years in IBD patients, compared with 28 and 33 per 100,000 person-years in their matched reference individuals. Although both CD (HR, 1.32; 95% CI, 1.16–1.50) and UC (HR, 1.09; 95% CI, 1.00–1.20) were associated with an increase in lymphoma, the 10-year cumulative incidence difference was low even in CD patients (0.08%; 95% CI, 0.02–0.13). HRs have increased in the past 2 decades, corresponding to increasing use of immunomodulators and biologics during the same time period. HRs were increased for aggressive B-cell non-Hodgkin lymphoma in CD and UC patients, and for T-cell non-Hodgkin lymphoma in CD patients. Although the highest HRs were observed in patients exposed to combination therapy (immunomodulators and biologics) or second-line biologics, we also found increased HRs in patients naïve to such drugs.Conclusions: During the past 20 years, the risk of lymphomas have increased in CD, but not in UC, and were driven mainly by T-cell lymphomas and aggressive B-cell lymphomas.
14.	Persson, Josefine, 1980, et al. (author) Stratification of COVID-19 patients based on quantitative immune-related gene expression in whole blood. 2022 In: Molecular immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 145, s. 17-26 Journal article (peer-reviewed)abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild symptoms in the majority of infected individuals, yet in some cases it leads to a life-threatening condition. Determination of early predictive biomarkers enabling risk stratification for coronavirus disease 2019 (COVID-19) patients can inform treatment and intervention strategies. Herein, we analyzed whole blood samples obtained from individuals infected with SARS-CoV-2, varying from mild to critical symptoms, approximately one week after symptom onset. In order to identify blood-specific markers of disease severity status, a targeted expression analysis of 143 immune-related genes was carried out by dual-color reverse transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA). The clinically well-defined subgroups of COVID-19 patients were compared with healthy controls. The transcriptional profile of the critically ill patients clearly separated from that of healthy individuals. Moreover, the number of differentially expressed genes increased by severity of COVID-19. It was also found that critically ill patients can be distinguished by reduced peripheral blood expression of several genes, which most likely reflects the lower lymphocyte counts. There was a notable predominance of IFN-associated gene expression in all subgroups of COVID-19, which was most profound in critically ill patients. Interestingly, the gene encoding one of the main TNF-receptors, TNFRS1A, had selectively lower expression in mild COVID-19 cases. This report provides added value in understanding COVID-19 disease, and shows potential of determining early immune transcript signatures in the blood of patients with different disease severity. These results can guide further explorations to uncover mechanisms underlying immunity and immunopathology in COVID-19.
15.	Solé-Padullés, Cristina, et al. (author) No Association Between Loneliness, Episodic Memory and Hippocampal Volume Change in Young and Healthy Older Adults : A Longitudinal European Multicenter Study 2022 In: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 14 Journal article (peer-reviewed)abstract Background: Loneliness is most prevalent during adolescence and late life and has been associated with mental health disorders as well as with cognitive decline during aging. Associations between longitudinal measures of loneliness and verbal episodic memory and brain structure should thus be investigated.Methods: We sought to determine associations between loneliness and verbal episodic memory as well as loneliness and hippocampal volume trajectories across three longitudinal cohorts within the Lifebrain Consortium, including children, adolescents (N = 69, age range 10–15 at baseline examination) and older adults (N = 1468 over 60). We also explored putative loneliness correlates of cortical thinning across the entire cortical mantle.Results: Loneliness was associated with worsening of verbal episodic memory in one cohort of older adults. Specifically, reporting medium to high levels of loneliness over time was related to significantly increased memory loss at follow-up examinations. The significance of the loneliness-memory change association was lost when eight participants were excluded after having developed dementia in any of the subsequent follow-up assessments. No significant structural brain correlates of loneliness were found, neither hippocampal volume change nor cortical thinning.Conclusion: In the present longitudinal European multicenter study, the association between loneliness and episodic memory was mainly driven by individuals exhibiting progressive cognitive decline, which reinforces previous findings associating loneliness with cognitive impairment and dementia.
16.	Andersson, Eva M., 1968, et al. (author) Is Cadmium a Risk Factor for Breast Cancer - Results from a Nested Case-Control Study Using Data from the Malmo Diet and Cancer Study 2021 In: Cancer Epidemiology Biomarkers & Prevention. - 1055-9965. ; 30:9, s. 1744-1752 Journal article (peer-reviewed)abstract Background: Some studies have shown that cadmium (Cd) is associated with breast cancer risk. One hypothesis is that Cd has estrogen-like properties. This case-control study investigated the association between breast cancer risk and blood Cd (BCd) levels. Methods: All breast cancers in the Malmo Diet and Cancer cohort were identified through linkage to the Swedish Cancer Registry, baseline (1991-1996) through 2014. Two controls per case were selected from the same cohort. BCd was analyzed at baseline. Associations were analyzed using logistic regression. Results: Mean BCd was 0.51 mg/L among 1,274 cases and 0.46 among 2,572 controls. There was an overall increased risk of breast cancer [OR, 1.18; 95% confidence interval (CI), 1.05-1.36] per mg/L of BCd. An increased risk was, however, only found at high BCd [OR, 1.34 (95% CI, 1.05-1.73)] for BCd more than 1.20 mg/L. The group with the highest BCd was mainly smokers. A spline indicated that at BCd less than 1.0 mg/L, the OR was not increased. The association with BCd was stronger in current smokers and at body mass index (BMI) above 25, while no modification due to receptor status was found. Conclusions: The results indicated increased risk of breast cancer only for high Cd exposure, which occurred mainly among smokers. This made it difficult to disentangle the effects of smoking and Cd, despite inclusion of smoking habits in the models. Impact: This study provides support for reducing Cd exposure through smoking cessation and dietary choice. On the population level, preventive measures against Cd pollution are warranted.
17.	Dahlin, Anna M., 1979-, et al. (author) A genome-wide association study on medulloblastoma 2020 In: Journal of Neuro-Oncology. - : Springer. - 0167-594X .- 1573-7373. ; 147:2, s. 309-315 Journal article (peer-reviewed)abstract Introduction: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.Methods: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.Results: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10–5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10–8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10–4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10–3).Conclusion: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.
18.	Forslund, Sofia K., et al. (author) Combinatorial, additive and dose-dependent drug–microbiome associations 2021 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505 Journal article (peer-reviewed)abstract During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
19.	Johansson, Jarkko, et al. (author) Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan 2023 In: Cell Reports. - 2211-1247. ; 42:9 Journal article (peer-reviewed)abstract Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.
20.	Karalija, Nina, 1984-, et al. (author) Longitudinal Dopamine D2 Receptor Changes and Cerebrovascular Health in Aging 2022 In: Neurology. - 1526-632X .- 0028-3878. ; 99 Journal article (peer-reviewed)abstract BACKGROUND AND OBJECTIVES: Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates. METHODS: We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with 11C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity. RESULTS: Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion. DISCUSSION: These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.
21.	Kilbo Edlund, Karl, et al. (author) Occupational particle exposure and chronic kidney disease: a cohort study in Swedish construction workers. 2024 In: Journal of Occupational and Environmental Medicine. - : BMJ Publishing Group Ltd. - 1351-0711 .- 1470-7926. ; 81:5, s. 238-243 Journal article (peer-reviewed)abstract Increasing epidemiological and experimental evidence suggests that particle exposure is an environmental risk factor for chronic kidney disease (CKD). However, only a few case-control studies have investigated this association in an occupational setting. Hence, our objective was to investigate associations between particle exposure and CKD in a large cohort of Swedish construction workers.We performed a retrospective cohort study in the Swedish Construction Workers' Cohort, recruited 1971-1993 (n=286089). A job-exposure matrix was used to identify workers exposed to nine different particulate exposures, which were combined into three main categories (inorganic dust and fumes, wood dust and fibres). Incident CKD and start of renal replacement therapy (RRT) were obtained from validated national registries until 2021 and analysed using adjusted Cox proportional hazards models.Exposure to inorganic dust and fumes was associated with an increased risk of CKD and RRT during working age (adjusted HR for CKD at age <65 years 1.15, 95%CI 1.05 to 1.26). The elevated risk did not persist after retirement age. Exposure to cement dust, concrete dust and diesel exhaust was associated with CKD. Elevated HRs were also found for quartz dust and welding fumes.Workers exposed to inorganic particles seem to be at elevated risk of CKD and RRT. Our results are in line with previous evidence of renal effects of ambient air pollution and warrant further efforts to reduce occupational and ambient particle exposure.
22.	Lundin, Samuel B, 1970, et al. (author) A novel precision-serology assay for SARS-CoV-2 infection based on linear B-cell epitopes of Spike protein 2023 In: Frontiers in Immunology. - 1664-3224. ; 14 Journal article (peer-reviewed)abstract IntroductionThe COVID-19 pandemic illustrates the need for serology diagnostics with improved accuracy. While conventional serology based on recognition of entire proteins or subunits thereof has made significant contribution to the antibody assessment space, it often suffers from sub-optimal specificity. Epitope-based, high-precision, serology assays hold potential to capture the high specificity and diversity of the immune system, hence circumventing the cross-reactivity with closely related microbial antigens. MethodsWe herein report mapping of linear IgG and IgA antibody epitopes of the SARS-CoV-2 Spike (S) protein in samples from SARS-CoV-2 exposed individuals along with certified SARS-CoV-2 verification plasma samples using peptide arrays. ResultsWe identified 21 distinct linear epitopes. Importantly, we showed that pre-pandemic serum samples contain IgG antibodies reacting to the majority of protein S epitopes, most likely as a result of prior infection with seasonal coronaviruses. Only 4 of the identified SARS-CoV-2 protein S linear epitopes were specific for SARS-CoV-2 infection. These epitopes are located at positions 278-298 and 550-586, just proximal and distal to the RBD, as well as at position 1134-1156 in the HR2 subdomain and at 1248-1271 in the C-terminal subdomain of protein S. To substantiate the applicability of our findings, we tested three of the high-accuracy protein S epitopes in a Luminex assay, using a certified validation plasma sample set from SARS-CoV-2 infected individuals. The Luminex results were well aligned with the peptide array results, and correlated very well with in-house and commercial immune assays for RBD, S1 and S1/S2 domains of protein S. ConclusionWe present a comprehensive mapping of linear B-cell epitopes of SARS-CoV-2 protein S, that identifies peptides suitable for a precision serology assay devoid of cross-reactivity. These results have implications for development of highly specific serology test for exposure to SARS-CoV-2 and other members of the coronaviridae family, as well as for rapid development of serology tests for future emerging pandemic threats.
23.	Nilsson Sommar, Johan, et al. (author) Long-term exposure to particulate air pollution and black carbon in relation to natural and cause-specific mortality: a multicohort study in Sweden 2021 In: Bmj Open. - : BMJ. - 2044-6055. ; 11:9 Journal article (peer-reviewed)abstract Objectives To estimate concentration-response relationships for particulate matter (PM) and black carbon (BC) in relation to mortality in cohorts from three Swedish cities with comparatively low pollutant levels. Setting Cohorts from Gothenburg, Stockholm and Umea, Sweden. Design High-resolution dispersion models were used to estimate annual mean concentrations of PM with aerodynamic diameter <= 10 mu m (PM10) and <= 2.5 mu m (PM2.5), and BC, at individual addresses during each year of follow-up, 1990-2011. Moving averages were calculated for the time windows 1-5 years (lag1-5) and 6-10 years (lag6-10) preceding the outcome. Cause-specific mortality data were obtained from the national cause of death registry. Cohort-specific HRs were estimated using Cox regression models and then meta-analysed including a random effect of cohort. Participants During the study period, 7 340 cases of natural mortality, 2 755 cases of cardiovascular disease (CVD) mortality and 817 cases of respiratory and lung cancer mortality were observed among in total 68 679 individuals and 689 813 person-years of follow-up. Results Both PM10 (range: 6.3-41.9 mu g/m(3)) and BC (range: 0.2-6.8 mu g/m(3)) were associated with natural mortality showing 17% (95% CI 6% to 31%) and 9% (95% CI 0% to 18%) increased risks per 10 mu g/m(3) and 1 mu g/m(3) of lag1-5 exposure, respectively. For PM2.5 (range: 4.0-22.4 mu g/m(3)), the estimated increase was 13% per 5 mu g/m(3), but less precise (95% CI -9% to 40%). Estimates for CVD mortality appeared higher for both PM10 and PM2.5. No association was observed with respiratory mortality. Conclusion The results support an effect of long-term air pollution on natural mortality and mortality in CVD with high relative risks also at low exposure levels. These findings are relevant for future decisions concerning air quality policies.
24.	Rogström, Lina, 1983-, et al. (author) Structural changes in Ti1-xAlxN coatings during turning : A XANES and EXAFS study of worn tools 2023 In: Applied Surface Science. - : Elsevier. - 0169-4332 .- 1873-5584. ; 612 Journal article (peer-reviewed)abstract Structural changes in Ti1-xAlxN coated tool inserts used for turning in 316L stainless steel were investigated by XANES, EXAFS, EDS, and STEM. For coarse-grained fcc-structured Ti1-xAlxN coatings, with 0 ≤ x ≤ 0.62, the XANES spectrum changes with Al-content. XANES Ti 1s line-scans across the rake face of the worn samples reveals that TiN-enriched domains have formed during turning in Ti0.47Al0.53N and Ti0.38Al0.62N samples as a result of spinodal decomposition. The XANES spectra reveal the locations on the tool in which the most TiN-rich domains have formed, indicating which part of the tool-chip contact area that experienced the highest temperature during turning. Changes in the pre-edge features in the XANES spectra reveal that structural changes occur also in the w-TiAlN phase in fine-grained Ti0.38Al0.62N during turning. EDS shows that Cr and Fe from the steel adhere to the tool rake face during machining. Cr 1s and Fe 1s XANES show that Cr is oxidized in the end of the contact length while the adhered Fe retains in the same fcc-structure as that of the 316L stainless steel.
25.	Al-Melh, M. A., et al. (author) Comparison between Topical and Injection Anesthetics on Pain Related to Orthodontic Miniscrew Placement : A Split-mouth Study 2021 In: Journal of Contemporary Dental Practice. - : Jaypee Brothers Medical Publishers (P) Ltd. - 1526-3711. ; 22:6, s. 637-643 Journal article (peer-reviewed)abstract Aims and objectives: The aims of this study were to compare the anesthetic effect of a lidocaine/prilocaine (L/P) topical anesthetic with placebo on pain from needle sticks and to compare the anesthetic effect of the L/P topical anesthetic with an infiltrative anesthetic on pain from orthodontic miniscrew placement. Materials and methods: Pain elimination was analyzed from two interventions: (a) needle stick and (b) miniscrew insertion. When assessing pain from needle stick, one side of the mandible received 2.5% lidocaine/2.5% prilocaine topical anesthetic, and the other side received placebo. When evaluating pain from miniscrew placement, one side of the mandible received L/P topical anesthetic and the other side received infiltrative anesthetic. The findings were recorded on a Visual Analogue Scale after needle stick and after miniscrew placement. Subjective assessment was analyzed by a questionnaire. Results: The L/P topical anesthetic significantly eliminated the pain from needle stick (Mann–Whitney test of medians, 29.0 vs 0.0, respectively, p<0.001). However, the injection anesthetic eliminated the pain from the miniscrew placement better than the L/P topical anesthetic (Mann–Whitney test of medians, 0.0 vs 5.5, respectively, p<0.001). Eighty percent of the subjects felt more comfortable with L/P topical anesthetic than injection anesthetic. Pain from needle stick pain was reported to be the most uncomfortable part of the study. Conclusion: The L/P topical anesthetic efficiently eliminated pain from needle stick. The L/P topical anesthetic did not completely eliminate pain from miniscrew placement as the injection anesthesia, but it did reduce pain to tolerable levels. Clinical significance: L/P topical anesthetics can significantly eliminate pain from needle stick injections, and L/P topical anesthetics can reduce pain from orthodontic miniscrew placement to tolerable levels. © Jaypee Brothers Medical Publishers. 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
26.	Andersson, Eva M., et al. (author) Is cadmium a risk factor for breast cancer - Results from a nested case-control study using data from the malmö diet and cancer study 2021 In: Cancer Epidemiology Biomarkers and Prevention. - 1055-9965. ; 30:9, s. 1744-1752 Journal article (peer-reviewed)abstract Background: Some studies have shown that cadmium (Cd) is associated with breast cancer risk. One hypothesis is that Cd has estrogen-like properties. This case-control study investigated the association between breast cancer risk and blood Cd (BCd) levels. Methods: All breast cancers in the Malmö Diet and Cancer cohort were identified through linkage to the Swedish Cancer Registry, baseline (1991-1996) through 2014. Two controls per case were selected from the same cohort. BCd was analyzed at baseline. Associations were analyzed using logistic regression. Results: Mean BCd was 0.51 mg/L among 1, 274 cases and 0.46 among 2, 572 controls. There was an overall increased risk of breast cancer [OR, 1.18; 95% confidence interval (CI), 1.05-1.36] per mg/L of BCd. An increased risk was, however, only found at high BCd [OR, 1.34 (95% CI, 1.05-1.73)] for BCd more than 1.20 mg/L. The group with the highest BCd was mainly smokers. A spline indicated that at BCd less than 1.0 mg/L, the OR was not increased. The association with BCd was stronger in current smokers and at body mass index (BMI) above 25, while no modification due to receptor status was found. Conclusions: The results indicated increased risk of breast cancer only for high Cd exposure, which occurred mainly among smokers. This made it difficult to disentangle the effects of smoking and Cd, despite inclusion of smoking habits in the models. Impact: This study provides support for reducing Cd exposure through smoking cessation and dietary choice. On the population level, preventive measures against Cd pollution are warranted.
27.	Andersson, Lars M, 1961-, et al. (author) Alvar Alsterdal - : en introduktion 2020 In: Antisemitism Antisionism.. - Malmö : Égalité. - 9789198420371 ; , s. 17-54 Book chapter (other academic/artistic)abstract Alsterdals bok gavs ursprungligen ut 1969. Den skildrar den våg av antisemitism i Polen som utlöstes efter junikriget 1967 mellan Israel och dess grannländer. Till nyutgåvan har historikern Lars M Andersson skrivit en utförlig introduktion om Alstersdals yrkesliv och författarskap, där arbetarrörelsen, europeisk kultur samt det judiska folkets historia och öden utgör centrala teman. I nyutgåvan finns två efterskrifter av Lars Dencik resp. Weddig Runquist.
28.	Andersson, Lars M, 1961- (author) Express-zionisten Isaac och den svenska nationen 2022 In: Issac Grünewald - konst och teater. - Stockholm : Prins Eugenes Waldemarsudde. - 9789186265588 Book chapter (other academic/artistic)
29.	Andersson, Lars M, 1961- (author) How do you Jew in Finland? : [Review of:] Mercédesz Czimbalmos: Intermarriage, Conversion and Jewish Identity in Contemporary Finland. A Study of Vernacular Religion in the Finnish Jewish Communities 2021 In: Nordisk judaistik - Scandinavian Jewish Studies. - : Nordisk judaistik/Scandinavian Jewish Studies. - 0348-1646 .- 2343-4929. ; 32:2, s. 94-98 Review (other academic/artistic)abstract Review of Mercédesz Czimbalmos's Intermarriage, Conversion and Jewish Identity in Contemporary Finland. A Study of Vernacular Religion in the Finnish Jewish Communities (Åbo Akademi University).
30.	Andersson, Lars M, 1961- (author) Mercédesz Czimbalmos “Intermarriage, Conversion, and Jewish Identity inContemporary Finland: A study of vernacular religion in the Finnish Jewish communities,” (Åbo Akademi University 2021), diss. 2021 In: Multiethnica. - : The Hugo Valentin Centre, Uppsala University. - 0284-396X .- 2002-3413. ; 41, s. 100-102 Review (peer-reviewed)
31.	Andersson, Lars M, 1961- (author) Redaktören har ordet 2022 In: Personhistorisk Tidskrift. - : Personhistoriska samfundet. - 0031-5699. ; :2 Journal article (other academic/artistic)
32.	Andersson, Lars M., 1961- (author) Svante Hansson (1938-2023) in memoriam 2023 Other publication (pop. science, debate, etc.)
33.	Aulin, Julia, et al. (author) Serial measurement of interleukin-6 and risk of mortality in anticoagulated patients with atrial fibrillation : Insights from ARISTOTLE and RE-LY trials. 2020 In: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 18:9, s. 2287-2295 Journal article (peer-reviewed)abstract BACKGROUND: The inflammatory biomarker interleukin-6 (IL-6) is associated with mortality in atrial fibrillation (AF).OBJECTIVE: To investigate if repeated IL-6 measurements improve the prognostication for stroke or systemic embolism, major bleeding, and mortality in anticoagulated patients with AF.METHODS: IL-6 levels by ELISA were measured at study entry and at 2 months in 4830 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with 1.8 years median follow-up. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, IL-6 was measured at study entry, 3, 6, and 12 months in 2559 patients with 2.0 years median follow-up. Associations between a second IL-6 measurement and outcomes, adjusted for baseline IL-6, clinical variables, and other cardiovascular biomarkers, were analyzed by Cox regression.RESULTS: Median IL-6 levels were 2.0 ng/L (interquartile range [IQR] 1.30-3.20) and 2.10 ng/L (IQR 1.40-3.40) at the two time-points in ARISTOTLE, and, in RE-LY, 2.5 ng/L (IQR 1.6-4.3), 2.5 ng/L (IQR 1.6-4.2), 2.4 ng/L (IQR 1.6, 3.9), and 2.4 ng/L (IQR 1.5, 3.9), respectively. IL-6 was associated with mortality; hazard ratios per 50% higher IL-6 at 2 or 3 months, respectively, were 1.32 (95% confidence interval, 1.23-1.41; P < .0001) in ARISTOTLE, and 1.11 (1.01-1.22, P = .0290) in RE-LY; with improved C index from 0.74 to 0.76 in ARISTOTLE, but not in the smaller RE-LY cohort. There were no consistent associations with second IL-6 and stroke or systemic embolism, or major bleeding.CONCLUSIONS: Persistent systemic inflammatory activity, assessed by repeated IL-6 measurements, is associated with mortality independent of established clinical risk factors and other strong cardiovascular biomarkers in anticoagulated patients with AF.
34.	Barregård, Lars, 1948, et al. (author) Cadmium Exposure and Coronary Artery Atherosclerosis: A Cross-Sectional Population-Based Study of Swedish Middle-Aged Adults 2021 In: Environmental health perspectives. - 1552-9924 .- 0091-6765. ; 129:6 Journal article (peer-reviewed)abstract The general population is ubiquitously exposed to the toxic metal cadmium through the diet and smoking. Cadmium exposure is associated with increased morbidity and mortality in myocardial infarction and stroke. Atherosclerosis is the main underlying mechanism of myocardial infarction. However, associations between cadmium and coronary artery atherosclerosis have not been examined.Our study sought to examine the hypothesis that blood cadmium (B-Cd) is positively associated with coronary artery calcification, as a measure of coronary artery atherosclerosis in the population-based Swedish SCAPIS study.Our analysis included 5,627 individuals (51% women), age 50-64 y, enrolled from 2013 to 2018. The coronary artery calcium score (CACS) was obtained from computed tomography. Blood cadmium was determined by inductively coupled plasma mass spectrometry (ICP-MS). Associations between B-Cd and coronary artery calcium score (CACS Agatston score) were evaluated using prevalence ratios (PRs) in models adjusted for sex, age, smoking, hypertension, diabetes, low-density cholesterol/high-density cholesterol ratio, and family history.The median B-Cd concentration was 0.24 μ g / L . The prevalence of positive coronary artery calcium ( CACS > 0 ) was 41% and the prevalence of CACS ≥ 100 was 13%. Relative to the lowest quartile (Q) of B-Cd ( < 0.16 μ g / L ), the highest quartile (median 0.63 μ g / L ) was associated with a small but significant increase in CACS > 0 (PR 1.1; 95% CI: 1.0, 1.3), and a greater relative increase in CACS ≥ 100 (PR 1.6; 95% CI: 1.3, 2.0). When restricted to 2,446 never-smokers, corresponding PRs were 1.1 (95% CI 0.9, 1.3) for CACS > 0 (63 cases in Q4) and 1.7 (95% CI 1.1, 2.7) for CACS ≥ 100 (17 cases in Q4).Blood cadmium in the highest quartile was associated with CACS in a general population sample with low to moderate cadmium exposure. This supports the hypothesis that atherosclerosis is an important mechanism underlying the associations between cadmium and incident cardiovascular disease. The findings suggest that public health measures to reduce cadmium exposure are warranted. https://doi.org/10.1289/EHP8523.
35.	Becker, Lior (author) A Mention to Those not Mentioned : Yizkor Books and Holocaust Memory 1943–2008 2022 Doctoral thesis (other academic/artistic)abstract Yizkor books are communal memorial books commemorating Jewish communities destroyed in the Holocaust, produced as a result of communal activity. This study analyses the production and function of Yizkor books. It answers questions regarding who produced them, why, when, where and in which languages and discusses the roles the books played, and the memory they produced in relation to Jewish, Iraeli and American memory culture.This is the largest survey of Yizkor books to date, using more than 1,500 texts by Yizkor book publishers, editors and other important figures as primary sources, as well as thirty complete books, It provides new historical knowledge on the people who initiated and took part in the publication process, the kind of Holocaust memory produced, and how the composition of the editorial and publishing groups, , the languages of publication and the memory of the Holocaust contained in the books changed over time and place. The results are further developed and contextualized using theories on collective memory.This research demonstrates that the publishers and editors of Yizkor books were a significantly more heterogeneous group than previously claimed. Four groups of publishers are identified: landsmanschaftn, other organizations, individuals without an organization around them and schoolchildren. A wide variety of editors are distinguished, from professional Yizkor book editors, to professionals in other fields and people with no relevant background in editing, who took it on themselves to complete this difficult task. The reasons for publication vary, but included personal and familial connections, the guilt felt by survivors and the urge to tell the world what had happened.The study also analyses the intended functions of the books according to their authors. Most notably, the books were used as “places of memory”, as gravestones and memorial candles, and as a place to say the kaddish for the many victims whose time and place of death were unknown. In the context of the collective memory of the Holocaust, three main aspects are discussed: the significant place of the diaspora in the commemoration of the community, the prevalence of Zionism in the communities before the war and the idea of universal martyrdom for all victims of the Holocaust, regardless of the circumstances of their life and death.
36.	Bonagas, Nadilly, et al. (author) Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress 2022 In: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156- Journal article (peer-reviewed)abstract The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
37.	Callesen, Katrine T., et al. (author) Characterization of Mast Cells from Healthy and Varicose Human Saphenous Vein 2022 In: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5 Journal article (peer-reviewed)abstract Mast cells (MCs) are distributed in tissues throughout the body and are highly involved in many physiological and pathophysiological processes. The potential and involvement of different MC phenotypes are still not well understood. MCs are present in blood vessel walls, but their specific phenotypic features are unknown. We aimed at characterizing MCs from human saphenous veins for localization, mediator content, and receptor expression. This was done in MCs from both healthy and varicose human saphenous veins (hSV and vSV, respectively). For both vSV and hSV, we found that vein MCs are mainly present in the tunica adventitia (99% MCs in adventitia) and that the population consists of both MCT and MCTC phenotypes (vSV: 55% MCT, hSV: 64% MCT). The vein MCs contained high levels of histamine (vSV: 27 pg/MC, hSV: 55 pg/MC) and tryptase (vSV: 98 pg/MC, hSV: 111 pg/MC), indicating a strong potential for regulatory effects on blood vessels. The receptor expression of FcɛRI, MRGPRX2, PTAFR, C3aR, and C5aR was found, even though the percentage of positive cells differed between vSV and hSV MCs. We conclude that vein MCs from the blood vessel wall have a high potential to affect the tissue around them.
38.	Erhardsson, Mikael, et al. (author) Acyl ghrelin increases cardiac output while preserving right ventricular-pulmonary arterial coupling in heart failure 2023 In: ESC Heart Failure. - : John Wiley & Sons. - 2055-5822. Journal article (peer-reviewed)abstract AIM: Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular-pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right-sided haemodynamics in HFrEF assessed by RVPAC.METHODS AND RESULTS: The Karolinska Acyl ghrelin Trial was a randomized double-blind placebo-controlled trial of acyl ghrelin versus placebo (120-min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5-4.6) to 4.6 (3.9-6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3-7.6) to 6.3 (4.8-7.5) mm·(m/s)-1 , P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3-6.4) to 4.8 (4.2-5.8) mm·(m/s)-1 , P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged.CONCLUSION: Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure.
39.	Hage, Camilla, et al. (author) Acyl ghrelin infusion increases circulating growth hormone in patients with heart failure and reduced ejection fraction 2023 In: European Journal of Heart Failure. - : John Wiley & Sons. - 1388-9842 .- 1879-0844. Journal article (peer-reviewed)
40.	Heimat Sverige? : tysk-judisk emigration till Sverige 1774-1945 2021 Editorial collection (other academic/artistic)
41.	Hoffmann, Mikael, et al. (author) Guiding principles for the use of knowledge bases and real-world data in clinical decision support systems : report by an international expert workshop at Karolinska Institutet 2020 In: Expert Review of Clinical Pharmacology. - : Taylor & Francis. - 1751-2433 .- 1751-2441. ; 13:9, s. 925-934 Journal article (peer-reviewed)abstract Introduction Technical and logical breakthroughs have provided new opportunities in medicine to use knowledge bases and large-scale clinical data (real-world) at point-of-care as part of a learning healthcare system to diminish the knowledge-practice gap. Areas covered The article is based on presentations, discussions and recommendations from an international scientific workshop. Value, research needs and funding avenues of knowledge bases and access to real-world data as well as transparency and incorporation of patient perspectives are discussed. Expert opinion Evidence-based, publicly funded, well-structured and curated knowledge bases are of global importance. They ought to be considered as a public responsibility requiring transparency and handling of conflicts of interest. Information has to be made accessible for clinical decision support systems (CDSS) for healthcare staff and patients. Access to rich and real-world data is essential for a learning health care ecosystem and can be augmented by data on patient-reported outcomes and preferences. This field can progress by the establishment of an international policy group for developing a best practice guideline on the development, maintenance, governance, evaluation principles and financing of open-source knowledge bases and handling of real-world data.
42.	Jiang, W., et al. (author) COVID-19 is associated with bystander polyclonal autoreactive B cell activation as reflected by a broad autoantibody production, but none is linked to disease severity 2023 In: Journal of Medical Virology. - : Wiley. - 0146-6615 .- 1096-9071. ; 95:1 Journal article (peer-reviewed)abstract Coronavirus disease 2019 (COVID-19) is associated with autoimmune features and autoantibody production in a small subset of the population. Pre-existing neutralizing antitype I interferons (IFNs) autoantibodies are related to the severity of COVID-19. Plasma levels of IgG and IgM against 12 viral antigens and 103 self-antigens were evaluated using an antibody protein array in patients with severe/critical or mild/moderate COVID-19 disease and uninfected controls. Patients exhibited increased IgGs against Severe acute respiratory syndrome coronavirus-2 proteins compared to controls, but no difference was observed in the two patient groups. 78% autoreactive IgGs and 93% autoreactive IgMs were increased in patients versus controls. There was no difference in the plasma levels of anti-type I IFN autoantibodies or neutralizing anti-type I IFN activity of plasma samples from the two patient groups. Increased anti-type I IFN IgGs were correlated with higher lymphocyte accounts, suggesting a role of nonpathogenic autoantibodies. Notably, among the 115 antibodies tested, only plasma levels of IgGs against human coronavirus (HCOV)-229E and HCOV-NL63 spike proteins were associated with mild disease outcome. COVID-19 was associated with a bystander polyclonal autoreactive B cell activation, but none of the autoantibody levels were linked to disease severity. Long-term humoral immunity against HCOV-22E and HCOV-NL63 spike protein was associated with mild disease outcome. Understanding the mechanism of life-threatening COVID-19 is critical to reducing mortality and morbidity.
43.	Johansson, Cecilia, et al. (author) Diabetes, prediabetes, and atrial fibrillation : a population-based cohort study based on national and regional registers 2023 In: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 294:5, s. 605-615 Journal article (peer-reviewed)abstract Background: Previous studies have shown an increased risk for atrial fibrillation and atrial flutter (AF) in people with type 2 diabetes and prediabetes. It is unclear whether this increase in AF risk is independent of other risk factors for AF.Objective: To investigate the association between diabetes and different prediabetic states, as independent risk factors for the onset of AF.Methods: We performed a population-based cohort study in Northern Sweden, including data on fasting plasma glucose, oral glucose tolerance test, major cardiovascular risk factors, medical history, and lifestyle factors. Participants were divided into six groups depending on glycemic status and followed through national registers for AF diagnosis. Cox proportional hazard model was used to assess the association between glycemic status and AF, using normoglycemia as reference.Results: The cohort consisted of 88,889 participants who underwent a total of 139,661 health examinations. In the model adjusted for age and sex, there was a significant association between glycemic status and development of AF in all groups except the impaired glucose tolerance group, with the strongest association for the group with known diabetes (p-value <0.001). In a model adjusted for sex, age, systolic blood pressure, body mass index, antihypertensive drugs, cholesterol, alcohol, smoking, education level, marital status, and physical activity, there was no significant association between glycemic status and AF.Conclusions/interpretation: The association between glycemic status and AF disappears upon adjustment for potential confounders. Diabetes and prediabetes do not appear to be independent risk factors for AF.
44.	Kilbo Edlund, Karl, et al. (author) Long-term ambient air pollution and coronary atherosclerosis : results from the Swedish SCAPIS study 2024 In: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. Journal article (peer-reviewed)abstract Background and aims: Despite firm evidence for an association between long-term ambient air pollution exposure and cardiovascular morbidity and mortality, results from epidemiological studies on the association between air pollution exposure and atherosclerosis have not been consistent. We investigated associations between long-term low-level air pollution exposure and coronary atherosclerosis.Methods: We performed a cross-sectional analysis in the large Swedish CArdioPulmonary bioImaging Study (SCAPIS, n = 30 154), a random general population sample. Concentrations of total and locally emitted particulate matter <2.5 μm (PM2.5), <10 μm (PM10), and nitrogen oxides (NOx) at the residential address were modelled using high-resolution dispersion models. We estimated associations between air pollution exposures and segment involvement score (SIS), coronary artery calcification score (CACS), number of non-calcified plaques (NCP), and number of significant stenoses, using ordinal regression models extensively adjusted for potential confounders.Results: Median 10-year average PM2.5 exposure was 6.2 μg/m3 (range 3.5–13.4 μg/m3). 51 % of participants were women and 51 % were never-smokers. None of the assessed pollutants were associated with a higher SIS or CACS. Exposure to PM2.5 was associated with NCP (adjusted OR 1.34, 95 % CI 1.13, 1.58, per 2.05 μg/m3). Associations with significant stenoses were inconsistent.Conclusions: In this large, middle-aged general population sample with low exposure levels, air pollution was not associated with measures of total burden of coronary atherosclerosis. However, PM2.5 appeared to be associated with a higher prevalence of non-calcified plaques. The results suggest that increased risk of early-stage atherosclerosis or rupture, but not increased total atherosclerotic burden, may be a pathway for long-term air pollution effects on cardiovascular disease.
45.	Kilbo Edlund, Karl, et al. (author) Long-term ambient air pollution and coronary atherosclerosis: Results from the Swedish SCAPIS study. 2024 In: Atherosclerosis. - 1879-1484. Journal article (peer-reviewed)abstract Despite firm evidence for an association between long-term ambient air pollution exposure and cardiovascular morbidity and mortality, results from epidemiological studies on the association between air pollution exposure and atherosclerosis have not been consistent. We investigated associations between long-term low-level air pollution exposure and coronary atherosclerosis.We performed a cross-sectional analysis in the large Swedish CArdioPulmonary bioImaging Study (SCAPIS, n=30154), a random general population sample. Concentrations of total and locally emitted particulate matter <2.5μm (PM2.5), <10μm (PM10), and nitrogen oxides (NOx) at the residential address were modelled using high-resolution dispersion models. We estimated associations between air pollution exposures and segment involvement score (SIS), coronary artery calcification score (CACS), number of non-calcified plaques (NCP), and number of significant stenoses, using ordinal regression models extensively adjusted for potential confounders.Median 10-year average PM2.5 exposure was 6.2μg/m3 (range 3.5-13.4μg/m3). 51% of participants were women and 51% were never-smokers. None of the assessed pollutants were associated with a higher SIS or CACS. Exposure to PM2.5 was associated with NCP (adjusted OR 1.34, 95% CI 1.13, 1.58, per 2.05μg/m3). Associations with significant stenoses were inconsistent.In this large, middle-aged general population sample with low exposure levels, air pollution was not associated with measures of total burden of coronary atherosclerosis. However, PM2.5 appeared to be associated with a higher prevalence of non-calcified plaques. The results suggest that increased risk of early-stage atherosclerosis or rupture, but not increased total atherosclerotic burden, may be a pathway for long-term air pollution effects on cardiovascular disease.
46.	Kilbo Edlund, Karl, et al. (author) Long-term exposure to air pollution, coronary artery calcification, and carotid artery plaques in the population-based Swedish SCAPIS Gothenburg cohort. 2022 In: Environmental research. - : Elsevier BV. - 1096-0953 .- 0013-9351. ; 214:Pt 2 Journal article (peer-reviewed)abstract Long-term exposure to air pollution is associated with cardiovascular events. A main suggested mechanism is that air pollution accelerates the progression of atherosclerosis, yet current evidence is inconsistent regarding the association between air pollution and coronary artery and carotid artery atherosclerosis, which are well-established causes of myocardial infarction and stroke. We studied associations between low levels of long-term air pollution, coronary artery calcium (CAC) score, and the prevalence and area of carotid artery plaques, in a middle-aged population-based cohort. The Swedish CArdioPulmonary bioImage Study (SCAPIS) Gothenburg cohort was recruited during 2013-2017 and thoroughly examined for cardiovascular risk factors, including computed tomography of the heart and ultrasonography of the carotid arteries. In 5070 participants (age 50-64 years), yearly residential exposures to air pollution (PM2.5, PM10, PMcoarse, NOx, and exhaust-specific PM2.5 1990-2015) were estimated using high-resolution dispersion models. We used Poisson regression to examine associations between long-term (26 years' mean) exposure to air pollutants and CAC score, and prevalence of carotid artery plaques, adjusted for potential confounders. Among participants with carotid artery plaques, we also examined the association with plaque area using linear regression. Mean exposure to PM2.5 was low by international standards (8.5μg/m3). There were no consistent associations between long-term total PM2.5 exposure and CAC score or presence of carotid artery plaques, but an association between total PM2.5 and larger plaque area in participants with carotid plaques. Associations with traffic-related air pollutants were consistently positive for both a high CAC score and bilateral carotid artery plaques. These associations were independent of road traffic noise. We found stronger associations among men and participants with cardiovascular risk factors. The results lend some support to atherosclerosis as a main modifiable pathway between low levels of traffic-related ambient air pollution and cardiovascular disease, especially in vulnerable individuals.
47.	Leach, Susannah, 1983, et al. (author) Comparable endemic coronavirus nucleoprotein-specific antibodies in mild and severe Covid-19 patients 2021 In: Journal of Medical Virology. - : Wiley. - 0146-6615 .- 1096-9071. ; 93:9, s. 5614-5617 Journal article (peer-reviewed)abstract The severity of disease of Covid-19 is highly variable, ranging from asymptomatic to critical respiratory disease and death. Potential cross-reactive immune responses between SARS-CoV-2 and endemic coronavirus (eCoV) may hypothetically contribute to this variability. We herein studied if eCoV nucleoprotein (N)-specific antibodies in the sera of patients with mild or severe Covid-19 are associated with Covid-19 severity. There were comparable levels of eCoV N-specific antibodies early and during the first month of infection in Covid-19 patients with mild and severe symptoms, and healthy SARS-CoV-2-negative subjects. These results warrant further studies to investigate the potential role of eCoV-specific antibodies in immunity to SARS-CoV-2 infection.
48.	Li, Huiqi, et al. (author) Smoking-Induced Risk of Osteoporosis Is Partly Mediated by Cadmium From Tobacco Smoke : The MrOS Sweden Study 2020 In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 35:8, s. 1424-1429 Journal article (peer-reviewed)abstract Cigarette smoking is a risk factor for osteoporosis and bone fracture. Moreover, smoking causes exposure to cadmium, which is a known risk factor for osteoporosis. It is hypothesized that part of smoking-induced osteoporosis may be mediated via cadmium from tobacco smoke. We investigated this hypothesis using mediation analysis in a Swedish cohort of elderly men. This study was performed in 886 elderly men from the Swedish cohort of the Osteoporotic Fractures in Men (MrOS) study. Urinary samples, bone mineral density (BMD), smoking data, and other background information were obtained at baseline in 2002–2004. Urinary cadmium was analyzed in baseline samples and adjusted for creatinine. The cohort was followed until August 2018 for fracture incidence, based on the X-ray register. Mediation analysis was conducted to evaluate the indirect effect (via cadmium) of smoking on both BMD and fractures. Time to first fracture was analyzed using the accelerated failure time (AFT) model and Aalen's additive hazard model. The mean level of urinary cadmium was 0.25 μg/g creatinine. There were significant inverse associations between smoking and total body, total hip, and trochanter BMD. The indirect effects via cadmium were estimated to be 43% of the total effects of smoking for whole-body BMD, and even more for total hip and trochanter BMD. Smoking was also associated with higher risk of all fractures and major osteoporosis fractures. The indirect effects via cadmium were largest in nonvertebral osteoporosis fractures and hip fractures, constituting at least one-half of the total effects, in both the AFT and Aalen's model. The findings in this study provide evidence that cadmium exposure from tobacco smoke plays an important role in smoking-induced osteoporosis
49.	Li, Lin, 1989-, et al. (author) Association Between Pharmacological Treatment of Attention-Deficit/Hyperactivity Disorder and Long-term Unemployment Among Working-Age Individuals in Sweden 2022 In: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 5:4 Journal article (peer-reviewed)abstract Importance: Adults with attention-deficit/hyperactivity disorder (ADHD) are at greater risk for unemployment. Pharmacological treatment is effective in reducing the core symptoms of ADHD, but whether it helps to reduce the unemployment rate among adult patients remains unclear.Objective: To investigate the association between use of ADHD medication and long-term unemployment in working-age adults with ADHD.Design, Setting, and Participants: Data for this population-based cohort study were extracted from Swedish national registers. Among 25 358 individuals with ADHD born from 1958 to 1978, 12 875 middle-aged adults among the workforce were included. The longitudinal cohort was followed up from January 1, 2008, to December 31, 2013. Data were analyzed from March 1, 2020, through May 31, 2021.Exposures: Use of medication for ADHD during the previous 2 years was the main exposure, as both categorical and continuous variables.Main Outcomes and Measures: Yearly accumulated unemployed days were derived from the Public Employment Service, and long-term unemployment was defined as 90 or more days of unemployment per year. Overall and sex-specific relative risks (RRs) with 95% CIs were estimated using generalized estimating equations.Results: Among 12 875 individuals with ADHD (5343 women [41.50%] and 7532 men [58.50%]; mean [SD] age, 37.9 [5.6] years), the use of ADHD medications during the previous 2 years was associated with a 10% lower risk of long-term unemployment in the following year (adjusted RR, 0.90 [95% CI, 0.87-0.95]). An association between use of ADHD medications and long-term unemployment was found among women (RR, 0.82 [95% CI, 0.76-0.89]) but not men (RR, 0.96 [95% CI, 0.91-1.01]). Longer treatment duration was associated with a lower risk of subsequent long-term unemployment among women (RR for use of 1-6 months, 0.86 [95% CI, 0.78-0.95]; RR for use of 18-24 months, 0.72 [95% CI, 0.58-0.90]; P < .001 for trend). Within-individual comparisons showed that the long-term unemployment rate was lower during periods of ADHD medication treatment compared with nontreatment periods (RR, 0.89; 95% CI, 0.85-0.94).Conclusions and Relevance: The findings of this cohort study suggest that the use of ADHD medication is associated with a lower risk of subsequent long-term unemployment for middle-aged women. These findings should be considered together with the existing knowledge of risks and benefits of ADHD medication when developing treatment plans for working-age adults.
50.	Lund, Lars H., et al. (author) Acyl ghrelin improves cardiac function in heart failure and increases fractional shortening in cardiomyocytes without calcium mobilization 2023 In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. Journal article (peer-reviewed)abstract Background and AimsGhrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes.Methods and resultsIn a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3.ConclusionIn patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials.

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