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- Forslund, Sofia K., et al.
(author)
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Combinatorial, additive and dose-dependent drug–microbiome associations
- 2021
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505
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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.
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| 2. |
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| 3. |
- Margaryan, Ashot, et al.
(author)
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Population genomics of the Viking world
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 585:7825, s. 390-396
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Journal article (peer-reviewed)abstract
- The maritime expansion of Scandinavian populations during the Viking Age (about ad750–1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
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| 4. |
- Molinaro, Antonio, et al.
(author)
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Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.
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| 5. |
- Glerup, Mia, et al.
(author)
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Long-term Outcomes of Temporomandibular Joints in Juvenile Idiopathic Arthritis.
- 2020
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In: The Journal of rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 47:4
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Journal article (peer-reviewed)abstract
- To determine the prevalence of orofacial symptoms, dysfunctions, and deformities of the temporomandibular joint (TMJ) in juvenile idiopathic arthritis (JIA) 17 years after disease onset.Drawn from a prospective, population-based Nordic JIA cohort with disease onset from 1997-2000, 420 consecutive cases were eligible for orofacial evaluation of TMJ involvement. The follow-up visit included demographic data, a standardized clinical orofacial examination, and fullface cone-beam computed tomography (CBCT). For comparison, 200 age-matched healthy controls were used.Of 420 eligible participants with JIA, 265 (63%) were included (mean age 23.5 ± 4.2 years) and completed a standardized clinical orofacial examination. Of these, 245 had a full-face CBCT performed. At least one orofacial symptom was reported by 33%. Compared to controls, the JIA group significantly more often reported TMJ pain, TMJ morning stiffness, and limitation on chewing. Furthermore, among participants reporting complaints, the number of symptoms was also higher in the JIA. The mean maximal incisal opening was lower in the JIA group (p<0.001), and TMJ pain on palpation was more frequent. Condylar deformities and/or erosions were observed in 61% as assessed by CBCT, showing bilateral changes in about 70%. Risk factors of condylar deformities were orofacial dysfunction or biologic treatment; enthesitis-related arthritis was protective.This first study on long-term consequences of TMJ involvement in a population-based JIA cohort reports persistence of comprehensive symptoms, dysfunctions, and damage of the TMJ into adulthood. We suggest interdisciplinary follow-up of JIA patients also in adulthood.
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| 6. |
- Munkvold, Bodil Karoline Ravn, et al.
(author)
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Variations in the management of diffuse low-grade gliomas : A Scandinavian multicenter study
- 2021
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In: Neuro-Oncology Practice. - : Oxford University Press. - 2054-2577 .- 2054-2585. ; 8:6, s. 706-717
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Journal article (peer-reviewed)abstract
- Background. Early extensive surgery is a cornerstone in treatment of diffuse low-grade gliomas (DLGGs), and an additional survival benefit has been demonstrated from early radiochemotherapy in selected "high-risk" patients. Still, there are a number of controversies related to DLGG management. The objective of this multicenter population-based cohort study was to explore potential variations in diagnostic work-up and treatment between treating centers in 2 Scandinavian countries with similar public health care systems.Methods. Patients screened for inclusion underwent primary surgery of a histopathologically verified diffuse WHO grade II glioma in the time period 2012 through 2017. Clinical and radiological data were collected from medical records and locally conducted research projects, whereupon differences between countries and inter-hospital variations were explored.Results. A total of 642 patients were included (male:female ratio 1:4), and annual age-standardized incidence rates were 0.9 and 0.8 per 100 000 in Norway and Sweden, respectively. Considerable inter-hospital variations were observed in preoperative work-up, tumor diagnostics, surgical strategies, techniques for intraoperative guidance, as well as choice and timing of adjuvant therapy.Conclusions. Despite geographical population-based case selection, similar health care organizations, and existing guidelines, there were considerable variations in DLGG management. While some can be attributed to differences in clinical implementation of current scientific knowledge, some of the observed inter-hospital variations reflect controversies related to diagnostics and treatment. Quantification of these disparities renders possible identification of treatment patterns associated with better or worse outcomes and may thus represent a step toward more uniform evidence-based care.
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| 7. |
- Nilsson, Maria, et al.
(author)
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Self-Disorders in Asperger Syndrome Compared to Schizotypal Disorder : A Clinical Study
- 2020
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In: Schizophrenia Bulletin. - : Oxford University Press (OUP). - 1745-1701 .- 0586-7614. ; 46:1, s. 121-129
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Journal article (peer-reviewed)abstract
- OBJECTIVE: There are historical and theoretical indications of a difference in subjective experience between autism spectrum disorder (ASD) and the schizophrenia spectrum. However, this difference has not been empirically explored. Therefore, to explore potential differences in subjective experience between the 2 spectra, we examined the presence/absence of self-disorders in Asperger syndrome/autism spectrum disorder (As/ASD) compared to schizotypal disorder (Sd). Self-disorders represent changes in basic self-awareness which have been found to accumulate within the schizophrenia spectrum. METHODS: All participants were recruited from clinical units and interviewed with a focus on the exploration of presence/absence of self-disorders, with the Examination of Anomalous Self-Experience (EASE) scale, and a general assessment of present psychopathology, with Schedules for Clinical Assessment in Neuropsychiatry (SCAN). RESULTS: A total of 51 participants (As/ASD, n = 22; Sd, n = 29) were included in the statistical analyses. When controlling for age, gender, years of education, mental problems before the age of 16, and special needs school attendance, there was a clear difference in presence/absence of self-disorders between the 2 groups, with significantly higher levels in the Sd group. Further, there was an overlap in SCAN-rated symptoms between the 2 groups. CONCLUSION: Our results indicate a significant difference between As/ASD and Sd at the level of the basic self, which, in turn, indicates that an exploration of anomalous self-experience is a valuable supplement in the clinical differentiation between As/ASD and Sd.
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| 8. |
- Vogelezang, Suzanne, et al.
(author)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Journal article (peer-reviewed)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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