| 1. |
- Kanai, M, et al.
(författare)
-
- 2023
-
swepub:Mat__t
|
|
| 2. |
- Niemi, MEK, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Bar, N., et al.
(författare)
-
A reference map of potential determinants for the human serum metabolome
- 2020
-
Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
-
Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
|
|
| 8. |
- Chen, Zhishan, et al.
(författare)
-
Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
|
|
| 9. |
- Slieker, Roderick C, et al.
(författare)
-
Identification of biomarkers for glycaemic deterioration in type 2 diabetes
- 2023
-
Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-18
-
Tidskriftsartikel (refereegranskat)abstract
- We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
|
|
| 10. |
- Thompson, Robin N., et al.
(författare)
-
Key questions for modelling COVID-19 exit strategies
- 2020
-
Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 287:1932
-
Tidskriftsartikel (refereegranskat)abstract
- Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.
|
|
| 11. |
- Dixon, P. H., et al.
(författare)
-
GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
- 2022
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility. Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.
|
|
| 12. |
- Slieker, Roderick C, et al.
(författare)
-
Replication and cross-validation of type 2 diabetes subtypes based on clinical variables : an IMI-RHAPSODY study
- 2021
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 64:9, s. 1982-1989
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic. Methods: In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide, and HDL-cholesterol. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort’s cluster centres. Finally, we compared the time to insulin requirement for each cluster. Results: Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6–90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression. Conclusions/interpretation: Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL-cholesterol, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts. Adding HDL-cholesterol to the clustering resulted in the identification of a cluster with very slow glycaemic deterioration. Graphical abstract: [Figure not available: see fulltext.]
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
- Hawthorne, Ian J., et al.
(författare)
-
Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma
- 2023
-
Ingår i: Molecular Therapy. - 1525-0016. ; 31:11, s. 3243-3258
-
Tidskriftsartikel (refereegranskat)abstract
- Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT7 mice but not in CATT5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).
|
|
| 16. |
|
|
| 17. |
- Slieker, Roderick C, et al.
(författare)
-
Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes : an IMIRHAPSODY Study
- 2021
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:11, s. 2683-2693
-
Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
- Craig, Wendy, et al.
(författare)
-
Social Media Use and Cyber-Bullying: A Cross-National Analysis of Young People in 42 Countries
- 2020
-
Ingår i: Journal of Adolescent Health. - : ELSEVIER SCIENCE INC. - 1054-139X .- 1879-1972. ; 66:6, s. S100-S108
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Social media use (SMU) has become an intrinsic part of adolescent life. Negative consequences of SMU for adolescent health could include exposures to online forms of aggression. We explored age, gender, and cross-national differences in adolescents engagement in SMU, then relationships between SMU and victimization and the perpetration of cyber-bullying. Methods: We used data on young people aged 11-15 years (weighted n = 180,919 in 42 countries) who participated in the 2017-2018 Health Behaviour in School-aged Children study to describe engagement in the three types of SMU (intense, problematic, and talking with strangers online) by age and gender and then in the perpetration and victimization of cyber-bullying. Relationships between SMU and cyber-bullying outcomes were estimated using Poisson regression (weighted n = 166,647 from 42 countries). Results: Variations in SMU and cyber-bullying follow developmental and gender-based patterns across countries. In pooled analyses, engagement in SMU related to cyber-bullying victimization (adjusted relative risks = 1.14 [95% confidence interval (CI): 1.10-1.19] to 1.48 [95% CI: 1.42-1.55]) and perpetration (adjusted relative risk = 1.31 [95% CI: 1.26-1.36] to 1.84 [95% CI: 1.74-1.95]). These associations were stronger for cyber-perpetration versus cyber-victimization and for girls versus boys. Problematic SMU was most strongly and consistently associated with cyber-bullying, both for victimization and perpetration. Stratified analyses showed that SMU related to cyber-victimization in 19%-45% of countries and to cyber-perpetration in 38%-86% of countries. Conclusions: Accessibility to social media and its pervasive use has led to new opportunities for online aggression. The time adolescents spend on social media, engage in problematic use, and talk to strangers online each relate to cyber-bullying and merit public health intervention. Problematic use of social media poses the strongest and most consistent risk. (C) 2020 Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine.
|
|
| 22. |
- Craig, Wendy, et al.
(författare)
-
Social Media Use and Cyber-Bullying: A Cross-National Analysis of Young People in 42 Countries
- 2020
-
Ingår i: Journal of Adolescent Health. - : Elsevier BV. - 1054-139X .- 1879-1972. ; 66:6
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Social media use (SMU) has become an intrinsic part of adolescent life. Negative consequences of SMU for adolescent health could include exposures to online forms of aggression. We explored age, gender, and cross-national differences in adolescents' engagement in SMU, then relationships between SMU and victimization and the perpetration of cyber-bullying. Methods: We used data on young people aged 11–15 years (weighted n = 180,919 in 42 countries) who participated in the 2017–2018 Health Behaviour in School-aged Children study to describe engagement in the three types of SMU (intense, problematic, and talking with strangers online) by age and gender and then in the perpetration and victimization of cyber-bullying. Relationships between SMU and cyber-bullying outcomes were estimated using Poisson regression (weighted n = 166,647 from 42 countries). Results: Variations in SMU and cyber-bullying follow developmental and gender-based patterns across countries. In pooled analyses, engagement in SMU related to cyber-bullying victimization (adjusted relative risks = 1.14 [95% confidence interval (CI): 1.10–1.19] to 1.48 [95% CI: 1.42–1.55]) and perpetration (adjusted relative risk = 1.31 [95% CI: 1.26–1.36] to 1.84 [95% CI: 1.74–1.95]). These associations were stronger for cyber-perpetration versus cyber-victimization and for girls versus boys. Problematic SMU was most strongly and consistently associated with cyber-bullying, both for victimization and perpetration. Stratified analyses showed that SMU related to cyber-victimization in 19%–45% of countries and to cyber-perpetration in 38%–86% of countries. Conclusions: Accessibility to social media and its pervasive use has led to new opportunities for online aggression. The time adolescents spend on social media, engage in problematic use, and talk to strangers online each relate to cyber-bullying and merit public health intervention. Problematic use of social media poses the strongest and most consistent risk.
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
- Forchini, Giovanni, et al.
(författare)
-
Report 28 : Excess non-COVID-19 deaths in England and Wales between 29th February and 5th June 2020
- 2020
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- There were 189,403 deaths from any cause reported in England from 29th February to 5th June 2020 inclusive, and 11,278 all-cause deaths in Wales over the same period. Of those deaths, 44,736 (23.6%) registered COVID-19 on the death certificate in England, and 2,294 (20.3%) in Wales, while 144,667 (76.4%) were not recorded as having been due to COVID-19 in England, and 8,984 (79.7%) in Wales. However, it could be that some of the ‘non-COVID-19’ deaths have in fact also been caused by COVID-19, either as the direct cause of death, or indirectly through provisions for the pandemic impeding access to care for other conditions. There is uncertainty in how many of the non-COVID-19 deaths were directly or indirectly caused by the pandemic. We estimated the excess deaths that were not recorded as associated with COVID-19 in the death certificate (excess non-COVID-19 deaths) as the deaths for which COVID-19 was not reported as the cause, compared to those we would have expected to occur had the pandemic not happened. Expected deaths were forecast with an analysis of historic trends in deaths between 2010 and April 2020 using data by the Office of National Statistics and a statistical time series model.According to the model, we expected 136,294 (95% CI 133,882 - 138,696) deaths in England, and 8,983 (CI 8,051 - 9,904) in Wales over this period, significantly fewer than the number of deaths reported. This means that there were 8,983 (95% CI 5,971 - 10,785) total excess non-COVID-19 deaths in England. For every 100 COVID-19 deaths during the period from 29th February to 5th June 2020 there were 19 (95% CI 13 – 24) cumulative excess non-COVID-19 deaths. The proportion of cumulative excess non-COVID-19 deaths of all reported deaths during this period was 4.4% (95% CI 3.2% - 5.7%) in England, with small regional variations. Excess deaths were highest in the South East at 2,213 (95% CI 327 - 4,047) and in London at 1,937 (95% CI 896 - 3,010), respectively. There is no evidence of non-COVID-19 excess deaths in Wales. Excess non-COVID-19 deaths are occurring in individuals aged 85+ and 75-84, and those aged 45-64. For those aged 85+, excess non-COVID-19 deaths are driven by females, with 6,115 (95% CI 206 – 11,795) deaths in total but no significant findings for males of those ages. For ages 75-84, excess non-COVID-19 deaths are nearly double for females at 2,070 (95% CI 393 – 3,887) than for males at 1,336 (95% CI 938 – 1,710), while for ages 45-64, excess non-COVID-19 deaths for females are at 347 (95% CI 90 – 603), almost half those of males at 681 (95% CI 282 – 1,091). There is no evidence of excess non-COVID-19 deaths for ages 65-74, and those below 45.Excess non-COVID-19 deaths could be due to non-reporting of COVID-19 on the death certificate or an increase in mortality for non-COVID-19 conditions. Severely ill patients may have been unable to access life-saving emergency treatment because of constraints in healthcare provision, or because they avoided seeking care due to concern over hospital-acquired infection, or to avoid burdening healthcare providers. Further research into reasons for excess non-COVID-19 deaths is warranted.This report accompanies the weekly update of excess death estimates on the Github website of the Abdul Latif Jameel Institute of Disease and Emergency Analytics (J-IDEA) (https://j-idea.github.io/ONSdeaths/) which has been set up to be regularly updated until June 2022.
|
|
| 29. |
|
|
| 30. |
- Stamatakis, Emmanuel, et al.
(författare)
-
A Physical Behaviour Partnership From Heaven : The Prospective Physical Activity, Sitting, and Sleep Consortium and the International Society for the Measurement of Physical Behaviour
- 2022
-
Ingår i: Journal for the Measurement of Physical Behaviour. - : Human Kinetics. - 2575-6605 .- 2575-6613. ; , s. 1-3
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The advancement of science demands people and organizations work together toward worthy goals, a need that is especially pronounced in nascent fields like physical behavior. Partnerships offer an ideal vehicle for long-term collaboration to build research capacity, develop new scientific endeavors, and nurture talent. In this commentary, we discuss the newly formed partnership between two key players of the field of physical behavior, the Prospective Physical Activity, Sitting, and Sleep consortium (ProPASS) and the International Society for the Measurement of Physical Behaviour (ISMPB).
|
|
