| 1. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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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.
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| 2. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 3. |
- Balercia, G., et al.
(författare)
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Thyroid function in Klinefelter syndrome: a multicentre study from KING group
- 2019
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Ingår i: Journal of Endocrinological Investigation. - : Springer Science and Business Media LLC. - 0391-4097 .- 1720-8386. ; 42:10, s. 1199-1204
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Tidskriftsartikel (refereegranskat)abstract
- - Purpose: The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. Methods: This is a case–control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student’s t test. Mann–Whitney test and Chi-square test. Results: FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto’s thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. Conclusions: We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype. © 2019, Italian Society of Endocrinology (SIE).
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| 4. |
- Schnell, O, et al.
(författare)
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CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes
- 2023
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Ingår i: Cardiovascular diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 22:1, s. 59-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10–12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year’s focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23–24, 2023 (http://www.cvot.org).
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| 5. |
- Swat, M. J., et al.
(författare)
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Pharmacometrics Markup Language (PharmML) : Opening New Perspectives for Model Exchange in Drug Development
- 2015
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Ingår i: CPT. - : American Society for Clinical Pharmacology & Therapeutics. - 2163-8306. ; 4:6, s. 316-319
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Tidskriftsartikel (refereegranskat)abstract
- The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.
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| 6. |
- D'Ambrosi, R., et al.
(författare)
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Good results after treatment of RAMP lesions in association with ACL reconstruction: a systematic review
- 2023
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Ingår i: Knee Surgery Sports Traumatology Arthroscopy. - : Springer Science and Business Media LLC. - 0942-2056 .- 1433-7347. ; 31:1, s. 358-371
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Forskningsöversikt (refereegranskat)abstract
- Purpose This study aimed to systematically evaluate the clinical, functional, and radiological outcomes, complications, and rate of return to sports among patients with RAMP lesion of the medial meniscus encountered during anterior cruciate ligament (ACL) reconstruction. Methods A systematic review was conducted based on the PRISMA guidelines. Two independent reviewers searched the PubMed, Scopus, Embase, and Cochrane Library databases using the terms "ACL" or "anterior cruciate ligament," and "RAMP lesion." The outcome measures extracted from the studies were the Short Form-12 (SF-12) in its mental and physical component (MCS and PCS), Lysholm score, Subjective IKDC, Marx Score, WOMAC Score, Tegner, Radiological changes, complications, failures and/or revision surgery, and rate of return to sports. Results The cohort of patients consisted of 1,243 participants with a mean age of 28.6 +/- 2.6. The mean postoperative follow-up was 40.9 +/- 6.3 months. A total of 1145 (92.1%) RAMP lesions were repaired with concomitant ACL reconstruction, while only 98 (7.9%) lesions were left untreated (or treated with abrasion only). The Lysholm score was used in 6 studies (in one only at final follow-up), with a significant improvement in all the studies (Lysholm(pre) 60.03 +/- 6.12; Lysholm(post) 89.9 +/- 5.0). Eight studies out of nine reported Subjective IKDC score, and a significant improvement was noted in all cases (IKDCpre 56.2 +/- 5.8. IKDCpost 84.9 +/- 3.7). Of 18 (1.4%) complications reported, 15 (1.2%) were related to RAMP/ACL surgery, and of the remaining three (0.2%) two (0.2%) were hematomas and one (0.1%) a contralateral ACL lesion. Of the 106 (8.5%) revision surgeries required, 5 (0.4%) were in non-treated lesions [two (0.2%) ACL re-ruptures and three (0.2%) medial meniscus re-injury]. In treated patients, the revision occurred for the following reasons: 75 (6.0%) meniscectomy, 14 (1.1%) meniscal suture revisions, 11 (0.9%) ACL failures and one (0.1%) arthrolysis. Conclusions It is not yet clear if, in all cases of ACL reconstruction in which a medial meniscal RAMP lesion is encountered, the lesion needs to undergo surgical repair. Accordingly, it is recommended that in the repair of all unstable medial meniscal RAMP lesions during an ACL reconstruction in cases associated with a stable RAMP lesion, the surgeon may decide on repair based on the patient profile.
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| 7. |
- De Pergola, G, et al.
(författare)
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Amount of G-protein alpha-subunit in rat white adipocytes: lack of difference between subcutaneous and visceral fat.
- 1993
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Ingår i: Acta endocrinologica. - 0001-5598. ; 129:4, s. 366-70
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Tidskriftsartikel (refereegranskat)abstract
- It has been the purpose of this study to examine possible differences in the amount of stimulatory (Gs) and inhibitory (Gi) G-protein alpha-subunits (measured with a quantitative enzyme-linked immunosorbent assay in fat cell membrane preparation) between subcutaneous and intra-abdominal regions in rats. The lipolytic response to isoproterenol and the number of beta-adrenergic binding sites were also examined. These parameters were all evaluated simultaneously in subcutaneous (inguinal), epididymal and perirenal fat samples collected from six male Sprague-Dawley rats. The membrane contents of the Gs and Gi alpha-subunits were similar in the three depots. Moreover, no difference was found among the different regions with regard to isoproterenol-stimulated glycerol release and beta-adrenoceptor number, expressed per cell number. In conclusion, the present study shows for the first time in rats that the abundance of inhibitory and stimulatory G-protein alpha-subunits is similar in subcutaneous and in visceral adipocytes. Moreover, the number of beta-adrenoceptors and the lipolytic response to isoproterenol do not show significant variations with the anatomical site. As the present results are apparently in contrast with those obtained previously in human adipocytes, there is a possibility that the different results observed in rat and in human fat cells could be explained by species differences.
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| 8. |
- Rodriguez-Espigares, Ismael, et al.
(författare)
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GPCRmd uncovers the dynamics of the 3D-GPCRome
- 2020
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Ingår i: Nature Methods. - : Springer Nature. - 1548-7091 .- 1548-7105. ; 17:8, s. 777-787
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Tidskriftsartikel (refereegranskat)abstract
- G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. Molecular dynamics (MD) simulations have become a widely established technique for exploring the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations require efficient storage resources and specialized software. Here we present GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyze and share GPCR MD data. GPCRmd originates from a community-driven effort to create an open, interactive and standardized database of GPCR MD simulations.
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| 9. |
- Schnell, Oliver, et al.
(författare)
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CVOT Summit Report 2023 : new cardiovascular, kidney, and metabolic outcomes
- 2024
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Ingår i: Cardiovascular Diabetology. - 1475-2840. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5–6, 2024 (http://www.cvot.org).
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| 10. |
- Schnell, O, et al.
(författare)
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Report from the CVOT Summit 2021: new cardiovascular, renal, and glycemic outcomes
- 2022
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Ingår i: Cardiovascular diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 21:1, s. 50-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18–19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year’s focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1–5, and STEP 1–5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed.Trial registrationThe 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10–11, 2022 (http://www.cvot.org)
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