| 1. |
- Edin, Carl, et al.
(author)
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Ectopic fat is associated with cardiac remodeling - A comprehensive assessment of regional fat depots in type 2 diabetes using multi-parametric MRI.
- 2022
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In: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 9
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Journal article (peer-reviewed)abstract
- Background: Different regional depots of fat have distinct metabolic properties and may relate differently to adverse cardiac remodeling. We sought to quantify regional depots of body fat and to investigate their relationship to cardiac structure and function in Type 2 Diabetes (T2D) and controls.Methods: From the SCAPIS cohort in Linköping, Sweden, we recruited 92 subjects (35% female, mean age 59.5 ± 4.6 years): 46 with T2D and 46 matched controls. In addition to the core SCAPIS data collection, participants underwent a comprehensive magnetic resonance imaging examination at 1.5 T for assessment of left ventricular (LV) structure and function (end-diastolic volume, mass, concentricity, ejection fraction), as well as regional body composition (liver proton density fat fraction, visceral adipose tissue, abdominal subcutaneous adipose tissue, thigh muscle fat infiltration, fat tissue-free thigh muscle volume and epicardial adipose tissue).Results: Compared to the control group, the T2D group had increased: visceral adipose tissue volume index (P < 0.001), liver fat percentage (P < 0.001), thigh muscle fat infiltration percentage (P = 0.02), LV concentricity (P < 0.001) and LV E/e'-ratio (P < 0.001). In a multiple linear regression analysis, a negative association between liver fat percentage and LV mass (St Beta -0.23, P < 0.05) as well as LV end-diastolic volume (St Beta -0.27, P < 0.05) was found. Epicardial adipose tissue volume and abdominal subcutaneous adipose tissue volume index were the only parameters of fat associated with LV diastolic dysfunction (E/e'-ratio) (St Beta 0.24, P < 0.05; St Beta 0.34, P < 0.01, respectively). In a multivariate logistic regression analysis, only visceral adipose tissue volume index was significantly associated with T2D, with an odds ratio for T2D of 3.01 (95% CI 1.28-7.05, P < 0.05) per L/m2 increase in visceral adipose tissue volume.Conclusions: Ectopic fat is predominantly associated with cardiac remodeling, independently of type 2 diabetes. Intriguingly, liver fat appears to be related to LV structure independently of VAT, while epicardial fat is linked to impaired LV diastolic function. Visceral fat is associated with T2D independently of liver fat and abdominal subcutaneous adipose tissue.
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| 2. |
- Edin, Carl, et al.
(author)
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Liver fibrosis is associated with left ventricular remodeling : insight into the liver-heart axis
- 2024
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In: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084.
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Journal article (peer-reviewed)abstract
- Objective: In non-alcoholic fatty liver disease (NAFLD), liver fibrosis is the strongest predictor of adverse outcomes. We sought to investigate the relationship between liver fibrosis and cardiac remodeling in participants from the general population using magnetic resonance imaging (MRI), as well as explore potential mechanistic pathways by analyzing circulating cardiovascular biomarkers.Methods: In this cross-sectional study, we prospectively included participants with type 2 diabetes and individually matched controls from the SCAPIS (Swedish CArdioPulmonary bioImage Study) cohort in Linköping, Sweden. Between November 2017 and July 2018, participants underwent MRI at 1.5 Tesla for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography), left ventricular (LV) structure and function, as well as myocardial native T1 mapping. We analyzed 278 circulating cardiovascular biomarkers using a Bayesian statistica lapproach.Results: In total, 92 participants were enrolled (mean age 59.5 ± 4.6 years, 32 women). The mean liver stiffness was 2.1 ± 0.4 kPa. 53 participants displayed hepatic steatosis. LV concentricity increased across quartiles of liver stiffness. Neither liver fat nor liver stiffness displayed any relationships to myocardial tissue characteristics (native T1). In a regression analysis, liver stiffness was related to increased LV concentricity. This association was independent of diabetes and liver fat (Beta = 0.26, p = 0.0053), but was attenuated (Beta = 0.17, p = 0.077) when also adjusting for circulating levels of interleukin-1 receptor type 2.Conclusion: MRI reveals that liver fibrosis is associated to structural LV remodeling, in terms of increased concentricity, in participants from the general population. This relationship could involve the interleukin-1 signaling.
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| 3. |
- Welen, Karin, et al.
(author)
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COVIDENZA - A prospective, multicenter, randomized PHASE II clinical trial of enzalutamide treatment to decrease the morbidity in patients with Corona virus disease 2019 (COVID-19): a structured summary of a study protocol for a randomised controlled trial.
- 2021
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In: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 22:1
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Journal article (peer-reviewed)abstract
- The main goal of the COVIDENZA trial is to evaluate if inhibition of testosterone signalling by enzalutamide can improve the outcome of patients hospitalised for COVID-19. The hypothesis is based on the observation that the majority of patients in need of intensive care are male, and the connection between androgen receptor signalling and expression of TMPRSS2, an enzyme important for SARS-CoV-2 host cell internalization.Hospitalised COVID-19 patients will be randomised (2:1) to enzalutamide plus standard of care vs. standard of care designed to identify superiority.Included participants, men or women above 50 years of age, must be hospitalised for PCR confirmed COVID-19 symptoms and not in need of immediate mechanical ventilation. Major exclusion criteria are breast-feeding or pregnant women, hormonal treatment for prostate or breast cancer, treatment with immunosuppressive drugs, current symptomatic unstable cardiovascular disease (see Additional file 1 for further details). The trial is registered at Umeå University Hospital, Region Västerbotten, Sweden and 8 hospitals are approved for inclusion in Sweden.Patients randomised to the treatment arm will be treated orally with 160 mg (4x40 mg) enzalutamide (Xtandi®) daily, for five consecutive days. The study is not placebo controlled. The comparator is standard of care treatment for patients hospitalised with COVID-19.The primary endpoints of the study are (time to) need of mechanical ventilation or discharge from hospital as assessed by a clinical 7-point ordinal scale (up to 30 days after inclusion).Randomisation was stratified by center and sex. Each strata was randomized separately with block size six with a 2:1 allocation ratio (enzalutamide + "standard of care": "standard of care"). The randomisation list, with consecutive subject numbers, was generated by an independent statistician using the PROC PLAN procedure of SAS version 9.4 software (SAS Institute, Inc, Cary, North Carolina) BLINDING (MASKING): This is an open-label trial.The trial is designed to have three phases. The first, an exploration phase of 45 participants (30 treatment and 15 control) will focus on safety and includes a more extensive laboratory assessment as well as more frequent safety evaluation. The second prolongation phase, includes the first 100 participants followed by an interim analysis to define the power of the study. The third phase is the continuation of the study up to maximum 600 participants included in total.The current protocol version is COVIDENZA v2.0 as of September 10, 2020. Recruitment started July 29, 2020 and is presently in safety pause after the first exploration phase. Recruitment is anticipated to be complete by 31 December 2021.Eudract number 2020-002027-10 ClinicalTrials.gov Identifier: NCT04475601 , registered June 8, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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| 4. |
- Bratt, Ola, 1963, et al.
(author)
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The Swedish national guidelines on prostate cancer, part 1: early detection, diagnostics, staging, patient support and primary management of non-metastatic disease
- 2022
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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:4, s. 265-273
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Journal article (peer-reviewed)abstract
- Objective There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. Methods This is part 1 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. It covers the early detection, diagnostics, staging, patient support and management of the non-metastatic disease. Part 2 covers recurrence after local treatment and management of the metastatic disease. Results The 2022 Swedish guidelines include several new recommendations: rectal iodine-povidone to reduce post-biopsy infections, external beam radiation with focal boost to the tumour, use of a pre-rectal spacer to reduce rectal side effects after external beam radiotherapy in some expert centres, 6 months' concomitant and adjuvant rather than neoadjuvant and concomitant hormonal treatment together with radiotherapy for unfavourable intermediate and high-risk disease, and adjuvant abiraterone plus prednisolone together with a GnRH agonist for a subgroup of men with very high-risk disease. The Swedish guidelines differ from the European by having more restrictive recommendations regarding genetic testing and pelvic lymph node dissection, the risk group classification, recommending ultra-hypofractionated (7 fractions) external radiotherapy for intermediate and selected high-risk cancers, by not recommending any hormonal treatment together with radiotherapy for favourable intermediate-risk disease, and by recommending bicalutamide monotherapy instead of a GnRH agonist for some patient groups. Conclusions The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.
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| 5. |
- Bratt, Ola, 1963, et al.
(author)
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The Swedish national guidelines on prostate cancer, part 2: recurrent, metastatic and castration resistant disease
- 2022
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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:4, s. 278-284
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Journal article (peer-reviewed)abstract
- Objective There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. Methods This is part 2 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. This part covers recurrence after local treatment and management of metastatic and castration resistant disease. Part 1 covers early detection, diagnostics, staging, patient support and management of non-metastatic disease. Results The 2022 Swedish guidelines include several new recommendations. Among these is a recommendation of a period of observation with repeated PSA tests for patients with approximately 10 years' life expectancy who experience a BCR more than 2-5 years after radical prostatectomy, to allow for estimating the PSA doubling time before deciding whether to give salvage radiotherapy or not. Recent results from the PEACE-1 trial led to the recommendation of triple-treatment with a GnRH agonist, abiraterone plus prednisolone and 6 cycles of docetaxel for patients with high-volume metastatic disease who are fit for chemotherapy. The Swedish guidelines differ from the European ones by having more restrictive recommendations about genetic testing of and high-dose zoledronic acid or denosumab treatment for men with metastatic prostate cancer, and by recommending considering bicalutamide monotherapy for selected patients with low-volume metastatic disease. Conclusions The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.
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| 6. |
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| 7. |
- Crippa, Alessio, et al.
(author)
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The ProBio trial : molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer
- 2020
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In: Trials. - : BioMed Central. - 1745-6215. ; 21:1
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Journal article (peer-reviewed)abstract
- Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis.Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.
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| 8. |
- El-Saadi, Walid, 1984-, et al.
(author)
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A head-to-head comparison of myocardial strain by fast-strain encoding and feature tracking imaging in acute myocardial infarction
- 2022
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In: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 9
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Journal article (peer-reviewed)abstract
- BackgroundMyocardial infarction (MI) is a major cause of heart failure. Left ventricular adverse remodeling is common post-MI. Several studies have demonstrated a correlation between reduced myocardial strain and the development of adverse remodeling. Cardiac magnetic resonance (CMR) with fast-strain encoding (fast-SENC) or feature tracking (FT) enables rapid assessment of myocardial deformation. The aim of this study was to establish a head-to-head comparison of fast-SENC and FT in post-ST-elevated myocardial infarction (STEMI) patients, with clinical 2D speckle tracking echocardiography (2DEcho) as a reference. MethodsThirty patients treated with primary percutaneous coronary intervention for STEMI were investigated. All participants underwent CMR examination with late gadolinium enhancement, cine-loop steady-state free precession, and fast-SENC imaging using a 1.5T scanner as well as a 2DEcho. Global longitudinal strain (GLS), segmental longitudinal strain (SLS), global circumferential strain (GCS), and segmental circumferential strain (SCS) were assessed along with the MI scar extent. ResultsThe GCS measurements from fast-SENC and FT were nearly identical: the mean difference was 0.01 (2.5)% (95% CI - 0.92 to 0.95). For GLS, fast-SENC values were higher than FT, with a mean difference of 1.8 (1.4)% (95% CI 1.31-2.35). Tests of significance for GLS did not show any differences between the MR methods and 2DEcho. Average strain in the infarct-related artery (IRA) segments compared to the remote myocardium was significantly lower for the left anterior descending artery and right coronary artery culprits but not for the left circumflex artery culprits. Fast-SENC displayed a higher area under the curve for detecting infarcted segments than FT for both SCS and SLS. ConclusionGLS and GCS did not significantly differ between fast-SENC and FT. Both showed acceptable agreement with 2DEcho for longitudinal strain. Segments perfused by the IRA showed significantly reduced strain values compared to the remote myocardium. Fast-SENC presented a higher sensitivity and specificity for detecting infarcted segments than FT.
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| 9. |
- Friberg-Fernros, Henrik, 1972, et al.
(author)
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An epistemic alternative to the public justification requirement
- 2024
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In: Philosophy & Social Criticism. - : SAGE Publications. - 0191-4537 .- 1461-734X. ; 50:6
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Journal article (peer-reviewed)abstract
- How should the state justify its coercive rules? Public reason liberalism endorses a public justification requirement: Justifications offered for authoritative regulations must be acceptable to all members of the relevant public. However, as a criterion of legitimacy, the public justification requirement is epistemically unreliable: It prioritizes neither the exclusion of false beliefs nor the inclusion of true beliefs in justifications of political rules. This article presents an epistemic alternative to the public justification requirement. Employing epistemological theories of argumentation, we demonstrate how this approach enables assessing the epistemic quality of justifications of political rules, even when the truth is difficult to establish.
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