Translucent zebrafish larvae represent an established model to analyze genetics of cardiac development and human cardiac disease. More recently adult zebrafish are utilized to evaluate mechanisms of cardiac regeneration and by benefiting from recent genome editing technologies, including TALEN and CRISPR, adult zebrafish are emerging as a valuable in vivo model to evaluate novel disease genes and specifically validate disease causing mutations and their underlying pathomechanisms. However, methods to sensitively and non-invasively assess cardiac morphology and performance in adult zebrafish are still limited. We here present a standardized examination protocol to broadly assess cardiac performance in adult zebrafish by advancing conventional echocardiography with modern speckle-tracking analyses. This allows accurate detection of changes in cardiac performance and further enables highly sensitive assessment of regional myocardial motion and deformation in high spatio-temporal resolution. Combining conventional echocardiography measurements with radial and longitudinal velocity, displacement, strain, strain rate and myocardial wall delay rates after myocardial cryoinjury permitted to non-invasively determine injury dimensions and to longitudinally follow functional recovery during cardiac regeneration. We show that functional recovery of cryoinjured hearts occurs in three distinct phases. Importantly, the regeneration process after cryoinjury extends far beyond the proposed 45 days described for ventricular resection with reconstitution of myocardial performance up to 180 days post-injury (dpi). The imaging modalities evaluated here allow sensitive cardiac phenotyping and contribute to further establish adult zebrafish as valuable cardiac disease model beyond the larval developmental stage.
Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We aimed to assess the efficacy and safety of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with ATTRv amyloidosis with polyneuropathy.
MethodsThis multi-country, multi-centre, open-label extension (OLE) trial enrolled patients at 43 sites in 19 countries as of 24 September 2018. Patients were eligible if they had completed the phase 3 APOLLO (randomised, double-blind, placebo-controlled [2:1], 18-month study) or phase 2 OLE (single-arm, 24-month study) parent studies and tolerated the study drug. Eligible patients from APOLLO (APOLLO-patisiran [received patisiran during APOLLO] and APOLLO-placebo [received placebo during APOLLO] groups) and the phase 2 OLE (phase 2 OLE patisiran group) studies enrolled in this Global OLE trial and receive patisiran 0•3 mg/kg by intravenous infusion every 3 weeks for up to 5 years. Efficacy assessments include measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress. Patients included in the current efficacy analyses are those who had completed 12-month efficacy assessments as of the data cut-off. Safety analyses included all patients who received ≥1 dose of patisiran up to the data cut-off. The Global OLE is ongoing with no new enrolment, and current findings are based on the 12-month interim analysis. The study is registered with ClinicalTrials.gov, NCT02510261.
No sex-specific bias was observed between male and female patients with wt-ATTR regarding age at onset and morphological characteristics. Multivariable analysis revealed MAPSE and NT-proBNP as independent predictors of survival in the whole cohort, whereas midventricular longitudinal strain was the only independent predictor in patients in sinus rhythm.
Using adult heterozygous zebrafish, we show that ELC S195 phosphorylation is pivotal for adaptation of cardiac function to augmented physical stress and we provide novel mechanistic insights into the pathogenesis of ELC-linked cardiomyopathy.
Background
Keeping up motivation to learn when socially isolated during a pandemic can be challenging. In medical schools, the COVID-19 pandemic required a complete switch to e-learning without any direct patient contact despite early reports showing that medical students preferred face-to-face teaching in clinical setting. We designed close to real-life patient e-learning modules to transmit competency-based learning contents to medical students and evaluated their responses about their experience.
Methods
Weekly e-learning cases covering a 10-week leading symptom-based curriculum were designed by a team of medical students and physicians. The internal medicine curriculum (HeiCuMed) at the Heidelberg University Medical School is a mandatory part of clinical medical education in the 6th or 7th semester. Case-design was based on routine patient encounters and covered different clinical settings: preclinical emergency medicine, in-patient and out-patient care and follow-up. Individual cases were evaluated online immediately after finishing the respective case. The whole module was assessed at the end of the semester. Free-text answers were analyzed with MaxQDa following Mayring`s principles of qualitative content analyses.
Results
N = 198 students (57.6% female, 42.4% male) participated and 1252 individual case evaluations (between 49.5% and 82.5% per case) and 51 end-of-term evaluations (25.8% of students) were collected. Students highly appreciated the offer to apply their clinical knowledge in presented patient cases. Aspects of clinical context, interactivity, game-like interface and embedded learning opportunities of the cases motivated students to engage with the asynchronously presented learning materials and work through the cases.
Conclusions
Solving and interpreting e-learning cases close to real-life settings promoted students’ motivation during the COVID-19 pandemic and may partially have compensated for missing bedside teaching opportunities.
We identified reduced peak V'O as an independent predictor of mortality in patients with cardiac involvement in different forms of systemic amyloidosis.
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