In-vitro antiplatelet effect of melatonin in healthy individuals and patients with type 2 diabetes mellitus.

PURPOSE: The incidence of acute myocardial infarctions (AMI) shows circadian variation typically peaking during morning hours with a decline at night. However, this variation does not occur in patients with diabetes mellitus (DM). The night's decline of AMI may be partially explained by melatonin-related platelet inhibition. Whether this effect is absent in diabetic patients is unknown. The aim was to study the effect of melatonin on in-vitro platelet aggregation in healthy individuals and patients with type 2 DM. METHODS: Platelet aggregation was measured in blood samples from healthy individuals (n = 15) and type 2 DM patients (n = 15) using multiple electrode aggregometry. Adenosine diphosphate (ADP), arachidonic acid (ASPI) and thrombin (TRAP) were used as agonists. Aggregability for each subject was tested after adding melatonin in two concentrations. RESULTS: In healthy individuals, melatonin inhibited platelet aggregation in both higher (10-5 M) and lower concentrations (10-9 M) induced by ADP, ASPI, and TRAP (p < 0.001, p = 0.002, p = 0.029, respectively). In DM patients, melatonin did not affect platelet aggregation in both concentrations induced by ADP, ASPI, and TRAP. Melatonin decreased platelet aggregation induced by ADP, ASPI, and TRAP significantly more in healthy individuals compared to patients with DM. (p = 0.005, p = 0.045 and p = 0.048, respectively). CONCLUSION: Platelet aggregation was inhibited by melatonin in healthy individuals. In-vitro antiplatelet effect of melatonin in type 2 DM patients is significantly attenuated.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Risks and benefits of dermatological machine learning health care applications-an overview and ethical analysis.

BACKGROUND: Visual data are particularly amenable for machine learning techniques. With clinical photography established for skin surveillance and documentation purposes as well as progress checks, dermatology is an ideal field for the development and application of emerging machine learning health care applications (ML-HCAs). To date, several ML-HCAs have detected malignant skin lesions on par with experts or found overlooked visual patterns that correlate with certain dermatological diseases. However, it is well established that ML-HCAs come with ethical and social implications. OBJECTIVES: Currently, there is a lack of research that establishes model design, training, usage and regulation of such technologies sufficient to ensure ethically and socially responsible development and clinical translation, specifically within the field of dermatology. With this paper, we aim to give an overview of currently discussed ethical issues relating to dermatological ML-HCAs. METHODS: On the basis of a thematic, keyword-based literature search, we performed an ethical analysis against established frameworks of biomedical ethics. We combined our results with current, relevant normative machine learning ethics literature to identify the status quo of the ethics of ML-HCAs in dermatology. We describe the benefits and risks of dermatological ML-HCAs that are currently being developed for clinical purposes. RESULTS: The potential benefits range from better patient outcomes to better knowledge accessibility to decreasing health care disparities, that is, standards of care between different population groups. The risks associated with ML-HCAs range from confidentiality issues to individual patient outcomes as well as the exacerbation of prevalent health care disparities. We discuss the practical implications for all stages of dermatological ML-HCA development. CONCLUSION: We found that ML-HCAs present stakeholder-specific risks for patients, health care professionals and society, which need to be considered separately. The discipline lacks sufficient biomedical ethics research that could standardize the approach to ML-HCA model design, training, use and regulation of such technologies.

Technical and practical aspects of artificial intelligence in cardiology.

Artificial intelligence (AI) is here to stay. It is not a future anymore, and there are many particular problems in cardiology that are already being solved via machine learning (ML), and many more are to come. AI cannot solve complex tasks yet, and probably this will not change in the upcoming years. Therefore, cardiologists do not have to be afraid that computers will replace them. However, cardiologists who will not be able to use ML algorithms in their clinical practice will be replaced by those who will. (Fig. 2, Ref. 50). Keywords: artificial intelligence, cardiology, potential machine learning, survival models, classification algorithms, computer vision, automated analysis of various imaging examinations, ECG interpretation, phenotype clustering, pathophysiological mechanisms.

Spatiotemporal distribution of thrombospondin-4 and -5 in cartilage during endochondral bone formation and repair.

During skeletal development most bones are first formed as cartilage templates, which are gradually replaced by bone. If later in life those bones break, temporary cartilage structures emerge to bridge the fractured ends, guiding the regenerative process. This bone formation process, known as endochondral ossification (EO), has been widely studied for its potential to reveal factors that might be used to treat patients with large bone defects. The extracellular matrix of cartilage consists of different types of collagens, proteoglycans and a variety of non-collagenous proteins that organise the collagen fibers in complex networks. Thrombospondin-5, also known as cartilage oligomeric matrix protein (TSP-5/COMP) is abundant in cartilage, where it has been described to enhance collagen fibrillogenesis and to interact with a variety of growth factors, matrix proteins and cellular receptors. However, very little is known about the skeletal distribution of its homologue thrombospondin-4 (TSP-4). In our study, we compared the spatiotemporal expression of TSP-5 and TSP-4 during postnatal bone formation and fracture healing. Our results indicate that in both these settings, TSP-5 distributes across all layers of the transient cartilage, while the localisation of TSP-4 is restricted to the population of hypertrophic chondrocytes. Furthermore, in fractured bones we observed TSP-4 sparsely distributed in the periosteum, while TSP-5 was absent. Last, we analysed the chemoattractant effects of the two proteins on endothelial cells and bone marrow stem cells and hypothesised that, of the two thrombospondins, only TSP-4 might promote blood vessel invasion during ossification. We conclude that TSP-4 is a novel factor involved in bone formation. These findings reveal TSP-4 as an attractive candidate to be evaluated for bone tissue engineering purposes.

Concentration of apelin inversely correlates with atrial fibrillation burden.

AIM: Asymptomatic atrial fibrillation (AF) detection and pulmonary veins isolation (PVI) outcome prediction remain challenging. Our aim was to study the association between apelin and paroxysmal AF in patients undergoing radiofrequency catheter PVI. METHODS: Sixty-three consecutive patients (55 ± 8years, 12 females) with paroxysmal AF without a structural heart disease and implanted ECG loop recorders undergoing PVI and healthy control group of 34 persons (41 ± 9.5years, 21 females) were included. Apelin plasmatic concentrations were measured before and three months after PVI. AF burden was continually assessed for three years. RESULTS: Apelin was significantly decreased in AF patients compared to the healthy controls (0.79 ± 0.09 vs 0.98 ± 0.06 ng/ml; p < 0.00001). Apelin plasmatic concentration of 0.89 ng/ml had 94 % specificity and 89 % sensitivity for AF prediction with the area under the curve (AUC) of 0.96. After propensity matching to sex, age and comorbidities, apelin concentration was significantly lower in AF group (0.78 ± 0.1 vs 0.99 ±0.06  ng/ml; p < 0.0001; AUC: 0.97). There was a significant inverse correlation between apelin concentration and AF burden both before and after PVI (Rho = ‒0.22; p = 0.05) and (Rho = ‒0.51; p = 0.006), respectively. There was no significant association between pre-PVI apelin and PVI long-term outcome. CONCLUSION: In patients without a structural heart disease apelin showed a significant specificity and sensitivity for AF prediction and inversely correlated with AF burden (Tab. 3, Fig. 3, Ref. 34).

Current status and needs for changes in critical care training: the voice of the young cardiologists.

AIMS: The implementation of the 2013 European Society of Cardiology (ESC) Core Curriculum guidelines for acute cardiovascular care (acc) training among European countries is unknown. We aimed to evaluate the current status of acc training among cardiology trainees and young cardiologists (<40 years) from ESC countries. METHODS AND RESULTS: The survey (March-July 2019) asked about details of cardiology training, self-confidence in acc technical and non-technical skills, access to training opportunities, and needs for further training in the field. Overall 614 young doctors, 31 (26-43) years old, 55% males were surveyed. Place and duration of acc training differed between countries and between centres in the same country. Although the majority of the respondents (91%) had completed their acc training, the average self-confidence to perform invasive procedures and to manage acc clinical scenarios was low-44% (27.3-70.4). The opportunities for simulation-based learning were scarce-18% (5.8-51.3), as it was previous leadership training (32%) and knowledge about key teamwork principles was poor (48%). The need for further acc training was high-81% (61.9-94.3). Male gender, higher level of training centres, professional qualifications of respondents, longer duration of acc/intensive care training, debriefings, and previous leadership training as well as knowledge about teamwork were related to higher self-confidence in all investigated aspects. CONCLUSIONS: The current cardiology training program is burdened by deficits in acc technical/non-technical skills, substantial variability in programs across ESC countries, and a clear gender-related disparity in outcomes. The forthcoming ESC Core Curriculum for General Cardiology is expected to address these deficiencies.

Characteristics, management, and outcome of infective endocarditis in the Czech Republic: prospective data from the ESC EORP EURO-ENDO registry.

INTRODUCTION: Data describing contemporary profile of infective endocarditis (IE) in the Czech Republic are lacking. The aim of this study was to describe the current profile and outcomes of IE patients. METHODS: Prospectively collected data on consecutive patients admitted for IE diagnosis between April 2016 and March 2018 to 11 main tertiary care cardiac centers in the Czech Republic were used for this analysis. RESULTS: Among 208 patients, 88 patients (42.3 %) had native valve IE (NVIE), 56 patients (26.9 %) had prosthetic valve IE (PVIE), and 57 patients (27.4 %) had intracardiac device-related IE (CDRIE). The mean age was 61.66±15.54 years. Staphylococcus aureus was the most common etiological agent of IE (27.4 %), whereas Culture negative IE was present in 26.4 % patients. Surgery was performed during hospitalization in 112 (53.8 %) patients. In-hospital death occurred in 21.2 % patients, while 1-year mortality was 40.3 %. In patients, who had an indication for surgery, but the procedure was not performed, mortality was significantly higher (p=0.002). CONCLUSION: High proportion of culture negative IE and IE related to artificial intra-cardiac materials calls for action. Furthermore, we show that cardiac surgery should be more often contemplated, especially in the presence of risk factors as septic shock and congestive heart failure (Tab. 6, Fig. 1, Ref. 32).

Association of apelin and AF in patients with implanted loop recorders undergoing catheter ablation.

BACKGROUND: Previous studies showed an association between apelin and atrial fibrillation (AF). The aim of this study was to analyse the effect of pulmonary vein isolation (PVI) in patients with paroxysmal AF on plasmatic apelin concentrations. METHODS: Nine consecutive patients (aged from 43 to 69 years, 3 females and 6 males) with documented paroxysmal atrial fibrillation and implanted loop recorders (ILR) for continuous ECG monitoring were included in this study. All the patients underwent a radiofrequency catheter ablation with PVI. RESULTS: The plasmatic concentration of apelin increased after PVI. The average plasmatic concentration of apelin before PVI was 0.299 ng/ml (±0.16), 3 months after PVI 0.462 ng/ml (±0.10) and 9 months after PVI 0.565 ng/ml (±0.146). There was an increase in the concentration of apelin 3 months and 9 months after the PVI by 0.163 ng/ml (p=0.07) and by 0.266 ng/ml (p=0.01), respectively. The concentration of apelin inversely correlated with the AF burden (r=-0.44, p=0.03). CONCLUSIONS: Our study showed a significant increase in apelin levels after the reduction of AF burden via PVI and an inverse correlation with AF burden. Apelin might be a promising marker of AF (Tab. 2, Fig. 2, Ref. 28).

Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesity.

OBJECTIVE: Although debated, metabolic health characterizes 10-25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown. METHODS: Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases. RESULTS AND CONCLUSIONS: Our study showed that glucose intolerance and insulin resistance co-operate to remodel adipocyte transcriptome. We also identified the Nuclear Export Mediator Factor (NEMF) and the Ectoderm-Neural Cortex 1 (ENC1) as novel potential targets in the management of metabolic health in human obesity.

Recruitment of osteogenic cells to bone formation sites during development and fracture repair.

Recruitment of osteoblast lineage cells to their bone-forming locations is essential for skeletal development and fracture healing. In developing bones, osteoprogenitor cells invade the cartilage mold to establish the primary ossification center. Similarly, osteogenic cells infiltrate and populate the callus tissue that is formed following an injury. Proper bone development and successful fracture repair must, therefore, rely on controlled temporal and spatial navigation cues guiding the cells to the sites where new bone formation is needed. Some cellular mechanisms and molecular pathways involved have been elucidated.

The relation between oxidative stress biomarkers and atrial fibrillation after pulmonary veins isolation.

INTRODUCTION: The current paradigm claims a link between oxidative stress and atrial fibrillation. The aim of our research was to study a relation between the percentage of time spent in atrial fibrillation (AF burden) and concentrations of oxidative stress biomarkers, before and after pulmonary veins isolation (PVI). METHODOLOGY: We included 19 patients (mean age 55±10years, 4 females and 15 males) with implanted loop recorders undergoing PVI. Plasmatic concentrations of advanced glycation end-products (AGEs), fructosamine, advanced oxidation protein products and thiobarbituric-acid reacting substances (TBARS) were measured and AF burden was recorded immediately before and 3months after the PVI. AF burden was also recorded 9months after the PVI. RESULTS: Post procedural AGEs concentration significantly negatively correlated with AF burden after 3months (ρ=-0.63; p<0.01) and 9months (ρ=-0.5; p=0.04), respectively as well as TBARS concentration significantly negatively correlated with AF burden after 9months (ρ=-0.61; p=0.01). CONCLUSION: Our study showed AGEs and TBARS to be potential predictors for AF burden after the PVI. We suppose that the more oxidative stress after the PVI is provoked, the more fibrotic tissue is produced. That means a better electrical isolation of pulmonary veins and consequently a lower AF burden.

[Recruitment of osteogenic cells to bone formation sites during development and fracture repair - German Version]. / Rekrutierung osteogener Zellen an den Ort der Knochenbildung während Entwicklung und Frakturheilung.

Recruitment of osteoblast lineage cells to their bone-forming locations is essential for skeletal development and fracture healing. In developing bones, osteoprogenitor cells invade the cartilage mold to establish the primary ossification center. Similarly, osteogenic cells infiltrate and populate the callus tissue that is formed following an injury. Proper bone development and successful fracture repair must, therefore, rely on controlled temporal and spatial navigation cues guiding the cells to the sites where new bone formation is needed. Some cellular mechanisms and molecular pathways involved have been elucidated.