The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases.

SGLT-2 Inhibitors in Cancer Treatment-Mechanisms of Action and Emerging New Perspectives.

A new group of antidiabetic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors), have recently been shown to have anticancer effects and their expression has been confirmed in many cancer cell lines. Given the metabolic reprogramming of these cells in a glucose-based model, the ability of SGLT-2 inhibitors to block the glucose uptake by cancer cells appears to be an attractive therapeutic approach. In addition to tumour cells, SGLT-2s are only found in the proximal tubules in the kidneys. Furthermore, as numerous clinical trials have shown, the use of SGLT-2 inhibitors is well-tolerated and safe in patients with diabetes and/or heart failure. In vitro cell culture studies and preclinical in vivo studies have confirmed that SGLT-2 inhibitors exhibit antiproliferative effects on certain types of cancer. However, the mechanisms of this action remain unclear. Even in those tumour cell types in which SGLT-2 is present, there is sometimes an SGLT-2-independent mechanism of anticancer action of this group of drugs. This article presents the current state of knowledge of the potential mechanisms of the anticancer action of SGLT-2 inhibitors and their possible future application in clinical oncology.

Analysis of Emergency Medical Response Team Performance during the International Winter Championships in Emergency Medicine.

Background and Objectives: Conducting advanced life support (ALS) according to the guidelines of the European Resuscitation Council (ERC) requires medical personnel to implement the appropriate emergency actions. In particular, these actions include chest compressions, airway management, artificial ventilation, defibrillation and the administering of medicines. An appropriate training system enables members of medical response teams (MRT) to acquire the essential knowledge and skills necessary to correctly conduct cardiopulmonary resuscitation (CPR). One way to improve the quality of interventions by MRT personnel is participation in emergency medicine championships. Materials and Methods: The research analysed assessment cards for tasks carried out during the International Winter Championships in Emergency Medicine in the years 2013-2020. The assessed tasks were prepared and led by European Resuscitation Council instructors of advanced life support. During ten-minute scenarios of simulated sudden cardiac arrest (SCA) in adults, the judges assessed the compliance of procedures with current ERC guidelines. This research analysed the performance of 309 teams from Poland made up of paramedics from medical response units from all over the country. Results: In most cases, the study showed significant differences in the percentage of correctly performed procedures between years. Most often, the highest percentage of correctly performed procedures was recorded in 2019 and 2020. The lowest percentage of correctly performed procedures was most often recorded in 2013. In subsequent years, the percentage of use of tracheal intubation decreased (from 54.76% to 31.25%) in favour of an increase in the use of supraglottic airway device SAD (from 35.71% to 59.38%). Conclusions: The research has shown that in subsequent years of the Championships, the quality of the majority of assessed procedures carried out by members of MRT gradually improved. The research authors also observed that in subsequent years, the percentage of intubations decreased in favour of SAD.

The Influence of Graphene Content on the Antibacterial Properties of Polycaprolactone.

This work contains an analysis of the impact of modifying a bioresorbable polymer-polycaprolactone (PCL)-with various additives on its antibacterial properties. To this end, samples of PCL filament containing various content levels of graphene (GNP), 0.5%, 5%, 10%, were obtained using injection molding. Polymer samples without additives were used for comparison. The next step was to assess the antimicrobial impact of the preparations under study against the following microorganisms: Staphylococcus aureus ATCC 25293, Escherichia coli ATCC 25922, Candida albicans ATCC 10231. Effective bactericidal activity of PCL with small amount of GNP, especially against C. albicans and S. aureus was confirmed. A decrease in this property or even multiplication of microorganisms was observed in direct proportion to the graphene content in the samples.

Analysis of the antibacterial properties of polycaprolactone modified with graphene, bioglass and zinc-doped bioglass.

PURPOSE: Innovative biomedical filaments for 3D printing in the form of short and biodegradable composite sticks modified with various additives were used to prepare biomaterials for further nasal implants. As the respiratory tract is considered to be potentially exposed to contamination during the implantation procedure there is a need to modify the implant with an antibacterial additives. The purpose of this work was to analyze the effect of biodegradable polymer - polycaprolactone (PCL) modification with various additives on its antibacterial properties. METHODS: PCL filament modified with graphene (0.5, 5, 10% wt.), bioglass (0.4% wt.) and zinc-doped bioglass (0.4% wt.) were used to print spatial biomaterials using FDM 3D printer. Pure polymer biomaterials without additives were used as reference samples. The key task was to assess the antimicrobial impact of the prepared biomaterials against the following microorganisms: Staphylococcus aureus ATCC 25293, Escherichia coli ATCC 25922, Candida albicans ATCC 10231. RESULTS: The research results point to a significant antibacterial efficacy of the tested materials against S. aureus and C. albicans, which, however, seems to decrease with increasing graphene content in the filaments. A complete lack of antibacterial efficacy against E. coli was determined. CONCLUSIONS: The tested biomaterials have important antibacterial properties, especially against C. albicans. The obtained results showed that biomaterials made of modified filaments can be successfully used in implantology, where a need to create temporary tissue scaffolds occurs.

Differences in Perceived Occupational Stress by Demographic Characteristics, of European Emergency Medical Services Personnel during the COVID-19 Virus Pandemic-An International Study.

OBJECTIVES: The outbreak of the COVID-19 pandemic has brought commercial, social, and economic consequences in every country that has experienced substantial SARS-CoV-2 infection rates. The complete change in the environment that took place due to the outbreak of the pandemic can lead to stressful situations, especially among healthcare personnel. MATERIAL AND METHODS: The research were conducted during the COVID-19 pandemic between the 27 March 2020 and the 20 April 2020. The research included 1984 employees of emergency medical systems in seven European countries. An internet-based questionnaire format was adopted for the study (ΩMc-Donald > 0.7). RESULTS: The highest level of stress was experienced by personnel in the United Kingdom M = 4.03, and the lowest by Norwegian employees M = 2.89. High levels of stress were also experienced by nurses from Spain and Poland. Women actively working in the healthcare system during the pandemic experienced higher stress levels than men. CONCLUSIONS: Women working in European emergency medical systems are more vulnerable to work-related stress, while carrying out emergency medical procedures during the pandemic. Differences in the level of stress experienced while carrying out duties in pre-hospital conditions were only found among Spanish emergency medical system personnel.

Endotracheal Tube Cuff Pressure - Comparison of the Two Filling Methods - Simulated Test.

INTRODUCTION: Tracheal intubation is the optimal method for opening up airways. Performed correctly, it prevents stomach contents from entering the respiratory tract and allows asynchronous cardiopulmonary resuscitation (CPR) to be conducted during sudden cardiac arrest. An important element of correct intubation is proper inflation of the endotracheal tube cuff. Research has shown that when medical personnel use the palpation technique, the cuff is usually inflated incorrectly. This can result in numerous health complications for the patient. METHODS: This research was conducted in 2020 on a group of paramedics participating in the 15th International Winter Championship of Medical Rescuers in Bielsko-Biala (Poland). The aim of the research was to assess two methods of inflating the endotracheal tube cuff. Method A involved inflating the cuff using a syringe and assessing the pressure in the control cuff using the palpation technique. Method B involved inflating the cuff using a manometer. During the inflation, both the cuff inflation pressure and the time required to complete the procedure were recorded. Analysis was also conducted on whether completion of certified Advanced Life Support (ALS) and Advanced Cardiovascular Life Support (ACLS) training had any influence on the effectiveness of the inflation procedure. RESULTS: The research showed that paramedics using Method B significantly more often inflated the endotracheal tube cuff to the correct pressure than those using Method A. However, when Method B was used, the procedure took longer to conduct. The study also showed that completion of certified ALS or ACLS training did not have a significant influence on proper inflation of the cuff. Those who had completed certified training courses took significantly longer to inflate the endotracheal tube cuff when using Method A. CONCLUSIONS: Inflation of the endotracheal tube cuff by use of a syringe, followed by the palpation technique for assessing the inflation of the cuff balloon, is ineffective. Paramedic teams should be equipped with manometers to be used for inflating the endotracheal tube cuff.

Predictors of stress among emergency medical personnel during the COVID-19 pandemic.

OBJECTIVES: The COVID-19 pandemic has forced emergency services to implement new standards of practice around the world. The dynamic and unpredictable nature of many clinical situations has placed emergency service personnel in direct danger of contracting the disease. This work uses a validated survey developed for the study to assess the predictors of stress that paramedics, nurses and doctors experience in the face of the COVID-19 pandemic. MATERIAL AND METHODS: The study group included 955 medical staff, and the level of significance adopted for statistical analysis was p = 0.05. Non-parametric Mann-Whitney and Kruskal-Wallis tests were used to analyze the qualitative variables divided into groups. The selection of tests was carried out based on the distribution of variables, verified using the Shapiro-Wilk test. In order to determine the predictors that caused the feelings of stress, it was necessary to use the linear regression model. RESULTS: During the COVID-19 pandemic, stress among emergency medical personnel has increased considerably due to new factors that did not previously exist. The predictors of stress in the professional environment include the fear of contracting COVID-19, a decrease in the level of safety while conducting emergency medical procedures, and the marginalization of treatment for patients not suffering from COVID-19. Additional socio-demographic factors that increase stress among emergency medical personnel are being female and working in the nursing profession. Appropriate training, the supply of personal protective equipment and opinions on the preparedness of the system to deal with the outbreak of the pandemic did not affect the level of stress among health service personnel. CONCLUSIONS: The factors that can be considered to act as predictors of occupational stress include the fear of contracting COVID-19, a decrease in the level of safety and security while conducting emergency medical procedures, and the marginalization of patients not suffering from COVID-19. Int J Occup Med Environ Health. 2021;34(2):139-49.

Sodium glucose cotransporter 2 inhibitors: mechanisms of action in heart failure.

Diabetes is a key independent risk factor in the development of heart failure (HF) and a strong, adverse prognostic factor in HF patients. HF remains the primary cause of hospitalisation for diabetics and, as previous studies have shown, when HF occurs in these patients, intensive glycaemic control does not directly improve the prognosis. Recent clinical studies assessing a new class of antidiabetic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT2is) showed some unexpected beneficial results. Patients treated with SGLT2is had a significant decrease in both cardiovascular (CV) and all-cause mortality and less hospitalisations due to HF compared to those given a placebo. These significant clinical benefits occurred quickly after the drugs were administered and were not solely due to improved glycaemic control. These groundbreaking clinical trials' results have already changed clinical practice in the management of patients with diabetes at high CV risk. These trials have triggered numerous experimental studies aimed at explaining the mechanisms of action of this unique group of drugs. This article presents the current state of knowledge about the mechanisms of action of SGLT2is developed for the treatment of diabetes and which, thanks to their cardioprotective effects, may, in the future, become a treatment for patients with HF.

Various aspects of inflammation in heart failure.

Despite significant advances in the prevention and treatment of heart failure (HF), the prognosis in patients who have been hospitalised on at least one occasion due to exacerbation of HF is still poor. Therefore, a better understanding of the underlying pathophysiological mechanisms of HF is crucial in order to achieve better results in the treatment of this clinical syndrome. One of the areas that, for years, has aroused the interest of researchers is the activation of the immune system and the elevated levels of biomarkers of inflammation in patients with both ischaemic and non-ischaemic HF. Additionally, it is intriguing that the level of circulating pro-inflammatory biomarkers correlates with the severity of the disease and prognosis in this group of patients. Unfortunately, clinical trials aimed at assessing interventions to modulate the inflammatory response in HF have been disappointing, and the modulation of the inflammatory response has had either no effect or even a negative effect on the HF prognosis. The article presents a summary of current knowledge on the role of immune system activation and inflammation in the pathogenesis of HF. Understanding the immunological mechanisms pathogenetically associated with left ventricular remodelling and progression of HF may open up new therapeutic possibilities for HF.

Comparison of standard and over-the-head method of chest compressions during cardiopulmonary resuscitation - a simulation study.

BACKGROUND: Maintaining highly effective cardiopulmonary resuscitation (CPR) can be particularly difficult when artificial ventilation using a bag-valve-mask device, combined with chest compression have to be carried out by one person. The aim of the study is to compare the quality of CPR conducted by one paramedic using chest compression from the patient's side with compression conducted from the 'over-the-head' position. METHODS: The subject of the study were two methods of CPR - 'standard' (STD) and 'over-the-head' (OTH). The STD method consisted of cycles of 30 chest compressions from the patient's side, and two attempts at artificial ventilation after moving round to behind the patient's head. In the OTH method, both compressions and ventilations were conducted from behind the patient's head. RESULTS: Both CPR methods were conducted by 38 paramedics working in medical response teams. Statistical analysis was conducted on the data collected, giving the following results: the average time of the interruptions between compression cycles (STD 9.184 s, OTH 7.316 s, p < 0.001); the depth of compression 50-60 mm (STD 50.65%, OTH 60.22%, p < 0.001); the rate of compression 100-120/min. (STD 46.39%, OTH 53.78%, p < 0.001); complete chest wall recoil (STD 84.54%, OTH 91.46%, p < 0.001); correct hand position (STD 99.32%, OTH method 99.66%, p < 0.001). A statistically significant difference was demonstrated in the results to the benefit of the OTH method in the above parameters. The remaining parameters showed no significant differences in comparison to reference values. CONCLUSIONS: The higher quality of CPR in the simulated research using the OTH method by a single person justifies the use of this method in a wider range of emergency interventions.