Pharmacokinetic and toxicological considerations affecting antiretroviral drug dosing in pregnant women.

INTRODUCTION: To prevent mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV) during pregnancy, the appropriate dosing regimens of antiretroviral (ARV) drugs need to be determined. Reliable data about pharmacokinetic (PK) characteristics of ARVs from randomized clinical trials (RCTs) are lacking, and post-marketing observational studies may offer valuable, but sometimes insufficient data, especially in pregnant people living with HIV (PLWHIV). This review article is focused PK and toxicological considerations affecting ARV dosing in pregnant PLWHIV. AREAS COVERED: In our search, we included studies focused on PKs of ARVs in pregnancy available on PubMed, abstracts from recent global conferences and data from modeling studies. There are no significant changes in PKs of nucleoside/nucleotide reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors throughout pregnancy. In contrast, the PKs of PIs and INSTIs are more variable, especially in the second and third trimesters. EXPERT OPINION: Pregnant women are left out of RCTs. To the greatest extent possible, future research should include pregnant persons in RCTs, including PK studies, strictly considering maternal and fetal safety. Alternative innovative approaches/models need to be developed to obtain reliable data about rational pharmacotherapy of ARVs in the effective PMTCT of HIV, with maximum safety.

Therapeutic Potential of Palmitoylethanolamide in Gastrointestinal Disorders.

Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator belonging to the family of N-acylethanolamines, most abundantly found in peanuts and egg yolk. When the gastrointestinal (GI) effects of PEA are discussed, it must be pointed out that it affects intestinal motility but also modulates gut microbiota. This is due to anti-inflammatory, antioxidant, analgesic, antimicrobial, and immunomodulatory features. Additionally, PEA has shown beneficial effects in several GI diseases, particularly irritable bowel syndrome and inflammatory bowel diseases, as various studies have shown, and it is important to emphasize its relative lack of toxicity, even at high dosages. Unfortunately, there is not enough endogenous PEA to treat disturbed gut homeostasis, even though it is produced in the GI tract in response to inflammatory stimuli, so exogenous intake is mandatory to achieve homeostasis. Intake of PEA could be through animal and/or vegetable food, but bearing in mind that a high dosage is needed to achieve a therapeutic effect, it must be compensated through dietary supplements. There are still open questions pending to be answered, so further studies investigating PEA's effects and mechanisms of action, especially in humans, are crucial to implementing PEA in everyday clinical practice.

Perspectives on the COVID-19 Vaccination Rollout in 17 Countries: Reflexive Thematic and Frequency Analysis Based on the Strengths, Weaknesses, Opportunities, and Threats (SWOT) Framework.

BACKGROUND: As the SARS-CoV-2 virus created a global pandemic and rapidly became an imminent threat to the health and lives of people worldwide, the need for a vaccine and its quick distribution among the population was evident. Due to the urgency, and on the back of international collaboration, vaccines were developed rapidly. However, vaccination rollouts showed different success rates in different countries and some also led to increased vaccine hesitancy. OBJECTIVE: The aim of this study was to identify the role of information sharing and context sensitivity in various vaccination programs throughout the initial COVID-19 vaccination rollout in different countries. Moreover, we aimed to identify factors in national vaccination programs related to COVID-19 vaccine hesitancy, safety, and effectiveness. Toward this end, multidisciplinary and multinational opinions from members of the Navigating Knowledge Landscape (NKL) network were analyzed. METHODS: From May to July 2021, 25 completed questionnaires from 27 NKL network members were collected. These contributors were from 17 different countries. The responses reflected the contributors' subjective viewpoints on the status and details of the COVID-19 vaccination rollout in their countries. Contributors were asked to identify strengths, weaknesses, opportunities, and threats (ie, SWOT) of the respective vaccination programs. The responses were analyzed using reflexive thematic analysis, followed by frequency analysis of identified themes according to the represented countries. RESULTS: The perspectives of NKL network members showed a link between organizational elements of the vaccination rollout and the accompanying societal response, both of which were related to strengths and weaknesses of the process. External sociocultural variables, improved public communication around vaccination-related issues, ethical controversies, and the spread of disinformation were the dominant themes related to opportunities and challenges. In the SWOT 2×2 matrix, Availability and Barriers emerged as internal categories, whereas Transparent communication and promotion and Societal divide emerged as key external categories. CONCLUSIONS: Inventory of themes and categories inspired by elements of the SWOT framework provides an informative multidisciplinary perspective for effective implementation of public health strategies in the battle against COVID-19 or any future pandemics of a similar nature.

Pharmacological effects of monoterpene carveol on the neuromuscular system of nematodes and mammals.

The control of parasitic nematode infections relies mostly on anthelmintics. The potential pharmacotherapeutic application of phytochemicals, in order to overcome parasite resistance and enhance the effect of existing drugs, is becoming increasingly important. The antinematodal effects of carveol was tested on the free-living nematode Caenorhabditis elegans and the neuromuscular preparation of the parasitic nematode Ascaris suum. Carveol caused spastic paralysis in C. elegans. In A. suum carveol potentiated contractions induced by acetylcholine (ACh) and this effect was confirmed with two-electrode voltage-clamp electrophysiology on the A. suum nicotinic ACh receptor expressed in Xenopus oocytes. However, potentiating effect of carveol on ACh-induced contractions was partially sensitive to atropine, indicates a dominant nicotine effect but also the involvement of some muscarinic structures. The effects of carveol on the neuromuscular system of mammals are also specific. In micromolar concentrations, carveol acts as a non-competitive ACh antagonist on ileum contractions. Unlike atropine, it does not change the EC50 of ACh, but reduces the amplitude of contractions. Carveol caused an increase in Electrical Field Stimulation-evoked contractions of the isolated rat diaphragm, but at higher concentrations it caused an inhibition. Also, carveol neutralized the mecamylamine-induced tetanic fade, indicating a possibly different pre- and post-synaptic action at the neuromuscular junction.

The Predictive Value of Risk Factors and Prognostic Scores in Hospitalized COVID-19 Patients.

INTRODUCTION: Risk stratification in patients with COVID-19 is a challenging task. Early warning scores (EWSs) are commonly used tools in the initial assessment of critical patients. However, their utility in patients with COVID-19 is still undetermined. AIM: This study aimed to discover the most valuable predictive model among existing EWSs for ICU admissions and mortality in COVID-19 patients. MATERIALS AND METHODS: This was a single-center cohort study that included 3608 COVID-19 patients admitted to the University Clinical Hospital Center Bezanijska Kosa, Belgrade, Serbia, between 23 June 2020, and 14 April 2021. Various demographic, laboratory, and clinical data were collected to calculate several EWSs and determine their efficacy. For all 3608 patients, five EWSs were calculated (MEWS, NEWS, NEWS2, REMS, and qSOFA). Model discrimination performance was tested using sensitivity, specificity, and positive and negative predictive values. C statistic, representing the area under the receiver operating characteristic (ROC) curve, was used for the overall assessment of the predictive model. RESULTS: Among the evaluated prediction scores for 3068 patients with COVID-19, REMS demonstrated the highest diagnostic performance with the sensitivity, PPV, specificity, and NPV of 72.1%, 20.6%, 74.9%, and 96.8%, respectively. In the multivariate logistic regression analysis, aside from REMS, age (p < 0.001), higher CT score (p < 0.001), higher values of urea (p < 0.001), and the presence of bacterial superinfection (p < 0.001) were significant predictors of mortality. CONCLUSIONS: Among all evaluated EWSs to predict mortality and ICU admission in COVID-19 patients, the REMS score demonstrated the highest efficacy.

Mechanisms of Prostate Cancer Cells Survival and Their Therapeutic Targeting.

Prostate cancer (PCa) is today the second most common cancer in the world, with almost 400,000 deaths annually. Multiple factors are involved in the etiology of PCa, such as older age, genetic mutations, ethnicity, diet, or inflammation. Modern treatment of PCa involves radical surgical treatment or radiation therapy in the stages when the tumor is limited to the prostate. When metastases develop, the standard procedure is androgen deprivation therapy, which aims to reduce the level of circulating testosterone, which is achieved by surgical or medical castration. However, when the level of testosterone decreases to the castration level, the tumor cells adapt to the new conditions through different mechanisms, which enable their unhindered growth and survival, despite the therapy. New knowledge about the biology of the so-called of castration-resistant PCa and the way it adapts to therapy will enable the development of new drugs, whose goal is to prolong the survival of patients with this stage of the disease, which will be discussed in this review.

Alcohol, Inflammation, and Microbiota in Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a consequence of excessive alcohol use. According to many studies, alcohol represents a significant socioeconomic and health risk factor in today's population. According to data from the World Health Organization, there are about 75 million people who have alcohol disorders, and it is well known that its use leads to serious health problems. ALD is a multimodality spectrum that includes alcoholic fatty liver disease (AFL) and alcoholic steatohepatitis (ASH), consequently leading to liver fibrosis and cirrhosis. In addition, the rapid progression of alcoholic liver disease can lead to alcoholic hepatitis (AH). Alcohol metabolism produces toxic metabolites that lead to tissue and organ damage through an inflammatory cascade that includes numerous cytokines, chemokines, and reactive oxygen species (ROS). In the process of inflammation, mediators are cells of the immune system, but also resident cells of the liver, such as hepatocytes, hepatic stellate cells, and Kupffer cells. These cells are activated by exogenous and endogenous antigens, which are called pathogen and damage-associated molecular patterns (PAMPs, DAMPs). Both are recognized by Toll-like receptors (TLRs), which activation triggers the inflammatory pathways. It has been proven that intestinal dysbiosis and disturbed integrity of the intestinal barrier perform a role in the promotion of inflammatory liver damage. These phenomena are also found in chronic excessive use of alcohol. The intestinal microbiota has an important role in maintaining the homeostasis of the organism, and its role in the treatment of ALD has been widely investigated. Prebiotics, probiotics, postbiotics, and symbiotics represent therapeutic interventions that can have a significant effect on the prevention and treatment of ALD.

Aging of Liver in Its Different Diseases.

The proportion of elderly people in the world population is constantly increasing. With age, the risk of numerous chronic diseases and their complications also rises. Research on the subject of cellular senescence date back to the middle of the last century, and today we know that senescent cells have different morphology, metabolism, phenotypes and many other characteristics. Their main feature is the development of senescence-associated secretory phenotype (SASP), whose pro-inflammatory components affect tissues and organs, and increases the possibility of age-related diseases. The liver is the main metabolic organ of our body, and the results of previous research indicate that its regenerative capacity is greater and that it ages more slowly compared to other organs. With age, liver cells change under the influence of various stressors and the risk of developing chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) and hepatocellular carcinoma (HCC) increases. It has been proven that these diseases progress faster in the elderly population and in some cases lead to end-stage liver disease that requires transplantation. The treatment of elderly people with chronic liver diseases is a challenge and requires an individual approach as well as new research that will reveal other safe and effective therapeutic modalities.

Point-of-Care Echocardiographic Characteristics of COVID-19 Patients with Pulmonary Embolism.

INTRODUCTION: Thrombotic complications, such as pulmonary embolism, are common in COVID-19 patients. Point-of-care ultrasound is a highly recommended tool for orientation in critically ill patients with suspected or confirmed complications. METHODS: An observational study was conducted on 32 consecutive patients with confirmed pulmonary embolism and COVID-19 infection treated in the Intensive Care Unit of the University Hospital Medical Center "Bezanijska kosa", Belgrade, Serbia, between April 2021 and March 2022. Predictors of the need for oxygen support were determined, while point-of-care echocardiographic parameters and various anamnestic, laboratory, and clinically significant parameters were correlated with the Pulmonary Embolism Severity Index (PESI) score. RESULTS: More than two-thirds of patients in our study had PE symptoms present at hospital admission (68.8%). The majority of patients had segmental pulmonary embolism (48.4%), with high to very high PESI score values in 31.3% of patients. Pneumonia was present in 68.8% of the study population. The PESI score was negatively correlated with diastolic blood pressure and SaO2 at the time of PE diagnosis, LV ejection fraction, and PVAT. A positive correlation was found between the PESI score, maximum CRP, and D-dimer at the time of PTE diagnosis. A larger right ventricular diameter was associated with a greater need for oxygen support. CONCLUSION: Point-of-care echocardiography is a valuable tool for the risk assessment of COVID-19 patients with pulmonary embolism. Right ventricular size stood out as a significant marker of disease severity.

Elevated Transaminases as Predictors of COVID-19 Pneumonia Severity.

BACKGROUND: This study aimed to calculate the frequency of elevated liver enzymes in hospitalized patients with coronavirus disease 2019 (COVID-19) infection and to test if liver enzyme biochemistry levels on admission could predict the computed tomography (CT) scan severity score of bilateral interstitial pneumonia. METHODS: This single-center study comprised of 323 patients including their demographic data, laboratory analyses, and radiological findings. All the information was taken from electronic health records, followed by statistical analysis. RESULTS: Out of 323 patients, 115 of them (35.60%) had aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) over 40 U/L on admission. AST was the best predictor of CT scan severity score of bilateral interstitial pneumonia (R2 = 0.313, Adjusted R2 = 0.299). CT scan severity score in the peak of the infection could be predicted with the value of AST, neutrophils, platelets, and monocytes count (R2 = 0.535, Adjusted R2 = 0.495). CONCLUSION: AST, neutrophils, platelets, and monocytes count on admission can account for almost half (49.5%) of the variability in CT scan severity score at peak of the disease, predicting the extensiveness of interstitial pneumonia related to COVID-19 infection. Liver enzymes should be closely monitored in order to stratify COVID-19 patients with a higher risk of developing severe forms of the disease and to plan the beforehand step-up treatment.

Obstructive Sleep Apnea and Cardiovascular Risk: The Role of Dyslipidemia, Inflammation, and Obesity.

Introduction: The present study aimed to establish the role of lipid abnormalities and inflammatory markers for developing cardiovascular risk, as well as to address the importance of obesity as a common comorbidity in patients with obstructive sleep apnea (OSA). Methods: The study was conducted as a prospective cohort study including 120 patients with newly diagnosed OSA between 2019 and 2020, at University Clinical Hospital Center "Bezanijska kosa", Belgrade, Serbia. The diagnosis was established by polysomnography. In all patients, sociodemographic data, respiratory, lipid, and inflammatory parameters were collected and complete echocardiographic study and 24-h blood pressure monitoring were performed. Results: The mean patient age was 55.7 ± 13.8 years. Study population was mostly male (70.0%) and obese (56.7%). At least 30 apneas or hypopneas per hour were present in 39.0% of patients. A strong positive correlation was found between OSA severity and BMI (r = 0.562, p < 0.001), both associated with lipid, inflammatory and respiratory parameters, and cardiovascular profile of patients with OSA (p < 0.05 for all). Echocardiographic study and 24-h blood pressure monitoring parameters were in turn correlated with lipid and inflammatory markers (p < 0.05 for all). Conclusion: The results of this study support the important role of dyslipidemia and inflammation, as well as coexistence of obesity in the pathogenesis of numerous conditions linked with an increased risk of cardiovascular morbidity and mortality in patients with OSA.

Correlation of Dyslipidemia and Inflammation With Obstructive Sleep Apnea Severity.

Introduction: Obstructive sleep apnea (OSA) is a serious condition linked with various metabolic disorders and associated with increased all-cause and cardiovascular mortality. Although the potential mechanisms of pathophysiological processes related to OSA are relatively well known, the data regarding the correlation between obstructive sleep apnea, dyslipidemia, and systemic inflammation are still inconclusive. Methods: The study was conducted as a retrospective cohort study including 328 patients with newly diagnosed obstructive sleep apnea during the period between April 2018, and May 2020, in University Clinical Hospital Center "Bezanijska kosa", Belgrade, Serbia. Polysomnography was performed in all patients according to the protocol. Numerous demographic, antropometric, laboratory, and clinical data were correlated to Apnea-Hypopnea Index (AHI) as a dependent variable, with a particular review on the relation between lipid abnormalities, inflammatory parameters, and obstructive sleep apnea severity. Multivariate logistic regression model was used to assess predictors of severe OSA (AHI ≥30 per hour). Results: A total of 328 patients were included in the study. The mean age of the patients was 54.0 ± 12.5 years and more than two-thirds were male (68.8%). The majority of the patients had an AHI of at least 30 events per hour. Patients with severe OSA were more frequently male, obese, hypertensive and hyperlipidemic, and had increased neck circumference (both male and female patients). One hundred and thirty-two patients had metabolic syndrome. Patients with severe OSA more frequently had metabolic syndrome and significantly higher levels of glucose, creatinine, uric acid, AST, ALT, CK, microalbumine/creatinine ratio, triglyceride, total cholesterol, HDL, total cholеsterol to HDL-C ratio, CRP, and ESR. In the multivariate linear regression model with AHI (≥30 per hour) as a dependent variable, of demographic and clinical data, triglycerides ≥1.7 mmol/L and CRP >5 mg/L were significantly associated with AHI≥30 per hour. Conclusion: The present study on 328 patients with newly diagnosed obstructive sleep apnea revealed significant relation of lipid abnormalities, inflammatory markers, and other clinically important data with obstructive sleep apnea severity. These results can lead to a better understanding of the underlying pathophysiological processes and open the door to a new world of potentially useful therapeutic modalities.

Characteristics and Outcomes of Patients with Acute Coronary Syndrome and COVID-19.

Acute coronary syndrome (ACS) in patients with COVID-19 is triggered by various mechanisms and can significantly affect the patient's further treatment and prognosis. The study aimed to investigate the characteristics, major complications, and predictors of mortality in COVID-19 patients with ACS. All consecutive patients hospitalized from 5 July 2020 to 5 May 2021 for ACS with confirmed SARS-Co-2 were prospectively enrolled and tracked for mortality until 5 June 2021. Data from the electronic records for age and diagnosis, matched non-COVID-19 and COVID-19 ACS group, were extracted and compared. Overall, 83 COVID-19 ACS patients, when compared to 166 non-COVID ACS patients, had significantly more prevalent comorbidities, unfavorable clinical characteristics on admission (acute heart failure 21.7% vs. 6.6%, p < 0.01) and higher rates of major complications, 33.7% vs. 16.8%, p < 0.01, and intrahospital 30-day mortality, 6.7% vs. 26.5%, p < 0.01. The strongest predictors of mortality were aortic regurgitation, HR 9.98, 95% CI 1.88; 52.98, p < 0.01, serum creatinine levels, HR 1.03, 95% CI 1.01; 1.04, p < 0.01, and respiratory failure therapy, HR 13.05, 95% CI 3.62; 47.01, p < 0.01. Concomitant ACS and COVID-19 is linked to underlying comorbidities, adverse presenting features, and poor outcomes. Urgent strategies are needed to improve the outcomes of these patients.

Risk factors for adverse drug reactions associated with clopidogrel therapy.

This study aimed to investigate the possible influence of genetic and non-genetic factors on the incidence of clopidogrel adverse drug reactions (ADRs) in cardiology patients, including the most important CYP2C19 alleles, namely *2 and *17, as well as compliance, dose, drug interactions, and clinical factors. A total of 102 clopidogrel-treated adult Caucasian patients hospitalized at the Cardiology Department of the Clinical Center of Montenegro were enrolled in the study. Data on clinical outcomes of interest were obtained by intensive monitoring ADRs during hospitalization and one year after hospital discharge. Genotyping for CYP2C19*2 and *17 was conducted using the real-time polymerase chain reaction method. ADRs were characterized using the Rawlins and Thompson classification and the World Health Organization criteria. Causality was assessed using the Naranjo probability scale. ADRs to clopidogrel were observed in 9 of 102 patients (8.8%). The observed frequencies of CYP2C19*2 and *17 were 13.2 and 25.5%, respectively. Our study, which is the first to report the frequency of CYP2C19 polymorphism in the Montenegrin population, as well as to link the pharmacovigilance of clopidogrel with CYP2C19 gene variability, shows that the incidence of ADRs of clopidogrel in cardiac patients is high and depends on CYP2C19 polymorphisms, comedication/drug interactions, and gastrointestinal comorbidity.

The Effects of a Meldonium Pre-Treatment on the Course of the LPS-Induced Sepsis in Rats.

A dysregulated and overwhelming response to an infection accompanied by the exaggerated pro-inflammatory state and metabolism disturbance leads to the fatal outcome in sepsis. Previously we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, strongly increases mortality in faecal-induced peritonitis (FIP) in rats. We postulated that the same mechanism that is responsible for the otherwise strong anti-inflammatory effects of meldonium could be the culprit of the increased mortality. In the present study, we applied the LPS-induced model of sepsis to explore the presence of any differences from and/or similarities to the FIP model. When it comes to energy production, despite some shared similarities, it is evident that LPS and FIP models of sepsis differ greatly. A different profile of sympathoadrenal activation may account for this observation, as it was lacking in the FIP model, whereas in the LPS model it was strong enough to overcome the effects of meldonium. Therefore, choosing the appropriate model of sepsis induction is of great importance, especially if energy homeostasis is the main focus of the study. Even when differences in the experimental design of the two models are acknowledged, the role of different patterns of energy production cannot be excluded. On that account, our results draw attention to the importance of uninterrupted energy production in sepsis but also call for much-needed revisions of the current recommendations for its treatment.

The Effects of a Meldonium Pre-Treatment on the Course of the Faecal-Induced Sepsis in Rats.

Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by an exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure. Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by shifting energy production from fatty acid oxidation to glycolysis, as a less oxygen-demanding pathway. Thus, we investigated the effects of a four-week meldonium pre-treatment on faecal-induced sepsis in Sprague-Dawley male rats. Surprisingly, under septic conditions, meldonium increased animal mortality rate compared with the meldonium non-treated group. However, analysis of the tissue oxidative status did not provide support for the detrimental effects of meldonium, nor did the analysis of the tissue inflammatory status showing anti-inflammatory, anti-apoptotic, and anti-necrotic effects of meldonium. After performing tissue lipidomic analysis, we concluded that the potential cause of the meldonium harmful effect is to be found in the overall decreased lipid metabolism. The present study underlines the importance of uninterrupted energy production in sepsis, closely drawing attention to the possible harmful effects of lipid-mobilization impairment caused by certain therapeutics. This could lead to the much-needed revision of the existing guidelines in the clinical treatment of sepsis while paving the way for discovering new therapeutic approaches.

Effects of C60 Fullerene on Thioacetamide-Induced Rat Liver Toxicity and Gut Microbiome Changes.

Thioacetamide (TAA) is widely used to study liver toxicity accompanied by oxidative stress, inflammation, cell necrosis, fibrosis, cholestasis, and hepatocellular carcinoma. As an efficient free radical's scavenger, C60 fullerene is considered a potential liver-protective agent in chemically-induced liver injury. In the present work, we examined the hepatoprotective effects of two C60 doses dissolved in virgin olive oil against TAA-induced hepatotoxicity in rats. We showed that TAA-induced increase in liver oxidative stress, judged by the changes in the activities of SOD, CAT, GPx, GR, GST, the content of GSH and 4-HNE, and expression of HO-1, MnSOD, and CuZnSOD, was more effectively ameliorated with a lower C60 dose. Improvement in liver antioxidative status caused by C60 was accompanied by a decrease in liver HMGB1 expression and an increase in nuclear Nrf2/NF-κB p65 ratio, suggesting a reduction in inflammation, necrosis and fibrosis. These results were in accordance with liver histology analysis, liver comet assay, and changes in serum levels of ALT, AST, and AP. The changes observed in gut microbiome support detrimental effects of TAA and hepatoprotective effects of low C60 dose. Less protective effects of a higher C60 dose could be a consequence of its enhanced aggregation and related pro-oxidant role.

Development and Validation of a Multivariable Predictive Model for Mortality of COVID-19 Patients Demanding High Oxygen Flow at Admission to ICU: AIDA Score.

INTRODUCTION: Risk stratification is an important aspect of COVID-19 management, especially in patients admitted to ICU as it can provide more useful consumption of health resources, as well as prioritize critical care services in situations of overwhelming number of patients. MATERIALS AND METHODS: A multivariable predictive model for mortality was developed using data solely from a derivation cohort of 160 COVID-19 patients with moderate to severe ARDS admitted to ICU. The regression coefficients from the final multivariate model of the derivation study were used to assign points for the risk model, consisted of all significant variables from the multivariate analysis and age as a known risk factor for COVID-19 patient mortality. The newly developed AIDA score was arrived at by assigning 5 points for serum albumin and 1 point for IL-6, D dimer, and age. The score was further validated on a cohort of 304 patients admitted to ICU due to the severe form of COVID-19. RESULTS: The study population included 160 COVID-19 patients admitted to ICU in the derivation and 304 in the validation cohort. The mean patient age was 66.7 years (range, 20-93 years), with 68.1% men and 31.9% women. Most patients (76.8%) had comorbidities with hypertension (67.7%), diabetes (31.7), and coronary artery disease (19.3) as the most frequent. A total of 316 patients (68.3%) were treated with mechanical ventilation. Ninety-six (60.0%) in the derivation cohort and 221 (72.7%) patients in the validation cohort had a lethal outcome. The population was divided into the following risk categories for mortality based on the risk model score: low risk (score 0-1) and at-risk (score > 1). In addition, patients were considered at high risk with a risk score > 2. By applying the risk model to the validation cohort (n = 304), the positive predictive value was 78.8% (95% CI 75.5% to 81.8%); the negative predictive value was 46.6% (95% CI 37.3% to 56.2%); the sensitivity was 82.4% (95% CI 76.7% to 87.1%), and the specificity was 41.0% (95% CI 30.3% to 52.3%). The C statistic was 0.863 (95% CI 0.805-0.921) and 0.665 (95% CI 0.598-0.732) in the derivation and validation cohorts, respectively, indicating a high discriminative value of the proposed score. CONCLUSION: In the present study, AIDA score showed a valuable significance in estimating the mortality risk in patients with the severe form of COVID-19 disease at admission to ICU. Further external validation on a larger group of patients is needed to provide more insights into the utility of this score in everyday practice.

Predictors of Mortality in Critically Ill COVID-19 Patients Demanding High Oxygen Flow: A Thin Line between Inflammation, Cytokine Storm, and Coagulopathy.

INTRODUCTION: Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality. METHODS: We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients. RESULTS: The mean patient age was 65.6 years (range, 29-92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25th to 75th percentile: 6-18), while the median total number of hospital stay was 18 (25th to 75th percentile: 12-28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis. CONCLUSION: In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.

ABCB1 polymorphism in clopidogrel-treated Montenegrin patients.

Clopidogrel is an antiplatelet drug that displays significant interindividual variability in treatment response. Its bioavailability depends on the function of P-glycoprotein (P-gp), which is coded by a highly polymorphic ABCB1 gene. Thus, the aim of this study was to investigate the effect of ABCB1 genetic polymorphism on clopidogrel efficacy and safety and to determine the frequency distribution of its most common single nucleotide polymorphisms (SNPs) in 106 Montenegrin cardiology patients. Clopidogrel efficacy and safety were followed up during 1 year after hospitalization, with the lack of efficacy and adverse drug reactions observed in 11 (10.4%) and 8 patients (7.5%), respectively. Genotyping for ABCB1 SNPs rs1128503 (1236C > T), rs2032582 (2677G > A/T), and rs1045642 (3435C > T) was performed by the real-time PCR method, and the variant alleles were detected with the frequencies of 42.9, 44.8, and 52.8%, respectively. No significant association was observed between any of the examined genotypes and clopidogrel efficacy (p = 0.253) or safety (p = 0.424). Due to small sample size, co-treatment with other drugs, and other genetic factors not taken into account, we believe the absence of correlation between ABCB1 genotypes and indicators of clopidogrel efficacy and safety in this study should be apprehended conditionally, and that larger and better-controlled studies are warranted.