Background: Response to the outbreak of poliomyelitis in mid-1950 led to recognition and consequent development of critical care. Seventy years later the humankind was struck by COVID-19, another major challenge for critical care medicine which was especially big in Low-Resources-Settings where more than two thirds of the world population live, including the population of the Republic of Srpska (RS). Design and methods: The main aim was to show an overview of all interventions in order to boost hospitals’ capacities to the level which is sufficient to manage high amount of critically ill COVID-19 patients in the RS. A before-after cohort study design was conducted to evaluate the effects of interventions for increase in preparedness and capacity of ICUs for admission and treatment of COVID-19 critically ill patients in nine hospitals in the RS. Results: Following interventions, the biggest and university affiliated hospital in the RS has increased ICU capacities: total number of ICU beds increased by 38% and number of ventilators by 114%. Availability of machines for veno-venous extracorporeal membrane oxygenation (vvECMO) increased by 100%. Number of doctors who were involved in treatment of critically ill patients increased by 47% and nurse/patient’s ratio reached 1:2.5. Similarly, all other hospitals experienced boosting of ICU beds by 189% and ventilators by 373% while number of doctors increased by 108% and nurse/patient’s ratio reached 1:4. Conclusion: All interventions implemented during COVID-19 pandemic outbreak in the RS resulted in increasing capacity for treatment of critically ill patients, but the education of health care professionals was identified as the most important conducted intervention.

Background and Objectives: Coronavirus disease 2019 (COVID-19) is a novel infectious disease that has spread worldwide. As of 5 March 2020, the COVID-19 pandemic has resulted in approximately 111,767 cases and 6338 deaths in the Republic of Srpska and 375,554 cases and 15,718 deaths in Bosnia and Herzegovina. Our objective in the present study was to determine the characteristics and outcomes of critically ill pregnant/postpartum women with COVID-19 in the Republic of Srpska. Materials and Methods: The retrospective observational study of prospectively collected data included all critically ill pregnant/postpartum women with COVID-19 in a university-affiliated hospital between 1 April 2020 and 1 April 2022. Infection was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) from nasopharyngeal swab specimens and respiratory secretions. Patients’ demographics, clinical and laboratory data, pharmacotherapy, and neonatal outcomes were analysed. Results: Out of the 153 registered pregnant women with COVID-19 treated at the gynaecology department of the University Clinical Centre of the Republic of Srpska, 19 (12.41%) critically ill pregnant/postpartum women (median age of 36 (IQR, 29–38) years) were admitted to the medical intensive care unit (MICU). The mortality rate was 21.05% (four patients) during the study period. Of all patients (19), 14 gave birth (73.68%), and 4 (21.05%) were treated with veno-venous extracorporeal membrane oxygenation (vvECMO). Conclusions: Fourteen infants were born prematurely and none of them died during hospitalisation. A high mortality rate was detected among the critically ill pregnant/postpartum patients treated with mechanical ventilation and vvECMO in the MICU. The preterm birth rate was high in patients who required a higher level of life support (vvECMO and ventilatory support).

INTRODUCTION: This study was created to analyze dynamic alterations in coagulation, hematological and biochemical parameters and their association with mortality of COVID-19 patients. To identify the most sensitive biomarkers as predictors of mortality more research is required. METHODS: The present study was a prospective, one-year-long observational study conducted on all critically ill, COVID–19 patients with respiratory failure. The following data were collected: demographic and clinical characteristics of the study population, comorbidities, coagulation, biochemical and hematological parameters. The primary outcome was the proportion of patients who died. RESULTS: 91 patients with median age 60 (50–67), 76.9% male, met the acute respiratory distress syndrome criteria. It was tested whether dynamic change (delta-Δ) of parameters that were found to be predictors of mortality is independently associated with poor outcome. Adjusted (multivariate) analysis was used, where tested parameters were corrected for basic and clinical patients characteristics. The only inflammatory parameter which dynamic change had statistically significant odds ratio was ΔCRP (p < 0.005), while among coagulation parameters statistically significant OR was found for Δ fibrinogen (p < 0.005) in predicting mortality. CONCLUSION: Monitoring of coagulation, hematological and biochemical parameters abnormalities and their dynamical changes can potentially improve management and predict mortality in critically ill COVID –19 patients.

Background and objectives: the aim of this study was to analyse the utilisation of proton pump inhibitors (PPIs) during a 12-year period and to show the characteristics and patterns of their prescribing. Materials and methods: firstly, in the pharmacoepidemiological analyses the ATC/DDD methodology was used to assess the utilisation of PPIs in the Republic of Srpska. The annual PPI utilisation was expressed as a number of DDD/1000 inhabitants/year. Secondly, the cross-sectional surveys were used to reveal the characteristics of PPIs prescribing and medicines use, namely the dose, duration and indication, and possible adverse reactions. For the purposes of the surveys, the adapted version of questionnaires related to physicians’ and patients’ perspectives of medicines prescribing and use were performed. Results: the utilisation of medicines for alimentary tract and metabolism (group A/ATC classification) increased by almost threefold in a 12-year period, which was consistent with the total medicine utilisation. Pantoprazole was the most prescribed medicine among the PPIs. With the exclusion of PPIs in the therapy of Helicobacter pylori eradication, more than half of family physicians prescribed PPIs with antibiotics, and only 53/239 physicians, noticed some adverse reactions of PPIs in their patients. Most of the patients knew how to use PPIs and were taking these medicines in recommended daily doses, but approximately 45% of them were using PPIs for a long period of time (>6 months). Conclusions: the overuse of PPIs is a major concern due to potential serious adverse reactions, especially in elderly patients and in a case of prolonged exposure.

Background: Our recent study has shown that pomegranate peel extract (PEx) showed significant immunomodulatory activity, which might be caused by ellagitannins. The aim of this work was to test the hypothesis that ellagitannin components act synergistically in the modulation of cytokine production. Methods: Human peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with phytohemagglutinin and treated with different concentrations of PEx or punicalagin (PG), punicalin (PN), and ellagic acid (EA), alone or with their combinations. Cytotoxicity, cell proliferation, and cytokine production were determined. Results: Non-cytotoxic concentrations of all compounds significantly inhibited cell proliferation. IC50 values (μg/mL) were: EA (7.56), PG (38.52), PEx (49.05), and PN (69.95). PEx and all ellagitannins inhibited the levels of TNF-α, IL-6, and IL-8, dose-dependently, and their combinations acted synergistically. PEx and all ellagitannins inhibited Th1 and Th17 responses, whereas the lower concentrations of PEx stimulated the production of IL-10, a Treg cytokine, as did lower concentrations of EA. However, neither component of ellagitannins increased Th2 response, as was observed with PEx. Conclusions: The combination of PG, PN, and EA potentiated the anti-inflammatory response without any significant synergistic down-modulatory effect on T-cell cytokines. The increased production of IL-10 observed with PEx could be attributable to EA, but the examined ellagitannins are not associated with the stimulatory effect of PEx on Th2 response.

Since the outbreak of the COVID-19 pandemic, it has been obvious that virus infection poses a serious threat to human health on a global scale. Certain plants, particularly those rich in polyphenols, have been found to be effective antiviral agents. The effectiveness of Alchemilla viridiflora Rothm. (Rosaceae) methanol extract to prevent contact between virus spike (S)-glycoprotein and angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors was investigated. In vitro results revealed that the tested samples inhibited 50% of virus-receptor binding interactions in doses of 0.18 and 0.22 mg/mL for NRP1 and ACE2, respectively. Molecular docking studies revealed that the compounds from A. viridiflora ellagitannins class had a higher affinity for binding with S-glycoprotein whilst flavonoid compounds more significantly interacted with the NRP1 receptor. Quercetin 3-(6″-ferulylglucoside) and pentagalloylglucose were two compounds with the highest exhibited interfering potential for selected target receptors, with binding energies of −8.035 (S-glycoprotein) and −7.685 kcal/mol (NRP1), respectively. Furthermore, computational studies on other SARS-CoV-2 strains resulting from mutations in the original wild strain (V483A, N501Y-K417N-E484K, N501Y, N439K, L452R-T478K, K417N, G476S, F456L, E484K) revealed that virus internalization activity was maintained, but with different single compound contributions.

Background and Objectives: Benzodiazepines (BZDs) are among the most prescribed psychotropic drugs and significant number of patients use these drugs for longer periods than recommended. The objective of this study was to determine the factors associated with prescribing of BZDs at the primary healthcare level. Materials and Methods: A retrospective analysis of family physicians’ prescriptions from the databases of family medicine teams of the Republic of Srpska was performed. The number of BZDs users, as well as the total number of prescriptions, were determined. Thereafter, it was determined which specific BZD had been prescribed, in which dose, for how long, as well as the specific social and demographic characteristics of patients to whom the drugs were prescribed. Results: The results showed that 38.47% of patients used the BZDs for a period longer than six months. The most frequent BZDs prescribed were the intermediate-acting BZDs, primarily bromazepam (58.69%). Two thirds of patients were women. The average age of the patients was 60, 60.46% of patients were single, and 69.68% lived in urban areas. The longer uses of BZDs were recorded in women, the elderly, single people and those who lived in urban areas, while higher doses of BZDs were prescribed to men, as well as younger and married people. The highest positive correlation was found between the dose and length of use of BZD. Conclusions: A significant percentage of patients used BZDs for a time period longer than recommended. Caution is necessary when prescribing BZDs to women, the elderly, patients that live in urban areas and patients who are single. When prescribing BZDs, family physicians should be aware of their potential interactions and addictive potentials.

Background: In last 2 decades, there have been substantial changes in the utilization patterns of antihypertensive medicines following new clinical trials and the introduction of new treatment guidelines. The aim of this study was to analyze utilization and prescribing patterns regarding antihypertensive medicines in the Republic of Srpska, Bosnia and Herzegovina during an 11-years follow-up according to national and European treatment guidelines. Methods: In this retrospective, observational study, medicine utilization data were analyzed between 2009–2019 period using the ATC/DDD methodology and expressed as the number of DDD/1,000 inhabitants/day (DID/TID). The medicine utilization 90% (DU90%) method was used for determine the quality of prescribing. Results: During the observed period, the use of antihypertensive medicines increased more than 3-times (125.97 DDD/TID in 2009 vs 414.95 DDD/TID in 2019), corresponding to a rise in the prevalence of hypertensive patients from 91.7/1,000 to 186.3/1,000 in the same period. This was mainly driven by increased use of angiotensin converting enzyme inhibitors with 241.69%, beta blockers with 146.87%, calcium channel blockers with 251.55%, and diuretics with 178.95%. Angiotensin receptor blockers were the fastest growing group of antihypertensive medicines in this period and their utilization increased nearly 40 times. Conclusions: The overall antihypertensive medicines utilization was largely influenced by national and ESH/ESC guidelines and strongly corresponded to the positive medicine list of the national health insurance fund. Antihypertensive medicines utilization is comparable with medicine utilization trends in other countries.

Pomegranate peel extract (PoPEx) has been shown to have antioxidant and anti-inflammatory properties, but its effect on the adaptive immune system has not been sufficiently investigated. In this study, the treatment of human peripheral blood mononuclear cells (PBMC) with PoPEx (range 6.25–400 µg/mL) resulted in cytotoxicity at concentrations of 100 µg/mL and higher, due to the induction of apoptosis and oxidative stress, whereas autophagy was reduced. At non-cytotoxic concentrations, the opposite effect on these processes was observed simultaneously with the inhibition of PHA-induced PBMC proliferation and a significant decrease in the expression of CD4. PoPEx differently modulated the expression of activation markers (CD69, CD25, ICOS) and PD1 (inhibitory marker), depending on the dose and T-cell subsets. PoPEx (starting from 12.5 µg/mL) suppressed the production of Th1 (IFN-γ), Th17 (IL-17A, IL-17F, and IL-22), Th9 (IL-9), and proinflammatory cytokines (TNF-α and IL-6) in culture supernatants. Lower concentrations upregulated Th2 (IL-5 and IL-13) and Treg (IL-10) responses as well as CD4+CD25hiFoxp3+ cell frequency. Higher concentrations of PoPEx increased the frequency of IL-10- and TGF-β-producing T-cells (much higher in the CD4+ subset). In conclusion, our study suggested for the first time complex immunoregulatory effects of PoPEx on T cells, which could assist in the suppression of chronic inflammatory and autoimmune diseases.

Carvacrol is the main compound of essential oils extracted primarily from Thymus and Origanum species. Its various biological activities were confirmed: antioxidant, anti-inflammatory, antibacterial, antifungal, anti-tumour, antinematodal and vasorelaxant action. Although vasodilation mediated by carvacrol was previously described, the exact mechanism of its action has not yet been established. Hence, the aim of this study was to investigate carvacrol vasoactivity on human umbilical arteries (HUA) and different pathways involved in its mechanism of action using tissue bath methodology. Carvacrol caused a significant decrease in vascular tension of 5-HT-pre-contracted umbilical arteries, with EC50 of 442.13 ± 33.8 µM (mean ± standard error of the mean - SEM). At 300 µM, carvacrol shifted downward the 5-HT concentration-response curve with statistical significance of p < 0.001 obtained for the four highest concentrations. At concentration of 1 mM, carvacrol completely abolished BaCl2-induced contraction in Ca2+-free Krebs-Ringer bicarbonate solution (p < 0.001). Isopentenyl pyrophosphate, the antagonist of TRPV3 channel, was able to decrease the efficacy of carvacrol (p < 0.001). The vasorelaxant effect of carvacrol seems to involve the blocking of L-type of Ca2+ channels on smooth muscle cells. However, the role of TRPV3 channels in carvacrol-induced vasodilation of HUA cannot be excluded either.

Introduction: The early approaches to prevent the spread of COVID-19 included lockdown and social distancing measures, leading to university closures. These measures forced unparalleled changes to the delivery of healthcare education. Concerns included the preparedness of faculty and students to e-learning as well as the routine availability and funding of equipment and internet bundles. This needed addressing with fully trained healthcare professionals required given rising inappropriate use of antibiotics in India, growing prevalence of non-communicable diseases as well as an increasing number of patients with joint comorbidities. Consequently, there is a need to ascertain the current impact of the pandemic on healthcare student education across India. Materials and Methods: This was a pilot study among 10 purposely selected healthcare educators in both private and public universities. The questionnaire built on published studies. Results: Identified challenges included a lack of familiarity with online education, no bedside teaching, lack of equipment and affordability of internet bundles, poor internet connectivity and postponed examinations. Ways forward included training faculty on e-learning, providing students with loans and other financial support to purchase equipment and internet bundles, establishing COVID-19 prevention protocols and protective equipment, recording lectures and tutorials to make up for lost time and simulated methods to teach clinical aspects. Conclusion: Despite challenges, there was a rapid move to online learning among surveyed universities. Alongside this, courses to address lack of familiarity with e-learning approaches with hybrid teaching approaches here to stay. The next step will be to undertake a wider study and to use the combined findings to provide future guidance.

Cardiovascular diseases are the leading cause of death and the main cause of disability. In the last decade, homocysteine has been found to be a risk factor or a marker for cardiovascular diseases, including myocardial infarction (MI) and heart failure (HF). There are indications that vitamin B6 plays a significant role in the process of transsulfuration in homocysteine metabolism, specifically, in a part of the reaction in which homocysteine transfers a sulfhydryl group to serine to form α-ketobutyrate and cysteine. Therefore, an elevated homocysteine concentration (hyperhomocysteinemia) could be a consequence of vitamin B6 and/or folate deficiency. Hyperhomocysteinemia in turn could damage the endothelium and the blood vessel wall and induce worsening of atherosclerotic process, having a negative impact on the mechanisms underlying MI and HF, such as oxidative stress, inflammation, and altered function of gasotransmitters. Given the importance of the vitamin B6 in homocysteine metabolism, in this paper, we review its role in reducing oxidative stress and inflammation, influencing the functions of gasotransmitters, and improving vasodilatation and coronary flow in animal models of MI and HF.