Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors.

The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II, and XII, with each containing a reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based drug design with the one-pot Ugi four-component reaction, we discovered one of the most potent noncovalent inhibitors, 23R (Jun8-76-3A) that is structurally distinct from the canonical Mpro inhibitor GC376. Significantly, 23R is highly selective compared with covalent inhibitors such as GC376, especially toward host proteases. The cocrystal structure of SARS-CoV-2 Mpro with 23R revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 Mpro inhibitors reported to date, and a novel binding pocket in Mpro that can be explored for inhibitor design.

Therapeutic hypothermia as a treatment option after out-ofhospital cardiac arrest: our experience.

Aim To examine the effects of therapeutic hypothermia on the outcome of patients with the diagnosis of out-of-hospital cardiac arrest (OHCA). Methods The study included 76 patients who were hospitalised at the Medical Intensive Care Unit (MICU) of the Clinical Centre University of Sarajevo, with the diagnosis of out-of-hospital cardiac arrest, following the return of spontaneous circulation. Therapeutic hypothermia was performed with an average temperature of 33oC (32.3 - 34.1o C) on the patients who had coma, according to the Glasgow Coma Scale (GCS). Results Multiple organ dysfunction syndrome (MODS) significantly affected survival (p=0.0001), as its presence reduced patients' survival by 96%. In addition, ventricular fibrillation (VF) as the presenting rhythm, also significantly affected survival (p=0.019). A degree of patient's coma, as measured by the GCS, significantly affected survival (p=0.011). For each increasing point on the GCS, the chance for survival increased twice. Moreover, other physiological factors such as the pH and the lactate serum levels significantly affected patients' survival (p=0.012 and p=0.01, respectively). Conclusion In patients with the diagnosis of OHCA who underwent to the treatment with therapeutic hypothermia, verified VF as a presenting rhythm was a positive predictive factor for their outcome. Therefore, therapeutic hypothermia represents an option of therapeutic modality for this type of patients.

Targeted temperature management after out-of-hospital cardiac arrest in three young patients.

OBJECTIVE: We present the use of targeted temperature management in a tertiary-level intensive care unit, in three patients who experienced an out-of-hospital cardiac arrest. CASE REPORT: Three young patients experienced an out-of-hospital non-coronary cardiac arrest. The causes of the cardiac arrest were: Wolf-Parkinson-White syndrome, drug overdose and long-QT syndrome. All patients were resuscitated according to the advanced cardiac life support guidelines, and treated with targeted temperature management, with a target temperature of 33°C for 24 hours. After completion of targeted temperature management, all the patients regained full consciousness and were discharged from hospital without any neurological sequelae. CONCLUSION: Targeted temperature management may improve survival and neurological outcome in patients after out-of-hospital cardiac arrest.

Hyperlactatemia and the Importance of Repeated Lactate Measurements in Critically Ill Patients.

OBJECTIVE: The aim of the study was to describe the prevalence of hyperlactatemia and emphasis on repeated lactate measurements in critically ill patients, and the associated mortality. MATERIALS AND METHODS: The study included 70 patients admitted in the Medical Intensive Care Unit at the Clinical Center, University of Sarajevo, in a 6-month period (July - December 2015). The following data were obtained: age, gender, reason for admission, Simplified Acute Physiology Score II, Acute Physiology and Chronic Health Evaluation, lactate concentrations upon admission, after 24 and 48 hours, and outcome (discharge from hospital or death). RESULTS: Upon admission,hyperlactatemia was present in 91.4% patients with a mean concentration of lactate 4.13 ±1.21 mmol/L. Lactate concentration at 48 hours was independently associated within creased in-hospital mortality (P = 0.018). CONCLUSION: Persistent hyperlactatemia is associated with adverse outcome in critically ill patients. Lactate concentration at 48 hours is independently associated within creased in-hospital mortality and it represents a statistically significant predictive marker of fatal outcomes of patients. Blood lactate concentrations > 2.25 mmol/L should be used by clinicians to identify patients at higher risk of death.

Predictive value of SAPS II and APACHE II scoring systems for patient outcome in a medical intensive care unit.

OBJECTIVE: The aim is to determine SAPS II and APACHE II scores in medical intensive care unit (MICU) patients, to compare them for prediction of patient outcome, and to compare with actual hospital mortality rates for different subgroups of patients. METHODS: One hundred and seventy-four patients were included in this analysis over a oneyear period in the MICU, Clinical Center, University of Sarajevo. The following patient data were obtained: demographics, admission diagnosis, SAPS II, APACHE II scores and final outcome. RESULTS: Out of 174 patients, 70 patients (40.2%) died. Mean SAPS II and APACHE II scores in all patients were 48.4±17.0 and 21.6±10.3 respectively, and they were significantly different between survivors and non-survivors. SAPS II >50.5 and APACHE II >27.5 can predict the risk of mortality in these patients. There was no statistically significant difference in the clinical values of SAPS II vs APACHE II (p=0.501). A statistically significant positive correlation was established between the values of SAPS II and APACHE II (r=0.708; p=0.001). Patients with an admission diagnosis of sepsis/septic shock had the highest values of both SAPS II and APACHE II scores, and also the highest hospital mortality rate of 55.1%. CONCLUSION: Both APACHE II and SAPS II had an excellent ability to discriminate between survivors and non-survivors. There was no significant difference in the clinical values of SAPS II and APACHE II. A positive correlation was established between them. Sepsis/septic shock patients had the highest predicted and observed hospital mortality rate.

Hyperglycemia in Critically Ill Patients: Management and Prognosis.

INTRODUCTION: Hyperglycemia is a common complication of critical illness. Patients in intensive care unit with stress hyperglycemia have significantly higher mortality (31%) compared to patients with previously confirmed diabetes (10%) or normoglycemia (11.3%). Stress hyperglycemia is associated with increased risk of critical illness polyneuropathy (CIP) and prolonged mechanical ventilation. Intensive monitoring and insulin therapy according to the protocol are an important part of the treatment of critically ill patients. OBJECTIVE: To evaluate the incidence of stress hyperglycemia, complications and outcome in critically ill patients in our Medical intensive care unit. MATERIALS AND METHODS: This study included 100 patients hospitalized in Medical intensive care unit during the period January 2014-March 2015 which were divided into three groups: Diabetes mellitus, stress-hyperglycemia and normoglycemia. During the retrospective-prospective observational clinical investigation the following data was obtained: age, gender, SAPS, admission diagnosis, average daily blood glucose, highest blood glucose level, glycemic variability, vasopressor and corticosteroid therapy, days on mechanical ventilation, total days of hospitalization in Medical intensive care unit, and outcome. RESULTS: Patients with DM treated with a continuous insulin infusion did not have significantly more complications than patients with normoglycemia, unlike patients with stress hyperglycemia, which had more severe prognosis. There was a significant difference between the maximum level of blood glucose in recovered and patients with adverse outcome (p = 0.0277). Glycemic variability (difference between max. and min. blood glucose) was the strongest predictor of adverse outcome. The difference in glycemic variability between the stress-hyperglycemia and normoglycemic group was statistically significant (p = 0.0066). There was no statistically significant difference in duration of mechanical ventilation and total days of hospitalization in the intensive care unit between the groups. CONCLUSION: Understanding of the objectives of glucose regulation and effective glycemic control is essential for the proper optimization of patient outcomes.