Antiviral Protein-Protein Interaction Inhibitors.

Continually repeating outbreaks of pathogenic viruses necessitate the construction of effective antiviral strategies. Therefore, the development of new specific antiviral drugs in a well-established and efficient manner is crucial. Taking into account the strong ability of viruses to change, therapies with diversified molecular targets must be sought. In addition to the widely explored viral enzyme inhibitor approach, inhibition of protein-protein interactions is a very valuable strategy. In this Perspective, protein-protein interaction inhibitors targeting HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya viruses are reviewed and discussed. Antibodies, peptides/peptidomimetics, and small molecules constitute three classes of compounds that have been explored, and each of them has some advantages and disadvantages for drug development.

Evaluation of the BioFire® FilmArray® Pneumonia plus Panel for Detecting Bacterial Etiological Agents of Lower Respiratory Tract Infections in an Oncologic Hospital. Comparison with Conventional Culture Method.

Conventional methods used to determine pneumonia pathogens are characterized by low sensitivity and long turnaround times. Introducing new tests with better parameters in patients at higher risk of infections is highly anticipated. The results of the conventional quantitative culture method (CM) in determining the bacterial etiology of pneumonia were compared with the results of the Pneumonia plus Panel test (PNP; BioFire® Diagnostics, USA) in 79 samples of bronchoalveolar lavage (BAL). Materials were collected from 79 patients with suspected pneumonia treated in an oncologic hospital due to solid tumors. Only 16/79 BAL samples (20.3%) were true positive (TP) for bacterial etiology in CM vs. 27/79 samples (34.2%) true positive in the PNP test. The total agreement between methods of interpreting the result (positive or negative) was 84.8%. The most prevalent pathogens in both methods were Staphylococcus aureus, followed by Escherichia coli, Pseudomonas aeruginosa, and Haemophilus influenzae. The PNP test identified several respiratory pathogens that were not grown in culture. The semiquantitative value reported by the PNP test was higher than that reported by culture. The PNP test vs. combined test (PNP test and CM methods) demonstrated positive predictive value (PPV) and negative predictive value (NPV) values of 100.0% and 98.1%, and the sensitivity and specificity were 96.4% and 100.0%. The PNP test is a good tool for determining the etiology of bacterial pneumonia and may support the care of an oncologic patient. However, further large-sample studies are needed to research in strictly defined groups of oncologic patients.

Intraoperative Hypotension and Its Association with Postoperative Acute Kidney Injury in Patients Undergoing Pancreaticoduodenectomy: A 5-Year, Single-Center, Retrospective Cohort Study.

BACKGROUND Intraoperative hypotension (IOH) is a common phenomenon in high-risk surgery and is often linked to postoperative acute kidney injury (AKI). Pancreaticoduodenectomy (PD), or Whipple's procedure, is a lengthy and complex surgical procedure to remove the head of the pancreas, gallbladder and bile duct, and the first part of the duodenum. This retrospective 5-year study from a single center in Poland included 303 patients who underwent PD and evaluated IOH as a factor associated with AKI. MATERIAL AND METHODS We analyzed perioperative data to assess how various IOH thresholds can predict AKI (according to KDIGO criteria). Several IOH definitions were applied, including absolute and relative thresholds, based on the mean arterial pressure (MAP). Statistically significant IOH thresholds were inserted into multivariable logistic regression models with previously established independent variables. RESULTS We included 303 patients over a 5-year period (2016-2021). There were 58 (19.1%) cases of postoperative AKI. MAP <55 mmHg and a maximal% drop from preinduction MAP were the only IOH definitions associated with AKI. Multivariable analysis revealed that max% drop from preinduction MAP (per 10%, OR=1.65; AUROC=0.70) was the IOH definition best suited for AKI prediction in patients undergoing PD. CONCLUSIONS In patients undergoing PD, it is important to prevent excessive blood pressure drops in regards to preinduction blood pressure values. In this cohort, relative IOH thresholds were better suited for prediction of AKI than the absolute IOH thresholds.

Hepatic Encephalopathy Confirmed by Magnetic Resonance Imaging in a Patient with Unobvious Cause of Chronic Liver Disease Decompensation.

Fifty-four-year old male was admitted to the intensive care unit (ICU) due to impaired consciousness. Past medical history included alcohol dependence, liver cirrhosis, esophageal varices, 2 esophageal varices banding procedures in the past, pathological obesity. Computed tomography (CT) examination of the head performed in the referring hospital was normal. At admission the CT examination of the head was repeated and showed no abnormalities. Urgent esophagogastroduodenoscopy revealed presence of esophageal varices and scarification following previous banding procedures located in the middle and lower part of the esophagus. Gastrointestinal bleeding being the most likely cause of chronic liver decompensation was therefore excluded. Multimodal neurologic diagnostic assessment was negative. Finally magnetic resonance imaging (MRI) of the head was performed. Taking into account clinical picture and the MRI result, the differential diagnosis included chronic liver encephalopathy, exacerbated acquired hepatocerebral degeneration, and acute liver encephalopathy. Due to history of umbilical hernia CT of the abdomen and pelvis was performed and showed intussusception of the ileum, confirming hepatic encephalopathy. In this case report the MRI suggested the diagnosis of hepatic encephalopathy and prompted search for alternative causes of decompensation of chronic liver disease.

Diagnostic Accuracy of Platelet-Derived Parameters in Prognostication in Neurosurgery.

Introduction. Platelets (PLT) are key mediators in thrombotic and inflammatory processes. Their activity increases with size, so the mean platelet volume (MPV) can be a potential predictor of perioperative complications. The aim of the study was to assess the suitability of platelet parameters in predicting the risk of hospital death in neurosurgery. Methods. Retrospective observation covered 452 patients undergoing surgery in the period March 2018−August 2018. High-risk patients accounted for 44% (i.e., ASA-PS class III+) and 9% (i.e., ≥1 Shoemaker criterion), respectively, and 14% of procedures were performed in the urgent mode. The preoperative platelet parameters that were assessed and analysed were: total platelet count (PLT), mean platelet volume (MPV), plateletcrit (PCT) and platelet distribution width (PDW). The end point of the study was a hospital death. Results. Before discharge from the hospital, 13 patients died. The medians (IQR) PLT, MPV PDW and PCT were, respectively: 230 × 106 L−1 (182−279); 9.2 fL (8.3−10.1); 14% (12.5−16.3); and 21% (17−26). PLT, PCT and PDW were not useful in the risk assessment. MPV was lower in patients who died (9.3 vs. 8.3 fL, p < 0.01) and predicted death occurred in 76% (AUC = 0.76, 95%CI 0.72−0.80, p < 0.01). Further, after adjustment for confounders, MPV remained a significant predictor of in-hospital death (logOR[MPV] = 0.31, AUC = 0.94, 95%CI 0.92−0.96, p = 0.02). Conclusion. The reduction in the average volume of platelets is associated with a worse prognosis in neurosurgical patients.

Usefulness of Selected Peripheral Blood Counts in Predicting Death in Patients with Severe and Critical COVID-19.

BACKGROUND: Immune dysregulation and hypoxemia are two important pathophysiological problems in patients with COVID-19 that affect peripheral blood count parameters. We hypothesized that assessment of the neutrophil-lymphocyte ratio (NLR) and red blood cell distribution width index (RDW-SD) could predict death in patients with severe and critical COVID-19. METHODS: Seventy patients admitted to the intensive care unit (ICU) for COVID-19 acute respiratory failure were included in the study. RDW-SD and NLR on the day of ICU admission and peak values during the entire hospitalization were assessed. The primary endpoint was death before ICU discharge. RESULTS: Patients who died had higher NLR on admission (20.3, IQR 15.3-30.2 vs. 11.0, IQR 6.8-16.9; p = 0.003) and higher RDW-SD (48.1 fL; IQR 43.1-50.5 vs. 43.9 fL; IQR 40.9-47.3, p = 0.01) than patients discharged from the ICU. NLR and RDW-SD values on ICU admission accurately predicted death in 76% (AUC = 0.76; 95%CI 0.65-0.86; p = 0.001; cut-off > 14.38) and 72% of cases (AUC = 0.72; 95%CI 0.60-0.82; p = 0.003; cut-off > 44.7 fL), respectively. Multivariable analysis confirmed that NLR > 14.38 on the day of ICU admission was associated with a 12-fold increased risk of death (logOR 12.43; 95%CI 1.61-96.29, p = 0.02), independent of other blood counts, clinical and demographic parameters. CONCLUSIONS: Neutrophil-lymphocyte ratio determined on the day of ICU admission may be a useful biomarker predicting death in patients with severe and critical COVID-19.

Hemodynamic Monitoring by Smartphone-Preliminary Report from a Comparative Prospective Observational Study.

BACKGROUND: Advanced hemodynamic monitoring supports making therapeutic decisions in critically ill patients. New technologies, including mobile health, have been introduced into the hemodynamic monitoring armamentarium. However, each monitoring method has potential limitations-content, technical and organizational. The aim of this study was to assess the comparability between measurements obtained with two arterial pressure cardiac output methods: Capstesia™ smartphone hemodynamic software (CS) and LiDCO Rapid™ uncalibrated hemodynamic monitor (LR). METHODS: The initial analysis included 16 patients in the period 06-09 2020 without limitations that could make the results obtained unreliable. Eighty pairs of cardiac output measurements were obtained. The comparability of cardiac output results obtained with both methods was assessed using the Spearman's rank correlation coefficient (R), the intra-class correlation (CCC) and the Bland-Altman curves analysis (B-A). RESULTS: The median (IQR) cardiac output measured with CS and LR were 4.6 (3.9-5.7) and 5.5 (4.6-7.4) L min-1, respectively. In the B-A analysis, CS cardiac output values were on average 1.2 (95% CI -2.1-4.4) L min-1 lower than LR values. The correlation between cardiac output with CS and LR was moderate (r = 0.5; p = 0.04). After adjusting for the presence of the dicrotic notch on the pulse waveform, in the group of eight patients with a visible dicrotic notch, the CS and LR results differed by only 0.1 (95% CI -0.8-1.1) L min-1, the correlation between CS and LR was close to complete (r = 0.96; p < 0.001), and the percentage error was 40%, with a CCC-CS of 0.98 (95% CI 0.95-0.99). CONCLUSIONS: The CapstesiaTM smartphone software can provide an alternative method of cardiac output assessment in patients meeting arterial pressure cardiac output evaluation criteria with a clearly discernible dicrotic notch on the arterial pulse pressure waveform. It is necessary to confirm the obtained observations on a larger group of patients; however, it may potentially make objective hemodynamic measurements ubiquitous in patients with invasive arterial pressure monitoring with a clearly discernible dicrotic notch.

Veno-Venous Extracorporeal Membrane Oxygenation in COVID-19-Where Are We Now?

The recent development in extracorporeal life support (ECLS) has created new therapeutic opportunities for critically ill patients. An interest in extracorporeal membrane oxygenation (ECMO), the pinnacle of ECLS techniques, has recently increased, as for the last decade, we have observed improvements in the survival of patients suffering from severe acute respiratory distress syndrome (ARDS) while on ECMO. Although there is a paucity of conclusive data from clinical research regarding extracorporeal oxygenation in COVID-19 patients, the pathophysiology of the disease makes veno-venous ECMO a promising option.

Fluid Therapy in Patients Undergoing Abdominal Surgery: A Bumpy Road Towards Individualized Management.

Prudent intraoperative fluid replacement therapy, inotropes, and vasoactive drugs should be guided by adequate hemodynamic monitoring. The study aimed to evaluate the single-centre practice on intraoperative fluid therapy in abdominal surgery (AS). The evaluation, based on a review of medical files, included 235 patients (103 men), aged 60 ± 15 years who underwent AS between September and November 2017. Fluid therapy was analyzed in terms of quality and quantity. There were 124 high-risk patients according to the American Society of Anaesthesiologists Classification (ASA Class 3+) and 89 high-risk procedures performed. The median duration of procedures was 175 (IQR 106-284) min. Eleven patients died post-operatively. The median fluids volume was 10.4 mL/kg/h of anaesthesia, including 9.1 mL/kg/h of crystalloids and 2.7 mL/kg/h of synthetic colloids. Patients undergoing longer than the median procedures received significantly fewer fluids than those who underwent shorter procedures. The volume of fluids in the longer procedures depended on the procedural risk classification and was significantly greater in high-risk patients undergoing high-risk surgery. Patients who died received significantly more fluids than survivors. In all patients, a non-invasive blood pressure monitoring was used and only six patients had therapy guided by metabolic equilibrium. The fluid therapy used was liberal but complied with the recommendations regarding the type of fluid and risk-adjusted dosing. Hemodynamic monitoring was suboptimal and requires modifications. In conclusion, the optimization of intraoperative fluid therapy requires a balanced and standardized approach consistent with treatment procedures.

Validation of APACHE II, APACHE III and SAPS II scores in in-hospital and one year mortality prediction in a mixed intensive care unit in Poland: a cohort study.

BACKGROUND: There are several scores used for in-hospital mortality prediction in critical illness. Their application in a local scenario requires validation to ensure appropriate diagnostic accuracy. Moreover, their use in assessing post-discharge mortality in intensive care unit (ICU) survivors has not been extensively studied. We aimed to validate APACHE II, APACHE III and SAPS II scores in short- and long-term mortality prediction in a mixed adult ICU in Poland. APACHE II, APACHE III and SAPS II scores, with corresponding predicted mortality ratios, were calculated for 303 consecutive patients admitted to a 10-bed ICU in 2016. Short-term (in-hospital) and long-term (12-month post-discharge) mortality was assessed. RESULTS: Median APACHE II, APACHE III and SAPS II scores were 19 (IQR 12-24), 67 (36.5-88) and 44 (27-56) points, with corresponding in-hospital mortality ratios of 25.8% (IQR 12.1-46.0), 18.5% (IQR 3.8-41.8) and 34.8% (IQR 7.9-59.8). Observed in-hospital mortality was 35.6%. Moreover, 12-month post-discharge mortality reached 17.4%. All the scores predicted in-hospital mortality (p < 0.05): APACHE II (AUC = 0.78; 95%CI 0.73-0.83), APACHE III (AUC = 0.79; 95%CI 0.74-0.84) and SAPS II (AUC = 0.79; 95%CI 0.74-0.84); as well as mortality after hospital discharge (p < 0.05): APACHE II (AUC = 0.71; 95%CI 0.64-0.78), APACHE III (AUC = 0.72; 95%CI 0.65-0.78) and SAPS II (AUC = 0.69; 95%CI 0.62-0.76), with no statistically significant difference between the scores (p > 0.05). The calibration of the scores was good. CONCLUSIONS: All the scores are acceptable predictors of in-hospital mortality. In the case of post-discharge mortality, their diagnostic accuracy is lower and of borderline clinical relevance. Further studies are needed to create scores estimating the long-term prognosis of subjects successfully discharged from the ICU.

Antipsychotic Drugs in Prevention of Postoperative Delirium-What Is Known in 2020?

Delirium is one of the most frequently reported neuropsychiatric complications in the perioperative period, especially in the population of elderly patients who often suffer from numerous comorbidities undergoing extensive or urgent surgery. It can affect up to 80% of patients who require hospitalization in an intensive care setting postoperatively. Delirium increases mortality, morbidity, length of hospital stay, and cost of treatment. An episode of delirium in the acute phase may lower the general quality of life and increases the risk of cognitive decline long-term. Since pharmacological treatment of delirium is not highly effective, focus of research has shifted towards developing preventive strategies. We aimed to perform a review of the topic based on the most recent literature. We conclude that, based on the available data, it seems impossible to make strong recommendations for using antipsychotic drugs in prophylaxis. Further research should answer the question what, if any, benefit patients receive from the pharmacological prevention of delirium, and which agents should be used.

Sensitivity of Ixodes ricinus (L., 1758) and Dermacentor reticulatus (Fabr., 1794) ticks to entomopathogenic fungi isolates: preliminary study.

Entomopathogenic fungi of the genus Beauveria and Metarhizium play an important role in controlling the population of arthropods. However, the data on their effectiveness against ticks focus mainly on species that do not occur in Europe. The aim of the study was to assess the effectiveness of entomopathogenic fungi against two of the most important tick species in Europe: Ixodes ricinus and Dermacentor reticulatus. In our study, the majority of tested entomopathogenic fungi strains showed potential efficacy against both tick species; however, D. reticulatus was less susceptible in comparison to I. ricinus. The observed mortality of ticks was up to 100% by using all commercial strains as well as three out of nine of the environmental strains. Among all tested fungi, the most effective against both tick species was environmental strain Metarhizium anisopliae LO4(1) with LC50 values: 2.6 × 103 cfu/ml-5.7 × 105 cfu/ml. Botanigard proved to be more effective than MET52 with LC50 values: 6.8 × 103 cfu/ml-3.3 × 106 cfu/ml. The conducted bioassays indicate the potential possibility of using the environmental isolates of entomopathogenic fungi, as well as commercial strains in control of local populations of I. ricinus and D. reticulatus; however, the possibility of using them in vivo requires more research.

Clinical practice in intraoperative haemodynamic monitoring in Poland: a point prevalence study in 31 Polish hospitals.

BACKGROUND: Appropriate use of haemodynamic monitoring tools facilitates the adjustment of management to the patient's individual needs. The aim of the study was to evaluate clinical practice in intraoperative monitoring of patients undergoing non-cardiac surgical procedures in selected hospitals in Poland. METHODS: A point prevalence cross-sectional study was carried out among 587 adult patients of 31 Polish hospitals on April 5th, 2018. The method of monitoring in relation to the estimated individual risk as well as to the type and mode of surgery was analysed. In addition, intraoperative fluid therapy and use of catecholamines were evaluated. RESULTS: Basic monitoring based on non-invasive arterial blood pressure measurements was implemented in 562 (96%) patients. More advanced methods of monitoring were used in 25 (4%) patients during moderate- (n = 16) and high-risk (n = 9) procedures, predominantly in high-risk patients (n = 16) and in university hospital settings (n = 21). Patients monitored basically received significantly higher amounts of fluids, i.e. 8.7 (IQR 6.1-12.6) vs. 6.1 (IQR 4.1-8.6) mL kg-1 h-1, respectively (P < 0.001). The most common vasoactive and inotropic drug was ephedrine, administered to 143 (24%) study patients in a dose of 15 mg (IQR 10-25) - without inter-group differences in categories of individual and procedure-related risk. CONCLUSIONS: The basic method of haemodynamic monitoring used in the study population was based on non-invasive arterial blood pressure measurements. The advanced tools of intraoperative haemodynamic monitoring were seldom used. Monitoring was not tailored to the perioperative risk.

Clinical practice on intra-operative fluid therapy in Poland: A point prevalence study.

Intra-operative fluid therapy (IFT) is the cornerstone of peri-operative management as it may significantly influence the treatment outcome. Therefore, we sought to evaluate nationwide clinical practice regarding IFT in Poland.A cross-sectional, multicenter, point-prevalence study was performed on April 5, 2018, in 31 hospitals in Poland. Five hundred eighty-seven adult patients undergoing non-cardiac surgery were investigated. The volume and type of fluids transfused with respect to the patient and procedure risk were assessed.The study group consisted of 587 subjects, aged 58 (interquartile range [IQR] 40-67) years, including 142 (24%) American Society of Anesthesiology Physical Status (ASA-PS) class III+ patients. The median total fluid dose was 8.6 mL kg h (IQR 6-12.5), predominantly including balanced crystalloids (7.0 mL kg h, IQR 4.9-10.6). The dose of 0.9% saline was low (1.6 mL kg h, IQR 0.8-3.7). Synthetic colloids were used in 66 (11%) subjects. The IFT was dependent on the risk involved, while the transfused volumes were lower in ASA-PS III+ patients, as well as in high-risk procedures (P < .05).The practice of IFT is liberal but is adjusted to the preoperative risk. The consumption of synthetic colloids and 0.9% saline is low.

Sensitivity of Ixodes ricinus (L., 1758) and Dermacentor reticulatus (Fabr., 1794) ticks to Bacillus thuringiensis isolates: preliminary study.

Bacillus thuringiensis is a highly specific entomopathogenic microorganism. Although defined as having properties which work against insects, its role in the control of tick populations is still insufficiently known. In our bioassay, four environmental strains of B. thuringiensis, along with one commercially available product (Vectobac), have been used against ticks. Vectobac turned out to be ineffective in the biocontrol of ticks; however, two of environmental B. thuringiensis strains proved to be efficient against both Ixodes ricinus and Dermacentor reticulatus. In those cases, the mortality rate for ticks was assessed as being up to 80%, and LC50 ranged between 9.1 × 106 and 1.3 × 1015 (cfu/ml). Dermacentor reticulatus males were the most sensitive to bacteria. The similarity between the most and least efficient B. thuringiensis strains in enzymatic profiles-including lipases, phosphatases, proteases, and chitinases-may indicate a limited role of detected enzymes in the pathogenicity profile of bacterial strains against ticks.

Non-Anaesthetic Effects of Volatile Anaesthetics: A Short Trip on the Sea of Translational Medicine.

BACKGROUND: Volatile Anaesthetics (VA) are commonly used worldwide for induction and/or maintenance of general anaesthesia. They act in the central nervous system to reduce sensation and motor response during surgical and invasive diagnostic procedures. VAs also have some non-anaesthetic properties in the brain when administrated to patients at the extremes of age. Their biological impact on other organs should be taken into account during administration of anaesthesia. OBJECTIVE: In this review we summarize the recent knowledge on the non-anaesthetic effects of inhaled halogenic ethers on cells and tissues. RESULTS AND CONCLUSION: Exposure to VAs may promote lasting neuro-behavioural deficits in the brains of developing children and deterioration in cognitive performance in elderly individuals. Preconditioning with VAs can prevent or minimise tissue ischaemia in the heart and brain. VAs act as an antiinflammatory in response to tissue damage during surgery and may attenuate both local and systemic inflammatory response. Further research is needed to elucidate a link between laboratory findings and their possible effects in humans. Because many questions remain unanswered in this field, translational medicine should be more focused on safety in anaesthesia for the improvement public health.

Modern science for better quality control of medicinal products "Towards global harmonization of 3Rs in biologicals": The report of an EPAA workshop.

This article summarizes the outcome of an international workshop organized by the European Partnership for Alternative Approaches to Animal Testing (EPAA) on Modern science for better quality control of medicinal products: Towards global harmonization of 3Rs in biologicals. As regards the safety testing of biologicals, the workshop participants agreed to actively encourage the deletion of abnormal toxicity tests and target animal batch safety tests from all relevant legal requirements and guidance documents (country-specific guidelines, pharmacopoeia monographs, WHO recommendations). To facilitate the global regulatory acceptance of non-animal methods for the potency testing of, e.g., human diphtheria and tetanus vaccines and veterinary swine erysipelas vaccines, international convergence on the scientific principles of the use of appropriately validated in vitro assays for replacing in vivo methods was identified as an overarching goal. The establishment of scientific requirements for new assays was recognized as a further means to unify regulatory approaches in different jurisdictions. It was recommended to include key regulators and manufacturers early in the corresponding discussions. Manufacturers and responsible expert groups, e.g. at the European Directorate for the Quality of Medicines and Health Care of the Council of Europe or the European Medicines Agency, were invited to consider leadership for international collaboration.

Local-scale spatio-temporal distribution of questing Ixodes ricinus L. (Acari: Ixodidae)-A case study from a riparian urban forest in Wroclaw, SW Poland.

This paper presents the distribution of questing Ixodes ricinus ticks in suburban forest intensively visited by people. The local-scale observations conducted during a 4-year study at 99 plots (of 100m2 each) located throughout the entire area of a riparian urban forest, showed a high variation in the density of ticks from year to year. Although I. ricinus is generally permanent in the study area, spatial distribution of sample plots harbouring I. ricinus is variable, i.e. mainly random for adults and larvae, and random or clustered for nymphs. Among the most common plant species in the herb layer, there were not any species which had a statistically significant and constant impact on the occurrence of any of the development stages of I. ricinus. Also relations between the density of tick development stages and vegetation variables, including cover of the herb layer, total species number, species number of the herb layer, and percentage coverage of particular species, as well as ecological indices for light, soil moisture, reaction, and nutrients, did not show any constant and predictable pattern in subsequent years of the study. Only tree and shrub layers were found as variables positively affecting the density of ticks. Although small, suburban forests can be considered as tick-borne risk areas, it is impossible to determine in details areas of tick-borne risk.