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In the monosomy 1p36 deletion syndrome, the role of DNA methylation in the genomic stability of the 1p36 region remains elusive. We hypothesize that changes in the methylation pattern at the 1p36 breakpoint hotspot region influenced the chromosomal breakage leading to terminal deletions. From the monosomy 1p36 material collection, four cases with 4.0 to 5.5 Mb terminal deletions and their parents were investigated. DNA samples were assessed by targeted bisulfite sequencing (NimbleGen SeqCap Epi) to examine DNA methylation status in the 1p36 hotspot region at single-base resolution as compared to the chromosomal hotspot regions, 9p22, 18q21.1, and 22q11.2. Additionally, in in silico assessment, the mean GC content of various classes of repeats in the genome and especially in the breakpoint regions was evaluated. A complex landscape of DNA methylation in the 1p36 breakpoint hotspot region was found. Changes in DNA methylation level in the vicinity of the breakpoint in the child's DNA when compared to parents' and control DNA were observed, with a shift from 15.1 to 70.8% spanning the breakpoint region. In the main classes of evaluated repeats, higher mean GC contents in the 1p36 breakpoint region (47.06%), 22q11.2 (48.47%), and 18q21.1 (44.21%) were found, compared to the rest of the genome (40.78%). The 9p22 region showed a lower GC content (39.42%) compared to the rest of the genome. Both dysregulation of DNA methylation and high GC content were found to be specific for the 1p36 breakpoint hotspot region suggesting that methylation abnormalities could contribute to aberrations at 1p36., (© 2024. The Author(s).)

Background: Reporting on the International Nosocomial Infection Control Consortium study results from 2015 to 2020, conducted in 630 intensive care units across 123 cities in 45 countries spanning Africa, Asia, Eastern Europe, Latin America, and the Middle East., Methods: Prospective intensive care unit patient data collected via International Nosocomial Infection Control Consortium Surveillance Online System. Centers for Disease Control and Prevention/National Health Care Safety Network definitions applied for device-associated health care-associated infections (DA-HAI)., Results: We gathered data from 204,770 patients, 1,480,620 patient days, 936,976 central line (CL)-days, 637,850 mechanical ventilators (MV)-days, and 1,005,589 urinary catheter (UC)-days. Our results showed 4,270 CL-associated bloodstream infections, 7,635 ventilator-associated pneumonia, and 3,005 UC-associated urinary tract infections. The combined rates of DA-HAIs were 7.28%, and 10.07 DA-HAIs per 1,000 patient days. CL-associated bloodstream infections occurred at 4.55 per 1,000 CL-days, ventilator-associated pneumonias at 11.96 per 1,000 MV-days, and UC-associated urinary tract infections at 2.91 per 1,000 UC days. In terms of resistance, Pseudomonas aeruginosa showed 50.73% resistance to imipenem, 44.99% to ceftazidime, 37.95% to ciprofloxacin, and 34.05% to amikacin. Meanwhile, Klebsiella spp had resistance rates of 48.29% to imipenem, 72.03% to ceftazidime, 61.78% to ciprofloxacin, and 40.32% to amikacin. Coagulase-negative Staphylococci and Staphylococcus aureus displayed oxacillin resistance in 81.33% and 53.83% of cases, respectively., Conclusions: The high rates of DA-HAI and bacterial resistance emphasize the ongoing need for continued efforts to control them., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) quickly reached the pandemic status, with 765.22 million confirmed cases of COVID-19 and 6.92 million COVID-19 deaths reported worldwide by May 2023. Due to its sudden and global nature, the COVID-19 pandemic has had a significant impact on the emotional and mental health of many people. A group of COVID-19 patients who frequently require intensive care are geriatric patients. The cognitive performance of these patients and their independence in instrumental activities of daily living (IADL) may be crucial to their prognosis and risk of in-hospital death., Objectives: The present study aimed to assess the level of independence in activities of daily living (ADL), mental fitness, the level of fear of COVID-19, and cognitive functions to determine their impact on in-hospital mortality in geriatric COVID-19 patients., Material and Methods: A total of 300 intensive care unit (ICU) patients with COVID-19 were included in the cross-sectional study, using the following questionnaires: the Lawton IADL scale, the Katz ADL index of independence, the fear of COVID-19 scale (FCV-19S), the abbreviated mental test score (AMTS), and the 15-item geriatric depression scale (GDS15)., Results: Patients aged 64 or below reported significantly greater independence on the IADL scale and the basic ADL scale, and showed a significantly higher level of mental fitness (Mann-Whitney U test; p = 0.001). Patient survival and in-hospital mortality were influenced by independence in basic and complex ADL., Conclusions: The level of independence is an important prognostic indicator for in-hospital mortality in geriatric COVID-19 patients. The higher the level of mental fitness, the higher the level of independence in basic and instrumental activities of daily living. Patients aged ≥65 years are less independent in basic and instrumental activities of daily living. Moreover, they show a significantly lower level of cognitive functions.

Anemia is one of the most common chronic kidney disease (CKD) complications. It negatively affects patients' quality of life and clinical outcomes. The pathophysiology of anemia in CKD involves the interplay of various factors such as erythropoietin (EPO) deficiency, iron dysregulation, chronic inflammation, bone marrow dysfunction, and nutritional deficiencies. Despite recent advances in understanding this condition, anemia still remains a serious clinical challenge in population of patients with CKD. Several guidelines have been published with the aim to systematize the diagnostic approach and treatment of anemia; however, due to emerging data, many recommendations vary between publications. Recent studies indicate a potential of novel biomarkers to evaluate anemia and related conditions such as iron deficiency, which is often present in CKD patients. Our article aims to summarize the pathophysiology of anemia in CKD, as well as the diagnosis and management of this condition, including novel therapeutic approaches such as hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI). Understanding these complex subjects is crucial for a targeted approach to diagnose and treat patients with anemia in CKD effectively.

Background: Central line (CL)-associated bloodstream infections (CLABSIs) occurring in the intensive care unit (ICU) are common and associated with a high burden., Methods: We implemented a multidimensional approach, incorporating an 11-element bundle, education, surveillance of CLABSI rates and clinical outcomes, monitoring compliance with bundle components, feedback of CLABSI rates and clinical outcomes, and performance feedback in 316 ICUs across 30 low- and middle-income countries. Our dependent variables were CLABSI per 1,000-CL-days and in-ICU all-cause mortality rates. These variables were measured at baseline and during the intervention, specifically during the second month, third month, 4 to 16 months, and 17 to 29 months. Comparisons were conducted using a two-sample t test. To explore the exposure-outcome relationship, we used a generalized linear mixed model with a Poisson distribution to model the number of CLABSIs., Results: During 1,837,750 patient-days, 283,087 patients, used 1,218,882 CL-days. CLABSI per 1,000 CL-days rates decreased from 15.34 at the baseline period to 7.97 in the 2nd month (relative risk (RR) = 0.52; 95% confidence interval [CI] = 0.48-0.56; P < .001), 5.34 in the 3rd month (RR = 0.35; 95% CI = 0.32-0.38; P < .001), and 2.23 in the 17 to 29 months (RR = 0.15; 95% CI = 0.13-0.17; P < .001). In-ICU all-cause mortality rate decreased from 16.17% at baseline to 13.68% (RR = 0.84; P = .0013) at 17 to 29 months., Conclusions: The implemented approach was effective, and a similar intervention could be applied in other ICUs of low- and middle-income countries to reduce CLABSI and in-ICU all-cause mortality rates., (Copyright © 2023 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To identify urinary catheter (UC)-associated urinary tract infection (CAUTI) incidence and risk factors., Design: A prospective cohort study., Setting: The study was conducted across 623 ICUs of 224 hospitals in 114 cities in 37 African, Asian, Eastern European, Latin American, and Middle Eastern countries., Participants: The study included 169,036 patients, hospitalized for 1,166,593 patient days., Methods: Data collection took place from January 1, 2014, to February 12, 2022. We identified CAUTI rates per 1,000 UC days and UC device utilization (DU) ratios stratified by country, by ICU type, by facility ownership type, by World Bank country classification by income level, and by UC type. To estimate CAUTI risk factors, we analyzed 11 variables using multiple logistic regression., Results: Participant patients acquired 2,010 CAUTIs. The pooled CAUTI rate was 2.83 per 1,000 UC days. The highest CAUTI rate was associated with the use of suprapubic catheters (3.93 CAUTIs per 1,000 UC days); with patients hospitalized in Eastern Europe (14.03) and in Asia (6.28); with patients hospitalized in trauma (7.97), neurologic (6.28), and neurosurgical ICUs (4.95); with patients hospitalized in lower-middle-income countries (3.05); and with patients in public hospitals (5.89).The following variables were independently associated with CAUTI: Age (adjusted odds ratio [aOR], 1.01; P < .0001), female sex (aOR, 1.39; P < .0001), length of stay (LOS) before CAUTI-acquisition (aOR, 1.05; P < .0001), UC DU ratio (aOR, 1.09; P < .0001), public facilities (aOR, 2.24; P < .0001), and neurologic ICUs (aOR, 11.49; P < .0001)., Conclusions: CAUTI rates are higher in patients with suprapubic catheters, in middle-income countries, in public hospitals, in trauma and neurologic ICUs, and in Eastern European and Asian facilities.Based on findings regarding risk factors for CAUTI, focus on reducing LOS and UC utilization is warranted, as well as implementing evidence-based CAUTI-prevention recommendations.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, in patients treated for SARS-CoV-2 infection, infections with the Klebsiella pneumoniae bacteria producing New Delhi metallo-B-lactamase (NDM) carbapenemase in the USA, Brazil, Mexico, and Italy were observed, especially in intensive care units (ICUs). This study aimed to assess the impact of Klebsiella pneumoniae NDM infection and other bacterial infections on mortality in patients treated in ICUs due to COVID-19., Methods: The 160 patients who qualified for the study were hospitalized in ICUs due to COVID-19. Three groups were distinguished: patients with COVID-19 infection only (N = 72), patients with COVID-19 infection and infection caused by Klebsiella pneumoniae NDM (N = 30), and patients with COVID-19 infection and infection of bacterial etiology other than Klebsiella pneumoniae NDM (N = 58). Mortality in the groups and chosen demographic data; biochemical parameters analyzed on days 1, 3, 5, and 7; comorbidities; and ICU scores were analyzed., Results: Bacterial infection, including with Klebsiella pneumoniae NDM type, did not elevate mortality rates. In the group of patients who survived the acute phase of COVID-19 the prolonged survival time was demonstrated: the median overall survival time was 13 days in the NDM bacterial infection group, 14 days in the other bacterial infection group, and 7 days in the COVID-19 only group. Comparing the COVID-19 with NDM infection and COVID-19 only groups, the adjusted model estimated a statistically significant hazard ratio of 0.28 (p = 0.002). Multivariate analysis revealed that age, APACHE II score, and CRP were predictors of mortality in all the patient groups., Conclusion: In patients treated for SARS-CoV-2 infection acquiring a bacterial infection due to prolonged hospitalization associated with the treatment of COVID-19 did not elevate mortality rates. The data suggests that in severe COVID-19 patients who survived beyond the first week of hospitalization, bacterial infections, particularly Klebsiella pneumoniae NDM, do not significantly impact mortality. Multivariate analysis revealed that age, APACHE II score, and CRP were predictors of mortality in all the patient groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Janc, Słabisz, Woźniak, Łysenko, Chabowski and Leśnik.)

Background: Due to the growing resistance to routinely used antibiotics, the search for new antibiotics or their combinations with effective inhibitors against multidrug-resistant microorganisms is ongoing. In our study, we assessed the in vitro drug susceptibility of Klebsiella pneumoniae strains producing New Delhi metallo-β-lactamases (NDM) to antibiotics included in the Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommendations., Methods: A total of 60 strains of NDM-producing K. pneumoniae were obtained from different patients hospitalized at the 4th Military Hospital in Wroclaw between 2019 and 2022 and subjected to drug susceptibility to selected antibiotics, including the effects of drug combinations., Results: Among the tested antibiotics, the highest sensitivity (100%) was observed for cefiderocol, eravacycline (interpreted according to the European Committee on Antimicrobial Susceptibility Testing [EUCAST]), and tigecycline. Sensitivity to intravenous fosfomycin varied depending on the method used. Using the "strip stacking" method, determining cumulative sensitivity to ceftazidime/avibactam and aztreonam demonstrated 100% in vitro sensitivity to this combination among the tested strains., Conclusion: The in vitro susceptibility assessment demonstrated that, the best therapeutic option for treating infections caused by carbapenemase-producing strains seems to be a combination of ceftazidime/avibactam with aztreonam. Due to the safety of using both drugs, cost effectiveness, and the broadest indications for use among the tested antibiotics, this therapy should be the first-line treatment for carbapenemase-producing Enterobacterales infections. Nevertheless, a comprehensive evaluation of the efficacy of treating infections caused by NDM-producing K. pneumoniae strains should include not only in vitro susceptibility assessment but also an analysis of clinical cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Słabisz, Leśnik, Janc, Fidut, Bartoszewicz, Dudek-Wicher and Nawrot.)

The immunotropic effects of aldosterone might play a role in COVID-19, as SARS-CoV-2 reportedly uses angiotensin-converting enzyme 2 receptors as an entry point into cells. Aldosterone function is closely linked to its action on mineralocorticoid receptors in kidneys; it increases the renal retention of sodium and the excretion of potassium, which increases blood pressure. Despite the large number of studies examining the effect of Ang-II and its blockers on the course of COVID-19 infection, there is still uncertainty about the role of aldosterone. The aim of the study was to assess the correlation of aldosterone, urea, creatinine, C-reactive protein (CRP), and procalcitonin (PCT) levels with 28 days of mortality in patients treated for COVID19 in an intensive care unit (ICU). This cross-selection study involved 115 adult patients who were divided into two groups: those who died within a 28-day period (n = 82) and those who survived (n = 33). The correlation of aldosterone, urea, creatinine, C-reactive protein (CRP), and procalcitonin (PCT) levels with 28 days of mortality in patients treated for COVID-19 were performed. The patients' age, sex, scores from the APACHE II, SAPS II, and SOFA scales and comorbidities like HA, IHD and DM were also analyzed. Remarkably, the individuals who survived for 28 days were of significantly lower mean age and achieved notably lower scores on the APACHE II, SAPS II, and SOFA assessment scales. Statistically significantly higher CRP levels were observed on days 3, 5, and 7 in individuals who survived for 28 days. Creatinine levels in the same group were also statistically significantly lower on days 1, 3, and 5 than those of individuals who died within 28 days. The investigation employed both univariate and multivariate Cox proportional hazard regression models to explore factors related to mortality. In the univariate analysis, variables with a p value of less than 0.50 were included in the multivariate model. Age, APACHE II, SAPS II, and SOFA demonstrated significance in univariate analysis and were considered to be associated with mortality. The outcomes of the multivariate analysis indicated that age (HR = 1.03, p = 0.033) served as a robust predictor of mortality in the entire study population. In conclusion the plasma aldosterone level is not associated with ICU mortality in patients with COVID-19. Other factors, including the patient's age, creatinine or CRP contribute to the severity and prognosis of the disease. This study was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) with registration no. ACTRN12621001300864 (27/09/2021: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382563&isReview=true )., (© 2024. The Author(s).)

Background: Ventilator associated pneumonia (VAP) occurring in the intensive care unit (ICU) are common, costly, and potentially lethal., Methods: We implemented a multidimensional approach and an 8-component bundle in 374 ICUs across 35 low and middle-income countries (LMICs) from Latin-America, Asia, Eastern-Europe, and the Middle-East, to reduce VAP rates in ICUs. The VAP rate per 1000 mechanical ventilator (MV)-days was measured at baseline and during intervention at the 2nd month, 3rd month, 4-15 month, 16-27 month, and 28-39 month periods., Results: 174,987 patients, during 1,201,592 patient-days, used 463,592 MV-days. VAP per 1000 MV-days rates decreased from 28.46 at baseline to 17.58 at the 2nd month (RR = 0.61; 95% CI = 0.58-0.65; P < 0.001); 13.97 at the 3rd month (RR = 0.49; 95% CI = 0.46-0.52; P < 0.001); 14.44 at the 4-15 month (RR = 0.51; 95% CI = 0.48-0.53; P < 0.001); 11.40 at the 16-27 month (RR = 0.41; 95% CI = 0.38-0.42; P < 0.001), and to 9.68 at the 28-39 month (RR = 0.34; 95% CI = 0.32-0.36; P < 0.001). The multilevel Poisson regression model showed a continuous significant decrease in incidence rate ratios, reaching 0.39 (p < 0.0001) during the 28th to 39th months after implementation of the intervention., Conclusions: This intervention resulted in a significant VAP rate reduction by 66% that was maintained throughout the 39-month period., Competing Interests: Declaration of Competing Interest All authors declare that don't have any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. All authors declare that don't have potential competing interests, such as employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. Submission of this article implies that the work described has not been published previously, that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Several initiatives have recently focused on raising awareness about limitations of treatment in Poland. We aimed to assess if the propensity to limit LST among elderly patients in 2018-2019 increased compared to 2016-2017., Methods: We analysed Polish cohorts from studies VIP1 (October 2016 - May 2017) and VIP2 (May 2018 - May 2019) that enrolled critical patients aged >80. We collected data on demographics, clinical features limitations of LST. Primary analysis assessed factors associated with prevalence of limitations of LST, A secondary analysis explored differences between patients with and without limitations of LST., Results: 601 patients were enrolled. Prevalence of LST limitations was 16.1% in 2016-2017 and 20.5% in 2018-2019. No difference was found in univariate analysis (p = 0.22), multivariable model showed higher propensity towards limiting LST in the 2018-2019 cohort compared to 2016-2017 cohort (OR 1.07;95%CI, 1.01-1.14). There was higher mortality and a longer length of stay of patients with limitations of LST compared to the patients without limitations of LST. (11 vs. 6 days, p = 0.001)., Conclusions: The clinicians in Poland have become more proactive in limiting LST in critically ill patients ≥80 years old over the studied period, however the prevalence of limitations of LST in Poland remains low., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Intensive care unit (ICU) patients are at high risk of infection due to multiple invasive procedures, malnutrition, or immunosuppression. The rapid increase in infections with multidrug-resistant organisms (MDRO) during the COVID-19 pandemic caused a dilemma, as the rules of the sanitary regime in ICU rooms were strictly adhered to in the prevailing epidemiological situation. The combat to reduce the number of infections and pathogen transmission became a priority for ICU staff. This study aimed to assess whether eliminating environmental reservoirs and implementing improved procedures for patient care and decontamination and washing equipment in the ICU reduced the incidence of infections caused by MDR strains. Material and methods: The study retrospectively analyzed data in the ICU during the COVID-19 pandemic. The samples were collected based on microbiological culture and medical records in the newly opened ICU (10 stations) and hospital wards where COVID-19 patients were hospitalized. Environmental inoculations were performed during the COVID-19 pandemic every 4-6 weeks unless an increase in the incidence of infections caused by MDR strains was observed. Through microbiological analysis, environmental reservoirs of MDR pathogens were identified. The observation time was divided into two periods, before and after the revised procedures. The relationship between isolated strains of Klebsiella pneumoniae NDM from patients and potential reservoirs within the ICU using ERIC-PCR and dice methods was analyzed. Results: An increased frequency of infections and colonization caused by MDRO was observed compared to the preceding years. A total of 23,167 microbiological tests and 6,985 screening tests for CPE and MRSA bacilli were collected. The pathogen spread was analyzed, and the findings indicated procedural errors. Assuming that the transmission of infections through the staff hands was significantly limited by the restrictive use of personal protective equipment, the search for a reservoir of microorganisms in the environment began. MDR strains were grown from the inoculations collected from the hand-wash basins in the wards and from inside the air conditioner on the ceiling outside the patient rooms. New types of decontamination mats were used in high-risk areas with a disinfectant based on Glucoprotamine. Active chlorine-containing substances were widely used to clean and disinfect surfaces. Conclusions: Infections with MDR strains pose a challenge for health care. Identification of bacterial reservoirs and comprehensive nursing care significantly reduce the number of nosocomial infections., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Prone position is used in acute respiratory distress syndrome and in coronavirus disease 2019 (Covid-19) acute respiratory distress syndrome (ARDS). However, physiological mechanisms remain unclear. The aim of this study was to determine whether improved oxygenation was related to pulmonary shunt fraction (Q's/Q't), alveolar dead space (Vd/Vtalv) and ventilation/perfusion mismatch (V' A /Q')., Methods: This was an international, prospective, observational, multicenter, cohort study, including six intensive care units in Sweden and Poland and 71 mechanically ventilated adult patients., Results: Prone position increased PaO 2 :FiO 2 after 30 min, by 78% (83-148 mm Hg). The effect persisted 120 min after return to supine (p < 0.001). The oxygenation index decreased 30 min after prone positioning by 43% (21-12 units). Q's/Q't decreased already after 30 min in the prone position by 17% (0.41-0.34). The effect persisted 120 min after return to supine (p < 0.005). Q's/Q't and PaO 2 :FiO 2 were correlated both in prone (Beta -137) (p < 0.001) and in the supine position (Beta -270) (p < 0.001). V' A /Q' was unaffected and did not correlate to PaO 2 :FiO 2 (p = 0.8). Vd/Vtalv increased at 120 min by 11% (0.55-0.61) (p < 0.05) and did not correlate to PaO 2 :FiO 2 (p = 0.3). The ventilatory ratio increased after 30 min in the prone position by 58% (1.9-3.0) (p < 0.001). PaO 2 :FiO 2 at baseline predicted PaO 2 :FiO 2 at 30 min after proning (Beta 1.3) (p < 0.001)., Conclusions: Improved oxygenation by prone positioning in COVID-19 ARDS patients was primarily associated with a decrease in pulmonary shunt fraction. Dead space remained high and the global V' A /Q' measure could not explain the differences in gas exchange., (© 2023. The Author(s).)

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and a syndrome shaped by pathogen and host factors evolving over time. During sepsis, the absolute number of lymphocytes decreases. CD4+ and CD8+ T cells, B cells, and NK cells are reduced. Lymphocytes are an essential element of the body's defence against pathogens. Interleukin 7 has strong anti-apoptotic properties and induces the proliferation of CD4+ and CD8+ T lymphocytes. IL-15 prompts the generation of mature NK cells in the bone marrow, plays an important role in the generation, cytotoxicity, and survival of CD8+ T lymphocytes, and is essential for the survival of natural killer T (NKT) and intestinal intraepithelial lymphocytes (IELs). The study highlights the importance of monitoring IL-7 levels in patients with sepsis and septic shock, as low levels of this cytokine were associated with an increased risk of mortality. Physicians should consider using IL-7 levels as a biomarker to identify patients who are at higher risk of mortality and may require more aggressive treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

BACKGROUND The combination of pectoserratus plane block (PSP) and superficial serratus anterior plane block (S-SAP) was established to reduce the risk of general anesthesia for subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation in patients with high operative risk (American Society of Anesthesiologistsgrade III or IV). This study compared outcomes from ultrasound-guided PSP and S-SAP in 16 patients requiring a subcutaneous implantable cardioverter-defibrillator (S-ICD) at a single center in Poland. MATERIAL AND METHODS A group of 16 patients with ASA grade III and IV qualified for S-ICD implantation was included. The pain assessment using numerical rating scale (NRS), patient's comfort using Quality of Recovery-15 (QoR-15), the operator's satisfaction using Operator's Comfort Scale, adverse event occurrence, and the parameters' stability were evaluated. RESULTS The mean volume of the local anesthetics mixture of PSP block was 19.4 mL; S-SAP was 34.7 mL (mean total volume, 54.1 mL). The mean duration of the block was 21.3 min; the mean time of the S-ICD implantation was 108.4 min. Neither circulatory nor respiratory instability was observed. In 8 patients (50%), non-opioid analgesics were administered intraoperatively; in 11 patients (69%), fentanyl bolus ≤200 μg was administered. The intraoperative NRS score was low (max 2 points); NRS 24 h after the procedure was low (max 4 points). The mean value of QoR-15 was 133.9 points. CONCLUSIONS S-SAP combined with PSP is feasible and safe in providing anesthesia/analgesia during S-ICD implantation and showed good effects in a group of patients with high operative risk (ASA III or IV).

Background: The International Nosocomial Infection Control Consortium has found a high ICU mortality rate. Our aim was to identify all-cause mortality risk factors in ICU-patients., Methods: Multinational, multicenter, prospective cohort study at 786 ICUs of 312 hospitals in 147 cities in 37 Latin American, Asian, African, Middle Eastern, and European countries., Results: Between 07/01/1998 and 02/12/2022, 300,827 patients, followed during 2,167,397 patient-days, acquired 21,371 HAIs. Following mortality risk factors were identified in multiple logistic regression: Central line-associated bloodstream infection (aOR:1.84; P<.0001); ventilator-associated pneumonia (aOR:1.48; P<.0001); catheter-associated urinary tract infection (aOR:1.18;P<.0001); medical hospitalization (aOR:1.81; P<.0001); length of stay (LOS), risk rises 1% per day (aOR:1.01; P<.0001); female gender (aOR:1.09; P<.0001); age (aOR:1.012; P<.0001); central line-days, risk rises 2% per day (aOR:1.02; P<.0001); and mechanical ventilator (MV)-utilization ratio (aOR:10.46; P<.0001). Coronary ICU showed the lowest risk for mortality (aOR: 0.34;P<.0001)., Conclusion: Some identified risk factors are unlikely to change, such as country income-level, facility ownership, hospitalization type, gender, and age. Some can be modified; Central line-associated bloodstream infection, ventilator-associated pneumonia, catheter-associated urinary tract infection, LOS, and MV-utilization. So, to lower the risk of death in ICUs, we recommend focusing on strategies to shorten the LOS, reduce MV-utilization, and use evidence-based recommendations to prevent HAIs., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To identify central-line (CL)-associated bloodstream infection (CLABSI) incidence and risk factors in low- and middle-income countries (LMICs)., Design: From July 1, 1998, to February 12, 2022, we conducted a multinational multicenter prospective cohort study using online standardized surveillance system and unified forms., Setting: The study included 728 ICUs of 286 hospitals in 147 cities in 41 African, Asian, Eastern European, Latin American, and Middle Eastern countries., Patients: In total, 278,241 patients followed during 1,815,043 patient days acquired 3,537 CLABSIs., Methods: For the CLABSI rate, we used CL days as the denominator and the number of CLABSIs as the numerator. Using multiple logistic regression, outcomes are shown as adjusted odds ratios (aORs)., Results: The pooled CLABSI rate was 4.82 CLABSIs per 1,000 CL days, which is significantly higher than that reported by the Centers for Disease Control and Prevention National Healthcare Safety Network (CDC NHSN). We analyzed 11 variables, and the following variables were independently and significantly associated with CLABSI: length of stay (LOS), risk increasing 3% daily (aOR, 1.03; 95% CI, 1.03-1.04; P < .0001), number of CL days, risk increasing 4% per CL day (aOR, 1.04; 95% CI, 1.03-1.04; P < .0001), surgical hospitalization (aOR, 1.12; 95% CI, 1.03-1.21; P < .0001), tracheostomy use (aOR, 1.52; 95% CI, 1.23-1.88; P < .0001), hospitalization at a publicly owned facility (aOR, 3.04; 95% CI, 2.31-4.01; P <.0001) or at a teaching hospital (aOR, 2.91; 95% CI, 2.22-3.83; P < .0001), hospitalization in a middle-income country (aOR, 2.41; 95% CI, 2.09-2.77; P < .0001). The ICU type with highest risk was adult oncology (aOR, 4.35; 95% CI, 3.11-6.09; P < .0001), followed by pediatric oncology (aOR, 2.51;95% CI, 1.57-3.99; P < .0001), and pediatric (aOR, 2.34; 95% CI, 1.81-3.01; P < .0001). The CL type with the highest risk was internal-jugular (aOR, 3.01; 95% CI, 2.71-3.33; P < .0001), followed by femoral (aOR, 2.29; 95% CI, 1.96-2.68; P < .0001). Peripherally inserted central catheter (PICC) was the CL with the lowest CLABSI risk (aOR, 1.48; 95% CI, 1.02-2.18; P = .04)., Conclusions: The following CLABSI risk factors are unlikely to change: country income level, facility ownership, hospitalization type, and ICU type. These findings suggest a focus on reducing LOS, CL days, and tracheostomy; using PICC instead of internal-jugular or femoral CL; and implementing evidence-based CLABSI prevention recommendations.

Aims: To assess the effect of cognitive function, performance of activities of daily living (ADLs), degree of depression, and fear of infection among geriatric patients hospitalized in internal medicine wards for COVID-19 on the duration of hospitalization and in-hospital mortality., Methods: This observational survey study was conducted during the second, third, and fourth waves of the COVID-19 pandemic. The study included elderly patients of both sexes, aged ≥ 65 years, hospitalized for COVID-19 in internal medicine wards. The following survey tools were used: AMTS, FCV-19S, Lawton IADL, Katz ADL, and GDS15. The duration of hospitalization and in-hospital mortality were also assessed., Results: A total of 219 patients were included in the study. The results showed that impaired cognitive function in geriatric patients (AMTS) was associated with higher in-hospital mortality among COVID-19 patients. There was no statistical significance between fear of infection (FCV-19S) and risk of death. The impaired ability to perform complex ADLs (Lawton IADL) before the onset of the disease was not associated with higher in-hospital mortality among COVID-19 patients. The diminished ability to perform basic ADLs (Katz ADL) before the onset of the disease was not associated with higher in-hospital mortality in COVID-19. The degree of depression (GDS15) was not associated with higher in-hospital mortality in COVID-19 patients. Statistically, significantly better survival was observed for patients with normal cognitive function (p = 0.005). No statistically significant differences in survival were observed in relation to the degree of depression or independence in performing ADLs. Cox proportional hazards regression analysis showed a statistically significant effect of age on mortality (p = 0.004, HR 1.07)., Conclusion: In this study, we observe that cognitive function impairments and the older age of patients treated for COVID-19 in the medical ward increase the in-hospital risk of death., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Janc et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Sepsis-associated liver dysfunction (SALD) is associated with a poor prognosis and increased mortality in the intensive care unit. Bilirubin is one of the components of Sequential Organ Failure Assessment used in Sepsis-3 criteria. Hyperbilirubinemia is a late and non-specific symptom of liver dysfunction. This study aimed to identify plasma biomarkers that could be used for an early diagnosis of SALD. This prospective, observational study was conducted on a group of 79 patients with sepsis and septic shock treated in the ICU. Plasma biomarkers-prothrombin time, INR, antithrombin III, bilirubin, aspartate transaminase (AST), alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, albumin, endothelin-1, hepcidin, plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex, and interferon-gamma inducible protein (10 kDa) were analysed. Plasma samples were obtained within 24 h after having developed sepsis/septic shock. Enrolled patients were followed for 14 days for developing SALD and 28 days for overall survival. A total of 24 patients (30.4%) developed SALD. PAI-1 with a cut-off value of 48.7 ng/mL was shown to be a predictor of SALD (AUC = 0.671, sensitivity 87.3%, and specificity 50.0%) and of 28-day survival in patients with sepsis/septic shock ( p = 0.001). Measuring PAI-1 serum levels at the onset of sepsis and septic shock may be useful in predicting the development of SALD. This should be verified in multicenter prospective clinical trials.

Objective: Rates of ventilator-associated pneumonia (VAP) in low- and middle-income countries (LMIC) are several times above those of high-income countries. The objective of this study was to identify risk factors (RFs) for VAP cases in ICUs of LMICs., Design: Prospective cohort study., Setting: This study was conducted across 743 ICUs of 282 hospitals in 144 cities in 42 Asian, African, European, Latin American, and Middle Eastern countries., Participants: The study included patients admitted to ICUs across 24 years., Results: In total, 289,643 patients were followed during 1,951,405 patient days and acquired 8,236 VAPs. We analyzed 10 independent variables. Multiple logistic regression identified the following independent VAP RFs: male sex (adjusted odds ratio [aOR], 1.22; 95% confidence interval [CI], 1.16-1.28; P < .0001); longer length of stay (LOS), which increased the risk 7% per day (aOR, 1.07; 95% CI, 1.07-1.08; P < .0001); mechanical ventilation (MV) utilization ratio (aOR, 1.27; 95% CI, 1.23-1.31; P < .0001); continuous positive airway pressure (CPAP), which was associated with the highest risk (aOR, 13.38; 95% CI, 11.57-15.48; P < .0001); tracheostomy connected to a MV, which was associated with the next-highest risk (aOR, 8.31; 95% CI, 7.21-9.58; P < .0001); endotracheal tube connected to a MV (aOR, 6.76; 95% CI, 6.34-7.21; P < .0001); surgical hospitalization (aOR, 1.23; 95% CI, 1.17-1.29; P < .0001); admission to a public hospital (aOR, 1.59; 95% CI, 1.35-1.86; P < .0001); middle-income country (aOR, 1.22; 95% CI, 15-1.29; P < .0001); admission to an adult-oncology ICU, which was associated with the highest risk (aOR, 4.05; 95% CI, 3.22-5.09; P < .0001), admission to a neurologic ICU, which was associated with the next-highest risk (aOR, 2.48; 95% CI, 1.78-3.45; P < .0001); and admission to a respiratory ICU (aOR, 2.35; 95% CI, 1.79-3.07; P < .0001). Admission to a coronary ICU showed the lowest risk (aOR, 0.63; 95% CI, 0.51-0.77; P < .0001)., Conclusions: Some identified VAP RFs are unlikely to change: sex, hospitalization type, ICU type, facility ownership, and country income level. Based on our results, we recommend focusing on strategies to reduce LOS, to reduce the MV utilization ratio, to limit CPAP use and implementing a set of evidence-based VAP prevention recommendations., (© The Author(s) 2023.)

BACKGROUND Acute kidney injury (AKI) is one of the most common organ failures. An early diagnosis of AKI using specific biomarkers is essential for effective treatment. This study determined the serum concentrations of selected amino acids and amines using targeted liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in patients with AKI during sepsis and septic shock treated in the Intensive Care Unit (ICU). MATERIAL AND METHODS A sample of 41 patients was divided into 2 groups: (1) patients with sepsis and septic shock along required continuous renal replacement therapy (CRRT) due to AKI (n=13), and (2) patients with sepsis and septic shock but without AKI (n=28). LC-MS/MS was used to measure a serum concentration of 6 amino acids and amines: arginine, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), dimethylamine (DMA), and citrulline. RESULTS There was a statistically significantly higher median DMA level in AKI patients compared to those without AKI (8.1 vs 5.2 umol/L; P=0.022). The results for the remaining molecules showed no significant differences (P>0.05). Patients with DMA ≥14.95 umol/L (n=5; 100%) and treated with CRRT presented DMA level below the cut-off point (n=7; 20%). Subjects with creatinine levels ≥1.19 mg/dL (n=11; 28%) and treated with CRRT presented creatinine levels below the cut-off point (n=1; 3%). CONCLUSIONS In patients with sepsis, increased serum levels of DMA were significantly associated with AKI requiring CRRT. It remains unclear whether increased DMA concentrations are secondary to sepsis-induced AKI or are a cause.

COVID-19 is a contagious disease that has spread globally, killing millions of people around the world. In order to reduce the likelihood of in-hospital death due to COVID-19, it is reasonable to select a group of patients with a low probability of survival and to implement measures in advance to minimize the risk of death. One way to do this is to establish cut-off values for the most commonly performed blood laboratory tests, above or below which the likelihood of death increases significantly. The aim of the study was to determine the basic laboratory parameters among unvaccinated patients hospitalized for COVID-19 with concomitant cardiovascular disease, which are the predictors of in-hospital death. Out of 1234 patients, 446 people who met the specific inclusion criteria were enrolled in the study. The multivariate regression analysis has shown that the independent predictors of death are: troponin levels of at least 0.033 μg/L (OR = 2.04 [1.10; 3.79]), creatinine of at least 1.88 mg/dL (OR = 2.88 [1.57; 5.30]), D-dimers of at least 0.97 g/L (OR = 2.04 [1.02; 4.07]), and C-reactive protein minimum of 0.89 mg/L (OR = 2.28 [1.24; 4.18]).

Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the host's response to an infection, where the dominant mechanism is tissue hypoperfusion. Currently, the marker used to define tissue disorders is lactate levels, which may be elevated in other disease states as well. Renin is an essential hormone for the proper functioning of the renin-angiotensin-aldosterone (RASS) system. It is secreted in the glomerular apparatus in response to hypoperfusion. This study aimed to assess the usefulness of renin as a marker of tissue hypoperfusion in patients with sepsis and septic shock. A final group of 48 patients treated for sepsis and septic shock in the intensive care unit was included. Blood samples for renin quantification were collected in the morning as a part of routine blood analysis on the first, third, and fifth days. Sepsis was diagnosed in 19 patients (39.6%), and septic shock was diagnosed in 29 patients (60.4%). There was no significant difference in renin concentration between patients who received and did not receive continuous renal replacement therapy (CRRT) on any study day. Therefore, all samples were analyzed together in subsequent analyses. There was a significant difference in renin concentration between sepsis survivors and non-survivors on the third (31.5 and 119.9 pg/mL, respectively) and fifth (18.2 and 106.7 pg/mL, respectively) days. As a survival marker, renin was characterized by 69% and 71% overall accuracy if determined on the third and fifth days, respectively. There was a significant difference in renin concentration between sepsis and septic shock patients on the first (45.8 and 103.4 pg/mL, respectively) and third (24.7 and 102.1 pg/mL, respectively) days. At an optimal cut-off of 87 pg/mL, renin had very good specificity and a positive likelihood ratio. Renin was a strong predictor of mortality in patients with sepsis and septic shock. Further, the level of renin in patients with septic shock was significantly higher than in patients with sepsis. In combination with the assessment of lactate concentration, renin seems to be the optimal parameter for monitoring tissue hypoperfusion and could be helpful for septic shock diagnosis, as well as for identifying candidate patients for CRRT.

Ultrasound-guided interfascial plane blocks performed on the anterior and lateral thoracic wall have become an important adjuvant method to general anesthesia and an independent method of local anesthesia and pain management. These procedures diminish the harmful effects of anesthesia on respiratory function and reduce the risk of phrenic nerve paralysis or iatrogenic pneumothorax. In postoperative pain management, interfascial plane blocks decrease the dosage of intravenous drugs, including opioids. They can also eliminate the complications associated with general anesthesia when used as the sole method of anesthesia for surgical procedures. The following procedures are classified as interfascial plane blocks of the anterior and lateral thoracic wall: pectoral nerve plane block (PECS), serratus anterior plane block (SAP), transversus thoracic muscle plane block (TTP), pectoral interfascial plane block (PIF), and intercostal nerve block (ICNB). These blocks are widely used in emergency medicine, oncologic surgery, general surgery, thoracic surgery, cardiac surgery, orthopedics, cardiology, nephrology, oncology, palliative medicine, and pain medicine. Regional blocks are effective for analgesic treatment, both as an anesthesia procedure for surgery on the anterior and lateral thoracic wall and as an analgesic therapy after trauma or other conditions that induce pain in this area. In the era of the COVID-19 pandemic, ultrasound-guided interfascial plane blocks are safe alternatives for anesthesia in patients with symptoms of respiratory distress related to SARS-CoV-2 and appear to reduce the risk of COVID-19 infection among medical personnel.

SARS-CoV-2 is a virus that causes severe respiratory distress syndrome. The pathophysiology of COVID-19 is related to the renin-angiotensin system (RAS). SARS-CoV-2, a vector of COVID-19, uses angiotensin-converting enzyme 2 (ACE-2), which is highly expressed in human lung tissue, nasal cavity, and oral mucosa, to gain access into human cells. After entering the cell, SARS-CoV-2 inhibits ACE-2, thus favouring the ACE/Ang II/angiotensin II type 1 receptor (AT1R) axis, which plays a role in the development of acute lung injury (ALI). This study aimed to analyse the influence of angiotensin 1 receptor (AT1R) levels in the serum on the course of the severity of symptoms in healthcare professionals who had a SARS-CoV-2 infection. This prospective observational study was conducted on a group of 82 participants. The study group included physicians and nurses who had a COVID-19 infection confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2. The control group consisted of healthy medical professionals who had not had a SARS-CoV-2 infection or who had no symptoms of COVID-19 and who tested negative for SARS-CoV-2 on the day of examination. We analysed the correlation between AT1R concentration and the severity of COVID-19, as well as with sex, age, blood group, and comorbidities. There were no statistically significant differences in the mean values of AT1R concentration in the recovered individuals and the non-COVID-19 subjects (3.29 vs. 3.76 ng/mL; p = 0.32). The ROC curve for the AT1R assay showed an optimal cut-off point of 1.33 (AUC = 0.44; 95% CI = 0.32-0.57; p = 0.37). There was also no correlation between AT1R concentration and the severity of symptoms associated with COVID-19. Blood type analysis showed statistically significantly lower levels of AT1R in COVID-19-recovered participants with blood group A than in those with blood group O. In conclusion, AT1R concentration does not affect the severity of symptoms associated with COVID-19 among healthcare professionals.

The vascular access port implantation procedure can be performed using the venesection method by inserting a catheter into the cephalic vein in the region of the deltopectoral groove. This method eliminates the need for catheter tunneling. An alternative method to infiltration anaesthesia for port implantation may be a modified pectoral nerve block type II (PECS II). This study aimed to evaluate the effectiveness of modified PECS II for vascular access port implantation using cephalic vein venesection. This retrospective observational study was conducted at the 4th Military Clinical Hospital in Wroclaw, Poland. A group of 114 patients underwent the modified PECS II block and additional cutaneous infiltration anesthesia at the incision line. Pain intensity was assessed on the NRS scale measured intraoperatively at four points. The QoR-15 questionnaire was used to assess patient satisfaction during the first 24 h after surgery. The operator's condition assessment score was used to assess surgical conditions and operator comfort. The analysis showed that the median pain intensity during vascular port implantation was 0. A statistically significant difference in pain intensity was demonstrated between the specialist's group and the resident's group at the second and third measurement points ( p < 0.008; p < 0.012). The mean value on the QoR-15 scale was 132. There was a significant difference between the pain scores of the groups. The mean score in the pain position in the specialist's group was 18 points and in the resident's group, it was 19 points ( p < 0.029). In conclusion, the present study revealed that the modified PECS II block is an effective and safe method of anesthesia for Port-A-Cath implantation.

Optimal fluid therapy significantly affects the maintenance of proper tissue perfusion and, consequently, kidney function. An adverse effect of colloids on kidney function is related to the incidence of postoperative kidney failure. The study aimed to assess the effect of a 3% gelatin solution on kidney function based on the urinary kidney injury molecule-1 (uKIM-1) level. This study used a parallel design and enrolled 64 adult patients with a mean age of 52.5 ± 13.1 years, all of whom underwent a thyroidectomy procedure under general anesthesia. Patients were randomly assigned to three comparison groups, each receiving a different dose of 3% gelatin solution during the thyroidectomy procedure. The patients from study groups A (n = 21) and B (n = 21) received a 3% gelatin solution at a dose of 30 ml/kg and 15 ml/kg body weight, respectively, during the first hour of the procedure. The patients from the control group C (n = 22) received an isotonic multi-electrolyte solution. Serum creatinine levels were determined, and urine samples were collected to determine levels of uKIM-1 before, 2 h, and 24 h after surgery. The patients' demographic data, type and volume of fluid and hemodynamic status during the surgery were collected from relevant anesthesia protocols and were included in the study data. There were no statistically significant changes between groups in hemodynamic parameters such as systolic and diastolic blood pressure, heart rate, and oxygen saturation values. A statistically significant increase in uKIM-1 level was noted in patients receiving the 3% gelatin solution regardless of the dose. A statistically significant difference in uKIM-1 level was observed between groups A, B, and C measured 24 h after surgery, with the highest uKIM-1 level in group A. Measurement of uKIM-1 level could be an early and sensitive biomarker of kidney injury. Kidney toxicity of a 3% gelatin solution, evaluated based on the level of uKIM-1 in urine, correlates with transfused fluid volume. This study was retrospectively registered in the ISRCTN clinical trials registry (ISRCTN73266049, 08/04/2021: https://www.isrctn.com/ISRCTN73266049 )., (© 2021. The Author(s).)

Background: We report the results of INICC surveillance study from 2013 to 2018, in 664 intensive care units (ICUs) in 133 cities, of 45 countries, from Latin-America, Europe, Africa, Eastern-Mediterranean, Southeast-Asia, and Western-Pacific., Methods: Prospective data from patients hospitalized in ICUs were collected through INICC Surveillance Online System. CDC-NHSN definitions for device-associated healthcare-associated infection (DA-HAI) were applied., Results: We collected data from 428,847 patients, for an aggregate of 2,815,402 bed-days, 1,468,216 central line (CL)-days, 1,053,330 mechanical ventilator (MV)-days, 1,740,776 urinary catheter (UC)-days. We found 7,785 CL-associated bloodstream infections (CLAB), 12,085 ventilator-associated events (VAE), and 5,509 UC-associated urinary tract infections (CAUTI). Pooled DA-HAI rates were 5.91% and 9.01 DA-HAIs/1,000 bed-days. Pooled CLAB rate was 5.30/1,000 CL-days; VAE rate was 11.47/1,000 MV-days, and CAUTI rate was 3.16/1,000 UC-days. P aeruginosa was non-susceptible (NS) to imipenem in 52.72% of cases; to colistin in 10.38%; to ceftazidime in 50%; to ciprofloxacin in 40.28%; and to amikacin in 34.05%. Klebsiella spp was NS to imipenem in 49.16%; to ceftazidime in 78.01%; to ciprofloxacin in 66.26%; and to amikacin in 42.45%. coagulase-negative Staphylococci and S aureus were NS to oxacillin in 91.44% and 56.03%, respectively. Enterococcus spp was NS to vancomycin in 42.31% of the cases., Conclusions: DA-HAI rates and bacterial resistance are high and continuous efforts are needed to reduce them., (Copyright © 2021. Published by Elsevier Inc.)

Ports are more and more often applied with patients requiring the permanent intravenous access, not only in the cancer treatment. Very devices, as well as procedures associated with applying them are determined in the heterogeneous way. Therefore during the last conference "Intravenous Port--implantation, care, complications" an attempt to systematize the applied terminology was made.

The synthesis of novel [1,2,4]oxadiazoles and their structure-activity relationship (SAR) for the inhibition of tryptase and related serine proteases is presented. Elaboration of the P'-side afforded potent, selective, and orally bioavailable tryptase inhibitors.

Synthesis and biological data of a novel selective and efficacious factor IXa inhibitor are described along with its crystal structure in factor VIIa.

Efforts to improve the potency and pharmacokinetic properties of small molecule factor VIIa inhibitors are described. Small structural modifications to existing leads allow the modulation of half-life and clearance, potentially making these compounds suitable candidates for drug development.

We describe and compare the pH dependencies of the potencies and of the bound structures of two inhibitor isosteres that form multicentered short hydrogen bond arrays at the active sites of trypsin, thrombin, and urokinase type plasminogen activator (urokinase or uPA) over certain ranges of pH. Depending on the pH, short hydrogen bond arrays at the active site are mediated by two waters, one in the oxyanion hole (H(2)O(oxy)) and one on the other (S2) side of the inhibitor (H(2)O(S2)), by one water (H(2)O(oxy)), or by no water. The dramatic variation in the length of the active site hydrogen bonds as a function of pH, of inhibitor, and of enzyme, along with the involvement or absence of ordered water, produces a large structural manifold of active site hydrogen bond motifs. Diverse examples of multicentered and two-centered short hydrogen bond arrays, both at and away from the active site, recently discovered in several protein crystal systems, suggest that short hydrogen bonds in proteins may be more common than has been recognized. The short hydrogen bond arrays resemble one another with respect to ionic nature, highly polar environment, multitude of associated ordinary hydrogen bonds, and disparate pK(a) values of participating groups. Comparison of structures and K(i) values of trypsin complexes at pH values where the multicentered short hydrogen bond arrays mediating inhibitor binding are present or absent indicate that these arrays have a minor effect on inhibitor potency. These features suggest little covalent nature within the short hydrogen bonds, despite their extraordinary shortness (as short as 2.0 A).