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Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Difficult-to-treat infections are often characterized by the presence of bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, referred to as persisters. In the present study, we investigated the presence of GAS persisters in tissue freshly debrided from patients as well as in an in vivo mouse model of NF and examined the phenomenon of antibiotic tolerance. Time-lapse imaging of GAS plated directly upon isolation from NF debrided tissue and an antibiotic challenge-based persisters assay were used to assess the presence of persisters. We show for the first time that GAS recovered directly from freshly debrided NF tissue is characterized by heterogeneous and overall delayed colony appearance time, suggesting the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro , led to a similar phenotypic heterogeneity and resulted in enhanced survival upon antibiotic challenge, confirming the presence of GAS persisters. GAS persisters might contribute to NF treatment failure, despite extensive surgery and adequate antibiotic treatment.IMPORTANCEDifficult-to-treat and recurrent infections are a global problem burdening society and the health care system alike. Unraveling the mechanisms by which bacteria can survive antibiotic treatment without developing genetic resistance is of utmost importance to lay the foundation for new, effective therapeutic approaches. For the first time, we describe the phenomenon of antibiotic tolerance in group A Streptococcus (GAS) isolated from necrotizing fasciitis (NF) patients. Dormant, non-replicating cells (persisters) are tolerant to antibiotics and their occurrence in vivo is reported in an increasing number of bacterial species. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to specifically target dormant bacteria causing difficult-to-treat and recurrent infections., Competing Interests: The authors declare no conflict of interest.

Background: Circulatory shock, defined as decreased tissue perfusion, leading to inadequate oxygen delivery to meet cellular metabolic demands, remains a common condition with high morbidity and mortality. Rapid restitution and restoration of adequate tissue perfusion are the main treatment goals. To achieve this, current hemodynamic strategies focus on adjusting global physiological variables such as cardiac output (CO), hemoglobin (Hb) concentration, and arterial hemoglobin oxygen saturation (SaO 2 ). However, it remains a challenge to identify optimal targets for these global variables that best support microcirculatory function. Weighting up the risks and benefits is especially difficult for choosing the amount of oxygen supplementation in critically ill patients. This review assesses the physiological basis for oxygen delivery to the tissue and provides an overview of the relevant literature to emphasize the importance of considering risks and benefits and support decision making at the bedside., Physiological Premises: Oxygen must reach the tissue to enable oxidative phosphorylation. The human body timely detects hypoxia via different mechanisms aiming to maintain adequate tissue oxygenation. In contrast to the pulmonary circulation, where the main response to hypoxia is arteriolar vasoconstriction, the regulatory mechanisms of the systemic circulation aim to optimize oxygen availability in the tissues. This is achieved by increasing the capillary density in the microcirculation and the capillary hematocrit thereby increasing the capacity of oxygen diffusion from the red blood cells to the tissue. Hyperoxia, on the other hand, is associated with oxygen radical production, promoting cell death., Current State of Research: Clinical trials in critically ill patients have primarily focused on comparing macrocirculatory endpoints and outcomes based on stroke volume and oxygenation targets. Some earlier studies have indicated potential benefits of conservative oxygenation. Recent trials show contradictory results regarding mortality, organ dysfunction, and ventilatory-free days. Empirical studies comparing various targets for SaO 2, or partial pressure of oxygen indicate a U-shaped curve balancing positive and negative effects of oxygen supplementation., Conclusion and Future Directions: To optimize risk-benefit ratio of resuscitation measures in critically ill patients with circulatory shock in addition to individual targets for CO and Hb concentration, a primary aim should be to restore tissue perfusion and avoid hyperoxia. In the future, an individualized approach with microcirculatory targets will become increasingly relevant. Further studies are needed to define optimal targets., (© 2024. The Author(s).)

Background: There is limited knowledge about gaze patterns of intensive care unit (ICU) trainee doctors during the insertion of a central venous catheter (CVC). The primary objective of this study was to examine visual patterns exhibited by ICU trainee doctors during CVC insertion. Additionally, the study investigated whether differences in gaze patterns could be identified between more and less experienced trainee doctors., Methods: In a real-life, prospective observational study conducted at the interdisciplinary ICU at the University Hospital Zurich, Switzerland, ICU trainee doctors underwent eye-tracking during CVC insertion in a real ICU patient. Using mixed-effects model analyses, the primary outcomes were dwell time, first fixation duration, revisits, fixation count, and average fixation time on different areas of interest (AOI). Secondary outcomes were above eye-tracking outcome measures stratified according to experience level of participants., Results: Eighteen participants were included, of whom 10 were inexperienced and eight more experienced. Dwell time was highest for CVC preparation table ( p  = 0.02), jugular vein on ultrasound image ( p  < 0.001) and cervical puncture location ( p  < 0.001). Concerning experience, dwell time and revisits on jugular vein on ultrasound image ( p  = 0.02 and p  = 0.04, respectively) and cervical puncture location ( p  = 0.004 and p  = 0.01, respectively) were decreased in more experienced ICU trainees., Conclusions: Various AOIs have distinct significance for ICU trainee doctors during CVC insertion. Experienced participants exhibited different gaze behavior, requiring less attention for preparation and handling tasks, emphasizing the importance of hand-eye coordination., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To examine the relationship between current and former smoking and the occurrence of delirium in surgical Intensive Care Unit (ICU) patients., Methods: We conducted a single center, case-control study involving 244 delirious and 251 non-delirious patients that were admitted to our ICU between 2018 and 2022. Using propensity score analysis, we obtained 115 pairs of delirious and non-delirious patients matched for age and Simplified Acute Physiology Score II (SAPS II). Both groups of patients were further stratified into non-smokers, active smokers and former smokers, and logistic regression was performed to further investigate potential confounders., Results: Our study revealed a significant association between former smoking and the incidence of delirium in ICU patients, both in unmatched (adjusted odds ratio (OR): 1.82, 95% confidence interval (CI): 1.17-2.83) and matched cohorts (OR: 3.0, CI: 1.53-5.89). Active smoking did not demonstrate a significant difference in delirium incidence compared to non-smokers (unmatched OR = 0.98, CI: 0.62-1.53, matched OR = 1.05, CI: 0.55-2.0). Logistic regression analysis of the matched group confirmed former smoking as an independent risk factor for delirium, irrespective of other variables like surgical history (p = 0.010). Notably, also respiratory and vascular surgeries were associated with increased odds of delirium (respiratory: OR: 4.13, CI: 1.73-9.83; vascular: OR: 2.18, CI: 1.03-4.59). Medication analysis showed that while Ketamine and Midazolam usage did not significantly correlate with delirium, Morphine use was linked to a decreased likelihood (OR: 0.27, 95% CI: 0.13-0.55)., Discussion: Nicotine's complex neuropharmacological impact on the brain is still not fully understood, especially its short-term and long-term implications for critically ill patients. Although our retrospective study cannot establish causality, our findings suggest that smoking may induce structural changes in the brain, potentially heightening the risk of postoperative delirium. Intriguingly, this effect seems to be obscured in active smokers, potentially due to the recognized neuroprotective properties of nicotine. Our results motivate future prospective studies, the results of which hold the potential to substantially impact risk assessment procedures for surgeries., 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 Komninou, Egli, Rossi, Ernst, Krauthammer, Schuepbach, Delgado and Bartussek.)

BackgroundWomen are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender) differences between women and men might account for this imbalance, yet their impact on PASC is unknown.AimWe assessed the impact of sex and gender on PASC in a Swiss population.MethodOur multicentre prospective cohort study included 2,856 (46% women, mean age 44.2 ± 16.8 years) outpatients and hospitalised patients with PCR-confirmed SARS-CoV-2 infection.ResultsAmong those who remained outpatients during their first infection, women reported persisting symptoms more often than men (40.5% vs 25.5% of men; p < 0.001). This sex difference was absent in hospitalised patients. In a crude analysis, both female biological sex (RR = 1.59; 95% CI: 1.41-1.79; p < 0.001) and a score summarising gendered sociocultural variables (RR = 1.05; 95% CI: 1.03-1.07; p < 0.001) were significantly associated with PASC. Following multivariable adjustment, biological female sex (RR = 0.96; 95% CI: 0.74-1.25; p = 0.763) was outperformed by feminine gender-related factors such as a higher stress level (RR = 1.04; 95% CI: 1.01-1.06; p = 0.003), lower education (RR = 1.16; 95% CI: 1.03-1.30; p = 0.011), being female and living alone (RR = 1.91; 95% CI: 1.29-2.83; p = 0.001) or being male and earning the highest income in the household (RR = 0.76; 95% CI: 0.60-0.97; p = 0.030).ConclusionSpecific sociocultural parameters that differ in prevalence between women and men, or imply a unique risk for women, are predictors of PASC and may explain, at least in part, the higher incidence of PASC in women. Once patients are hospitalised during acute infection, sex differences in PASC are no longer evident.

Background: Patients in intensive care units are prone to the occurrence of medication errors. Look-alike, sound-alike drugs with similar drug names can lead to medication errors and therefore endanger patient safety. Capitalisation of distinct text parts in drug names might facilitate differentiation of medication labels. The aim of this study was to test whether the use of such 'tall man' lettering (TML) reduces the error rate and to examine effects on the visual attention of critical care nurses while identifying syringe labels., Methods: This was a prospective, randomised in situ simulation conducted at the University Hospital Zurich, Zurich, Switzerland. Under observation by eye tracking, 30 nurses were given 10 successive tasks involving the presentation of a drug name and its selection from a dedicated set of 10 labelled syringes that included look-alike and sound-alike drug names, half of which had TML-coded labels.Error rate as well as dwell time, fixation count, fixation duration and revisits were analysed using a linear mixed-effects model analysis to compare TML-coded with non-TML-coded labels., Results: TML coding of syringe labels led to a significant decrease in the error rate (from 5.3% (8 of 150 in non-TML-coded sets) to 0.7% (1 of 150 in TML-coded sets), p<0.05). Eye tracking further showed that TML affects visual attention, resulting in longer dwell time (p<0.01), more and longer fixations (p<0.05 and p<0.01, respectively) on the drug name as well as more frequent revisits (p<0.01) compared with non-TML-coded labels. Detailed analysis revealed that these effects were stronger for labels using TML in the mid-to-end position of the drug name., Conclusions: TML in drug names changes visual attention while identifying syringe labels and supports critical care nurses in preventing medication errors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The coronavirus disease 2019 (COVID-19) pandemic demands reliable prognostic models for estimating the risk of long COVID. We developed and validated a prediction model to estimate the probability of known common long COVID symptoms at least 60 days after acute COVID-19., Methods: The prognostic model was built based on data from a multicentre prospective Swiss cohort study. Included were adult patients diagnosed with COVID-19 between February and December 2020 and treated as outpatients, at ward or intensive/intermediate care unit. Perceived long-term health impairments, including reduced exercise tolerance/reduced resilience, shortness of breath and/or tiredness (REST), were assessed after a follow-up time between 60 and 425 days. The data set was split into a derivation and a geographical validation cohort. Predictors were selected out of twelve candidate predictors based on three methods, namely the augmented backward elimination (ABE) method, the adaptive best-subset selection (ABESS) method and model-based recursive partitioning (MBRP) approach. Model performance was assessed with the scaled Brier score, concordance c statistic and calibration plot. The final prognostic model was determined based on best model performance., Results: In total, 2799 patients were included in the analysis, of which 1588 patients were in the derivation cohort and 1211 patients in the validation cohort. The REST prevalence was similar between the cohorts with 21.6% (n = 343) in the derivation cohort and 22.1% (n = 268) in the validation cohort. The same predictors were selected with the ABE and ABESS approach. The final prognostic model was based on the ABE and ABESS selected predictors. The corresponding scaled Brier score in the validation cohort was 18.74%, model discrimination was 0.78 (95% CI: 0.75 to 0.81), calibration slope was 0.92 (95% CI: 0.78 to 1.06) and calibration intercept was -0.06 (95% CI: -0.22 to 0.09)., Conclusion: The proposed model was validated to identify COVID-19-infected patients at high risk for REST symptoms. Before implementing the prognostic model in daily clinical practice, the conduct of an impact study is recommended., (© 2022. The Author(s).)

Background: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic., Methods: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic., Results: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO 2 /FiO 2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic., Conclusion: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic., (© 2022. The Author(s).)

Study Aim: The surge of admissions due to severe COVID-19 increased the patients-to-critical care staffing ratio within the ICUs. We investigated whether the daily level of staffing was associated with an increased risk of ICU mortality (primary endpoint), length of stay (LOS), mechanical ventilation and the evolution of disease (secondary endpoints)., Methods: We employed a retrospective multicentre analysis of the international Risk Stratification in COVID-19 patients in the ICU (RISC-19-ICU) registry, limited to the period between March 1 and May 31, 2020, and to Switzerland. Hierarchical regression models were used to investigate crude and adjusted effects of the critical care staffing ratio on study endpoints. We adjusted for disease severity and weekly caseload., Results: Among the 38 participating Swiss ICUs, 17 recorded staffing information. The study population included 437 patients and 2,342 daily assessments of patient-to-critical care staffing ratio. Median of daily patient-to-nurse ratio started at 1.0 [IQR 0.5-1.5; calendar week 9] and peaked at 2.4 (IQR 0.4-2.0; calendar week 16), while the median of daily patient-to-physician ratio started at 4.0 (IQR 2.1-5.0; calendar week 9) and peaked at 6.8 (IQR 6.3-7.3; calendar week 19). Neither the patient-to-nurse (adjusted OR 1.28, 95% CI 0.85-1.93; doubling of ratio) nor the patient-to-physician ratio (adjusted OR 1.07, 95% CI 0.87-1.32; doubling of ratio) were associated with ICU mortality. We found no association of daily critical care staffing on the secondary endpoints in adjusted models., Conclusion: We found no association of reduced availability of critical care staffing resources in Swiss ICUs with overall ICU length of stay nor mortality. Whether long-term outcome of critically ill patients with COVID-19 have been affected remains to be studied.

Patient safety is a priority in healthcare, yet it is unclear how sources of errors should best be analyzed. Eye tracking is a tool used to monitor gaze patterns in medicine. The aim of this study was to analyze the distribution of visual attention among critical care nurses performing non-simulated, routine patient care on invasively ventilated patients in an ICU. ICU nurses were tracked bedside in daily practice. Eight specific areas of interest were pre-defined (respirator, drug preparation, medication, patient data management system, patient, monitor, communication and equipment/perfusors). Main independent variable and primary outcome was dwell time, secondary outcomes were hit ratio, revisits, fixation count and average fixation time on areas of interest in a targeted tracking-time of 60 min. 28 ICU nurses were analyzed and the average tracking time was 65.5 min. Dwell time was significantly higher for the respirator (12.7% of total dwell time), patient data management system (23.7% of total dwell time) and patient (33.4% of total dwell time) compared to the other areas of interest. A similar distribution was observed for fixation count (respirator 13.3%, patient data management system 25.8% and patient 31.3%). Average fixation time and revisits of the respirator were markedly elevated. Apart from the respirator, average fixation time was highest for the patient data management system, communication and equipment/perfusors. Eye tracking is helpful to analyze the distribution of visual attention of critical care nurses. It demonstrates that the respirator, the patient data management system and the patient form cornerstones in the treatment of critically ill patients. This offers insights into complex work patterns in critical care and the possibility of improving work flows, avoiding human error and maximizing patient safety., (© 2020. The Author(s).)

Introduction: Closed-loop ventilation modes are increasingly being used in intensive care units to ensure more automaticity. Little is known about the visual behavior of health professionals using these ventilation modes. The aim of this study was to analyze gaze patterns of intensive care nurses while ventilating a patient in the closed-loop mode with Intellivent adaptive support ventilation® (I-ASV) and to compare inexperienced with experienced nurses. Materials and Methods: Intensive care nurses underwent eye-tracking during daily care of a patient ventilated in the closed-loop ventilation mode. Five specific areas of interest were predefined (ventilator settings, ventilation curves, numeric values, oxygenation Intellivent, ventilation Intellivent). The main independent variable and primary outcome was dwell time. Secondary outcomes were revisits, average fixation time, first fixation and fixation count on areas of interest in a targeted tracking-time of 60 min. Gaze patterns were compared between I-ASV inexperienced ( n = 12) and experienced ( n = 16) nurses. Results: In total, 28 participants were included. Overall, dwell time was longer for ventilator settings and numeric values compared to the other areas of interest. Similar results could be obtained for the secondary outcomes. Visual fixation of oxygenation Intellivent and ventilation Intellivent was low. However, dwell time, average fixation time and first fixation on oxygenation Intellivent were longer in experienced compared to inexperienced intensive care nurses. Discussion: Gaze patterns of intensive care nurses were mainly focused on numeric values and settings. Areas of interest related to traditional mechanical ventilation retain high significance for intensive care nurses, despite use of closed-loop mode. More visual attention to oxygenation Intellivent and ventilation Intellivent in experienced nurses implies more routine and familiarity with closed-loop modes in this group. The findings imply the need for constant training and education with new tools in critical care, especially for inexperienced professionals., 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 © 2021 Buehler, Herling, Bienefeld, Klinzing, Wegner, Wendel Garcia, Karbach, Lohmeyer, Schaubmayr, Schuepbach and Hofmaenner.)

The continued digitalization of medicine has led to an increased availability of longitudinal patient data that allows the investigation of novel and known diseases in unprecedented detail. However, to accurately describe any underlying pathophysiology and allow inter-patient comparisons, individual patient trajectories have to be synchronized based on temporal markers. In this pilot study, we use longitudinal data from critically ill ICU COVID-19 patients to compare the commonly used alignment markers "onset of symptoms," "hospital admission," and "ICU admission" with a novel objective method based on the peak value of the inflammatory marker C-reactive protein (CRP). By applying our CRP-based method to align the progression of neutrophils and lymphocytes, we were able to define a pathophysiological window that improved mortality risk stratification in our COVID-19 patient cohort. Our data highlights that proper synchronization of longitudinal patient data is crucial for accurate interpatient comparisons and the definition of relevant subgroups. The use of objective temporal disease markers will facilitate both translational research efforts and multicenter trials., 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 © 2021 Maibach, Allam, Hilty, Perez Gonzalez, Buehler, Wendel Garcia, Brugger, Ganter, The CoViD-19 ICU-Research Group Zurich, The RISC-19-ICU Investigators, Krauthammer, Schuepbach and Bartussek.)

Background: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates., Methods: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups., Results: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016)., Conclusion: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Similar to the influenza A pandemic in 1918/1919, the new Coronavirus disease 2019 (COVID-19) has spread globally. The causes of death in COVID-19 are frequently compared to a seasonal influenza outbreak. Complete COVID-19 autopsy studies were almost non-existent in the first months of the outbreak and are still rare with respect to the number of deaths. It has been recently reported that capillary microthrombi are significantly more prevalent in patients with COVID-19 than in patients with influenza A. To date, the contribution of macrothrombi, i.e. visible thrombi in pulmonary arteries, to the death of patients with influenza A in comparison to COVID-19 remains unaddressed. Here, we report autopsy findings in 411 patients who died from the 'Spanish' influenza A pandemic between May 1918 and April 1919 at the University Hospital Zurich, Switzerland. We compare these results with influenza A autopsies from 2009 to 2020, other influenza A autopsy series and all COVID-19 autopsies published to date. No descriptions of any macroscopic thromboembolic events were mentioned in influenza A autopsy reports. In 75 published COVID-19 autopsies, pulmonary artery thrombosis/embolism was reported in 36%. The direct comparison of macroscopic autopsy findings suggests a significantly greater degree of grossly visible pulmonary macrothrombi in patients with COVID-19 in comparison to influenza A autopsies even though most patients received empiric thromboprophylaxis. This is consistent with the concept of a SARS-related de novo coagulopathy with generalised in situ clot formation, which could explain the high incidence of pulmonary thrombosis/embolism with or without underlying deep vein thrombosis and in the absence of a history of venous thromboembolic events., (© 2020 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)

Group A Streptococcus (GAS) has acquired an arsenal of virulence factors, promoting life-threatening invasive infections such as necrotizing fasciitis. Current therapeutic regimens for necrotizing fasciitis include surgical debridement and treatment with cell wall-active antibiotics. Addition of clindamycin (CLI) is recommended, although clinical evidence is lacking. Reflecting the current clinical dilemma, an observational study showed that only 63% of the patients with severe invasive GAS infection received CLI. This work thus aimed to address whether CLI improves necrotizing fasciitis outcome by modulating virulence factors of CLI-susceptible and CLI-resistant GAS in vitro and in vivo. Treatment with CLI reduced extracellular DNase Sda1 and streptolysin O (SLO) activity in vivo, whereas subinhibitory CLI concentrations induced expression and activity of SLO, DNase, and Streptococcus pyogenes cell envelope protease in vitro. Our in vivo results suggest that CLI should be administered as soon as possible to patients with necrotizing fasciitis, while our in vitro studies emphasize that a high dosage of CLI is essential., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Neutrophils and monocytes are crucial for controlling bacterial infections. More-frequent bacterial infections are accordingly encountered in neutropenic patients undergoing chemotherapy. This is not the case for pegylated interferon α (IFN-α)-induced neutropenia. We hypothesized that IFN-α induces a compensatory innate antibacterial state that prevents bacterial infections despite the neutropenia., Methods: To investigate whether patients with hepatitis C virus infection treated with IFN-α killed group A Streptococcus (GAS) better than before initiating therapy, whole blood was used to perform ex vivo GAS killing assays before, during, and after IFN-α therapy., Results: We found that IFN-α therapy enhanced GAS killing in whole blood ex vivo despite the decreased neutrophil and monocyte numbers during IFN-α therapy. IFN-α also boosted neutrophil- and monocyte-mediated GAS killing in vitro. Underlying mechanisms included increased production of the antibacterial properdin, a regulator of the complement activation, as well as reactive oxygen species., Conclusions: These findings help to explain the rather discrepant facts of neutropenia but preserved antibacterial immune defenses in patients treated with IFN-α., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Objective: To examine the demographics, evolution and outcome of patients suffering from malignancies admitted to a medical intensive care unit., Patients and Methods: Single centre retrospective cohort study of patients with malignancies. Data on demographics, diagnosis laboratory tests, provided therapy and outcome were retrospectively collected. Data was analysed for differences between patients suffering from solid compared to haematological malignancies as well as for predictors of one year survival., Results: A total of 74 consecutive patients with a median age of 62 years were enrolled. From these, 42 (57%) suffered from solid and 32 (43%) from haematological malignancies. In total, 64% of patients with solid malignancies presented with metastatic disease. The main reason for intensive care unit admission in patients with solid malignancies was acute cardiovascular failure (39%) and infections in patients with haematological malignancies (38%). Intensive care unit mortality, hospital mortality and one year mortality were 26%, 35% and 71% overall; 17%, 29% and 69% respectively in patients with solid and 38%, 44% and 73% respectively in patients with haematological malignancies. Survival was close to 40% in patients with no or one organ failure. Survival dropped to 20% with 2 and 13% with ≥3 organs in failure. The number of organs in failure predicted hospital fatality with an AUCRoc of 0.87., Conclusion: The number of failing organs rather than malignancy itself drives outcome even in patients with malignancies. Thus the number of organs in failure rather than diagnosis should guide intensive care unit management in patients with malignancies.

Thrombin and activated protein C (APC) signaling can mediate opposite biologic responses in endothelial cells. Given that thrombin induces procoagulant tissue factor (TF), we examined how TF activity is affected by APC. Exogenous or endogenously generated APC led to increased TF-dependent factor Xa activity. Induction required APC's proteolytic activity and binding to endothelial cell protein C receptor but not protease activated receptors. APC did not affect total TF antigen expression or the availability of anionic phospholipids on the apical cell membrane. Western blotting and cell surface immunoassays demonstrated that APC sheds the Kunitz 1 domain from tissue factor pathway inhibitor (TFPI). A TFPI Lys86Ala mutation between the Kunitz 1 and 2 domains eliminated both cleavage and the enhanced TF activity in response to APC in overexpression studies, indicating that APC up-regulates TF activity by endothelial cell protein C receptor-dependent shedding of the Kunitz 1 domain from membrane-associated TFPI. Our results demonstrate an unexpected procoagulant role of the protein C pathway that may have important implications for the regulation of TF- and TFPI-dependent biologic responses and for fine tuning of the hemostatic balance in the vascular system.

Iron deficiency is known to cause symptoms such as fatigue, depression and restless legs syndrome resulting in impaired quality of life and working capacity. We sought to examine the iron status of reportedly healthy individuals by a framed study design in 58 highly educated Swiss hospital employees and to compare the use of non invasive tests for assessing iron deficiency (ID). A structured interview was used to assess health status, nutritional intake and potential blood loss, blood counts as well as parameters proposed to diagnose iron deficiency were determined. All subjects felt well and were working at their maximum capacity. The male subjects were neither anaemic nor had decreased iron parameters however 50% (23/46) of the women had a serum ferritin of below 22 μg/L, still 33% (15/46) of the women had a ferritin value below the more stringent cut off value of 15 μg/L. In 15% (7/46) of the women we diagnosed iron deficient anaemia. Red meat consumption correlated with ferritin values as did the menstrual blood loss which was estimated by asking the amount of tampons used. Of the additionally analysed iron parameters only the percentage of hypochromic erythrocytes, soluble transferrin receptor and transferrin values were significantly correlated with ferritin and reached an AUCROC of ≥0.7 indicating good predictive tests. Nevertheless neither soluble transferrin receptor nor transferrin showed diagnostic advantages for the diagnosis of ID compared to ferritin alone or together with erythrocyte parameters. Working in a hospital environment and having access to health education does not seem to correlate with prevention of ID or ID anaemia in female hospital employees.

Activated protein C (APC) reduces mortality in severe sepsis patients. APC exerts anticoagulant activities via inactivation of factors Va and VIIIa and cytoprotective activities via endothelial protein C receptor and protease-activated receptor-1. APC mutants with selectively altered and opposite activity profiles, that is, greatly reduced anticoagulant activity or greatly reduced cytoprotective activities, are compared here. Glu149Ala-APC exhibited enhanced in vitro anticoagulant and in vivo antithrombotic activity, but greatly diminished in vitro cytoprotective effects and in vivo reduction of endotoxin-induced murine mortality. Thus, residue Glu149 and the C-terminal region of APC's light chain are identified as functionally important for expression of multiple APC activities. In contrast to Glu149Ala-APC, 5A-APC (Lys191-193Ala + Arg229/230Ala) with protease domain mutations lacked in vivo antithrombotic activity, although it was potent in reducing endotoxin-induced mortality, as previously shown. These data imply that APC molecular species with potent antithrombotic activity, but without robust cytoprotective activity, are not sufficient to reduce mortality in endotoxemia, emphasizing the need for APC's cytoprotective actions, but not anticoagulant actions, to reduce endotoxin-induced mortality. Protein engineering can provide APC mutants that permit definitive mechanism of action studies for APC's multiple activities, and may also provide safer and more effective second-generation APC mutants with reduced bleeding risk.