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Objectives: Bromelain-based enzymatic debridement has emerged as an alternative to surgical eschar removal. Indications include partial thickness, mixed pattern, and full-thickness burns. Enzymatic debridement has been approved by the European Medicines Agency for treating burn wounds affecting <15% total body surface area (TBSA). Data and evidence for the treatment of areas >15% TBSA in one session is scarce. The aim of this retrospective study was to retrospectively analyze off-label use of enzymatic debridement in a single burn center for large TBSA burns.Methods: Between 01/2017 and 12/2018, 59 patients with partial- to full-thickness burns underwent enzymatic debridement in a single center study. Patients were categorized into two groups: the regular use group with a treated area less than 15% TBSA and the off-label group (OG) with larger TBSA debrided in one session. Treatment was evaluated for systemic inflammatory reaction, bleeding, hemodynamic instability and electrolyte shifts.Results: In total, 49 patients were treated in the regular use group with a median application area of 6% (IQR 2.5-9.5) and 10 patients were treated in the off-label group with a median application area of 18% (IQR 15-19) TBSA. We found no significant differences regarding blood pressure, body temperature or hemodynamic stability during and after enzymatic debridement. No treatment-related serious adverse events were observed in either group. Catecholamine use was similar in both groups. No differences in leukocyte counts, CRP, PCT and lactate prior to application and during the following three days were observed. Sodium, potassium, chloride and phosphate levels did not differ. We found no evidence of an electrolyte shift. Survival was 49 of 49 patients (100%) in the RG and 7 of 10 patients (70%) in the OG (p = 0.004).Conclusion: Enzymatic debridement did not result in any expected or unexpected side effects in the patient groups investigated. These preliminary results indicate the potential safety of bromelain-based enzymatic debridementin the treatment of burns greater than 15% TBSA. [ABSTRACT FROM AUTHOR]

In female mammals, reproduction, and in particular lactation, is the energetically most exigent life-history phase. Reproduction is strongly controlled by body reserves and food availability, so females with better body condition or food supply are believed to have higher reproductive output. Additionally, the growth and mortality of young mammals depends on their postnatal development. Therefore, the degree of precociality affects energetic demands for both mothers and young. To study the reproductive performance of the precocial European hare (Lepus europaeus), we analysed relationships between six predictor variables describing maternal and environmental effects and nine response variables relating to reproduction from 217 captive females. We compared the data with those of precocial and altricial mammal species from an extensive literature search. For hares, we found: (1) Heavier females had heavier litters at birth. (2) In summer and spring, total litter mass was larger than in winter. (3) At the end of lactation, the litters of multiparous females were heavier than those of primiparous females. (4) Both older females and females giving birth for the first time had relatively high leveret mortality during lactation. Comparing our results with the literature for other mammals revealed that the body condition (i.e., body mass) of females before birth is predictive of reproductive parameters in both precocial and altricial species. In the precocial hare, female body condition is no longer predictive of reproductive parameters at the end of lactation, whereas in altricial species, female body condition remains predictive of reproduction (litter mass at the end of lactation, offspring mortality) until the end of lactation. We conclude that these effects are caused by precocial offspring feeding on solid food soon after birth and, thus, being less dependent on the mother's body condition during lactation than altricial offspring. In line with this, precociality might have evolved as a way of buffering offspring against maternal effects. [ABSTRACT FROM AUTHOR]

Imaging often plays an important role in pivotal clinical trials of drugs or devices that have been submitted for approval to regulatory agencies that grant approval for the marketing and sale of these products on the basis of documentation of their safety and efficacy. Imaging biomarkers can help substantiate either or both of these characteristics. This article focuses on how to successfully incorporate imaging biomarkers into clinical trials through a process of careful planning and diligent execution. Planning starts with posing and then answering a number of questions that pertain to the product under study. What will the claimed benefit of the product be? Is there a current standard of care that involves imaging, and will that standard of care help in the documentation of safety and efficacy? Are there relevant novel imaging biomarkers? Are there any relevant guidance documents issued by the regulatory agencies? After imaging biomarkers are identified, their role and benefit must be understood. Will they help diagnose subjects? Will they stratify subjects for enrollment? Will they identify those who are more likely to benefit? Will they help document progression of disease and effectiveness of intervention? Execution must occur in close collaboration with regulatory agencies and with the involvement of imaging experts and imaging core laboratories to ensure attention to key components: imaging charter, investigator training and certification, 21 CFR Part 11 (Part 11 of Title 21 of the U.S. Code of Federal Regulations)-compliant data management, real-time incoming image quality control for eligibility reads and investigator feedback, and centralized image analysis for safety and efficacy by certified readers. [ABSTRACT FROM AUTHOR]

Background: Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO-VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology. Methods: Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22–89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ2 and Mann-Whitney U tests. Results: Severe pulmonary endotheliitis (p = 0.031, p = 0.029) and multi-organ involvement (p = 0.026, p = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either. Conclusions: Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO-VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess a potential organ protective effect of volatile sedation in a scenario of severe inflammation with an early cytokine storm (in particular IL-6 elevation) in patients suffering from COVID-19-related lung injury with invasive mechanical ventilation and sedation. Methods: This is a small-scale pilot multicenter randomized controlled trial from four tertiary hospitals in Switzerland, conducted between April 2020 and May 2021. 60 patients requiring mechanical ventilation due to severe COVID-19-related lung injury were included and randomized to 48-hour sedation with sevoflurane vs. continuous intravenous sedation (= control) within 24 h after intubation. The primary composite outcome was determined as mortality or persistent organ dysfunction (POD), defined as the need for mechanical ventilation, vasopressors, or renal replacement therapy at day 28. Secondary outcomes were the length of ICU and hospital stay, adverse events, routine laboratory parameters (creatinine, urea), and plasma inflammatory mediators. Results: 28 patients were randomized to sevoflurane, 32 to the control arm. The intention-to-treat analysis revealed no difference in the primary endpoint with 11 (39%) sevoflurane and 13 (41%) control patients (p = 0.916) reaching the primary outcome. Five patients died within 28 days in each group (16% vs. 18%, p = 0.817). Of the 28-day survivors, 6 (26%) and 8 (30%) presented with POD (p = 0.781). There was a significant difference regarding the need for vasopressors (1 (4%) patient in the sevoflurane arm, 7 (26%) in the control one (p = 0.028)). Length of ICU stay, hospital stay, and registered adverse events within 28 days were comparable, except for acute kidney injury (AKI), with 11 (39%) sevoflurane vs. 2 (6%) control patients (p = 0.001). The blood levels of IL-6 in the first few days after the onset of the lung injury were less distinctly elevated than expected. Conclusions: No evident benefits were observed with short sevoflurane sedation on mortality and POD. Unexpectedly low blood levels of IL-6 might indicate a moderate injury with therefore limited improvement options of sevoflurane. Acute renal issues suggest caution in using sevoflurane for sedation in COVID-19. Trial registration: The trial was registered on ClinicalTrials.gov (NCT04355962) on 2020/04/21. [ABSTRACT FROM AUTHOR]

Bromelain-based enzymatic debridement has emerged as a valuable option to the standard surgical intervention for debridement in burn injuries. Adverse effects on coagulation parameters after enzymatic debridement have been described. The purpose of this study was to compare the effect of enzymatic and surgical debridement on coagulation. Between 03/2017 and 02/2021 patients with burn injuries with a total body surface area (TBSA) ≥ 1% were included in the study. Patients were categorized into two groups: the surgically debrided group and the enzymatically debrided group. Coagulation parameters were assessed daily for the first seven days of hospitalization. In total 132 patients with a mean TBSA of 17% were included in this study, of which 66 received enzymatic debridement and 66 received regular surgical-debridement. Patients receiving enzymatic debridement presented significantly higher factor-V concentration values over the first seven days after admission (p = <0.01). Regarding coagulation parameters, we found no difference in INR-, aPTT-, fibrinogen-, factor-XIII- and thrombocyte-concentrations over the first seven days (p = >0.05). Enzymatic debridement in burned patients does not appear to increase the risk of coagulation abnormalities compared with the regular surgical approach. • Enzymatic debridement (ED) in burned patients does not increase the risk of coagulation. • ED emerges are safe and an alternative to standard treatment without significant effect of the coagulation. • This is the first analysis of coagulation-specific laboratory markers including coagulation factor-V and factor-XIII concentrations in ED. [ABSTRACT FROM AUTHOR]

Hypothermia in severely burned patients is associated with a significant increase in morbidity and mortality. The use of an oesophageal heat exchanger tube (EHT) can improve perioperative body temperatures in severely burned patients. The aim of this study was to investigate the intraoperative warming effect of oesophageal heat transfer in severe burn patients. Single-centre retrospective study performed at the Burns Centre of the University Hospital Zurich. Between January 2020 and May 2021 perioperative temperature management with EHT was explored in burned patients with a total body surface area (TBSA) larger than 30%. Data from patients, who received perioperative temperature management by EHT, were compared to data from the same patients during interventions performed under standard temperature management matching for length and type of intervention. A total of 30 interventions (15 with and 15 without EHT) in 10 patients were analysed. Patient were 38 [26−48] years of age, presented with severe burns covering a median of 50 [42−64] % TBSA and were characterized by an ABSI of 10 [8−12] points. When receiving EHT management patients experienced warming at 0.07 °C per minute (4.2 °C/h) compared to a temperature loss of − 0.03 °C per minute (1.8 °C/h) when only receiving standard temperature management (p < 0.0001). No adverse or serious adverse events were reported. The use of an oesophageal heat transfer device was effective and safe in providing perioperative warming to severely burned patients when compared to a standard temperature management protocol. By employing an EHT as primary temperature management device perioperative hypothermia in severely burned patients can possibly be averted, potentially leading to reduced hypothermia-associated complications. • EHT was associated with intraoperative warming as opposed to standard temperature management. • This study shows that the use of an EHT was effective and safe. • EHT can potentially leading to reduced hypothermia-associated complications. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease‐2019 (COVID‐19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID‐19 may impact the development of the MDR. Methods: Blood and skin samples from COVID‐19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID‐MDR), healthy controls, non‐COVID‐19—related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high‐throughput multiplexed proteomic profiling of serum were performed. Results: IMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8+ T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID‐MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID‐MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID‐MDR patients revealed upregulation of various inflammatory mediators (IL‐4, IL‐5, IL‐6, TNF, and IFN‐γ), eosinophil and Mo/Mac ‐attracting chemokines (MCP‐2, MCP‐3, MCP‐4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID‐MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features. Conclusion: A systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8+ T cells in severe COVID‐19 patients, which in turn may impact the development of MDR. [ABSTRACT FROM AUTHOR]

Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro.[4] Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix). She developed progressive respiratory failure due to COVID-19 and subsequently developed multi-organ failure and needed renal replacement therapy. [Extracted from the article]

Coronavirus disease 19 (COVID‐19) is a rapidly evolving pandemic caused by the coronavirus Sars‐CoV‐2. Clinically manifest central nervous system symptoms have been described in COVID‐19 patients and could be the consequence of commonly associated vascular pathology, but the detailed neuropathological sequelae remain largely unknown. A total of six cases, all positive for Sars‐CoV‐2, showed evidence of cerebral petechial hemorrhages and microthrombi at autopsy. Two out of six patients showed an elevated risk for disseminated intravascular coagulopathy according to current criteria and were excluded from further analysis. In the remaining four patients, the hemorrhages were most prominent at the grey and white matter junction of the neocortex, but were also found in the brainstem, deep grey matter structures and cerebellum. Two patients showed vascular intramural inflammatory infiltrates, consistent with Sars‐CoV‐2‐associated endotheliitis, which was associated by elevated levels of the Sars‐CoV‐2 receptor ACE2 in the brain vasculature. Distribution and morphology of patchy brain microbleeds was clearly distinct from hypertension‐related hemorrhage, critical illness‐associated microbleeds and cerebral amyloid angiopathy, which was ruled out by immunohistochemistry. Cerebral microhemorrhages in COVID‐19 patients could be a consequence of Sars‐ CoV‐2‐induced endotheliitis and more general vasculopathic changes and may correlate with an increased risk of vascular encephalopathy. [ABSTRACT FROM AUTHOR]

Background: Allogeneic blood transfusions are common in the treatment of severely burned patients as surgery may lead to major blood loss. However, transfusions are associated with a number of adverse events. Therefore, the purpose of our study was to investigate the impact of allogeneic blood transfusions on clinical outcomes in severely burned patients.Methods: This retrospective study included all adult patients admitted to the burn center of the University Hospital Zurich between January 2004 and December 2014, with burn injuries greater than 10% of total body surface area and receiving both surgical and intensive care treatment. Primary Endpoints were infectious or thromboembolic complications and mortality and secondary endpoints were length of hospital and ICU stay. Simple and multivariable logistic and linear regression models, adjusted for injury severity and confounders, were applied.Results: 413 patients met inclusion criteria of which 212 patients (51%) received allogenic blood products. After adjustment for injury severity and confounders, red blood cell transfusion was independently associated with wound infection (OR 13.5, 95% CI 1.7-107, p = 0.014), sepsis (OR 8.3, 4.2-16.3; p < 0.001), pneumonia (OR 4.7, 2.2-10.0; p < 0.001), thrombosis (OR 3.0, 1.2-7.4; p = 0.015), central line infection (OR 34.7, 4.6-260; p = 0.001) and a longer ICU and hospital stay (difference 17.7, CI 12.1-23.4, p < 0.001 and 22.0, 15.8-28.2, p < 0.001, respectively). Fresh frozen plasma transfusion was independently associated with a longer ICU and hospital stay (difference 13.7, 95% CI 5.5-21.8, p = 0.001 and 13.5, 4.6-22.5, p = 0.003, respectively). Platelet transfusion was independently associated with systemic inflammatory response syndrome (OR 4.5, 1.3-15.5; p = 0.018) and mortality (OR 5.8, 2.1-16.0; p = 0.001).Conclusion: Transfusion of allogeneic blood products is associated with an increased infection rate and thromboembolic morbidity and a longer hospital stay in severely burned patients. [ABSTRACT FROM AUTHOR]

We thank Cynthia Goldsmith and colleagues for their interest in our recent Correspondence.[1] We described autopsy findings from patients who had died from COVID-19 and showed a systemic endotheliitis with evidence of loss of integrity of the endothelial monolayer.[1] The framework of endotheliitis provides an explanation for the unique predilection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in those individuals with hypertension, diabetes, or established cardiovascular disease, a group known to have pre-existing endothelial dysfunction. In another recent study,[6] virus-like particles in patients with confirmed SARS-CoV-2 infection were 70-110 nm in diameter. This notwithstanding, these observed particles in patients with COVID-19 should be best designated as virus-like particles because definitive assignment of these structures as SARS-CoV-2 virions requires immuno-EM. [Extracted from the article]

Background: In 2013 the Swiss Diagnosis Related Groups ((Swiss)-DRG) was implemented in Intensive Care Units (ICU). Its impact on hospitalizations has not yet been examined. We compared the number of ICU admissions, according to clinical severity and referring institution, and screened whether implementation of Swiss-DRG affected admission policy, ICU length-of-stay (ICU-LOS) or ICU mortality.Methods: Retrospective, single centre, cohort study conducted at the University Hospital Zurich, Switzerland between January 2009 and end of September 2013. Demographic and clinical data was retrieved from a quality assurance database.Results: Admissions (n = 17,231) before the introduction of Swiss-DRG were used to model expected admissions after DRG, and then compared to the observed admissions. Forecasting matched observations in patients with a high clinical severity admitted from internal units and external hospitals (admitted / predicted: 709 / 703, [95% Confidence Interval (CI), 658-748] and 302 / 332, [95% CI, 269-365] respectively). In patients with low severity of disease, in-house admissions became more frequent than expected and external admission were less frequent (admitted / predicted: 1972 / 1910, [95% CI, 1898-1940] and 436 / 518, [95% CI, 482-554] respectively). Various mechanisms related to Swiss-DRG may have led to these changes. DRG could not be linked to significant changes in regard to ICU-LOS and ICU mortality.Conclusions: DRG introduction had not affected ICU admissions policy, except for an increase of in-house patients with a low clinical severity of disease. DRG had neither affected ICU mortality nor ICU-LOS. [ABSTRACT FROM AUTHOR]

Ethical problems and dilemmas in intensive care units are not fundamentally different from those of other contexts of inpatient treatment. However, the intensity of the implemented resources, the temporal density of decisionmaking on the meaningfulness of the use or omission of medical measures in patients who are often unable to make judgements, the availability and quantity of human and technical resources lead to the much greater visibility of the "ethical component" in clinical decisionmaking processes. After an introduction outlining different forms of ethics support and their effects, we describe experiences of interprofessional cooperation in facing clinical ethical questions in intensive care medicine from the University Hospital Zurich (USZ). Our experience shows that an excellent, patientoriented medicine in an intensive care unit depends less on favored ethical "models" than on the respective department culture, the lowthreshold and constant availability, and the contextsensitive adaptation of the offer of clinical ethics support to all disciplines and professions involved in the care process in the unit. On the basis of this experience, we discuss which framework conditions are conducive to ensuring a sufficient standard of ethical case resolution in intensive care units in the long term. [ABSTRACT FROM AUTHOR]

We describe the methods and reliability of radiographic vertebral fracture assessment in MrOS, a cohort of community dwelling men aged ≥ 65yrs. Lateral spine radiographs were obtained at Visit 1 (2000-2) and 4.6years later (Visit 2). Using a workflow tool (SpineAnalyzer™, Optasia Medical), a physician reader completed semi-quantitative (SQ) scoring. Prior to SQ scoring, technicians performed "triage" to reduce physician reader workload, whereby clearly normal spine images were eliminated from SQ scoring with all levels assumed to be SQ=0 (no fracture, "triage negative"); spine images with any possible fracture or abnormality were passed to the physician reader as "triage positive" images. Using a quality assurance sample of images (n=20 participants; 8 with baseline only and 12 with baseline and follow-up images) read multiple times, we calculated intra-reader kappa statistics and percent agreement for SQ scores. A subset of 494 participants' images was read regardless of triage classification to calculate the specificity and sensitivity of triage. Technically adequate images were available for 5958 of 5994 participants at Visit 1, and 4399 of 4423 participants at Visit 2. Triage identified 3215 (53.9%) participants with radiographs that required further evaluation by the physician reader. For prevalent fractures at Visit 1 (SQ≥1), intra-reader kappa statistics ranged from 0.79 to 0.92; percent agreement ranged from 96.9% to 98.9%; sensitivity of the triage was 96.8% and specificity of triage was 46.3%. In conclusion, SQ scoring had excellent intra-rater reliability in our study. The triage process reduces expert reader workload without hindering the ability to identify vertebral fractures. [ABSTRACT FROM AUTHOR]

Abstract: Polyethersulfone (PES) microfiltration membranes with remarkably improved filtration performance were recently developed. Subtle changes in the conditions of the phase separation process lead to a very pronounced anisotropic (“hour glass”-like) cross-section morphology of these novel membranes named DuraPES®. Furthermore, due to macromolecular additives, the membranes are permanently hydrophilic. The properties and performance of the DuraPES® membranes are compared to other membranes available on the market, such as AMC Accupor, Osmonics Micron PES, Pall Supor, Sartorius Sartopore, and Millipore Express. Parameters investigated are on the one hand focussed on membrane structure such as pore morphology (from SEM), volume porosity, trans-membrane pore size distribution, contact angles and wetting with water, and trans-membrane streaming potential. On the other hand, membrane performance is evaluated with respect to water permeability, the filtration of a protein solution and the correlated fouling, as well as other filtration tests with more complex feed solutions. Up to >10 times higher filtrate fluxes are observed for the DuraPES® membranes as compared to the other membranes having the same nominal pore size. However, such higher performance is only achieved with the macroporous surface upstream to the feed. The overall analysis of all data shows that the significant advantages of DuraPES® membranes resulted from their special surface and pore morphology. [Copyright &y& Elsevier]

Uses single-photon absorptiometry in determining whether measurement of bone density predicts hip fracture in women. Inverse correlation between bone density in appendicular skeleton and risk of hip fracture; Age-related increase in risk of hip fracture among older women; Incidence of hip fracture by age-adjusted quartile of bone mineral density; Causes of hip fracture.

Study Design: Study design randomized intra- and inter-reader reproducibility study. Objective: To evaluate reproducibility of quantitative morphometry (QM) and agreement of dichotomous fracture/no-fracture status on lateral spinal radiographs acquired during routine clinical practice using a clinical workflow tool. Summary Of Background Data: Several recent guidelines have underlined the importance of Genant semi-quantitative scoring and selective QM to confirm and grade suspected vertebral fractures in clinical practice. Methods: Thoracic and lumbar spine radiographs were acquired from 98 consecutive subjects (mean age, 60.1 ± 11.7 yr) attending the clinic for osteoporosis evaluation. For each subject, QM and Genant semi-quantitative scoring were performed on all evaluable vertebrae from L4 to T4 using a software workflow tool. A radiologist and an experienced radiographical technician performed 2 repeat reading sessions of the radiographs 12 months apart, blinded to each other's results; for the second read, the cases were anonymized and the order was randomized. Results: Inter-reader reproducibility results were 3.1% and 3.2% coefficient of variation (%) for heights, 0.030 and 0.031 root mean square standard deviation for height ratios. For intrareader reproducibility, these values were 2.2% and 3.5% coefficient of variation %; 0.023 and 0.034 root mean square standard deviation. Kappa score results for agreement of dichotomous fracture/no-fracture status were 0.67 and 0.72 (inter-rater) and 0.50 and 0.67 (intrarater). Conclusion: The software assessed in this study is a reliable clinical tool that facilitates QM and Genant semi-quantitative scoring of the spine in routine clinical practice. Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]