Early sevoflurane sedation in severe COVID-19-related lung injury patients. A pilot randomized controlled trial.

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.

Impact of CytoSorb Hemoadsorption Therapy on Fluid Balance in Patients with Septic Shock.

Recent in vitro studies have investigated the effects of hemoadsorption therapy on endothelial function in sepsis showing a reduction in markers of endothelial dysfunction, but, to this day, there are no clinical studies proving whether this approach could actually positively influence the disturbed vascular barrier function in septic conditions. We retrospectively analyzed data on administered fluid volumes and catecholamines in 124 septic shock patients. We collected catecholamine and volume requirements and calculated the volume balance within different time periods to obtain an assumption on the stability of the vascular barrier. Regarding the entire study cohort, our findings revealed a significant reduction in fluid balance at 72 h (T72) compared to both baseline (T0) and the 24 h mark (T24). Fluid balances from T72-T0 were significantly lower in hospital survivors compared with non-survivors. Patients who received a second catecholamine had a significantly lower in-hospital mortality. Our findings suggest that the applied treatment regimen including hemoadsorption therapy is associated with a reduced positive fluid balance paralleled by reductions in vasopressor needs, suggesting a potential positive effect on endothelial integrity. These results, derived from a large cohort of patients, provide valuable insights on the multiple effects of hemoadsorption treatment in septic shock patients.

HEAR4Health: a blueprint for making computer audition a staple of modern healthcare.

Recent years have seen a rapid increase in digital medicine research in an attempt to transform traditional healthcare systems to their modern, intelligent, and versatile equivalents that are adequately equipped to tackle contemporary challenges. This has led to a wave of applications that utilise AI technologies; first and foremost in the fields of medical imaging, but also in the use of wearables and other intelligent sensors. In comparison, computer audition can be seen to be lagging behind, at least in terms of commercial interest. Yet, audition has long been a staple assistant for medical practitioners, with the stethoscope being the quintessential sign of doctors around the world. Transforming this traditional technology with the use of AI entails a set of unique challenges. We categorise the advances needed in four key pillars: Hear, corresponding to the cornerstone technologies needed to analyse auditory signals in real-life conditions; Earlier, for the advances needed in computational and data efficiency; Attentively, for accounting to individual differences and handling the longitudinal nature of medical data; and, finally, Responsibly, for ensuring compliance to the ethical standards accorded to the field of medicine. Thus, we provide an overview and perspective of HEAR4Health: the sketch of a modern, ubiquitous sensing system that can bring computer audition on par with other AI technologies in the strive for improved healthcare systems.

Fate of Horizontal-Gene-Transfer Markers and Beta-Lactamase Genes during Thermophilic Composting of Human Excreta.

Thermophilic composting is a suitable treatment for the recycling of organic wastes for agriculture. However, using human excreta as feedstock for composting raises concerns about antibiotic resistances. We analyzed samples from the start and end of a thermophilic composting trial of human excreta, together with green cuttings and straw, with and without biochar. Beta-lactamase genes blaCTX-M, blaIMP, and blaTEM conferring resistance to broad-spectrum beta-lactam antibiotics, as well as horizontal gene transfer marker genes, intI1 and korB, were quantified using qPCR. We found low concentrations of the beta-lactamase genes in all samples, with non-significant mean decreases in blaCTX-M and blaTEM copy numbers and a mean increase in blaIMP copy numbers. The decrease in both intI1 and korB genes from start to end of composting indicated that thermophilic composting can decrease the horizontal spread of resistance genes. Thus, thermophilic composting can be a suitable treatment for the recycling of human excreta.

Metagenomic Insights Into the Changes of Antibiotic Resistance and Pathogenicity Factor Pools Upon Thermophilic Composting of Human Excreta.

In times of climate change, practicing a form of sustainable, climate-resilient and productive agriculture is of primordial importance. Compost could be one form of sustainable fertilizer, which is increasing humus, water holding capacity, and nutrient contents of soils. It could thereby strengthen agriculture toward the adverse effects of climate change, especially when additionally combined with biochar. To get access to sufficient amounts of suitable materials for composting, resources, which are currently treated as waste, such as human excreta, could be a promising option. However, the safety of the produced compost regarding human pathogens, pharmaceuticals (like antibiotics) and related resistance genes must be considered. In this context, we have investigated the effect of 140- and 154-days of thermophilic composting on the hygienization of human excreta and saw dust from dry toilets together with straw and green cuttings with and without addition of biochar. Compost samples were taken at the beginning and end of the composting process and metagenomic analysis was conducted to assess the fate of antibiotic resistance genes (ARGs) and pathogenicity factors of the microbial community over composting. Potential ARGs conferring resistance to major classes of antibiotics, such as beta-lactam antibiotics, vancomycin, the MLSB group, aminoglycosides, tetracyclines and quinolones were detected in all samples. However, relative abundance of ARGs decreased from the beginning to the end of composting. This trend was also found for genes encoding type III, type IV, and type VI secretion systems, that are involved in pathogenicity, protein effector transport into eukaryotic cells and horizontal gene transfer between bacteria, respectively. The results suggest that the occurrence of potentially pathogenic microorganisms harboring ARGs declines during thermophilic composting. Nevertheless, ARG levels did not decline below the detection limit of quantitative PCR (qPCR). Thresholds for the usage of compost regarding acceptable resistance gene levels are yet to be evaluated and defined.

DeepSpectrumLite: A Power-Efficient Transfer Learning Framework for Embedded Speech and Audio Processing From Decentralized Data.

Deep neural speech and audio processing systems have a large number of trainable parameters, a relatively complex architecture, and require a vast amount of training data and computational power. These constraints make it more challenging to integrate such systems into embedded devices and utilize them for real-time, real-world applications. We tackle these limitations by introducing DeepSpectrumLite, an open-source, lightweight transfer learning framework for on-device speech and audio recognition using pre-trained image Convolutional Neural Networks (CNNs). The framework creates and augments Mel spectrogram plots on the fly from raw audio signals which are then used to finetune specific pre-trained CNNs for the target classification task. Subsequently, the whole pipeline can be run in real-time with a mean inference lag of 242.0 ms when a DenseNet121 model is used on a consumer-grade Motorola moto e7 plus smartphone. DeepSpectrumLite operates decentralized, eliminating the need for data upload for further processing. We demonstrate the suitability of the proposed transfer learning approach for embedded audio signal processing by obtaining state-of-the-art results on a set of paralinguistic and general audio tasks, including speech and music emotion recognition, social signal processing, COVID-19 cough and COVID-19 speech analysis, and snore sound classification. We provide an extensive command-line interface for users and developers which is comprehensively documented and publicly available at https://github.com/DeepSpectrum/DeepSpectrumLite.

Thermophilic Composting of Human Feces: Development of Bacterial Community Composition and Antimicrobial Resistance Gene Pool.

In times of climate change, practicing sustainable, climate-resilient, and productive agriculture is of primordial importance. Compost from different resources, now treated as wastes, could be one form of sustainable fertilizer creating a resilience of agriculture to the adverse effects of climate change. However, the safety of the produced compost regarding human pathogens, pharmaceuticals, and related resistance genes must be considered. We have assessed the effect of thermophilic composting of dry toilet contents, green cuttings, and straw, with and without biochar, on fecal indicators, the bacterial community, and antibiotic resistance genes (ARGs). Mature compost samples were analyzed regarding fecal indicator organisms, revealing low levels of Escherichia coli that are in line with German regulations for fertilizers. However, one finding of Salmonella spp. exceeded the threshold value. Cultivation of bacteria from the mature compost resulted in 200 isolates with 36.5% of biosafety level 2 (BSL-2) species. The majority is known as opportunistic pathogens that likewise occur in different environments. A quarter of the isolated BSL-2 strains exhibited multiresistance to different classes of antibiotics. Molecular analysis of total DNA before and after composting revealed changes in bacterial community composition and ARGs. 16S rRNA gene amplicon sequencing showed a decline of the two most abundant phyla Proteobacteria (start: 36-48%, end: 27-30%) and Firmicutes (start: 13-33%, end: 12-16%), whereas the abundance of Chloroflexi, Gemmatimonadetes, and Planctomycetes rose. Groups containing many human pathogens decreased during composting, like Pseudomonadales, Bacilli with Bacillus spp., or Staphylococcaceae and Enterococcaceae. Gene-specific PCR showed a decline in the number of detectable ARGs from 15 before to 8 after composting. The results reveal the importance of sufficiently high temperatures lasting for a sufficiently long period during the thermophilic phase of composting for reducing Salmonella to levels matching the criteria for fertilizers. However, most severe human pathogens that were targeted by isolation conditions were not detected. Cultivation-independent analyses also indicated a decline in bacterial orders comprising many pathogenic bacteria, as well as a decrease in ARGs. In summary, thermophilic composting could be a promising approach for producing hygienically safe organic fertilizer from ecological sanitation.

Reply to Supady et al. On the Use of Hemadsorption with CytoSorb in Patients with Septic Shock. Comment on "Kogelmann et al. First Evaluation of a New Dynamic Scoring System Intended to Support Prescription of Adjuvant CytoSorb Hemoadsorption Therapy in Patients with Septic Shock. J. Clin. Med. 2021, 10, 2939".

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First Evaluation of a New Dynamic Scoring System Intended to Support Prescription of Adjuvant CytoSorb Hemoadsorption Therapy in Patients with Septic Shock.

INTRODUCTION: Despite advances in critical care medicine, adjunctive approaches in sepsis therapy have failed to prove their efficacy. Notwithstanding promising results using hemoadsorption (CytoSorb), questions remain concerning timing and dosing. We created a dynamic scoring system (DSS) to assess patients with early septic shock and performed a first evaluation of the system in this patient population. METHODS: Data from 502 patients with septic shock according to Sepsis-3 criteria were retrospectively analyzed. Score parameters were documented at the time of diagnosis (T0) and 6 h later (T6) to calculate a dynamic score. Survival on day 7 and 56 as well as ICU and hospital mortality were analyzed in regard to the score as well as the delay of hemoadsorption therapy. RESULTS: Of the 502 patients analyzed, 198 received adjunctive CytoSorb treatment and 304 received standard therapy. Septic shock was typically represented by 5 points, while >6 points indicated a situation refractory to standard therapy with the worst outcome in patients shown by >8 points. The differences in mortality between the score groups (<6, 6-8, >8 points) were significant. Analysis further showed a significant 56-day, ICU and hospital survival advantage in CytoSorb patients when therapy was started early. CONCLUSION: We created a scoring system allowing for the assessment of the clinical development of patients in the early phase of septic shock. Applying this approach, we were able to detect populations with a distinct mortality pattern. The data also showed that an early start of CytoSorb therapy was associated with significantly improved survival. As a next step, this easy-to-apply scoring system would require validation in a prospective manner to learn whether patients to be treated with hemoadsorption therapy in the course of septic shock could thereby be identified.

Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

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.

Hydrothermal Oxidation of Fecal Sludge: Experimental Investigations and Kinetic Modeling.

Hydrothermal oxidation (HTO) provides an efficient technique to completely destroy wet organic wastes. In this study, HTO was applied to treat fecal sludge at well-defined experimental conditions. Four different kinetic models were adjusted to the obtained data. Among others, a distributed activation energy model (DAEM) was applied. A total of 33 experiments were carried out in an unstirred batch reactor with pressurized air as the oxidant at temperatures of <470 °C, oxygen-to-fuel equivalence ratios between 0 and 1.9, feed concentrations between 3.9 and 9.8 molTOC L-1 (TOC = total organic carbon), and reaction times between 86 and 1572 s. Decomposition of the fecal sludge was monitored by means of the conversion of TOC to CO2 and CO. In the presence of oxygen, ignition of the reaction was observed around 300 °C, followed by further rapid decomposition of the organic material. The TOC was completely decomposed to CO2 within 25 min at 470 °C and an oxygen-to-fuel equivalence ratio of 1.2. CO was formed as an intermediate product, and no other combustible products were found in the gas. At certain reaction conditions, the formation of unwanted coke and tarlike products occurred. The reaction temperature and oxygen-to-fuel equivalence ratio showed a significant influence on TOC conversion, while the initial TOC concentration did not. Conversion of TOC to CO2 could be well described with a first-order rate law and an activation energy of 39 kJ mol-1.

Integration of pyrolysis and anaerobic digestion--use of aqueous liquor from digestate pyrolysis for biogas production.

Anaerobic digestion of aqueous pyrolysis liquor derived from pyrolysis of solid digestate was tested in batch mode using an un-adapted inoculum. Three pyrolysis liquors produced at 330°C, 430°C and 530°C in four COD-based concentrations of 3, 6, 12 and 30 g L(-1) were investigated. The three lower concentrations showed considerable biogas production, whereas the 30 g L(-1) dosage caused process inhibition. The highest methane yield of 199.1±18.5 mL g(COD)(-1) (COD removal: 56.9±5.3%) was observed for the 330°C pyrolysis liquor, followed by the 430°C sample with only slightly lower values. The 530°C sample dropped to a yield of 129.3±19.7 mL g(COD)(-1) (COD removal: 36.9±5.6%). Most VOCs contained in the pyrolysis liquor (i.e. furfural, phenol, catechol, guaiacol, and levoglucosan) were reduced below detection limit (cresol by 10-60%). Consequently, integrated pyrolysis and anaerobic digestion in addition to thermochemical conversion of digestate also promises bioconversion of pyrolysis liquors.

Drug efflux transporter multidrug resistance-associated protein 5 affects sensitivity of pancreatic cancer cell lines to the nucleoside anticancer drug 5-fluorouracil.

Pancreatic adenocarcinoma is one of the malignancies that is highly resistant to therapy and among the leading causes of cancer-related death. Several factors may influence pancreatic cancer resistance, and expression of ATP-binding cassette transport proteins is one of the major mechanisms of drug resistance. Members of this family's C-branch, also referred to as multidrug resistance-associated proteins (MRPs), might be of particular interest because they are able to efflux nucleoside analogs used in the treatment of pancreatic cancer. Expression of MRP1, MRP3, MRP4, and MRP5 in human pancreas and pancreatic carcinoma has been reported. However, contributions of MRPs to chemoresistance of pancreatic cancer are not fully understood. MRP5 mRNA expression in pancreatic adenocarcinoma cell lines correlated significantly with cellular sensitivity to 5-fluorouracil (5-FU) (r = 0.738, p < 0.05). Long-term treatment with 5-FU increased expression of MRP5 by 2.4-fold and was associated with significant drug resistance [IC(50) values for control and 5-fluorouracil (5-FU)-resistant Patu-T cell lines were 11.3 ± 5.3 and 33.2 ± 6.9 µM, respectively (p < 0.05)]. Consequently, overexpression of MRP5 in Colo-357 cells resulted in significantly reduced accumulation of 5-FU related radioactivity and 5-FU cytotoxicity. Knockdown of MRP5 significantly increased cellular cytotoxicity of 5-FU to Patu-02 cells and enhanced accumulation of radioactivity related to 5-FU and its metabolites. Our results suggest that MRP5 is expressed and functionally active and contributes to variable sensitivities of pancreatic adenocarcinoma cell lines to 5-FU. Further investigations using models that resemble human pancreas tumors are necessary to prove a causative relation between expression and activity of MRP5 and tumor resistance to 5-FU.