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Abstract The effects of prolonged infrasound (IS) exposure on brain function and behavior are largely unknown, with only one prior study investigating functional connectivity (FC) changes. In a long-term randomized-controlled trial, 38 participants were exposed to inaudible airborne IS (6 Hz, 80–90 dB) or sham devices for four weeks (8 h/night). We assessed FC changes in resting-state networks (auditory, default mode (DMN), sensorimotor (SMN), and executive control (ECN)), and explored IS ‘sensitivity’ as a predictor of identified significant FC changes. We also examined correlations between somatic symptoms and FC. IS exposure led to decreased FC in the right precuneus (DMN) and increased FC in the Vermis IV and V (SMN). In the ECN, we observed increased FC in the right frontal middle gyrus (BA8) and the right inferior parietal lobe, and decreased FC in another region of the right frontal middle gyrus. Changes in the ECN (right inferior parietal lobe) were negatively associated with self-reported annoyance from IS/low-frequency noise. A significant negative association was found between FC changes in the DMN (right precuneus) and somatic symptoms. Our study is the first to investigate prolonged IS exposure effects on brain FC, revealing changes in the vDMN, SMN, and ECN, but not in the auditory network. Future studies should assess annoyance and sensitivity markers, fine-grained measures of somatic symptoms, and stratify samples by sensitivity to uncover individual differences in response to IS.

Abstract Background Despite the global increase in older employees, workplace physical activity interventions (WPAIs) for this target group have not yet been sufficiently developed. The major drawback of existing WPAIs is low adherence due to lack of time or limited motivation. A novel approach could be to integrate tailored neuromotor and strength exercises into everyday working tasks to prevent the functional decline of older employees at the workplace without needing much additional time for training. This approach was tested in the present study by evaluating the proof-of-concept of a novel WPAI based on the Lifestyle-integrated Functional Exercise (LiFE) program integrated into a working environment (wLiFE55 +). Methods The proof-of-concept of wLiFE55 + was quantified within a 4-week pre-post exercise intervention study by measuring (1) feasibility including adherence, activity frequency, adverse events and acceptance (integrability of wLiFE55 + activities, perceived improvement and safety, satisfaction, physical demand, personal trainer session, intervention content) and (2) pre-to-post changes in neuromotor function (12-Level Balance Scale, 12-LBS; Community Balance and Mobility Scale, CBM), strength (60sec Chair Stand Test), and PA (1-week activity monitoring). For statistical analysis, the median and interquartile range (IQR) were computed. For pre-to-post changes, Wilcoxon signed-rank tests with effect size (r) were also performed. Results Seventeen older employees (mean age 59 years, 8 female) were included of which fifteen completed the study. The intervention adherence was 100%, and the activity adherence was 58% (9 out of 12 maximum possible wLiFE55 + activities implemented). Depending on the specific activity, the frequency of practice ranged between 25–75% of the days of the intervention period, and single wLiFE55 + activities were practiced between one and three times per day. No adverse events occurred, and acceptance was high. Pre-to-post increases with medium effect sizes were found for neuromotor function (CBM, 12-LBS) and specific PA variables (total sedentary time, sedentary bouts > 30 min). Conclusion The results of the study highlight the feasibility of wLiFE55 + in a work setting with older employees. The pre-to-post increases observed in neuromotor measures and reductions in sedentary time suggest that wLiFE55 + may counteract the age-related functional decline in older employees and justifies future studies in this field. The next steps are program adjustments to boost exercise frequency and evaluating wLiFE55 + in a randomized controlled trial.

Abstract Background Chronic heart failure (HF) is frequent in elderly patients undergoing non-cardiac surgery. Preoperative risk stratification is vital and can be achieved using simple clinical risk scores or preoperative N-terminal prohormone of brain natriuretic peptide (NT-proBNP) measurement. This study aimed to compare the predictivity of the revised cardiac risk index (RCRI), the American University of Beirut cardiovascular risk index (AUB-HAS2), and a score proposed by Andersson et al. for postoperative 30-day morbidity to preoperative NT-proBNP. Methods Preoperative NT-proBNP was measured in 199 consecutive patients aged ≥ 65 years undergoing elective non-cardiac surgery with intermediate or high surgical risk. The areas under the receiver operating characteristic curve (AUCROC) for the composite morbidity endpoint (CME) comprising the incidence of any rehospitalisation, acute decompensated HF, acute kidney injury, and any infection at postoperative day 30 were assessed. Multivariable logistic regression analysis derived new scores from the simple risk scores and the NT-proBNP cut-off of 450 pg/mL. Results AUB-HAS2, but not RCRI or Andersson score, significantly predicted the CME (AUB-HAS2: AUCROC 0.646, p

BackgroundThe unique ability of the respiratory tract to protect the integrity of the airways by removing potentially harmful substances is defined as mucociliary clearance. This complex physiological mechanism protects the lower airways by ridding them of pollutants and pathogens. This study aimed to evaluate the potential influence of clinically relevant vasopressors on mucociliary clearance.Material and methodsThe particle transport velocity (PTV) of isolated murine tracheae was measured as a surrogate for mucociliary clearance under the influence of dopamine, norepinephrine, and vasopressin. Inhibitory substances were applied to elucidate relevant signal transduction cascades and the value and origin of calcium ions. Reverse-transcription polymerase chain reactions (RT-PCR) were performed to identify the expression of vasopressin receptor subtypes.ResultsDopamine, norepinephrine, and vasopressin significantly increased the PTV in a dose-dependent manner with half maximal effective concentrations of 0.58 µM, 1.21 µM, and 0.10 µM, respectively. Each substance increased the PTV via separate receptor pathways. While dopamine acted on D1-like receptors to increase the PTV, norepinephrine acted on β-adrenergic receptors, and vasopressin acted on V1a receptors. RT-PCR revealed the expression of V1a in the murine whole trachea and tracheal epithelium. PTV increased when protein kinase A was inhibited and norepinephrine or vasopressin were applied, but not when dopamine was applied. Phospholipase C inhibition decreased the PTV when vasopressin was applied. In general, maximum PTV was significantly reduced when extracellular calcium entry was inhibited. When intracellular calcium stores were depleted, no increase in PTV was observed after administering all three substances. Inositol trisphosphate receptor activation was found to be pivotal in the increase in murine PTV after applying dopamine and vasopressin.DiscussionDopamine, norepinephrine, and vasopressin accelerate the murine PTV via substance-specific receptor pathways. Further investigations should assess the value and interaction of these substances on mucociliary clearance in clinical practice.

Abstract Background Chronic heart failure (HF) is a common clinical condition associated with adverse outcomes in elderly patients undergoing non-cardiac surgery. This study aimed to estimate a clinically applicable NT-proBNP cut-off that predicts postoperative 30-day morbidity in a non-cardiac surgical cohort. Methods One hundred ninety-nine consecutive patients older than 65 years undergoing elective non-cardiac surgery with intermediate or high surgical risk were analysed. Preoperative NT-proBNP was measured, and clinical events were assessed up to postoperative day 30. The primary endpoint was the composite morbidity endpoint (CME) consisting of rehospitalisation, acute decompensated heart failure (ADHF), acute kidney injury (AKI), and infection at postoperative day 30. Secondary endpoints included perioperative fluid balance and incidence, duration, and severity of perioperative hypotension. Results NT-proBNP of 443 pg/ml had the highest accuracy in predicting the composite endpoint; a clinical cut-off of 450 pg/ml was implemented to compare clinical endpoints. Although 35.2% of patients had NT-proBNP above the threshold, only 10.6% had a known history of HF. The primary endpoint was the composite morbidity endpoint (CME) consisting of rehospitalisation, acute decompensated heart failure (ADHF), acute kidney injury (AKI), and infection. Event rates were significantly increased in patients with NT-proBNP > 450 pg/ml (70.7% vs. 32.4%, p 450 pg/ml was an independent predictor of the CME in a multivariable Cox regression model (hazard ratio 2.92 [1.72–4.94]). Conclusions Patients with NT-proBNP > 450 pg/ml exhibited profoundly increased postoperative morbidity. Further studies should focus on interdisciplinary approaches to improve outcomes through integrated interventions in the perioperative period. Trial registration German Clinical Trials Register: DRKS00027871, 17/01/2022

Abstract TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.

Background Urinary Chemokine (C–C motif) ligand 14 (CCL14) is a biomarker associated with persistent severe acute kidney injury (AKI). There is limited data to support the implementation of this AKI biomarker to guide therapeutic actions.Methods Sixteen AKI experts with clinical CCL14 experience participated in a Delphi-based method to reach consensus on when and how to potentially use CCL14. Consensus was defined as ≥ 80% agreement (participants answered with ‘Yes’, or three to four points on a five-point Likert Scale).Results Key consensus areas for CCL14 test implementation were: identifying challenges and mitigations, developing a comprehensive protocol and pairing it with a treatment plan, and defining the target population. The majority agreed that CCL14 results can help to prioritize AKI management decisions. CCL14 levels above the high cutoff (> 13 ng/mL) significantly changed the level of concern for modifying the AKI treatment plan (p 13 ng/mL. The level of concern for discussion on RRT initiation between High and Low, and between Medium and Low CCL14 levels, showed significant differences.Conclusion Real world urinary CCL14 use appears to provide improved care options to patients at risk for persistent severe AKI. Experts believe there is a role for CCL14 in AKI management and it may potentially reduce AKI-disease burden. There is, however, an urgent need for evidence on treatment decisions and adjustments based on CCL14 results.

The application of venovenous (VV) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance for the treatment of acute severe respiratory failure. Since no rat model of VV ECMO therapy with femoral drainage has yet been described, although this cannulation strategy is commonly used in humans, this study aimed to establish such a model. Twenty male Lewis rats were randomly assigned to receive a sham procedure or VV ECMO therapy. After the inhalative induction of anesthesia, animals were intubated and the vascular accesses were placed surgically. While venous drainage was achieved through a modified multi-orifice 18 G cannula that was placed in the inferior vena cava through the femoral vein over a guide wire with an ultra-flexible tip, the venous return was realized via a shortened 20 G cannula into the jugular vein. Hemodynamic data were obtained from a tail artery and left ventricular pressure–volume catheter. Repetitive blood gas analyses were carried out, and systemic inflammation was measured using an enzyme-linked immunosorbent assay. While animals in the ECMO group showed adequate oxygenation and decarboxylation, there was no evidence of recirculation. VV ECMO therapy increased stroke volume (SV), cardiac output (CO), and left ventricular end-diastolic volume (LVEDV). ECMO-induced inflammation was reflected in increased levels of tumor necrosis factor alpha. However, no differences in interleukins 6 and 10 were seen. This study describes a frequently used cannulation strategy in humans for a rat model of VV ECMO. Despite successful oxygenation and decarboxylation, the oxygenated blood may reduce pulmonary vascular resistance and lead to an increased LVEDV, which is associated with increased SV and CO. This model allows us to answer research questions about topics such as intestinal microcirculation in further studies.

Mit dem wachsenden Anteil älterer Menschen an der Bevölkerung und der steigenden Lebenserwartung in der Schweiz gewinnt auch die Diagnose «Depression im Alter» zunehmend an Bedeutung. Da die Erkrankung für die Patienten oft mit einem hohen Leidensdruck verbunden ist, müssen Depressionen beim älteren Menschen frühzeitig erkannt und behandelt werden. Diagnose und Therapie erfolgen grundsätzlich in gleicher Weise wie bei jüngeren Patienten. Allerdings sind bei älteren Menschen einige Besonderheiten zu beachten. With the growing proportion of older people in the population and increasing life expectancy in Switzerland, the diagnosis of "depression in later life" is also becoming increasingly important. As the illness is often associated with a high level of suffering for patients, depression in older people must be recognised and treated at an early stage. Diagnosis and treatment are basically the same as for younger patients. However, there are some special features to consider in older people. PEER REVIEWED ARTICLE Peer reviewers: PD Dr. Thorsten Mikoteit, Solothurner Spitäler, Solothurn, Schweiz Dr. Dan Georgescu, Psychiatrische Dienste Aargau AG, Windisch, Schweiz Received: January 17, 2024; Accepted after peer review: April 8, 2024

Summary: Mitochondria consist of hundreds of proteins, most of which are inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions remains poorly understood. Here, we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Two different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble, aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis, presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 is part of a second type of intramitochondrial aggregate that transiently sequesters proteins and promotes their folding or Pim1-mediated degradation. Thus, mitochondrial proteins actively control the formation of distinct types of intramitochondrial protein aggregates, which cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.

Reliable assessment of airborne infrasound emitted by natural and technical sources has been gaining importance, while technology is limited and regulations are not sufficient in the infrasound frequency range. This paper provides a comparison of measurement microphones and microbarometers used for infrasound measurements in the field near wind power plants. Simultaneous measurements with both sensor systems were conducted at multiple sites in the vicinity of a wind park. Based on these measurements, it was shown that wind-induced noise is a major concern when measuring infrasound in the field. For this reason, additional experiments were conducted in an aeroacoustic wind tunnel to further investigate the sensitivity to wind of the sensors used. A combination of field measurements and laboratory experiments was applied to determine the influence of wind-induced noise in a real-life situation and multiple strategies are discussed for establishing quality criteria and controlling the influence of wind on such measurements.

Abstract Mucociliary clearance is a pivotal physiological mechanism that protects the lung by cleaning the airways from pollution and colonization, thereby preventing infection. Ciliary function is influenced by various signal transduction cascades, and Ca2+ represents a key second messenger. A fixed 20:1 combination of cafedrine and theodrenaline has been widely used to treat perioperative hypotension and emergency hypotensive states since the 1960s; however, its effect on the intracellular Ca2+ concentration ([Ca2+]i) of respiratory epithelium remains unknown. Therefore, human tracheal epithelial cells were exposed to the clinically applied 20:1 mixture of cafedrine/theodrenaline and the individual substances separately. [Ca2+]i was assessed by FURA-2 340/380 fluorescence ratio. Pharmacological inhibitors were applied to elucidate relevant signal transduction cascades, and reverse transcription polymerase chain reaction (RT-PCR) was performed on murine tracheal epithelium to analyze ryanodine receptor (RyR) subtype expression. All three pharmacological preparations instantaneously induced a steep increase in [Ca2+]i that quickly returned to its baseline value despite the persistence of each substance. Peak [Ca2+]i following the administration of 20:1 cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone increased in a dose-dependent manner, with median effective concentrations of 0.35 mM (7.32 mM cafedrine and 0.35 mM theodrenaline), 3.14 mM, and 3.45 mM, respectively. When extracellular Ca2+ influx was inhibited using a Ca2+-free buffer solution, the peak [Ca2+]i following the administration of cafedrine alone and theodrenaline alone were reduced but not abolished. No alteration in [Ca2+]i compared with baseline [Ca2+]i was observed during β-adrenergic receptor inhibition. Depletion of caffeine-sensitive stores and inhibition of RyR, but not IP3 receptors, completely abolished any increase in [Ca2+]i. However, [Ca2+]i still increased following the depletion of mitochondrial Ca2+ stores using 2,4-dinitrophenol. RT-PCR revealed RyR-2 and RyR-3 expression on murine tracheal epithelium. Although our experiments showed that cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone release Ca2+ from intracellular stores through mechanisms that are exclusively triggered by β-adrenergic receptor stimulation, which most probably lead to RyR activation, clinical plasma concentrations are considerably lower than those used in our experiments to elicit an increase in [Ca2+]i; therefore, further studies are needed to evaluate the ability of cafedrine/theodrenaline to alter mucociliary clearance in clinical practice.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.

Treatment of critically ill patients with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance in the last few decades. However, the use of V-V ECMO in septic shock remains controversial. The effect of ECMO-induced inflammation on the microcirculation of the intestine, liver, and critically damaged lungs is unknown. Therefore, the aim of this study was to measure the hepatic and intestinal microcirculation and pulmonary inflammatory response in a model of V-V ECMO and septic shock in the rat. Twenty male Lewis rats were randomly assigned to receive V-V ECMO therapy or a sham procedure. Hemodynamic data were measured by a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by the intravenous infusion of lipopolysaccharide (1 mg/kg). During V-V ECMO therapy, rats received lung-protective ventilation. The hepatic and intestinal microcirculation was assessed by micro-lightguide spectrophotometry after median laparotomy for 2 h. Systemic and pulmonary inflammation was measured by enzyme-linked immunosorbent assays of plasma and bronchoalveolar lavage (BAL), respectively, which included tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-10, C-X-C motif ligand 2 (CXCL2), and CXCL5. Reduced oxygen saturation and relative hemoglobin concentration were measured in the hepatic and intestinal microcirculation during treatment with V-V ECMO. These animals also showed increased systolic, mean, and diastolic blood pressures. While no differences in left ventricular ejection fraction were observed, animals in the V-V ECMO group presented an increased heart rate, stroke volume, and cardiac output. Blood gas analysis showed dilutional anemia during V-V ECMO, whereas plasma analysis revealed a decreased concentration of IL-10 during V-V ECMO therapy, and BAL measurements showed increased concentrations of TNF-α, CXCL2, and CXCL5. Rats treated with V-V ECMO showed impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Despite lung-protective ventilation, increased pulmonary inflammation was recognized during V-V ECMO therapy in septic shock.

Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms.

BackgroundNucleated red blood cells (nRBC) are precursor cells of the erythropoiesis that are absent from the peripheral blood under physiological conditions. Their presence is associated with adverse outcomes in critically ill patients. This study aimed to evaluate the predictive value of nRBC on mortality in intensive care unit (ICU) patients with COVID-19 acute respiratory distress syndrome (ARDS).Material and methodsThis retrospective, observational cohort study analyzed data on 206 ICU patients diagnosed with COVID-19 ARDS between March 2020 and March 2022. The primary endpoint was ICU mortality, and secondary endpoints included ICU and hospital stay lengths, ventilation hours, and the time courses of disease severity scores and clinical and laboratory parameters.ResultsAmong the included patients, 68.9% tested positive for nRBC at least once during their ICU stay. A maximum nRBC of 105 µl-1 had the highest accuracy in predicting ICU mortality (area under the curve of the receiver operating characteristic [AUCROC] 0.780, p < 0.001, sensitivity 69.0%, specificity 75.5%). Mortality was significantly higher among patients with nRBC >105 µl-1 than ≤105 µl-1 (86.5% vs. 51.3%, p = 0.008). Compared to patients negative for nRBC in their peripheral blood, those positive for nRBC required longer mechanical ventilation (127 [44 - 289] h vs. 517 [255 - 950] h, p < 0.001), ICU stays (12 [8 – 19] vs. 27 [13 – 51] d, p < 0.001), and hospital stays (19 [12 - 29] d vs. 31 [16 - 58] d, p < 0.001). Peak Sepsis-related Organ Failure Assessment (SOFA), Simplified Acute Physiology Score, PaO2/FiO2, interleukin-6, and procalcitonin values were reached before the peak nRBC level. However, the predictive performance of the SOFA (AUCROC 0.842, p < 0.001) was considerably improved when a maximum SOFA score >8 and nRBC >105 µl-1 were combined.DiscussionnRBC predict ICU mortality and indicate disease severity among patients with COVID-19 ARDS, and they should be considered a clinical alarm signal for a worse outcome. nRBC are a late predictor of ICU mortality compared to other established clinical scoring systems and laboratory parameters but improve the prediction accuracy when combined with the SOFA score.

Modular Cloning (MoClo) allows the combinatorial assembly of plasmids from standardized genetic parts without the need of error-prone PCR reactions. It is a very powerful strategy which enables highly flexible expression patterns without the need of repetitive cloning procedures. In this study, we describe an advanced MoClo toolkit that is designed for the baker’s yeast Saccharomyces cerevisiae and optimized for the targeting of proteins of interest to specific cellular compartments. Comparing different targeting sequences, we developed signals to direct proteins with high specificity to the different mitochondrial subcompartments, such as the matrix and the intermembrane space (IMS). Furthermore, we optimized the subcellular targeting by controlling expression levels using a collection of different promoter cassettes; the MoClo strategy allows it to generate arrays of expression plasmids in parallel to optimize gene expression levels and reliable targeting for each given protein and cellular compartment. Thus, the MoClo strategy enables the generation of protein-expressing yeast plasmids that accurately target proteins of interest to various cellular compartments.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the coagulation system is not fully understood. SARS-CoV-2 penetrates cells through angiotensin-converting enzyme 2 (ACE2) receptors, leading to its downregulation. Des-arginine9-bradykinin (DA9B) is degraded by ACE2 and causes vasodilation and increased vascular permeability. Furthermore, DA9B is associated with impaired platelet function. Therefore, the aim of this study was to evaluate the effects of DA9B on platelet function and coagulopathy in critically ill coronavirus disease 2019 (COVID-19) patients. In total, 29 polymerase-positive SARS-CoV-2 patients admitted to the intensive care unit of the University Hospital of Giessen and 29 healthy controls were included. Blood samples were taken, and platelet impedance aggregometry and rotational thromboelastometry were performed. Enzyme-linked immunosorbent assays measured the concentrations of DA9B, bradykinin, and angiotensin 2. Significantly increased concentrations of DA9B and angiotensin 2 were found in the COVID-19 patients. A negative effect of DA9B on platelet function and intrinsic coagulation was also found. A sub-analysis of moderate and severe acute respiratory distress syndrome patients revealed a negative association between DA9B and platelet counts and fibrinogen levels. DA9B provokes inhibitory effects on the intrinsic coagulation system in COVID-19 patients. This negative feedback seems reasonable as bradykinin, which is transformed to DA9B, is released after contact activation. Nevertheless, further studies are needed to confirm our findings.

Background: Mucociliary clearance is a pivotal physiological mechanism that protects the lung by ridding the lower airways of pollution and colonization by pathogens, thereby preventing infections. The fixed 20:1 combination of cafedrine and theodrenaline has been used to treat perioperative hypotension or hypotensive states due to emergency situations since the 1960s. Because mucociliary clearance is impaired during mechanical ventilation and critical illness, the present study aimed to evaluate the influence of cafedrine/theodrenaline on mucociliary clearance.Material and Methods: The particle transport velocity (PTV) of murine trachea preparations was measured as a surrogate for mucociliary clearance under the influence of cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone. Inhibitory substances were applied to elucidate relevant signal transduction cascades.Results: All three applications of the combination of cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone induced a sharp increase in PTV in a concentration-dependent manner with median effective concentrations of 0.46 µM (consisting of 9.6 µM cafedrine and 0.46 µM theodrenaline), 408 and 4 μM, respectively. The signal transduction cascades were similar for the effects of both cafedrine and theodrenaline at the murine respiratory epithelium. While PTV remained at its baseline value after non-selective inhibition of β-adrenergic receptors and selective inhibition of β1 receptors, cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone increased PTV despite the inhibition of the protein kinase A. However, IP3 receptor activation was found to be the pivotal mechanism leading to the increase in murine PTV, which was abolished when IP3 receptors were inhibited. Depleting intracellular calcium stores with caffeine confirmed calcium as another crucial messenger altering the PTV after the application of cafedrine/theodrenaline.Discussion: Cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone exert their effects via IP3 receptor-associated calcium release that is ultimately triggered by β1-adrenergic receptor stimulation. Synergistic effects at the β1-adrenergic receptor are highly relevant to alter the PTV of the respiratory epithelium at clinically relevant concentrations. Further investigations are needed to assess the value of cafedrine/theodrenaline-mediated alterations in mucociliary function in clinical practice.

Abstract Background The chemokines, CXCL12 and CXCL11, are upregulated in tumors from many organs and control their progression. CXCL12 and CXCL11 affect tumor cell functions by either binding their prime receptors, CXCR4 and CXCR3, respectively, and/or CXCR7 as a common second chemokine receptor. In humans, CXCR3 exists in the functional splice variants, CXCR3A and CXCR3B, which either have pro- or anti-tumor activity, respectively. Despite the intimate crosstalk between the CXCL12- and CXCL11-system, the impact of a combination of CXCL12 and CXCL11 on tumor progression remains vague. Methods In the present work, we have analyzed CXCL12 and CXCL11 for combined effects on migration, invasion, proliferation, and cytostatic-induced apoptosis of the human tumor cells, A549, A767, A772, DLD-1, and MDA-MB-231. Results We demonstrate that the mode of interaction differs with respect to cell type and function and allows for either potentiation, attenuation or no changes of cellular responses. The divergent responses are not the result of the distinct use of different CXCL12- and CXCL11-receptors by the respective tumor cells, but in case of cell migration seem to be associated with the activation of p38 signaling pathways. Conclusions Our findings point to therapeutic limitations of ongoing efforts to selectively target CXCR3, CXCR4, or CXCR7 in cancer patients, and rather favor individualized targeting strategies.

Abstract Background Fluid therapy, including the choice of a crystalloid or colloid infusion, the execution time of a volume bolus, and the expected volume need of a patient during surgery, varies greatly in clinical practice. Different goal directed fluid protocols have been developed, where fluid boluses guided by dynamic preload parameters are administered within a specific period. Objective To study the efficacy of two fluid bolus infusion rates measured by the response of hemodynamic parameters. Design Monocentric randomized controlled interventional trial. Setting University hospital. Patients Forty patients undergoing elective major spinal neurosurgery in prone position were enrolled, thirty-one were finally analyzed. Interventions Patients were randomly assigned to receive 250 ml crystalloid and colloid boluses within 5 min (group 1) or 20 min (group 2) when pulse pressure variation (PPV) exceeded 14%. Main outcome measures Changes in stroke volume (SV), mean arterial pressure (MAP), and catecholamine administration. Results Group 1 showed a greater increase in SV (P = 0.031), and MAP (P = 0.014), while group 2 still had higher PPV (P = 0.005), and more often required higher dosages of noradrenalin after fluid administration (P = 0.033). In group 1, fluid boluses improved CI (P

The Helmholtz Association (Anonymous 2022d), the largest association of large-scale research centres in Germany, covers a wide range of research fields employing more than 43.000 researchers. In 2019, the Helmholtz Metadata Collaboration (HMC) (Anonymous 2022f) Platform as a joint endeavor across all research areas of the Helmholtz Association was started to make the depth and breadth of research data produced by Helmholtz Centres findable, accessible, interoperable, and reusable (FAIR) for the whole science community. To reach this goal, the concept of FAIR Digital Objects (FAIR DOs) has been chosen as top-level commonality for existing and future infrastructures of all research fields.In doing so, HMC follows the original approach of realizing FAIR DOs based on globally unique, Persistent Identifiers (PID), e.g., provided by https://handle.net/, machine actionable PID Records and strong typing using Data Types like https://dtr-test.pidconsortium.eu/#objects/21.T11148/1c699a5d1b4ad3ba4956 registered in a Data Type Registry, e.g., http://dtr-test.pidconsortium.eu/. In all these areas, HMC can build on the great groundwork of the Research Data Alliance and the FAIR DO Forum. However, when it comes to realization, there are still some gaps that will have to be addressed during our work and will be raised in this presentation. For single FAIR DO components like PIDs and Data Types, existing infrastructures are already available. Here, the Gesellschaft für wissenschaftliche Datenverarbeitung mbH Göttingen (GWDG) (Anonymous 2022e) provides strong support with their many years of experience in this field. Within the framework of the ePIC consortium (Anonymous 2022c), the GWDG is offering on the one hand PID prefixes based on a sustainable business model, on the other hand GWDG is very active in terms of providing base services required for realizing FAIR DOs, e.g., different instances of Data Type Registries for accessing, creating, and managing Data Types required by FAIR DOs. Besides that, in the context of HMC we developed a couple of technical components to support the creation and management of FAIR DOs: The Typed PID Maker (Pfeil 2022b) providing machine actionable interfaces for creating, validating, and managing PIDs with machine-actionable metadata stored in their PID record, or the FAIR DO testbed, currently evolving into the FAIR DO Lab (Pfeil 2022a), serving as reference implementation for setting up a FAIR DO ecosystem. However, introducing FAIR DOs is not only about providing technical services, but also requires the definition and agreement on interfaces, policies, and processes.A first step in this direction was made in the context of HMC by agreeing on a Helmholtz Kernel Information Profile (http://dtr-test.pidconsortium.eu/#objects/21.T11148/b9b76f887845e32d29f7). In the concept of FAIR DOs, PID Kernel Information as defined by Weigel et al. (Weigel et al. 2018) is key to machine actionability of digital content. Strongly relying on Data Types and stored in the PID record directly at the PID resolution service, PID Kernel Information can be used by machines for fast decision making. The Helmholtz Kernel Information Profile is an attempt to introduce a top-level commonality across all digital assets produced within the Helmholtz Association and beyond to establish a basis for FAIR research data based on FAIR DOs.Hereby, the Helmholtz Kernel Information Profile integrates the recommendations of the RDA PID Kernel Information Working Group (Anonymous 2022b) as far as possible. By extending the Draft Kernel Information Profile (Weigel et al. 2018) with additional, mostly optional attributes, the Helmholtz Kernel Information Profile allows the adding of contextual information to FAIR DOs, e.g., research topic, or contact information, which is then available for machine decisions. Furthermore, additional properties for representing relationships between FAIR DOs, e.g, hasMetadata and isMetadataFor, were introduced to allow mutual relations between FAIR DOs.Currently, a demonstrator is implemented integrating the above components and services, i.e., PID Service, Data Type Registry, and Typed PID Maker. Fig. 1 outlines the architecture overview of the first version of the demonstrator.In this first version, in a semi-automatic workflow, a user enters a Zenodo (Anonymous 2022a) PID in a graphical Web frontend. A mapping component tries to fill automatically at least the properties required by the Helmholtz Kernel Information Profile using the obtained Zenodo metadata record. In a manual validation loop, the user may add or update certain properties before they are sent to an instance of the Typed PID Maker, validated against the Helmholtz Kernel Information Profile, and stored in the record of a newly registered PID using the services of the ePIC consortium. In addition, registered PID records are made searchable via the graphical frontend on top of a search index, e.g., realized using https://www.elastic.co/.After implementing this generic workflow, additional mappers supporting other repository platforms will be implemented based on the lessons learned, which will lead to a growing number of FAIR DOs and holds potential for providing significant benefits to scientists, e.g., a central point of contact for research data sets stored in different repositories, machine-actionable identification of relevant datasets, and creation of knowledge graphs representing relationships between data sets, repository platforms, researchers and research organizations.Furthermore, the gathered experience and its documentation will help others to apply the FAIR DO concept more easily, which will lead to an ever-growing collection of available FAIR DOs with an increasing quality and level of automation at creation time.

Abstract The early identification of sepsis in surgical intensive care patients is challenging due to the physiological postoperative alterations of vital signs and inflammatory biomarkers. Soluble Delta-like protein 1 (sDLL1) may be a potential discriminatory biomarker for this purpose. For this reason, this study aimed to evaluate sDLL1 for the identification of sepsis in a cohort of surgical intensive care patients. This study comprises a secondary analysis of a prospective observational study including 80 consecutive patients. The study groups included 20 septic shock patients, 20 patients each undergoing major abdominal surgery (MAS) and cardiac artery bypass surgery (CABG), and 20 matched control subjects (CTRL). The surveillance period was 72 h. The plasma concentration of sDLL1 was measured with ELISA. The plasma levels of sDLL1 were significantly elevated in septic patients compared to both surgical cohorts (septic vs. all postoperative time points, data are shown as median and interquartile range [IQR]; septic shock: 17,363 [12,053–27,299] ng/mL, CABG 10,904 [8692–16,250] ng/mL; MAS 6485 [4615–9068] ng/mL; CTRL 5751 [3743–7109] ng/mL; septic shock vs. CABG: p

Concerns about potential health risks from infrasound exposure require objective investigation methods for the perception of infrasound by humans. Neural-network methods were applied to identify weak infrasound evoked potentials and to investigate the efficacy of these techniques. Two simple networks – a fully connected three-layer feed-forward network and a two-layer autoencoder – were designed for the analysis of electroencephalography (EEG) data recorded in response to infrasound stimuli presented. Late auditory evoked potentials (LAEPs) were detected and correlation factors between the target and the output of the networks were determined to assess the differentiation ability of the two networks. Both networks were able to differentiate infrasound evoked potentials from noise but showed different performance levels with respect to a differentiation threshold. The results can be applied to objectively identify perception events by infrasound in humans.

Planar growth of nanowire arrays involves interactions between materials that affect the electronic behavior of the effective heterojunction. Here, authors show how core curvature and cross-section morphology affect shell growth, demonstrating how strain at the core-shell interface induces electronic band modulations in ZnSe@ZnTe nanowires.

Glucose plays a central role in numerous physiological processes in dairy cows related to immune defence and milk production. A lack of glucose impairs both objectives, although to different degrees. A method for the estimation of glucose balance (GB) in dairy cows was developed to assess glucose reserves in the intermediary metabolism. Digestive fluxes of glucogenic carbon were individually estimated via the Systool Web application based on data on body weight (BW), dry matter intake (DMI), and chemical analyses of feedstuffs. Fluxes of endogenous precursors glycerol, alanine and L-lactate and the glucose demand imposed by major glucose-consuming organs were deduced from BW, lactose yield and lactation stage. GB was calculated for 201 lactations (1 to 105 DIM) of 157 cows fed isoenergetic rations. Individual DMI, BW and milk yield were assessed on a daily basis. The results showed that the GB varied greatly between cows and lactation stages. In the first week of lactation, average daily GB reached levels close to zero (3.2 ± 13.5 mol C) and increased as lactation progressed. Most cows risk substantial shortages of glucose for maintenance during the first weeks of lactation. In face of the specific role of glucose for the functional capability of the immune function, the assessment of glucose reserves is a promising measure for the identification of cows at risk of impaired immunocompetence.

Traditionally, the energy supply of dairy cows is based on the average performance of the herd. Because this contradicts the great variation in requirements between individual animals, the objective of the present study was to quantify both the extent and consequences of variation in the relevant sub-variables used to calculate the energy balance (EB) on an individual animal basis. Total energy supply (TES) and requirements (TER) of 28 multiparous German Holstein dairy cows fed TMR with 7.0 MJ NEL were studied between the 2nd and 15th week after calving. TES, mainly influenced by DMI, increased from 100.1 (week 2) to 152.1 MJ NEL/d (week 15; p < 0.01). Weekly coefficients of variation (CV) ranged between 0.10 and 0.16 and were similar to the CV of DMI (0.09 to 0.17). TER, as the sum of energy requirement for maintenance (body weight) and production (milk yield), decreased from 174.8 (week 2) to 164.5 MJ NEL/d (week 15; p < 0.01) and CV varied between 0.16 (week 2) and 0.07 (week 11). EB increased from −74.8 (week 2) to −12.4 MJ NEL/d (week 15; p < 0.01) and CV varied from 0.32 (week 3) to 1.01 (week 10). The results indicate that calculating EB on an individual animal basis is a prerequisite to identify animals with an increased risk of failing to cope with their energy situation, which cause failure costs that drain the profit of affected cows.

Abstract Background Venoarterial extracorporeal membrane oxygenation (V-A ECMO) with femoral access has gained wide acceptance in the treatment of critically ill patients. Since the patient´s cardiac output (CO) can compete with the retrograde aortic ECMO-flow, the aim of this study was to examine the impact of the inspiratory oxygen fraction on the cardiac function during V-A ECMO therapy. Methods Eighteen male Lewis rats (350–400 g) received V-A ECMO therapy. The inspiratory oxygen fraction on the ventilator was randomly set to 0.5 (group A), 0.21 (group B), or 0 in order to simulate apnea (group C), respectively. Each group consisted of six animals. Arterial blood pressure, central venous saturation (ScvO2), CO, stroke volume, left ventricular ejection fraction (LVEF), end diastolic volume, and pressure were measured. Cardiac injury was determined by analyzing the amount of lactate dehydrogenase (LDH). Results During anoxic ventilation the systolic, mean and diastolic arterial pressure, CO, stroke volume, LVEF and ScvO2 were significantly impaired compared to group A and B. The course of LDH values revealed no significant differences between the groups. Conclusion Anoxic ventilation during V-A ECMO with femoral cannulation leads to cardiogenic shock in rats. Therefore, awake V-A ECMO patients might be at risk for hypoxia-induced complications.

Background Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common adverse event of CD19-directed chimeric antigen receptor (CAR) T cell therapy. Other neurological adverse events, however, have not methodically been described and studied. Furthermore, safety data on CAR-T cell therapy in patients with central nervous system (CNS) lymphoma remain limited.Main body We here report occurrence of a Guillain-Barré-like syndrome (GBS) and central diabetes insipidus (cDI) following tisagenlecleucel therapy for relapsed high-grade lymphoma with CNS involvement. Both complications were refractory to standard treatment of ICANS. Weakness of respiratory muscles required mechanical ventilation and tracheostomy while cDI was treated with desmopressin substitution for several weeks. Muscle-nerve biopsy and nerve conduction studies confirmed an axonal pattern of nerve damage. T cell-rich infiltrates and detection of the CAR transgene in muscle-nerve sections imply a direct or indirect role of CAR-T cell-mediated inflammation. In line with current treatment guidelines for GBS, intravenous immunoglobulin was administered and gradual but incomplete recovery was observed over the course of several months.Conclusions This case report highlights the risk of rare but severe neurological adverse events, such as acute GBS or cDI, in patients treated with CAR-T cells. It further underlines the importance of appropriate patient surveillance and systematic reporting of rare complications to eventually improve treatment.

Abstract Background COVID-19 can induce acute respiratory distress syndrome (ARDS). In patients with congenital heart disease, established treatment strategies are often limited due to their unique cardiovascular anatomy and passive pulmonary perfusion. Case presentation We report the first case of an adult with single-ventricle physiology and bidirectional cavopulmonary shunt who suffered from severe COVID-19 ARDS. Treatment strategies were successfully adopted, and pulmonary vascular resistance was reduced, both medically and through prone positioning, leading to a favorable outcome. Conclusion ARDS treatment strategies including ventilatory settings, prone positioning therapy and cannulation techniques for extracorporeal oxygenation must be adopted carefully considering the passive venous return in patients with single-ventricle physiology.

Abstract Introduction Treatment of high-risk pulmonary embolism (PE) in perioperative patients remains challenging. Systemic thrombolysis is associated with a high risk of major bleedings and intracranial haemorrhage. High mortality rates are reported for open pulmonary embolectomy. Therefore, postoperative surgical patients may benefit substantially from catheter-directed ultrasound-accelerated thrombolysis (USAT). Case presentation We report two cases of high-risk perioperative PE. Both patients developed severe haemodynamic instability leading to cardiac arrest. After the implantation of a veno-arterial extracorporeal membrane oxygenation (ECMO), they were both successfully treated with USAT. Adequate improvement of right ventricular function was achieved; thus, ECMO could be successfully weaned after 3 and 4 days, respectively. Both patients showed favourable outcomes and could be discharged to rehabilitation. Conclusion Current guidelines on treatment of PE offer no specific therapies for perioperative patients with high-risk PE. However, systemic thrombolysis is often excluded due to the perioperative setting and the risk of major bleeding. Catheter-directed thrombolysis was shown to utilise less thrombolytic agent while obtaining comparable thrombolytic effects. The risk for major bleeding (including intracranial haemorrhage) is also significantly lowered. Until further trials determining the value of adopted treatment strategies of high-risk PE in perioperative patients are available, USAT should be considered in similar cases.

Abstract Background Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451.

Abstract Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients suffering from respiratory or cardiac failure. The ECMO-associated morbidity and mortality depends to a large extent on the underlying disease and is often related to systemic inflammation, consecutive immune paralysis and sepsis. Here we tested the hypothesis that human α1-antitrypsin (SERPINA1) due to its anti-protease and anti-inflammatory functions may attenuate ECMO-induced inflammation. We specifically aimed to test whether intravenous treatment with α1-antitrypsin reduces the release of cytokines in response to 2 h of experimental ECMO. Adult rats were intravenously infused with α1-antitrypsin immediately before starting veno-arterial ECMO. We measured selected pro- and anti-inflammatory cytokines and found, that systemic levels of tumor necrosis factor-α, interleukin-6 and interleukin-10 increase during experimental ECMO. As tachycardia and hypertension developed in response to α1-antitrypsin, a single additional bolus of fentanyl and midazolam was given. Treatment with α1-antitrypsin and higher sedative doses reduced all cytokine levels investigated. We suggest that α1-antitrypsin might have the potential to protect against both ECMO-induced systemic inflammation and immune paralysis. More studies are needed to corroborate our findings, to clarify the mechanisms by which α1-antitrypsin inhibits cytokine release in vivo and to explore the potential application of α1-antitrypsin in clinical ECMO.

Erosion damage and particle deposition are crucial wear phenomena in gas turbine engines. As a result, compressor efficiency decreases, stability margin reduces, and maintenance cost increases. Hence, predicting these phenomena in an accurate manner is of paramount importance for a cost-efficient, safe, and sustainable operation. Erosion and particle deposition in the annulus are affected by particle transportation in the fluid and particle-wall interaction. The latter involves the particle impact, the potential damage of the surface and/or the particle, and the particle rebound. Particle rebounds are statistical in nature due to the target surface roughness, the variability in particle sizes, and superimposed effects caused by particle shapes as well as particle rotation and particle break-up during contact. Multiple studies investigated the statistics of particle rebound, providing empirical-based models for median and spread. However, modeling the particle-wall interaction and its data spread on a transparent physical basis allows separating the effect of target roughness from superimposed effects. The presented article pursues this objective by assessing the statistical spread of particle rebound data through multiple techniques and utilizing their interdependencies. It combines experimental, numerical, and analytical considerations. For the first time, coherent boundary conditions for the experimental, numerical and analytical setup allow the distinction of the effect of roughness from the integral effect of the superimposed phenomena. A sandblast test rig equipped with laser measurement equipment was used to measure particle rebound from flat titanium and stainless steel plates at different angles. The numerical setup is developed under OpenFOAM 6 using a RANS solver for transient simulations with compressible media in combination with one-way coupled particle flows. The numerical model includes the rebound spread model proposed by Altmeppen et al. combined with the quasi-analytical rebound model proposed by Bons et al. The statistical spread of particle rebound is investigated for roughness levels that are similar to the ones of deteriorated high-pressure compressor blades as discussed by Gilge et al. The measured surface roughness of the experimentally investigated targets is used as input parameters to the numerical framework. The rebound statistics obtained in the numerical simulation are compared to the rebound data measured in the experiment. Based on this study, conclusions are drawn about which part of the rebound spread is attributable to surface roughness and which is caused by superimposed effects. It was found that the effect of surface roughness as characterized by Altmeppen et al. contributes in the order of 46 % to the rebound spread for small impact angles. However, the share in spread due to roughness gradually decreases with increasing global impact angles to a level of 13 % for angles close to 90°. The remaining percentage of rebound spread is attributed to superimposing phenomena. In addition to the rolling and sliding of aspherical particles, further phenomena such as plastic deformation and erosion of the roughness peaks during contact and the associated dissipation of energy gain in importance for steeper impact angles. Therefore, the effect of surface roughness should not be neglected in numerical simulations of particle-laden flows. Modeling the superimposed phenomena which are observed to be dominating at high impact angles opens up a further field of research.

Abstract Metabolic consequences of an energy and protein rich diet can compromise metabolic health of cattle by promoting a pro-inflammatory phenotype. Laminitis is a common clinical sign, but affected metabolic pathways, underlying pathophysiology and causative relationships of a systemic pro-inflammatory phenotype are unclear. Therefore, the aim of this study was to elucidate changes in metabolome profiles of 20 months old Holstein bulls fed a high energy and protein diet and to identify novel metabolites and affected pathways, associated with diet-related laminitis. In a randomized controlled feeding trial using bulls fed a high energy and protein diet (HEP; metabolizable energy [ME] intake 169.0 ± 1.4 MJ/day; crude protein [CP] intake 2.3 ± 0.02 kg/day; calculated means ± SEM; n = 15) versus a low energy and protein diet (LEP; ME intake 92.9 ± 1.3 MJ/day; CP intake 1.0 ± 0.01 kg/day; n = 15), wide ranging effects of HEP diet on metabolism were demonstrated with a targeted metabolomics approach using the AbsoluteIDQ p180 kit (Biocrates Life Sciences). Multivariate statistics revealed that lower concentrations of phosphatidylcholines and sphingomyelins and higher concentrations of lyso-phosphatidylcholines, branched chain amino acids and aromatic amino acids were associated with an inflammatory state of diet-related laminitis in Holstein bulls fed a HEP diet. The latter two metabolites share similarities with changes in metabolism of obese humans, indicating a conserved pathophysiological role. The observed alterations in the metabolome provide further explanation on the underlying metabolic consequences of excessive dietary nutrient intake.

Abstract Over-conditioned dairy cows, classified by body condition score (BCS) and backfat thickness (BFT) are less able to metabolically adapt to the rapidly increasing milk yield after parturition. Based on serum metabolome and cluster analyses, high BCS cows (HBCS) could be classified into metabotypes that are more similar to normal (NBCS) cows, i.e., HBCS predicted normal (HBCS-PN) than the HBCS predicted high (HBCS-PH) cows—similar to the concept of obese but metabolically healthy humans. Our objective was to compare muscle metabolome and mRNA abundance of genes related to lipogenesis and lipolysis in adipose tissue between HBCS-PH (n = 13), HBCS-PN (n = 6), and NBCS-PN (n = 15). Tail-head subcutaneous fat was biopsied on d −49, 3, 21, and 84 relative to parturition. Potential differences in the oxidative capacity of skeletal muscle were assessed by targeted metabolomics in M. semitendinosus from d 21. Besides characteristic changes with time, differences in the mRNA abundance were limited to lipogenesis-related genes on d −49 (HBCS-PH > HBCS-PN). The HBCS-PH had more than two-fold higher muscle concentrations of short (C2, C4-OH, C6-OH) and long-chain acylcarnitines (C16, C18, and C18:1) than HBCS-PN, indicating a greater oxidative capacity for fatty acids (and utilization of ketones) in muscle of HBCS-PN than HBCS-PH cows.

Erosion is an essential deterioration mechanism in compressors of jet engines. Erosion damage predictions require the determination of erosion rates through flat plate experiments. The applicability of the erosion rates is limited to conditions that are comparable to the prevailing boundary conditions of the flat plate experiment. A performed dimensional analysis enables the correct transfer of the flat plate erosion rates to the presented physical calculation model through limits in spatial and time resolution. This efficient approach avoids computationally intensive single-impact computations. The approach features a re-meshing procedure that adheres to the limits derived by the dimensional analysis. The computation approach is capable of describing local geometry changes on cascade compressor blades which are exposed to erosive particles. A linear erosion cascade experiment performed on NASA Rotor 37 provides validation data for the calculated erosion-induced shape change. Arizona Road Dust particles are used to deteriorate Ti-Al6-4V compressor blades. The experiment is performed at an incidence of i = 7°and Ma = 0.76 representing ground idle conditions. The presented parametric study for element size and time step revealed preferable values for the presented computation. Calculations performed with the determined values showed that the erosion prediction is within the measurement tolerance of the experiment and, therefore, high accordance between the computation and the experiment is achieved. To extend the current state of the art, it is demonstrated that the derived discretization is decisive for the correct reproduction of the eroded geometries and fitting parameters are no longer needed. The good agreement between the experimental measurements and the calculated results confirms the correct application of the physical model to the phenomenology of erosion. Thus, the presented physical model offers a novel approach to adapting deterioration mechanisms caused by erosion to any compressor blade geometry.

Wastewater from factories producing polysulfone-based membranes mainly contains the used organic solvent, i.e., dimethylacetamide (DMAc). Due to the environmental impact of DMAc, wastewater treatment is mandatory. Several biological treatment options based on the activated sludge process are described in the literature. Due to artificial aeration, these techniques have high energy requirements. Near-nature processes such as vertical flow constructed wetlands (VF wetlands) have a low energy demand, high tolerance to load fluctuations, and low maintenance requirements. Therefore, high-loaded, two-stage VF wetlands are an efficient option for treating wastewater. However, constructed wetlands have so far only been used to a limited extent for the treatment of industrial wastewater. In the present study, the ability of laboratory-scale, high-load, two-stage VF wetlands to treat DMAc was investigated. This included their DMAc degradation efficiency and corresponding pathways, removal of the total organic carbon (TOC), nitrification and denitrification of the nitrogen, as well as the ecotoxicological effects (mutagenicity, genotoxicity, reactive oxygen species) of untreated and treated wastewater. The focus was to determine the effect of different grain size distributions on removal rates, the maximum inflow loading, and the effect of high inflow concentrations on effluent concentrations. In general, DMAc was completely degraded using VF wetlands, with dimethylamine (DMA) identified as the main intermediate. TOC removal rates reached more than 99%. The nitrogen bound to DMAc was completely nitrified. However, the start-up of the VF wetlands without seeded filter material temporarily leads to high nitrite accumulation. This may affect the mutagenicity of the treated wastewater. The results show that high-loaded, two-stage VF wetlands are an effective option for treating wastewater containing DMAc with higher efficiency than comparable biological processes.

Heat stress (HS) during late gestation implies unfavorable effects on dairy cows and their in-utero heat stressed offspring. The objective of the present study was to elucidate the effect of intrauterine (maternal) HS during the last week of gestation on blood metabolite concentrations of female dairy calves during their first week of life. We defined the mean temperature humidity index (mTHI) during the last gestation week of ≥60 as threshold for maternal HS. In this regard, we compared differences in metabolite concentrations of maternally heat stressed (MHSCALVES) (n = 14) and not heat stressed (NMHSCALVES) (n = 33) calves. We identified 15 metabolites from five different biochemical classes (phosphatidylcholines, cholesteryl esters, sphingomyelins, cresols and hexoses) as potential biomarkers for maternal HS in calves. The plasma concentrations of all significantly affected metabolites were lower in MHSCALVES when compared to NMHSCALVES. The effect of maternal HS during the last week of gestation on blood metabolite concentrations of the female offspring during the first week after birth might be due to HS induced intergenerational physiological alterations, impaired colostrum quality or epigenetic modifications of the calf genome. The results of this pilot study should be validated in ongoing fully standardized studies.

Abstract Background We hypothesised that supplementation of green tea extract (GTE) in dairy cows during the transition period can attenuate proinflammatory conditions and prevent endoplasmic reticulum (ER) stress in the liver of these cows. Thirty Holstein cows with an average parity of 3.06 (± 1.31, SD) were divided into a control group and a group that received a daily amount of 10 g of GTE from d 7 before the calving day and a daily amount of 20 g of GTE from the day of calving until d 7 of lactation. Results Cows supplemented with GTE did not show differences in energy intake or milk yield in weeks 2–7 of lactation. However, these cows had a lower milk fat concentration and a lower energy corrected milk yield than the control cows and showed a trend of improved energy balance. The relative mRNA concentrations of proinflammatory genes, genes involved in the acute phase reaction and antioxidant genes in the liver in weeks 1, 4 and 7 of lactation were not different between the two groups of cows. The concentrations of α-tocopherol and the Trolox equivalent antioxidant capacity in plasma were not different between the two groups. However, the group supplemented with GTE showed significant reductions of some genes of the unfolded protein response (UPR) in week 1 and a trend of lower liver triacylglycerol (TAG) concentrations in the liver compared to the control group. Conclusions This study shows that supplementation of GTE in dairy cows lowers the fat concentration in the milk but overall has no effect on the expression of inflammatory genes and the antioxidative status in dairy cows during early lactation. The finding of reduced mRNA levels of genes involved in the UPR at week 1, however, supports other results showing that supplementation of polyphenols could prevent the development of ER stress in the liver of cows during early lactation. The finding of a tendency towards a reduced TAG concentration in the liver of cows supplemented with GTE might be due to an improved energy balance in these cows.

Abstract Background Extracorporeal membrane oxygenation (ECMO) has gained widespread acceptance for the treatment of critically ill patients suffering from cardiac and/or respiratory failure. Various animal models have been developed to investigate the adverse effects induced by ECMO. Different membrane oxygenators have been used with varying priming volumes and membrane surfaces (Micro-1, small animal membrane oxygenator (SAMO)). Methods Sixteen male Lewis rats (350–400 g) were randomly assigned to receive ECMO with Micro-1 or SAMO (n = 8, respectively). Venoarterial ECMO was established after cannulation of the femoral artery and the jugular vein. The cardiac output was measured using a left-ventricular conductance catheter. The oxygen fraction of the ECMO was set to 1.0, 0.75, 0.5 and 0.21 after a stabilisation period of 15 min. Further, arterial blood gas analyses were performed at baseline, and during the first hour every 15 min after commencing the ECMO, and subsequently every 30 min. Dilutional anaemia was calculated using haemoglobin concentration at baseline, and 15 min after the start of ECMO therapy. Moreover, inflammation was determined by measuring tumour necrosis factor alpha, interleukin-6 and -10 at baseline and every 30 min. Results Animals of the Micro-1 group showed a significantly lower dilutional anaemia (ΔHaemoglobin t0 – t0.25: SAMO 6.3 [5.6–7.5] g/dl vs. Micro-1 5.6 [4.6–5.8] g/dl; p = 0.028). Further, significantly higher oxygen partial pressure was measured in the SAMO group, at an oxygen fraction of 0.75, 0.5 and 0.21 (380 [356–388] vs. 314 [263–352] mmHg, p = 0.002; 267 [249–273] mmHg vs. 197 [140–222] mmHg, p = 0.002; 87 [82–106] mmHg vs. 76 [60–79] mmHg, p = 0.021, respectively). However, no differences were found regarding the oxygen fraction of 1.0, in terms of carbon-dioxide partial pressure and cardiac output. Moreover, in the Micro-1 group tumour necrosis factor alpha was increased after 60 min and interleukin-6 after 120 min. Conclusion While the dilutional anaemia was increased after commencing the ECMO, the oxygenation was augmented in the SAMO group. The inflammatory response was elevated in the Micro-1 group.

Abstract Objective This study aimed to investigate the association of anesthetists’ academic and educational status with self-confidence, self-rated knowledge and objective knowledge about rational antibiotic application. Therefore, anesthetists in Germany were asked about their self-confidence, self-rated knowledge and objective knowledge on antibiotic therapy via the Multiinstitutional Reconnaissance of practice with Multiresistant bacteria (MR2) survey. Other analysis from the survey have been published elsewhere, before. Results 361 (52.8%) questionnaires were completed by specialists and built the study group. In overall analysis the Certification in Intensive Care (CIC) was significantly associated with self-confidence (p

Air-conducted ultrasound (> 17.8 kHz; US) is produced by an increasing number of technical devices in our daily environment. While several studies indicate that exposure to US in public spaces can lead to subjective symptoms such as ‘annoyance’ or ‘difficulties in concentration’, the effects of US on brain activity are poorly understood. In the present study, individual hearing thresholds (HT) for sounds in the US frequency spectrum were assessed in 21 normal-hearing participants. The effects of US were then investigated by means of functional magnetic resonance imaging (fMRI). 15 of these participants underwent three resting-state acquisitions, two with a 21.5 kHz tone presented monaurally at 5 dB above (ATC) and 10 dB below (BTC) the HT and one without auditory stimulation (NTC), as well as three runs of an n-back working memory task involving similar stimulus conditions (n-ATC, n-BTC, n-NTC). Comparing data gathered during n-NTC vs. fixation, we found that task performance was associated with the recruitment of regions within the cognitive control network, including prefrontal and parietal areas as well as the cerebellum. Direct contrasts of the two stimulus conditions (n-ATC & n-BTC) vs. n-NTC showed no significant differences in brain activity, irrespective of whether a whole-brain or a region of interest approach with primary auditory cortex as the seed was used. Likewise, no differences were found when the resting-state runs were compared. However, contrast analysis (n-BTC vs. n-ATC) revealed a strong activation in bilateral inferior frontal gyrus (IFG, triangular part) only when US was presented below the HT (p < 0.001, cluster > 30). In addition, IFG activation was also associated with faster reaction times during n-BTC (p = 0.033) as well as with verbal reports obtained after resting-state, i.e., the more unpleasant sound was perceived during BTC vs. ATC, the higher activation in bilateral IFG was and vice versa (p = 0.003). While this study provides no evidence for activation of primary auditory cortex in response to audible US (even though participants heard the sounds), it indicates that US can lead to changes in the cognitive control network and affect cognitive performance only when presented below the HT. Activation of bilateral IFG could reflect an increase in cognitive demand when focusing on task performance in the presence of slightly unpleasant and/or distracting US that may not be fully controllable by attentional mechanisms.

Induction of FGF21 expression in the liver and a significant increase in plasma FGF21 concentration have been demonstrated in cows during early lactation, but knowledge about the function of FGF21 in dairy cows remains limited. In order to improve the understanding of the physiological role of FGF21 in dairy cows, the present study aimed to investigate differences in metabolic pathways between dairy cows with high and low hepatic expression of FGF21 at week 1 of lactation (n = 8/group) by liver transcriptomics, targeted plasma metabolomics, and analysis of inflammatory and oxidative stress-related parameters. Dry matter intake, energy balance, milk yield, and energy-corrected milk yield at days 8–14 postpartum did not differ between cows with high and low hepatic FGF21 expression. However, cows with high FGF21 expression showed an upregulation of genes involved in endoplasmic reticulum stress, inflammation, and nuclear factor E2-related factor 2 (Nrf2)-dependent cytoprotection compared to cows with low FGF21 expression at week 1 postpartum (p < 0.05). Concentrations of important antioxidants (tocopherols, β-carotene, and glutathione) in the liver and plasma, trolox equivalent antioxidant capacity in plasma, concentrations of oxidative stress-related compounds (thiobarbituric acid-reactive substances and protein carbonyls), and levels of most acute phase proteins at week 1 postpartum did not differ between cows with high or low FGF21 expression. Moreover, among a total of >200 metabolites assayed in the plasma, concentrations of only 7 metabolites were different between cows with high or low FGF21 expression (p < 0.05). Overall, the results showed that cows with high and low FGF21 hepatic expression had only moderate differences in metabolism, but FGF21 might be important in the adaptation of dairy cows to stress conditions during early lactation.

Construction simulation has been widely used in academia for research purposes. However, it has been neglected by the industry for various reasons, including the amount of data, skills, effort, and time required to develop complex simulation models, the difficulty of model reuse, and the abstract and confusing way in which simulation results are usually presented. This article demonstrates how BIM can be employed to facilitate the development of a construction simulation model that considers constraints related to resource allocation and task interdependencies. Furthermore, it shows how a game engine can be used as a platform to implement the proposed framework for the integration of BIM and construction simulation and to produce animations from simulation results. The feasibility of the framework is demonstrated through a case study on masonry construction. Results of implementing the framework reveal that BIM-based simulations can reduce the skills, effort, and time required to develop simulation models and enable model reuse. The integration of simulation-based animations provides a model verification and validation mechanism and a means to communicate model results to stakeholders unfamiliar with simulation.

Objective: Auditory research and complaints about environmental noise indicate that there exists a significant, small subgroup within the population which is sensitive towards infra- and low-frequency or ultra- and high-frequency sounds (ILF/UHF). This paper reports on the development, factorization and validation of measures of sensitivity towards frequencies outside the common hearing range. Design: A multinational, cross-sectional survey study was run. Principal component analyses and exploratory factor analyses were conducted in a sample of 267 Europeans (from the UK, Slovenia, and Germany). Results: The factor analyses suggested that ILF versus UHF sensitivity constitute different factors, each characterized by sensory perception, stress-responsivity, and behavioral avoidance. A third factor comprising beliefs of dangerousness of ILF and UHF emerged. The factors explained 72% of the variance. The factor-solution was replicated separately for the English (n = 98) and German (n = 169) versions of the questionnaire (Slovenians and UK residents filled out the English version). Acceptable to excellent reliability was found. ILF and UHF sensitivity were moderately related to noise sensitivity in the normal hearing range, suggesting the new measures are not redundant. Correlations with psychiatric and somatic symptoms were small to moderate. ILF sensitivity correlated with neuroticism (small effect) and daytime sleepiness (moderate effect). ILF and UHF sensitivity were related to agreeableness (small effects). Overall, the novel ILF and UHF sensitivity scales seems to provide a solid tool for conducting further research on the role of sensitivity concerning adverse effects of ILF and UHF sound (e.g. health outcomes, annoyance ratings). The questionnaire consortium recommends using the new scales in combination with established measures of normal hearing range sensitivity.

Paper-based data acquisition and manual transfer between incompatible software or data formats during inspections of bridges, as done currently, are time-consuming, error-prone, cumbersome, and lead to information loss. A fully digitized workflow using open data formats would reduce data loss, efforts, and the costs of future inspections. On the one hand, existing studies proposed methods to automatize data acquisition and visualization for inspections. These studies lack an open standard to make the gathered data available for other processes. On the other hand, several studies discuss data structures for exchanging damage information among different stakeholders. However, those studies do not cover the process of automatic data acquisition and transfer. This study focuses on a framework that incorporates automatic damage data acquisition, transfer, and a damage information model for data exchange. This enables inspectors to use damage data for subsequent analyses and simulations. The proposed framework shows the potentials for a comprehensive damage information model and related (semi-)automatic data acquisition and processing.

Introduction Sepsis is a major cause of preventable deaths in hospitals. This study aims to investigate if sepsis incidence and quality of care can be assessed using inpatient administrative health data (IAHD).Methods and analysis Design: Retrospective observational validation study using routine data to assess the diagnostic accuracy of sepsis coding in IAHD regarding sepsis diagnosis based on medical record review. Procedure: A stratified sample of 10 000 patients with an age ≥15 years treated in between 2015 and 2017 in 10 German hospitals is investigated. All available information of medical records is screened by trained physicians to identify true sepsis cases (‘gold standard’) both according to current (‘sepsis-1’) definitions and new (‘sepsis-3’) definitions. Data from medical records are linked to IAHD on patient level using a pseudonym. Analyses: Proportions of cases with sepsis according to sepsis-1 and sepsis-3 definitions are calculated and compared with estimates from coding of sepsis in IAHD. Predictive accuracy (sensitivity, specificity) of different coding abstraction strategies regarding the gold standard is estimated. Predictive accuracy of mortality risk factors obtained from IAHD regarding the respective risk factors obtained from medical records is calculated. An IAHD-based risk model for hospital mortality is compared with a record-based risk model regarding model-fit and predicted risk of death. Analyses adjust for sampling weights. The obtained estimates of sensitivity and specificity for sepsis coding in IAHD are used to estimate adjusted incidence proportions of sepsis based on German national IAHD.Ethics and dissemination The study has been approved by the ethics commission of the Jena University Hospital (No. 2018-1065-Daten). The results of the study will be discussed in an expert panel to write a memorandum on improving the utility of IAHD for epidemiological surveillance and quality management of sepsis care.Trial registration number DRKS00017775; Pre-results.

Model-based predictive maintenance using high-frequency in-flight data requires digital twins that can model the dynamics of their physical twin with high precision. The models of the twins need to be fast and dynamically updatable. Machine learning offers the possibility to address these challenges in modeling the transient performance of aero engines. During transient operation, heat transferred between the engine’s structure and the annulus flow plays an important role. Diabatic performance modeling is demonstrated using non-dimensional transient heat transfer maps and transfer learning to extend turbomachinery transient modeling. The general form of such a map for a simple system similar to a pipe is reproduced by a Multilayer Perceptron neural network. It is trained using data from a finite element simulation. In a next step, the network is transferred using measurements to model the thermal transients of an aero engine. Only a limited number of parameters measured during selected transient maneuvers is needed to generate suitable non-dimensional transient heat transfer maps. With these additional steps, the extended performance model matches the engine thermal transients well.