The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.

Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.

Understanding the biases to sepsis surveillance and quality assurance caused by inaccurate coding in administrative health data.

PURPOSE: Timely and accurate data on the epidemiology of sepsis are essential to inform policy decisions and research priorities. We aimed to investigate the validity of inpatient administrative health data (IAHD) for surveillance and quality assurance of sepsis care. METHODS: We conducted a retrospective validation study in a disproportional stratified random sample of 10,334 inpatient cases of age ≥ 15 years treated in 2015-2017 in ten German hospitals. The accuracy of coding of sepsis and risk factors for mortality in IAHD was assessed compared to reference standard diagnoses obtained by a chart review. Hospital-level risk-adjusted mortality of sepsis as calculated from IAHD information was compared to mortality calculated from chart review information. RESULTS: ICD-coding of sepsis in IAHD showed high positive predictive value (76.9-85.7% depending on sepsis definition), but low sensitivity (26.8-38%), which led to an underestimation of sepsis incidence (1.4% vs. 3.3% for severe sepsis-1). Not naming sepsis in the chart was strongly associated with under-coding of sepsis. The frequency of correctly naming sepsis and ICD-coding of sepsis varied strongly between hospitals (range of sensitivity of naming: 29-71.7%, of ICD-diagnosis: 10.7-58.5%). Risk-adjusted mortality of sepsis per hospital calculated from coding in IAHD showed no substantial correlation to reference standard risk-adjusted mortality (r = 0.09). CONCLUSION: Due to the under-coding of sepsis in IAHD, previous epidemiological studies underestimated the burden of sepsis in Germany. There is a large variability between hospitals in accuracy of diagnosing and coding of sepsis. Therefore, IAHD alone is not suited to assess quality of sepsis care.

Assessment of risk factors for adverse events in analgosedation for pediatric endoscopy: A 10-year retrospective analysis.

OBJECTIVES: Data regarding the occurrence of complications specifically during pediatric anesthesia for endoscopic procedures is limited. By evaluating such data, factors could be identified to assure proper staffing and preparation to minimize adverse events and improve patient safety during flexible endoscopy. METHODS: This retrospective cohort study included children undergoing anesthesia for gastroscopy, colonoscopy, bronchoscopy, or combined endoscopic procedures over 10-year period. The primary study aim was to evaluate the incidence of complications and identify risk factors for adverse events. RESULTS: Overall, 2064 endoscopic procedures including 1356 gastroscopies (65.7%), 93 colonoscopies (4.5%), 235 bronchoscopies (11.4%), and 380 combined procedures (18.4%) were performed. Of the 1613 patients, 151 (7.3%) patients exhibited an adverse event, with respiratory complications being the most common (65 [3.1%]). Combination of gastrointestinal endoscopies did not lead to an increased adverse event rate (gastroscopy: 5.5%, colonoscopy: 3.2%). Diagnostic endoscopy as compared to interventional had a lower rate. If bronchoscopy was performed, the rate was similar to that of bronchoscopy alone (19.5% vs. 20.4%). Age < 5.8 years or body weight less than 20 kg, bronchoscopy, American Society of Anesthesiologists status ≥ 2 or pre-existing anesthesia-relevant diseases, and urgency of the procedure were independent risk factors for adverse events. For each risk factor, the risk for events increased 2.1-fold [1.8-2.4]. CONCLUSIONS: This study identifies multiple factors that increase the rate of adverse events associated anesthesia-based endoscopy. Combined gastrointestinal procedures did not increase the risk for adverse events while combination of bronchoscopy to gastrointestinal endoscopy showed a similar risk as bronchoscopy alone.

Cardiac index-guided therapy to maintain optimised postinduction cardiac index in high-risk patients having major open abdominal surgery: the multicentre randomised iPEGASUS trial.

BACKGROUND: It is unclear whether optimising intraoperative cardiac index can reduce postoperative complications. We tested the hypothesis that maintaining optimised postinduction cardiac index during and for the first 8 h after surgery reduces the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. METHODS: In three German and two Spanish centres, high-risk patients having elective major open abdominal surgery were randomised to cardiac index-guided therapy to maintain optimised postinduction cardiac index (cardiac index at which pulse pressure variation was <12%) during and for the first 8 h after surgery using intravenous fluids and dobutamine or to routine care. The primary outcome was the incidence of a composite outcome of moderate or severe complications within 28 days after surgery. RESULTS: We analysed 318 of 380 enrolled subjects. The composite primary outcome occurred in 84 of 152 subjects (55%) assigned to cardiac index-guided therapy and in 77 of 166 subjects (46%) assigned to routine care (odds ratio: 1.87, 95% confidence interval: 1.03-3.39, P=0.038). Per-protocol analyses confirmed the results of the primary outcome analysis. CONCLUSIONS: Maintaining optimised postinduction cardiac index during and for the first 8 h after surgery did not reduce, and possibly increased, the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. Clinicians should not strive to maintain optimised postinduction cardiac index during and after surgery in expectation of reducing complications. CLINICAL TRIAL REGISTRATION: NCT03021525.

Thoracic Epidural Analgesia Is Not Associated With Improved Survival After Pancreatic Surgery: Long-Term Follow-Up of the Randomized Controlled PAKMAN Trial.

BACKGROUND: Perioperative thoracic epidural analgesia (EDA) and patient-controlled intravenous analgesia (PCIA) are common forms of analgesia after pancreatic surgery. Current guidelines recommend EDA over PCIA, and evidence suggests that EDA may improve long-term survival after surgery, especially in cancer patients. The aim of this study was to determine whether perioperative EDA is associated with an improved patient prognosis compared to PCIA in pancreatic surgery. METHODS: The PAKMAN trial was an adaptive, pragmatic, international, multicenter, randomized controlled superiority trial conducted from June 2015 to October 2017. Three to five years after index surgery a long-term follow-up was performed from October 2020 to April 2021. RESULTS: For long-term follow-up of survival, 109 patients with EDA were compared to 111 patients with PCIA after partial pancreatoduodenectomy (PD). Long-term follow-up of quality of life (QoL) and pain assessment was available for 40 patients with EDA and 45 patients with PCIA (questionnaire response rate: 94%). Survival analysis revealed that EDA, when compared to PCIA, was not associated with improved overall survival (OS, HR, 1.176, 95% HR-CI, 0.809-1.710, P = .397, n = 220). Likewise, recurrence-free survival did not differ between groups (HR, 1.116, 95% HR-CI, 0.817-1.664, P = .397, n = 220). OS subgroup analysis including only patients with malignancies showed no significant difference between EDA and PCIA (HR, 1.369, 95% HR-CI, 0.932-2.011, P = .109, n = 179). Similar long-term effects on QoL and pain severity were observed in both groups (EDA: n = 40, PCIA: n = 45). CONCLUSIONS: Results from this long-term follow-up of the PAKMAN randomized controlled trial do not support favoring EDA over PCIA in pancreatic surgery. Until further evidence is available, EDA and PCIA should be considered similar regarding long-term survival.

Preoperative routine measurement of NT-proBNP predicts postoperative morbidity after non-cardiac surgery with intermediate or high surgical risk: an observational study.

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 < 0.001), which was due to the incidence of cardiac rehospitalisation (4.4% vs. 0%, p = 0.018), ADHF (20.1% vs. 4.0%, p < 0.001), AKI (39.8% vs. 8.3%, p < 0.001), and infection (46.3% vs. 24.4%, p < 0.01). Perioperative fluid balance and perioperative hypotension were comparable between groups. Preoperative NT-proBNP > 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.

Assessing the role of Chemokine (C-C motif) ligand 14 in AKI: a European consensus meeting.

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 < 0.001). The highest level of concern to modify the treatment plan was for discussions on renal replacement therapy (RRT) initiation for CCL14 levels > 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 Role of the Kinin System and the Effect of Des-Arginine9-Bradykinin on Coagulation and Platelet Function in Critically Ill COVID-19 Patients: A Secondary Analysis of a Prospective Observational Study.

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.

New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Venovenous Extracorporeal Membrane Oxygenation in the Rat.

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.

On the mechanism of painful burn sensation in tattoos on magnetic resonance imaging (MRI). Magnetic substances in tattoo inks used for permanent makeup (PMU) identified: Magnetite, goethite, and hematite.

BACKGROUND: Persons with cosmetic tattoos occasionally experience severe pain and burning sensation on magnetic resonance imaging (MRI). OBJECTIVE: To explore the culprit magnetic substances in commonly used permanent makeup inks. MATERIAL AND METHODS: 20 inks used for cosmetic tattooing of eyebrows, eyeliners, and lips were selected. Ink bottles were tested for magnetic behavior with a neodymium magnet. Eight iron oxide inks qualified for the final study. Metals were analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The magnetic fraction of inks was isolated and analyzed by X-ray fluorescence (XRF). Magnetic iron compounds were characterized by Mössbauer spectroscopy and powder X-ray diffraction (XRD). RESULTS: ICP-MS showed iron in all magnetic samples, and some nickel and chromium. Mössbauer spectroscopy and XRD detected ferromagnetic minerals, particularly magnetite, followed by goethite and hematite. CONCLUSION: This original study of cosmetic ink stock products made with iron oxide pigments reports magnetic impurities in inks for cosmetic tattooing, e.g., magnetite, goethite, and hematite. These may be the main cause of MRI burn sensation in cosmetic tattoos. The mechanism behind sensations is hypothesized to be induction of electrical stimuli of axons from periaxonal pigment/impurity activated by magnetic force. Magnetite is considered the lead culprit.

Interactions of the chemokines CXCL11 and CXCL12 in human tumor cells.

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.

Immune Checkpoint Inhibitor Therapy in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) occur in various regions of the body and present with complex clinical and biochemical phenotypes. The molecular underpinnings that give rise to such varied manifestations have not been completely deciphered. The management of neuroendocrine tumors (NETs) involves surgery, locoregional therapy, and/or systemic therapy. Several forms of systemic therapy, including platinum-based chemotherapy, temozolomide/capecitabine, tyrosine kinase inhibitors, mTOR inhibitors, and peptide receptor radionuclide therapy have been extensively studied and implemented in the treatment of NETs. However, the potential of immune checkpoint inhibitor (ICI) therapy as an option in the management of NETs has only recently garnered attention. Till date, it is not clear whether ICI therapy holds any distinctive advantage in terms of efficacy or safety when compared to other available systemic therapies for NETs. Identifying the characteristics of NETs that would make them (better) respond to ICIs has been challenging. This review provides a summary of the current evidence on the value of ICI therapy in the management of ICIs and discusses the potential areas for future research.

Impact of the inspiratory oxygen fraction on the cardiac output during jugulo-femoral venoarterial extracorporeal membrane oxygenation in the rat.

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.

Impact of the fluid challenge infusion rate on cardiac stroke volume during major spinal neurosurgery: a prospective single center randomized interventional trial.

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 < 0.01), SV (P < 0.01), and MAP (P < 0.01), irrespective of whether crystalloids or colloids were used. In group 2, CI and SV did not change, while MAP was slightly increased (P = 0.011) only after colloid infusion. CONCLUSIONS: A fluid bolus within 5 min is more effective than those administered within 20 min and should therefore be the primary treatment option. Furthermore, bolus infusions administered within 20 min may result in volume overload without achieving relevant hemodynamic improvements. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00022917.

Investigation of resolution and microphone size for measurements of airborne ultrasound.

The growth of ultrasound technologies has entailed the presence of airborne ultrasound emissions in industry and public and private spaces. For occupational safety and health, procedural and technical recommendations are needed that allow measurements to be performed in the field within a short time and with little effort. This study aims to answer two research questions concerning the minimum spatial resolution and microphone size required to determine a spatial distribution of sound pressure levels with sufficient accuracy within a given measurement uncertainty. The investigation focused on high spatial resolution datasets of the airborne ultrasound field of an ultrasonic welding machine acquired using a laboratory measuring system. Based on these datasets, datasets with lower resolutions were generated and measurements with microphones of different sizes were simulated. Subsequently, four different methods of parameterization were applied to the datasets to characterize the airborne ultrasound field with respect to the structure and sound pressure levels. Comparing the parameters of datasets with high precision (high resolution and small microphone size) to those of datasets with reduced precision (lower resolution and larger microphone size) allowed a quantitative assessment of the influence of the reduction in precision. Corresponding recommendations on resolution and microphone size are given.

Echinocandins Accelerate Particle Transport Velocity in the Murine Tracheal Epithelium: Dependency on Intracellular Ca2+ Stores.

The mucociliary clearance of lower airways is modulated by different physiologic stimuli and also by pathophysiologic agents like polluting substances or pharmaceutical molecules. In the present investigation, we measured the particle transport velocity (PTV) of mouse tracheae as a surrogate for mucociliary clearance. In mouse tracheal preparations, we detected a sustained increase in the PTV under the application of the echinocandins caspofungin, anidulafungin, and micafungin. In further experiments, we observed the effects of echinocandins on the PTV were dependent on intracellular Ca2+ homeostasis. In Ca2+-free buffer solutions, the amplitude of the echinocandin-evoked rise in the PTV was significantly reduced relative to that in the experiments in Ca2+-containing solutions. Depletion of intracellular Ca2+ stores of the endoplasmic reticulum (ER) by caffeine completely prevented an increase in the PTV with subsequent caspofungin applications. Mitochondrial Ca2+ stores seemed to be unaffected by echinocandin treatment. We also observed no altered generation of reactive oxygen species under the application of echinocandins as probable mediators of the PTV. Consequently, the observed echinocandin effects on the PTV depend upon the Ca2+ influx and Ca2+ contents of the ER. We assume that all three echinocandins act intracellularly on ER Ca2+ stores to activate Ca2+-dependent signal transduction cascades, enhancing the PTV.

Identification of CXCL11 as part of chemokine network controlling skeletal muscle development.

The chemokine, CXCL12, and its receptors, CXCR4 and CXCR7, play pivotal roles during development and maintenance of limb muscles. CXCR7 additionally binds CXCL11, which uses CXCR3 as its prime receptor. Based on this cross-talk, we investigate whether CXCL11 would likewise affect development and/or function of skeletal muscles. Western blotting and immunolabelling demonstrated the developmentally restricted expression of CXCL11 in rat limb muscles, which was contrasted by the continuous expression of its receptors in proliferating and differentiating C2C12 cells as well as in late embryonic to adult rat limb muscle fibres. Consistent with a prime role in muscle formation, functional studies identified CXCL11 as a potent chemoattractant for undifferentiated C2C12 cells and further showed that CXCL11 does neither affect myoblast proliferation and differentiation nor metabolic/catabolic pathways in formed myotubes. The use of selective receptor antagonists unravelled complementary effects of CXCL11 and CXCL12 on C2C12 cell migration, which either require CXCR3/CXCR7 or CXCR4, respectively. Our findings provide new insights into the chemokine network controlling skeletal muscle development and function and, thus, might provide a base for future therapies of muscular diseases.

Climate Change and Obesity.

Global warming and the rising prevalence of obesity are well described challenges of current mankind. Most recently, the COVID-19 pandemic arose as a new challenge. We here attempt to delineate their relationship with each other from our perspective. Global greenhouse gas emissions from the burning of fossil fuels have exponentially increased since 1950. The main contributors to such greenhouse gas emissions are manufacturing and construction, transport, residential, commercial, agriculture, and land use change and forestry, combined with an increasing global population growth from 1 billion in 1800 to 7.8 billion in 2020 along with rising obesity rates since the 1980s. The current Covid-19 pandemic has caused some decline in greenhouse gas emissions by limiting mobility globally via repetitive lockdowns. Following multiple lockdowns, there was further increase in obesity in wealthier populations, malnutrition from hunger in poor populations and death from severe infection with Covid-19 and its virus variants. There is a bidirectional relationship between adiposity and global warming. With rising atmospheric air temperatures, people typically will have less adaptive thermogenesis and become less physically active, while they are producing a higher carbon footprint. To reduce obesity rates, one should be willing to learn more about the environmental impact, how to minimize consumption of energy generating carbon dioxide and other greenhouse gas emissions, and to reduce food waste. Diets lower in meat such as a Mediterranean diet, have been estimated to reduce greenhouse gas emissions by 72%, land use by 58%, and energy consumption by 52%.

Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort.

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.

Severe COVID-19 acute respiratory distress syndrome in an adult with single-ventricle physiology: a case report.

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.