The work Lifestyle-integrated Functional Exercise program for preventing functional decline in employees aged 55 years and older: development and initial evaluation.

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.

Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells.

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

Fas (CD95) expression in adipocytes contributes to diet-induced obesity.

OBJECTIVE: Induction of browning in white adipose tissue (WAT) increases energy expenditure and may be an attractive target for the treatment of obesity. Since activation of Fas (CD95) induces pathways known to blunt expression of uncoupling protein 1 (UCP1), we hypothesized that Fas expression in adipocytes inhibits WAT browning and thus contributes to the development of obesity. METHODS: Adipocyte-specific Fas knockout (FasΔadipo) and control littermate (FasF/F) mice were fed a regular chow diet or a high-fat diet (HFD) for 20 weeks. Energy expenditure was assessed by indirect calorimetry, and browning was determined in subcutaneous WAT. In vitro, UCP1 was analyzed in subcutaneous murine adipocytes treated with or without Fas ligand. Moreover, FAS expression in WAT was correlated to UCP1 and percentage of body fat in human individuals. RESULTS: HFD-fed FasΔadipo mice displayed reduced body weight gain and blunted adiposity compared to control littermates. Concomitantly, whole-body energy expenditure and WAT browning were elevated. In cultured adipocytes, Fas ligand treatment blunted isoproterenol-induced UCP1 protein levels. In support of these findings in rodents, FAS expression in WAT correlated negatively with UCP1 but positively with adiposity in human individuals. CONCLUSIONS: Fas activation in adipocytes contributes to HFD-associated adiposity in rodents and may be a therapeutic target to reduce obesity and associated diseases.

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

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.

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.

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.

Comparison of preoperative NT-proBNP and simple cardiac risk scores for predicting postoperative morbidity after non-cardiac surgery with intermediate or high surgical risk.

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 < 0.001; RCRI: AUCROC 0.560, p = 0.126; Andersson: AUCROC 0.487, p = 0.760). The AUCROC was comparable between preoperative NT-proBNP (0.679, p < 0.001) and AUB-HAS2 (p = 0.334). Multivariable analyses revealed a preoperative NT-proBNP ≥ 450 pg/mL to be the strongest predictor of CME among the individual score components (p < 0.001). Adding preoperative NT-proBNP improved the predictive value of AUB-HAS2 and RCRI (modified AUB-HAS2: AUCROC 0.703, p < 0.001; modified RCRI: AUCROC 0.679, p < 0.001; both p < 0.001 vs original scores). The predictive value of the modified RCRI and AUB-HAS2 was comparable to preoperative NT-proBNP alone (p = 0.988 vs modified RCRI, p = 0.367 vs modified AUB-HAS2). CONCLUSIONS: The predictive value of postoperative morbidity varies significantly between the available simple perioperative risk scores and can be enhanced by preoperative NT-proBNP. New scores, including preoperative NT-proBNP, should be evaluated in large multicentre cohorts. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00027871.

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.

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.

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.

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.

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.

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.

Thyroid Hormone Suppresses Medulloblastoma Progression Through Promoting Terminal Differentiation of Tumor Cells.

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). A possible link between thyroid hormone (TH) signaling and MB pathogenicity has not been reported. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.

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.

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.

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.

Nucleated red blood cells are a late biomarker in predicting intensive care unit mortality in patients with COVID-19 acute respiratory distress syndrome: an observational cohort study.

Background: Nucleated 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 methods: This 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. Results: Among 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. Discussion: nRBC 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.

Characterizing emerging companies in computational drug development.

Computation promises to accelerate, de-risk and optimize drug research and development. An increasing number of companies have entered this space, specializing in the design of new algorithms, computing on proprietary data, and/or development of hardware to improve distinct drug pipeline stages. The large number of such companies and their unique strategies and deals have created a highly complex and competitive industry. We comprehensively analyze the companies in this space to highlight trends and opportunities, identifying highly occupied areas of risk and currently underrepresented niches of high value.