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The host immune response plays a critical role in the immunopathology of SARS-CoV2. Here the authors combine a systems biology approach to implicate monocytes as key drivers of cytokine storm and disturbed neutrophil activation in COVID-19 disease severity.

Abstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

An amendment to this paper has been published and can be accessed via the original article.

Background: Both global ischemia caused by circulatory arrest and extracorporeal circulation circuits have been shown to trigger cytokine release. We hypothesized that inserting a hemoadsorption device during thoraco-abdominal normothermic regional perfusion (TA-NRP) in the donation after circulatory death setting would mitigate the inflammatory response, potentially resulting in improved cardiac allograft function., Methods: In 15 pigs, circulatory arrest was induced by hypoxia. After a 15-min no-touch-period, TA-NRP was performed for 60 min. Eight pigs had a hemoadsorption device incorporated in the ECC, while seven did not. Plasma concentrations of IFN-α, IFN-γ, TNF-α, IL-1β, IL-4, IL-6, IL-8, IL-10, and IL-12p40 were assessed by ELISA at baseline, immediately at start of TA-NRP, 60 min after start of TA-NRP (just before weaning from ECC), and at 30 and 60 min after weaning from ECC. Cardiac function was assessed with pressure-volume loop analysis., Results: Hemoadsorption had no relevant effects on systemic cytokine levels post TA-NRP. IL-6 plasma levels gradually rose throughout the procedure for both groups. Hemoadsorption did not affect systolic or diastolic left ventricular function, nor were global hemodynamics improved by hemoadsorption., Conclusions: The insertion of a hemoadsorption device did not significantly affect plasma cytokine levels or cardiac function. Further research is necessary to assess the role of the inflammatory response in DCD heart transplantation and its modulation by TA-NRP., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency., Methods: We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome., Results: Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control., Conclusions: In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.)., (Copyright © 2023 Massachusetts Medical Society.)

Percutaneous ventricular assist devices (pVADs) are increasingly being used because of improved experience and availability. The Impella (Abiomed), a percutaneous microaxial, continuous-flow, short-term ventricular assist device, requires meticulous postimplantation management to avoid the 2 most frequent complications, namely, bleeding and hemolysis. A standardized approach to the prevention, detection, and treatment of these complications is mandatory to improve outcomes. The risk for hemolysis is mostly influenced by pump instability, resulting from patient- or device-related factors. Upfront echocardiographic assessment, frequent monitoring, and prompt intervention are essential. The precarious hemostatic balance during pVAD support results from the combination of a procoagulant state, due to critical illness and contact pathway activation, together with a variety of factors aggravating bleeding risk. Preventive strategies and appropriate management, adapted to the impact of the bleeding, are crucial. This review offers a guide to physicians to tackle these device-related complications in this critically ill pVAD-supported patient population., Competing Interests: Funding Support and Author Disclosures Drs Vandenbriele, Baldetti, Chieffo, Dauwe, Meyns, Panoulas, Pappalardo, Rosenberg, Scandroglio, Schaubroeck, Schrage, Stone, Vlasselaers, and Westermann have received research and/or travel funding and speaker fees from Abiomed outside this work. Drs Vandenbriele and Dauwe are supported by a grant from University Hospitals Leuven (Klinische Onderzoeks-en Opleidingsraad). Dr Beneduce has received speaker fees from Boston Scientific. Dr Chieffo has received consultant and speaker fees from Biosensor, Boston Scientific, Medtronic, Menarini, and Shockwave Medical. Dr Gorog has received speaker honoraria from AstraZeneca; and has received institutional research grants from Bayer, Medtronic, AstraZeneca, Werfen and Alpha MD. Dr Huber has received honoraria for consulting and lecturing from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Novartis, Pfizer, and Sanofi. Dr Pöss has received research funding from the German Cardiac Society, the German Foundation of Heart Research, and the Dr Rolf M. Schwiete Foundation. Dr Schrage has received speaker fees from AstraZeneca. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, and Abbott; has served as a consultant to Daiichi Sankyo, Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, Millennia Biopharma; and has equity or options in Ancora, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Stone’s daughter is an employee of IQVIA. Dr Stone’s employer, Mount Sinai Hospital, has received research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Philips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-Wave. Dr Vranckx has received personal fees from Bayer, Daiichi Sankyo, CLS Behring, Pfizer–Bristol Myers Squibb, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The ARC predictor is a prediction model for augmented renal clearance (ARC) on the next intensive care unit (ICU) day that showed good performance in a general ICU setting. In this study, we performed a retrospective external validation of the ARC predictor in critically ill coronavirus disease 19 (COVID-19) patients admitted to the ICU of the University Hospitals Leuven from February 2020 to January 2021. All patient-days that had serum creatinine levels available and measured creatinine clearance on the next ICU day were enrolled. The performance of the ARC predictor was evaluated using discrimination, calibration, and decision curves. A total of 120 patients (1064 patient-days) were included, and ARC was found in 57 (47.5%) patients, corresponding to 246 (23.1%) patient-days. The ARC predictor demonstrated good discrimination and calibration (AUROC of 0.86, calibration slope of 1.18, and calibration-in-the-large of 0.14) and a wide clinical-usefulness range. At the default classification threshold of 20% in the original study, the sensitivity and specificity were 72% and 81%, respectively. The ARC predictor is able to accurately predict ARC in critically ill COVID-19 patients. These results support the potential of the ARC predictor to optimize renally cleared drug dosages in this specific ICU population. Investigation of dosing regimen improvement was not included in this study and remains a challenge for future studies.

Background: To inform future research and practice, we aimed to investigate the outcomes of patients who received extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) due to different variants of SARS-CoV-2., Methods: This retrospective study included consecutive adult patients with laboratory-confirmed SARS-CoV-2 infection who received ECMO for ARDS in 21 experienced ECMO centres in eight European countries (Austria, Belgium, England, France, Germany, Italy, Portugal, and Spain) between Jan 1, 2020, and Sept 30, 2021. We collected data on patient characteristics, clinical status, and management before and after the initiation of ECMO. Participants were grouped according to SARS-CoV-2 variant (wild type, alpha, delta, or other) and period of the pandemic (first [Jan 1-June 30] and second [July 1-Dec 31] semesters of 2020, and first [Jan 1-June 30] and second [July 1-Sept 30] semesters of 2021). Descriptive statistics and Kaplan-Meier survival curves were used to analyse evolving characteristics, management, and patient outcomes over the first 2 years of the pandemic, and independent risk factors of mortality were determined using multivariable Cox regression models. The primary outcome was mortality 90 days after the initiation of ECMO, with follow-up to Dec 30, 2021., Findings: ECMO was initiated in 1345 patients. Patient characteristics and management were similar for the groups of patients infected with different variants, except that those with the delta variant had a younger median age and less hypertension and diabetes. 90-day mortality was 42% (569 of 1345 patients died) overall, and 43% (297/686) in patients infected with wild-type SARS-CoV-2, 39% (152/391) in those with the alpha variant, 40% (78/195) in those with the delta variant, and 58% (42/73) in patients infected with other variants (mainly beta and gamma). Mortality was 10% higher (50%) in the second semester of 2020, when the wild-type variant was still prevailing, than in other semesters (40%). Independent predictors of mortality were age, immunocompromised status, a longer time from intensive care unit admission to intubation, need for renal replacement therapy, and higher Sequential Organ Failure Assessment haemodynamic component score, partial pressure of arterial carbon dioxide, and lactate concentration before ECMO. After adjusting for these variables, mortality was significantly higher with the delta variant than with the other variants, the wild-type strain being the reference., Interpretation: Although crude mortality did not differ between variants, adjusted risk of death was highest for patients treated with ECMO infected with the delta variant of SARS-CoV-2. The higher virulence and poorer outcomes associated with the delta strain might relate to higher viral load and increased inflammatory response syndrome in infected patients, reinforcing the need for a higher rate of vaccination in the population and updated selection criteria for ECMO, should a new and highly virulent strain of SARS-CoV-2 emerge in the future. Mortality was noticeably lower than in other large, multicentre series of patients who received ECMO for COVID-19, highlighting the need to concentrate resources at experienced centres., Funding: None., Competing Interests: Declaration of interests MS reports lecture fees from Getinge, Drager, and Xenios, outside of the submitted work. AM-D reports grants from Addmedica, Baxter, Ferring, Fisher & Paykel, and Philips, and personal fees from Air Liquide, outside of the submitted work. PSc reports lecture fees from Getinge and scientific grants from the European Society of Intensive Medicine (ESICM) and the European Commission (Horizon 2020 Fast Track to Innovation; NCT04115709), and has co-organised an ARDS fellowship for the ESICM sponsored by Medtronic. BL reports fees from Abiomed, Getinge, Baxter, Novartis, Sanofi, Amomed, and Orion, outside of the submitted work. GG has received personal fees (payment for lectures) from Getinge, Draeger Medical, Biotest, GSK, Pfizer, Fisher & Paykel, and Cook Medical, and research grants from MSD and Fisher & Paykel. CG reports fees from Xenios, outside of the submitted work. JR reports lecture fees from Werfen and Gilead, and advisory fees from Medtronic, outside of the submitted work. AC reports grants from Getinge, and personal fees from Getinge, Baxter, and Xenios, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

Background: Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients., Methods: In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge., Findings: Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N  = 67 vs. SOC N  = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p  = 0.24) or mortality (intervention n  = 3 [4.6%] vs. SOC n  = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p  = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding., Conclusions: In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Although venovenous extracorporeal membrane oxygenation (VV ECMO) has been used in case of COVID-19 induced acute respiratory distress syndrome (ARDS), outcomes and criteria for its application should be evaluated., Objectives: To describe patient characteristics and outcomes in patients receiving VV ECMO due to COVID-19-induced ARDS and to assess the possible impact of COVID-19 on mortality., Design Setting and Participants: Multicenter retrospective study in 15 ICUs worldwide. All adult patients (> 18 yr) were included if they received VV ECMO with ARDS as main indication. Two groups were created: a COVID-19 cohort from March 2020 to December 2020 and a "control" non-COVID ARDS cohort from January 2018 to July 2019., Main Outcomes and Measures: Collected data consisted of patient demographics, baseline variables, ECMO characteristics, and patient outcomes. The primary outcome was 60-day mortality. Secondary outcomes included patient characteristics, COVID-19-related therapies before and during ECMO and complication rate. To assess the influence of COVID-19 on mortality, inverse probability weighted (IPW) analyses were used to correct for predefined confounding variables., Results: A total of 193 patients with COVID-19 received VV ECMO. The main indication for VV ECMO consisted of refractory hypoxemia, either isolated or combined with refractory hypercapnia. Complications with the highest occurrence rate included hemorrhage, an additional infectious event or acute kidney injury. Mortality was 35% and 45% at 28 and 60 days, respectively. Those mortality rates did not differ between the first and second waves of COVID-19 in 2020. Furthermore, 60-day mortality was equal between patients with COVID-19 and non-COVID-19-associated ARDS receiving VV ECMO (hazard ratio 60-d mortality, 1.27; 95% CI, 0.82-1.98; p = 0.30)., Conclusions and Relevance: Mortality for patients with COVID-19 who received VV ECMO was similar to that reported in other COVID-19 cohorts, although no differences were found between the first and second waves regarding mortality. In addition, after IPW, mortality was independent of the etiology of ARDS., Competing Interests: Dr. Broman is a member of the Medical Advisory Boards of Eurosets Srl., Medolla, Italy, and Xenios AG, Heilbronn, Germany. Dr. Taccone is a member of the Medical Advisory Boards of Eurosets Srl., Medolla, Italy, and Xenios AG, Heilbronn, Germany. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Ventricular suction is a common adverse event in ventricular assist device (VAD) patients and can be due to multiple underlying causes. The aim of this study is to analyze the potential of different therapeutic interventions to mitigate suction events induced by different pathophysiological conditions. To do so, a suction module was embedded in a cardiovascular hybrid (hydraulic-computational) simulator reproducing the entire cardiovascular system. An HVAD system (Medtronic) was connected between a compliant ventricular apex and a simulated aorta. Starting from a patient profile with severe dilated cardiomyopathy, four different pathophysiological conditions leading to suction were simulated: hypovolemia (blood volume: -900 ml), right ventricular failure (contractility -70%), hypotension (systemic vascular resistance: 8.3 Wood Units), and tachycardia (heart rate:185 bpm). Different therapeutic interventions such as volume infusion, ventricular contractility increase, vasoconstriction, heart rate increase, and pump speed reduction were simulated. Their effects were compared in terms of general hemodynamics and suction mitigation. Each intervention elicited a different effect on the hemodynamics for every pathophysiological condition. Pump speed reduction mitigated suction but did not ameliorate the hemodynamics. Administering volume and inducing a systemic vasoconstriction were the most efficient interventions in both improving the hemodynamics and mitigating suction. When simulating volume infusion, the cardiac powers increased, respectively, by 38%, 25%, 42%, and 43% in the case of hypovolemia, right ventricular failure, hypotension, and tachycardia. Finally, a management algorithm is proposed to identify a therapeutic intervention suited for the underlying physiologic condition causing suction., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Background: Venous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID-19). The optimal dose of anticoagulation for thromboprophylaxis in COVID-19 is unknown., Aims: To report VTE incidence and bleeding before and after implementing a hospital-wide intensified thromboprophylactic protocol in patients with COVID-19., Methods: On March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti-Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID-19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible., Results: We included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed., Conclusion: In hospitalized patients with COVID-19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight-adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Purpose: Rotating hinge prostheses for total knee arthroplasty (TKA) are mostly used in revision setting; however, evidence on the use of these constrained devices in primary setting is scarce and inconsistent. Therefore, we aimed to evaluate the functional outcomes after third-generation rotating hinge implants in primary TKA with a minimal follow-up of two years in a large dual-centre observational retrospective clinical trial., Methods: The hospital databases of two centres were searched for primary rotating hinge arthroplasty from January 2007 to January 2015. A minimum follow-up of at least two years was assured. Patients meeting the inclusion criteria were asked to fill out two self-reported functional scores, the Oxford Knee Score (OKS) and Forgotten Joint Score (FJS), to measure the functional status of the knee., Results: In total, 267 primary rotating hinge knee arthroplasties in 242 patients were performed in two centres. The three major indications were axial malalignment (valgus/varus > 15°), 87/267 (33%), persistent ligamentous instability (28%) and neuromuscular disorders (12%). 184 patients with 202 primary rotating hinge knee arthroplasties could be included that provided data of the self-reported outcome measures (OKS and FJS). A mean OKS score of 37.71 (± 9.23) and a mean FJS score of 63.65 (± 31.01) could be obtained., Conclusion: This large clinical study suggests that constrained devices provide the best results when treating bone-on-bone tricompartimental osteoarthritis of the knee with severe axial deviation (valgus/varus > 15°) and/or persistent ligamentous instability., (© 2021. SICOT aisbl.)

Rotating-hinge knee implants are fully constrained knee prostheses commonly used for revision total knee arthroplasty. Nevertheless, rotating-hinge devices have been increasingly utilized in primary setting. Complications are inevitable in orthopedic surgery, however, implant breakage after RHK arthroplasty has been rarely described in medical literature. We present a rare case of 70-year-old Caucasian, male patient who suffered an atraumatic femoral stem breakage in a primary NexGen ® Rotating Hinge Knee (Zimmer-Biomet ® , Warsaw, IN, USA).

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8 + resident-memory (T RM ) and CD4 + T-helper-17 (T H17 ) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4 + T-cells with T-helper-1 characteristics (T H1 -like) and CD8 + T-cells expressing exhaustion markers (T EX -like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.

Background: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19., Methods: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement., Discussion: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome., Trial Registration: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Background: Blood outgrowth endothelial cells (BOECs) mediate therapeutic neovascularization in experimental models, but outgrowth characteristics and functionality of BOECs from patients with ischemic cardiomyopathy (ICMP) are unknown. We compared outgrowth efficiency and in vitro and in vivo functionality of BOECs derived from ICMP with BOECs from age-matched (ACON) and healthy young (CON) controls., Methods and Results: We isolated 3.6±0.6 BOEC colonies/100×10(6) mononuclear cells (MNCs) from 60-mL blood samples of ICMP patients (n=45; age: 66±1 years; LVEF: 31±2%) versus 3.5±0.9 colonies/100×10(6) MNCs in ACON (n=32; age: 60±1 years) and 2.6±0.4 colonies/100×10(6) MNCs in CON (n=55; age: 34±1 years), P=0.29. Endothelial lineage (VEGFR2(+)/CD31(+)/CD146(+)) and progenitor (CD34(+)/CD133(-)) marker expression was comparable in ICMP and CON. Growth kinetics were similar between groups (P=0.38) and not affected by left ventricular systolic dysfunction, maladaptive remodeling, or presence of cardiovascular risk factors in ICMP patients. In vitro neovascularization potential, assessed by network remodeling on Matrigel and three-dimensional spheroid sprouting, did not differ in ICMP from (A)CON. Secretome analysis showed a marked proangiogenic profile, with highest release of angiopoietin-2 (1.4±0.3×10(5) pg/10(6) ICMP-BOECs) and placental growth factor (5.8±1.5×10(3) pg/10(6) ICMP BOECs), independent of age or ischemic disease. Senescence-associated β-galactosidase staining showed comparable senescence in BOECs from ICMP (5.8±2.1%; n=17), ACON (3.9±1.1%; n=7), and CON (9.0±2.8%; n=13), P=0.19. High-resolution microcomputed tomography analysis in the ischemic hindlimb of nude mice confirmed increased arteriogenesis in the thigh region after intramuscular injections of BOECs from ICMP (P=0.025; n=8) and CON (P=0.048; n=5) over vehicle control (n=8), both to a similar extent (P=0.831)., Conclusions: BOECs can be successfully culture-expanded from patients with ICMP. In contrast to impaired functionality of ICMP-derived bone marrow MNCs, BOECs retain a robust proangiogenic profile, both in vitro and in vivo, with therapeutic potential for targeting ischemic disease., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: To date, few PET tracers for in vivo labeling of red blood cells (RBCs) are available. In this study, we report the radiosynthesis and in vitro and in vivo evaluation of 11C and 18F sulfonamide derivatives targeting carbonic anhydrase II (CA II), a metallo-enzyme expressed in RBCs, as potential blood pool tracers. A proof-of-concept in vivo imaging study was performed to demonstrate the feasibility to assess cardiac function and volumes using electrocardiogram (ECG)-gated positron emission tomography (PET) acquisition in comparison with cine magnetic resonance imaging (cMRI) in rats and a pig model of myocardial infarction., Methods: The inhibition constants (Ki) of CA II were determined in vitro for the different compounds by assaying CA-catalyzed CO2 hydration activity. Binding to human RBCs was estimated after in vitro incubation of the compounds with whole blood. Biodistribution studies were performed to evaluate tracer kinetics in NMRI mice. ECG-gated PET acquisition was performed in Wistar rats at rest and during pharmacological stress by infusing dobutamine at 10 μg/kg/min and in a pig model of myocardial infarction. Left ventricular ejection fraction (LVEF) and volumes were compared with values from cMRI., Results: The Ki of the investigated compounds for human CA II was found to be in the range of 8 to 422 nM. The fraction of radioactivity associated with RBCs was found to be ≥90% at 10- and 60-min incubation of tracers with heparinized human blood at room temperature for all tracers studied. Biodistribution studies in mice indicated that 30% to 67% of the injected dose was retained in the blood pool at 60 min post injection. A rapid and sustained tracer uptake in the heart region with an average standardized uptake value of 2.5 was observed from micro-PET images. The LVEF values obtained after pharmacological stress in rats closely matched between the cMRI and micro-PET values, whereas at rest, a larger variation between LVEF values obtained by both techniques was observed. In the pig model, a good agreement was observed between PET and MRI for quantification of left ventricular volumes and ejection fraction., Conclusions: The 11C and 18F sulfonamide derivatives can be used for efficient in vivo radiolabeling of RBCs, and proof-of-concept in vivo imaging studies have shown the feasibility and potential of these novel tracers to assess cardiac function.

Despite state-of-the-art therapy, clinical outcome remains poor in myocardial infarction (MI) patients with reduced left ventricular (LV) function. Stem cell-mediated repair of the damaged heart is a promising new development in cardiovascular medicine. Embryonic stem cells and adult progenitor cells have been extensively studied for their capacity to improve LV function recovery in preclinical MI models but underlying mechanisms remain incompletely understood. Recent placebo-controlled, randomized bone marrow cell transfer trials in MI patients have shown mixed results with cell-mediated effects on global or regional LV function recovery of variable magnitude and duration. There is now growing consensus that the observed effects of bone marrow-(BM)-derived progenitor cell transfer, as applied in post-MI patients thus far, occur independently of cardiomyocyte formation. Subgroup and meta-analysis of currently available randomized and observational pilot trials have highlighted limitations of current cell-based cardiac repair and provided suggestions for future focused clinical trial design. However, the two most recently reported randomized clinical trials failed to confirm a significant biological effect. A better understanding of underlying molecular mechanisms and modalities of cell-based repair is therefore mandatory to facilitate translation of innovative cell-mediated therapies for functional recovery after MI in the years to come. Rapidly growing insights in the biology of cardiac resident cells and technological advances in generation of patient-specific induced pluripotent stem cells may hold great promise to accomplish cardio-myogenesis and directly restore contractile force generation capacity.

KB130015 [KB; 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran] is a novel amiodarone derivative designed to retain the antiarrhythmic effects without the side effects. Unlike amiodarone, KB slows Na(+) current inactivation and could, via an increase in [Na(+)](i), potentially lead to Ca(2+) overload. Therefore, we studied the effects of KB on Na(+) and Ca(2+) handling in single pig ventricular myocytes using the whole-cell ruptured patch-clamp technique and K(5)fluo-3 as [Ca(2+)](i) indicator. KB at 10 microM did not prolong action potential duration but slightly increased the early plateau; spontaneous afterdepolarizations were not observed. The amplitude of the [Ca(2+)](i) transient was larger (434.9 +/- 37.2 versus 326.8 +/- 39.8 nM at baseline, n = 13, P < 0.05), and the time to peak [Ca(2+)](i) was prolonged. During voltage-clamp pulses, [Ca(2+)](i) transient peak was also larger (578.1 +/- 98.9 versus 346.4 +/- 52.6 nM at baseline, P < 0.05). Although L-type Ca(2+) current was reduced (by 21.9% at +10 mV, n = 9, P < 0.05), sarcoplasmic reticulum Ca(2+) content was significantly enhanced with KB. Forward Na(+)/Ca(2+) exchange was significantly decreased after KB application, but reverse mode of the Na(+)/Ca(2+) exchanger was significantly larger, suggesting an increase in [Na(+)](i) with KB. This was confirmed by a 2-fold increase of the [Na(+)]-dependent current generated by the Na/K-ATPase (from 0.17 +/- 0.02 to 0.38 +/- 0.06 pA/pF, P < 0.05). In conclusion, as predicted from the slowing of I(Na) inactivation, KB130015 leads to an increase in [Na(+)](i) and consequently in cellular Ca(2+) load. This effect is partially offset by a decrease in I(CaL) resulting in a mild inotropic effect without the signs of Ca(2+) overload and related arrhythmias usually associated with Na(+) channel openers.

In order to evaluate diagnostic and therapeutic wrist arthroscopy we analyzed 129 arthroscopies with a follow-up of at least 6 months. Seventy-seven arthroscopies were performed for therapeutic purposes; 52 arthroscopies were diagnostic. There were diagnostic benefits in 55 arthroscopies (42.5%), therapeutic benefits in 29 arthroscopies (22.5%), combined diagnostic and therapeutic benefits in 39 (30%) and no benefits in six (5%). In 65 cases of the therapeutic group (with preoperative diagnosis) the authors found that the arthroscopy had been worthwhile. For the diagnostic group without a preoperative diagnosis, an arthroscopic diagnosis was made in 44 cases. Complications occurred in two patients: one tendon incision over a Kirschner wire in the therapeutic group and one superficial infection in the diagnostic group.

The arthroscopic treatments (suture, debridement and "wafer" resection of the distal ulna) performed for TFCC lesions in 42 patients were retrospectively reviewed. Overall results were disappointing, with a better outcome for isolated lesions, for sutured TFCC's and degenerative lesions.

51 wrists of 30 embalmed cadavers have been used to perform an anatomical and radiological study relating cartilaginous and ligamentous lesions of the wrist with sex, age, ulnar variance (UV) and the state of the triangular fibrocartilage complex (TFCC) in an elderly population (mean 76.6 years). Two-thirds of all wrists (66%) showed cartilaginous lesions, mainly on the lunate (22, or 44%). The TFCC was perforated in 23 wrists (46%), and most were central degenerative perforations. Correlations were found between ulnar variance and TFCC thickness (P < 0.05) and ulnar variance and TFCC perforations (P < 0.05). A significant relation was observed between age and proximal row intercarpal ligamentous ruptures (P < 0.05) and between age and ulnar variance (P < 0.05). No statistical correlation was seen between ulnar variance and cartilaginous lesions on the lunate (P < 0.05) in this slightly ulnar negative population (mean-0.37 mm).

Two cases of closed ruptures of the flexor carpi radialis which resulted from attrition of the tendon caused by bony spurs secondary to Scapho Trapezo Trapezoidal (STT) osteoarthritis are described. Treatment is conservative.

A developing extra-uterine intra-abdominal gestation is very rare. In the literature the incidence varies from 1 : 6389 to 1 : 10,200. Our case concerns an abdominal ectopic twin gestation, exclusively in relation with the peritoneal surface, which developed normally until 13 weeks and then died.