Modes of p53 regulation.

The traditional view of p53 activation includes three steps-p53 stabilization, DNA binding, and transcriptional activation. However, recent studies indicate that each step of p53 activation is more complex than originally anticipated. Moreover, both genetic studies in mice and in vitro studies with purified components suggest that the classical model may not be sufficient to explain all aspects of p53 activation in vivo. To reconcile these differences, we propose that antirepression, the release of p53 from repression by factors such as Mdm2 and MdmX, is a key step in the physiological activation of p53.

Association of hyperfibrinolysis with poor prognosis in refractory circulatory arrest: implications for extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Identifying candidates for extracorporeal cardiopulmonary resuscitation (eCPR) is challenging, and novel predictive markers are urgently needed. Hyperfibrinolysis is linked to tissue hypoxia and is associated with poor outcomes in out-of-hospital cardiac arrest (OHCA). Rotational thromboelastometry (ROTEM) can detect or rule out hyperfibrinolysis, and could, therefore, provide decision support for initiation of eCPR. We explored early detection of hyperfibrinolysis in patients with refractory OHCA referred for eCPR. METHODS: We analysed ROTEM results and resuscitation parameters of 57 adult patients with ongoing OHCA who presented to our ICU for eCPR evaluation. RESULTS: Hyperfibrinolysis, defined as maximum lysis ≥15%, was present in 36 patients (63%) and was associated with higher serum lactate, lower arterial blood pH, and increased low-flow intervals. Of 42 patients who achieved return of circulation, 28 had a poor 30-day outcome. The incidence of hyperfibrinolysis was higher in the poor outcome group compared with patients with good outcomes (75% [21 of 28] vs 7.1% [1 of 14]; P<0.001). The ratio of EXTEM A5 to lactate concentration showed good predictive value in detecting hyperfibrinolysis (AUC of 0.89 [95% confidence interval 0.8-1]). CONCLUSIONS: Hyperfibrinolysis was common in patients with refractory cardiac arrest, and was associated with poor prognosis. The combination of high lactate with early clot firmness values, such as EXTEM A5, appears promising for early detection of hyperfibrinolysis. This finding could facilitate decisions to perform eCPR, particularly for patients with prolonged low-flow duration but lacking hyperfibrinolysis.

Interdisciplinary perspectives on computed tomography in sepsis: survey among medical doctors at a large university medical center.

OBJECTIVES: This study aims to describe physicians' perspectives on the use of computed tomography (CT) in patients with sepsis. METHODS: In January 2022, physicians of a large European university medical center were surveyed using a web-based questionnaire asking about their views on the role of CT in sepsis. A total of 371 questionnaires met the inclusion criteria and were analyzed using work experience, workplace, and medical specialty of physicians as variables. Chi-square tests were performed. RESULTS: Physicians considered the ability to detect an unknown focus as the greatest benefit of CT scans in sepsis (70.9%, n = 263/371). Two clinical criteria - "signs of decreased vigilance" (89.2%, n = 331/371) and "increased catecholamine demand" (84.7%, n = 314/371) - were considered highly relevant for a CT request. Elevated procalcitonin (82.7%, n = 307/371) and lactate levels (83.6%, n = 310/371) were consistently found to be critical laboratory values to request a CT. As long as there is evidence of infection in one organ region, most physicians (42.6%, n = 158/371) would order a CT scan based on clinical assessment. Combined examination of the chest, abdomen, and pelvis was favored (34.8%, n = 129/371) in cases without clinical clues of an infection source. A time window of ≥ 1-6 h was preferred for both CT examinations (53.9%, n = 200/371) and CT-guided interventions (59.3%, n = 220/371) in patients with sepsis. CONCLUSION: Despite much consensus, there are significant differences in attitudes towards the use of CT in septic patients among physicians from different workplaces and medical specialties. Knowledge of these perspectives may improve patient management and interprofessional communication. KEY POINTS: Despite interdisciplinary consensus on the use of CT in sepsis, statistically significant differences in the responses are apparent among physicians from different workplaces and medical specialties. The detection of a previously unknown source of infection and the ability to plan interventions and/or surgery based on CT findings are considered key advantages of CT in septic patients. Timing of CT reflects the requirements of specific disciplines.

Multimodal Analysis of Light-Driven Water Oxidation in Nanoporous Block Copolymer Membranes.

Heterogeneous light-driven catalysis is a cornerstone of sustainable energy conversion. Most catalytic studies focus on bulk analyses of the hydrogen and oxygen evolved, which impede the correlation of matrix heterogeneities, molecular features, and bulk reactivity. Here, we report studies of a heterogenized catalyst/photosensitizer system using a polyoxometalate water oxidation catalyst and a model, molecular photosensitizer that were co-immobilized within a nanoporous block copolymer membrane. Via operando scanning electrochemical microscopy (SECM), light-induced oxygen evolution was determined using sodium peroxodisulfate (Na2 S2 O8 ) as sacrificial electron acceptor. Ex situ element analyses provided spatially resolved information on the local concentration and distribution of the molecular components. Infrared attenuated total reflection (IR-ATR) studies of the modified membranes showed no degradation of the water oxidation catalyst under the reported light-driven conditions.

Patients with Severe Lactic Acidosis in the Intensive Care Unit: A Retrospective Study of Contributing Factors and Impact of Renal Replacement Therapy.

INTRODUCTION: Hyperlactatemia is a regular condition in the intensive care unit, which is often associated with adverse outcomes. Control of the triggering condition is the most effective treatment of hyperlactatemia, but since this is mostly not readily possible, extracorporeal renal replacement therapy (RRT) is often tried as a last resort. The present study aims to evaluate the factors that may contribute to the decision whether to start RRT or not and the potential impact of the start of RRT on the outcome in patients with severe lactic acidosis (SLA) (lactate ≥5 mmol/L). MATERIALS AND METHODS: We conducted a retrospective single-center cohort analysis over a 3-year period including all patients with a lactate level ≥5 mmol/L. Patients were considered as treated with RRT because of SLA if RRT was started within 24 h after reaching a lactate level ≥5 mmol/L. RESULTS: Overall, 90-day mortality in patients with SLA was 34.5%. Of the 1,203 patients who matched inclusion/exclusion criteria, 11% (n = 133) were dialyzed within 24 h. The propensity to receive RRT was related to the lactate level and to the SOFA renal and cardio score. The most frequently used modality was continuous RRT. Patients who were started on RRT versus those who did not have 2.3 higher odds of mortality, even after adjustment for the propensity to start RRT. CONCLUSIONS: Our analysis confirms the high mortality rate of patients with SLA. It adds that odds for mortality is even higher in patients who were started on RRT versus not. We suggest keeping an open mind to the factors that may influence the decision to start dialysis and bear in mind that without being a bridge to correction of the underlying condition, dialysis is unlikely to affect the outcome.

A Molecular Photosensitizer in a Porous Block Copolymer Matrix-Implications for the Design of Photocatalytically Active Membranes.

Recently, porous photocatalytically active block copolymer membranes were introduced, based on heterogenized molecular catalysts. Here, we report the integration of the photosensitizer, i. e., the light absorbing unit in an intermolecular photocatalytic system into block copolymer membranes in a covalent manner. We study the resulting structure and evaluate the orientational mobility of the photosensitizer as integral part of the photocatalytic system in such membranes. To this end we utilize transient absorption anisotropy, highlighting the temporal reorientation of the transition dipole moment probed in a femtosecond pump-probe experiment. Our findings indicate that the photosensitizer is rigidly bound to the polymer membrane and shows a large heterogeneity of absolute anisotropy values as a function of location probed within the matrix. This reflects the sample inhomogeneity arising from different protonation states of the photosensitizer and different intermolecular interactions of the photosensitizers within the block copolymer membrane scaffold.

Cardiac arrhythmias in patients with COVID-19: Lessons from 2300 telemetric monitoring days on the intensive care unit.

BACKGROUND: Patients with COVID-19 seem to be prone to the development of arrhythmias. The objective of this trial was to determine the characteristics, clinical significance and therapeutic consequences of these arrhythmias in COVID-19 patients requiring intensive care unit (ICU) treatment. METHODS AND RESULTS: A total of 113 consecutive patients (mean age 64.1 ± 14.3 years, 30 (26.5%) female) with positive PCR testing for SARS-CoV2 as well as radiographically confirmed pulmonary involvement admitted to the ICU from March to May 2020 were included and observed for a cumulative time of 2321 days. Fifty episodes of sustained atrial tachycardias, five episodes of sustained ventricular arrhythmias and thirty bradycardic events were documented. Sustained new onset atrial arrhythmias were associated with hemodynamic deterioration in 13 cases (35.1%). Patients with new onset atrial arrhythmias were older, showed higher levels of Hs-Troponin and NT-proBNP, and a more severe course of disease. The 5 ventricular arrhythmias (two ventricular tachycardias, two episodes of ventricular fibrillation, and one torsade de pointes tachycardia) were observed in 4 patients. All episodes could be terminated by immediate defibrillation/cardioversion. Five bradycardic events were associated with hemodynamic deterioration. Precipitating factors could be identified in 19 of 30 episodes (63.3%), no patient required cardiac pacing. Baseline characteristics were not significantly different between patients with or without bradycardic events. CONCLUSION: Relevant arrhythmias are common in severely ill ICU patients with COVID-19. They are associated with worse courses of disease and require specific treatment. This makes daily close monitoring of telemetric data mandatory in this patient group.

Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis.

BACKGROUND: There is emerging evidence for enhanced blood coagulation in coronavirus 2019 (COVID-19) patients, with thromboembolic complications contributing to morbidity and mortality. The mechanisms underlying this prothrombotic state remain enigmatic. Further data to guide anticoagulation strategies are urgently required. METHODS: We used viscoelastic rotational thromboelastometry (ROTEM) in a single-center cohort of 40 critically ill COVID-19 patients. RESULTS: Clear signs of a hypercoagulable state due to severe hypofibrinolysis were found. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction. CONCLUSIONS: The study identifies a reduction in fibrinolysis as an important mechanism in COVID-19-associated coagulopathy. The combination of ROTEM and D-dimer concentrations may prove valuable in identifying patients requiring higher intensity anticoagulation.

Different Routes to Ampholytic Polydehydroalanine: Orthogonal versus Simultaneous Deprotection.

Polydehydroalanine (PDha) is a polyampholyte featuring both a -NH2 and a -COOH in every repeat unit and with that presents a rather high charge density. The synthesis and polymerization of two monomers, benzyl 2-tert-butoxycarbonylaminoacrylate and methyl 2-benzyloxycarbonylaminoacrylate is herein reported, which feature different protective groups and, after polymerization, the resulting PtBABA and PBOMA can be transformed into PDha using polymer-analogous modification reactions. More important, the current choice of protective groups allows either simultaneous deprotection in one step in both cases, but also the orthogonal deprotection of either -NH2 or -COOH moiety for PtBABA, given that appropriate conditions are chosen. The polymers are prepared using free radical polymerization and all (intermediate) polymeric materials are investigated using a combination of NMR spectroscopy and size exclusion chromatography.

Isoflurane Sedation on the ICU in Cardiac Arrest Patients Treated With Targeted Temperature Management: An Observational Propensity-Matched Study.

OBJECTIVE: Targeted temperature management after cardiac arrest requires deep sedation to prevent shivering and discomfort. Compared to IV sedation, volatile sedation has a shorter half-life and thus may allow more rapid extubation and neurologic assessment. DESIGN: Observational analysis of clinical data. SETTING: University hospital, medical ICU. PATIENTS: Four hundred thirty-two cardiac arrest survivors underwent targeted temperature management; of those, 110 were treated with volatile sedation using an anesthetic conserving device and isoflurane, and 322 received standard IV sedation. INTERVENTION: No intervention. MEASUREMENT AND MAIN RESULTS: A matched pairs analysis revealed that time on ventilator (difference of median, 98.5 hr; p = 0.003) and length of ICU stay (difference of median, 4.5 d; p = 0.006) were significantly shorter in patients sedated with isoflurane when compared with IV sedation although no differences in neurologic outcome (45% of patients with cerebral performance category 1-2 in both groups) were observed. Significant hypercapnia occurred more frequently during anesthetic conserving device use (6.4% vs 0%; p = 0.021). CONCLUSIONS: Volatile sedation is feasible in cardiac arrest survivors. Prospective controlled studies are necessary to confirm the beneficial effects on duration of ventilation and length of ICU stay observed in our study. Our data argue against a major effect on neurologic outcome. Close monitoring of PaCO2 is necessary during sedation via anesthetic conserving device.

Simplified lung ultrasound protocol shows excellent prediction of extravascular lung water in ventilated intensive care patients.

INTRODUCTION: Ultrasound of the lung and quantification of B lines was recently introduced as a novel tool to detect overhydration. In the present study, we aimed to evaluate a four-region protocol of lung ultrasound to determine the pulmonary fluid status in ventilated patients in the intensive care unit. METHODS: Fifty patients underwent both lung ultrasound and transpulmonary thermodilution measurement with the PiCCO system. An ultrasound score based on number of single and confluent B lines per intercostal space was used to quantify pulmonary overhydration. To check for reproducibility, two different intensivists who were blinded as to the ultrasound pictures reassessed and classified them using the same scoring system. The results were compared with those obtained using other methods of evaluating hydration status, including extravascular lung water index (EVLWI) and intrathoracic blood volume index calculated with data from transpulmonary thermodilution measurements. Moreover, chest radiographs were assessed regarding signs of pulmonary overhydration and categorized based on a numeric rating scale. RESULTS: Lung water assessment by ultrasound using a simplified protocol showed excellent correlation with EVLWI over a broad range of lung hydration grades and ventilator settings. Correlation of chest radiography and EVLWI was less accurate. No correlation whatsoever was found with central venous pressure measurement. CONCLUSION: Lung ultrasound is a useful, non-invasive tool in predicting hydration status in mechanically ventilated patients. The four-region protocol that we used is time-saving, correlates well with transpulmonary thermodilution measurements and performs markedly better than chest radiography.

Negative regulation of the deacetylase SIRT1 by DBC1.

SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1alpha directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.

Sarcoma Patients Admitted to the Intensive Care Unit (ICU): Predictive Relevance of Common Sepsis and Performance Parameters.

Purpose: Prognosis of sarcoma patients is improving, with a better understanding of sarcomagenesis revealing novel therapeutic targets. However, aggressive chemotherapy remains an essential part of treatment, bearing the risk of severe side effects that require intensive medical treatment. Available data on the characteristics and clinical outcome of sarcoma patients admitted to intensive care units (ICU) are sparse. Patients and Methods: We performed a retrospective analysis of sarcoma patients admitted to the ICU from 2005 to 2022. Patients ≥18 years with histologically proven sarcoma were included in our study. Results: Sixty-six patients were eligible for analysis. The following characteristics had significant impact on overall survival: sex (p=0.046), tumour localization (p=0.02), therapeutic intention (p=0.02), line of chemotherapy (p<0.001), SAPS II score (p=0.03) and SOFA score (p=0.02). Conclusion: Our study confirms the predictive relevance of established sepsis and performance scores in sarcoma patients. For overall survival, common clinical characteristics are also of significant value. Further investigation is needed to optimize ICU treatment of sarcoma patients.

Hepatobiliary long-term consequences of COVID-19: dramatically increased rate of secondary sclerosing cholangitis in critically ill COVID-19 patients.

BACKGROUND: Increasing evidence suggests that secondary sclerosing cholangitis (SSC), which can lead to cirrhosis or liver failure, may be a hepatobiliary long-term complication of COVID-19. The aim of this study was to estimate the frequency and outcome of this COVID-19 sequela and to identify possible risk factors. METHODS: This observational study, conducted at University Hospital Charité Berlin and Unfallkrankenhaus Berlin, Germany, involved hospitalized patients with COVID-19 pneumonia, including 1082 ventilated COVID-19 patients. We compared COVID-19 patients who developed SSC with a COVID-19 control group by univariate and multivariate analyses. RESULTS: SSC occurrence after COVID-19 was observed exclusively in critically ill patients with invasive ventilation, albeit with extreme clustering among them. One in every 43 invasively ventilated COVID-19 patients developed this complication. Risk factors preceding the development of secondary sclerosing cholangitis in critically ill COVID-19 patients (SSC-CIP) were signs of systemic reduced blood oxygen supply (e.g., low PaO2/FiO2, ischemic organ infarctions), multi-organ failure (high SOFA score) at admission, high fibrinogen levels and intravenous ketamine use. Multivariate analysis confirmed fibrinogen and increased plasma lactate dehydrogenase as independent risk factors associated with cholangiopathy onset. The 1-year transplant-free survival rate of COVID-19-associated SSC-CIP was 40%. CONCLUSIONS: COVID-19 causes SSC-CIP in a substantial proportion of critically ill patients. SSC-CIP most likely develops due to severe tissue hypoxia and fibrinogen-associated circulatory disturbances. A significant increase of patients with SSC-CIP is to be expected in the post-COVID era.

Subjective concepts of chronically ill patients using distant healing.

Distant healing procedures consist of benevolent intentions, often taking the form of prayers for a patient. Despite inconclusive evidence regarding distant healing, prayers are a widespread health-related technique. We studied subjective concepts of distant healing in 17 patients suffering from chronic fatigue syndrome and multiple chemical sensitivity who were given distant healing during a randomized controlled trial. We applied reconstructive interview analysis when analyzing the results. The overall theme was the tension between mainstream medicine and the immaterial healing procedure. Several components highlighted this tension: (a) patterns of legitimizing the use of distant healing, (b) distant healing and the social setting, (c) integrating distant healing into their belief system, and (d) reconstruction of effects by means of hindsight. The interviews showed that patients felt the need to legitimize having tried distant healing. They had to bear the full ambiguity of biomedicine being in competition with distant healing, though also experiencing distant healing as giving support.

How Can Science and Research Work Well? Toward a Critique of New Public Management Practices in Academia From a Socio-Philosophical Perspective.

While New Public Management practices (NPM) have been adopted in academia and higher education over the past two decades, this paper is investigating their role in a specifically socio-philosophical way: The preeminent question is what organization of science is likely to make science and research work well in the context of a complex society. The starting point is an obvious intuition: that academia would be "economized" by NPM (basically, that something is coming from the outside and is disturbing the inside). Habermas provides a sophisticated theorization for this intuition. In contrast, the thesis advanced here is that we should consider NPM potentially problematic-but not for descending from economics or administration outside academia. It is because NPM often cannot help research and science to function well. In this (rather "essayistic" than strictly deductive) consideration, I will therefore tentatively discuss an alternative approach that takes up critical intuitions while transposing them into a different setting. If we understand science and research as a form of life, a different picture emerges that can still bring immanent standards to bear, but at the same time compose them more broadly. This outlines a socio-philosophical critique of NPM. Accordingly, the decisive factor is not NPM's provenance. What is decisive is that it addresses some organizational problems while at the same time creating new ones. At the end, an outlook is sketched on how the specific situation of NPM allows some hypotheses on academy's [by "academy", I am referring to the whole research community (like "academia")] future organization. Ex negativo, it seems likely that qualitative evaluation criteria and creative freedom will have to play a greater role.

Efficacy and complications of regional citrate anticoagulation during continuous renal replacement therapy in critically ill patients with COVID-19.

BACKGROUND: We compared filter survival and citrate-induced complications during continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA) in COVID-19 and Non-COVID-19 patients. METHODS: In this retrospective study we included all consecutive adult patients (n = 97) treated with RCA-CRRT. Efficacy and complications of RCA-CRRT were compared between COVID-19 and Non-COVID-19 patients. RESULTS: Mean filter run-time was significantly higher in COVID-19 patients compared to Non-COVID-19 patients (68.4 (95%CI 67.0-69.9) vs. 65.2 (95%CI 63.2-67.2) hours, respectively; log-rank 0.014). COVID-19 patients showed significantly higher activated partial thromboplastin time (aPTT) throughout the CRRT due to intensified systemic anticoagulation compared to Non-COVID-19 patients (54 (IQR 45-61) vs. 47 (IQR 41-58) seconds, respectively; p < 0.001). A significantly higher incidence of metabolic alkalosis, hypercalcemia and hypernatremia, consistent with reduced filter patency and citrate overload, was observed in COVID-19 patients compared to Non-COVID-19 patients (19.1% vs. 12.7%, respectively; p = 0.04). These metabolic disarrangements were resistant to per-protocol adjustments and disappeared after replacement of the CRRT-filter. CONCLUSIONS: RCA-CRRT in COVID-19 patients with intensified systemic anticoagulation provides an adequate filter lifespan. However, close monitoring of the acid-base balance appears warranted, as these patients tend to develop reduced filter patency leading to a higher incidence of citrate overload and metabolic disturbances. TRIAL REGISTRATION (LOCAL AUTHORITY): EA1/285/20 (Ethikkommission der Charité - Universitätsmedizin Berlin); date of registration 08.10.2020.

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity.

Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4+ T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.

One-year follow-up of the CAPSID randomized trial for high-dose convalescent plasma in severe COVID-19 patients.

BACKGROUNDResults of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODSOf 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTSThe median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSIONThe trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registrationEudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health).