Ketone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection.

Severe COVID-19 is characterized by profound CD8+ T-cell dysfunction, which cannot be specifically treated to date. We here investigate whether metabolic CD8+ T-cell reprogramming by ketone bodies could be a promising strategy to overcome the immunoparalysis in COVID-19 patients. This approach was triggered by our recent pioneering study, which has provided evidence that CD8+ T-cell capacity in healthy subjects could be significantly empowered by a Ketogenic Diet. These improvements were achieved by immunometabolic rewiring toward oxidative phosphorylation. We here report similar strengthening of CD8+ T cells obtained from severely diseased COVID-19 patients: Flow cytometry and ELISA revealed elevated cytokine expression and secretion (up to + 24%) upon ketone treatment and enhanced cell lysis capacity (+ 21%). Metabolic analyses using Seahorse technology revealed upregulated mitochondrial respiratory chain activity (+ 25%), enabling both superior energy supply (+ 44%) and higher mitochondrial reactive oxygen species signaling. These beneficial effects of ketones might represent evolutionary conserved mechanisms to strengthen human immunity. Our findings pave the road for metabolic treatment studies in COVID-19.

Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate to severe ARDS in a randomized, placebo-controlled, double-blind trial: preliminary evaluation of safety and feasibility in light of the COVID-19 pandemic.

BACKGROUND: In May 2018, the first patient was enrolled in the phase-IIb clinical trial "Safety and Preliminary Efficacy of Sequential Multiple Ascending Doses of Solnatide to Treat Pulmonary Permeability Edema in Patients with Moderate to Severe ARDS." With the onset of the COVID-19 pandemic in early 2020, the continuation and successful execution of this clinical study was in danger. Therefore, before the Data Safety Monitoring Board (DSMB) allowed proceeding with the study and enrollment of further COVID-19 ARDS patients into it, additional assessment on possible study bias was considered mandatory. METHODS: We conducted an ad hoc interim analysis of 16 patients (5 COVID-19- ARDS patients and 11 with ARDS from different causes) from the phase-IIB clinical trial. We assessed possible differences in clinical characteristics of the ARDS patients and the impact of the pandemic on study execution. RESULTS: COVID-19 patients seemed to be less sick at baseline, which also showed in higher survival rates over the 28-day observation period. Trial specific outcomes regarding pulmonary edema and ventilation parameters did not differ between the groups, nor did more general indicators of (pulmonary) sepsis like oxygenation ratio and required noradrenaline doses. CONCLUSION: The DSMB and the investigators did not find any evidence that patients suffering from ARDS due to SARS-CoV-2 may be at higher (or generally altered) risk when included in the trial, nor were there indications that those patients might influence the integrity of the study data altogether. For this reason, a continuation of the phase IIB clinical study activities can be justified. Researchers continuing clinical trials during the pandemic should always be aware that the exceptional circumstances may alter study results and therefore adaptations of the study design might be necessary.

Early Use of Methylene Blue in Vasoplegic Syndrome: A 10-Year Propensity Score-Matched Cohort Study.

BACKGROUND: Vasoplegic syndrome is associated with increased morbidity and mortality in patients undergoing cardiac surgery. This retrospective, single-center study aimed to evaluate the effect of early use of methylene blue (MB) on hemodynamics after an intraoperative diagnosis of vasoplegic syndrome (VS). METHODS: Over a 10-year period, all patients diagnosed with intraoperative VS (hypotension despite treatment with norepinephrine ≥0.3 µg/kg/min and vasopressin ≥1 IE/h) while undergoing heart surgery and cardiopulmonary bypass were identified, and their data were examined. The intervention group received MB (2 mg/kg intravenous) within 15 min after the diagnosis of vasoplegia, while the control group received standard therapy. The two groups were matched using propensity scores. RESULTS: Of the 1022 patients identified with VS, 221 received MB intraoperatively, and among them, 60 patients received MB within 15 min after the diagnosis of VS. After early MB application, mean arterial pressure was significantly higher, and vasopressor support was significantly lower within the first hour (p = 0.015) after the diagnosis of vasoplegia, resulting in a lower cumulative amount of norepinephrine (p = 0.018) and vasopressin (p = 0.003). The intraoperative need of fresh frozen plasma in the intervention group was lower compared to the control group (p = 0.015). Additionally, the intervention group had higher creatinine values in the first three postoperative days (p = 0.036) without changes in dialysis incidence. The 90-day survival did not differ significantly (p = 0.270). CONCLUSION: Our results indicate the additive effects of MB use during VS compared to standard vasopressor therapy only. Early MB administration for VS may significantly improve the patients' hemodynamics with minor side effects.

Impairment of Cognitive Function in Different Domains Early After Lung Transplantation.

In this prospective observational pilot study patients with the diagnosis of end-stage lung disease and listed for lung transplantation underwent a cognitive function test battery before and after lung transplantation to investigate postoperative cognitive function in three domains (visual and verbal memory, executive functioning, concentration/speed of processing). Additionally we investigated intraoperative risk factors for postoperative cognitive dysfunction. In total, 24 patients were included in this pilot study. The incidence of postoperative cognitive dysfunction was 58.3%. In the cognitive dysfunction group, the domains executive functioning and concentration/attention were significantly impaired whereas memory was not affected. Patients with cognitive impairment had a significantly longer ICU stay. The strongest independent risk factor for the development of cognitive dysfunction was operation time. No influence of cerebral oxygen desaturations on cognitive dysfunction was found. This might have important implications for early psychological rehabilitation strategies in this high-risk patient collective.

Evidence for increased SARS-CoV-2 susceptibility and COVID-19 severity related to pre-existing immunity to seasonal coronaviruses.

The importance of pre-existing immune responses to seasonal endemic coronaviruses (HCoVs) for the susceptibility to SARS-CoV-2 infection and the course of COVID-19 is the subject of an ongoing scientific debate. Recent studies postulate that immune responses to previous HCoV infections can either have a slightly protective or no effect on SARS-CoV-2 pathogenesis and, consequently, be neglected for COVID-19 risk stratification. Challenging this notion, we provide evidence that pre-existing, anti-nucleocapsid antibodies against endemic α-coronaviruses and S2 domain-specific anti-spike antibodies against ß-coronavirus HCoV-OC43 are elevated in patients with COVID-19 compared to pre-pandemic donors. This finding is particularly pronounced in males and in critically ill patients. Longitudinal evaluation reveals that antibody cross-reactivity or polyclonal stimulation by SARS-CoV-2 infection are unlikely to be confounders. Thus, specific pre-existing immunity to seasonal coronaviruses may increase susceptibility to SARS-CoV-2 and predispose individuals to an adverse COVID-19 outcome, guiding risk management and supporting the development of universal coronavirus vaccines.

Value of Geriatric Assessment in Patients With Genitourinary Carcinoma.

Objectives: This work aims to evaluatecomprehensive geriatric assessment (CGA) tools to better guide patients with urogenital carcinomas perioperatively and, consequently, to intensify or reduce hospital resource use. Methods: After informed consent, 111patients were included, all aged more than 65 years, with oncological surgery (with proof of a malignancy), a Mini Mental State Examination (MMSE) score of at least 23 points, and a prospective life expectancy of more than 2 months. Patients were divided into 2 groups: prostate cancer (n = 88) and distal urinary tract cancer (n = 29). Further CGA tools were Instrumental Activities of Daily Living (iADL), Activities of Daily Living (ADL), and the Charlson Comorbidity Index (CCI). The relationships between CGA and complications, hospital duration, death rate, and baseline characteristics were analyzed. Results: In comparison with the patients with prostate cancer, those with kidney/distal urinary tract cancer had higher CCI scores (median, 3 vs 2; P <.001), MMSE scores (29 vs 28; P = .031), complication rates (55.2% vs 22.0%; P = .001), and hospital duration (16 vs 10 days; P <.001), as well as more deaths in the group (8 vs 0). Comorbidities (6 vs 2; P <.001), Physical Status Classification System (ASA state [3 vs 2; P <.001]), and median age (74 vs 71 years; P =.008) were all higher in the kidney/distal urinary tract group, and they had fewer problems with postoperative ADL items, which were significantly lower than those of the prostate group (P = .043). Intra- and intergroup comparisons of preoperative and 1-year ADL/iADL values did not differ significantly. Conclusion: These study results underscore the importance of CGA in patients with genitourinary carcinoma; most patients have high regenerative potential. Patients with kidney/distal urinary tract cancers are older, have more comorbidities, and have more postoperative impairments than patients with prostate cancer.

Genomic epidemiology reveals multiple introductions of SARS-CoV-2 followed by community and nosocomial spread, Germany, February to May 2020.

BackgroundIn the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data.AimWe applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata.MethodsWe investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission.ResultsWe identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions.ConclusionsEarly spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.

Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS-a randomized, placebo-controlled, double-blind trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients. METHODS: This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days. DISCUSSION: The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion. TRIAL REGISTRATION: This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47 .

Anthropometric analysis of body habitus and outcomes in critically ill COVID-19 patients.

AIMS: This study aimed to determine whether anthropometric markers of thoracic skeletal muscle and abdominal visceral fat tissue correlate with outcome parameters in critically ill COVID-19 patients. METHODS: We retrospectively analysed thoracic CT-scans of 67 patients in four ICUs at a university hospital. Thoracic skeletal muscle (total cross-sectional area (CSA); pectoralis muscle area (PMA)) and abdominal visceral fat tissue (VAT) were quantified using a semi-automated method. Point-biserial-correlation-coefficient, Spearman-correlation-coefficient, Wilcoxon rank-sum test and logistic regression were used to assess the correlation and test for differences between anthropometric parameters and death, ventilator- and ICU-free days and initial inflammatory laboratory values. RESULTS: Deceased patients had lower CSA and PMA values, but higher VAT values (p < 0.001). Male patients with higher CSA values had more ventilator-free days (p = 0.047) and ICU-free days (p = 0.017). Higher VAT/CSA and VAT/PMA values were associated with higher mortality (p < 0.001), but were negatively correlated with ICU length of stay in female patients only (p < 0.016). There was no association between anthropometric parameters and initial inflammatory biomarker levels. Logistic regression revealed no significant independent predictor for death. CONCLUSION: Our study suggests that pathologic body composition assessed by planimetric measurements using thoracic CT-scans is associated with worse outcome in critically ill COVID-19 patients.

[Tranexamic acid for bleeding prophylaxis in orthopedic surgery and trauma-standard or customized therapy?] / Tranexamsäure zur Blutungsprophylaxe bei Trauma und orthopädischen Eingriffen ­ Standard oder individualisierte Anwendung?

The use of tranexamic acid (TXA) is established in the treatment of bleeding, especially of bleeding due to hyperfibrinolysis. In recent years the prophylactic use of TXA in trauma and orthopedic surgery has increased leading to open questions regarding potentially associated risks and a possible classification as off label use. The available literature provides a sound basis for the recommendation that TXA can be used in these indications provided that an individual risk assessment is done in patients with increased risks for thromboembolic complications. Although the prophylactic use of TXA in orthopedic surgery and trauma is not explicitly listed in the product characteristics, it should not be regarded as an off label use.

Testing mechanical chest compression devices of different design for their suitability for prehospital patient transport - a simulator-based study.

BACKGROUND: Mechanical chest compression (mCPR) offers advantages during transport under cardiopulmonary resuscitation. Little is known how devices of different design perform en-route. Aim of the study was to measure performance of mCPR devices of different construction-design during ground-based pre-hospital transport. METHODS: We tested animax mono (AM), autopulse (AP), corpuls cpr (CC) and LUCAS2 (L2). The route had 6 stages (transport on soft stretcher or gurney involving a stairwell, trips with turntable ladder, rescue basket and ambulance including loading/unloading). Stationary mCPR with the respective device served as control. A four-person team carried an intubated and bag-ventilated mannequin under mCPR to assess device-stability (displacement, pressure point correctness), compliance with 2015 ERC guideline criteria for high-quality chest compressions (frequency, proportion of recommended pressure depth and compression-ventilation ratio) and user satisfaction (by standardized questionnaire). RESULTS: All devices performed comparable to stationary use. Displacement rates ranged from 83% (AM) to 11% (L2). Two incorrect pressure points occurred over 15,962 compressions (0.013%). Guideline-compliant pressure depth was > 90% in all devices. Electrically powered devices showed constant frequencies while muscle-powered AM showed more variability (median 100/min, interquartile range 9). Although physical effort of AM use was comparable (median 4.0 vs. 4.5 on visual scale up to 10), participants preferred electrical devices. CONCLUSION: All devices showed good to very good performance although device-stability, guideline compliance and user satisfaction varied by design. Our results underline the importance to check stability and connection to patient under transport.