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Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases. We observed the presence of autosomal-recessive or likely compound heterozygous monogenic disorders in six individuals, all of which were hospitalized and significantly younger than the rest of the cohort. We did not observe any suggestive causal variants in or around the established risk gene TLR7. Burden testing in the largest population subgroup (i.e., Europeans) suggested nominal enrichments of rare variants in coding and non-coding regions of interferon immune response genes in the overall analysis and male subgroup. Case-control analyses of more common variants confirmed associations with previously reported risk loci, with the key locus at 3p21 reaching genome-wide significance. Polygenic scores accurately captured risk in an age-dependent manner. By enabling joint analyses of different types of variation across the entire frequency spectrum, this data will continue to contribute to the elucidation of COVID-19 etiology.

Abstract In order to identify biomarkers for earlier prediction of COVID-19 outcome, we collected blood samples from patients with fatal outcomes (non-survivors) and with positive clinical outcomes (survivors) at ICU admission and after seven days. COVID-19 survivors and non-survivors showed significantly different transcript levels for 93 genes in whole blood already at ICU admission as revealed by RNA-Seq. These differences became even more pronounced at day 7, resulting in 290 differentially expressed genes. Many identified genes play a role in the differentiation of hematopoietic cells. For validation, we designed an RT-qPCR assay for C-type lectin domain family 12 member A (CLEC12A) and acetylcholinesterase (ACHE), two transcripts that showed highest potential to discriminate between survivors and non-survivors at both time points. Using our combined RT-qPCR assay we examined 33 samples to accurately predict patient survival with an AUROC curve of 0.931 (95% CI = 0.814–1.000) already at ICU admission. CLEC12A and ACHE showed improved prediction of patient outcomes compared to standard clinical biomarkers including CRP and PCT in combination (AUROC = 0.403, 95% CI = 0.108–0.697) or SOFA score (AUROC = 0.701 95% CI = 0.451–0.951) at day 0. Therefore, analyzing CLEC12A and ACHE gene expression from blood may provide a promising approach for early risk stratification of severely ill COVID-19 patients.

Introduction: High altitude exposure may lead to high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE). The pathophysiologic processes of both entities have been linked to decreased nitric oxide (NO) availability.Methods: We studied the effect of acute high altitude exposure on the plasma concentrations of asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-arginine, L-ornithine, and L-citrulline in two independent studies. We further investigated whether these biomarkers involved in NO metabolism were related to HAPH and HAPE, respectively. Fifty (study A) and thirteen (study B) non-acclimatized lowlanders were exposed to 4,559 m for 44 and 67 h, respectively. In contrast to study A, the participants in study B were characterized by a history of at least one episode of HAPE. Arterial blood gases and biomarker concentrations in venous plasma were assessed at low altitude (baseline) and repeatedly at high altitude. HAPE was diagnosed by chest radiography, and HAPH by measuring right ventricular to atrial pressure gradient (RVPG) with transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and the AMS-C score.Results: In both studies SDMA concentration significantly increased at high altitude. ADMA baseline concentrations were higher in individuals with HAPE susceptibility (study B) compared to those without (study A). However, upon high altitude exposure ADMA only increased in individuals without HAPE susceptibility, while there was no further increase in those with HAPE susceptibility. We observed an acute and transient decrease of L-ornithine and a more delayed but prolonged reduction of L-citrulline during high altitude exposure. In both studies SDMA positively correlated and L-ornithine negatively correlated with RVPG. ADMA was significantly associated with the occurrence of HAPE (study B). ADMA and SDMA were inversely correlated with alveolar PO2, while L-ornithine was inversely correlated with blood oxygenation and haemoglobin levels, respectively.Discussion: In non-acclimatized individuals ADMA and SDMA, two biomarkers decreasing endothelial NO production, increased after acute exposure to 4,559 m. The observed biomarker changes suggest that both NO synthesis and arginase pathways are involved in the pathophysiology of HAPH and HAPE.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused millions of COVID-19 cases and deaths worldwide. Severity of pulmonary pathologies and poor prognosis were reported to be associated with the activation non-virus-specific bystander T cells. In addition, high concentrations of the macrophage migration inhibitory factor (MIF) were found in serum of COVID-19 patients. We hypothesized that these two pathogenic factors might be related and analyzed the expression of receptors for MIF on T cells in COVID-19. T cells from PBMCs of hospitalized patients with mild and severe COVID-19 were characterized. A significantly higher proportion of CD4+ and CD8+ T cells from COVID-19 patients expressed CD74 on the cell surface compared to healthy controls. To induce intracellular signaling upon MIF binding, CD74 forms complexes with CD44, CXCR2, or CXCR4. The vast majority of CD74+ T cells expressed CD44, whereas expression of CXCR2 and CXCR4 was low in controls but increased upon SARS-CoV-2 infection. Hence, T cells in COVID-19 patients express receptors that render them responsive to MIF. A detailed analysis of CD74+ T cell populations revealed that most of them had a central memory phenotype early in infection, while cells with an effector and effector memory phenotype arose later during infection. Furthermore, CD74+ T cells produced more cytotoxic molecules and proliferation markers. Our data provide new insights into the MIF receptor and co-receptor repertoire of bystander T cells in COVID-19 and uncovers a novel and potentially druggable aspect of the immunological footprint of SARS-CoV-2.

Abstract The complex process of manual biomarker extraction from body composition analysis (BCA) has far restricted the analysis of SARS-CoV-2 outcomes to small patient cohorts and a limited number of tissue types. We investigate the association of two BCA-based biomarkers with the development of severe SARS-CoV-2 infections for 918 patients (354 female, 564 male) regarding disease severity and mortality (186 deceased). Multiple tissues, such as muscle, bone, or adipose tissue are used and acquired with a deep-learning-based, fully-automated BCA from computed tomography images of the chest. The BCA features and markers were univariately analyzed with a Shapiro–Wilk and two-sided Mann–Whitney-U test. In a multivariate approach, obtained markers were adjusted by a defined set of laboratory parameters promoted by other studies. Subsequently, the relationship between the markers and two endpoints, namely severity and mortality, was investigated with regard to statistical significance. The univariate approach showed that the muscle volume was significant for female (p severity ≤ 0.001, p mortality ≤ 0.0001) and male patients (p severity = 0.018, p mortality ≤ 0.0001) regarding the severity and mortality endpoints. For male patients, the intra- and intermuscular adipose tissue (IMAT) (p ≤ 0.0001), epicardial adipose tissue (EAT) (p ≤ 0.001) and pericardial adipose tissue (PAT) (p ≤ 0.0001) were significant regarding the severity outcome. With the mortality outcome, muscle (p ≤ 0.0001), IMAT (p ≤ 0.001), EAT (p = 0.011) and PAT (p = 0.003) remained significant. For female patients, bone (p ≤ 0.001), IMAT (p = 0.032) and PAT (p = 0.047) were significant in univariate analyses regarding the severity and bone (p = 0.005) regarding the mortality. Furthermore, the defined sarcopenia marker (p ≤ 0.0001, for female and male) was significant for both endpoints. The cardiac marker was significant for severity (pfemale = 0.014, pmale ≤ 0.0001) and for mortality (pfemale ≤ 0.0001, pmale ≤ 0.0001) endpoint for both genders. The multivariate logistic regression showed that the sarcopenia marker was significant (p severity = 0.006, p mortality = 0.002) for both endpoints (ORseverity = 0.42, 95% CIseverity: 0.23–0.78, ORmortality = 0.34, 95% CImortality: 0.17–0.67). The cardiac marker showed significance (p = 0.018) only for the severity endpoint (OR = 1.42, 95% CI 1.06–1.90). The association between BCA-based sarcopenia and cardiac biomarkers and disease severity and mortality suggests that these biomarkers can contribute to the risk stratification of SARS-CoV-2 patients. Patients with a higher cardiac marker and a lower sarcopenia marker are at risk for a severe course or death. Whether those biomarkers hold similar importance for other pneumonia-related diseases requires further investigation.

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Abstract Background Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections. Methods The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient’s quality of life is expected. Discussion The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence. Trial registrations DRKS-ID DRKS00022782 . Registered on August 25, 2020 ClinicalTrials.gov NCT04571801 . Registered October 1, 2020

Background: It is widely accepted that SARS-CoV-2 causes a dysregulation of immune and coagulation processes. In severely affected patients, viral sepsis may result in life endangering multiple organ dysfunction. Furthermore, most therapies for COVID-19 patients target either the immune system or coagulation processes. As the exact mechanism causing SARS-CoV-2-induced morbidity and mortality was unknown, we started an in-depth analysis of immunologic and coagulation processes. Methods: 127 COVID-19 patients were treated at the University Hospital Essen, Germany, between May 2020 and February 2022. Patients were divided according to their maximum COVID-19 WHO ordinal severity score (WHO 0–10) into hospitalized patients with a non-severe course of disease (WHO 4–5, n = 52) and those with a severe course of disease (WHO 6–10, n = 75). Non-infected individuals served as healthy controls (WHO 0, n = 42). Blood was analyzed with respect to cell numbers, clotting factors, as well as pro- and anti-inflammatory mediators in plasma. As functional parameters, phagocytosis and inflammatory responses to LPS and antigen-specific stimulation were determined in monocytes, granulocytes, and T cells using flow cytometry. Findings: In the present study, immune and coagulation systems were analyzed simultaneously. Interestingly, many severe COVID-19 patients showed an upregulation of pro-inflammatory mediators and at the same time clear signs of immunosuppression. Furthermore, severe COVID-19 patients not only exhibited a disturbed immune system, but in addition showed a pronounced pro-coagulation phenotype with impaired fibrinolysis. Therefore, our study adds another puzzle piece to the already complex picture of COVID-19 pathology implying that therapies in COVID-19 must be individualized. Conclusion: Despite years of research, COVID-19 has not been understood completely and still no therapies exist, fitting all requirements and phases of COVID-19 disease. This observation is highly reminiscent to sepsis. Research in sepsis has been going on for decades, while the disease is still not completely understood and therapies fitting all patients are lacking as well. In both septic and COVID-19 patients, immune activation can be accompanied by immune paralysis, complicating therapeutic intervention. Accordingly, therapies that lower immune activation may cause detrimental effects in patients, who are immune paralyzed by viral infections or sepsis. We therefore suggest individualizing therapies and to broaden the spectrum of immunological parameters analyzed before therapy. Only if the immune status of a patient is understood, can a therapeutic intervention be successful.

Background: Pulmonary hypertension (PH) is common in patients with left-side valvular diseases, especially with mitral regurgitation (MR). Measurement using pulmonal artery catheter (PAC) is the gold standard to asses pulmonary vascular pressures. During mitral valve surgery echocardiography is routinely used for valvular management and to evaluate pulmonary hemodynamic. The accuracy of echocardiographic measurements is controversial in the literature. We aimed to evaluate the reliability and accuracy of the noninvasive measurement for systolic pulmonary artery pressure (SPAP) using Doppler echocardiography compared to the invasive measurement using PAC in patients presenting with MR undergoing surgery. Methods: This prospective observational study evaluated 146 patients with MR undergoing cardiac surgery between 09/2020 and 10/2021. All patients underwent simultaneous SPAP assessment by PAC and transesophageal echocardiography at three different time points: before heart-lung-machine (HLM), after weaning from HLM and at the end of surgery. Results: Mean patients’ age was 61 ± 11.5 years, and 51 (35%) patients were female. Most of patients presented with severe MR (n = 126; 86.3%) or endocarditis (n = 18; 12.3%). Patients underwent either isolated mitral valve surgery (n = 65; 44.5%) or mitral valve surgery combined with other surgeries (n = 81; 55.5%). Mean SPAP was underestimated by transesophageal echocardiographic measurement in comparison to PAC measurement before HLM (41.9 ± 13.1 mmHg vs. 44.8 ± 13.8 mmHg, p < 0.001), after weaning from HLM (37.6 ± 9.3 mmHg vs. 42.4 ± 10.1 mmHg, p < 0.001), and at the end of surgery (35.6 ± 9.1 mmHg vs. 39.9 ± 9.9 mmHg, p < 0.001). This difference remained within the sub-analysis in patients presented with moderate or severe PH during all the time points. Bland-Altman analysis showed that transesophageal echocardiographic measurement underestimate SPAP in comparison to PAC as these two approaches are significantly different from one another. Conclusions: In patients presented with MR, transesophageal Doppler echocardiography could asses the presence of PH with high probability. This assessment is however underestimated and the use of PAC in those patients to diagnose, classify and monitor the therapy of PH remains recommended if required.

Summary: T cell immunity toward SARS-CoV-2 spike (S-), membrane (M-), and nucleocapsid (N-) proteins may define COVID-19 severity. Therefore, we compare the SARS-CoV-2-reactive T cell responses in moderate, severe, and critical COVID-19 patients and unexposed donors. Overlapping peptide pools of all three proteins induce SARS-CoV-2-reactive T cell response with dominance of CD4+ over CD8+ T cells and demonstrate interindividual immunity against the three proteins. M-protein induces the highest frequencies of CD4+ T cells, suggesting its relevance for diagnosis and vaccination. The T cell response of critical COVID-19 patients is robust and comparable or even superior to non-critical patients. Virus clearance and COVID-19 survival are not associated with either SARS-CoV-2 T cell kinetics or magnitude of T cell responses, respectively. Thus, our data do not support the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. Conversely, it indicates that activation of differentiated memory effector T cells could cause hyperreactivity and immunopathogenesis in critical patients.

Background: With an ageing population, the demand for joint arthroplasties and the burden of postoperative delirium is likely to increase. Given the lack of large-scale data, we investigated associations between perioperative risk factors and postoperative delirium in arthroplasty surgery.Methods: This retrospective population-based cohort study, utilized national claims data from the all-payer Premier Healthcare database containing detailed billing information from >25% nationwide hospitalizations. Patients undergoing elective total hip/knee arthroplasty surgery (2006-2016) were included.The primary outcome was postoperative delirium, while potential risk factors included age, gender, race, insurance type, and modifiable exposures including anesthesia type, opioid prescription dose (low/medium/high), benzodiazepines, meperidine, non-benzodiazepine hypnotics, ketamine, corticosteroids, and gabapentinoids.Results: Among 1 694 795 patients' postoperative delirium was seen in 2.6% (14 785/564 226) of hip and 2.9% (32 384/1 130 569) of knee arthroplasties. Multivariable models revealed that the utilization of long acting (OR 2.10 CI 1.82 to 2.42), combined long/short acting benzodiazepines (OR 1.74 CI 1.56 to 1.94), and gabapentinoids (OR 1.26 CI 1.16 to 1.36) was associated with increased odds of postoperative delirium. Lower odds of postoperative delirium were seen for neuraxial versus general anesthesia (OR 0.81 CI 0.70 to 0.93) and with the utilization of non-steroidal anti-inflammatory drugs (OR 0.85 CI 0.79 to 0.91) as well as cyclooxygenase-2 inhibitors (OR 0.82 CI 0.77 to 0.89). Age-stratified analysis revealed lower odds with high versus low opioid dose (OR 0.86 CI 0.76 to 0.98) in patients >65 years. Findings were consistent between hip and knee arthroplasties.Conclusions: In this large national cohort, we identified various modifiable risk factors (including anesthesia type and pharmaceutical agents) for postoperative delirium, demonstrating possible prevention pathways. [ABSTRACT FROM AUTHOR]

Background and Objectives: The significance of intravenous over oral acetaminophen (APAP) as part of multimodal analgesic protocols is contested, particularly when considering its relatively high price and use in a surgical cohort such as total hip or knee arthroplasty (THA/TKA), which generally tolerates oral medications. This study aims to elucidate APAP's effectiveness in a large, population-based patient sample.Methods: 1 039 647 THA/TKA procedures were sampled from the Premier Healthcare claims database 2011-2016. APAP use was categorized by intravenous/oral and use on the day of surgery, postoperative day 1 and thereafter. Outcomes were opioid utilization (in oral morphine equivalents), length and cost of hospitalization, and opioid-related adverse effects (respiratory, gastrointestinal, and naloxone use as a proxy). Mixed-effects models measured the associations between intravenous/oral APAP use and outcomes. Percent (%) change and 95% CIs are reported.Results: Overall, 23.6% (n=245 454) of patients received intravenous APAP; of these, 56.3% (n=138 180) received just one dose on the day of surgery. After adjustment for relevant covariates, particularly use of >1 dose of intravenous APAP (compared with no use) on postoperative day 1 was associated with -6.0% (CI -7.2% to -4.7%) reduced opioid utilization; this was -10.7% (CI -11.4% to -9.9%) for use of > 1 dose oral APAP on postoperative day 1. Further comparisons regarding other outcomes also favored oral (over intravenous) APAP.Conclusions: These results do not support the routine use of intravenous APAP in patients undergoing lower joint arthroplasty, especially since oral APAP shows more beneficial outcome patterns. [ABSTRACT FROM AUTHOR]