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Background: In multiple sclerosis (MS), iron rim lesions (IRLs) are associated with pronounced tissue damage, higher disease severity and have been suggested as an imaging marker of chronic active inflammation behind the blood–brain barrier indicating progression. Furthermore, chronic intrathecal compartmentalized inflammation has been suggested to be a mediator of a cerebrospinal fluid (CSF)–related tissue damage. Objective: To investigate CSF markers of intrathecal inflammation in patients with at least one IRL compared to patients without IRLs and to investigate tissue damage in lesions and normal-appearing white matter (NAWM) with proximity to CSF spaces. Methods: A total of 102 patients (51 with at least 1 IRL and 51 age-/sex-matched patients without IRL) scanned with the same 3T magnetic resonance imaging (MRI) and having CSF analysis data were included. Results: Patients with at least one IRL had higher disability scores, higher lesion volumes, lower brain volumes and a higher intrathecal immunoglobulin G (IgG) synthesis. Apparent diffusion coefficient (ADC) values in IRLs were higher compared to non-IRLs. We observed a negative linear correlation of ADC values in all tissue classes and distance to CSF, which was stronger in patients with high IgG quotients. Conclusion: IRLs are associated with higher intrathecal IgG synthesis. CSF-mediated intrathecal smouldering inflammation could explain a CSF-related gradient of tissue damage.

Background: Severe courses and high hospitalization rates were ubiquitous during the first pandemic SARS-CoV-2 waves. Thus, we aimed to examine whether integrative diagnostics may aid in identifying vulnerable patients using crucial data and materials obtained from COVID-19 patients hospitalized between 2020 and 2021 (n = 52). Accordingly, we investigated the potential of laboratory biomarkers, specifically the dynamic cell decay marker cell-free DNA and radiomics features extracted from chest CT. Methods: Separate forward and backward feature selection was conducted for linear regression with the Intensive-Care-Unit (ICU) period as the initial target. Three-fold cross-validation was performed, and collinear parameters were reduced. The model was adapted to a logistic regression approach and verified in a validation naïve subset to avoid overfitting. Results: The adapted integrated model classifying patients into “ICU/no ICU demand” comprises six radiomics and seven laboratory biomarkers. The models’ accuracy was 0.54 for radiomics, 0.47 for cfDNA, 0.74 for routine laboratory, and 0.87 for the combined model with an AUC of 0.91. Conclusion: The combined model performed superior to the individual models. Thus, integrating radiomics and laboratory data shows synergistic potential to aid clinic decision-making in COVID-19 patients. Under the need for evaluation in larger cohorts, including patients with other SARS-CoV-2 variants, the identified parameters might contribute to the triage of COVID-19 patients.

Background: Despite improved risk stratification tools and identification of novel biomarkers, sepsis-related mortality has not significantly improved during the past years. Objective: This study investigates the diagnostic and prognostic role of the serum albumin and cholinesterase (ChE) in patients with sepsis and septic shock. Methods: Consecutive patients with sepsis and septic shock from 2019 to 2021 were included. Blood samples were retrieved from day of disease onset (day 1), day 2,3,5 and 7. Firstly, the diagnostic value of the serum albumin for the diagnosis of a septic shock was compared to the ChE. Secondly, the prognostic value of the serum albumin and the ChE for 30-day all-cause mortality was tested. Results: A total of 239 patients were included. With an area under the curve (AUC) of 0.641 to 0.762 on day 3 and 5, the ChE revealed a moderate but better diagnostic discrimination between sepsis and septic shock than the serum albumin. Furthermore, the ChE was able to discriminate between non-survivors and survivors of the 30-day time inter-val (range of AUC 0.612 to 0.686). Patients with a ChE below the median had higher rates of 30-days all-cause mortality in comparison to patients with a ChE above the median (65% vs. 42%, log rank p = 0.001; HR = 1.820; 95% CI 1.273 – 2.601; p = 0.001). Conclusion: The ChE reflects a reliable diagnostic and prognostic tool in patients with sepsis and septic shock.

Cardiogenic Shock (CS) complicated by in-hospital (IHCA) or out-of-hospital cardiac arrest (OHCA) has a poor outcome. However, studies regarding the prognostic differences between IHCA and OHCA in CS are limited. In this prospective, observational study, consecutive patients with CS were included in a monocentric registry from June 2019 to May 2021. The prognostic impact of IHCA and OHCA on 30-day all-cause mortality was tested within the entire group and in the subgroups of patients with acute myocardial infarction (AMI) and coronary artery disease (CAD). Statistical analyses included univariable t-test, Spearman’s correlation, Kaplan–Meier analyses, as well as uni- and multivariable Cox regression analyses. A total of 151 patients with CS and cardiac arrest were included. IHCA on ICU admission was associated with higher 30-day all-cause mortality compared to OHCA in univariable COX regression and Kaplan–Meier analyses. However, this association was solely driven by patients with AMI (77% vs. 63%; log rank p = 0.023), whereas IHCA was not associated with 30-day all-cause mortality in non-AMI patients (65% vs. 66%; log rank p = 0.780). This finding was confirmed in multivariable COX regression, in which IHCA was solely associated with higher 30-day all-cause mortality in patients with AMI (HR = 2.477; 95% CI 1.258–4.879; p = 0.009), whereas no significant association could be seen in the non-AMI group and in the subgroups of patients with and CAD. CS patients with IHCA showed significantly higher all-cause mortality at 30 days compared to patients with OHCA. This finding was primarily driven by a significant increase in all-cause mortality at 30 days in CS patients with AMI and IHCA, whereas no difference could be seen when differentiated by CAD.

This study evaluated the prognostic impact of age on patients presenting with ventricular tachyarrhythmias (VTA) and aborted cardiac arrest.The present registry-based, monocentric cohort study included all consecutive patients presenting at the University Medical Center Mannheim (UMM) between 2002 and 2016 with ventricular tachycardia (VT), ventricular fibrillation (VF) and aborted cardiac arrest. Middle-aged (40-60 years old) were compared to older patients ( 60 years old). Furthermore, age was analyzed as a continuous variable. The primary endpoint was all-cause mortality at 2.5 years. The secondary endpoints were cardiac death at 24 h, all-cause mortality at index hospitalization, all-cause mortality after index hospitalization and the composite endpoint at 2.5 years of cardiac death at 24 h, recurrent VTA, and appropriate implantable cardioverter defibrillator (ICD) treatment.A total of 2259 consecutive patients were included (28% middle-aged, 72% older). Older patients were more often associated with all-cause mortality at 2.5 years (27% vs. 50%; hazard ratio, HR = 2.137; 95% confidence interval, CI 1.809-2.523, p = 0.001) and the secondary endpoints. Even patient age as a continuous variable was independently associated with mortality at 2.5 years in all types of VTA. Adverse prognosis in older patients was demonstrated by multivariate Cox regression analyses and propensity score matching. Chronic kidney disease (CKD), systolic left ventricular dysfunction (LVEF) 35%, cardiopulmonary resuscitation (CPR) and cardiogenic shock worsened the prognosis for both age groups, whereas acute myocardial infarction (STEMI/NSTEMI) and the presence of an ICD improved prognosis.The results of this study suggest that increasing age is associated with increased mortality in VTA patients. Compared to the middle-aged, older patients were associated with higher all-cause mortality at 2.5 years and the secondary endpoints.HINTERGRUND: In dieser Studie wurde der prognostische Einfluss des Alters bei Patienten mit ventrikulärer Tachyarrhythmie (VTA) und überlebtem Herzstillstand untersucht.Die vorliegende registerbasierte, monozentrische Kohortenstudie umfasste alle konsekutiven Patienten, die zwischen 2002 und 2016 mit ventrikulärer Tachykardie (VT), Kammerflimmern (VF) und überlebtem Herzstillstand in der Universitätsmedizin Mannheim (UMM) vorgestellt wurden. Patienten mittleren Alters (40–60 Jahre) wurden mit älteren Patienten ( 60 Jahre) verglichen. Außerdem wurde das Alter als kontinuierliche Variable analysiert. Der primäre Endpunkt war die Gesamtmortalität nach 2,5 Jahren. Die sekundären Endpunkte waren der Herztod innerhalb von 24 h, die Gesamtmortalität bei der Indexeinweisung, die Gesamtmortalität nach der Indexeinweisung und der zusammengesetzte Endpunkt nach 2,5 Jahren bestehend aus: Herztod nach 24 h, rezidivierende VTA und angemessene Behandlung mit einem implantierbaren Kardioverter-Defibrillator (ICD).Insgesamt wurden 2259 konsekutive Patienten eingeschlossen (28 % mittleren Alters, 72 % älter). Ältere Patienten waren häufiger mit der Gesamtmortalität nach 2,5 Jahren (27 % vs. 50 %; Hazard-Ratio [HR] = 2,137; 95 % Konfidenzintervall [KI] 1,809–2,523; p = 0,001) und den sekundären Endpunkten assoziiert. Selbst das Alter der Patienten als kontinuierliche Variable war bei allen Arten von VTA unabhängig mit der Sterblichkeit nach 2,5 Jahren verbunden. Eine ungünstige Prognose bei älteren Patienten wurde durch multivariate Cox-Regressionsanalysen und Propensity-Score-Matching nachgewiesen. Chronische Nierenerkrankung (CKD), hochgradig reduzierte systolische linksventrikuläre Funktion (LVEF) 35 %, kardiopulmonale Reanimation (CPR) und kardiogener Schock verschlechterten die Prognose für beide Altersgruppen, während ein akuter Myokardinfarkt (STEMI/NSTEMI) und das Vorhandensein eines ICD die Prognose verbesserten.Die Ergebnisse dieser Studie deuten darauf hin, dass zunehmendes Alter mit einer erhöhten Sterblichkeit bei VTA-Patienten verbunden ist. Im Vergleich zu Patienten mittleren Alters waren ältere Patienten mit einer höheren Gesamtmortalität nach 2,5 Jahren und den sekundären Endpunkten assoziiert.

In patients with cardiogenic shock (CS) due to myocardial infarction, elevated lactate levels are known to be negative predictors. Studies regarding the prognostic impact in patients with CS complicated by out-of-hospital cardiac arrest (OHCA) are limited. Two hundred and sixty-three consecutive patients with CS were included. The prognostic value of lactate on days 1, 2, 3, 4 and 8 was tested stratified by OHCA and non-OHCA. Statistical analyses included the univariable t-test, Spearman’s correlation, C-statistics, Kaplan–Meier analyses, as well as multivariable mixed analysis of variance (ANOVA) and Cox proportional regression analyses. The primary endpoint of all-cause mortality occurred in 49.4% of the non-OHCA group and in 63.4% of the OHCA group. Multivariable regression models showed an association of lactate values with 30-day all-cause mortality in the non-OHCA (p = 0.024) and OHCA groups (p = 0.001). In Kaplan–Meier analyses, patients with lactate levels ≥ 4 mmol/L (log-rank p = 0.001) showed the highest risk for 30-day all-cause mortality in the non-OHCA as well as in the OHCA group. However, in C-statistics lactate on days 1 and 8 had a better discrimination for 30-day all-cause mortality in the OHCA group compared to the non-OHCA group. In conclusion, patients presenting with CS lactate levels showed a good prognostic performance, with and without OHCA. Especially, lactate levels on days 1 and 8 were more accurate in the discrimination for all-cause mortality in CS-patients with OHCA.

This study evaluates the prognostic impact of anemia in patients presenting with ventricular tachyarrhythmias. The present longitudinal, observational, registry-based, monocentric cohort study included retrospectively all consecutive patients presenting with ventricular tachyarrhythmias on admission from 2002 to 2016. Anemic patients (hemoglobin levels12.0 g/dl) were compared with non-anemic patients (hemoglobin levels ≥12.0 g/dl). The primary endpoint was all-cause mortality at 2.5 years. Secondary endpoints were cardiac death at 24 hours, all-cause mortality at index hospitalization, and the composite endpoint of cardiac death at 24 hours, recurrent ventricular tachyarrhythmias, and appropriate ICD therapies at 2.5 years. A total of 2,184 consecutive patients were included, of whom 30% were anemic and 70% non-anemic. Anemia was associated with the primary endpoint of all-cause mortality at 2.5 years (65% vs 29%, p = 0.001; HR = 2.441; 95% CI 2.086 to 2.856), cardiac death at 24 hours (26% vs 11%, p = 0.001), all-cause mortality at index hospitalization (45% vs 20%, p = 0.001), and the composite endpoint (35% vs 27%, p = 0.001; HR = 2.923; 95% CI 2.564 to 4.366). After multivariable adjustment, anemia was no longer associated with the composite endpoint. Predictors of adverse prognosis for anemics were CKD (HR = 2.191), LVEF35% (HR = 1.651), cardiogenic shock (HR = 1.591), CPR (HR = 1.460), male gender (HR = 1.379), and age (HR = 1.017). In conclusion, anemic patients presenting with ventricular tachyarrhythmias were associated with increased long-term mortality at 2.5 years but not with the composite arrhythmic endpoint at 2.5 years. Predictors of adverse prognosis at 2.5 years were CKD, LVEF35%, cardiogenic shock, CPR, male gender, and age.

INTRODUCTION: The longevity of antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the duration of immunity are current topics of major scientific interest. Antibody kinetics during the acute phase are well studied, whereas the long-term kinetics are yet to be determined, with contradictory results from the studies to date. Here, we present a longitudinal analysis of the serological responses to a SARS-CoV-2 infection following convalescence and the association with post-COVID syndrome (PCS). MATERIALS AND METHODS: A total of 237 serum samples were prospectively collected from 61 participants who had had a SARS-CoV-2 infection, which was confirmed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). For each participant, anti-nucleocapsid (N) and anti-spike subunit 1 receptor binding domain (RBD/S1) immunoglobulin (Ig) levels were regularly determined over a period of 8 months. COVID-19-associated symptoms were assessed using a standardized questionnaire at study entry and again after 6 months. RESULTS: Antibodies were detectable in 56 of the 61 participants. No substantial decline in anti-SARS-CoV-2 pan-Ig levels was observed for the duration of the follow-up period. Antibody levels correlated positively with the disease severity, body mass index, fever, and smoking status. It was found that 46.8% of the participants suffered from PCS, with olfactory and gustatory dysfunctions being the most commonly reported symptoms. CONCLUSION: The results demonstrate stable anti-SARS-CoV-2 antibody titers and thus may indicate a long-lasting immunity. The results are in line with recently published data and provide further insight concerning asymptomatic to mildly-affected patients, the association with clinical features, and the frequency of PCS.

Background The detection of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mandatory for the diagnosis, retrospective assessment of disease progression, and correct evaluation of the current infection situation in the population. Many such assays have been launched by various manufacturers. Unfortunately, the new US Food and Drug Administration emergency use regulations have resulted in a situation where laboratories have to perform their own validation studies but many of these laboratories do not have the biobank needed to conduct the studies. Methods We introduce a method that allows institutions to quickly perform a verification study in a low-prevalence infection situation. As proof of concept, we used the Roche Elecsys® anti-SARS-CoV-2 electrochemiluminescence immunoassay and an SAP-based hospital information system. The Shenzhen YHLO Biotech IgM and IgG assay targeting other surface patterns was used as a confirmatory test. Results The Roche assay demonstrated a limit of detection of 0.069 cutoff index and successfully passed the performance validation according to Clinical and Laboratory Standards Institute EP15-A3. The study population of 627 inpatients has a median age of 64 years, and approximately 13% of the group were under intensive care at the respective time point. All patients included tested negative for SARS-CoV-2 infection by quantitative reverse transcription polymerase chain reaction (cobas® 6800, Roche, Mannheim, Germany). Only one false-positive result was obtained, resulting in a specificity for the Roche Elecsys anti-SARS-CoV-2 test of 99.84% and a negative predictive value of 99.98%. Conclusions The anonymized use of residual material enables quick evaluation of anti-SARS-CoV-2 immunoassays, as shown in this work with the Roche Elecsys assay. Comparison of the control population with economic data makes it possible to validate the sampling set and therefore to determine diagnostic specificity. By use of the approach chosen, it was shown that the Roche test achieved very good results in terms of diagnostic specificity, reproducibility, and limit of detection.

Highlights • FDA-EUA approved anti-SARS-CoV-2 tests compare favorably with others. • longitudinal patterns of antibody development are subject to high individual variability. • comparing the assays of leading manufacturers, there are considerable differences in terms of achieved and stated sensitivity/specificity. • Immune response relies on disease severity, thus need to be considered for validation., Objective Numerous immunoassays for detecting antibodies directed against SARS-CoV-2 have rapidly been developed and released. Validations of these have been performed with a limited number of samples. The lack of standardization might lead to significantly different results. This study compares ten automated assays from six vendors in terms of sensitivity, specificity, and reproducibility. Methods This study compared ten fully automated IAs from the following vendors: Diasorin, Epitope Diagnostics, Euroimmun, Roche, YHLO, and Snibe. The retrospective part of the study included patients with a laboratory-confirmed COVID-19 infection and controls comprised patients with a suspected infection, in whom the disease was excluded. Furthermore, biobanked sera were taken as negative controls (n = 97). The retrospective part involved four classes: 1) laboratory-confirmed COVID-19 infection (n = 183); 1B) suspected COVID-19 infection (n = 167) without qRT-PCR result but positive serological results from at least two different assays, and suspected COVID-19 infection due to a positive serological result from the Roche assay (n = 295); 2) biobanked sera obtained from patients before the emergence of SARS-CoV-2 (n = 97) as negative controls. 2A) probably COVID-19-negative sera with negative serological results from at least two different assays (n = 152). Results Overall diagnostic sensitivities were: Euroimmun(IgA) 87%; Epitope Diagnostics(IgG) 83%; YHLO(IgG) 77%; Roche(IgM/IgG) 77%; Euroimmun(IgG) 75%; Diasorin(IgG) 53%; Epitope Diagnostics(IgM) 52%; Snibe(IgG) 47%; YHLO(IgM) 35%; Snibe(IgM) 26%. Diagnostic specificities were: YHLO(IgG) 100%; Roche, 100%; Snibe(IgM/IgG) 100%; Diasorin(IgG) 97%; Euroimmun(IgG), 94%; YHLO(IgM) 94%; Euroimmun(IgA) 83%. Conclusion Assays from different vendors vary substantially in terms of their performance. Our findings might facilitate the selection of appropriate serological assays.

This study examines the prognostic impact of C-reactive protein (CRP) and white blood cell (WBC) counts in patients with cardiogenic shock (CS). Data regarding the prognostic impact of inflammatory biomarkers in CS are scarce. All consecutive patients with CS from 2019 to 2021 admitted to a cardiac intensive care unit (ICU) were included at one institution. Laboratory measurements were retrieved from the day of admission (i.e., day 1), as well as days 2, 3, 4, and 8. The primary endpoint was 30-day all-cause mortality. Statistical analyses included univariate t-tests, Spearman’s correlations, C-statistics, Kaplan–Meier, and Cox regression analyses. From a total of 240 consecutive patients admitted with CS, 55% died within 30 days. CRP levels on days 3 to 8 were associated with reliable discrimination for 30-day all-cause mortality (area under the curve (AUC): 0.623–0.754), whereas CRP on day 1 was not (AUC = 0.514). In line, CRP > 100 mg/L on day 3 (56% vs. 37%; log-rank p = 0.023; HR = 1.702; 95% CI 1.060–2.735; p = 0.028) and especially a CRP increase of at least 200% from days 1 to day 3 (51% vs. 35%; log-rank p = 0.040; HR = 1.720; 95% CI 1.006–2.943; p = 0.048) were associated with an increased risk of all-cause mortality. Furthermore, WBC on day 1 discriminated 30-day all-cause mortality (AUC = 0.605; p = 0.005) with an increased risk of all-cause mortality in patients admitted with WBC > 10 × 106/mL (59% vs. 40%; log-rank p = 0.036; HR = 1.643; 95% CI 1.010–2.671; p = 0.045). In conclusion, WBC count on admission as well as CRP levels during the course of ICU treatment were associated with 30-day all-cause mortality. Specifically, an increase of CRP levels by at least 200% from day 1 to day 3 during the course of ICU treatment was associated with an increased risk of 30-day all-cause mortality. The present study is one of the first to describe the prognostic value of inflammatory biomarkers in consecutive all-comer CS patients treated at a cardiac ICU.

Vaccination is the key element for protection against COVID-19. Increased vaccination breakthroughs raise the question of whether additional prevention is necessary in case of individual risk factors for a severe course with hospitalization or death despite vaccination.Since July 13, 2021, there is an extended reporting requirement by German law. We analyzed our hospitalized patients with vaccine breakthrough infection during the first 8 weeks.Nine of 67 patients (13.4%) hospitalized for COVID-19 (median age 75 years) were fully vaccinated. Five of these patients received intensive care; two patients died. All had received two doses of BNT162b2 vaccines (Pfizer-BioNTech). There was a median of 99 days between complete immunization and symptom onset. All patients suffered from ≥ three comorbidities. Six patients (66.7%) showed a negative Anti-SARS-CoV-2-N titer at the time of vaccine breakthrough, five of these also had Anti-SARS-CoV-2-S titers 100 U/ml. All determinable cases were Delta variant B.1.617.2.Advanced age, underlying cardiorespiratory disease, and the Delta variant of SARS-CoV-2 were associated with hospitalization of our patients, suffering from vaccine breakthrough infection. Avoidance of face masks, lack of immunization of close contacts, and travel to high-risk areas have been observed as modifiable behavioural circumstances. Consistent personal protective measures, vaccination of close caregivers, and increased awareness might be effective measures in addition to COVID-19 booster vaccination for patients at a high risk to suffer a severe course of infection.

Data regarding the prognostic value of cardiac biomarkers in patients suffering from sepsis or septic shock is scarce. Studies investigating the prognostic role of cardiac biomarkers in patients with sepsis and septic shock were commonly published prior to the sepsis-3 criteria and were often not restricted to septic patients only, too. This study investigated the diagnostic and prognostic value of the aminoterminal pro-B-type Natriuretic Peptide (NT-pro BNP) and cardiac troponin I (cTNI) in patients with sepsis and septic shock. Consecutive patients with sepsis and septic shock were included from 2019 to 2021. Blood samples were retrieved from the day of disease onset (i.e., day 1), day 2 and 3. Firstly, the diagnostic value of the NT-pro BNP and cTNI to diagnose sepsis or septic shock was tested. Secondly, the prognostic value of the NT-pro BNP and cTNI was examined with regard to the 30-day all-cause mortality. The statistical analyses included univariable t-tests, Spearman’s correlations, C-statistics, Kaplan–Meier analyses and Cox proportional regression analyses. A total of 162 patients were included prospectively, of which 57% had a sepsis and 43% a septic shock. The overall rate of all-cause mortality at 30 days was 53%. With an area under the curve (AUC) of 0.658 on day 1 and 0.885 on day 3, cTNI expressed a better diagnostic value than NT-pro BNP, especially on day 3 (ΔAUCd3 = 0.404; p = 0.022). Furthermore, cTNI displayed a moderate but slightly better prognostic value than NT-pro BNP on all examined days (AUC for cTNI, d1 = 0.635; 95% CI 0.541–0.729; p = 0.007 vs. AUC for NT-pro BNP, d1 = 0.582; 95% CI 0.477–0.687; p = 0.132). In conclusion, cTNI was a reliable diagnostic parameter for the diagnosis of sepsis and septic shock, as well as a reliable prognostic tool with regard to 30-day all-cause mortality in patients suffering from sepsis and septic shock.

Background Serum biomarker S100B has been explored for its potential benefit to improve clinical decision-making in the management of patients suffering from traumatic brain injury (TBI), especially as a pre-head computed-tomography screening test for patients with mild TBI. Although being already included into some guidelines, its implementation into standard care is still lacking. This might be explained by a turnaround time (TAT) too long for serum S100B to be used in clinical decision-making in emergency settings. Methods S100B concentrations were determined in 136 matching pairs of serum and lithium heparin blood samples. The concordance of the test results was assessed by linear regression, Passing Pablok regression and Bland-Altman analysis. Bias and within- and between-run imprecision were determined by a 5 × 4 model using pooled patient samples. CT scans were performed as clinically indicated. Results Overall, S100B levels between both blood constituents correlated very well. The suitability of S100B testing from plasma was verified according to ISO15189 requirements. Using a cut-off of 0.105 ng/ml, a sensitivity and negative predictive value of 100% were obtained for identifying patients with pathologic CT scans. Importantly, plasma-based testing reduced the TAT to 26 min allowing for quicker clinical decision-making. The clinical utility of integrating S100B in TBI management is highlighted by two case reports. Conclusions Plasma-based S100B testing compares favorably with serum-based testing, substantially reducing processing times as the prerequisite for integrating S100B level into management of TBI patients. The proposed new clinical decision algorithm for TBI management needs to be validated in further prospective large-scale studies., Highlights • Plasma-based S100B testing reduces turnaround time to 26 minutes and thus enables its use in the emergency department. • Plasma- and serum-based S100B testing demonstrate commutability of results. • Clinical cases demonstrate the benefit of elevated S100B levels as an indicator for second-look CT re-evaluation.

During the ongoing COVID-19 pandemic, PCR testing and antigen tests have proven critical for helping to stem the spread of its causative agent, SARS-CoV-2. However, these methods suffer from either general applicability and/or sensitivity. Moreover, the emergence of variant strains creates the need for flexibility to correctly and efficiently diagnose the presence of substrains. To address these needs we developed the diagnostic test ADESSO (Accurate Detection of Evolving SARS-CoV-2 through SHERLOCK (Specific High Sensitivity Enzymatic Reporter UnLOCKing) Optimization) which employs Cas13 to diagnose patients in 1 h without sophisticated equipment. Using an extensive panel of clinical samples, we demonstrate that ADESSO correctly identifies infected individuals at a sensitivity and specificity comparable to RT-qPCR on extracted RNA and higher than antigen tests for unextracted samples. Altogether, ADESSO is a fast, sensitive and cheap method that can be applied in a point of care setting to diagnose COVID-19 and can be quickly adjusted to detect new variants.

With the coronavirus disease 19 (COVID-19) pandemic now deep into its second year, widespread testing for the detection of the causative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental. The gold standard reverse transcription quantitative PCR (RT-qPCR) cannot keep up with the high demand alone, therefore alternative diagnostic tests are needed. Here we present ADESSO (Accurate Detection of Evolving SARS-CoV-2 through SHERLOCK Optimisation), an optimised version of the CRISPR-based SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) assay. After an extensive validation on 983 clinical samples, we demonstrated that ADESSO has a sensitivity of 96% and a specificity of 100% on extracted RNA, comparable to RT-qPCR. Its performance on unextracted samples still allows the detection of the more infectious 75% of the COVID-19 positive population, making it suitable for point-of-care (POC) testing. Interestingly, our in parallel comparison of 390 matching swab and gargle samples showed consistently lower viral loads in gargle specimens. We also validated ADESSO for the detection of the B.1.1.7 variant and demonstrated that ADESSO is adaptable to any variant of concern in less than one week, a critical feature now that worrisome SARS-CoV-2 variants are spreading all around the world.

Cardiovascular diseases are accompanied by disorders in the cardiac metabolism. Furthermore, comorbidities often associated with cardiovascular disease can alter systemic and myocardial metabolism contributing to worsening of cardiac performance and health status. Biomarkers such as natriuretic peptides or troponins already support diagnosis, prognosis and treatment of patients with cardiovascular diseases and are represented in international guidelines. However, as cardiovascular diseases affect various pathophysiological pathways, a single biomarker approach cannot be regarded as ideal to reveal optimal clinical application. Emerging metabolomics technology allows the measurement of hundreds of metabolites in biological fluids or biopsies and thus to characterize each patient by its own metabolic fingerprint, improving our understanding of complex diseases, significantly altering the management of cardiovascular diseases and possibly personalizing medicine. This review outlines current knowledge, perspectives as well as limitations of metabolomics for diagnosis, prognosis and treatment of cardiovascular diseases such as heart failure, atherosclerosis, ischemic and non-ischemic cardiomyopathy. Furthermore, an ongoing research project tackling current inconsistencies as well as clinical applications of metabolomics will be discussed. Taken together, the application of metabolomics will enable us to gain more insights into pathophysiological interactions of metabolites and disease states as well as improving therapies of patients with cardiovascular diseases in the future.

Background The increasing number of multi-drug resistant (MDR) bacteria provides enormous challenges for choosing an appropriate antibiotic therapy in the early phase of sepsis. While bacterial identification has been greatly accelerated by the introduction of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), the antibiotic susceptibility testing (AST) remains time-consuming. Here, we present a rapid susceptibility testing method for testing Gram-negative bacteria, exemplarily validated for Escherichia coli and Klebsiella spp. Methods Gram-negative isolates (E. coli and Klebsiella spp.) were either taken as single colonies from agar plates (n=136) or directly extracted and identified from positive blood cultures (n=42) using MALDI-TOF MS. Bacteria were incubated in glucose-supplemented Luria broths (LBs) each containing one antibiotic (ceftazidime, piperacillin, imipenem and ciprofloxacin), routinely used to classify Gram-negative bacteria in Germany. To determine susceptibility the dynamics of glucose utilization in bacterial suspensions were quantitatively measured in the presence or absence of antibiotics designated liquid-AST (L-AST). Results The L-AST can be run on clinical-chemistry analyzers and integrated into laboratory routines. It yields critical resistance information within 90–150 min downstream of a MS-based identification. The results showed a high concordance with routine susceptibility testing, with less than 1% very major errors (VME) and 3.51% major errors (ME) for 178 assessed isolates. Analysis of turnaround time (TAT) for 42 clinical samples indicated that L-AST results could be obtained 34 h earlier than the routine results. Conclusions As exemplified for E. coli and Klebsiella spp., L-AST provides substantial acceleration of susceptibility testing following MALDI-TOF MS identification. The assay is a simple and low-cost method that can be integrated into clinical laboratory to allow for 24/7 AST. This approach could improve antibiotic therapy.

Besides the diagnostic role in acute myocardial infarction, cardiac troponin I levels (cTNI) may be increased in various other clinical conditions, including heart failure, valvular heart disease and sepsis. However, limited data are available regarding the prognostic role of cTNI in the setting of ventricular tachyarrhythmias. Therefore, the present study sought to assess the prognostic impact of cTNI in patients with ventricular tachyarrhythmias (i.e., ventricular tachycardia (VT) and fibrillation (VF)) on admission. A large retrospective registry was used, including all consecutive patients presenting with ventricular tachyarrhythmias from 2002 to 2015. The prognostic impact of elevated cTNI levels was investigated for 30-day all-cause mortality (i.e., primary endpoint) using Kaplan–Meier, receiver operating characteristic (ROC), multivariable Cox regression analyses and propensity score matching. From a total of 1104 patients with ventricular tachyarrhythmias and available cTNI levels on admission, 46% were admitted with VT and 54% with VF. At 30 days, high cTNI was associated with the primary endpoint (40% vs. 22%; log rank p = 0.001; HR = 2.004; 95% CI 1.603–2.505; p = 0.001), which was still evident after multivariable adjustment and propensity score matching (30% vs. 18%; log rank p = 0.003; HR = 1.729; 95% CI 1.184–2.525; p = 0.005). Significant discrimination of the primary endpoint was especially evident in VT patients (area under the curve (AUC) 0.734; 95% CI 0.645–0.823; p = 0.001). In contrast, secondary endpoints, including all-cause mortality at 30 months and a composite arrhythmic endpoint, were not affected by cTNI levels. The risk of cardiac rehospitalization was lower in patients with high cTNI, which was no longer observed after propensity score matching. In conclusion, high cTNI levels were associated with increased risk of all-cause mortality at 30 days in patients presenting with ventricular tachyarrhythmias.

Objectives To evaluate the prognostic value of fully automatic lung quantification based on spectral computed tomography (CT) and laboratory parameters for combined outcome prediction in COVID-19 pneumonia. Methods CT images of 53 hospitalized COVID-19 patients including virtual monochromatic reconstructions at 40-140keV were analyzed using a fully automated software system. Quantitative CT (QCT) parameters including mean and percentiles of lung density, fibrosis index (FIBI-700, defined as the percentage of segmented lung voxels ≥-700 HU), quantification of ground-glass opacities and well-aerated lung areas were analyzed. QCT parameters were correlated to laboratory and patient outcome parameters (hospitalization, days on intensive care unit, invasive and non-invasive ventilation). Results Best correlations were found for laboratory parameters LDH (r = 0.54), CRP (r = 0.49), Procalcitonin (r = 0.37) and partial pressure of oxygen (r = 0.35) with the QCT parameter 75th percentile of lung density. LDH, Procalcitonin, 75th percentile of lung density and FIBI-700 were the strongest independent predictors of patients’ outcome in terms of days of invasive ventilation. The combination of LDH and Procalcitonin with either 75th percentile of lung density or FIBI-700 achieved a r2 of 0.84 and 1.0 as well as an area under the receiver operating characteristic curve (AUC) of 0.99 and 1.0 for the prediction of the need of invasive ventilation. Conclusions QCT parameters in combination with laboratory parameters could deliver a feasible prognostic tool for the prediction of invasive ventilation in patients with COVID-19 pneumonia.

Background Data is limited evaluating novel biomarkers in right ventricular dysfunction. Normal right heart function improves the prognosis of patients with heart failure. Therefore, this study investigates the association between the novel biomarker copeptin and right heart function compared to NT-proBNP. Methods Patients undergoing routine echocardiography were enrolled prospectively. Right ventricular function was assessed by tricuspid annular plane systolic excursion (TAPSE) and further right ventricular and atrial parameters. Exclusion criteria were age under 18 years, left ventricular ejection fraction Results Ninety-one patients were included. Median values of copeptin increased significantly according to decreasing values of TAPSE ( P = 0.001; right heart function grade I: tricuspid annular plane systolic excursion; TAPSE > 24 mm: 5.20 pmol/L; grade II: TAPSE 18–24 mm: 8.10 pmol/L; grade III: TAPSE Conclusions This study demonstrates that the novel biomarker copeptin reflects longitudinal right heart function assessed by standardized transthoracic echocardiography compared with NT-proBNP.

Despite increasing COVID-19 infection rates, low overall prevalence resulting in a poor positive predictive value (PPV) of serological tests requires strategies to increase specificity. We therefore investigated a dual diagnostic strategy and evaluated the correlation between the severity of a SARS-CoV-2 infection and the detectable immune-response.Participants were systematically categorized into positive and control cohorts and a probability score of COVID-19 was calculated based on clinical symptoms. Six hundred eighty-two serum samples were analyzed using a highly specific high-throughput system. Combining the serological test result and probability score was performed as a dual diagnostic strategy.Specificity of 99.61% and sensitivity of 86.0% were the basis of our approach. A dual diagnostic strategy led to increased pre-test probability and thus to a test specificity of 100%. In a flu-like symptomatic population, we estimated a COVID-prevalence of 4.79%. Moreover, we detected significantly higher antibody values in patients with fever than without fever.Based on sensitivity and specificity results of our study being in line with previous findings, we demonstrated a dual assessment strategy including a symptom-based probability score and serological testing to increase the PPV. Moreover, the presence of fever seems to trigger a stronger immune-response.

Background In recent years, remarkable progress has been made in deep learning technology and successful use cases have been introduced in the medical domain. However, not many studies have considered high-performance computing to fully appreciate the capability of deep learning technology. Objective This paper aims to design a solution to accelerate an automated Gram stain image interpretation by means of a deep learning framework without additional hardware resources. Methods We will apply and evaluate 3 methodologies, namely fine-tuning, an integer arithmetic–only framework, and hyperparameter tuning. Results The choice of pretrained models and the ideal setting for layer tuning and hyperparameter tuning will be determined. These results will provide an empirical yet reproducible guideline for those who consider a rapid deep learning solution for Gram stain image interpretation. The results are planned to be announced in the first quarter of 2021. Conclusions Making a balanced decision between modeling performance and computational performance is the key for a successful deep learning solution. Otherwise, highly accurate but slow deep learning solutions can add value to routine care. International Registered Report Identifier (IRRID) DERR1-10.2196/16843

Highlights • FDA-EUA approved anti-SARS-CoV-2 tests compare favorably with others. • Diagnostic sensitivity remains behind the manufacturer’s specifications. • Plasma and serum cannot both be used equally for anti-SARS-CoV-2 IgG detection. • Immune response relies on disease severity, thus need to be considered for validation., Background For epidemiologic, social and economic reasons, assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prevalence and immunity are important to adapt decisions to current demands. Hence, immunoassays for detection of anti-SARS-CoV-2 antibodies are introduced rapidly without requiring FDA emergency use authorization approval. Thus, evaluation of test performance predominantly relies on laboratories. This study aimed to evaluate the test performance of recently launched commercial immunoassays in serum and plasma samples. Methods 51 serum samples from 26 patients with confirmed SARS-CoV-2 infection after end of quarantine and 25 control patients were analyzed using anti-SARS-CoV-2 IgG immunoassays from Roche, Euroimmun and Epitope to assess diagnostic sensitivity and specificity. 20 matching pairs of serum and plasma samples were included to analyze comparability between different specimens. Results Overall, a diagnostic sensitivity of 92.3%, 96.2–100% and 100% with a respective diagnostic specificity of 100%, 100% and 84–86% for the immunoassays from Roche, Euroimmun and Epitope were determined. In total, 84–96% of samples were correctly classified as negative and 92.3–95.2% as positive. The level of concordance between plasma- and serum-based testing diverged between the assays (Epitope r2 = 0.97; Euroimmun r2 = 0.91; Roche r2 = 0.76). Conclusions The immunoassays from Euroimmun and Roche revealed a higher specificity than the Epitope assay without a substantial drop of diagnostic sensitivity. Significant differences between plasma- and serum-based testing highlights the need for determination of appropriate cut-offs per specimen type. Hence, there is an urgent need for test harmonization and establishment of quality standards for an appropriate use of COVID-19 serological tests.

BACKGROUND In recent years, remarkable progress has been made in deep learning technology and successful use cases have been introduced in the medical domain. However, not many studies have considered high-performance computing to fully appreciate the capability of deep learning technology. OBJECTIVE This paper aims to design a solution to accelerate an automated Gram stain image interpretation by means of a deep learning framework without additional hardware resources. METHODS We will apply and evaluate 3 methodologies, namely fine-tuning, an integer arithmetic–only framework, and hyperparameter tuning. RESULTS The choice of pretrained models and the ideal setting for layer tuning and hyperparameter tuning will be determined. These results will provide an empirical yet reproducible guideline for those who consider a rapid deep learning solution for Gram stain image interpretation. The results are planned to be announced in the first quarter of 2021. CONCLUSIONS Making a balanced decision between modeling performance and computational performance is the key for a successful deep learning solution. Otherwise, highly accurate but slow deep learning solutions can add value to routine care. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/16843

Only few data evaluating the prognostic impact of blood-derived potassium levels (K) on arrhythmic endpoints in patients with implantable cardioverter-defibrillators (ICD) is available. Therefore, this study evaluates the prognostic impact of potassium levels on recurrences of ventricular tachyarrhythmias in consecutive ICD recipients.A large retrospective registry was used including all consecutive patients presenting with ventricular tachyarrhythmias on admission from 2002 to 2016 at one institution. Patients were divided into three subgroups: hypokalemia (i.e., K3.3 mmol/L), normokalemia (i.e., K 3.3 - 4.5 mmol/L), and hyperkalemia (i.e., K4.5 mmol/L). Kaplan-Meier and Cox regression analyses were applied for the evaluation of the primary endpoint of first recurrences of ventricular tachyarrhythmias at one year. Secondary endpoints comprised of first appropriate ICD therapy, first cardiac rehospitalization, and all-cause mortality at one year.Five hundred and thirty ICD recipients with a median potassium level of 4.23 mmol/L were included (67%: normokalemia, 27%: hyperkalemia, and 6%: hypokalemia). Whereas hyperkalemia was not associated with increasing risk of recurrent ventricular tachyarrhythmias, hypokalemia was associated with decreasing freedom from recurrent ventricular tachyarrhythmias (HR = 2.135; 95% CI 1.158 - 3.937; p = 0.015), even after mul-tivariable adjustment (HR = 2.577; 95% CI 1.236 - 5.372; p = 0.012). Higher risk of recurrences was especially attributed to higher rates of electrical storm in the presence of hypokalemia (15% vs. 3 - 4%). Negative impact of hypokalemia was mainly attributed to secondary preventive ICD (HR = 2.637; 95% CI 1.325 - 5.248; p = 0.006). Moreover, hypokalemia was associated with increasing risk of appropriate ICD therapies (HR = 1.920; 95% CI 0.912 - 4.042; statistical trend: p = 0.086), which was still demonstrated after multivariable adjustment. In contrast, risk of first cardiac rehospitalization and all-cause mortality were not affected by potassium levels.In consecutive ICD recipients with ventricular tachyarrhythmias at index, hypokalemia - but not hyperkalemia - was associated with increasing risk of recurrent ventricular tachyarrhythmias and appropriate ICD therapies.

To analyse whether patients with transient global amnesia (TGA) have concomitant cardiac injury by assessing clinical symptoms, as well as blood and cardiologic test results. In this retrospective observational study, we analysed 202 consecutive patients presenting with isolated TGA and treated at our institution between March 2010 and December 2018. We examined the incidence of high-sensitivity cardiac troponin I (hs-cTNI) level elevation, electrocardiogram (ECG) findings, and data on clinical management. Among the TGA patients, 17 (8.4%) exhibited elevated levels of hs-cTNI. Although none of the patients had ST elevation, 12 (6.7%) showed QTc prolongation and 11 (6.1%) an inverted T wave on ECG. No typical clinical symptoms suggestive of myocardial infarction were present in any of the cases, however, 17 (8.4%) patients complained of mild somatic symptoms. Patients with hs-cTNI level elevation had a significantly greater likelihood of a history of coronary heart disease (p = 0.03) and a significantly shorter TGA duration at presentation (p

BACKGROUND This study evaluates the association between high sensitivity troponin I (hsTnI) and T (hsTnT) in patients with suspected stable Coronary Artery Disease (CAD) undergoing Coronary Computed Tomography Angiography (CCTA). METHODS Patients undergoing CCTA were enrolled prospectively. CCTA was indicated in patients with angina and a low to intermediate pre-test probability for CAD during routine clinical care. Blood samples were taken at the time of CCTA to measure cardiac biomarkers. RESULTS A total of 99 patients were enrolled with 43 % revealing no CAD, 30 % with non-obstructive and 26 % with obstructive CAD. Out of these, 61 % had single-vessel and 39 % had multi-vessel CAD. Both hsTnI and hsTnT levels increased significantly according to the presence and extent of CAD (p = 0.0001) and were able to discriminate the presence of both obstructive (AUC range: 0.775 - 0.785; p = 0.0001) and multi-vessel CAD (AUC range: 0.740 - 0.749; p = 0.01). In multivariate logistic regression models adjusted for cardiovascular risk factors and NT-proBNP, both hsTn were still associated significantly with obstructive CAD (range of odds ratios (OR): 8.3-32.3; p < 0.02). DISCUSSION This study shows that high sensitivity troponin I and T reflect the presence and extent of CAD being diagnosed by CCTA in patients with a low to intermediate pretest probability for CAD.