Electrical Detection and Nucleation of a Magnetic Skyrmion in a Magnetic Tunnel Junction Observed via Operando Magnetic Microscopy.

Magnetic skyrmions are topological spin textures which are envisioned as nanometer scale information carriers in magnetic memory and logic devices. The recent demonstrations of room temperature skyrmions and their current induced manipulation in ultrathin films were first steps toward the realization of such devices. However, important challenges remain regarding the electrical detection and the low-power nucleation of skyrmions, which are required for the read and write operations. Here, we demonstrate, using operando magnetic microscopy experiments, the electrical detection of a single magnetic skyrmion in a magnetic tunnel junction (MTJ) and its nucleation and annihilation by gate voltage via voltage control of magnetic anisotropy. The nucleated skyrmion can be manipulated by both gate voltages and external magnetic fields, leading to tunable intermediate resistance states. Our results unambiguously demonstrate the readout and voltage controlled write operations in a single MTJ device, which is a major milestone for low power skyrmion based technologies.

Clinical accuracy of instrument-based SARS-CoV-2 antigen diagnostic tests: a systematic review and meta-analysis.

BACKGROUND: During the COVID-19 pandemic, antigen diagnostic tests were frequently used for screening, triage, and diagnosis. Novel instrument-based antigen tests (iAg tests) hold the promise of outperforming their instrument-free, visually-read counterparts. Here, we provide a systematic review and meta-analysis of the SARS-CoV-2 iAg tests' clinical accuracy. METHODS: We systematically searched MEDLINE (via PubMed), Web of Science, medRxiv, and bioRxiv for articles published before November 7th, 2022, evaluating the accuracy of iAg tests for SARS-CoV-2 detection. We performed a random effects meta-analysis to estimate sensitivity and specificity and used the QUADAS-2 tool to assess study quality and risk of bias. Sub-group analysis was conducted based on Ct value range, IFU-conformity, age, symptom presence and duration, and the variant of concern. RESULTS: We screened the titles and abstracts of 20,431 articles and included 114 publications that fulfilled the inclusion criteria. Additionally, we incorporated three articles sourced from the FIND website, totaling 117 studies encompassing 95,181 individuals, which evaluated the clinical accuracy of 24 commercial COVID-19 iAg tests. The studies varied in risk of bias but showed high applicability. Of 24 iAg tests from 99 studies assessed in the meta-analysis, the pooled sensitivity and specificity compared to molecular testing of a paired NP swab sample were 76.7% (95% CI 73.5 to 79.7) and 98.4% (95% CI 98.0 to 98.7), respectively. Higher sensitivity was noted in individuals with high viral load (99.6% [95% CI 96.8 to 100] at Ct-level ≤ 20) and within the first week of symptom onset (84.6% [95% CI 78.2 to 89.3]), but did not differ between tests conducted as per manufacturer's instructions and those conducted differently, or between point-of-care and lab-based testing. CONCLUSION: Overall, iAg tests have a high pooled specificity but a moderate pooled sensitivity, according to our analysis. The pooled sensitivity increases with lower Ct-values (a proxy for viral load), or within the first week of symptom onset, enabling reliable identification of most COVID-19 cases and highlighting the importance of context in test selection. The study underscores the need for careful evaluation considering performance variations and operational features of iAg tests.

Triggering receptor expressed on myeloid cells-1 in sepsis, and current insights into clinical studies.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions.

Tranexamic Acid Administration During Liver Transplantation Is Not Associated With Lower Blood Loss or With Reduced Utilization of Red Blood Cell Transfusion.

BACKGROUND: Current clinical guidelines recommend antifibrinolytic treatment for liver transplantation to reduce blood loss and transfusion utilization. However, the clinical relevance of fibrinolysis during liver transplantation is questionable, a benefit of tranexamic acid (TXA) in this context is not supported by sufficient evidence, and adverse effects are also conceivable. Therefore, we tested the hypothesis that use of TXA is associated with reduced blood loss. METHODS: We performed a retrospective cohort study on patients who underwent liver transplantation between 2004 and 2017 at Heidelberg University Hospital, Heidelberg, Germany. Univariable and multivariable linear regression analyses were used to determine the association between TXA administration and the primary end point intraoperative blood loss and the secondary end point intra- and postoperative red blood cell (RBC) transfusions. For further secondary outcome analyses, the time to the first occurrence of a composite end point of hepatic artery thrombosis, portal vein thrombosis, and thrombosis of the inferior vena cava were analyzed using a univariable and multivariable Cox proportional hazards model. RESULTS: Data from 779 transplantations were included in the final analysis. The median intraoperative blood loss was 3000 mL (1600-5500 mL). Intraoperative TXA administration occurred in 262 patients (33.6%) with an average dose of 1.4 ± 0.7 g and was not associated with intraoperative blood loss (regression coefficient B, -0.020 [-0.051 to 0.012], P = .226) or any of the secondary end points (intraoperative RBC transfusion; regression coefficient B, 0.023 [-0.006 to 0.053], P = .116), postoperative RBC transfusion (regression coefficient B, 0.007 [-0.032 to 0.046], P = .717), and occurrence of thrombosis (hazard ratio [HR], 1.110 [0.903-1.365], P = .321). CONCLUSIONS: Our data do not support the use of TXA during liver transplantation. Physicians should exercise caution and consider individual factors when deciding whether or not to administer TXA.

Thoracic Epidural Analgesia Is Not Associated With Improved Survival After Pancreatic Surgery: Long-Term Follow-Up of the Randomized Controlled PAKMAN Trial.

BACKGROUND: Perioperative thoracic epidural analgesia (EDA) and patient-controlled intravenous analgesia (PCIA) are common forms of analgesia after pancreatic surgery. Current guidelines recommend EDA over PCIA, and evidence suggests that EDA may improve long-term survival after surgery, especially in cancer patients. The aim of this study was to determine whether perioperative EDA is associated with an improved patient prognosis compared to PCIA in pancreatic surgery. METHODS: The PAKMAN trial was an adaptive, pragmatic, international, multicenter, randomized controlled superiority trial conducted from June 2015 to October 2017. Three to five years after index surgery a long-term follow-up was performed from October 2020 to April 2021. RESULTS: For long-term follow-up of survival, 109 patients with EDA were compared to 111 patients with PCIA after partial pancreatoduodenectomy (PD). Long-term follow-up of quality of life (QoL) and pain assessment was available for 40 patients with EDA and 45 patients with PCIA (questionnaire response rate: 94%). Survival analysis revealed that EDA, when compared to PCIA, was not associated with improved overall survival (OS, HR, 1.176, 95% HR-CI, 0.809-1.710, P = .397, n = 220). Likewise, recurrence-free survival did not differ between groups (HR, 1.116, 95% HR-CI, 0.817-1.664, P = .397, n = 220). OS subgroup analysis including only patients with malignancies showed no significant difference between EDA and PCIA (HR, 1.369, 95% HR-CI, 0.932-2.011, P = .109, n = 179). Similar long-term effects on QoL and pain severity were observed in both groups (EDA: n = 40, PCIA: n = 45). CONCLUSIONS: Results from this long-term follow-up of the PAKMAN randomized controlled trial do not support favoring EDA over PCIA in pancreatic surgery. Until further evidence is available, EDA and PCIA should be considered similar regarding long-term survival.

A 29-mRNA host-response classifier identifies bacterial infections following liver transplantation - a pilot study.

PURPOSE: Infections are common complications in patients following liver transplantation (LTX). The early diagnosis and prognosis of these infections is an unmet medical need even when using routine biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT). Therefore, new approaches are necessary. METHODS: In a prospective, observational pilot study, we monitored 30 consecutive patients daily between days 0 and 13 following LTX using the 29-mRNA host classifier IMX-BVN-3b that determine the likelihood of bacterial infections and viral infections. True infection status was determined using clinical adjudication. Results were compared to the accuracy of CRP and PCT for patients with and without bacterial infection due to clinical adjudication. RESULTS: Clinical adjudication confirmed bacterial infections in 10 and fungal infections in 2 patients. 20 patients stayed non-infected until day 13 post-LTX. IMX-BVN-3b bacterial scores were increased directly following LTX and decreased until day four in all patients. Bacterial IMX-BVN-3b scores detected bacterial infections in 9 out of 10 patients. PCT concentrations did not differ between patients with or without bacterial, whereas CRP was elevated in all patients with significantly higher levels in patients with bacterial infections. CONCLUSION: The 29-mRNA host classifier IMX-BVN-3b identified bacterial infections in post-LTX patients and did so earlier than routine biomarkers. While our pilot study holds promise future studies will determine whether these classifiers may help to identify post-LTX infections earlier and improve patient management. CLINICAL TRIAL NOTATION: German Clinical Trials Register: DRKS00023236, Registered 07 October 2020, https://drks.de/search/en/trial/DRKS00023236.

Evaluating time until ligation in a novel tourniquet - A crossover randomized-controlled trial.

INTRODUCTION AND AIM: Severe external hemorrhage is a significant reason for morbidity and mortality in adults; thus, the swift and correct application of a tourniquet by laypersons can be lifesaving. We conducted this randomized-controlled cross-over study to investigate the use of a novel tourniquet. METHODS: Participants were recruited at the Heidelberg University Hospital. Eligible participants were ≥ 18 years old with a medical background but without prior experience in applying a tourniquet. Participants were 1:1 randomized to the intervention group (PAX tourniquet) or the control group (SAM or CAT tourniquet). In the control group, participants underwent another randomization to either the SAM or CAT tourniquet without a predefined allocation ratio. Hyperspectral measurements were undertaken (i) before ligation, (ii) 30 s after ligation, and (iii) 30 s after the reopening of the tourniquet. The primary outcome was time until ligation before crossover between the respective groups. The analysis of secondary endpoints included all attempts to assess a possible learning effect, intraoperator variability, and hyperspectral measurements. Participants were crossed to the other study group after a brief wash-out phase. RESULTS: In total, 50 participants were recruited, resulting in 100 attempts. A success rate of 98% was observed across the study population. Time until ligation was 49 s and 56 s (p = 0.572) in the intervention and control group, respectively. However, there was a significant difference between the PAX and SAM (54 vs 75 s; p = 0.037) and the SAM and CAT tourniquet (75 vs. 47 s; p = 0.015). Further, we observed a significant learning effect in participants allocated to the control group first, with a median reduction of 9 s in the time until ligation. Hyperspectral measurements showed a significant decrease in perfusion and tissue oxygenation after ligation. Further, a significant increase in perfusion and tissue oxygenation was found after reopening the tourniquet compared to the baseline measurement. CONCLUSION: The novel PAX tourniquet can be applied quickly and effectively by medical personnel without prior experience in applying a tourniquet.

Direct Observation of Propagating Spin Waves in the 2D van der Waals Ferromagnet Fe5GeTe2.

Magnetism in reduced dimensionalities is of great fundamental interest while also providing perspectives for applications of materials with novel functionalities. In particular, spin dynamics in two dimensions (2D) have become a focus of recent research. Here, we report the observation of coherent propagating spin-wave dynamics in a ∼30 nm thick flake of 2D van der Waals ferromagnet Fe5GeTe2 using X-ray microscopy. Both phase and amplitude information were obtained by direct imaging below TC for frequencies from 2.77 to 3.84 GHz, and the corresponding spin-wave wavelengths were measured to be between 1.5 and 0.5 µm. Thus, parts of the magnonic dispersion relation were determined despite a relatively high magnetic damping of the material. Numerically solving an analytic multilayer model allowed us to corroborate the experimental dispersion relation and predict the influence of changes in the saturation magnetization or interlayer coupling, which could be exploited in future applications by temperature control or stacking of 2D-heterostructures.

Efficacy of therapies for post dural puncture headache.

PURPOSE OF REVIEW: Clinical management of postdural puncture headache (PDPH) remains an interdisciplinary challenge with significant impact on both morbidity and quality of life. This review aims to give an overview of the most recent literature on prophylactic and therapeutic measures and to discuss novel findings with regard to currently published consensus practice guideline recommendations. RECENT FINDINGS: Although current evidence does not support a recommendation of any specific prophylactic measure, new data is available on the use of intrathecal catheters to prevent PDPH and/or to avoid invasive procedures. In case of disabling or refractory symptoms despite conservative treatments, the epidural blood patch (EBP) remains the therapeutic gold standard and its use should not be delayed in the absence of contraindications. However, recent clinical studies and meta-analyses provide additional findings on the therapeutic use of local anesthetics as potential noninvasive alternatives for early symptom control. SUMMARY: There is continuing research focusing on both prophylactic and therapeutic measures offering promising data on potential alternatives to invasive procedures, although there is currently no treatment option that comes close to the effectiveness of an EBP. A better understanding of PDPH pathophysiology is not only necessary to identify new therapeutic targets, but also to recognize patients who benefit most from current treatments, as this might enhance their therapeutic efficacy.

[The Immune System of the Critically Ill Patient]. / Das Immunsystem des kritisch Kranken.

Critically ill patients often experience a dysregulated immune response, leading to immune dysfunction. Sepsis, trauma, severe infections, and certain medical conditions can trigger a state of systemic inflammation, known as the cytokine storm. This hyperactive immune response can cause collateral damage to healthy tissues and organs, exacerbating the patient's condition. On the other hand, some critically ill patients may suffer from immune paralysis which can increase the risk of nosocomial infections.Fever is an evolutionary adaptation that evolved as an effective defense mechanism to fight invading pathogens. By raising body temperature, fever enhances the immune response, inhibits pathogen growth, promotes recovery, and aids in the formation of immune memory. Understanding the role of fever in the context of immune defense is crucial for optimizing medical interventions and supporting the body's natural ability to combat infections.Future Directions: Advancements in immunology research and technology hold promise for better understanding the immune system's complexities in critically ill patients. Personalized medicine approaches may be developed to tailor therapies to individual patients based on their immune profile, optimizing treatment outcomes. Based on recent studies prognostic parameters such as lymphocyte count, IL-10 concentration and mHLA-DR expression can be used to stratify the immunological response pattern in septic patients.Conclusion: The immune system's response in critically ill patients is a multifaceted process, involving intricate interactions between various immune cells, cytokines, and organs. Striking the delicate balance between immune activation and suppression remains a significant challenge in clinical practice. Continued research and therapeutic innovations are vital to improve patient outcomes and reduce the burden of critical illness on healthcare systems.

Differential Effects of Intra-Abdominal Hypertension and ARDS on Respiratory Mechanics in a Porcine Model.

Background and Objectives: Intra-abdominal hypertension (IAH) and acute respiratory distress syndrome (ARDS) are common concerns in intensive care unit patients with acute respiratory failure (ARF). Although both conditions lead to impairment of global respiratory parameters, their underlying mechanisms differ substantially. Therefore, a separate assessment of the different respiratory compartments should reveal differences in respiratory mechanics. Materials and Methods: We prospectively investigated alterations in lung and chest wall mechanics in 18 mechanically ventilated pigs exposed to varying levels of intra-abdominal pressures (IAP) and ARDS. The animals were divided into three groups: group A (IAP 10 mmHg, no ARDS), B (IAP 20 mmHg, no ARDS), and C (IAP 10 mmHg, with ARDS). Following induction of IAP (by inflating an intra-abdominal balloon) and ARDS (by saline lung lavage and injurious ventilation), respiratory mechanics were monitored for six hours. Statistical analysis was performed using one-way ANOVA to compare the alterations within each group. Results: After six hours of ventilation, end-expiratory lung volume (EELV) decreased across all groups, while airway and thoracic pressures increased. Significant differences were noted between group (B) and (C) regarding alterations in transpulmonary pressure (TPP) (2.7 ± 0.6 vs. 11.3 ± 2.1 cmH2O, p < 0.001), elastance of the lung (EL) (8.9 ± 1.9 vs. 29.9 ± 5.9 cmH2O/mL, p = 0.003), and elastance of the chest wall (ECW) (32.8 ± 3.2 vs. 4.4 ± 1.8 cmH2O/mL, p < 0.001). However, global respiratory parameters such as EELV/kg bodyweight (-6.1 ± 1.3 vs. -11.0 ± 2.5 mL/kg), driving pressure (12.5 ± 0.9 vs. 13.2 ± 2.3 cmH2O), and compliance of the respiratory system (-21.7 ± 2.8 vs. -19.5 ± 3.4 mL/cmH2O) did not show significant differences among the groups. Conclusions: Separate measurements of lung and chest wall mechanics in pigs with IAH or ARDS reveals significant differences in TPP, EL, and ECW, whereas global respiratory parameters do not differ significantly. Therefore, assessing the compartments of the respiratory system separately could aid in identifying the underlying cause of ARF.

Asynchronous current-induced switching of rare-earth and transition-metal sublattices in ferrimagnetic alloys.

Ferrimagnetic alloys are model systems for understanding the ultrafast magnetization switching in materials with antiferromagnetically coupled sublattices. Here we investigate the dynamics of the rare-earth and transition-metal sublattices in ferrimagnetic GdFeCo and TbCo dots excited by spin-orbit torques with combined temporal, spatial and elemental resolution. We observe distinct switching regimes in which the magnetizations of the two sublattices either remain synchronized throughout the reversal process or switch following different trajectories in time and space. In the latter case, we observe a transient ferromagnetic state that lasts up to 2 ns. The asynchronous switching of the two magnetizations is ascribed to the master-agent dynamics induced by the spin-orbit torques on the transition-metal and rare-earth sublattices and their weak antiferromagnetic coupling, which depends sensitively on the alloy microstructure. Larger antiferromagnetic exchange leads to faster switching and shorter recovery of the magnetization after a current pulse. Our findings provide insight into the dynamics of ferrimagnets and the design of spintronic devices with fast and uniform switching.

Out-of-hospital cardiac arrest in children: an epidemiological study based on the German Resuscitation Registry identifying modifiable factors for return of spontaneous circulation.

AIM: This work provides an epidemiological overview of out-of-hospital cardiac arrest (OHCA) in children in Germany between 2007 and 2021. We wanted to identify modifiable factors associated with survival. METHODS: Data from the German Resuscitation Registry (GRR) were used, and we included patients registered between 1st January 2007 and 31st December 2021. We included children aged between > 7 days and 17 years, where cardiopulmonary resuscitation (CPR) was started, and treatment was continued by emergency medical services (EMS). Incidences and descriptive analyses are presented for the overall cohort and each age group. Multivariate binary logistic regression was performed on the whole cohort to determine the influence of (1) CPR with/without ventilation started by bystander, (2) OHCA witnessed status and (3) night-time on the outcome hospital admission with return of spontaneous circulation (ROSC). RESULTS: OHCA in children aged < 1 year had the highest incidence of the same age group, with 23.42 per 100 000. Overall, hypoxia was the leading presumed cause of OHCA, whereas trauma and drowning accounted for a high proportion in children aged > 1 year. Bystander-witnessed OHCA and bystander CPR rate were highest in children aged 1-4 years, with 43.9% and 62.3%, respectively. In reference to EMS-started CPR, bystander CPR with ventilation were associated with an increased odds ratio for ROSC at hospital admission after adjusting for age, sex, year of OHCA and location of OHCA. CONCLUSION: This study provides an epidemiological overview of OHCA in children in Germany and identifies bystander CPR with ventilation as one primary factor for survival. Trial registrations German Clinical Trial Register: DRKS00030989, December 28th 2022.

Single Skyrmion Generation via a Vertical Nanocontact in a 2D Magnet-Based Heterostructure.

Skyrmions have been well studied in chiral magnets and magnetic thin films due to their potential application in practical devices. Recently, monochiral skyrmions have been observed in two-dimensional van der Waals magnets. Their atomically flat surfaces and capability to be stacked into heterostructures offer new prospects for skyrmion applications. However, the controlled local nucleation of skyrmions within these materials has yet to be realized. Here, we utilize real-space X-ray microscopy to investigate a heterostructure composed of the 2D ferromagnet Fe3GeTe2 (FGT), an insulating hexagonal boron nitride layer, and a graphite top electrode. Upon a stepwise increase of the voltage applied between the graphite and FGT, a vertically conducting pathway can be formed. This nanocontact allows the tunable creation of individual skyrmions via single nanosecond pulses of low current density. Furthermore, time-resolved magnetic imaging highlights the stability of the nanocontact, while our micromagnetic simulations reproduce the observed skyrmion nucleation process.

Deterministic Generation and Guided Motion of Magnetic Skyrmions by Focused He+-Ion Irradiation.

Magnetic skyrmions are quasiparticles with nontrivial topology, envisioned to play a key role in next-generation data technology while simultaneously attracting fundamental research interest due to their emerging topological charge. In chiral magnetic multilayers, current-generated spin-orbit torques or ultrafast laser excitation can be used to nucleate isolated skyrmions on a picosecond time scale. Both methods, however, produce randomly arranged skyrmions, which inherently limits the precision on the location at which the skyrmions are nucleated. Here, we show that nanopatterning of the anisotropy landscape with a He+-ion beam creates well-defined skyrmion nucleation sites, thereby transforming the skyrmion localization into a deterministic process. This approach allows control of individual skyrmion nucleation as well as guided skyrmion motion with nanometer-scale precision, which is pivotal for both future fundamental studies of skyrmion dynamics and applications.

Notch Signaling in Acute Inflammation and Sepsis.

Notch signaling, a highly conserved pathway in mammals, is crucial for differentiation and homeostasis of immune cells. Besides, this pathway is also directly involved in the transmission of immune signals. Notch signaling per se does not have a clear pro- or anti-inflammatory effect, but rather its impact is highly dependent on the immune cell type and the cellular environment, modulating several inflammatory conditions including sepsis, and therefore significantly impacts the course of disease. In this review, we will discuss the contribution of Notch signaling on the clinical picture of systemic inflammatory diseases, especially sepsis. Specifically, we will review its role during immune cell development and its contribution to the modulation of organ-specific immune responses. Finally, we will evaluate to what extent manipulation of the Notch signaling pathway could be a future therapeutic strategy.

Extracellular Vesicles as Possible Plasma Markers and Mediators in Patients with Sepsis-Associated Delirium-A Pilot Study.

Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known to maintain normal physiology but also have been linked to numerous disease states. Here, we sought to identify differentially expressed proteins in plasma EVs from SAD patients as potential biomarkers for SAD. Plasma EVs from 11 SAD patients and 11 age-matched septic patients without delirium (non-SAD) were isolated by differential centrifugation, characterized by nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis. Differential EV protein expression was determined by mass spectrometry and the resulting proteomes were characterized by Gene Ontology term and between-group statistics. As preliminary results because of the small group size, five distinct proteins showed significantly different expression pattern between SAD and non-SAD patients (p ≤ 0.05). In SAD patients, upregulated proteins included paraoxonase-1 (PON1), thrombospondin 1 (THBS1), and full fibrinogen gamma chain (FGG), whereas downregulated proteins comprised immunoglobulin (IgHV3) and complement subcomponent (C1QC). Thus, plasma EVs of SAD patients show significant changes in the expression of distinct proteins involved in immune system regulation and blood coagulation as well as in lipid metabolism in this pilot study. They might be a potential indicator for to the pathogenesis of SAD and thus warrant further examination as potential biomarkers, but further research is needed to expand on these findings in longitudinal study designs with larger samples and comprehensive polymodal data collection.

Evaluation of the Novel Sepsis Biomarker Host-Derived Delta-like Canonical Notch Ligand 1-A Secondary Analysis of 405 Patients Suffering from Inflammatory or Infectious Diseases.

Sepsis is defined as organ failure caused by dysregulated host response to infection. While early antibiotic treatment in patients with acute infection is essential, treating non-infectious patients must be avoided. Current guidelines recommend procalcitonin (PCT) to guide discontinuation of antibiotic treatment. For initiation of therapy, there is currently no recommended biomarker. In this study, we evaluated Host-Derived Delta-like Canonical Notch Ligand 1 (DLL1), a monocyte membrane ligand that has shown promising results in differentiating infectious from non-infectious critically ill patients. Soluble DLL1 levels were measured in plasma samples of six different cohorts. The six cohorts comprise two cohorts with non-infectious inflammatory auto-immune diseases (Hidradenitis Suppurativa, Inflammatory Bowel Disease), one cohort of bacterial skin infection, and three cohorts of suspected systemic infection or sepsis. In total, soluble DLL1 plasma levels of 405 patients were analyzed. Patients were divided into three groups: inflammatory disease, infection, and sepsis (defined according to the Sepsis-3 definition), followed by the evaluation of its diagnostic performance via Area Under the Receiver Operating Characteristics (AUROC) analyses. Patients of the sepsis group showed significantly elevated plasma DLL1 levels compared to patients with uncomplicated infections and sterile inflammation. However, patients with infections had significantly higher DLL1 levels than patients with inflammatory diseases. Diagnostic performance was evaluated and showed better performance for DLL1 for the recognition of sepsis (AUC: 0.823; CI 0.731-0.914) than C-reactive protein (AUC 0.758; CI 0.658-0.857), PCT (AUC 0.593; CI 0.474-0.711) and White Blood Cell count (AUC 0.577; CI 0.46-0.694). DLL1 demonstrated promising results for diagnosing sepsis and was able to differentiate sepsis from other infectious and inflammatory diseases.

Rapid Development of Cefiderocol Resistance in Carbapenem-resistant Enterobacter cloacae During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor cirA.

We report a case of resistance development toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.

Accuracy of rapid point-of-care antigen-based diagnostics for SARS-CoV-2: An updated systematic review and meta-analysis with meta-regression analyzing influencing factors.

BACKGROUND: Comprehensive information about the accuracy of antigen rapid diagnostic tests (Ag-RDTs) for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is essential to guide public health decision makers in choosing the best tests and testing policies. In August 2021, we published a systematic review and meta-analysis about the accuracy of Ag-RDTs. We now update this work and analyze the factors influencing test sensitivity in further detail. METHODS AND FINDINGS: We registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched preprint and peer-reviewed databases for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 until August 31, 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity with reverse transcription polymerase chain reaction (RT-PCR) testing as a reference. To evaluate factors influencing test sensitivity, we performed 3 different analyses using multivariable mixed-effects meta-regression models. We included 194 studies with 221,878 Ag-RDTs performed. Overall, the pooled estimates of Ag-RDT sensitivity and specificity were 72.0% (95% confidence interval [CI] 69.8 to 74.2) and 98.9% (95% CI 98.6 to 99.1). When manufacturer instructions were followed, sensitivity increased to 76.3% (95% CI 73.7 to 78.7). Sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values (97.9% [95% CI 96.9 to 98.9] and 90.6% [95% CI 88.3 to 93.0] for Ct-values <20 and <25, compared to 54.4% [95% CI 47.3 to 61.5] and 18.7% [95% CI 13.9 to 23.4] for Ct-values ≥25 and ≥30) and was estimated to increase by 2.9 percentage points (95% CI 1.7 to 4.0) for every unit decrease in mean Ct-value when adjusting for testing procedure and patients' symptom status. Concordantly, we found the mean Ct-value to be lower for true positive (22.2 [95% CI 21.5 to 22.8]) compared to false negative (30.4 [95% CI 29.7 to 31.1]) results. Testing in the first week from symptom onset resulted in substantially higher sensitivity (81.9% [95% CI 77.7 to 85.5]) compared to testing after 1 week (51.8%, 95% CI 41.5 to 61.9). Similarly, sensitivity was higher in symptomatic (76.2% [95% CI 73.3 to 78.9]) compared to asymptomatic (56.8% [95% CI 50.9 to 62.4]) persons. However, both effects were mainly driven by the Ct-value of the sample. With regards to sample type, highest sensitivity was found for nasopharyngeal (NP) and combined NP/oropharyngeal samples (70.8% [95% CI 68.3 to 73.2]), as well as in anterior nasal/mid-turbinate samples (77.3% [95% CI 73.0 to 81.0]). Our analysis was limited by the included studies' heterogeneity in viral load assessment and sample origination. CONCLUSIONS: Ag-RDTs detect most of the individuals infected with SARS-CoV-2, and almost all (>90%) when high viral loads are present. With viral load, as estimated by Ct-value, being the most influential factor on their sensitivity, they are especially useful to detect persons with high viral load who are most likely to transmit the virus. To further quantify the effects of other factors influencing test sensitivity, standardization of clinical accuracy studies and access to patient level Ct-values and duration of symptoms are needed.