Tissue factor binds to and inhibits interferon-α receptor 1 signaling.

Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.

Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain.

Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that cognitive impairment driven by CKD is therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single nuclei RNA sequencing and single cell thallium autometallography), human samples and in vitro experiments we demonstrate that microglia activation impairs neuronal potassium homeostasis and cognition in CKD. CKD disrupts the barrier of brain endothelial cells in vitro and the blood-brain barrier in vivo, establishing that the uremic state modifies vascular permeability in the brain. Exposure to uremic conditions impairs calcium homeostasis in microglia, enhances microglial potassium efflux via the calcium-dependent channel KCa3.1, and induces p38-MAPK associated IL-1ß maturation in microglia. Restoring potassium homeostasis in microglia using a KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1ß receptor 1 (IL-R1) using anakinra or genetically abolishing neuronal IL-1R1 expression in neurons prevent CKD-mediated reduced neuronal potassium turnover and CKD-induced impaired cognition. Accordingly, in CKD mice, impaired cognition can be ameliorated by either preventing microglia activation or inhibiting IL-1R-signaling in neurons. Thus, our data suggest that potassium efflux from microglia triggers their activation, which promotes microglia IL-1ß release and IL-1R1-mediated neuronal dysfunction in CKD. Hence, our study provides new mechanistic insight into cognitive impairment in association with CKD and identifies possible new therapeutic approaches.

Myosteatosis predicts short-term mortality in patients with COVID-19: A multicenter analysis.

OBJECTIVES: Body composition on computed tomography can predict prognosis in patients with COVID-19. The reported data are based on small retrospective studies. The aim of the present study was to analyze the prognostic relevance of skeletal muscle parameter derived from chest computed tomography for prediction of 30-d mortality in patients with COVID-19 in a multicenter setting. METHODS: The clinical databases of three centers were screened for patients with COVID-19 between 2020 and 2022. Overall, 447 patients (142 female; 31.7%) were included into the study. The mean age at the time of computed tomography acquisition was 63.8 ± 14.7 y and median age was 65 y. Skeletal muscle area and skeletal muscle density were defined on level T12 of the chest. RESULTS: Overall, 118 patients (26.3%) died within the 30-d observation period. Of the patient sample, 255 patients (57.0%) were admitted to an intensive care unit and 122 patients needed mechanical ventilation (27.3%). The mean skeletal muscle area of all patients was 96.1 ± 27.2 cm² (range = 23.2-200.7 cm²). For skeletal muscle density, the mean was 24.3 ± 11.1 Hounsfield units (range = -5.6 to 55.8 Hounsfield units). In survivors, the mean skeletal muscle density was higher compared with the lethal cases (mean 25.8 ± 11.2 versus 20.1 ± 9.6; P < 0.0001). Presence of myosteatosis was independently associated with 30-d mortality: odds ratio = 2.72 (95% CI, 1.71-4.32); P = 0.0001. CONCLUSIONS: Myosteatosis is strongly associated with 30-d mortality in patients COVID-19. Patients with COVID-19 with myosteatosis should be considered a risk group.

A Specific Pattern of Routine Cerebrospinal Fluid Parameters Might Help to Identify Cases of West Nile Virus Neuroinvasive Disease.

BACKGROUND: Viral meningitis/encephalitis (ME) is a rare but potentially harmful disease. The prompt identification of the respective virus is important to guide not only treatment but also potential public health countermeasures. However, in about 40% of cases, no virus is identified despite an extensive diagnostic workup. The aim of the present study was to analyze demographic, seasonal, and routine cerebrospinal fluid (CSF) parameters in cases of viral ME and assess their utility for the prediction of the causative virus. METHODS: Demographic data, season, and routine CSF parameters (total leucocytes, CSF cell differentiation, age-adjusted CSF/serum albumin ratio, and total immunoglobulin ratios) were retrospectively assessed in cases of viral ME. RESULTS: In total, 156 cases of acute viral ME (74 female, median age 40.0 years) were treated at a tertiary-care hospital in Germany. Specific viral infections were detected in 93 (59.6%) cases. Of these, 14 (9.0%) cases were caused by herpes simplex virus (HSV), 36 (23.1%) by varicella-zoster virus (VZV), 27 (17.3%) by enteroviruses, 9 (5.8%) by West Nile virus (WNV), and 7 (4.5%) by other specific viruses. Additionally, 64 (41.0%) cases of ME of unknown viral etiology were diagnosed. Cases of WNV ME were older, predominantly male, showed a severe disruption of the blood-CSF-barrier, a high proportion of neutrophils in CSF, and an intrathecal total immunoglobulin M synthesis in the first CSF sample. In a multinominal logistic regression analysis, the accuracy of these CSF parameters together with age and seasonality was best for the prediction of WNV (87.5%), followed by unknown viral etiology (66.7%), VZV (61.8%), and enteroviruses (51.9%). CONCLUSIONS: Cases with WNV ME showed a specific pattern of routine CSF parameters and demographic data that allowed for their identification with good accuracy. These findings might help to guide the diagnostic workup in cases with viral ME, in particular allowing the timely identification of cases with ME due to WNV.

Elevated serum levels of anti-collagen type I antibodies in patients with spontaneous cervical artery dissection and ischemic stroke: a prospective multicenter study.

Introduction: Spontaneous cervical artery dissection (sCAD) is a rare vasculopathy whose trigger is still unknown. We hypothesized that autoimmunity against components of the vascular wall might play a critical role in sCAD and examined anti-collagen type I antibodies in patients with sCAD, acute ischemic stroke, patients with thromboendarterectomy, and controls. Methods: Fifty-seven patients with sCAD (age 45.7 ± 10.2 years, female 18 (31.6%)) were prospectively enrolled in four German stroke centers. Blood samples were collected at baseline, at day 10 ± 3, and after 6 ± 1 months. Patients with ischemic stroke not related to CAD (n=54, age 56.7 ± 13.7 years, female 15 (27.8%)), healthy probands (n=80, age 57.4 ± 12.9 years, female 56 (70%)), and patients undergoing thromboendarterectomy of the carotid artery (n=9, age 70.7 ± 9.3 years, female 2 (22.2%)) served as controls. Anti-collagen type I antibodies were determined by enzyme-linked immunosorbent assays (ELISAs). Results: Patients with acute sCAD had higher serum levels of anti-collagen type I antibodies (33.9 ± 24.6 µg/ml) than probands (18.5 ± 11.0 µg/ml; p <0.001) but lower levels than patients with ischemic stroke not related to sCAD (47.8 ± 28.4 µg/ml; p=0.003). In patients with sCAD, serum levels of anti-collagen type I antibodies were similar in the acute, subacute, and chronic phase. Levels of anti-collagen type I antibodies significantly correlated with circulating collagen type I (rho=0.207, p=0.003). Conclusion: Anti-collagen type I antibodies seem not to represent a trigger for acute sCAD or ischemic stroke but may rather be linked to the metabolism and turnover of collagen type I.

Fat tissue quantity, waist circumference or waist-to-hip ratio in patients with chronic kidney disease: A systematic review and meta-analysis.

The BMI predicts mortality and cardiovascular disease (CVD) in the general population, while in patients with end-stage chronic kidney disease (CKD) a high BMI is associated with improved survival, a phenomenon referred to as the "obesity paradox". While BMI is easy to determine and helps to categorize patients, it does not differentiate between fat tissue, lean tissue and bone mass. As the BMI may be altered in CKD, e.g. by muscle wasting, we determined in this meta-analysis (i) the association of mortality with fat tissue quantity in CKD and (ii) the association of mortality with abdominal obesity (as measured by waist circumference (WC) or waist-to-hip ratio (WHR)) in CKD. We systematically reviewed databases for prospective or retrospective cohort studies. In eleven studies with 23,523 patients the association between mortality and high fat tissue quantity in CKD was calculated. The pooled hazard ratio (HR) for this association in the CKD group in the dialysis group 0.91 (CI 0.84- 0.98, p = 0.01) which is comparable to the HR for the association with BMI. The HR in patients without dialysis was 0.7 (95% CI 0.53- 0.93, p = 0.01), suggesting a better risk prediction of high fat tissue content with mortality as compared to higher BMI with mortality in patients with CKD without dialysis. Importantly, both BMI and fat tissue quantity in CKD are described by the "obesity paradox": the higher the fat tissue content or BMI, the lower the mortality risk. In thirteen studies with 55,175 patients the association between mortality and high WC or WHR in CKD (with or without dialysis) was calculated. We observed, that the HR in the WHR group was 1.31 (CI 1.08-1.58, p = 0.007), whereas the overall hazard ratio of both groups was 1.09 (CI 1.01-1.18, p = 0.03), indicating that a higher abdominal obesity as measured by WHR is associated with higher mortality in CKD. Our analysis suggests gender-specific differences, which need larger study numbers for validation. This meta-analysis confirms the obesity paradox in CKD using fat tissue quantity as measure and further shows that using abdominal obesity measurements in the routine in obese CKD patients might allow better risk assessment than using BMI or fat tissue quantity. Comparable to the overall population, here, the higher the WHR, the higher the mortality risk.

Impact of quantitative CT texture analysis on the outcome of CT-guided bone biopsy.

Texture analysis can provide new imaging-based biomarkers. Texture analysis derived from computed tomography (CT) might be able to better characterize patients undergoing CT-guided percutaneous bone biopsy. The present study evaluated this and correlated texture features with bioptic outcome in patients undergoing CT-guided bone biopsy. Overall, 123 patients (89 female patients, 72.4 %) were included into the present study. All patients underwent CT-guided percutaneous bone biopsy with an 11 Gauge coaxial needle. Clinical parameters and quantitative imaging features were investigated. Random forest classifier was used to predict a positive biopsy result. Overall, 69 patients had osteolytic metastasis (56.1 %) and 54 had osteoblastic metastasis (43.9 %). The overall positive biopsy rate was 72 %. The developed radiomics model demonstrated a prediction accuracy of a positive biopsy result with an AUC of 0.75 [95 %CI 0.65 - 0.85]. In a subgroup of breast cancer patients, the model achieved an AUC of 0.85 [95 %CI 0.73 - 0.96]. In the subgroup of non-breast cancer patients, the signature achieved an AUC of 0.80 [95 %CI 0.60 - 0.99]. Quantitative CT imaging findings comprised of conventional and texture features can aid to predict the bioptic result of CT-guided bone biopsies. The developed radiomics signature aids in clinical decision-making, and could identify patients at risk for a negative biopsy.