IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections

Introduction: We aimed to investigate several blood-based biomarkers related to inflammation, immunity, and stress response in a cohort of patients without stroke-associated infections regarding their predictive abilities for functional outcome and explore whether they correlate with MRI markers, such as infarct size or location. Methods: We combined the clinical and radiological data of patients participating in two observational acute stroke cohorts: the PREDICT and 1000Plus studies. The following blood-based biomarkers were measured in these patients: monocytic HLA-DR, IL-6, IL-8, IL-10, LBP, MRproANP, MRproADM, CTproET, Copeptin, and PCT. Multiparametric stroke MRI was performed including T2*, DWI, FLAIR, TOF-MRA, and perfusion imaging. Standard descriptive sum statistics were used to describe the sample. Associations were analyzed using Fischer's exact test, independent samples t-test and Spearmans correlation, where appropriate. Results: Demographics and stroke characteristics were as follows: 94 patients without infections, mean age 68 years (SD 10.5), 32.2% of subjects were female, median NIHSS score at admission 3 (IQR 2-5), median mRS 3 months after stroke 1 (IQR 0-2), mean volume of DWI lesion at admission 5.7 ml (SD 12.8), mean FLAIR final infarct volume 10 ml (SD 14.9), cortical affection in 61% of infarctions. Acute DWI lesion volume on admission MRI was moderately correlated to admission/maximum IL-6 as well as maximum LBP. Extent of perfusion deficit and mismatch were moderately correlated to admission/maximum IL-6 levels. Final lesion volume on FLAIR was moderately correlated to admission IL-6 levels. Conclusion: We found IL-6 to be associated with several parameters from acute stroke MRI (acute DWI lesion, perfusion deficit, final infarct size, and affection of cortex) in a cohort of patients not influenced by infections

risk factors and impact on quality of life

Objectives Emerging evidence suggests that fatigue in myasthenia gravis (MG) is a relevant problem that negatively impacts activities of daily living (ADL). The relationship between fatigue and quality of life (QoL) has never been systematically explored in MG patients. The study aimed to assess the prevalence of fatigue and its relation to ADL and QoL as well as to identify factors associated with fatigue in MG. Material and Methods This was a cross- sectional observational study in patients with confirmed diagnosis of MG independent of disease severity. Prevalence of fatigue was assessed using the Chalder Fatigue Scale (CFQ). Impact of fatigue on ADL and QoL was assessed by the MG activities of daily living profile (MG-ADL) and the MG-specific quality-of-life instrument (MG-QoL), respectively. Association of fatigue with sociodemographics, clinical characteristics of MG, and comorbidities including mood and anxiety disorders as well as sleep disorders was investigated using multivariable logistic regression analyses. Results Overall, 200 MG patients were included. The observed rate of fatigue was 56.1%, of those 70.4% fulfilled the criteria of chronic fatigue (CF) with a duration of ≥6 months. Relevant fatigue was strongly associated to ADL and QoL. Factors associated with relevant fatigue were disease severity and depressive state. Furthermore, positive muscle-specific tyrosine kinase (MuSK) antibody status showed a strong association with relevant fatigue. Conclusions MG patients have a high prevalence of fatigue which negatively impacts ADL and QoL. MG-specific clinical characteristics are related to fatigue and might help to identify MG patients at risk for fatigue

Procalcitonin-Guided Antibiotic Therapy after Stroke

Background: Pneumonia is among the most common acute complications after stroke and is associated with poor long-term outcome. Biomarkers may help identifying stroke patients at high risk for developing stroke-associated pneumonia (SAP) and to guide early treatment. Aims: This trial investigated whether procalcitonin (PCT) ultrasensitive (PCTus)-guided antibiotic treatment of SAP can improve functional outcome after stroke. Methods: In this international, multicenter, randomized, controlled clinical trial with blinded assessment of outcomes, patients with severe ischemic stroke in the middle cerebral artery territory were randomly assigned within 40 h after symptom onset to PCTus-based antibiotic therapy guidance in addition to stroke unit care or standard stroke unit care alone. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale (mRS) and dichotomized as acceptable (≤4) or unacceptable (≥5). Secondary endpoints included usage of antibiotics, infection rates, days of fever, and mortality. The trial was registered with http://ClinicalTrials.gov (Identifier NCT01264549). Results: In the intention-to-treat-analysis based on 227 patients (112 in PCT and 115 in control group), 197 patients completed the 3-month follow-up. Adherence to PCT guidance was 65%. PCT-guided therapy did not improve functional outcome as measured by mRS (odds ratio 0.79; 95% confidence interval 0.45–1.35, p = 0.47). Pneumonia rate and mortality were similar in both groups. Days with fever tended to be lower (p = 0.055), whereas total number of days treated with antibiotics were higher (p = 0.004) in PCT compared to control group. A post hoc analysis including all PCT values in the intention-to-treat population demonstrated a significant increase on the first day of infection in patients with pneumonia and sepsis compared to patients with urinary tract infections or without infections (p < 0.0001). Conclusion: PCTus-guided antibiotic therapy did not improve functional outcome at 3 months after severe ischemic stroke. PCT is a promising biomarker for early detection of pneumonia and sepsis in acute stroke patients

a pilot study

Muscular weakness in myasthenia gravis (MG) is commonly assessed using Quantitative Myasthenia Gravis Score (QMG). More objective and quantitative measures may complement the use of clinical scales and might detect subclinical affection of muscles. We hypothesized that muscular weakness in patients with MG can be quantified with the non-invasive Quantitative Motor (Q-Motor) test for Grip Force Assessment (QGFA) and Involuntary Movement Assessment (QIMA) and that pathological findings correlate with disease severity as measured by QMG. Methods This was a cross-sectional pilot study investigating patients with confirmed diagnosis of MG. Data was compared to healthy controls (HC). Subjects were asked to lift a device (250 and 500 g) equipped with electromagnetic sensors that measured grip force (GF) and three- dimensional changes in position and orientation. These were used to calculate the position index (PI) and orientation index (OI) as measures for involuntary movements due to muscular weakness. Results Overall, 40 MG patients and 23 HC were included. PI and OI were significantly higher in MG patients for both weights in the dominant and non-dominant hand. Subgroup analysis revealed that patients with clinically ocular myasthenia gravis (OMG) also showed significantly higher values for PI and OI in both hands and for both weights. Disease severity correlates with QIMA performance in the non-dominant hand. Conclusion Q-Motor tests and particularly QIMA may be useful objective tools for measuring motor impairment in MG and seem to detect subclinical generalized motor signs in patients with OMG. Q-Motor parameters might serve as sensitive endpoints for clinical trials in MG

Concomitant statin use does not impair the clinical outcome of patients with diffuse large B cell lymphoma treated with rituximab-CHOP

Preclinical data indicated a detrimental effect of statins on the anti-lymphoma activity of rituximab. We evaluated the impact of concomitant statin medication on the response and survival of patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as first-line therapy. Medical histories of patients with DLBCL who were treated with R-CHOP as first-line therapy were assessed for concomitant statin use, response after completion of chemotherapy, event-free survival (EFS), and overall survival (OS). Furthermore, 2-[18F]fluor-2-deoxyglucose (FDG)-PET/CT results after completion of first-line therapy were compared between the groups. Overall, 145 patients with DLBCL treated with R-CHOP from January 2001 to December 2009 were analyzed. Twenty-one (15%) patients received statins throughout therapy. Five-year EFS was 67.3% in patients without statins compared with 79% in patients receiving statins during R-CHOP (HR, 0.47; 95% CI, 0.15-1.54, p = 0.2). Five-year OS was 81.4% for patients without statins compared with 93.3% for patients taking statins (HR, 0.58; 95% CI 0.07-4.55, p = 0.6). There were no statistically significant differences in the rates of complete remissions between the two groups (75% in the non-statin group versus 86% in the statin group, p = 0.45). A trend toward a lower rate of complete metabolic responses in FDG-PET/CT after chemotherapy was seen in patients without statin medication compared with the patients taking statins (84% versus 92%, p = 0.068). Concomitant statin use had no adverse impact on response to chemotherapy, EFS, and OS in patients treated with R-CHOP for DLBC

Hemmung des GM2-Gangliosid Metabolismus in, aus humanen Monozyten generierten, Dendritischen Zellen

Seitdem man Ende der 80er Jahre mit der Verwendung von dendritischen Zellen in der immuntherapeutischen Behandlung von Krebs begann, wurden in klinischen Studien bereits einige Fortschritte, die zu einer verbesserten Prognose von Patienten beitrugen, erzielt. Jedoch sind DC-basierte Antitumorvakzinierungen bislang nur Chemotherapie-begleitend einsetzbar, da den induzierten Immunantworten eine ausreichende Aggressivität zur Auslöschung jeglicher Tumorzelle fehlt. Durch ihre Zelltyp-spezifische und Differenzierungsgrad-abhängige endogene Expression auf eukaryotischen Zellen und durch ihre extrinsische immunsupprimierende Wirkungsweise, wenn sie in charakteristischen Sekretionsprofilen von Tumorzellen abgegeben werden, wurde gezeigt, dass Ganglioside wichtige Modulatoren von Immunantworten sind. Durch die Beobachtung, dass eine GM2- bzw. GM2A-Expression in Monozyten fehlt, aber kontinuierlich während der Differenzierung zu unreifen MDCs steigt um dann in LPS-gereiften MDCs wieder verringert zu sein, lässt sich schlussfolgern, dass dieses Gangliosid eine essentielle Rolle hinsichtlich Überleben und Funktion in DCs haben könnte. In Anlehnung an die durch GM2-Akkumulation charakterisierten neurodegenerativen und letztendlich fatalen GM2-Gangliosidosen, Tay-Sachs (HexA), Sandhoff (HexA/HexB) und AB Variant (GM2A), wurden während dieser Arbeit beide am GM2-Metabolismus beteiligten Komponenten herunterreguliert; zum einen durch Anwendung von PUGNAc – ein chemischer Inhibitor der HexA – und zum anderen durch Elektrotransfektion mit einer GM2A-spezifischen siRNA. Während sich für die Hemmung des GM2-Aktivatorproteins keine phänotypischen und funktionellen Veränderungen nachweisen ließen – was wahrscheinlich auf einer verbliebenen Restaktivität durch eine nicht vollständige Hemmung des GM2A basiert – , konnten für die PUGNAc-bedingte Hemmung der HexA sowohl morphologische als auch funktionelle Beeinträchtigungen, deren Vehemenz in Korrelation zur angewandten Inhibitorkonzentration stand, nachgewiesen werden. Je höher die angewandte Inhibitorkonzentration war, desto drastischer war das Ausmaß der Beeinträchtigungen. Es konnte ein PUGNAc-bedingter Verlust der Phagozytoseaktivität unreifer MDCs, eine reduzierte Migrationsfähigkeit und allostimulatorische Kapazität in LPS-gereiften MDCs einhergehend mit einer Herunterregulierung der Expression bestimmter CD-Moleküle und einer stark verminderte Produktion proinflammatorischer Zytokine und Chemokine nachgewiesen werden. Aufgrund des funktionellen Einflusses und der deutlich gewordenen regulatorischen Importanz hinsichtlich der Immunogenität von MDCs stellt das GM2-Gangliosid und die, zu seinem Metabolismus unabdingbaren Komponenten, potente Faktoren zur Modifikation und Optimierung der DC-Immunogenität zu Zwecken der Tumorvakzinierung dar.Inhibition of the GM2 ganglioside metabolism in human monocyte derived dendritic cells Since the late 80’s when usage of dendritic cells in immunotherapeutic treatment of cancer began, some progress within clinical trials could be achieved, contributing to improved prognosis of patients. However, DC-based anti-tumor vaccinations are so far only chemotherapy concomitantly used, since the induced immune responses lack sufficient aggressiveness to remove all tumor cells. By their cell type-specific and differentiation-dependent endogenous expression on eukaryotic cells and their extrinsic immunosuppressive action, when submitted in characteristic secretion-profiles by tumor cells it could be shown that gangliosides are important modulators of immune responses. By the observation that the expression of GM2 (and GM2A resp.) is lacking in monocytes, but increases continuously during differentiation to MDCs to then again decrease in LPS-matured MDCs, the conclusion that there might be an essential role of this ganglioside towards DC-survival and function could be assumed. Relating to by GM2-accumulation characterized neurodegenerative and ultimately fatal GM2-gangliosidosis, Tay-Sachs (HexA), Sandhoff (HexA / HexB) and AB Variant (GM2a), both components involved in the GM2-metabolism were down-regulated during this work; on the one hand by the application of PUGNAc - a chemical inhibitor of HexA - and on the other hand by electrotransfection with a GM2A-specific siRNA. While no phenotypic and functional changes could be detected for the inhibition of the GM2-activator protein - which is probably based on a residual activity due to an incomplete inhibition of GM2A - for the PUGNAc-induced inhibition of HexA both morphological and functional impairments, with a vehemence correlating to the applied inhibitor concentrations, could be demonstrated. The higher the inhibitor concentration applied, the more drastic was the extent of deterioration. A PUGNAc-induced loss of phagocytic activity of immature MDCs, a reduced migratory ability and allostimulatory capacity in LPS-matured MDCs, accompanied by a down-regulated expression of certain CD-molecules and a greatly reduced production of proinflammatory cytokines and chemokines, was demonstrated. Due to the functional influence and the regulatory importancy regarding the immunogenicity of MDCs the GM2 ganglioside and the indispensable components to its metabolism, are potent factors for the modification and optimization of DC immunogenicity for tumor vaccination purposes

Daratumumab for treatment‐refractory antibody‐mediated diseases in neurology

Background and purpose A fraction of patients with antibody-mediated autoimmune diseases remain unresponsive to first-/second-line and sometimes even to escalation immunotherapies. Because these patients are still affected by poor outcome and increased mortality, we investigated the safety and efficacy of the plasma cell-depleting anti-CD38 antibody daratumumab in life-threatening, antibody-mediated autoimmune diseases. Methods In this retrospective, single-center case series, seven patients with autoantibody-driven neurological autoimmune diseases (autoimmune encephalitis, n = 5; neurofascin antibody-associated chronic inflammatory demyelinating polyneuropathy associated with sporadic late onset nemaline myopathy, n = 1; seronegative myasthenia gravis, n = 1) unresponsive to a median of four (range = 4–9) immunotherapies were treated with four to 20 cycles of 16 mg/kg daratumumab. Results Daratumumab allowed a substantial clinical improvement in all patients, as measured by modified Rankin Scale (mRS; before treatment: mRS =5, n = 7; after treatment: median mRS =4, range = 0–5), Clinical Assessment Scale in Autoimmune Encephalitis (from median 21 to 3 points, n = 5), Inflammatory Neuropathy Cause and Treatment disability score (from 7 to 0 points, n = 1), and Quantitative Myasthenia Gravis score (from 16 to 8 points, n = 1). Daratumumab induced a substantial reduction of disease-specific autoreactive antibodies, total IgG (serum, 66%, n = 7; cerebrospinal fluid, 58%, n = 5), and vaccine-induced titers for rubella (50%) and tetanus toxoid (74%). Treatment-related toxicities Grade 3 or higher occurred in five patients, including one death. Conclusions Our findings suggest that daratumumab provided a clinically relevant depletion of autoreactive long-lived plasma cells, identifying plasma cell-targeted therapies as promising escalation therapy for highly active, otherwise treatment-refractory autoantibody-mediated neurological diseases

STEAM Powered: An Argument for the Robust Integration of Artistic and Engineering Practices in Design for Additive Manufacturing

Additive manufacturing (AM) has been widely integrated in engineering institutions as it can enable designs of seemingly infinite complexity. Despite this potential, research has demonstrated the difficulty in encouraging engineering students to think beyond traditional manufacturing boundaries. Undergraduate programs in the arts have likewise embraced AM for the complex artistic concepts it enables. But, when contrasted against engineers, art students may be more inclined to leverage the geometric freedom of AM by virtue of fundamental differences in which creativity manifests in STEM practitioners and artists. As such, there is a need for the robust convergence of STEM and Arts disciplines in an undergraduate STEAM design framework, which encourages engineering students to adopt arts-based practices to create new, innovative, products outside the realm of conventional design concepts. In this paper, the authors make an argument for such a framework, grounding it in fundamental epistemic practices within both engineering and artistic design.Mechanical Engineerin

Machine learning from wristband sensor data for wearable, noninvasive seizure forecasting

Objective: Seizure forecasting may provide patients with timely warnings to adapt their daily activities and help clinicians deliver more objective, personalized treatments. Although recent work has convincingly demonstrated that seizure risk assessment is in principle possible, these early approaches relied largely on complex, often invasive setups including intracranial electrocorticography, implanted devices, and multichannel electroencephalography, and required patient-specific adaptation or learning to perform optimally, all of which limit translation to broad clinical application. To facilitate broader adaptation of seizure forecasting in clinical practice, noninvasive, easily applicable techniques that reliably assess seizure risk without much prior tuning are crucial. Wristbands that continuously record physiological parameters, including electrodermal activity, body temperature, blood volume pulse, and actigraphy, may afford monitoring of autonomous nervous system function and movement relevant for such a task, hence minimizing potential complications associated with invasive monitoring and avoiding stigma associated with bulky external monitoring devices on the head. Methods: Here, we applied deep learning on multimodal wristband sensor data from 69 patients with epilepsy (total duration > 2311 hours, 452 seizures) to assess its capability to forecast seizures in a statistically significant way. Results: Using a leave-one-subject-out cross-validation approach, we identified better-than-chance predictability in 43% of the patients. Time-matched seizure surrogate data analyses indicated forecasting not to be driven simply by time of day or vigilance state. Prediction performance peaked when all sensor modalities were used, and did not differ between generalized and focal seizure types, but generally increased with the size of the training dataset, indicating potential further improvement with larger datasets in the future. Significance: Collectively, these results show that statistically significant seizure risk assessments are feasible from easy-to-use, noninvasive wearable devices without the need of patient-specific training or parameter optimization