Improved assessment of hypoperfusion, blood-brain barrier disruption, and ischemic cellular damage in stroke patients using magnetic resonance imaging

Introduction Emerging magnetic resonance imaging (MRI) techniques can potentially improve clinical decision-making in acute stroke. First, however, these techniques need to be investigated in a routine clinical setting and their use thoroughly validated by comparing them to established methods and relevant clinical outcomes. In this dissertation, we studied three MRI methods for assessment of cerebral perfusion without exogenous contrast agents, quantification of blood-brain barrier disruption, and improved detection of infratentorial ischemic damage. Methods In Study I, we compared a contrast agent-free method for measuring perfusion, known as BOLD delay (from the blood-oxygenation-level-dependent signal), to the clinical reference standard, dynamic susceptibility contrast MRI (DSC-MRI) in 30 stroke patients within 24 hours of symptom onset. In Study II, we used dynamic contrast-enhanced MRI (DCE-MRI) to quantify blood-brain barrier (BBB) leakage in 54 stroke patients within 48 hours of symptom onset. In Study III, we compared the diagnostic performance of a stimulated echo acquisition mode (STEAM) diffusion weighted imaging (DWI) sequence to that of the clinical reference standard, an echo planar imaging (EPI) DWI sequence, in 57 patients with suspected infratentorial stroke. Results BOLD delay was closely related to DSC-MRI parameters that reflect both macrovascular delay and microvascular perfusion and was capable of distinguishing severe hypoperfusion from milder blood flow changes (Study I). We quantified BBB permeability and observed an increase in leakage over time in ischemic lesions. Leakage was also present in contralateral tissue, where it decreased over time (Study II). STEAM-DWI showed good agreement with EPI-DWI and a high sensitivity to ischemia, with far fewer intraparenchymal artifacts than EPI-DWI (Study III). Conclusions This dissertation shows that BOLD delay, DCE-MRI, and STEAM-DWI can be incorporated into routine MRI protocols for the assessment of stroke patients. They provide useful information regarding perfusion, BBB permeability, and infratentorial ischemic damage and have the potential to influence acute stroke diagnosis and management. The dissertation also highlights several weaknesses of these methods, opening up paths for further research and improvement.Einführung Innovative Magnetresonanztomographie-Techniken (MRT) bergen das Potential klinische Therapieentscheidungen beim akuten Schlaganfall positiv beeinflussen zu können. Diese Techniken müssen jedoch zuerst in der klinischen Routine evaluiert und genau validiert werden, indem man sie mit etablierten Methoden und deren Ergebnissen vergleicht. In dieser Dissertation wurden drei MRT-Techniken zum verbesserten Nachweis infratentorieller Schlaganfälle, Beurteilung der Bluthirnschranken-Störung und Kontrastmittel-freien Perfusion untersucht. Methoden In Studie I wurde eine Kontrastmittel-freie Methode der Perfusionsmessung, bekannt als "BOLD („blood-oxygenation-level-dependent“) delay" mit dem klinischen Referenzstandard, der DSC-MRT („dynamic susceptibility contrast“) bei 30 Schlaganfallpatienten innerhalb von 24 Stunden nach Symptombeginn verglichen. In Studie II wurde die DCE-MRT („dynamic contrast-enhanced“) eingesetzt, um eine Störung der Bluthirnschranke bei 54 Schlaganfallpatienten innerhalb von 48 Stunden nach Symptombeginn quantitativ erfassen zu können. In Studie III wurde die diagnostische Aussagekraft der STEAM („stimulated echo acquisition mode“) diffusions-gewichtete (DWI) Sequenz mit der klinischen Referenzmethode, der echoplanaren (EPI=echo planar imaging) DWI bei 57 Patienten mit fraglichen infratentoriellen Schlaganfall evaluiert. Ergebnisse Die BOLD Technik zeigte einen engen Zusammenhang mit DSC-MRT Parametern hinsichtlich Folgen von Stenosen/Verschlüssen der zerebralen Arterien. Eine schwere Minderdurchblutung konnte von leichten Veränderungen der Blutflusses unterschieden werden (Studie I). Störungen der Bluthirnschranke konnten quantitativ erfaßt und eine weitere Zunahme im ischämischen Areal im zeitlichen Verlauf beobachtet werden. Eine Störung der Bluthirnschranke fand sich auch im „gesunden“ kontraläsionalen Hirngewebe, die sich im zeitlichen Verlauf besserte (Studie II). Die STEAM-DWI zeigte eine gute Übereinstimmung mit der EPI-DWI und eine hohe Sensitivität mit deutlich weniger intraparenchymalen Artefakten als die EPI-DWI (Studie III). Schlußfolgerungen Diese Dissertation konnte zeigen, daß der BOLD delay, die DCE-Technik und die STEAM-DWI für die MRT Schlaganfalldiagnostik in Routine-Protokolle inkorporiert werden könnte. Damit stünden aussagekräftige Zusatzinformationen zu Perfusion, Bluthirnschrankenpermeabilität und Detektion von infratentoriellen Schlaganfällen zur Verfügung mit der Möglichkeit besserer Therapieoptionen. Diese Dissertation zeigt auch die Schwächen dieser Methoden auf und eröffnet damit einen Weg für weitere Forschungsmöglichkeiten und Verbesserungen

Histological Sequences of Long Bone Development in the New Zealand White Rabbits

Long bone development occurred through endochondral ossification. The current study investigated the main histological changes associated with the development of humerus from the New Zealand white rabbits. The upper limb or humerus during embryonic (12, 14, 15, 16, 18, 21, 24 and 27 days) and neonatal (3 and 7 days) development was processed for light microscopy. Three stages preceded endochondral ossification; limb bud (mesenchymal cells), cartilage primordia (mesenchymal condensation and differentiation into chondrocytes) and cartilage template (organization of chondrocytes into proliferative and hypertrophic zones) by 12, 14 and 15 days, respectively. At day 16, cartilage template elongated forming a cartilaginous diaphysis of the prospective humerus. At day 18, cartilaginous epiphyses were formed. Medullary cavity was established by day 21 with no signs of calcification in the bone collar. Primary ossification center appeared within the diaphysis at day 24 of embryonic development. Secondary ossification centers were seen within the epiphyses by day 3 of neonatal development. Two types of cartilage canals were investigated; short epiphyseal canals appeared from day 21 and long transphyseal canals appeared from day 27. At day 7 of neonatal development, the cartilage of the humerus was limited in two places; articular epiphyseal growth cartilage between articular surface and secondary ossification center, epiphyseal physeal growth cartilage between the secondary and primary ossification centers. The current study summarized the main histological stages of development of rabbit humerus. These results should be considered in molecular studies of endochondral bone formation

The Effect of Scan Length on the Assessment of BOLD Delay in Ischemic Stroke

Objectives: To evaluate the impact of resting-state functional MRI scan length on the diagnostic accuracy, image quality and lesion volume estimation of BOLD delay maps used for brain perfusion assessment in acute ischemic stroke. Methods: Sixty-three acute ischemic stroke patients received a 340 s resting-state functional MRI within 24 h of stroke symptom onset. BOLD delay maps were calculated from the full scan and four shortened versions (68 s, 136 s, 204 s, 272 s). The BOLD delay lesions on these maps were compared in terms of spatial overlap and volumetric agreement with the lesions derived from the full scans and with time-to-maximum (Tmax) lesions derived from DSC-MRI in a subset of patients (n = 10). In addition, the interpretability and quality of these maps were compared across different scan lengths using mixed models. Results: Shortened BOLD delay scans showed a small volumetric bias (ranging from 0.05 to 5.3mL; between a 0.13%volumetric underestimation and a 7.7%overestimation relative to the mean of the volumes, depending on scan length) compared to the full scan. Decreased scan length was associated with decreased spatial overlap with both the BOLD delay lesions derived from the full scans and with Tmax lesions. Only the two shortest scan lengths (68 and 136 s) were associated with substantially decreased interpretability, decreased structure clarity, and increased noisiness of BOLD delay maps. Conclusions: BOLD delay maps derived from resting-state fMRI scans lasting 272 and 204 s provide sufficient diagnostic quality and adequate assessment of perfusion lesion volumes. Such shortened scans may be helpful in situations where quick clinical decisions need to be made

Opening the black box of artificial intelligence for clinical decision support: A study predicting stroke outcome

State-of-the-art machine learning (ML) artificial intelligence methods are increasingly leveraged in clinical predictive modeling to provide clinical decision support systems to physicians. Modern ML approaches such as artificial neural networks (ANNs) and tree boosting often perform better than more traditional methods like logistic regression. On the other hand, these modern methods yield a limited understanding of the resulting predictions. However, in the medical domain, understanding of applied models is essential, in particular, when informing clinical decision support. Thus, in recent years, interpretability methods for modern ML methods have emerged to potentially allow explainable predictions paired with high performance. To our knowledge, we present in this work the first explainability comparison of two modern ML methods, tree boosting and multilayer perceptrons (MLPs), to traditional logistic regression methods using a stroke outcome prediction paradigm. Here, we used clinical features to predict a dichotomized 90 days post-stroke modified Rankin Scale (mRS) score. For interpretability, we evaluated clinical features' importance with regard to predictions using deep Taylor decomposition for MLP, Shapley values for tree boosting and model coefficients for logistic regression. With regard to performance as measured by Area under the Curve (AUC) values on the test dataset, all models performed comparably: Logistic regression AUCs were 0.83, 0.83, 0.81 for three different regularization schemes; tree boosting AUC was 0.81; MLP AUC was 0.83. Importantly, the interpretability analysis demonstrated consistent results across models by rating age and stroke severity consecutively amongst the most important predictive features. For less important features, some differences were observed between the methods. Our analysis suggests that modern machine learning methods can provide explainability which is compatible with domain knowledge interpretation and traditional method rankings. Future work should focus on replication of these findings in other datasets and further testing of different explainability methods

RLOps:Development Life-cycle of Reinforcement Learning Aided Open RAN

Radio access network (RAN) technologies continue to witness massive growth, with Open RAN gaining the most recent momentum. In the O-RAN specifications, the RAN intelligent controller (RIC) serves as an automation host. This article introduces principles for machine learning (ML), in particular, reinforcement learning (RL) relevant for the O-RAN stack. Furthermore, we review state-of-the-art research in wireless networks and cast it onto the RAN framework and the hierarchy of the O-RAN architecture. We provide a taxonomy of the challenges faced by ML/RL models throughout the development life-cycle: from the system specification to production deployment (data acquisition, model design, testing and management, etc.). To address the challenges, we integrate a set of existing MLOps principles with unique characteristics when RL agents are considered. This paper discusses a systematic life-cycle model development, testing and validation pipeline, termed: RLOps. We discuss all fundamental parts of RLOps, which include: model specification, development and distillation, production environment serving, operations monitoring, safety/security and data engineering platform. Based on these principles, we propose the best practices for RLOps to achieve an automated and reproducible model development process.Comment: 17 pages, 6 figrue

Tutors, The Valuable Resource to Enhance Medical Students’ Motivation.

Background: Students’ academic performance is largely affected by their motivation. Moreover, health professions’ education needs motivated students who are keen to tolerate the burden of clinical work along with the academic excellence to graduate competently. This study assessed the effect of tutors on students’ motivation. Method: A cross-sectional, institution-based study of the first-year medical students at University of Khartoum, Sudan was conducted. A self-administered questionnaire was used comprising a modified Motivated Strategies for Learning Questionnaire (MSLQ) with students’ evaluation of their tutors after semester one community medicine course. A total of 237 out of 324 students responded. Pearson productmoment correlation coefficient was used to test the relationship between motivation and evaluation. Hierarchical multiple regression model tested the ability of evaluation factors to predict motivation score. Results: There was a significant association between tutor’s characteristics regarding creativity in conducting the sessions, igniting discussion, and adequacy of knowledge about the course contents and the motivation score (p-value = 0.001). There was a strong, positive correlation between the perceived evaluation score and perceived motivation score (r = 0.505, n = 206, p < 0.0005). After controlling age, gender, paternal educational levels, and scores of Sudanese certificate upon entry, R squared change = 0.28, F change (9.181) = 8.416, p <0.001. In the final model, the content of the course was statistically significant, standardized Beta = 0.285, indicating that content uniquely explains 5.7% of the variance in total perceived motivation score. Conclusion: The evaluation score explained 28% of the variance in student motivation. Students’ motivation issignificantly associated with tutor’s teaching skills concerning knowledge, creativity, students’ involvement, and attractiveness in conducting the tutorials. Improving course content can enhance students’ motivation toward community medicine

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Teaching

A miscellaneous collection of teaching resource

2018 - Improving [Your] Science Course - Charité Universitätsmedizin Berlin

Resources for the course (aimed at graduate students

Behavior of I-beam

Pretensioned extended, bolted end-plate moment connections are very popular due to ease of fabrication and erection. In order to identify the effect of different parameters on the behavior of the connection, a three-dimensional finite element model that accounts for both geometrical and material non-linearities is developed using the multi-purpose software package ANSYS. A parametric study is conducted using this model on two end-plate configurations: four bolts and multiple row extended end plates. The studied parameters were as follows: beam depth, end-plate thickness, bolts diameter, bolts pitch, bolts gage, and end-plate stiffener. Then, yield line analysis is used to propose equations for the end-plate bending capacity. A design model is assumed for bolt forces analysis, and design equations are proposed. The proposed equations are compared to the finite element results and the current design codes