Functional transcranial Doppler: Selection of methods for statistical analysis and representation of changes in flow velocity

INTRODUCTION Transcranial Doppler (TCD) is a method used to study cerebral hemodynamics. In the majority of TCD studies, regression analysis and analysis of variance are the most frequently applied statistical methods. However, due to the dynamic and interdependent nature of flow velocity, nonparametric tests may allow for better statistical analysis and representation of results. METHOD The sample comprised 30 healthy participants, aged 33.87 ± 7.48 years; with 33% (n = 10) females. During a visuo-motor task, the mean flow velocity (MFV) in the middle cerebral artery (MCA) was measured using TCD. The MFV was converted to values relative to the resting state. The results obtained were analyzed using the general linear model (GLM) and the general additional model (GAM). The fit indices of both analysis methods were compared with each other. RESULTS Both MCAs showed a steady increase in MFV during the visuo-motor task, smoothly returning to resting state values. During the first 20 seconds of the visuo-motor task, the MFV increased by a factor of 1.06 ± 0.07 in the right-MCA and by a factor of 1.08 ± 0.07 in the left-MCA. GLM and GAM showed a statistically significant change in MFV (GLM:F(2, 3598) = 16.76, P < .001; GAM:F(2, 3598) = 21.63, P < .001); together with effects of hemispheric side and gender (GLM:F(4, 3596) = 7.83, P < .005; GAM:F(4, 3596) = 2.13, P = .001). Comparing the models using the χ$^{2}$ test for goodness of fit yields a significant difference χ$^{2}$ (9.9556) = 0.6836, P < .001. CONCLUSIONS Both the GLM and GAM yielded valid statistical models of MFV in the MCA in healthy subjects. However, the model using the GAM resulted in improved fit indices. The GAM's advantage becomes even clearer when the MFV curves are visualized; yielding a more realistic approach to brain hemodynamics, thus allowing for an improvement in the interpretation of the mathematical and statistical results. Our results demonstrate the utility of the GAM for the analysis and representation of hemodynamic parameters

Psychopathological Symptom Load and Distinguishable Cerebral Blood Flow Velocity Patterns in Patients With Schizophrenia and Healthy Controls: A Functional Transcranial Doppler Study

Introduction: Schizophrenia is a severe psychiatric disorder, with executive dysfunction and impaired processing speed playing a pivotal role in the course of the disease. In patients with schizophrenia, neurocognitive deficits appear to be related to alterations in cerebral hemodynamics. It is not fully understood if psychopathological symptom load (i.e., presence and severity of symptoms) is also related to alterations in cerebral hemodynamics. We aim to study the relationship between psychopathological symptom load and cerebral hemodynamics in the Middle Cerebral Artery (MCA) during a cognitive task in patients with schizophrenia and healthy controls. Methodology: Cerebral hemodynamics in the MCA were examined in 30 patients with schizophrenia and 15 healthy controls using functional Transcranial Doppler (fTCD) during the Trail Making Test (TMT). Psychopathological symptoms were measured using the Brief Psychiatric Rating Scale (BPRS). Patients were dichotomized according to BPRS scores: mild-moderate (BPRS < 41, n = 15) or marked-severe (BPRS ≧ 41, n = 15). Mean blood flow velocity (MFV) in the MCA and processing speed of the TMT were analyzed. Cerebral hemodynamics were analyzed using the general additional model (GAM) with a covariate analysis of variance (ANCOVA) for group comparisons. Results: Patients and healthy controls were comparable regarding demographics. Patients had a slower processing speed for the TMT-A (patients-severe: 52s, patients-moderate: 40s, healthy-controls: 32s, p = 0.019) and TMT-B [patients-severe: 111s, patients-moderate: 76s, healthy-controls: 66s, p < 0.001)]. Patients demonstrated differing hemodynamic profiles in both TMTs: TMT- A [F(6, 1,792) = 17, p < 0.000); TMT-B [F(6, 2,692) = 61.93, p < 0.000], with a delay in increase in MFV and a failure to return to baseline values. Conclusions: Patients with schizophrenia demonstrated slower speeds of processing during both the TMT-A and TMT-B. The speed of processing deteriorated with increasing psychopathological symptom load, additionally a distinct cerebral hemodynamic pattern in the MCA was observed. Our results further support the view that severity of schizophrenia, particularly psychopathological symptom load, influences performance in neurocognitive tasks and is related to distinct patterns of brain hemodynamics

Deep Brain Stimulation for Parkinson's Disease with Early Motor Complications: A UK Cost-Effectiveness Analysis

This is the final version of the article. Available from Public Library of Science via the DOI in this record.BACKGROUND: Parkinson's disease (PD) is a debilitating illness associated with considerable impairment of quality of life and substantial costs to health care systems. Deep brain stimulation (DBS) is an established surgical treatment option for some patients with advanced PD. The EARLYSTIM trial has recently demonstrated its clinical benefit also in patients with early motor complications. We sought to evaluate the cost-effectiveness of DBS, compared to best medical therapy (BMT), among PD patients with early onset of motor complications, from a United Kingdom (UK) payer perspective. METHODS: We developed a Markov model to represent the progression of PD as rated using the Unified Parkinson's Disease Rating Scale (UPDRS) over time in patients with early PD. Evidence sources were a systematic review of clinical evidence; data from the EARLYSTIM study; and a UK Clinical Practice Research Datalink (CPRD) dataset including DBS patients. A mapping algorithm was developed to generate utility values based on UPDRS data for each intervention. The cost-effectiveness was expressed as the incremental cost per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were undertaken to explore the effect of parameter uncertainty. RESULTS: Over a 15-year time horizon, DBS was predicted to lead to additional mean cost per patient of £26,799 compared with BMT (£73,077/patient versus £46,278/patient) and an additional mean 1.35 QALYs (6.69 QALYs versus 5.35 QALYs), resulting in an incremental cost-effectiveness ratio of £19,887 per QALY gained with a 99% probability of DBS being cost-effective at a threshold of £30,000/QALY. One-way sensitivity analyses suggested that the results were not significantly impacted by plausible changes in the input parameter values. CONCLUSION: These results indicate that DBS is a cost-effective intervention in PD patients with early motor complications when compared with existing interventions, offering additional health benefits at acceptable incremental cost. This supports the extended use of DBS among patients with early onset of motor complications.Funding: Medtronic funded the development of the model, including consulting fees to physicians and health economic specialists, sponsored a medical writer and reviewed the manuscript. The funders provided input on the study design, decision to publish, and preparation of the manuscript. HTA Consulting provided support in the form of salaries for authors [TF], and staff resources to support evidence review and synthesis. They did not have any additional role in the study design and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

Attracting cavities for docking. Replacing the rough energy landscape of the protein by a smooth attracting landscape.

Molecular docking is a computational approach for predicting the most probable position of ligands in the binding sites of macromolecules and constitutes the cornerstone of structure-based computer-aided drug design. Here, we present a new algorithm called Attracting Cavities that allows molecular docking to be performed by simple energy minimizations only. The approach consists in transiently replacing the rough potential energy hypersurface of the protein by a smooth attracting potential driving the ligands into protein cavities. The actual protein energy landscape is reintroduced in a second step to refine the ligand position. The scoring function of Attracting Cavities is based on the CHARMM force field and the FACTS solvation model. The approach was tested on the 85 experimental ligand-protein structures included in the Astex diverse set and achieved a success rate of 80% in reproducing the experimental binding mode starting from a completely randomized ligand conformer. The algorithm thus compares favorably with current state-of-the-art docking programs

Where do ICU trainees really look? An eye-tracking analysis of gaze patterns during central venous catheter insertion

Background: There is limited knowledge about gaze patterns of intensive care unit (ICU) trainee doctors during the insertion of a central venous catheter (CVC). The primary objective of this study was to examine visual patterns exhibited by ICU trainee doctors during CVC insertion. Additionally, the study investigated whether differences in gaze patterns could be identified between more and less experienced trainee doctors. Methods: In a real-life, prospective observational study conducted at the interdisciplinary ICU at the University Hospital Zurich, Switzerland, ICU trainee doctors underwent eye-tracking during CVC insertion in a real ICU patient. Using mixed-effects model analyses, the primary outcomes were dwell time, first fixation duration, revisits, fixation count, and average fixation time on different areas of interest (AOI). Secondary outcomes were above eye-tracking outcome measures stratified according to experience level of participants. Results: Eighteen participants were included, of whom 10 were inexperienced and eight more experienced. Dwell time was highest for CVC preparation table ( p = 0.02), jugular vein on ultrasound image ( p < 0.001) and cervical puncture location ( p < 0.001). Concerning experience, dwell time and revisits on jugular vein on ultrasound image ( p = 0.02 and p = 0.04, respectively) and cervical puncture location ( p = 0.004 and p = 0.01, respectively) were decreased in more experienced ICU trainees. Conclusions: Various AOIs have distinct significance for ICU trainee doctors during CVC insertion. Experienced participants exhibited different gaze behavior, requiring less attention for preparation and handling tasks, emphasizing the importance of hand-eye coordination

Association between two distinct executive tasks in schizophrenia: a functional transcranial Doppler sonography study

BACKGROUND: Schizophrenia is a severe mental disorder involving impairments in executive functioning, which are important cognitive processes that can be assessed by planning tasks such as the Stockings of Cambridge (SOC), and tasks of rule learning/abstraction such as the Wisconsin Card Sorting Test (WCST). We undertook this study to investigate the association between performance during separate phases of SOC and WCST, including mean cerebral blood flow velocity (MFV) measurements in chronic schizophrenia. METHODS: Functional transcranial Doppler sonography (fTCD) was used to assess bilateral MFV changes in the middle (MCA) and anterior (ACA) cerebral arteries. Twenty-two patients with chronic schizophrenia and 20 healthy subjects with similar sociodemographic characteristics performed SOC and WCST during fTCD measurements of the MCA and the ACA. The SOC was varied in terms of easy and difficult problems, and also in terms of separate phases, namely mental planning and movement execution. The WCST performance was assessed separately for maintaining set and set shifting. This allowed us to examine the impact of problem difficulty and the impact of separate phases of a planning task on distinct intervals of WCST. Simultaneous registration of MFV was carried out to investigate the linkage of brain perfusion during the tasks. RESULTS: In patients, slowing of movement execution during easy problems (SOC) was associated with slowing during maintaining set (WCST) (P < 0.01). In healthy subjects, faster planning and movement execution during predominantly difficult problems were associated with increased performance of WCST during set shifting (P < 0.01). In the MCA, patients showed a significant and positive correlation of MFV between movement execution and WCST (P < 0.01). CONCLUSION: The results of this study demonstrate performance and brain perfusion abnormalities in the association pattern of two different tasks of executive functioning in schizophrenia, and they support the notion that executive functions have a pathological functional correlate predominantly in the lateral hemispheres of the brain. This study also underpins the scientific potential of fTCD in assessing brain perfusion in patients with schizophrenia

Gender and rapid alterations of hemispheric dominance during planning

BACKGROUND: Mental planning and carrying out a plan provoke specific cerebral hemodynamic responses. Gender aspects of hemispheric laterality using rapid cerebral hemodynamics have not been reported. METHOD: Here, we applied functional transcranial Doppler sonography to examine lateralization of cerebral hemodynamics of the middle cerebral arteries of 28 subjects (14 women and 14 men) performing a standard planning task. There were easy and difficult problems, and mental planning without motor activity was separated from movement execution. RESULTS: Difficult mental planning elicited lateralization to the right hemisphere after 2 or more seconds, a feature that was not observed during movement execution. In females, there was a dominance to the left hemisphere during movement execution. Optimized problem solving yielded an increased laterality change to the right during mental planning. CONCLUSIONS: Gender-related hemispheric dominance appears to be condition-dependent, and change of laterality to the right may play a role in optimized performance. Results are of relevance when considering laterality from a perspective of performance enhancement of higher cognitive functions, and also of psychiatric disorders with cognitive dysfunctions and abnormal lateralization patterns such as schizophrenia

Subthalamic nucleus activity dynamics and limb movement prediction in Parkinson’s disease

Whilst exaggerated bursts of beta frequency band oscillatory synchronization in the subthalamic nucleus have been associated with motor impairment in Parkinson’s disease, a plausible mechanism linking the two phenomena has been lacking. Here we test the hypothesis that increased synchronization denoted by beta bursting might compromise information coding capacity in basal ganglia networks. To this end we recorded local field potential activity in the subthalamic nucleus of 18 patients with Parkinson’s disease as they executed cued upper and lower limb movements. We used the accuracy of local field potential-based classification of the limb to be moved on each trial as an index of the information held by the system with respect to intended action. Machine learning using the naïve Bayes conditional probability model was used for classification. Local field potential dynamics allowed accurate prediction of intended movements well ahead of their execution, with an area under the receiver operator characteristic curve of 0.80 ± 0.04 before imperative cues when the demanded action was known ahead of time. The presence of bursts of local field potential activity in the alpha, and even more so, in the beta frequency band significantly compromised the prediction of the limb to be moved. We conclude that low frequency bursts, particularly those in the beta band, restrict the capacity of the basal ganglia system to encode physiologically relevant information about intended actions. The current findings are also important as they suggest that local subthalamic activity may potentially be decoded to enable effector selection, in addition to force control in restorative brain-machine interface applications

An intensive care unit outbreak with multi-drug-resistant Pseudomonas aeruginosa – spotlight on sinks

Background: Pseudomonas aeruginosa and other Gram-negative bacteria have the ability to persist in moist environments in healthcare settings, but their spread from these areas can result in outbreaks of healthcare-associated infections. Methods: This study reports the investigation and containment of a multi-drug-resistant P. aeruginosa outbreak in three intensive care units of a Swiss university hospital. In total, 255 patients and 276 environmental samples were screened for the multi-drug-resistant P. aeruginosa outbreak strain. The environmental sampling and molecular characterization of patient and environmental strains, and control strategies implemented, including waterless patient care, are described. Results: Between March and November 2019, the outbreak affected 29 patients. Environmental sampling detected the outbreak strain in nine samples of sink siphons of three different intensive care units with a common water sewage system, and on one gastroscope. Three weeks after replacement of the sink siphons, the outbreak strain re-grew in siphon-derived samples and newly affected patients were identified. The outbreak ceased after removal of all sinks in the proximity of patients and in medication preparation areas, and minimization of tap water use. Multi-locus sequence typing indicated clonality (sequence type 316) in 28/29 patient isolates and all 10 environmental samples. Conclusions: Sink removal combined with the introduction of waterless patient care terminated the multi-drug-resistant P. aeruginosa outbreak. Sinks in intensive care units may pose a risk for point source outbreaks with P. aeruginosa and other bacteria persisting in moist environments. Keywords: Intensive care; Multi-drug resistance; Outbreak; Pseudomonas aeruginosa; Sink; Siphon; Waterless patient care

Diagnosis of ischemic heart disease with cardiogoniometry – Linear discriminant analysis versus support vector machines

The Ischemic Heart Disease (IHD) is characterized by an insufficient supply with blood of the myocardium usually caused by an artherosclerotic disease of the coronary arteries (coronary artery disease CAD). The IHD and its consequences have become a leading problem in the industrialized nations. The aim of this study was to evaluate a new diagnosing method, the cardiogoniometry, using two different classifying techniques: the method of linear discriminant function analysis (LDA) and the method of Support Vector Machines (SVM). Data of a group of 109 female subjects (62 healthy, 47 with IHD) were analyzed on the basis of extracted parameters from the three-dimensional vector loops of the heart. The LDA achieved an accuracy of 83,5% (Sensitivity 78,7%, Specificity 87,1%), whereas the SVM achieved an accuracy of 86% (Sensitivity 80,5%, Specificity 89,8%). It could be shown that cardiogoniometry, an electrophysiological diagnostic method performed at rest, detects variables that are helpful in identifying ischemic heart disease. As it is easy to apply, non-invasive, and provides an automated interpretation it may become an inexpensive addition to the cardiologic diagnostic armamentarium, possibly useful for early diagnosis of IHD or CAD, as well as in patients who do not tolerate exercise testing. It was also proven that by applying Support Vector Machines an increased diagnostic precision in comparison to the conventional discriminant function analysis can be achieved.Peer ReviewedPostprint (published version