A web application for follow-up of results from a mobile device test battery for parkinson’s disease patients

Background: A test battery consisting of self-assessments and motor tests (tapping and spiral drawing) was developed for a hand computer with touch screen in a telemedicine setting. Objectives: To develop and evaluate a web-based system that delivers decision support information to the treating clinical staff for assessing PD symptoms in their patients based on the test battery data. Methods: The test battery is currently being used in a clinical trial (DAPHNE, EudraCT No. 2005-002654-21) by sixty five patients with advanced Parkinson’s disease (PD) on 9991 test occasions (four tests per day during in all 362 week-long test periods) at nine clinics around Sweden. Test results are sent continuously from the hand unit over a mobile net to a central computer and processed with statistical methods. They are summarized into scores for different dimensions of the symptom state and an ‘overall test score’ reflecting the overall condition of the patient during a test period. The information in the web application is organized and presented graphically in a way that the general overview of the patient performance per test period is emphasized. Focus is on the overall test score, symptom dimensions and daily summaries. In a recent preliminary user evaluation, the web application was demonstrated to the fifteen study nurses who had used the test battery in the clinical trial. At least one patient per clinic was shown. Results: In general, the responses from nurses were positive. They claimed that the test results shown in the system were consistent with their own clinical observations. They could follow complications, changes and trends within their patients. Discussion: In conclusion, the system is able to summarise the various time series of motor test results and self-assessments during test periods and present them in a useful manner. Its main contribution is a novel and reliable way to capture and easily access symptom information from patients’ home environment. The convenient access to current symptom profile as well as symptom history provides a basis for individualized evaluation and adjustment of treatments.

Computerized identification of motor complications in Parkinson's disease

Objective: To investigate whether spirography-based objective measures are able to effectively characterize the severity of unwanted symptom states (Off and dyskinesia) and discriminate them from motor state of healthy elderly subjects. Background: Sixty-five patients with advanced Parkinson’s disease (PD) and 10 healthy elderly (HE) subjects performed repeated assessments of spirography, using a touch screen telemetry device in their home environments. On inclusion, the patients were either treated with levodopa-carbidopa intestinal gel or were candidates for switching to this treatment. On each test occasion, the subjects were asked trace a pre-drawn Archimedes spiral shown on the screen, using an ergonomic pen stylus. The test was repeated three times and was performed using dominant hand. A clinician used a web interface which animated the spiral drawings, allowing him to observe different kinematic features, like accelerations and spatial changes, during the drawing process and to rate different motor impairments. Initially, the motor impairments of drawing speed, irregularity and hesitation were rated on a 0 (normal) to 4 (extremely severe) scales followed by marking the momentary motor state of the patient into 2 categories that is Off and Dyskinesia. A sample of spirals drawn by HE subjects was randomly selected and used in subsequent analysis. Methods: The raw spiral data, consisting of stylus position and timestamp, were processed using time series analysis techniques like discrete wavelet transform, approximate entropy and dynamic time warping in order to extract 13 quantitative measures for representing meaningful motor impairment information. A principal component analysis (PCA) was used to reduce the dimensions of the quantitative measures into 4 principal components (PC). In order to classify the motor states into 3 categories that is Off, HE and dyskinesia, a logistic regression model was used as a classifier to map the 4 PCs to the corresponding clinically assigned motor state categories. A stratified 10-fold cross-validation (also known as rotation estimation) was applied to assess the generalization ability of the logistic regression classifier to future independent data sets. To investigate mean differences of the 4 PCs across the three categories, a one-way ANOVA test followed by Tukey multiple comparisons was used. Results: The agreements between computed and clinician ratings were very good with a weighted area under the receiver operating characteristic curve (AUC) coefficient of 0.91. The mean PC scores were different across the three motor state categories, only at different levels. The first 2 PCs were good at discriminating between the motor states whereas the PC3 was good at discriminating between HE subjects and PD patients. The mean scores of PC4 showed a trend across the three states but without significant differences. The Spearman’s rank correlations between the first 2 PCs and clinically assessed motor impairments were as follows: drawing speed (PC1, 0.34; PC2, 0.83), irregularity (PC1, 0.17; PC2, 0.17), and hesitation (PC1, 0.27; PC2, 0.77). Conclusions: These findings suggest that spirography-based objective measures are valid measures of spatial- and time-dependent deficits and can be used to distinguish drug-related motor dysfunctions between Off and dyskinesia in PD. These measures can be potentially useful during clinical evaluation of individualized drug-related complications such as over- and under-medications thus maximizing the amount of time the patients spend in the On state.

Visualization of spirography-based objective measures in Parkinson's disease

Objective: To investigate whether advanced visualizations of spirography-based objective measures are useful in differentiating drug-related motor dysfunctions between Off and dyskinesia in Parkinson’s disease (PD). Background: During the course of a 3 year longitudinal clinical study, in total 65 patients (43 males and 22 females with mean age of 65) with advanced PD and 10 healthy elderly (HE) subjects (5 males and 5 females with mean age of 61) were assessed. Both patients and HE subjects performed repeated and time-stamped assessments of their objective health indicators using a test battery implemented on a telemetry touch screen handheld computer, in their home environment settings. Among other tasks, the subjects were asked to trace a pre-drawn Archimedes spiral using the dominant hand and repeat the test three times per test occasion. Methods: A web-based framework was developed to enable a visual exploration of relevant spirography-based kinematic features by clinicians so they can in turn evaluate the motor states of the patients i.e. Off and dyskinesia. The system uses different visualization techniques such as time series plots, animation, and interaction and organizes them into different views to aid clinicians in measuring spatial and time-dependent irregularities that could be associated with the motor states. Along with the animation view, the system displays two time series plots for representing drawing speed (blue line) and displacement from ideal trajectory (orange line). The views are coordinated and linked i.e. user interactions in one of the views will be reflected in other views. For instance, when the user points in one of the pixels in the spiral view, the circle size of the underlying pixel increases and a vertical line appears in the time series views to depict the corresponding position. In addition, in order to enable clinicians to observe erratic movements more clearly and thus improve the detection of irregularities, the system displays a color-map which gives an idea of the longevity of the spirography task. Figure 2 shows single randomly selected spirals drawn by a: A) patient who experienced dyskinesias, B) HE subject, and C) patient in Off state. Results: According to a domain expert (DN), the spirals drawn in the Off and dyskinesia motor states are characterized by different spatial and time features. For instance, the spiral shown in Fig. 2A was drawn by a patient who showed symptoms of dyskinesia; the drawing speed was relatively high (cf. blue-colored time series plot and the short timestamp scale in the x axis) and the spatial displacement was high (cf. orange-colored time series plot) associated with smooth deviations as a result of uncontrollable movements. The patient also exhibited low amount of hesitation which could be reflected both in the animation of the spiral as well as time series plots. In contrast, the patient who was in the Off state exhibited different kinematic features, as shown in Fig. 2C. In the case of spirals drawn by a HE subject, there was a great precision during the drawing process as well as unchanging levels of time-dependent features over the test trial, as seen in Fig. 2B. Conclusions: Visualizing spirography-based objective measures enables identification of trends and patterns of drug-related motor dysfunctions at the patient’s individual level. Dynamic access of visualized motor tests may be useful during the evaluation of drug-related complications such as under- and over-medications, providing decision support to clinicians during evaluation of treatment effects as well as improve the quality of life of patients and their caregivers. In future, we plan to evaluate the proposed approach by assessing within- and between-clinician variability in ratings in order to determine its actual usefulness and then use these ratings as target outcomes in supervised machine learning, similarly as it was previously done in the study performed by Memedi et al. (2013).

A web-based system for visualizing upper limb motor performance of Parkinson’s disease patients

Objective To design, develop and set up a web-based system for enabling graphical visualization of upper limb motor performance (ULMP) of Parkinson’s disease (PD) patients to clinicians. Background Sixty-five patients diagnosed with advanced PD have used a test battery, implemented in a touch-screen handheld computer, in their home environment settings over the course of a 3-year clinical study. The test items consisted of objective measures of ULMP through a set of upper limb motor tests (finger to tapping and spiral drawings). For the tapping tests, patients were asked to perform alternate tapping of two buttons as fast and accurate as possible, first using the right hand and then the left hand. The test duration was 20 seconds. For the spiral drawing test, patients traced a pre-drawn Archimedes spiral using the dominant hand, and the test was repeated 3 times per test occasion. In total, the study database consisted of symptom assessments during 10079 test occasions. Methods Visualization of ULMP The web-based system is used by two neurologists for assessing the performance of PD patients during motor tests collected over the course of the said study. The system employs animations, scatter plots and time series graphs to visualize the ULMP of patients to the neurologists. The performance during spiral tests is depicted by animating the three spiral drawings, allowing the neurologists to observe real-time accelerations or hesitations and sharp changes during the actual drawing process. The tapping performance is visualized by displaying different types of graphs. Information presented included distribution of taps over the two buttons, horizontal tap distance vs. time, vertical tap distance vs. time, and tapping reaction time over the test length. Assessments Different scales are utilized by the neurologists to assess the observed impairments. For the spiral drawing performance, the neurologists rated firstly the ‘impairment’ using a 0 (no impairment) – 10 (extremely severe) scale, secondly three kinematic properties: ‘drawing speed’, ‘irregularity’ and ‘hesitation’ using a 0 (normal) – 4 (extremely severe) scale, and thirdly the probable ‘cause’ for the said impairment using 3 choices including Tremor, Bradykinesia/Rigidity and Dyskinesia. For the tapping performance, a 0 (normal) – 4 (extremely severe) scale is used for first rating four tapping properties: ‘tapping speed’, ‘accuracy’, ‘fatigue’, ‘arrhythmia’, and then the ‘global tapping severity’ (GTS). To achieve a common basis for assessment, initially one neurologist (DN) performed preliminary ratings by browsing through the database to collect and rate at least 20 samples of each GTS level and at least 33 samples of each ‘cause’ category. These preliminary ratings were then observed by the two neurologists (DN and PG) to be used as templates for rating of tests afterwards. In another track, the system randomly selected one test occasion per patient and visualized its items, that is tapping and spiral drawings, to the two neurologists. Statistical methods Inter-rater agreements were assessed using weighted Kappa coefficient. The internal consistency of properties of tapping and spiral drawing tests were assessed using Cronbach’s α test. One-way ANOVA test followed by Tukey multiple comparisons test was used to test if mean scores of properties of tapping and spiral drawing tests were different among GTS and ‘cause’ categories, respectively. Results When rating tapping graphs, inter-rater agreements (Kappa) were as follows: GTS (0.61), ‘tapping speed’ (0.89), ‘accuracy’ (0.66), ‘fatigue’ (0.57) and ‘arrhythmia’ (0.33). The poor inter-rater agreement when assessing “arrhythmia” may be as a result of observation of different things in the graphs, among the two raters. When rating animated spirals, both raters had very good agreement when assessing severity of spiral drawings, that is, ‘impairment’ (0.85) and irregularity (0.72). However, there were poor agreements between the two raters when assessing ‘cause’ (0.38) and time-information properties like ‘drawing speed’ (0.25) and ‘hesitation’ (0.21). Tapping properties, that is ‘tapping speed’, ‘accuracy’, ‘fatigue’ and ‘arrhythmia’ had satisfactory internal consistency with a Cronbach’s α coefficient of 0.77. In general, the trends of mean scores of tapping properties worsened with increasing levels of GTS. The mean scores of the four properties were significantly different to each other, only at different levels. In contrast from tapping properties, kinematic properties of spirals, that is ‘drawing speed’, ‘irregularity’ and ‘hesitation’ had a questionable consistency among them with a coefficient of 0.66. Bradykinetic spirals were associated with more impaired speed (mean = 83.7 % worse, P < 0.001) and hesitation (mean = 77.8% worse, P < 0.001), compared to dyskinetic spirals. Both these ‘cause’ categories had similar mean scores of ‘impairment’ and ‘irregularity’. Conclusions In contrast from current approaches used in clinical setting for the assessment of PD symptoms, this system enables clinicians to animate easily and realistically the ULMP of patients who at the same time are at their homes. Dynamic access of visualized motor tests may also be useful when observing and evaluating therapy-related complications such as under- and over-medications. In future, we foresee to utilize these manual ratings for developing and validating computer methods for automating the process of assessing ULMP of PD patients.

Spiral drawing during self-rated dyskinesia is more impaired than during self-rated off

Background: A mobile device test battery, consisting of a patient diary collection section with disease-related questions and a fine motor test section (including spiral drawing tasks), was used by 65 patients with advanced Parkinson's disease (PD)(treated with intraduodenal levodopa/carbidopa gel infusion, Duodopa®, or candidates for this treatment) on 10439 test occasions in their home environments. On each occasion, patients traced three pre-drawn Archimedes spirals using an ergonomic stylus and self-assessed their motor function on a global Treatment Response Scale (TRS) ranging from -3 = very 'off' to 0 = 'on' to +3 = very dyskinetic. The spirals were processed by a computer-based method that generates a "spiral score" representing the PD-related drawing impairment. The scale for the score was based on a modified Bain & Findley rating scale in the range from 0 = no impairment to 5 = moderate impairment to 10 = extremely severe impairment. Objective: To analyze the test battery data for the purpose to find differences in spiral drawing performance of PD patients in relation to their self-assessments of motor function. Methods: Three motor states were used in the analysis; OFF state (including moderate and very 'off'), ON state ('on') and a dyskinetic (DYS) state (moderate and very dyskinetic). In order to avoid the problem of multiple test occasions per patient, 200 random samples of single test occasions per patient were drawn. One-way analysis of variance, ANOVA, test followed by Tukey multiple comparisons test was used to test if mean values of spiral test parameters, i.e. the spiral score and drawing completion times (in seconds), were different among the three motor states. Statistical significance was set at p<0.05. To investigate changes in the spiral score over the time-of-day test sessions for the three motor states, plots of statistical summaries were inspected. Results: The mean spiral score differed significantly across the three self-assessed motor states (p<0.001, ANOVA test). Tukey post-hoc comparisons indicate that the mean spiral score (mean ± SD; [95% CI for mean]) in DYS state (5.2 ± 1.8; [5.12, 5.28]) was higher than the mean spiral score in OFF (4.3 ± 1.7; [4.22, 4.37]) and ON (4.2 ± 1.7; [4.17, 4.29]) states. The mean spiral score was also significantly different among individual TRS values of slightly 'off' (4.02 ± 1.63), 'on' (4.07 ± 1.65) and slightly dyskinetic (4.6 ± 1.71), (p<0.001). There were no differences in drawing completion times among the three motor states (p=0.509). In the OFF and ON states, patients drew slightly more impaired spirals in the afternoon whereas in the DYS state the spiral drawing performance was more impaired in the morning. Conclusion: It was found that when patients considered themselves as being dyskinetic spiral drawing was more impaired (nearly one unit change in a 0-10 scale) compared to when they considered themselves as being 'off' and 'on'. The spiral drawing at patients that self-assessed their motor state as dyskinetic was slightly more impaired in the morning hours, between 8 and 12 o'clock, a situation possibly caused by the morning dose effect.

Validity and responsiveness of at-home touch-screen assessments in advanced Parkinson's disease

The aim of this study was to investigate if a telemetry test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression in patients with fluctuations. Sixty-five patients diagnosed with advanced PD were recruited in an open longitudinal 36-month study; 35 treated with levodopa-carbidopa intestinal gel (LCIG) and 30 were candidates for switching from oral PD treatment to LCIG. They utilized a test battery, consisting of self-assessments of symptoms and fine motor tests (tapping and spiral drawings), four times per day in their homes during week-long test periods. The repeated measurements were summarized into an overall test score (OTS) to represent the global condition of the patient during a test period. Clinical assessments included ratings on Unified PD Rating Scale (UPDRS) and 39-item PD Questionnaire (PDQ-39) scales. In LCIG-naïve patients, mean OTS compared to baseline was significantly improved from the first test period on LCIG treatment until month 24. In LCIG-non-naïve patients, there were no significant changes in mean OTS until month 36. The OTS correlated adequately with total UPDRS (rho = 0.59) and total PDQ-39 (0.59). Responsiveness measured as effect size was 0.696 and 0.536 for OTS and UPDRS respectively. The trends of the test scores were similar to the trends of clinical rating scores but dropout rate was high. Correlations between OTS and clinical rating scales were adequate indicating that the test battery contains important elements of the information of well-established scales. The responsiveness and reproducibility were better for OTS than for total UPDRS.

Children's recall of words spoken in their first and second language : Effects of Signal-to-Noise Ratio and Reverberation Time

Speech perception runs smoothly and automatically when there is silence in the background, but when the speech signal is degraded by background noise or by reverberation, effortful cognitive processing is needed to compensate for the signal distortion. Previous research has typically investigated the effects of signal-to-noise ratio (SNR) and reverberation time in isolation, whilst few have looked at their interaction. In this study, we probed how reverberation time and SNR influence recall of words presented in participants' first- (L1) and second-language (L2). A total of 72 children (10 years old) participated in this study. The to-be-recalled wordlists were played back with two different reverberation times (0.3 and 1.2 s) crossed with two different SNRs (+3 dBA and +12 dBA). Children recalled fewer words when the spoken words were presented in L2 in comparison with recall of spoken words presented in L1. Words that were presented with a high SNR (+12 dBA) improved recall compared to a low SNR (+3 dBA). Reverberation time interacted with SNR to the effect that at +12 dB the shorter reverberation time improved recall, but at +3 dB it impaired recall. The effects of the physical sound variables (SNR and reverberation time) did not interact with language. © 2016 Hurtig, Keus van de Poll, Pekkola, Hygge, Ljung and Sörqvist.

Opening the Windows of the Church to the World: The Creation of Nostra Aetate and Its Impact on the Christian-Jewish relationship

It is important to assert that this study is not a work to inflict guilt on the Catholics or Catholicism for their silence and indifference during the Holocaust. Instead, this study is about the process of moving on from the Catholic Church's past to where the Jewish community's theological existence was finally recognized and the Jewish people were no longer seen as the Others who killed Christ. This was, achieved through a church declaration titled Nostra Aetate (In Our Time). This study records the journey traversed by this declaration, the insurmountable odds it faced in its creation until its promulgation and the impact it has on the Jewish-Christian relationship.

Gravitational Capture of Asteroids by Gas Drag

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Survey radiography and computerized tomography imaging of the thorax in female dogs with mammary tumors

Background: Accurate early diagnosis of lung metastases is important for establishing therapeutic measures. Therefore, the present study aimed to compare survey thoracic radiographs and computerized tomography (CT) scans to specifically identify lung metastases in female dogs with mammary tumors.Methods: Twenty-one female dogs, weighing 3 to 34 kg and aged from 5 years to 14 years and 10 months, with mammary tumors were studied. In all dogs before the imaging examinations, fine-needle aspiration cytology of the mammary tumors was performed to confirm the diagnosis. Three-view thoracic radiographs were accomplished: right lateral, left lateral and ventrodorsal views. Sequential transverse images of the thorax were acquired on a spiral Scanner, before and after intravenous bolus injection of nonionic iodine contrast. Soft-tissue and lung windows were applied. All the mammary tumors were surgically removed and examined histologically.Results: The correlation between the cytological and histological results regarding presence of malignancy was observed in only 17 cases. In radiographic examinations, no dog displayed signs of lung metastases or thorax chest lesions. CT detected lung metastasis in two cases, while small areas of lung atelectasis located peripherally were found in 28.57% of the dogs.Conclusion: In this study population, spiral CT showed higher sensitivity than chest radiographies to detect lung metastasis; this indicates that CT should be performed on all female dogs with malignant mammary tumors.

Silk formation mechanisms in the larval salivary glands of Apis mellifera (Hymenoptera : Apidae)

The mechanism of silk formation in Apis mellifera salivary glands, during the 5th instar, was studied. Larval salivary glands were dissected and prepared for light and polarized light microscopy, as well as for scanning and transmission electron microscopy. The results showed that silk formation starts at the middle of the 5th instar and finishes at the end of the same instar. This process begins in the distal secretory portion of the gland, going towards the proximal secretory portion; and from the periphery to the center of the gland lumen. The silk proteins are released from the secretory cells as a homogeneous substance that polymerizes in the lumen to form compact birefringent tactoids. Secondly, the water absorption from the lumen secretion, carried out by secretory and duct cells, promotes aggregation of the tactoids that form a spiral-shape filament with a zigzag pattern. This pattern is also the results of the silk compression in the gland lumen and represents a high concentration of macromolecularly well-oriented silk proteins.

Phylogeny of Celastraceae Subfamily Salacioideae and Tribe Lophopetaleae Inferred from Morphological Characters and Nuclear and Plastid Genes

The phylogeny of Celastraceae subfamily Salacioideae (ca. 255 species in the Old and New World tropics) and tribe Lophopetaleae (ca. 29 species in southern Asia and the Austral-Pacific) was inferred using morphological characters together with plastid (matK, trnL-F) and nuclear (ITS and 26S rDNA) genes. Brassiantha, a monotypic genus endemic to New Guinea, is inferred to be more closely related to the clade of Dicarpellum (New Caledonia) and Hypsophila (Queensland, Australia) than it is to Hippocrateoideae or Salacioideae. This unambiguously supported resolution indicates that a nectary disk positioned outside the stamens has been convergently derived in these two lineages. The clade of Kokoona and Lophopetalum is resolved as more closely related to Breria and Elaeodendron than it is to Hippocrateoideae or Salacioideae. Sarawakodendron, a monotypic genus endemic to Borneo, is resolved as sister to Salacioideae. Salacioideae are inferred to have an Old World origin that was followed by a single successful radiation within Central and South America. We infer that capsular fruits are primitive within the clade of Hippocrateoideae + Sarawakodendron + Salacioideae, with berries a synapomorphy for Salacioideae. Based on the resolution of Sarawakodendron as sister to Salacioideae, we hypothesize that the filaments of Sarawakodendron arils are homologous to the spiral filaments in the mucilagenous pulp of Salacioideae.

Contributions to the floral anatomy of Juncaceae (Poales - Monocotyledons)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Secretion of salivary glands of the Brazilian termite Serritermes serrifer Hagen&Bates (Isoptera: Serritermitidae)

The salivary glands of termites are composed of several secretory acini connected by ducts. These glands, in the Brazilian termite Serritermes serrifer, were examined through the electron microscope. The ultrastructure of worker salivary acinus revealed central ductule cells and four different types of cells. Cells of type I contain an abundance of electron-lucid vacuoles of various sizes which fuse to form enormous vacuolar structures that fill up most of the cell. Cells of type II are narrow cells in which the secretion is contained in small clear vacuoles of approximately equal diameter. Both of these cellular types have numerous Golgi bodies and rough endoplasmic reticulum. Type III or parietal cells have an apical plasma membrane deeply infolded and lined by microvilli. This type of cell is located in the acinar periphery and occurs in pairs. Cells of type IV are completely filled with electrondense secretion. The secretory granules can be small in some cells or large and similar to fingerprints in others. This is the first report of the occurrence of these spiral or concentric rings of dense material in the salivary gland of Isoptera.

Vascular organization of the hystricomorph placenta: a comparative study in the Agouti, capybara, guinea pig, paca and rock cavy

The placental vasculature of five hystricomorph rodents was examined by latex injection of the blood vessels, immunohistochemistry and scanning electron microscopy of vessel casts. The pattern of branching of the vessels is described at the level of fine structure. The placenta is divided into lobes separated by interlobular trophoblast. Fetal arteries course through the interlobular areas and give rise to capillaries from which blood drains into veins at the centre of the lobes. Maternal blood reaches the placenta through spiral arteries that pass around the perimeter of the subplacenta. They supply large maternal blood sinuses, lined by trophoblast, which run through the interlobular areas and into the centre of the lobes. Here they supply fine channels that run parallel to the fetal capillaries, so that maternal blood flows from the centre of the lobe to the periphery. This arrangement provides the morphological basis for countercurrent exchange. The maternal channels of the labyrinth drain into spaces formed by the latticework of the interlobular trophoblast and thence through venous lacunae to a basal venous lacunar ring. The subplacenta is supplied by a single fetal artery. The vessels within the subplacenta pursue a tortuous course with dilatations and constrictions as in an endocrine gland. (C) 2003 Elsevier Ltd. All rights reserved.