A data mining approach for classification of orthostatic and essential tremor based on MRI‐derived brain volume and cortical thickness

[Abstract] Objective - Orthostatic tremor (OT) is an extremely rare, misdiagnosed, and underdiagnosed disorder affecting adults in midlife. There is debate as to whether it is a different condition or a variant of essential tremor (ET), or even, if both conditions coexist. Our objective was to use data mining classification methods, using magnetic resonance imaging (MRI)‐derived brain volume and cortical thickness data, to identify morphometric measures that help to discriminate OT patients from those with ET. Methods - MRI‐derived brain volume and cortical thickness were obtained from 14 OT patients and 15 age‐, sex‐, and education‐matched ET patients. Feature selection and machine learning methods were subsequently applied. Results - Four MRI features alone distinguished the two, OT from ET, with 100% diagnostic accuracy. More specifically, left thalamus proper volume (normalized by the total intracranial volume), right superior parietal volume, right superior parietal thickness, and right inferior parietal roughness (i.e., the standard deviation of cortical thickness) were shown to play a key role in OT and ET characterization. Finally, the left caudal anterior cingulate thickness and the left caudal middle frontal roughness allowed us to separate with 100% diagnostic accuracy subgroups of OT patients (primary and those with mild parkinsonian signs). Conclusions - A data mining approach applied to MRI‐derived brain volume and cortical thickness data may differentiate between these two types of tremor with an accuracy of 100%. Our results suggest that OT and ET are distinct conditions.National Institutes of Health (United States); #R01, NS39422National Institutes of Health (United States), #R01, NS094607National Institutes of Health (United States); #R01, NS085136National Institutes of Health (United States); #R01, NS073872National Institutes of Health (United States); #R01, NS085136National Institutes of Health (United States); #R01, NS088257European Commission; ICT‐2011‐287739Ministerio de Economía y Competitividad; RTC‐2015‐3967‐1Agencia Española de Investigación de la Salud; FIS PI12/01602Agencia Española de Investigación de la Salud; FIS PI16/00451Madrid Robotics Digital Innovation Hub; S2018/NMT‐433

Diffusion tensor imaging in orthostatic tremor: a tract‐based spatial statistics study

[Abstract] Objective The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT‐related white matter changes and their correlations with scores from a neuropsychological testing battery. Methods Diffusion tensor imaging measures were compared between 14 OT patients and 14 age‐ and education‐matched healthy controls, using whole‐brain tract‐based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed. Results In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients’ cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients. Interpretation White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal–thalamic–cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences.National Institutes of Health; R01 NS39422National Institutes of Health; R01 NS094607National Institutes of Health; R01 NS085136National Institutes of Health; R01 NS073872National Institutes of Health; R01 NS088257European Commission. Grant Number: ICT‐2011‐287739Ministerio de Ecnomía y Competitividad; RTC‐2015‐3967‐1Spanish Health Research Agency; FIS PI12/01602Spanish Health Research Agency; FIS PI16/00451Ministerio de Ecnomía y Competitividad; DPI‐2015‐68664‐C4‐1‐

Diffusion tensor imaging in orthostatic tremor: a tract-based spatial statistics study.

Objective: The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT-related white matter changes and their correlations with scores from a neuropsychological testing battery. Methods: Diffusion tensor imaging measures were compared between 14 OT patients and 14 age- and educationmatched healthy controls, using whole-brain tract-based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed. Results: In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients’ cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients. Interpretation: White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal–thalamic–cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences.post-print404 K

In vivo neurometabolic profiling in orthostatic tremor

The pathogenesis of orthostatic tremor (OT) remains unclear, although some evidence points to dysfunction in the brainstem or cerebellum. We used single voxel proton magnetic resonance spectroscopy (1H-MRS) (3 T) to investigate whether neurochemical changes underlie abnormal cerebellar or cortical function in OT. Fourteen OT patients and 14 healthy controls underwent 1H-MRS studies with voxels placed in midparietal gray matter and cerebellum (vermis and central white matter). Spectral analysis was analyzed using the software package LCModel (version 6.3). The absolute metabolite concentrations and ratios of total N-acetylaspartate + N-acetylaspartyl glutamate (NAA), choline-containing compounds, myoinositol, and glutamate + glutamine to creatine were calculated. In midparietal gray matter spectra, we found a significant decrease in the absolute concentration of NAA in OT patients versus healthy controls (7.76 ± 0.25 vs 8.11 ± 0.45, P = 0.017). A similar decrease in NAA was seen in the cerebellar vermis (7.33 ± 0.61 vs 8.55 ± 1.54, P = 0.014) and cerebellar white matter (8.54 ± 0.79 vs 9.95 ± 1.57, P = 0.010). No differences in the other metabolites or their ratios were observed. Reductions in both cerebral cortical and cerebellar NAA suggest that there is neuronal damage or loss in OT, raising the intriguing question as to whether OT is a neurodegenerative disease. Along with clinical history and electrophysio0logical examination, 1H-MRS could serve as a useful diagnostic aid for OT

Discovery of the Optical Transient of the Gamma Ray Burst 990308

The optical transient of the faint Gamma Ray Burst 990308 was detected by the QUEST camera on the Venezuelan 1-m Schmidt telescope starting 3.28 hours after the burst. Our photometry gives $V = 18.32 \pm 0.07$, $R = 18.14 \pm 0.06$, $B = 18.65 \pm 0.23$, and $R = 18.22 \pm 0.05$ for times ranging from 3.28 to 3.47 hours after the burst. The colors correspond to a spectral slope of close to $f_{\nu} \propto \nu^{1/3}$. Within the standard synchrotron fireball model, this requires that the external medium be less dense than $10^{4} cm^{-3}$, the electrons contain $> 20$ of the shock energy, and the magnetic field energy must be less than 24% of the energy in the electrons for normal interstellar or circumstellar densities. We also report upper limits of $V > 12.0$ at 132 s (with LOTIS), $V > 13.4$ from 132-1029s (with LOTIS), $V > 15.3$ at 28.2 min (with Super-LOTIS), and a 8.5 GHz flux of $< 114 \mu Jy$ at 110 days (with the Very Large Array). WIYN 3.5-m and Keck 10-m telescopes reveal this location to be empty of any host galaxy to $R > 25.7$ and $K > 23.3$. The lack of a host galaxy likely implies that it is either substantially subluminous or more distant than a red shift of $\sim 1.2$.Comment: ApJ Lett submitted, 5 pages, 2 figures, no space for 12 coauthor

Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016

Altres ajuts: We wish to thank I Bustillo, H del Pozo and P Higueras for their technical assistance. We also sincerely wish to thank all technical staff from microbiology departments and medical staff from paediatrics departments from all participating hospitals. Some of the samples are included in an ongoing project (PI15CIII-00020) which was supported by a grant by the Health Research System (AES).Introduction: Enterovirus A71 (EV-A71) is an emerging pathogen that causes a wide range of disorders including severe neurological manifestations. In the past 20 years, this virus has been associated with large outbreaks of hand, foot and mouth disease with neurological complications in the Asia-Pacific region, while in Europe mainly sporadic cases have been reported. In spring 2016, however, an EV-A71 outbreak associated with severe neurological cases was reported in Catalonia and spread further to other Spanish regions. Aim: Our objective was to investigate the epidemiology and clinical characteristics of the outbreak. Methods: We carried out a retrospective study which included 233 EV-A71-positive samples collected during 2016 from hospitalised patients. We analysed the clinical manifestations associated with EV-A71 infections and performed phylogenetic analyses of the 3'-VP1 and 3Dpol regions from all Spanish strains and a set of EV-A71 from other countries. Results: Most EV-A71 infections were reported in children (mean age: 2.6 years) and the highest incidence was between May and July 2016 (83%). Most isolates (218/233) were classified as subgenogroup C1 and 217 of them were grouped in one cluster phylogenetically related to a new recombinant variant strain associated with severe neurological diseases in Germany and France in 2015 and 2016. Moreover, we found a clear association of EV-A71-C1 infection with severe neurological disorders, brainstem encephalitis being the most commonly reported. Conclusion: An emerging recombinant variant of EV-A71-C1 was responsible for the large outbreak in 2016 in Spain that was associated with many severe neurological cases

Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016

IntroductionEnterovirus A71 (EV-A71) is an emerging pathogen that causes a wide range of disorders including severe neurological manifestations. In the past 20 years, this virus has been associated with large outbreaks of hand, foot and mouth disease with neurological complications in the Asia-Pacific region, while in Europe mainly sporadic cases have been reported. In spring 2016, however, an EV-A71 outbreak associated with severe neurological cases was reported in Catalonia and spread further to other Spanish regions.AimOur objective was to investigate the epidemiology and clinical characteristics of the outbreak.MethodsWe carried out a retrospective study which included 233 EV-A71-positive samples collected during 2016 from hospitalised patients. We analysed the clinical manifestations associated with EV-A71 infections and performed phylogenetic analyses of the 3'-VP1 and 3Dpol regions from all Spanish strains and a set of EV-A71 from other countries.ResultsMost EV-A71 infections were reported in children (mean age: 2.6 years) and the highest incidence was between May and July 2016 (83%). Most isolates (218/233) were classified as subgenogroup C1 and 217 of them were grouped in one cluster phylogenetically related to a new recombinant variant strain associated with severe neurological diseases in Germany and France in 2015 and 2016. Moreover, we found a clear association of EV-A71-C1 infection with severe neurological disorders, brainstem encephalitis being the most commonly reported.ConclusionAn emerging recombinant variant of EV-A71-C1 was responsible for the large outbreak in 2016 in Spain that was associated with many severe neurological cases.S

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies

Surface softening in metal-ceramic sliding contacts: An experimental and numerical investigation

This study investigates the tribolayer properties at the interface of ceramic/metal (i.e., WC/W) sliding contacts using various experimental approaches and classical atomistic simulations. Experimentally, nanoindentation and micropillar compression tests, as well as adhesion mapping by means of atomic force microscopy, are used to evaluate the strength of tungsten?carbon tribolayers. To capture the influence of environmental conditions, a detailed chemical and structural analysis is performed on the worn surfaces by means of XPS mapping and depth profiling along with transmission electron microscopy of the debris particles. Experimentally, the results indicate a decrease in hardness and modulus of the worn surface compared to the unworn one. Atomistic simulations of nanoindentation on deformed and undeformed specimens are used to probe the strength of the WC tribolayer and despite the fact that the simulations do not include oxygen, the simulations correlate well with the experiments on deformed and undeformed surfaces, where the difference in behavior is attributed to the bonding and structural differences of amorphous and crystalline W-C. Adhesion mapping indicates a decrease in surface adhesion, which based on chemical analysis is attributed to surface passivation

Clinical Audits in Outpatient Clinics for Chronic Obstructive Pulmonary Disease: Methodological Considerations and Workflow

Objectives: Previous clinical audits for chronic obstructive pulmonary disease (COPD) have provided valuable information on the clinical care delivered to patients admitted to medical wards because of COPD exacerbations. However, clinical audits of COPD in an outpatient setting are scarce and no methodological guidelines are currently available. Based on our previous experience, herein we describe a clinical audit for COPD patients in specialized outpatient clinics with the overall goal of establishing a potential methodological workflow.Methods: A pilot clinical audit of COPD patients referred to respiratory outpatient clinics in the region of Andalusia, Spain (over 8 million inhabitants), was performed. The audit took place between October 2013 and September 2014, and 10 centers (20% of all public hospitals) were invited to participate. Cases with an established diagnosis of COPD based on risk factors, clinical symptoms, and a post-bronchodilator FEV1/FVC ratio of less than 0.70 were deemed eligible. The usefulness of formally scheduled regular follow-up visits was assessed. Two different databases (resources and clinical database) were constructed. Assessments were planned over a year divided by 4 three-month periods, with the goal of determining seasonal-related changes. Exacerbations and survival served as the main endpoints.Conclusions: This paper describes a methodological framework for conducting a clinical audit of COPD patients in an outpatient setting. Results from such audits can guide health information systems development and implementation in real-world settings.This study was financially supported by an unrestricted grant from Laboratorios Menarini, SA (Barcelona, Spain)