Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports

Introduction: Since vascular endothelial growth factor (VEGF) regulates several aspects of the central nervous system, particularly in dopaminergic neurons, VEGF inhibitors may be linked to Parkinson-like events and dementia, or variants of these diseases. Two recent case reports have found a potential link between intravitreal anti-VEGF use and Parkinson’s disease (PD) and dementia. Aim: To evaluate disproportionality in a large spontaneous reporting database concerning intravitreal anti-VEGF drugs and PD or dementia, and related conditions. Methods: Using VigiBase, individual case safety reports (ICSRs) attributed to intravitreal ranibizumab, aflibercept, pegaptanib, and bevacizumab were identified from 2010 to 2016. Within Standardised Narrow Medical Dictionary for Regulatory Activities (MedDRA®) Queries (SMQs) for “Parkinson-like events” and “Dementia,” suspected events were identified using preferred terms (PTs). The Proportional Reporting Ratio (PRR) was estimated with the lower 95% confidence intervals (CIs) for all drug-event pairs with ≥3 suspected events. The vigiGrade completeness score was reported for the ICSRs. The analyses were repeated, including only persons aged 65 and over. Results: Out of 18.9 million ICSRs, 7,945 (0.004%) concerned intravitreal anti-VEGF drugs. Of these, 27 (0.34%) were identified concerning the SMQs “Dementia” (N = 17, 62.96%) and “Parkinson-like events” (N = 10, 37.94%) in persons of all ages. Among persons age 65 and over, 4,758 (59.88% of relevant ICSRs) ICSRs were identified for anti-VEGF drugs. When restricting disproportionality analysis to persons aged 65 and over, no disproportionality was seen for any of the drug-event pairs at the level of SMQ. However, on analysing disproportionality by PT, a potential signal emerged for intravitreal ranibizumab and Parkinson’s disease [N = 6 ICSRs; PRR: 3.05 (95% CI: 1.36-6.81)]. In general, the vigiGrade completeness score was low for all the ICSRs of interest, as no ICSR had a score >0.8. Conclusion: Present findings suggest a potential signal for Parkinson’s disease related to intravitreal ranibizumab. This is supported by several biologically plausible mechanisms but requires confirmation through pharmacoepidemiological studies, especially because of the low number of cases

Atomic density and temperature distributions in magneto-optical traps

A theoretical investigation into density, pressure, and temperature distributions in magneto-optical traps is presented. After a brief overview of the forces that arise from reradiation and absorption, a condition that the absorptive force be conservative is used to show that, if the temperature is uniform throughout the trap, any. density solutions to the force equations will not be physical. Further, consistent density solutions are unlikely to exist at all. In contrast, with a varying temperature reasonable solutions are demonstrated, with some restrictions. Doppler forces involved in ring-shaped trap structures are used to calculate orbit radii in racetrack geometry traps, and corrections to the present discrepancy between theoretical and experimental studies are discussed in the context of reradiation and diffusion

Creating Supply Chain Resilience Through Scenario Planning: How a Digital Twin Can Be Used To Enhance Supply Chain Resilience Through Scenario Planning

This book focusses on the concept of supply chain disruptions and how supply chain resilience can contribute to both preparing for and reacting to the event causing disruption. For building a digital twin of a supply chain, a software named Supply Chain Guru has been used. The software is a supply chain design tool which can be used for different kinds of supply chain network optimisation. The book outlines four scenarios: Covid-19 lockdown, Brexit without deal, Conflagration at a dairy and Political regulations on transport. The scenarios all contain a problem that needs to be solved. This problem is considered as the main disruption for the supply chain. Running the scenario in Supply Chain Guru, constraints are added to the AS-IS model. The constraints are identified as implications of the event in the scenarios. By adding the constraints and running the model, Supply Chain Guru identifies suggestions to solve the problems which were described. The solutions within the scenarios are held up against the theory of supply chain resilience, to describe how the scenario planning can be used to enhance supply chain resilience. Finally, the book discuss how scenario planning can be related to supply chain resilience as well as how scenario planning can be used to increase supply chain resilience

Effects of motor imagery training of Parkinson's disease: a protocol for a randomized clinical trial

Background Gait disorders in individuals with Parkinson’s disease (PD) may be associated with alterations in the motor control system and aggravated by psychoemotional and cognitive issues. Therapeutic strategies aimed at self-perception and motor regulation seem to be promising. Motor imagery (MI) has been shown to be one of these strategies, but there is still no clear evidence of its applicability in this population. The aim of this trial is to determine the effects of motor-imagery training on the gait and electroencephalographic activity of individuals with PD. Methods/design The sample will consist of 40 individuals, aged between 45 and 75 years, in the mild and moderate phase of the disease, with the ability to generate voluntary mental images. They will be assessed for cognitive level, degree of physical disability, mental-image clarity, kinematic gait variables, electroencephalographic activity and mobility. Next, subjects will be randomly assigned to an experimental group (EG) and a control group (CG). The EG will perform motor imagery and gait, while the CG will only engage in gait exercises. Twelve training sessions will be conducted lasting up to 90 min each, three times a week, for 4 weeks. The subjects will be reassessed on the kinematic variables of gait, electroencephalographic activity and mobility at 1, 7 and 30 days after the final training session. Discussion The results may provide an important advance in neurological rehabilitation where an easy-access and low-cost intervention may help to improve gait, electroencephalographic activity and mobility in individuals with PD

Influência do treino em esteira na marcha em dupla tarefa em indivíduos com Doença de Parkinson: estudo de caso

The loss in the automaticity of gait hinders the performance of concurrent activities - Dual Task (DT) - in individuals with Parkinson's disease (PD). One hypothesis for the negative interference of DT on gait is related to the limitation of attention resources in the brain for different activities. When the automation of a task occurs, the negative interference of DT on the gait can be minimized. Because the treadmill promotes automaticity of a better locomotion pattern, due to the repetition that promotes motor learning, the study sought to investigate whether treadmill training can improve the performance of gait on DT in people with PD. Three individuals were evaluated in the on-phase of the antiparkinsonian medication regarding the kinematics (Qualisys Motion Capture System) while in gait, simultaneously performing cognitive activities. Subsequently, the subjects performed a 20-minute workout on the treadmill and were reassessed during gait in cognitive activities. There were increases in the length of the cycle (p=0.01), the length of the step (p=0.01) and in total swing time (p=0.03), and a decrease in the total length of support (p=0.03). These results indicate that treadmill training can promote improvement in the performance of DT on gait in individuals with PD. Longitudinal studies with this focus of research are needed.La pérdida en el automatismo de la marcha dificulta la realización de actividades simultáneas - Doble Tarea (DT) - en personas con enfermedad de Parkinson (EP). Una hipótesis para la interferencia negativa de la DT en la marcha está relacionada con la limitación de recursos cerebrales de atención para diferentes actividades. Cuando se produce la automatización de una de las tareas, la interferencia negativa de la DT sobre la marcha podrá ser minimizada. Como la cinta de correr promueve la automaticidad de un mejor patrón locomotor, debido a la repetición que favorece el aprendizaje motor, el estudio trató de investigar si el entrenamiento en cinta de correr puede mejorar el desempeño de marcha en DT en personas con EP. Tres individuos fueron evaluados en la fase on del medicamento antiparkinsoniano en cuanto a la cinemática (Qualisys Motion Capture System), mientras se realizaba la marcha simultáneamente a actividades cognitivas. Posteriormente, los individuos realizaron un entrenamiento de 20 minutos en la cinta y fueron evaluados de nuevo durante la marcha en actividades cognitivas. Hubo aumentos en longitud de la pasada (p=0,01), la longitud del paso (p=0,01) y en el tiempo total del abalanzar (p=0,03) y una disminución de en tiempo total de apoyo (p=0,03). Estos resultados indican que el entrenamiento en cinta puede promover la mejora en el rendimiento de marcha en DT en personas con EP, y que se necesitan estudios longitudinales con este enfoque de investigación.A perda na automaticidade da marcha dificulta a realização de atividades concorrentes - Dupla Tarefa (DT) - em indivíduos com Doença de Parkinson (DP). Uma hipótese para a interferência negativa da DT sobre a marcha está relacionada à limitação de recursos cerebrais atentivos para as diferentes atividades. Caso ocorra a automatização de uma das tarefas, a interferência negativa da DT sobre a marcha poderá ser minimizada. Como a esteira promove automaticidade de um melhor padrão locomotor, devido à repetição que favorece a aprendizagem motora, o estudo buscou investigar se o treino em esteira pode melhorar o desempenho de marcha em DT em pessoas com DP. Três indivíduos foram avaliados na fase on do medicamento antiparkinsoniano quanto à cinemetria (Qualisys Motion Capture System), enquanto realizavam a marcha simultaneamente a atividades cognitivas. Posteriormente, os indivíduos realizaram um treino de 20 minutos na esteira e foram reavaliados durante a marcha em atividades cognitivas. Houve aumentos no comprimento da passada (p=0,01), no comprimento do passo (p=0,01) e no tempo total de apoio (p=0,03). Esses resultados indicam que o treino em esteira pode promover melhora no desempenho de marcha em DT em indivíduos com DP, sendo necessários estudos longitudinais com esse foco de investigação

Cosmic Rays X. The cosmic ray knee and beyond: Diffusive acceleration at oblique shocks

Our purpose is to evaluate the rate of the maximum energy and the acceleration rate that cosmic rays acquire in the non-relativistic diffusive shock acceleration as it could apply during their lifetime in various astrophysical sites, where highly oblique shocks exist. We examine numerically (using Monte Carlo simulations) the effect of the diffusion coefficients on the energy gain and the acceleration rate, by testing the role between the obliquity of the magnetic field to the shock normal, and the significance of both perpendicular cross-field diffusion and parallel diffusion coefficients to the acceleration rate. We find (and justify previous analytical work - Jokipii 1987) that in highly oblique shocks the smaller the perpendicular diffusion gets compared to the parallel diffusion coefficient values, the greater the energy gain of the cosmic rays to be obtained. An explanation of the cosmic ray spectrum in high energies, between $10^{15}$eV and about $10^{18}$eV is claimed, as we estimate the upper limit of energy that cosmic rays could gain in plausible astrophysical regimes; interpreted by the scenario of cosmic rays which are injected by three different kind of sources, (a) supernovae which explode into the interstellar medium, (b) Red Supergiants, and (c) Wolf-Rayet stars, where the two latter explode into their pre-supernovae winds.Comment: Accepted in Astronomy and Astrophysics, 9 pages, 8 figures (for the 'Cosmic Rays' series papers

Contributions of individual cover crop species to rainfed maize production in semi-arid cropping systems

Cover crop (CC) species selection can contribute to reducing soil penetration resistance (brassica species), improved soil nitrogen (N) cycling (legume species), and suppression of weeds (grass species). However, one of the main concerns about including CCs in water-limited environments is soil water use and the consequences to subsequent crops. To determine the effects of individual CC species under water-limited environments, we evaluated fall and spring CC biomass produced, and soil water and N content, penetration resistance, weed density and biomass during the maize growing season, and maize grain yield. The experiment was conducted under a winter wheat-maize-fallow rotation at two locations (North Platte and Grant, NE) during 2016−2017 and 2017−2018 (four site-years). Treatments consisted of seven popular CC species plus a control (fallow), planted after winter wheat harvest. Spring oats, Siberian kale, and purple top turnip produced greater fall biomass, while cereal rye produced the greatest amount of spring biomass. However, cereal rye reduced soil volumetric water content in North Platte 2016−2017 and increased soil penetration resistance from 20–30 cm soil depth across site-years likely due to soil water use. Spring cover crop growth suppressed weeds early in the maize growing season. Due to its aboveground biomass production, cereal rye decreased weed density and biomass by 80 and 88 %, respectively, compared to the fallow treatment. On the other hand, except for brassicas, CCs decreased N levels in the soil during maize growing season, and all CC species reduced maize grain yield up to 30 % compared to fallow (except spring oats). Spring oats can be an alternative to cereal rye as CC species for semi-arid regions. However, since CCs did not promote any maize yield gain, our findings suggest that producers should use caution when incorporating CCs in their cropping systems in water-limited environments. This research provides valuable information on the potential impact of CCs on rainfed maize production, as well as help producers and agronomists develop better CC management programs for cropping systems in semi-arid regions

ESI FTICR-MS Analysis of Larvae from the Marine Sponge Luffariella variabilis

The viviparous Great Barrier Reef sponge Luffariella variabilis (Poléjaeff 1884) contains a range of secondary metabolites, including manoalide (1) and manoalide monoacetate (3). ESI (+) FTICR-MS accurate mass determination has, for the first time, been used to detected the presence of 3 only in an organic extract of a single L. variabilis larva showing that the parentally produced 3 is sequestered in the larva. As 3 has previously been shown to have antibacterial and quorum sensing inhibition activity, and readily converts to 1, which also exhibits similar activity, it may provide a chemical defence against predation and microbial attack

Tensor Regression with Applications in Neuroimaging Data Analysis

Classical regression methods treat covariates as a vector and estimate a corresponding vector of regression coefficients. Modern applications in medical imaging generate covariates of more complex form such as multidimensional arrays (tensors). Traditional statistical and computational methods are proving insufficient for analysis of these high-throughput data due to their ultrahigh dimensionality as well as complex structure. In this article, we propose a new family of tensor regression models that efficiently exploit the special structure of tensor covariates. Under this framework, ultrahigh dimensionality is reduced to a manageable level, resulting in efficient estimation and prediction. A fast and highly scalable estimation algorithm is proposed for maximum likelihood estimation and its associated asymptotic properties are studied. Effectiveness of the new methods is demonstrated on both synthetic and real MRI imaging data.Comment: 27 pages, 4 figure

Effects of adding load to the gait of children with cerebral palsy: a three-case report

El objetivo de este estudio fue analizar los efectos inmediatos del entrenamiento locomotor en la estera con diferentes cargas, sobre los parámetros cinemáticos de la marcha de niños con parálisis cerebral hemipléjica espástica (PCHE), e investigar cómo la carga promueve respuestas motoras más adecuadas para favorecer la propulsión del Miembro Inferior Parético (MIP). Participaron de este caso, 3 niños de ambos sexos, con edades de 8-12 años. Los niños realizaron entrenamiento en la estera rodante con carga en los tobillos equivalente a 40, 50 y 60% del peso de la miembro (MI), en 3 días distintos y no consecutivos. Los parámetros cinemáticos fueron evaluados en las fases de pre entrenamiento (FPT), e inmediatamente después del entrenamiento (FI). Las variables espacio-temporales no cambiaron inmediatamente después del ejercicio de marcha con carga. Sin embargo, fue observado aumento de los ángulos articulares de la cadera y la rodilla durante la fase de balanceo inmediatamente después del entrenamiento, especialmente con carga de 60% del peso de la extremidad inferior. Estos resultados indican que la carga de 60% es la más apropiada para solicitar cambios inmediatos en la cinemática articular del MIP. Tales cambios pueden ser importantes para fomentar la propulsión durante la fase de balanceo de la marcha de niños con PCHE.O objetivo deste estudo foi analisar os efeitos imediatos do treino locomotor na esteira com diferentes cargas, sobre os parâmetros cinemáticos da marcha de crianças com Paralisia Cerebral Hemiparética Espástica (PCHE), e investigar qual carga promove repostas motoras mais adequadas para favorecer a propulsão do Membro Inferior Parético (MIP). Participaram deste relato de caso 3 crianças de ambos os sexos, com idades de 8-12 anos. As crianças realizaram treino na esteira com carga nos tornozelos equivalentes a 40, 50 e 60% do peso do Membro Inferior (MI), em 3 dias diferentes e não consecutivos. Os parâmetros cinemáticos foram avaliados nas fases pré-treinamento (FPT) e imediatamente após o treino (FI). As variáveis espaço-temporais não sofreram alterações imediatamente após o treino de marcha com carga. Por outro lado, foi observado aumento dos ângulos articulares de quadril e joelho durante a fase de balanço imediatamente após o treino, principalmente com carga de 60% do peso do membro inferior. Estes achados indicam que a carga de 60% seja a mais apropriada para solicitar alterações imediatas na cinemática articular do MIP. Tais alterações podem ser importantes para favorecer a propulsão durante a fase de balanço da marcha de crianças com PCHE.Our purpose in this study was to analyze the immediate effects of locomotor gait training with different loads on a treadmill on the kinematic parameters of gait in children with Spastic Hemiparetic Cerebral Palsy (SHCP), as well as investigating which load prompted the most adequate motor responses to promote the propulsion of the Paretic Lower Limb (PLL). This case report included 3 children of both sexes, aged 8-12 years. The children walked on the treadmill with loads on their ankles that corresponded to 40, 50 and 60% of the weight of the Lower Limb (LL), on 3 different non-consecutive days. The kinematic parameters were assessed during the pre-training phase (PTPH) and immediately after training (PHI). The spatiotemporal variables did not change immediately after gait training with the aforementioned loads. On the other hand, we observed wider joint angles in the hip and knee during the swing phase immediately after training, especially with a load of 60% of the weight of the lower limb. These findings indicate that the 60% load is the most appropriate to prompt immediate changes in the joint kinematics of the PLL. These alterations can be important in improving propulsion during the swing phase of gait in children with SHCP