Search

Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was recently approved for migraine prophylaxis. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between galcanezumab concentration and inhibition of capsaicin-induced dermal blood flow (CIDBF) was evaluated using first-in-human data following 6 single subcutaneous doses (1 to 600 mg) or multiple (4) 150-mg doses every 2 weeks in 7 cohorts (7 actively treated subjects and 2 placebo-treated healthy subjects). Galcanezumab pharmacokinetics were best described by a 1-compartment model with delayed first-order absorption/linear elimination. Apparent estimates (between-subject variability) of clearance, volume of distribution, absorption rate constant, and lag time were 0.0106 L/h (27%CV), 11.2 L (21%CV), 0.0192 h-1 (89%CV), and 0.202 hours, respectively. Estimated elimination half-life was about 30 days. An effect compartment link model described the concentration-effect relationship; estimated maximum inhibitory effect was 70.5%, and 50% maximum inhibitory effect concentration (IC50 ) was 1060 ng/mL. Galcanezumab showed dose- and concentration-dependent potent and durable inhibition of CIDBF. Simulated effect compartment concentrations were maintained above IC50 after 12 weeks of dosing. Near-maximal CIDBF inhibition occurred with 150 mg biweekly for 12 weeks lasting ≥24 weeks or with ≥30 mg every 2 weeks or 195 mg every 13 weeks. Quantitative modeling of galcanezumab PK/PD supported dose selection for the phase 2 proof-of-concept study.

COVID-19 has radically changed society as we know it. To reduce the spread of the virus, millions across the globe have been forced to work remotely, often in make-shift home offices, and using a plethora of new, unfamiliar digital technologies. In this article, we critically analyse cyber security and privacy concerns arising due to remote working during the coronavirus pandemic. Through our work, we discover a series of security risks emerging because of the realities of this period. For instance, lack of remote-working security training, heightened stress and anxiety, rushed technology deployment, and the presence of untrusted individuals in a remote-working environment (e.g., in flatshares), can result in new cyber-risk. Simultaneously, we find that as organisations look to manage these and other risks posed by their remote workforces, employee's privacy (including personal information and activities) is often compromised. This is apparent in the significant adoption of remote workplace monitoring, management and surveillance technologies. Such technologies raise several privacy and ethical questions, and further highlight the tension between security and privacy going forward., HCI International 2021 (HCII 2021)

Alzheimer’s Disease (AD) tau pathology originates in the brainstem and subsequently spreads to the entorhinal cortex, hippocampus and finally to temporal, parietal and prefrontal association cortices in a relatively stereotyped progression. Current evidence attributes this orderly progression to trans-neuronal spread of misfolded tau protein along the projection pathways of affected neurons. The aggregation of tau is being increasingly recognized as a trustworthy biomarker preceding the appearance of Alzheimer’s disease (AD) symptoms. One major goals of disease modifying therapies has been to stop or slow down the tau aggregation process. In order to evaluate drug efficacy, it would be desirable to have an accurate model predictive of a patient’s future tau burden, against which the tau measurements from drug-receiving cohorts could be compared. Here we report the development of such a model, evaluated in a cohort of 88 subjects clinically diagnosed as Mild Cognitively Impaired (MCI = 60) or Alzheimer’s disease (AD = 28) and tracked over a period of 18 months. Our approach combined data-driven and model-based methodologies, with the goal of predicting changes in tau within suitably specified target regions. We show that traditional statistical methods, allied to a network diffusion model for tau propagation in the brain, provide a remarkable prediction of the magnitude of incremental tau deposited in particular cortical areas of the brain over this period (MCI: R2 = 0.65±0.16; AD: R2 = 0.71±0.11) from baseline data. Our work has the potential to greatly strengthen the repertoire of analysis tools used in AD clinical trials, opening the door to future interventional trials with far fewer sample sizes than currently required.

Background Previous studies found that [18F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [18F]LSN3316612 for human clinical research. Methods Kinetic evaluation of [18F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was conducted in 10 of these volunteers; another 6 volunteers had whole-body scans to measure radiation exposure to body organs. Total distribution volume (VT) estimates were compared for the one- and two-tissue compartment models with the arterial input function. Test-retest variability and reliability were evaluated via mean difference and intraclass correlation coefficient (ICC). The time stability of VT was assessed down to a 30-min scan time. An alternative quantification method for [18F]LSN3316612 binding without blood was also investigated to assess the possibility of eliminating arterial sampling. Results Brain uptake was generally high and could be quantified as VT with excellent identifiability using the two-tissue compartment model. [18F]LSN3316612 exhibited good absolute test-retest variability (12.5%), but the arithmetic test-retest variability was far from 0 (11.3%), reflecting a near-uniform increase of VT on the retest scan in nine of 10 volunteers. VT values were stable after 110 min in all brain regions, suggesting that no radiometabolites accumulated in the brain. Measurements obtained using only brain activity (i.e., area under the curve (AUC) from 150–180 min) correlated strongly with regional VT values during test-retest conditions (R2 = 0.84), exhibiting similar reliability to VT (ICC = 0.68 vs. 0.64). Estimated radiation exposure for [18F]LSN3316612 PET was 20.5 ± 2.1 μSv/MBq, comparable to other 18F-labeled radioligands for brain imaging. Conclusions [18F]LSN3316612 is an excellent PET radioligand for imaging O-GlcNAcase in the human brain. Alternative quantification without blood is possible, at least for within-subject repeat studies. However, the unexplained increase of VT under retest conditions requires further investigation.

Biomimetic robots that resemble companion animals, and that replicate aspects of animal social behavior, could play a useful therapeutic role in the treatment of disorders such as anxiety and depression, and could act as an alternative or complement to animal-assisted therapy (AAT). Previous work in AAT has noted the importance of feelings of care, love, self-esteem to the success of a therapeutic animal intervention. These feelings, alongside safety, have been measured in human-human interaction studies using a questionnaire-based measure called the Felt Security Scale (FSS). This paper presents the translation of the FSS into Japanese in order to produce a cross-cultural instrument for evaluating the effectiveness of robot-assisted therapy (RAT). We describe the development of the new Japanese Felt Security Scale (JFSS), its validation with native Japanese speakers, and a comparison of outcomes as measured against the Japanese Experiences in Close Relationships Scale (Japanese ECR). We propose that the FSS provides a useful tool for investigating the effectiveness of biomimetic robots as therapeutic tools in English- and Japanese-speaking cultural settings.

LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.

Background: Calcitonin gene-related peptide (CGRP) is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742) binds to CGRP and may be effective in migraine prophylaxis. Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement. Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596) with single escalating and multiple subcutaneous (SC) doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab (n = 7/dose) or placebo (n = 2/dose) were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4) 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF). Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1-600 mg SC) and consecutive doses (150 mg SC). There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients. ispartof: Frontiers in Pharmacology vol:8 issue:OCT pages:740- ispartof: location:Switzerland status: published

This research investigated the associations between personality traits and both normal and problematic massively multiplayer online role playing game (MMORPGs) play, as measured by a self report scale. A total of 225 participants completed the online questionnaire, 66 of whom played MMORPGs. Correlational analyses indicated that low levels of functional impulsivity and agreeableness alongside high levels of verbal aggression and video game dependency were associated with greater amount of time spent playing MMORPGs. When comparing problematic and non-problematic MMORPG players directly, problematic players were found to be lower in self regulation, dysfunctional impulsivity and agreeableness, suggesting that these traits may be important in the development and maintenance of problematic MMORPG use.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5 months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease., Highlights • We analyzed the microstructural changes in rTg4510 and wild type mice at 8.5 months. • We correlated microstructural findings with histological measures of tau burden • We compare two diffusion MR models: DTI and NODDI. • Both models revealed changes in tissue microstructure due to tau pathology. • The NODDI metrics demonstrated a good correlation with histological measures of tau burden.

Observational studies of situated displays have suggested that they are rarely looked at, and when they are it is typically only for a short period of time. Using a mobile eye tracker during a realistic shopping task in a shopping center, we show that people look at displays more than would be predicted from these observational studies, but still only short glances and often from quite far away. We characterize the patterns of eye-movements that precede looking at a display and discuss some of the design implications for the design of situated display technologies that are deployed in public space.

Vascular abnormalities are a key feature of Alzheimer's disease (AD). Imaging of cerebral vascular reactivity (CVR) is a powerful tool to investigate vascular health in clinical populations although the cause of reduced CVR in AD patients is not fully understood. We investigated the specific role of tau pathology in CVR derangement in AD using the rTg4510 mouse model. We observed an increase in CVR in cortical regions with tau pathology. These data suggest that tau pathology alone does not produce the clinically observed decreases in CVR and implicates amyloid pathology as the dominant etiology of impaired CVR in AD patients.

Background 18F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging of atherosclerosis in the clinic is based on preferential accumulation of radioactive glucose analog in atherosclerotic plaques. FDG-PET is challenging in mouse models due to limited resolution and high cost. We aimed to quantify accumulation of nonradioactive glucose metabolite, FDG-6-phosphate, in the mouse atherosclerotic plaques as a simple alternative to PET imaging. Methodology/Principal Findings Nonradioactive FDG was injected 30 minutes before euthanasia. Arteries were dissected, and lipids were extracted. The arteries were re-extracted with 50% acetonitrile-50% methanol-0.1% formic acid. A daughter ion of FDG-6-phosphate was quantified using liquid chromatography and mass spectrometry (LC/MS/MS). Thus, both traditional (cholesterol) and novel (FDG-6-phosphate) markers were assayed in the same tissue. FDG-6-phosphate was accumulated in atherosclerotic lesions associated with carotid ligation of the Western diet fed ApoE knockout mice (5.9 times increase compare to unligated carotids, p