Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder.

Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.

An In-Depth Study of Vibration Sensors for Condition Monitoring.

Heavy machinery allows for the efficient, precise, and safe management of large-scale operations that are beyond the abilities of humans. Heavy machinery breakdowns or failures lead to unexpected downtime, increasing maintenance costs, project delays, and leading to a negative impact on personnel safety. Predictive maintenance is a maintenance strategy that predicts possible breakdowns of equipment using data analysis, pattern recognition, and machine learning. In this paper, vibration-based condition monitoring studies are reviewed with a focus on the devices and methods used for data collection. For measuring vibrations, different accelerometers and their technologies were investigated and evaluated within data collection contexts. The studies collected information from a wide range of sources in the heavy machinery. Throughout our review, we came across some studies using simulations or existing datasets. We concluded in this review that due to the complexity of the situation, we need to use more advanced accelerometers that can measure vibration.

"No pain, no gain": The impact of autonomous sensory meridian response on pain perception.

Autonomous sensory meridian response (ASMR) is a phenomenon characterised by a static-like tingling sensation spreading from the scalp and neck to the periphery in response to a variety of audio, visual, and tactile triggers resulting in a highly relaxed state and boosted positive affect. The limited literature on this phenomenon points to a potential of ASMR to alleviate pain. Emerging evidence also suggests that ASMR may be linked to increased sensory sensitivity more broadly. This study aimed to objectively address these claims by administering an algometer (measure of pain tolerance), and a visual analog scale (VAS) (measure of subjective pain sensitivity) to ASMR experiencers and controls at baseline, following an ASMR video, and a control video. Findings indicate that ASMR experiencers have a higher pain sensitivity than controls; however, there was no difference between the two groups in terms of pain tolerance. In addition, any potential analgesic properties associated with experiencing ASMR may reflect protective properties of ASMR buffering against the increased pain sensitivity among ASMR experiencers relative to controls.

Key Challenges and Emerging Technologies in Industrial IoT Architectures: A Review.

The Industrial Internet of Things (IIoT) is bringing evolution with remote monitoring, intelligent analytics, and control of industrial processes. However, as the industrial world is currently in its initial stage of adopting full-stack development solutions with IIoT, there is a need to address the arising challenges. In this regard, researchers have proposed IIoT architectures based on different architectural layers and emerging technologies for the end-to-end integration of IIoT systems. In this paper, we review and compare three widely accepted IIoT reference architectures and present a state-of-the-art review of conceptual and experimental IIoT architectures from the literature. We identified scalability, interoperability, security, privacy, reliability, and low latency as the main IIoT architectural requirements and detailed how the current architectures address these challenges by using emerging technologies such as edge/fog computing, blockchain, SDN, 5G, Machine Learning, and Wireless Sensor Networks (WSN). Finally, we discuss the relation between the current challenges and emergent technologies and present some opportunities and directions for future research work.

Sensor and Sensor Fusion Technology in Autonomous Vehicles: A Review.

With the significant advancement of sensor and communication technology and the reliable application of obstacle detection techniques and algorithms, automated driving is becoming a pivotal technology that can revolutionize the future of transportation and mobility. Sensors are fundamental to the perception of vehicle surroundings in an automated driving system, and the use and performance of multiple integrated sensors can directly determine the safety and feasibility of automated driving vehicles. Sensor calibration is the foundation block of any autonomous system and its constituent sensors and must be performed correctly before sensor fusion and obstacle detection processes may be implemented. This paper evaluates the capabilities and the technical performance of sensors which are commonly employed in autonomous vehicles, primarily focusing on a large selection of vision cameras, LiDAR sensors, and radar sensors and the various conditions in which such sensors may operate in practice. We present an overview of the three primary categories of sensor calibration and review existing open-source calibration packages for multi-sensor calibration and their compatibility with numerous commercial sensors. We also summarize the three main approaches to sensor fusion and review current state-of-the-art multi-sensor fusion techniques and algorithms for object detection in autonomous driving applications. The current paper, therefore, provides an end-to-end review of the hardware and software methods required for sensor fusion object detection. We conclude by highlighting some of the challenges in the sensor fusion field and propose possible future research directions for automated driving systems.

Representation Learning for Fine-Grained Change Detection.

Fine-grained change detection in sensor data is very challenging for artificial intelligence though it is critically important in practice. It is the process of identifying differences in the state of an object or phenomenon where the differences are class-specific and are difficult to generalise. As a result, many recent technologies that leverage big data and deep learning struggle with this task. This review focuses on the state-of-the-art methods, applications, and challenges of representation learning for fine-grained change detection. Our research focuses on methods of harnessing the latent metric space of representation learning techniques as an interim output for hybrid human-machine intelligence. We review methods for transforming and projecting embedding space such that significant changes can be communicated more effectively and a more comprehensive interpretation of underlying relationships in sensor data is facilitated. We conduct this research in our work towards developing a method for aligning the axes of latent embedding space with meaningful real-world metrics so that the reasoning behind the detection of change in relation to past observations may be revealed and adjusted. This is an important topic in many fields concerned with producing more meaningful and explainable outputs from deep learning and also for providing means for knowledge injection and model calibration in order to maintain user confidence.

Recovering From the Suicide of a Client With Schizophrenia: Recommendations for Case Managers.

Many case managers in mental health settings occasionally experience a client's suicide, and this can be an emotionally devastating event. The symptoms of schizophrenia, including the difficulties those client face in forming trusting relationships with others, brings special challenges to the case manager's recovery because of the efforts put into developing that relationship. The purposes of this article are to describe a range of possible reactions of case managers following the suicide of a client with schizophrenia and how those persons can be helped to make a positive recovery from such an event. A summary of suicide risk factors for case managers to assess when working with clients who have schizophrenia is included.

Atherosclerotic plaque uptake of a novel integrin tracer ¹8F-Flotegatide in a mouse model of atherosclerosis.

INTRODUCTION: Rupture of unstable atherosclerotic plaque that leads to stroke and myocardial infarction may be induced by macrophage infiltration and neovessel formation. A tracer that selectively binds to integrin αvß3 a protein expressed by macrophages and neovascular endothelium may identify rupture prone plaque. METHODS: (18)F-labeled "R-G-D" containing tripeptide (Flotegatide), a click chemistry derived radiotracer that binds to integrin αvß3 was injected in ApoE knockout mice fed a high fat diet. Uptake of Flotegatide by atherosclerotic plaque was visualized by micro-PET, autoradiography, and correlated to histologic markers of inflammation and angiogenesis. RESULTS: We found that Flotegatide preferentially binds to aortic plaque in an ApoE knockout mouse model of atherosclerosis. The tracer's uptake is strongly associated with presence of histologic markers for macrophage infiltration and integrin expression. There is a weaker but detectable association between Flotegatide uptake and presence of an immunohistochemical marker for neovascularization. DISCUSSION: We hypothesize that Flotegatide may be a useful tracer for visualization of inflamed plaque in clinical subjects with atherosclerosis and may have potential for detecting vulnerable plaque.

Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging.

Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [(18)F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [(18)F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [(18)F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [(18)F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [(18)F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [(18)F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [(18)F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.

[(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease.

OBJECTIVE: We wished to develop a highly selective positron emission tomography (PET) imaging agent targeting PHF-tau in human Alzheimer's disease (AD) brains. METHODS: To screen potential tau binders, human AD brain sections were used as a source of native paired helical filament (PHF)-tau and Aß rather than synthetic tau aggregates or Aß fibrils generated in vitro to measure the affinity and selectivity of [(18)F]T807 to tau and Aß. Brain uptake and biodistribution of [(18)F]T807 in mice were also tested. RESULTS: In vitro autoradiography results show that [(18)F]T807 exhibits strong binding to PHF-tau-positive human brain sections. A dissociation constant (Kd) of [(18)F]T807 (14.6 nM) was measured using brain sections from the frontal lobe of AD patients. A comparison of autoradiography and double immunohistochemical staining of PHF-tau and Aß on adjacent sections demonstrated that [(18)F]T807 binding colocalized with immunoreactive PHF-tau pathology, but did not highlight Aß plaques. In vivo studies in mice demonstrated that [(18)F]T807 was able to cross the blood-brain barrier and washed out quickly. CONCLUSIONS: [(18)F]T807 demonstrates high affinity and selectivity to PHF-tau as well as favorable in vivo properties, making this a promising candidate as an imaging agent for AD.

Continuous transcriptome analysis reveals novel patterns of early gene expression in Drosophila embryos.

The transformative events during early organismal development lay the foundation for body formation and long-term phenotype. The rapid progression of events and the limited material available present major barriers to studying these earliest stages of development. Herein, we report an operationally simple RNA sequencing approach for high-resolution, time-sensitive transcriptome analysis in early (≤3 h) Drosophila embryos. This method does not require embryo staging but relies on single-embryo RNA sequencing and transcriptome ordering along a developmental trajectory (pseudo-time). The resulting high-resolution, time-sensitive mRNA expression profiles reveal the exact onset of transcription and degradation for thousands of transcripts. Further, using sex-specific transcription signatures, embryos can be sexed directly, eliminating the need for Y chromosome genotyping and revealing patterns of sex-biased transcription from the beginning of zygotic transcription. Our data provide an unparalleled resolution of gene expression during early development and enhance the current understanding of early transcriptional processes.

Effects of melatonin and its receptor antagonist on retinal pigment epithelial cells against hydrogen peroxide damage.

PURPOSE: Recently, we reported finding that circulating melatonin levels in age-related macular degeneration patients were significantly lower than those in age-matched controls. The purpose of this study was to investigate the hypothesis that melatonin deficiency may play a role in the oxidative damage of the retinal pigment epithelium (RPE) by testing the protective effect of melatonin and its receptor antagonist on RPE cells exposed to H(2)O(2) damage. METHODS: Cultured human RPE cells were subjected to oxidative stress induced by 0.5 mM H(2)O(2). Cell viability was measured using the microculture tetrazoline test (MTT) assay. Cells were pretreated with or without melatonin for 24 h. Luzindole (50 µM), a melatonin membrane-receptor antagonist, was added to the culture 1 h before melatonin to distinguish direct antioxidant effects from indirect receptor-dependent effects. All tests were performed in triplicate. RESULTS: H(2)O(2) at 0.5 mM decreased cell viability to 20% of control levels. Melatonin showed dose-dependent protective effects on RPE cells against H(2)O(2). Cell viability of RPE cells pretreated with 10(-10), 10(-8), 10(-6), and 10(-4) M melatonin for 24 h was 130%, 160%, 187%, and 230% of cells treated with H(2)O(2) alone (all p<0.05). Using cells cultured without H(2)O(2) as the control, cell viability of cells treated with H(2)O(2) after pretreatment with 10(-10)-10(-4) M melatonin was still significantly lower than that of the controls, suggesting that melatonin significantly decreased but did not completely abolish the in vitro cytotoxic effects of H(2)O(2). Luzindole completely blocked melatonin's protective effects at low concentrations of melatonin (10(-10)-10(-8) M) but not at high concentrations (10(-6)-10(-4) M). CONCLUSIONS: Melatonin has a partial protective effect on RPE cells against H(2)O(2) damage across a wide range of concentrations (10(-10)-10(-4) M). This protective effect occurs through the activation of melatonin membrane receptors at low concentrations (10(-10)-10(-8) M) and through both the direct antioxidant and indirect receptor activation effects at high concentrations (10(-6)-10(-4) M).

A Resilience Model for Moderating Outcomes Related to Electronic Medical Record Downtime.

The objective of this scoping review is to develop a model to understand the factors that influence clinical downtimes or clinical activities in a healthcare organization. To report on the results of searches preformed using seven bibliographic databases, using the logical search criteria of (downtime AND (EMR OR Electronic Medical Record OR EHR OR Electronic Health Record). After a title, abstract and full-text review 26 articles remained. The articles were coded and analyzed for themes. Downtime planning activities mitigate the effects of disasters on patient safety outcomes and clinical delays. A model was developed representing the relationships between disasters, the moderating variable of downtime planning activities and patient safety as well as clinical outcomes. Disasters can have significant impact on patients and health professionals. Downtime planning activities can be enacted when a disaster occurs to moderate the effects of the downtime on patients and clinical activities and can improve safety.

In vivo, transcutaneous glucose sensing using surface-enhanced spatially offset Raman spectroscopy: multiple rats, improved hypoglycemic accuracy, low incident power, and continuous monitoring for greater than 17 days.

This paper presents the latest progress on quantitative, in vivo, transcutaneous glucose sensing using surface enhanced spatially offset Raman spectroscopy (SESORS). Silver film over nanosphere (AgFON) surfaces were functionalized with a mixed self-assembled monolayer (SAM) and implanted subcutaneously in Sprague-Dawley rats. The glucose concentration was monitored in the interstitial fluid of six separate rats. The results demonstrated excellent accuracy and consistency. Remarkably, the root-mean-square error of calibration (RMSEC) (3.6 mg/dL) and the root-mean-square error of prediction (RMSEP) (13.7 mg/dL) for low glucose concentration (<80 mg/dL) is lower than the current International Organization Standard (ISO/DIS 15197) requirements. Additionally, our sensor demonstrated functionality up 17 days after implantation, including 12 days under the laser safety level for human skin exposure with only one time calibration. Therefore, our SERS based sensor shows promise for the challenge of reliable continuous glucose sensing systems for optimal glycemic control.

The disruptive effects of pain on the early allocation of attentional resources: An attentional blink study.

BACKGROUND: Recent evidence suggests that pain dampens attentional processes. However, much of this work has been based on higher-order attentional tasks that involve only spatial attention. Other aspects of the process through which pain engages and holds attention are relatively understudied, in particular, temporal attention. The present set of studies explored how naturally occurring pain (i.e. acute headache) and pain-valenced stimuli affect the ability to recall the second of two targets presented in rapid succession. METHODS: Across both experiments participants were required to indicate the presence of a predefined probe (T2) and, in the dual task, identify a target (T1). The probe (T2) was placed in three different temporal proximities (ranging from 70 to 1000 ms) following presentation of the target (T1). In Experiment 1, 36 participants completed a task that comprised a rapid stream of letters. Experiment 2 manipulated the threat value, and the complexity, of the stimuli by replacing letters with words. In the dual task condition, T1 was a word from one of four valence categories (neutral, positive, negative, pain). RESULTS: Being in acute pain reduced the accuracy of identification. This reduction in performance occurred regardless of the temporal positioning of the probe, consistent with previous work that suggests pain has an overall dampening effect. Furthermore, when the valence category of the word was pain-related, T2 accuracy performance was negatively affected. CONCLUSION: These findings add to the previous evidence that pain has a general dampening effect on attention and that pain-related stimuli are difficult to disengage from. SIGNIFICANCE: Pain captures attention to allow cognate resources to be directed appropriately in response. However, the temporal effects of this attentional capture are poorly understood. Findings indicate that acute headache pain has a negative impact on participants' performance when identifying the second of two targets presented in close temporal proximity, and that pain-valenced stimuli exacerbate this effect. These findings demonstrate how pain affects early attention and highlights the potential role of disengagement, rather than orientation, of attention in the pain experience.

MACULAR VORTEX VEIN IN A HIGHLY MYOPIC EYE IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To report a case of macular vortex vein imaged with indocyanine green angiography, spectral domain optical coherence tomography, and optical coherence tomography angiography. METHODS: Observational case report. RESULTS: A 51-year-old myopic man presented with the complaint of a floater in his left eye for the previous 2 weeks. His visual acuity was 20/25 in the right eye and 20/40 in the left eye. Biomicroscopy was normal. Retinoscopy revealed lattice degeneration and posterior vitreous detachment of both eyes with dilated submacular vasculature in the right eye and submacular hemorrhage in the left eye. Spectral domain optical coherence tomography demonstrated dilated vessels in the choroid of the right eye and a choroidal neovascular membrane in the left eye. Fluorescein angiography and indocyanine green angiography showed a macular vortex vein in the right eye. Optical coherence tomography angiography demonstrated normal vessel densities in the superficial and deep capillary plexuses. No abnormalities were detected in the outer retina or choriocapillaris. Optical coherence tomography angiography delineated the macular vortex vein with a relative flow void in the right eye. His vision remained stable in the right eye. CONCLUSION: Macular vortex veins may be a prominent, albeit rare, incidental finding in highly myopic eyes. Further studies with application of newer optical coherence tomography angiography modalities, such as swept-source optical coherence tomography angiography, are recommended to improve our understanding and monitoring of these structures.

Attentional Biases Towards Body Expressions of Pain in Men and Women.

This study investigated whether there are gender differences in attention to bodily expressions of pain and core emotions. Three experiments are reported using the attentional dot probe task. Images of men and women displaying bodily expressions, including pain, were presented. The task was used to determine whether participants' attention was drawn towards or away from target expressions. Inconsistent evidence was found for an attentional bias towards body expressions, including pain. While biases were affected by gender, patterns varied across the Experiments. Experiment 1, which had a presentation duration of 500 ms, found a relative bias towards the location of male body expressions compared to female expressions. Experiments 2 and 3 varied stimulus exposure times by including both shorter and longer duration conditions (e.g., 100 vs. 500 vs. 1250 ms). In these experiments, a bias towards pain was confirmed. Gender differences were also found, especially in the longer presentation conditions. Expressive body postures captured the attention of women for longer compared to men. These results are discussed in light of their implications for why there are gender differences in attention to pain, and what impact this has on pain behaviour. PERSPECTIVE: We show that men and women might differ in how they direct their attention towards bodily expressions, including pain. These results have relevance to understanding how carers might attend to the pain of others, as well as highlighting the wider role that social-contextual factors have in pain.

Validation of a molecular assay to detect SARS-CoV-2 in saliva.

AIM: To validate a reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) assay to detect SARS-CoV-2 in saliva in two independent Aotearoa New Zealand laboratories. METHODS: An RT-qPCR assay developed at University of Illinois Urbana-Champaign, USA, was validated in two New Zealand laboratories. Analytical measures, such as limit of detection (LOD) and cross-reactivity, were performed. One hundred and forty-seven saliva samples, each paired with a contemporaneously collected nasal swab, mainly of nasopharyngeal origin, were received. Positive (N=33) and negative (N=114) samples were tested blindly in each laboratory. Diagnostic sensitivity and specificity were then calculated. RESULTS: The LOD was <0.75 copy per µL and no cross-reactivity with MERS-CoV was detected. There was complete concordance between laboratories for all saliva samples with the quantification cycle values for all three genes in close agreement. Saliva had 98.7% concordance with paired nasal samples: and a sensitivity, specificity and accuracy of 97.0%, 99.1% and 99.1%, respectively. CONCLUSION: This saliva RT-qPCR assay produces reproducible results with a low LOD. High sensitivity and specificity make it a reliable option for SARS-CoV-2 testing, including for asymptomatic people requiring regular screening.

NMR studies on domain diffusion and alignment in modular GB1 repeats.

Modular proteins contain individual domains that are often connected by flexible, unstructured linkers. Using a model system based on the GB1 domain, we constructed tandem repeat proteins and investigated the rotational diffusion and long-range angular ordering behavior of individual domains by measuring NMR relaxation parameters and residual dipolar couplings. Although they display almost identical protein-solvent interfaces, each domain exhibits distinct rotational diffusion and alignment properties. The diffusion tensor anisotropy of the N-terminal domain (NTD) is D(‖)/D(⊥) = 1.5-1.6, similar to that of single-GB1 domains (D(‖)/D(⊥) = 1.6-1.7), whereas the value for the C-terminal domain (CTD) is D(‖)/D(⊥) = 2.0-2.2. In addition, the two domains have different rotational correlation times. These effects are observed for linkers of three to 24 residues, irrespective of linker length. The NTD and CTD also differ in their degree of magnetic alignment, even with a flexible linker of 18 residues, exhibiting D(a) values of 7.7 Hz and 9.7 Hz, respectively. Our results suggest that diffusion differences and long-range influences may persist in modular protein systems, even for systems that have highly flexible linkers and exhibit no domain-domain or domain-linker interactions.