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A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ian M. Bell reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Donnette D. Staas reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Christopher S. Burgey reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. James Z. Deng reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Anthony W. Shaw reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Heather Stevenson reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Craig A. Stump reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. C. Blair Zartman reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Eric L. Moore reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Scott D. Mosser reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Rebecca B. White reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Christopher A. Salvatore reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. Mark E. Fraley reports a relationship with Merck & Co Inc that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background/objective: Dark adaptation measures photoreceptor recovery following intense light stimulation. Time to recovery reflects retinal function. We describe a novel method of relative foveal dark adaptation using an iPhone. Data from a small number of healthy subjects were studied to assess reproducibility, effects of age, and consider potential clinical utility., Methods: Relative foveal dark adaption was studied in 6 normal subjects across ages from 20 to 81 years and across differing testing conditions. Foveal bleaching is produced by fixating a bright white circle on an iPhone for variable times. After foveal bleaching an annular surround appears to complete a bullseye stimulus with surround initially brighter than centre. As the fovea recovers the centre regains brightness. Relative foveal dark adaptation, the time for the visual anchor to shift from surround to centre, was studied across a range of bleaching times, ages, and testing conditions., Results: Dispersion of dark adaptation times grows with increasing age. Foveal bleaching for 30 s was as effective as longer times. Testing times with a 30 s bleach were less than 1 min. Foveal dark adaptation was reproducible within each subject and was unaffected by ambient room lighting, pupil size, and light attenuation. Repeat, immediately sequential testing was similarly reproducible except after long bleaching., Conclusions: This method of dark adaptation is intuitive, repeatable, and relatively unaffected by testing condition. Testing times are brief, requiring only an iPhone screen positioned at reading distance. Relative foveal dark adaptation may be a useful tool to assess macular health., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

The ability to upright quickly and efficiently when overturned on the ground (terrestrial self-righting) is crucial for living organisms and robots. Previous studies have mapped the diverse behaviors used by various animals to self-right on different substrates, and proposed physical models to explain how body morphology can favor specific self-righting methods. However, to our knowledge, no studies have quantified and modeled all of an animal's limb motions during these complicated behaviors. Here, we studied terrestrial self-righting by immature invasive spotted lanternflies (Lycorma delicatula), an insect species that must frequently recover from being overturned after jumping and falling in its native habitat. These nymphs self-righted successfully in 92-100% of trials on three substrates with different friction and roughness, with no significant difference in the time or number of attempts required. They accomplished this using three stereotypic sequences of movements. To understand these motions, we combined 3D poses tracked on multi-view high-speed video with articulated 3D models created using photogrammetry and Blender rendering software. The results were used to calculate the mechanical properties (e.g., potential and kinetic energy, angular speed, stability margin, torque, force, etc.) of these insects during righting trials. We used an inverted physical pendulum model (a "template") to estimate the kinetic energy available in comparison to the increase in potential energy required to flip over. While these insects began righting using primarily quasistatic motions, they also used dynamic leg motions to achieve final tip-over. However, this template did not describe important features of the insect's center of mass trajectory and rotational dynamics, necessitating the use of an "anchor" model comprising the 3D rendered body model and six articulated two-segment legs to model the body's internal degrees of freedom and capture the role of the legs' contribution to inertial reorientation. This anchor elucidated the sequence of highly coordinated leg movements these insects used for propulsion, adhesion, and inertial reorientation during righting, and how they frequently pivot about a body contact point on the ground to flip upright. In the most frequently used method, diagonal rotation, these motions allowed nymphs to spin their bodies to upright with lower force with a greater stability margin compared to the other less frequently used methods. We provide a concise overview of necessary background on 3D orientation and rotational dynamics, and the resources required to apply these low-cost modeling methods to other problems in biomechanics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Detection canines are deployed to detect explosives in a wide range of environmental conditions. These environmental conditions may have negative impacts on canine capabilities as a sensor. This study leveraged an air dilution olfactometer to present controlled odor concentrations of four different energetic materials (double base smokeless powder, Composition C4, ammonium nitrate, and flake Trinitrotoluene) to dogs working in a range of high temperature, standard, and low temperature conditions with high and low humidity conditions. The air dilution olfactometer controlled concentrations independent of environmental condition. Dogs' detection threshold limits were measured using a descending staircase procedure. We measured dogs' threshold twice for each energetic under each environmental condition. Results indicated heterogeneity in effects based on energetic, but all odors were detected at their lowest concentrations under standard conditions. Smokeless powder detection was reduced under all environmental conditions compared to standard and was least detectable under high temperature and humidity conditions. AN detection was poorest under high temperature high and low humidity conditions. C4 in contrast, was least detectable at low temperatures with high humidity. TNT detection was difficult under all conditions, so decrements due to environmental conditions were not statistically detectable. Additional measures were also found to be associated with detection limits. Under high temperature conditions, correlations were observed between canine mean subcutaneous temperature and detection limits, such that dogs experiencing greater temperature increases showed poorer detection limits. In addition, dog's latency to sample the odor port from the onset of a trial was longest in the high temperature conditions. Longer latencies were also predictive of poorer detection performance. Overall, dogs showed deficits in detection sensitivity limits under all environmental conditions for at least one energetic material when the concentration of that energetic material was not directly impacted by the environmental conditions. These results suggest that behavioral factors related to environmental exposure can have important impacts on canine detection sensitivity and should be considered in operational environments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fernandez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Canines are one of the best biological detectors of energetic materials available; however, canine detection of explosives is impacted by a number of factors, including environmental conditions. The objectives of this study were: 1) determine how canine detection limits vary when both the canine and odorant are tested in varying temperature and humidity conditions (canine and odor interactive effects); and 2) determine if an acclimatization plan can improve detection limits in an adverse environmental condition. Eight working line canines were trained to detect four energetics: prill ammonium nitrate (AN), Composition 4 (C4), trinitrotoluene (TNT) and double base smokeless powder (SP). In Experiment 1, canines completed a 3-alternative forced choice 3-down-1-up staircase threshold assessment in five environmental conditions: 40°C and 70% relative humidity (RH), 40°C and 40% RH, 0°C and 90% RH, 0°C and 50% RH and 21°C and 50% RH. Canines showed a 3.5-fold detection limit increase (poorer detection) for C4 in 40°C and 70% RH compared to their detection limit at 21°C and 50% RH. In Experiment 2, the eight canines were split into two groups (n = 4), control and acclimation groups. The control group completed the threshold assessment for C4 at 21°C and 50% RH each day for 20 days, with 5 minutes of petting prior to testing. The acclimation group completed the same assessment daily starting at 21°C and 50% RH but temperature and RH were incremented daily over the course of 6 days to the 40°C and 70% RH condition. After the initial six days, the acclimation group completed daily assessments at 40°C and 70% RH condition for the remainder of the experiment. All acclimatization group canines started their session with 5 minutes of toy or food retrieves. Detection limits for C4 for all dogs were tested in 40°C and 70% RH on day 11 and day 22. The acclimatization plan improved detection limits in the 40°C and 70% RH condition for C4 compared to the non-acclimated group. In this set of experiments, canine detection limits for four explosive odorants were found to vary based on environmental condition and were mostly driven by impacts on the canine rather than odor availability. The acclimatization plan did result in lower detection limits (i.e., increased performance). Future work should determine what factor (exercise or environmental exposure) is more effective in acclimatization for odor detection work., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kane et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic wasting disease (CWD) is a fatal transmissible spongiform encephalopathy that affects both free-ranging and farmed cervid species, including mule deer, white-tailed deer, and elk ( Odocoileus hemionus, Odocoileus virginianus , and Cervus canadensis ). Due to the long incubation period and variability of clinical signs, CWD can expand and spread to new areas before they reach diagnostically detectable levels. Antemortem testing methods currently available can be difficult to obtain and to be applied to the large numbers required for adequate surveillance. However, key volatile biomarkers could be harnessed for non-invasive antemortem surveillance. Detection dogs are the most effective tool currently available for volatile detection; dogs can effectively complete wildlife surveys at rates surpassing that of humans. This study is the first to demonstrate that trained detection dogs can be used as an antemortem test for CWD. First, we trained three dogs to differentiate between CWD-positive and CWD-negative white-tailed deer faeces in a laboratory setting. Dogs spent significantly more time at the positive sample than the negative samples, suggesting that they differentiated between the positive and negative volatile signatures. We then trained the same dogs to search for CWD-positive faecal samples in a more naturalistic field setting. In the field, dogs found 8/11 CWD-positive samples and had an average false detection rate of 13%. These results suggest that dogs can be trained to differentiate CWD-positive faeces from CWD-negative faeces in both laboratory and field settings. Future studies will compare canine accuracy to other antemortem methods, as well as improved canine training methods.

How animals jump and land on diverse surfaces is ecologically important and relevant to bioinspired robotics. Here, we describe the jumping biomechanics of the planthopper Lycorma delicatula (spotted lanternfly), an invasive insect in the USA that jumps frequently for dispersal, locomotion and predator evasion. High-speed video was used to analyze jumping by spotted lanternfly nymphs from take-off to impact on compliant surfaces. These insects used rapid hindleg extensions to achieve high take-off speeds (2.7-3.4 m s-1) and accelerations (800-1000 m s-2), with mid-air trajectories consistent with ballistic motion without drag forces or steering. Despite rotating rapidly (5-45 Hz) about time-varying axes of rotation, they landed successfully in 58.9% of trials. They also attained the most successful impact orientation significantly more often than predicted by chance, consistent with their using attitude control. Notably, these insects were able to land successfully when impacting surfaces at all angles, pointing to the importance of collisional recovery behaviors. To further understand their rotational dynamics, we created realistic 3D rendered models of spotted lanternflies and used them to compute their mechanical properties during jumping. Computer simulations based on these models and drag torques estimated from fits to tracked data successfully predicted several features of the measured rotational kinematics. This analysis showed that the rotational inertia of spotted lanternfly nymphs is predominantly due to their legs, enabling them to use posture changes as well as drag torque to control their angular velocity, and hence their orientation, thereby facilitating predominately successful landings when jumping., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

A major ongoing research effort seeks to understand the behavior, ecology and control of the spotted lanternfly (SLF) (Lycorma delicatula), a highly invasive pest in the U.S. and South Korea. These insects undergo four nymphal stages (instars) before reaching adulthood, and appear to shift host plant preferences, feeding, dispersal and survival patterns, anti-predator behaviors, and response to traps and chemical controls with each stage. However, categorizing SLF life stage is challenging for the first three instars, which have the same coloration and shape. Here we present a dataset of body mass and length for SLF nymphs throughout two growing seasons and compare our results with previously-published ranges of instar body lengths. An analysis using two clustering methods revealed that 1st-3rd instar body mass and length fell into distinct clusters consistently between years, supporting using these metrics to stage nymphs during a single growing season. The length ranges for 2nd-4th instars agreed between years in our study, but differed from those reported by earlier studies for diverse locations, indicating that it is important to obtain these metrics relevant to a study's region for most accurate staging. We also used these data to explore the scaling of SLF instar bodies during growth. SLF nymph body mass scaled with body length varied between isometry (constant shape) and growing somewhat faster than predicted by isometry in the two years studied. Using previously published data, we also found that SLF nymph adhesive footpad area varies in direct proportion to weight, suggesting that footpad adhesion is independent of nymphal stage, while their tarsal claws display positive allometry and hence disproportionately increasing grasp (mechanical adhesion). By contrast, mouthpart dimensions are weakly correlated with body length, consistent with predictions that these features should reflect preferred host plant characteristics rather than body size. We recommend future studies use the body mass vs length growth curve as a fitness benchmark to study how SLF instar development depends on factors such as hatch date, host plant, temperature, and geographic location, to further understanding of life history patterns that help prevent further spread of this invasive insect., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background/objective: Can measuring interocular brightness disparity, acuity, and colour vision classify children with amblyopia?, Subjects/methods: Two hundred eight subjects (3-14 years) were recruited for a prospective, observational protocol to measure interocular brightness disparity, uniocular acuities with and without a pinhole, and colour vision using an iPad. Subjects looked through polarizing filters and chose the brighter of two spaceships to measure interocular brightness disparity. The differential brightness of image pairs was varied through a staircase algorithm until equal brightness was perceived. Acuities and colour vision were tested with tumbling Es and AO-HRR colour plates, respectively. Unilateral amblyopia was later confirmed in two subjects., Results: Binocular brightness balance on the iPad detected amblyopes with 100% sensitivity and specificity. Using 20/30 as cutoff for normal acuity, 1 of the amblyopes was detected, and non-amblyopes were excluded by visual acuity pinhole testing. The mean difference between iPad and E-Chart visual acuities with pinhole was 0.02 logMAR with limits of agreement from -0.08 to +0.11 logMAR. iPad and printed plates Colour vision testing produced identical results. Testing times were brief and exit pleasure responses were positive. Mean and range testing times for Brightness Sense, Colour vision, and Visual Acuity were 32.7 s (range = 12-63 s), 52.8 min (range = 17-95 s), and 88.75 s (range = 41-188 s), respectively., Conclusions: Interocular brightness disparity, acuity, and colour vision can be measured in children as young as 3 years old solely through playing a game on a mobile device. Interocular brightness disparity is a sensitive and specific method to detect unilateral amblyopia., (© 2021. The Author(s).)

Currently known structural colors in feathers are caused by light scattering from periodic or amorphous arrangements of keratin, melanin, and air within barbs and barbules that comprise the feather vane. Structural coloration in the largest part of the feather, the central rachis, is rare. Here, we report on an investigation of the physical mechanisms underlying the only known case of structural coloration in the rachis, the blue rachis of great argus ( Argusianus argus) flight feathers. Spectrophotometry revealed a reflectance peak at 344 nm that is diffuse and well matched to the blue and UV-sensitive cone sensitivities of this species' visual system. A combination of electron microscopy and optical modeling confirmed blue coloration is generated by scattering from amorphous wrinkle nanostructures 125 nm deep and 385 nm apart, a new avian coloration mechanism. These findings have implications for understanding how novel courtship phenotypes arise through evolutionary modification of existing ontogenetic templates., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Ovarian cancer has a high mortality rate due to its unclear symptomology and the lack of precise early detection tools. If detected in the first stage, over 90% of patients reach remission. As such, developing a reliable method of early detection is crucial in reducing the mortality rate of the disease. One potential method would be to identify specific biomarkers that are unique to ovarian cancer, which could be detected using a blood test. While this can be done using gas chromatography - mass spectrometry (GC-MS), identifying these biomarkers is an enormous task. One way to expedite the process is to utilize trained scent detection canines. In this study, dogs who were previously trained to respond to positive blood samples from ovarian cancer patients were then tested on their ability to recognize samples prepared by micro-preparative gas chromatography (MP-GC) techniques. MP-GC employed a gradient-cooled glass tube connected to the GC outlet to collect GC eluents containing the plasma-derived volatiles in positive blood samples. These post-column fractions were collected at the exit of the GC according to their eluent times (i.e., 0-15 min, 15-25 min and 25-35 min or 0-35 min) and these full or fractional collections were presented to the trained dogs to judge their responses. Dogs' time spent investigating the odor was used as an indication of odor recognition and was significantly longer on the early (0-15 min) and middle (15-25 min) fractions of the ovarian cancer than the late (25-35 min) fraction of plasma odorants or either the negative fractions or distractors odorants. These findings suggest that characteristic odor biomarkers of ovarian cancer for dogs may exist in the relatively small and more volatile compounds. Additionally, variation between dogs suggests that there may be a number of different biomarkers that can be used to identify ovarian cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The spread of SARS-CoV-2, which causes the disease COVID-19, is difficult to control as some positive individuals, capable of transmitting the disease, can be asymptomatic. Thus, it remains critical to generate noninvasive, inexpensive COVID-19 screening systems. Two such methods include detection canines and analytical instrumentation, both of which detect volatile organic compounds associated with SARS-CoV-2. In this study, the performance of trained detection dogs is compared to a noninvasive headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) approach to identifying COVID-19 positive individuals. Five dogs were trained to detect the odor signature associated with COVID-19. They varied in performance, with the two highest-performing dogs averaging 88% sensitivity and 95% specificity over five double-blind tests. The three lowest-performing dogs averaged 46% sensitivity and 87% specificity. The optimized linear discriminant analysis (LDA) model, developed using HS-SPME-GC-MS, displayed a 100% true positive rate and a 100% true negative rate using leave-one-out cross-validation. However, the non-optimized LDA model displayed difficulty in categorizing animal hair-contaminated samples, while animal hair did not impact the dogs' performance. In conclusion, the HS-SPME-GC-MS approach for noninvasive COVID-19 detection more accurately discriminated between COVID-19 positive and COVID-19 negative samples; however, dogs performed better than the computational model when non-ideal samples were presented.

The bacterium Bordetella bronchiseptica is responsible for serious respiratory disease in dogs, most often associated with 'kennel cough' (canine infectious tracheobronchitis). It is recommended that dogs are vaccinated against the bacterium every 6-12 months, either by oral or intranasal administration. Any impairment of dogs' olfactory capabilities due to medical treatments may impact their efficiency and accuracy in their jobs. This study examined (1) the effect of intranasal and oral vaccines on the olfactory capabilities of detection dogs; as well as (1) effects of the vaccines on canine behavior. Dogs that were vaccinated initially with the oral and 28 days later with intranasal B. bronchiseptica were generally slower to find the target odor than the dogs that were assigned intranasal then oral vaccine. This result prompted a second between-subjects study to further investigate any impact of intranasal administration of the B. bronchiseptica vaccine on the olfactory capabilities of dogs. The intranasal vaccine was of particular interest due to its prevalent use and potential for nasal inflammation leading to decreased olfactory capabilities. Neither odor threshold nor time spent searching for odor were affected by the intranasal vaccine. Behavioral analyses showed that behaviors associated with the dogs' positive and negative motivation affected their time spent finding the target odor; this suggests that behavior should be considered in future studies of olfactory performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Collins, Bear, Mallikarjun, Kane, Essler, Kaynaroglu, Feuer, Smith and Otto.)

Unlike large animals, insects and other very small animals are so unsusceptible to impact-related injuries that they can use falling for dispersal and predator evasion. Reorienting to land upright can mitigate lost access to resources and predation risk. Such behaviours are critical for the spotted lanternfly (SLF) ( Lycorma delicatula ), an invasive, destructive insect pest spreading rapidly in the USA. High-speed video of SLF nymphs released under different conditions showed that these insects self-right using both active midair righting motions previously reported for other insects and novel post-impact mechanisms that take advantage of their ability to experience near-total energy loss on impact. Unlike during terrestrial self-righting, in which an animal initially at rest on its back uses appendage motions to flip over, SLF nymphs impacted the surface at varying angles and then self-righted during the rebound using coordinated body rotations, foot-substrate adhesion and active leg motions. These previously unreported strategies were found to promote disproportionately upright, secure landings on both hard, flat surfaces and tilted, compliant host plant leaves. Our results highlight the importance of examining biomechanical phenomena in ecologically relevant contexts, and show that, for small animals, the post-impact bounce period can be critical for achieving an upright landing.

The spotted lanternfly (Lycorma delicatula) is an invasive species first detected in 2014. The insect feeds on plants causing severe damage in vineyards such as the occurrence of sooty mold fungus that impairs leaf photosynthesis. Currently, there is extensive research on how to track and ultimately prevent the spread of this species. It lays eggs that persist through the winter, while the adults die out, which presents a unique opportunity to enter infested or suspected infested areas to begin quarantine and management of the spread while the species is dormant. Detection dogs may be a tool that can be used to search out the spotted lanternfly egg masses during this overwintering period, however it is not known whether dogs can detect any specific odor from the spotted lanternfly eggs. Moreover, as the eggs are only available during certain times of the year, and hatch based on temperature, finding training aids for the dogs could prove difficult. In this study, we investigated whether three detection dogs could learn the odor from dead spotted lanternfly egg masses and if so, whether that would allow them to recognize live spotted lanternfly egg masses. We found that dogs could be trained to find dead spotted lanternfly egg masses, and could learn to ignore relevant controls, with high levels of sensitivity and specificity (up to 94.6% and 92.8%, respectively). Further, we found that after the training, dogs could find live spotted lanternfly egg masses without additional training and returned to previous levels of sensitivity and specificity within a few sessions. Coded videos of training and testing sessions showed that dogs spent more time at the egg masses than at controls, as expected from training. These results suggest that dead spotted lanternfly egg masses could be a useful training aid for spotted lanternfly detection dogs., Competing Interests: The authors have declared that no competing interests exist.

While the world awaits a widely available COVID-19 vaccine, availability of testing is limited in many regions and can be further compounded by shortages of reagents, prolonged processing time and delayed results. One approach to rapid testing is to leverage the volatile organic compound (VOC) signature of SARS-CoV-2 infection. Detection dogs, a biological sensor of VOCs, were utilized to investigate whether SARS-CoV-2 positive urine and saliva patient samples had a unique odor signature. The virus was inactivated in all training samples with either detergent or heat treatment. Using detergent-inactivated urine samples, dogs were initially trained to find samples collected from hospitalized patients confirmed with SARS-CoV-2 infection, while ignoring samples collected from controls. Dogs were then tested on their ability to spontaneously recognize heat-treated urine samples as well as heat-treated saliva from hospitalized SARS-CoV-2 positive patients. Dogs successfully discriminated between infected and uninfected urine samples, regardless of the inactivation protocol, as well as heat-treated saliva samples. Generalization to novel samples was limited, particularly after intensive training with a restricted sample set. A unique odor associated with SARS-CoV-2 infection present in human urine as well as saliva, provides impetus for the development of odor-based screening, either by electronic, chemical, or biological sensing methods. The use of dogs for screening in an operational setting will require training with a large number of novel SARS-CoV-2 positive and confirmed negative samples., Competing Interests: Pat Nolan owns Tactical Directional Canine which was contracted to conduct the canine training. This commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: To report the surgical results of goniosurgery for children with glaucoma associated with Sturge-Weber syndrome., Methods: Retrospective review of medical records of patients who had initial goniosurgery for glaucoma associated with Sturge-Weber syndrome., Results: A total of 46 eyes of 42 patients who had glaucoma associated with Sturge-Weber syndrome and were treated with initial goniosurgery were identified to determine the efficacy of therapeutic goniotomy and trabeculotomy (goniosurgery). The average age at the time of goniosurgery was 1.5 years (range: 1 month to 23 years). Office intraocular pressure (IOP) measurements before goniosurgery were recorded in 76% of patients (32 of 42 patients) with an average measurement of 35 mm Hg (range: 25 to 50 mm Hg). The average interval to failure was 4 months (range: 1 to 48 months). Forty-six eyes underwent goniosurgery with a rate of failure of 98% (45 of 46 eyes) and a qualified success rate of 2% (1 of 46 eyes). Fifty-one goniotomy and 11 trabeculotomy procedures were performed. On gonioscopy, the filtration angles were all abnormal with variable width and visibility of the ciliary body band and less visible scleral spur. The trabecular meshwork was seen preoperatively in 100% of eyes (41 of 41 eyes) examined, all of which underwent goniosurgery. Five eyes underwent goniosurgery without documented gonioscopy. The ciliary body band was seen in 39% of eyes (16 of 41 eyes) and the scleral spur was visible in 10% of eyes (4 of 41 eyes)., Conclusions: Goniosurgery is not an effective initial glaucoma surgery for glaucoma associated with Sturge-Weber syndrome. It can be used to temporize the IOP, but ultimately other forms of glaucoma surgery must be considered when indicated. [J Pediatr Ophthalmol Strabismus. 2020;57(6):384-387.]., (Copyright 2020, SLACK Incorporated.)

Colorful feathers have long been assumed to be conspicuous to predators, and hence likely to incur costs due to enhanced predation risk. However, many mammals that prey on birds have dichromatic visual systems with only two types of color-sensitive visual receptors, rather than the three and four photoreceptors characteristic of humans and most birds, respectively. Here, we use a combination of multispectral imaging, reflectance spectroscopy, color vision modelling and visual texture analysis to compare the visual signals available to conspecifics and to mammalian predators from multicolored feathers from the Indian peacock (Pavo cristatus), as well as red and yellow parrot feathers. We also model the effects of distance-dependent blurring due to visual acuity. When viewed by birds against green vegetation, most of the feathers studied are estimated to have color and brightness contrasts similar to values previously found for ripe fruit. On the other hand, for dichromat mammalian predators, visual contrasts for these feathers were only weakly detectable and often below detection thresholds for typical viewing distances. We also show that for dichromat mammal vision models, the peacock's train has below-detection threshold color and brightness contrasts and visual textures that match various foliage backgrounds. These findings are consistent with many feathers of similar hue to those studied here being inconspicuous, and in some cases potentially cryptic, in the eyes of common mammalian predators of adult birds. Given that birds perform many conspicuous motions and behaviors, this study suggests that mammalian predators are more likely to use other sensory modalities (e.g., motion detection, hearing, and olfaction), rather than color vision, to detect avian prey. This suggests new directions for future behavioral studies and emphasizes the importance of understanding the influence of the sensory ecology of predators in the evolution of animal coloration., Competing Interests: The authors have declared that no competing interests exist.

Feathers act as vibrotactile sensors that can detect mechanical stimuli during avian flight and tactile navigation, suggesting that they may also detect stimuli during social displays. In this study, we present the first measurements of the biomechanical properties of the feather crests found on the heads of birds, with an emphasis on those from the Indian peafowl (Pavo cristatus). We show that in peafowl these crest feathers are coupled to filoplumes, small feathers known to function as mechanosensors. We also determined that airborne stimuli with the frequencies used during peafowl courtship and social displays couple efficiently via resonance to the vibrational response of their feather crests. Specifically, vibrational measurements showed that although different types of feathers have a wide range of fundamental resonant frequencies, peafowl crests are driven near-optimally by the shaking frequencies used by peacocks performing train-rattling displays. Peafowl crests were also driven to vibrate near resonance in a playback experiment that mimicked the effect of these mechanical sounds in the acoustic very near-field, reproducing the way peafowl displays are experienced at distances ≤ 1.5m in vivo. When peacock wing-shaking courtship behaviour was simulated in the laboratory, the resulting airflow excited measurable vibrations of crest feathers. These results demonstrate that peafowl crests have mechanical properties that allow them to respond to airborne stimuli at the frequencies typical of this species' social displays. This suggests a new hypothesis that mechanosensory stimuli could complement acoustic and visual perception and/or proprioception of social displays in peafowl and other bird species. We suggest behavioral studies to explore these ideas and their functional implications., Competing Interests: The authors have declared that no competing interests exist.

Objective: To describe a characteristic paroxysmal eye-head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS)., Methods: We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients., Results: A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually <5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye movements were separated by clear intervals of fixation, usually ranging from 200 to 800 ms. The movements were consistent with eye-head gaze saccades. These movements can be distinguished from opsoclonus by the presence of a clear intermovement fixation interval and the association of a same-direction head movement., Conclusions: Paroxysmal eye-head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, I Kur , has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current I Ks , whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for I Kur over I Ks (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Blood pressure (BP) monitors rely on pulse detection. Some blood pressure monitors use pulse timings to analyse pulse interval variability for arrhythmia screening, but this assumes that the pulse interval timings detected from BP cuffs are accurate compared with RR intervals derived from ECG. In this study we compared the accuracy of pulse intervals detected using an ambulatory blood pressure monitor (ABPM) with single lead ECG. Twenty participants wore an ABPM for three hours and a data logger which synchronously measured cuff pressure and ECG. RR intervals were compared with corresponding intervals derived from the cuff pressure tracings using three different pulse landmarks. Linear mixed effects models were used to assess differences between ECG and cuff pressure timings and to investigate the effect of potential covariates. In addition, the maximum number of successive oscillometric beats detectable in a measurement was assessed. From 243 BP measurements, the landmark at the foot of the oscillometric pulse was found to be associated with fewest covariates and had a random error of 9.5 ms. 99% of the cuff pressure recordings had more than 10 successive detectable oscillometric beats. RR intervals can be accurately estimated using an ABPM.

Background: Atrial fibrillation (AF) affects around 2% of the population and early detection is beneficial, allowing patients to begin potentially life-saving anticoagulant therapies. Blood pressure (BP) monitors may offer an opportunity to screen for AF., Aim: To identify and appraise studies which report the diagnostic accuracy of automated BP monitors used for opportunistic AF detection., Methods: A systematic search was performed of the MEDLINE, MEDLINE In-Process and EMBASE literature databases. Papers were eligible if they described primary studies of the evaluation of a BP device for AF detection, were published in a peer-reviewed journal and reported values for the sensitivity and specificity. Included studies were appraised using the QUADAS-2 tool to assess their risk of bias and applicability to opportunistic AF detection. Values for the sensitivity and specificity of AF detection were extracted from each paper and compared., Results and Conclusions: We identified seven papers evaluating six devices from two manufacturers. Only one study scored low risk in all of the QUADAS-2 domains. All studies reported specificity >85% and 6 reported sensitivity >90%. The studies showed that BP devices with embedded algorithms for detecting arrhythmias show promise as screening tools for AF, comparing favourably with manual pulse palpation. But the studies used different methodologies and many were subject to potential bias. More studies are needed to more precisely define the sensitivity and specificity of opportunistic screening for AF during BP measurement before its clinical utility in the population of interest can be assessed fully.

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Video filmed by a camera mounted on the head of a Northern Goshawk (Accipiter gentilis) was used to study how the raptor used visual guidance to pursue prey and land on perches. A combination of novel image analysis methods and numerical simulations of mathematical pursuit models was used to determine the goshawk's pursuit strategy. The goshawk flew to intercept targets by fixing the prey at a constant visual angle, using classical pursuit for stationary prey, lures or perches, and usually using constant absolute target direction (CATD) for moving prey. Visual fixation was better maintained along the horizontal than vertical direction. In some cases, we observed oscillations in the visual fix on the prey, suggesting that the goshawk used finite-feedback steering. Video filmed from the ground gave similar results. In most cases, it showed goshawks intercepting prey using a trajectory consistent with CATD, then turning rapidly to attack by classical pursuit; in a few cases, it showed them using curving non-CATD trajectories. Analysis of the prey's evasive tactics indicated that only sharp sideways turns caused the goshawk to lose visual fixation on the prey, supporting a sensory basis for the surprising frequency and effectiveness of this tactic found by previous studies. The dynamics of the prey's looming image also suggested that the goshawk used a tau-based interception strategy. We interpret these results in the context of a concise review of pursuit-evasion in biology, and conjecture that some prey deimatic 'startle' displays may exploit tau-based interception., (© 2015. Published by The Company of Biologists Ltd.)