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"WHITE, David"
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How distinct sources of nuisance variability in natural images and scenes limit human stereopsis
Stimulus variability—a form of nuisance variability—is a primary source of perceptual uncertainty in everyday natural tasks. How do different properties of natural images and scenes contribute to this uncertainty? Using binocular disparity as a model system, we report a systematic investigation of how various forms of natural stimulus variability impact performance in a stereo-depth discrimination task. With stimuli sampled from a stereo-image database of real-world scenes having pixel-by-pixel ground-truth distance data, three human observers completed two closely related double-pass psychophysical experiments. In the two experiments, each human observer responded twice to ten thousand unique trials, in which twenty thousand unique stimuli were presented. New analytical methods reveal, from this data, the specific and nearly dissociable effects of two distinct sources of natural stimulus variability—variation in luminance-contrast patterns and variation in local-depth structure—on discrimination performance, as well as the relative importance of stimulus-driven-variability and internal-noise in determining performance limits. Between-observer analyses show that both stimulus-driven sources of uncertainty are responsible for a large proportion of total variance, have strikingly similar effects on different people, and—surprisingly—make stimulus-by-stimulus responses more predictable (not less). The consistency across observers raises the intriguing prospect that image-computable models can make reasonably accurate performance predictions in natural viewing. Overall, the findings provide a rich picture of stimulus factors that contribute to human perceptual performance in natural scenes. The approach should have broad application to other animal models and other sensory-perceptual tasks with natural or naturalistic stimuli.
Journal Article
Illustrated trees of Britain & Europe
Trees are of enduring interest to naturalists and gardeners alike. This book covers all European species, as well as many introduced species from all over the world.
Book
Metrics of sleep apnea severity: beyond the apnea-hypopnea index
Abstract
Obstructive sleep apnea (OSA) is thought to affect almost 1 billion people worldwide. OSA has well established cardiovascular and neurocognitive sequelae, although the optimal metric to assess its severity and/or potential response to therapy remains unclear. The apnea-hypopnea index (AHI) is well established; thus, we review its history and predictive value in various different clinical contexts. Although the AHI is often criticized for its limitations, it remains the best studied metric of OSA severity, albeit imperfect. We further review the potential value of alternative metrics including hypoxic burden, arousal intensity, odds ratio product, and cardiopulmonary coupling. We conclude with possible future directions to capture clinically meaningful OSA endophenotypes including the use of genetics, blood biomarkers, machine/deep learning and wearable technologies. Further research in OSA should be directed towards providing diagnostic and prognostic information to make the OSA diagnosis more accessible and to improving prognostic information regarding OSA consequences, in order to guide patient care and to help in the design of future clinical trials.
Journal Article
VEGF-A, PDGF-BB and HB-EGF engineered for promiscuous super affinity to the extracellular matrix improve wound healing in a model of type 1 diabetes
Chronic non-healing wounds, frequently caused by diabetes, lead to lower quality of life, infection, and amputation. These wounds have limited treatment options. We have previously engineered growth factors to bind to exposed extracellular matrix (ECM) in the wound environment using the heparin-binding domain of placental growth factor-2 (PlGF-2123–144), which binds promiscuously to ECM proteins. Here, in the type 1 diabetic (T1D) NOD mouse model, engineered growth factors (eGFs) improved both re-epithelialization and granulation tissue formation. eGFs were even more potent in combination, and the “triple therapy” of vascular endothelial growth factor-A (VEGF-PlGF-2123–144), platelet-derived growth factor-BB (PDGF-BB-PlGF-2123–144), and heparin-binding epidermal growth factor (HB-EGF-PlGF-2123–144) both improved wound healing and remained at the site of administration for significantly longer than wild-type growth factors. In addition, we also found that changes in the cellular milieu of a wound, including changing amounts of M1 macrophages, M2 macrophages and effector T cells, are most predictive of wound-healing success in the NOD mouse model. These results suggest that the triple therapy of VEGF-PlGF-2123–144, PDGF-BB-PlGF-2123–144, and HB-EGF-PlGF-2123–144 may be an effective therapy for chronic non-healing wounds in that occur as a complication of diabetes.
Journal Article
Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets
Abstract
Rationale
The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized.
Objectives
To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA.
Methods
Seventy-five men and women with and without OSA aged 20–65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA.
Measurements and Main Results
Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [−1.5 to 1.9] vs. −6.2 [−12.4 to −3.6] cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, −2 to −5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than −2 cm H2O (−5.9 [−8.8 to −4.5] vs. −3.2 [−4.8 to −2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA.
Conclusions
This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.
Journal Article
The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial
Abstract
Rationale
There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep.
Objectives
We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea–hypopnea index [AHI]; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA.
Methods
A total of 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing 1 night of 80 mg atomoxetine plus 5 mg oxybutynin (ato–oxy) to placebo administered before sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in-laboratory polysomnography. In a subgroup of nine patients, the AHI was also measured when the drugs were administered separately.
Measurements and Main Results
The participants’ median (interquartile range) age was 53 (46–58) years and body mass index was 34.8 (30.0–40.2) kg/m2. ato–oxy lowered AHI by 63% (34–86%), from 28.5 (10.9–51.6) events/h to 7.5 (2.4–18.6) events/h (P < 0.001). Of the 15/20 patients with OSA on placebo (AHI > 10 events/hr), AHI was lowered by 74% (62–88%) (P < 0.001) and all 15 patients exhibited a ≥50% reduction. Genioglossus responsiveness increased approximately threefold, from 2.2 (1.1–4.7)%/cm H2O on placebo to 6.3 (3.0 to 18.3)%/cm H2O on ato–oxy (P < 0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately.
Conclusions
A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on 1 night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA.
Clinical trial registered with www.clinicaltrials.gov (NCT02908529).
Journal Article