Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101, a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent.

Purpose: To evaluate the pharmacokinetic profiles of the ocular hypotensive agent QLS-101, a novel ATP-sensitive potassium channel opening prodrug, and its active moiety levcromakalim, following topical ophthalmic and intravenous dosing of normotensive rabbits and dogs. Methods: Dutch belted rabbits (n = 85) and beagle dogs (n = 32) were dosed with QLS-101 (0.16-3.2 mg/eye/dose) or formulation buffer for 28 days. Pharmacokinetic profiles of QLS-101 and levcromakalim were evaluated in ocular tissues and blood by LC-MS/MS. Tolerability was assessed by clinical and ophthalmic examinations. Maximum systemic tolerated dose was evaluated in beagle dogs (n = 2) following intravenous bolus administrations of QLS-101 (0.05 to 5 mg/kg). Results: Plasma analysis following topical dosing of QLS-101 (0.8-3.2 mg/eye/dose) for 28 days indicated an elimination half-life (T1/2) of 5.50-8.82 h and a corresponding time (Tmax) range of 2-12 h in rabbits, and a T1/2 of 3.32-6.18 h with a Tmax range of 1-2 h in dogs. Maximum tissue concentration (Cmax) values ranged from 54.8-540 (day 1) to 50.5-777 ng/mL (day 28) in rabbits, and 36.5-166 (day 1) to 47.0-147 ng/mL (day 28) in dogs. Levcromakalim plasma T1/2 and Tmax were similar to QLS-101, while Cmax was consistently lower. Topical ophthalmic delivery of QLS-101 was well tolerated in both species, with sporadic mild ocular hyperemia noted in the group treated with the highest concentration (3.2 mg/eye/dose). Following topical ophthalmic dosing, QLS-101 and levcromakalim were found primarily in the cornea, sclera, and conjunctiva. Maximum tolerated dose was determined to be 3 mg/kg. Conclusions: QLS-101 was converted to its active moiety levcromakalim and showed characteristic absorption, distribution, and safety profiles of a well-tolerated prodrug.

The turn of the dice: Patrick Hughes' Hollow Dice and Reverspectives.

Patrick Hughes' Reverspectives demonstrate the importance of perspective as a source of information about the structure and layout of the three-dimensional (3D) world. More recently, he has created a new work of art-Hollow Dice-in which the actual concave structure of the dice is seen as convex. In this article, we examine the similarities and differences between these two perceptual phenomena as well as attempting to explain how and why they arise. Popular interest in both effects is based on the fact that "what we perceive" does not correspond to "what the reality is." As a consequence, Reverspectives and Hollow Dice are often categorized and labeled as "illusions." However, if we consider the information that is available in patterns of light reaching our eyes-rather than the "actual" 3D structure of the Reverspectives and the Hollow Dice-we are in a better position to explain how the size, the viewing distance, the perspective features, the convexity bias, and observer movements determine what we see when viewing these novel and fascinating visual effects.

Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer.

PURPOSE: Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures. METHODS: In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis. RESULTS: In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04). CONCLUSION: Combining a computer prognosis model with care coaches increased ACP documentation.

When is a disparity not a disparity? Toward an old theory of three-dimensional vision.

The aims of this paper are twofold: first, to discuss and analyze the concept of binocular disparity and second, to contrast the traditional "air theory" of three-dimensional vision with the much older "ground theory," first suggested by Ibn al-Haytham more than a thousand years ago. The origins of an "air theory" of perception can be traced back to Descartes and subsequently to the philosopher George Berkeley, who claimed that distance "could not be seen" because points lying along the same line of sight (in an empty space) would all project to the same location on the retina. However, Descartes was also aware that the angle of convergence of the two eyes could solve the problem of the "missing" information for the monocular observer and, since then, most visual scientists have assumed that eye vergence plays an important role both in judging absolute distance and for scaling retinal size and binocular disparities. In contrast, al-Haytham's and Gibson's "ground theories," which are based on the geometry of the textured ground plane surface that has surrounded us throughout evolution and during our lifetimes, are not just more ecologically based but they also obviate the need for disparity scaling.

When is an illusion not an illusion? An alternative view of the illusion concept.

What is an "illusion"? I would like to argue that (A) there is no coherent and meaningful definition of the word "illusion" and (B) the majority of the things we have previously labelled as "illusions" can be better categorised into three classes of perceptual effects: (i) those that should not be regarded as illusory according to any definition; (ii) those that are simply consequences of "how our perceptual systems work" and (iii) those that are a consequence of using artificial or impoverished stimulus situations.

Optic Flow: Perceiving and Acting in a 3-D World.

In 1979, James Gibson completed his third and final book "The Ecological Approach to Visual Perception". That book can be seen as the synthesis of the many radical ideas he proposed over the previous 30 years - the concept of information and its sufficiency, the necessary link between perception and action, the need to see perception in relation to an animal's particular ecological niche and the meanings (affordances) offered by the visual world. One of the fundamental concepts that lies beyond all of Gibson's thinking is that of optic flow: the constantly changing patterns of light that reach our eyes and the information it provides. My purpose in writing this paper has been to evaluate the legacy of Gibson's conceptual ideas and to consider how his ideas have influenced and changed the way we study perception.

Validity of The Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS): a daily activity criterion checklist for infants and toddlers.

BACKGROUND: The Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) is a 50-item, criterion-specified questionnaire that assesses a child's adaptive skills in everyday context and can be used in high-risk follow-up settings to identify risk for adverse neurodevelopmental outcome. Our aim was to validate the WIDEA-FS by comparing a sample of typically developing children to children with special health needs and to compare results to the Capute Scales, which include domains of including both the Cognitive Adaptive Test (CAT) and the Clinical Linguistic and Auditory Milestone Scale (CLAMS). METHODS: Six hundred and sixty children (typically developing and having special healthcare needs) aged 0-36 months completed the WIDEA-FS, the CAT, and the CLAMS assessments. RESULTS: Children with special health needs scored significantly lower on the WIDEA than those with typical development. WIDEA-FS subscales were significantly associated with the CAT (WIDEA-FS self-care 0.87, social cognition 0.89) and the CLAMS (WIDEA-FS communication 0.96, social cognition 0.92) tests. CONCLUSIONS: The WIDEA-FS has concurrent validity with the CAT and CLAMS and construct validity in that children with special health needs have significantly poorer performance on the WIDEA-FS than children with typical development. IMPACT: The WIDEA-FS demonstrated both construct validity and concurrent validity with the Capute Scales, including the Cognitive Adaptive Test (CAT) and the Clinical Linguistic and Auditory Milestone Scale (CLAMS). This is the first study to validate the use of the WIDEA-FS in children with typical development and children with special healthcare needs. The WIDEA-FS is a quick and valid checklist that can be used to assess neurodevelopmental functioning during daily activities in typically developing children and those at risk for neurodevelopmental differences.

Study of the Effect of Methyldiethanolamine Initiator on the Recording Properties of Acrylamide Based Photopolymer.

The use of Holographic Optical Elements (HOEs) in applications, such as in light shaping and redirection, requires certain characteristics such as a high Diffraction Efficiency, low angular selectivity and stability against UV damage. In order to maximize the performance of the HOEs, photosensitive materials are needed that have been optimised for the characteristics that are of particular importance in that application. At the core of the performance of these devices is the refractive index modulation created during holographic recording. Typically, a higher refractive index modulation will enable greater light Diffraction Efficiency and also operation with thinner devices, which in turn decreases the angular selectivity and the stability of the refractive index modulation introduced during recording, which is key to the longevity of the device. Solar concentrators based on volume HOEs can particularly benefit from thinner devices, because, for a solar concentrator to have a high angular working range, thinner photopolymer layers with a smaller angular selectivity are required. This paper presents an optimisation of an acrylamide-based photopolymer formulation for an improved refractive index modulation and recording speed. This was achieved by studying the effect of the concentration of acrylamide and the influence of different initiators in the photopolymer composition on the diffraction efficiency of holographic gratings. Two initiators of different molecular weights were compared: triethanolamine (TEA) and methyldiethanolamine (MDEA). A fivefold increase in the rate of grating formation was achieved through the modification of the acrylamide concentration alone, and it was also found that holograms recorded with MDEA as the initiator performed the best and recorded up to 25% faster than a TEA-based photopolymer. Finally, tests were carried out on the stability of the protected and unprotected photopolymer layers when subjected to UV light. The properties exhibited by this photopolymer composition make it a promising material for the production of optical elements and suitable for use in applications requiring prolonged exposure to UV light when protected by a thin melinex cover.

Metastatic Ovarian Clear Cell Carcinoma in the Context of In Vitro Fertilization Pregnancy.

Adnexal masses are routinely encountered in the clinical practice. However, adnexal masses during pregnancy are incidental findings and usually resolve spontaneously or can be managed conservatively during pregnancy due to their benign nature. Ovarian malignancy is a rare event to occur during pregnancy. Only a few cases of ovarian clear cell carcinoma (OCCC), a subtype of epithelial ovarian cancers, have been reported in pregnancy and all of which have undergone cystectomy or pregnancy termination prior to the last trimester of pregnancy. We present a unique case of OCCC in a pregnant 38-year old female of Asian ethnicity with endometriosis and an in vitro fertilization (IVF) pregnancy. The OCCC, initially suspected to be of benign nature, was removed via emergency cesarean section during delivery in the late preterm period. The Positron Emission Tomography scan performed a few weeks after delivery confirmed metastatic lesions. Our case study not only emphasizes the need for definitive treatment option for endometriosis but also a close surveillance of all masses diagnosed during pregnancy, in particular with a background of other risk factors such as endometriosis and Asian ethnicity. In addition, our study advocates the need for the guidelines for management of such rare cases.

Reversed Phi and the "Phenomenal Phenomena" Revisited.

Reversed apparent motion (or reversed phi) can be seen during a continuous dissolve between a positive and a spatially shifted negative version of the same image. Similar reversed effects can be seen in stereo when positive and spatially shifted negative images are presented separately to the two eyes or in a Vernier alignment task when the two images are juxtaposed one above the other. Gregory and Heard reported similar effects that they called "phenomenal phenomena." Here, we investigate the similarities between these different effects and put forward a simple, spatial-smoothing explanation that can account for both the direction and magnitude of the reversed effects in the motion, stereo and Vernier domains. In addition, we consider whether the striking motion effects seen when viewing Kitaoka's colour-dependent Fraser-Wilcox figures are related to the reversed phi illusion, given the similarity of the luminance profiles.

Toward a new theory of stereopsis: A critique of Vishwanath (2014).

The title of Dhanraj Vishwanath's (2014) Psychological Review article is, of course, adapted from the title of George Berkeley's (1709/1922) book, "Towards a New Theory of Vision," and, as a consequence, it promises to provide us with a radically new understanding of 3D vision. Does it succeed? Vishwanath certainly raised important questions about what we mean by stereopsis, and he does a good job in reviewing some of the more recent findings on how particular viewing conditions affect stereopsis; however, it disappoints with respect to the claim that it offers a "new theory of stereopsis." (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Quantification of nutritive sucking among preterm and full-term infants.

PURPOSE: We developed summaries of oral bottle-feeding skills among preterm (<37 gestational weeks) and full-term (≥37 gestational weeks) infants using a mechanical device (Orometer) to measure intraoral pressure changes, with accompanying automated software and analytics. We then compared the rates of change in feeding skills over several weeks (feeding trends) between preterm and full-term infants. We also compared group means at 40 weeks post menstrual age (PMA). PATIENTS AND METHODS: Healthy full-term and preterm infants capable of oral feeding were recruited from the Pediatric Outpatient Clinic at University of California San Francisco, Fresno, and from the Oregon Health & Science University Doernbecher Neonatal Critical Care Unit, respectively. Feeding skill was quantified using an Orometer and automated suck-analysis software. Factor analysis reduced the >40 metrics produced by the Orometer system to the following seven factors that accounted for >99% of the sample covariance: suck vigor, endurance, resting, irregularity, frequency, variability, and bursting. We proposed that these factors represent feeding skills and they served as the dependent variables in linear models estimating trends in feeding skills over time for full-term and preterm infants (maturation). At approximately 40 weeks PMA we compared mean feedings skills between infants born preterm and those born full-term using predictions from our models. RESULTS: Feeding skills for 117 full-term infants and 82 preterm infants were first captured at mean PMA of 42.3 and 36.0 weeks, respectively. For some feeding skills, preterm and full-term infants showed different trends over time. At 37-40 weeks PMA, preterm infants took approximately 15% fewer sucks than infants born full-term (p=0.06) and generally had weaker suck vigor, greater resting, and less endurance than full-term babies. Preterm infant-feeding skills appeared similar to those of full-term infants upon reaching ≥40 weeks PMA, although preterm infants showed greater variability for all factors. CONCLUSION: The Orometer device, accompanying software, and analytic methods provided a framework for describing trends in oral feeding, thereby allowing us to characterize differences in maturation of feeding between healthy preterm and full-term infants.

Partnering with Insurers in Caring for the Most Vulnerable Youth with Diabetes: NICH as an Integrator.

PURPOSE OF REVIEW: In this review, we outline barriers to appropriately caring for high-risk youth with diabetes and discuss efforts in partnering with insurers through Alternative Payment Models to achieve the Triple Aim (improved health, improved care, and reduced costs) for this population. RECENT FINDINGS: Current approaches in caring for youth with diabetes who evidence a high degree of social complexity are woefully ineffective. These youth are vulnerable to repeat diabetic ketoacidosis episodes, poor glycemic control, and excessive utilization of healthcare resources. To effectively pursue the Triple Aim, an "integrator" (i.e., an entity that accepts responsibility for all components of the Triple Aim for a specified population) must be identified; however, this does not fit into current fee-for-service models. Integrators for youth with diabetes are limited, but early examples of integrator efforts are promising. We present one successful "integrator," Novel Interventions in Children's Healthcare (NICH), and detail this program's efforts in partnering with insurers to serve high-risk youth with diabetes.

Revisiting Motion Parallax as a Source of 3-D Information.

There are many similarities between binocular disparity and motion parallax as sources of information about the structure and layout of 3-D objects and surfaces. The former can be thought of as a transformation that maps one eye's image onto the other while the latter is a transformation that maps the changes in one eye's image over time. There are many empirical similarities in the ways we use the two sources of information but there are also significant differences. A consideration of those differences leads to the conclusion that, rather than seeing motion parallax as a close analogue of binocular stereopsis, motion parallax is better thought of as a special case of the kinetic depth effect in which the depth order of the depicted 3-D object or surface can be disambiguated by vertical perspective information.

The Effectiveness of Vertical Perspective and Pursuit Eye Movements for Disambiguating Motion Parallax Transformations.

In the kinetic depth effect, the direction of the perceived depth and the direction of apparent rotation of a 3-D structure are linked, and typically ambiguous, whereas depth from motion parallax during both observer- and object-movement is stable and unambiguous. Rogers and Rogers demonstrated that the vertical perspective transformations play an important role in disambiguating the direction of the perceived depth in parallax-defined surfaces but more recently Nawrot et al. have proposed that pursuit eye movements provide the crucial disambiguating information. Theoretical considerations suggest that pursuit eye movements could not, in principle, provide the necessary information because 3-D objects as surfaces may rotate during observer- or object-movement. The empirical evidence presented here shows that vertical perspective transformations are sufficient for the unambiguous perception of parallax depth whereas pursuit eye movements are not necessary and may not even be sufficient.

Perception of straightness and parallelism with minimal distance information.

The ability of human observers to judge the straightness and parallelism of extended lines has been a neglected topic of study since von Helmholtz's initial observations 150 years ago. He showed that there were significant misperceptions of the straightness of extended lines seen in the peripheral visual field. The present study focused on the perception of extended lines (spanning 90° visual angle) that were directly fixated in the visual environment of a planetarium where there was only minimal information about the distance to the lines. Observers were asked to vary the curvature of 1 or more lines until they appeared to be straight and/or parallel, ignoring any perceived curvature in depth. When the horizon between the ground and the sky was visible, the results showed that observers' judgements of the straightness of a single line were significantly biased away from the veridical, great circle locations, and towards equal elevation settings. Similar biases can be seen in the jet trails of aircraft flying across the sky and in Rogers and Anstis's new moon illusion (Perception, 42(Abstract supplement) 18, 2013, 2016). The biasing effect of the horizon was much smaller when observers were asked to judge the straightness and parallelism of 2 or more extended lines. We interpret the results as showing that, in the absence of adequate distance information, observers tend to perceive the projected lines as lying on an approximately equidistant, hemispherical surface and that their judgements of straightness and parallelism are based on the perceived separation of the lines superimposed on that surface.