Bispecific VEGF-A and Angiopoietin-2 Antagonist RO-101 Preclinical Efficacy in Model of Neovascular Eye Disease.

Objective: To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases. Design: Experimental study. Subjects: Brown Norway rats and New Zealand White Cross rabbits. Methods: Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents. Main Outcome Measures: Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101. Results: RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo. Conclusions: RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Average fixation duration in infancy: Stability and predictive utility.

The current study examined the stability, consistency, and predictive utility of average fixation durations in infancy. In Study 1, infants' (N = 80) average fixation duration when viewing social stimuli was found to show strong relative stability from 3.5 to 9 months of age. In Study 2, strong within-infant consistency was found in 3.5-month-old infants' (N = 73) average fixation durations to social and nonsocial stimuli. In Study 3, 3.5- to 9-month-old infants' (N = 89) average fixation duration was found to systematically vary with parent-reported symptoms of attention deficit hyperactivity disorder (ADHD) at 4-6 years of age. These results suggest that average fixation duration serves as a stable and systematic measure of individual differences in cognitive development beginning early in life.

India's need for long-term solutions to COVID-19-like pandemics: A policy paper by Organized Medicine Academic Guild.

The entire world seems to have responded to COVID-19 pandemic in a knee-jerk manner with a short mindset without building on the existing strengths of public health infrastructure. National governments cannot be blamed for this as we are dealing with a crisis that comes once in a lifetime. Realising this, the Organized Medicine Academic Guild (OMAG) an association of major health associations in this country has suggested measures for long-term solutions to COVID-19-like pandemics in the form of a policy paper by OMAG.

Are we prepared? Lessons from Covid-19 and OMAG position paper on epidemic preparedness.

Covid-19 has once again brought into focus our limited preparedness to deal with epidemics. Most nations, across the globe, have responded with a resolve to come stronger out of this crisis and leaderships across the world have shown great commitment to protecting its people from Covid-19. Covid-19 has also taught us a few things for the future. One such learning has been that a strong shift in focus towards non-communicable diseases driving health infrastructure across the globe for the last few decades has come at neglect of communicable diseases. In that sense, therefore, the current pandemic has been a wake-up call. Organised Medicine Academic Guild (OMAG), an umbrella organization of professional associations gathered a group of health experts to develop a policy document on epidemic preparedness to limit the influence of epidemics like Covid-19.

Waist-to-Hip Ratio Sensitivity in Early Infancy.

The waist-to-hip ratio (WHR) is correlated with health and associated with sex, attractiveness, and age judgments by adults. We examined the development of sensitivity to the WHR by testing 3.5-month-old infants' (N = 71) preference between images depicting different WHRs. Female 3.5-month-olds exhibited a preference for the WHR associated with attractiveness and mate value by adults (0.7) over a larger WHR (0.9). This preference was exhibited when infants were tested on upright stimuli but not when they were tested on inverted stimuli, indicating that low-level differences (e.g., curviness) were not driving performance. This sensitivity to WHR may lay the foundation for more explicit preferences and categorical associations later in life. In contrast to females, male infants failed to exhibit a significant preference for the 0.7 WHR in either orientation, replicating previous findings of female infants' superior processing of social stimuli. Implications for theories of the development of body knowledge and sex differences in social information processing are discussed.

A health care delivery model focusing on development of a cadre of primary care physicians-Recommendations of Organized Medicine Academic Guild.

Organized medicine is the academic guild of professional medical organizations in India. It was founded at the annual conference of Indian Academy of Pediatrics (PEDICON) on January 7, 2018. Organized medicine is constituted by leading professional medical organizations and mandated to support the sustainability of health agenda of the Government of India. A group of experts on behalf of Organized Medicine Academic Guild (OMAG) of India was constituted to facilitate adequate theories and models on how to make primary care integral to participation of people and intersectoral collaboration in equitable delivery of health care. A subtle, flexible, and comprehensive approach instead of a "compartmentalized existing in silos" approach is likely to be needed. This paper is a formal recommendation on behalf of OMAG with an aspiration to deliver to the people of India, what they need, focusing on discrete objectives with long-term plans.

Experimental Evidence of Structural Representation of Hands in Early Infancy.

Hands convey important social information, such as an individual's emotions, goals, and desires, are used to direct attention through pointing, and are a major organ for haptic perception. However, very little is known about infants' representation of human hands. In Experiment 1, infants tested in a familiarization/novelty preference task discriminated between images of intact hands and ones that contained first-order structure distortions (i.e., with locations of fingers altered to result in an unnatural configuration). In Experiment 2, infants tested in a spontaneous preference task exhibited a preference for scrambled hand images over intact images, indicating that 3.5-month-olds have gained sufficient sensitivity to the configural properties of hands to discriminate between intact versus scrambled images without any training in the laboratory. In both procedures, infants' performance was disrupted by inversion of images, suggesting that infants' performance in the upright conditions was not based on low-level features. These results indicate that sensitivity to the structure of hands develops early in life. This early development may lay the foundation for the development of the functional use of hand information for social communication.

Sex-specific scanning in infancy: Developmental changes in the use of face/head and body information.

The current investigation sought to differentiate between contrasting perspectives of body knowledge development by determining whether infants' adult-like scanning of male and female bodies is dependent on relevant information from the face/head alone, the body alone, or a combination of both sources. Scanning patterns of 3.5-, 6.5-, and 9-month-olds (N = 80) in response to images that contained information relevant to sex classification in either the face/head or the body were examined. The results indicate that sex-specific scanning in the presence of only one source of relevant information (i.e., face/head or body) is present only at 9 months. Thus, although sex-specific scanning of bodies emerges as early as 3.5 months, information from both faces/heads and bodies is required until sometime between 6.5 and 9 months of age. These findings constrain theories of the development of social perception by documenting the complex interplay between body and face/head processing early in life.

Categorical Perception of Facial Emotions in Infancy.

Categorical perception, indicated by superior discrimination between stimuli that cross categorical boundaries than between stimuli within a category, is an efficient manner of classification. The current study examined the development of categorical perception of emotional stimuli in infancy. We used morphed facial images to investigate whether infants find contrasts between emotional facial images that cross categorical boundaries to be more salient than those that do not, while matching the degree of differences in the two contrasts. Five-month-olds exhibited sensitivity to the categorical boundary between sadness and disgust, between happiness and surprise, as well as between sadness and anger but not between anger and disgust. Even 9-month-olds failed to exhibit evidence of a definitive category boundary between anger and disgust. These findings indicate the presence of discrete boundaries between some, but not all, of the basic emotions early in life. Implications of these findings for the major theories of emotion representation are discussed.

Tracking the Development of Functional Connectomes for Face Processing.

Face processing capacities become more specialized and advanced during development, but neural underpinnings of these processes are not fully understood. The present study applied graph theory-based network analysis to task-negative (resting blocks) and task-positive (viewing faces) functional magnetic resonance imaging data in children (5-17 years) and adults (18-42 years) to test the hypothesis that the development of a specialized network for face processing is driven by task-positive processing (face viewing) more than by task-negative processing (visual fixation) and by both progressive and regressive changes in network properties. Predictive modeling was used to predict age from node-based network properties derived from task-positive and task-negative states in a whole-brain network (WBN) and a canonical face network (FN). The best-fitting model indicated that FN maturation was marked by both progressive and regressive changes in information diffusion (eigenvector centrality) in the task-positive state, with regressive changes outweighing progressive changes. Hence, FN maturation was characterized by reductions in information diffusion potentially reflecting the development of more specialized modules. In contrast, WBN maturation was marked by a balance of progressive and regressive changes in hub-connectivity (betweenness centrality) in the task-negative state. These findings suggest that the development of specialized networks like the FN depends on dynamic developmental changes associated with domain-specific information (e.g., face processing), but maturation of the brain as a whole can be predicted from task-free states.

The role of shape recognition in figure/ground perception in infancy.

In this study we sought to determine whether infants, like adults, utilize previous experience to guide figure/ground processing. After familiarization to a shape, 5-month-olds preferentially attended to the side of an ambiguous figure/ground test stimulus corresponding to that shape, suggesting that they were viewing that portion as the figure. Infants' failure to exhibit this preference in a control condition in which both sides of the test stimulus were displayed as figures indicated that the results in the experimental condition were not due to a preference between two figure shapes. These findings demonstrate for the first time that figure/ground processing in infancy is sensitive to top-down influence. Thus, a critical aspect of figure/ground processing is functional early in life.

Dichotomous Perception of Animal Categories in Infancy.

Although there is a wealth of knowledge on categorization early in life, there are still many unanswered questions about the nature of category representation in infancy. For example, it is unclear whether infants are sensitive to boundaries between complex categories, such as types of animals, or whether young infants exhibit such sensitivity without explicit experience in the lab. Using a morphing technique, we linearly altered the category composition of images and measured 6.5-month-olds' attention to pairs of animal faces that either did or did not cross the categorical boundary, with the stimuli in each pair being equally dissimilar from one another across the two types of image pairs. Results indicated that infants dichotomize the continua between cats and dogs and between cows and otters, but only when the images are presented in their canonical, upright orientations. These findings demonstrate a propensity to dichotomize early in life that could have implications for social categorizations, such as race and gender.

Size and orientation cue figure-ground segregation in infants.

Adult perceivers segregate figure from ground based on image cues such as small size and main axis orientation. The current study examined whether infants can use such cues to perceive figure-ground segregation. Three- to 7-month-olds were familiarized with a pie-shaped stimulus in which some pieces formed a + and other pieces formed an x. The infants were then presented with a novelty preference test pairing the + and x. The bases for the pieces forming the + or x were size and orientation (Experiment 1), size (Experiment 2), and orientation (Experiment 3). In each experiment, infants responded as if they recognized as familiar the shape specified by small size, main axis orientation, or their combination. Control conditions showed that infant performance could not be attributed to spontaneous preference. The findings suggest that infants can achieve figure-ground segregation based on some of the same cues used by adults.

Development of body emotion perception in infancy: From discrimination to recognition.

Research suggests that infants progress from discrimination to recognition of emotions in faces during the first half year of life. It is unknown whether the perception of emotions from bodies develops in a similar manner. In the current study, when presented with happy and angry body videos and voices, 5-month-olds looked longer at the matching video when they were presented upright but not when they were inverted. In contrast, 3.5-month-olds failed to match even with upright videos. Thus, 5-month-olds but not 3.5-month-olds exhibited evidence of recognition of emotions from bodies by demonstrating intermodal matching. In a subsequent experiment, younger infants did discriminate between body emotion videos but failed to exhibit an inversion effect, suggesting that discrimination may be based on low-level stimulus features. These results document a developmental change from discrimination based on non-emotional information at 3.5 months to recognition of body emotions at 5 months. This pattern of development is similar to face emotion knowledge development and suggests that both the face and body emotion perception systems develop rapidly during the first half year of life.

Visual scanning of male and female bodies in infancy.

This study addressed the development of attention to information that is socially relevant to adults by examining infants' (N=64) scanning patterns of male and female bodies. Infants exhibited systematic attention to regions associated with sex-related scanning by adults, with 3.5- and 6.5-month-olds looking longer at the torsos of females than of males and looking longer at the legs of males than of females. However, this pattern of looking was not found when infants were tested on headless bodies in Experiment 2, suggesting that infants' differential gaze pattern in Experiment 1 was not due to low-level stimulus features, such as clothing, and also indicating that facial/head information is necessary for infants to exhibit sex-specific scanning. We discuss implications for models of face and body knowledge development.

Integrated Emotion Processing in Infancy: Matching of Faces and Bodies.

Accurate assessment of emotion requires the coordination of information from different sources such as faces, bodies, and voices. Adults readily integrate facial and bodily emotions. However, not much is known about the developmental origin of this capacity. Using a familiarization paired-comparison procedure, 6.5-month-olds in the current experiments were familiarized to happy, angry, or sad emotions in faces or bodies and tested with the opposite image type portraying the familiar emotion paired with a novel emotion. Infants looked longer at the familiar emotion across faces and bodies (except when familiarized to angry images and tested on the happy/angry contrast). This matching occurred not only for emotions from different affective categories (happy, angry) but also within the negative affective category (angry, sad). Thus, 6.5-month-olds, like adults, integrate emotions from bodies and faces in a fairly sophisticated manner, suggesting rapid development of emotion processing early in life.

Further evidence of early development of attention to dynamic facial emotions: Reply to Grossmann and Jessen.

Adults exhibit enhanced attention to negative emotions like fear, which is thought to be an adaptive reaction to emotional information. Previous research, mostly conducted with static faces, suggests that infants exhibit an attentional bias toward fearful faces only at around 7months of age. In a recent study (Journal of Experimental Child Psychology, 2016, Vol. 147, pp. 100-110), we found that 5-month-olds also exhibit heightened attention to fear when tested with dynamic face videos. This indication of an earlier development of an attention bias to fear raises questions about developmental mechanisms that have been proposed to underlie this function. However, Grossmann and Jessen (Journal of Experimental Child Psychology, 2016, Vol. 153, pp. 149-154) argued that this result may have been due to differences in the amount of movement in the videos rather than a response to emotional information. To examine this possibility, we tested a new sample of 5-month-olds exactly as in the original study (Heck, Hock, White, Jubran, & Bhatt, 2016) but with inverted faces. We found that the fear bias seen in our study was no longer apparent with inverted faces. Therefore, it is likely that infants' enhanced attention to fear in our study was indeed a response to emotions rather than a reaction to arbitrary low-level stimulus features. This finding indicates enhanced attention to fear at 5months and underscores the need to find mechanisms that engender the development of emotion knowledge early in life.

Perceptual learning and face processing in infancy.

Configural information (spacing between features) contributes to face-processing expertise in adulthood. We examined whether infants can be "trained" to process this information. In Experiment 1, 3.5-month-olds failed to discriminate changes in the spacing between facial features. However, in Experiments 2 and 3, infants processed the same information after being primed with faces in which the spacing was repeatedly altered. Experiment 4 found that priming was not effective with inverted faces or with faces depicting changes in features but not relations among features, indicating that the priming exhibited in Experiments 2 and 3 was specific to upright faces depicting spacing changes. Thus, even young infants who do not readily process facial configural information can be induced to do so through priming. These findings suggest that learning to encode critical structural information contributes to the development of face processing expertise.

Pruning or tuning? Maturational profiles of face specialization during typical development.

INTRODUCTION: Face processing undergoes significant developmental change with age. Two kinds of developmental changes in face specialization were examined in this study: specialized maturation, or the continued tuning of a region to faces but little change in the tuning to other categories; and competitive interactions, or the continued tuning to faces accompanied by decreased tuning to nonfaces (i.e., pruning). METHODS: Using fMRI, in regions where adults showed a face preference, a face- and object-specialization index were computed for younger children (5-8 years), older children (9-12 years) and adults (18-45 years). The specialization index was scaled to each subject's maximum activation magnitude in each region to control for overall age differences in the activation level. RESULTS: Although no regions showed significant face specialization in the younger age group, regions strongly associated with social cognition (e.g., right posterior superior temporal sulcus, right inferior orbital cortex) showed specialized maturation, in which tuning to faces increased with age but there was no pruning of nonface responses. Conversely, regions that are associated with more basic perceptual processing or motor mirroring (right middle temporal cortex, right inferior occipital cortex, right inferior frontal opercular cortex) showed competitive interactions in which tuning to faces was accompanied by pruning of object responses with age. CONCLUSIONS: The overall findings suggest that cortical maturation for face processing is regional-specific and involves both increased tuning to faces and diminished response to nonfaces. Regions that show competitive interactions likely support a more generalized function that is co-opted for face processing with development, whereas regions that show specialized maturation increase their tuning to faces, potentially in an activity-dependent, experience-driven manner.