What is the role of the film viewer? The effects of narrative comprehension and viewing task on gaze control in film

Film is ubiquitous, but the processes that guide viewers' attention while viewing film narratives are poorly understood. In fact, many film theorists and practitioners disagree on whether the film stimulus (bottom-up) or the viewer (top-down) is more important in determining how we watch movies. Reading research has shown a strong connection between eye movements and comprehension, and scene perception studies have shown strong effects of viewing tasks on eye movements, but such idiosyncratic top-down control of gaze in film would be anathema to the universal control mainstream filmmakers typically aim for. Thus, in two experiments we tested whether the eye movements and comprehension relationship similarly held in a classic film example, the famous opening scene of Orson Welles' Touch of Evil (Welles & Zugsmith, Touch of Evil, 1958). Comprehension differences were compared with more volitionally controlled task-based effects on eye movements. To investigate the effects of comprehension on eye movements during film viewing, we manipulated viewers' comprehension by starting participants at different points in a film, and then tracked their eyes. Overall, the manipulation created large differences in comprehension, but only produced modest differences in eye movements. To amplify top-down effects on eye movements, a task manipulation was designed to prioritize peripheral scene features: a map task. This task manipulation created large differences in eye movements when compared to participants freely viewing the clip for comprehension. Thus, to allow for strong, volitional top-down control of eye movements in film, task manipulations need to make features that are important to narrative comprehension irrelevant to the viewing task. The evidence provided by this experimental case study suggests that filmmakers' belief in their ability to create systematic gaze behavior across viewers is confirmed, but that this does not indicate universally similar comprehension of the film narrative

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

On the Surveillance and Spread of Drug Resistant Malaria in Sub-Saharan Africa

Artemisinin-based combination therapies (ACTs) are among the most important tools in our arsenal to treat and control malaria. ACTs and other antimalarial drugs have contributed to significant declines in global malaria-attributed morbidity and mortality over the past few decades. However, progress is the effort to eradicate the disease has not been equally distributed: sub-Saharan Africa continues to experiences the vast majority of the burden of the disease. Recent reports of ACT resistance in Rwanda and Uganda confirm longstanding expectations that artemisinin-resistant parasites will eventually emerge in Africa. To delay the spread of artemisinin resistance across the malaria endemic sub-continent, it is essential to protect the efficacy of the ACT partner drugs that provide additional mechanisms of parasite clearance. Drug sensitivity can be measured using standardized clinical, parasitological, and molecular criteria. The assessment of molecular markers can provide rapid evidence of partner drug sensitivity at the population level, helping to monitor the geospatial distribution of resistant parasites. This dissertation begins with a scoping review to identify the state of molecular surveillance efforts related to ACT partner drug resistance. Through a systematic search, we identified over 500 surveys assessing the prevalence of four molecular markers in two key transporter genes (pfcrt 76T and pfmdr1 86Y, 184F, and 1246Y) in sub-Saharan Africa from 2004-2018, corresponding to the uptake and widespread usage of ACTs. We observed a median time lag of over three years from final sample acquisition to publication. Nearly half of all countries conducted, on average, less than one study every three years. Surveys were more likely to be conducted in urban settings and resourced by institutions external to malaria endemic countries. Overall, surveillance efforts likely failed to capture the heterogenous, spatially-dependent nature of partner drug resistance. In Chapter 2, molecular data from Chapter 1 were collated to estimate the spatial distribution of key partner drug-associated molecular markers across the sub-continent. To predict the prevalence of markers in regions without any sampling data, we fit hierarchical Bayesian spatial models to molecular data aggregated from these surveys. From the interpolated maps, we observed significant increases in the prevalence of pfcrt K76, pfmdr1 N86 and D1246 over the study period (in over 90% of study regions), suggesting widespread decreased susceptibility to lumefantrine, the partner drug component of AL. Rainfall seasonality was the strongest predictor of the prevalence of wild-type genotypes, with other covariates, including first-line drug policy and transmission intensity, more weakly associated. The models also enabled identification of regions with potential decreased susceptibility to local first-line ACTs that may be prioritized for enhanced surveillance. Our results may be used to infer the degree of molecular resistance and magnitude of change in regions without survey data. Surveillance typically relies on invasive blood samples collected from infected individuals, yet such studies are limited by costly infrastructure, regulatory oversight, and significant reporting delays. In Chapter 3, we hypothesized that mosquito blood meals could be used to efficiently and economically monitor markers of resistance in parasite populations. We conducted a series of cross-sectional surveys in southwest Burkina Faso to compare molecular markers in humans and blood-fed mosquitos. We found that infection rates in mosquito blood meals remained constant over time despite fluctuations in human prevalence. The frequency of molecular markers in humans and mosquitos were significantly impacted by multiclonal infections. We found that rates of molecular markers in humans and mosquitos were comparable, particularly for markers circulating at lower mutation frequencies. Xenosurveillance may therefore be a useful, supplementary surveillance tool for less prevalent or emergent drug resistance mutations

Improvement in Disease Activity in Refractory Juvenile Dermatomyositis Following Abatacept Therapy

OBJECTIVE: An open-label 24-week study was conducted to evaluate the safety and efficacy of abatacept in patients with refractory juvenile dermatomyositis (JDM). METHODS: Ten patients \u3e7 years of age with moderate disease activity were enrolled in a 24-week study to examine the safety and treatment response of subcutaneous abatacept. The primary endpoint was the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI). Secondary endpoints included safety, change in core set activity measures (CSMs) of IMACS and Pediatric Rheumatology International Trials Organization (PRINTO), and the ACR-EULAR response criteria for JDM. Blinded radiologists assessed thigh magnetic resonance imaging (MRI). Interferon gene score (IFNGS) was performed on whole-blood RNA by NanoString and cytokines were assessed by Luminex. RESULTS: Five patients achieved DOI at week 12, and nine achieved DOI at week 24, including two with minimal, four moderate, and three with major improvement by ACR-EULAR response criteria using IMACS CSMs. All CSMs improved from baseline at weeks 12 and 24, except muscle enzymes. Daily corticosteroid dose decreased from a mean of 16.7 mg at baseline to 10.2 mg at week 24 (p=0.002). Average MRI muscle edema score decreased from baseline 5.3 to 2.3 at week 24 (p=0.01). Six patients had down-trending IFNGS and galectin-9 at week 24. Decreases in IFNGS, IP-10, galectin-9 and IL-2 correlated with improvement in disease activity and in MRI muscle edema. Eleven Grade 2 or 3 treatment-emergent adverse events were observed. CONCLUSIONS: This open-label study demonstrated abatacept may be beneficial for treatment-refractory JDM

From hospitalization records to surveillance: The use of local patient profiles to characterize cholera in Vellore, India

<div><p>Despite availability of high quality medical records, health care systems often do not have the resources or tools to utilize these data efficiently. Yet, hospital-based, laboratory-confirmed records may pave the way for building reliable surveillance systems capable of monitoring temporal trends of emerging infections. In this communication, we present a new tool to compress and visualize medical records with a local population profile (LPP) approach, which transforms information into statistically comparable patterns. We provide a step-by-step tutorial on how to build, interpret, and expand the use of LPP using hospitalization records of laboratory-confirmed cholera. We abstracted case information from the databases maintained by the Department of Clinical Microbiology at Christian Medical College in Vellore, India. We used a single-year age distribution to construct LPPs for O1, O139, and non O1/O139 serotypes of <i>Vibrio cholerae</i>. Disease counts and hospitalization rates were converted into fitted kernel-based probability densities. We formally compared LPPs with the Kolmogorov-Smirnov test, and created multi-panel visuals to depict temporal trend, age distribution, and hospitalization rates simultaneously. Our first implementation of LPPs revealed information that is typically gathered from surveillance systems such as: i) estimates of the demographic distribution of diseases and identification of a population at risk, ii) changes in the dominant pathogen presence; and iii) trends in disease occurrence. The LPP demonstrated the benefit of increased resolution in pattern detection of disease for different <i>Vibrio cholerae</i> serotypes and two demographic categories by showing patterns and anomalies that would be obscured by traditional methods of analysis and visualization. LPP can be used effectively to compile basic patient information such as age, sex, diagnosis, location, and time into compact visuals. Future development of the proposed approach will allow public health researchers and practitioners to broadly utilize and efficiently compress large volumes of medical records without loss of information.</p></div

Descriptive statistics^* of cholera patient ages from Vellore.

<p>Descriptive statistics^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182642#t001fn001" target="_blank">*</a>} of cholera patient ages from Vellore.</p

Location-specific patient profile plots for cholera patients.

<p>a) plot highlights the inflection points of disease probability of all Vellore patients; b) probability plots by sex with subscripts M and F referring to males and females; c) probability plot by serotype with subscripts 1, 2 and 3 referring to serotype O1, serotype O139, and non O1/O139 serotypes; d) probability plot by sex and serotype with subscripts as a combination from plot b and c. N is the total number of patients.</p

The results of Kolmogorov-Smirnov (KS) test.

<p>The results of Kolmogorov-Smirnov (KS) test.</p

Population and outcome pyramids.

<p>a) original census data for Vellore population in 2011 and b) cholera patients, respectively.</p