Smartphone-based gaze estimation for in-home autism research.

Atypical gaze patterns are a promising biomarker of autism spectrum disorder. To measure gaze accurately, however, it typically requires highly controlled studies in the laboratory using specialized equipment that is often expensive, thereby limiting the scalability of these approaches. Here we test whether a recently developed smartphone-based gaze estimation method could overcome such limitations and take advantage of the ubiquity of smartphones. As a proof-of-principle, we measured gaze while a small sample of well-assessed autistic participants and controls watched videos on a smartphone, both in the laboratory (with lab personnel) and in remote home settings (alone). We demonstrate that gaze data can be efficiently collected, in-home and longitudinally by participants themselves, with sufficiently high accuracy (gaze estimation error below 1° visual angle on average) for quantitative, feature-based analysis. Using this approach, we show that autistic individuals have reduced gaze time on human faces and longer gaze time on non-social features in the background, thereby reproducing established findings in autism using just smartphones and no additional hardware. Our approach provides a foundation for scaling future research with larger and more representative participant groups at vastly reduced cost, also enabling better inclusion of underserved communities.

Comparing data quality from an online and in-person lab sample on dynamic theory of mind tasks.

Nearly half the published research in psychology is conducted with online samples, but the preponderance of these studies rely primarily on self-report measures. The current study validated data quality from an online sample on a novel, dynamic task by comparing performance between an in-lab and online sample on two dynamic measures of theory of mind-the ability to infer others' mental states. Theory of mind is a cognitively complex construct that has been widely studied across multiple domains of psychology. One task was based on the show The Office®, and has been previously validated by the authors with in-lab samples. The second was a novel task based on the show Nathan for You®, which was selected to account for familiarity effects associated with The Office. Both tasks measured various dimensions of theory of mind (inferring beliefs, understanding motivations, detecting deception, identifying faux pas, and understanding emotions). The in-person lab samples (N = 144 and 177, respectively) completed the tasks between-subject, whereas the online sample (N = 347 from Prolific Academic) completed them within-subject, with order counterbalanced. The online sample's performance across both tasks was reliable (Cronbach's α = .66). For The Office, the in-person sample outperformed the online sample on some types of theory of mind, but this was driven by their greater familiarity with the show. Indeed, for the relatively unfamiliar show Nathan for You, performance did not differ between the two samples. Together, these results suggest that crowdsourcing platforms elicit reliable performance on novel, dynamic, complex tasks.

Observed humidity trends in dry regions contradict climate models.

Arid and semi-arid regions of the world are particularly vulnerable to greenhouse gas-driven hydroclimate change. Climate models are our primary tool for projecting the future hydroclimate that society in these regions must adapt to, but here, we present a concerning discrepancy between observed and model-based historical hydroclimate trends. Over the arid/semi-arid regions of the world, the predominant signal in all model simulations is an increase in atmospheric water vapor, on average, over the last four decades, in association with the increased water vapor-holding capacity of a warmer atmosphere. In observations, this increase in atmospheric water vapor has not happened, suggesting that the availability of moisture to satisfy the increased atmospheric demand is lower in reality than in models in arid/semi-arid regions. This discrepancy is most clear in locations that are arid/semi-arid year round, but it is also apparent in more humid regions during the most arid months of the year. It indicates a major gap in our understanding and modeling capabilities which could have severe implications for hydroclimate projections, including fire hazard, moving forward.

The AACP Academic Affairs Committee's Final 2022 Curricular Outcomes and Entrustable Professional Activities (COEPA) for Pharmacy Graduates to Replace 2013 CAPE and 2016 EPAs.

The American Association of Colleges of Pharmacy (AACP) Academic Affairs Committee was charged with revising both the 2013 Center for the Advancement of Pharmacy Education (CAPE) Educational Outcomes (EOs) and the 2016 Entrustable Professional Activities (EPAs). The Committee changed the document name from the CAPE outcomes to COEPA, (Curricular Outcomes and Entrustable Professional Activities) since the EOs and EPAs would now be housed together. A draft of the COEPA EOs and EPAs was released at the AACP July 2022 Annual meeting. After receiving additional stakeholder feedback during and after the meeting, the Committee made additional revisions. The final COEPA document was submitted to and approved by the AACP Board of Directors in November 2022. This COEPA document contains the final version of the 2022 EOs and EPAs. The revised EOs have been reduced to 3 domains and 12 subdomains (from 4 domains and 15 subdomains previously in CAPE 2013) and the revised EPAs have been reduced from 15 to 13 activities.

The AACP Academic Affairs Committee's Guidance for Use of the Curricular Outcomes and Entrustable Professional Activities (COEPA) for Pharmacy Graduates.

The 2021-2023 American Association of Colleges of Pharmacy Academic Affairs Committee (AAC) was charged with and completed the revision of the 2013 Center for the Advancement of Pharmacy Education Outcomes and the 2016 Entrustable Professional Activity (EPA) statements for new pharmacy graduates. This work resulted in a new combined document, the Curricular Outcomes and Entrustable Professional Activities (COEPA) that was unanimously approved by the American Association of Colleges of Pharmacy Board of Directors and was published in the Journal. The AAC was also charged with providing stakeholders with guidance about how to use the new COEPA document. To achieve this charge, the AAC created example objectives for all 12 Educational Outcomes (EOs) and example tasks for all 13 EPAs. Although programs are asked to retain the EO domains, subdomains, one-word descriptors, and descriptions, unless they are adding more EOs or increasing the taxonomy level of a description, colleges and schools of pharmacy can expand or edit the example objectives and example tasks to meet local needs, as these are not designed to be prescriptive. This guidance document is published separately from the COEPA EOs and EPAs to reinforce the message that the example objectives and tasks are modifiable.

Finalizing the Work Related to the Curriculum Outcomes and Example Objectives and Entrustable Professional Activities (COEPA) Document: The Report of the 2022-2023 Academic Affairs Standing Committee.

The 2022-2023 Academic Affairs Committee (AAC) was charged to (1) complete the Center for the Advancement of Pharmacy Education Outcomes and Entrustable Professional Activities (EPAs) revisions (now renamed as COEPA - Curriculum Outcomes and Entrustable Professional Activities) after receiving feedback at the 2022 American Association of Colleges of Pharmacy (AACP) Annual Meeting; (2) offer guidance on how the revised COEPA education outcomes and EPA statements should be used by member institutions, faculty, preceptor, and students; (3) guide input into the ongoing revision of the Accreditation Council for Pharmacy Education (ACPE) standards for the Doctor of Pharmacy program. The published report of the 2021-2022 AAC outlines the work of the Committee through the spring of 2022.1 This 2022-2023 AAC report focuses on the work related to finalizing the COEPA educational outcomes, EPAs, preamble, and glossary and formally receiving approval from the AACP Board of Directors.2 This report also describes the creation of a COEPA guidance document, including educational outcomes example learning objectives, and EPA example tasks for the Academy, however, the actual guidance document will be published separately. Finally, this current report outlines the feedback the AAC sought, received, synthesized, summarized, and prioritized from key interested and affected parties about the ACPE 2016 standards revisions for the ACPE 2025 draft standards.3 The Committee offers revisions for 1 AACP policy statement pertaining to diversity, equity, inclusion, accessibility, justice, and anti-racism. One new policy statement is also offered that urges ACPE to create accreditation standards for pharmacy education that support diversity, equity, inclusion, accessibility, justice, and anti-racism, despite presence of laws, executive orders, and policies that oppose these concepts.

Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic.

Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC50 in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian cancer, where the rate of rise of CA-125 was significantly reduced following treatment with zafirlukast, while no severe adverse events were reported. Thiol isomerase inhibition with zafirlukast represents a novel, well-tolerated therapeutic in the treatment of ovarian cancer.

Characterizing uncertainty in Community Land Model version 5 hydrological applications in the United States.

Land surface models such as the Community Land Model Version 5 (CLM5) are essential tools for simulating the behavior of the terrestrial system. Despite the extensive application of CLM5, limited attention has been paid to the underlying uncertainties associated with its hydrological parameters and how these uncertainties affect water resource applications. To address this long-standing issue, we use five meteorological datasets to conduct a comprehensive hydrological parameter uncertainty characterization of CLM5 over the hydroclimatic gradients of the conterminous United States. Key datasets produced from the uncertainty characterization experiment include: a benchmark dataset of CLM5 default hydrological performance, parameter sensitivities for 28 hydrological metrics, and large-ensemble outputs for CLM5 hydrological predictions. The presented datasets will assist CLM5 calibration and support broad applications, such as evaluating drought and flood vulnerabilities. The datasets can be used to identify the hydroclimatological conditions under which parametric uncertainties demonstrate substantial effects on hydrological predictions and clarify where further investigations are needed to understand how hydrological prediction uncertainties interact with other Earth system processes.

Revising the Center for the Advancement of Pharmacy Education (CAPE) Educational Outcomes and Entrustable Professional Activities (EPAs): The Report of the 2021-2022 Academic Affairs Standing Committee.

EXECUTIVE SUMMARY. The 2021-22 Academic Affairs Committee was charged to 1) Update the Center for the Advancement of Pharmacy Education (CAPE) Outcomes and Entrustable Professional Activity (EPA) statements for new pharmacy graduates; 2) Nominate at least one person for an elected AACP or Council Office; and 3) Consider ways that AACP can improve its financial health. This report primarily focuses on the process undertaken by the committee to revise the CAPE Educational Outcomes and EPAs. Proposed changes to the current outcomes are discussed and the reasoning behind these revisions are described. AACP members will have the opportunity to provide feedback prior to the final document being approved and published later this year.

Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl.

Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities (Ka ~ 100-200 M-1) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of Ka = 66,500 M-1, the largest value reported for such an inclusion complex to date. One dimensional 1H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.

Determining Whether Older Adults Use Similar Strategies to Young Adults in Theory of Mind Tasks.

OBJECTIVES: Theory of mind-the ability to infer others' mental states-declines over the life span, potentially due to cognitive decline. However, it is unclear whether deficits emerge because older adults use the same strategies as young adults, albeit less effectively, or use different or no strategies. The current study compared the similarity of older adults' theory of mind errors to young adults' and a random model. METHODS: One hundred twenty older adults (MAge = 74.68 years; 64 female) and 111 young adults (MAge = 19.1; 61 female) completed a novel theory of mind task (clips from an episode of the sitcom The Office®), and a standard measure of cognitive function (Logical Memory II). Monte Carlo resampling estimated the likelihood that older adults' error patterns were more similar to young adults' or a random distribution. RESULTS: Age deficits emerged on the theory of mind task. Poorer performance was associated with less similarity to young adults' response patterns. Overall, older adults' response patterns were ~2.7 million times more likely to match young adults' than a random model. Critically, one fourth of older adults' errors were more similar to the random distribution. Poorer memory ability contributed to this relationship. DISCUSSION: Age deficits in theory of mind performance may be driven by a subset of older adults and be related to disparities in strategy use. A certain amount of cognitive ability may be necessary for older adults to engage similar strategies to young adults' during theory of mind.

Remimazolam: A Novel Option for Procedural Sedation in High Risk Patients.

PURPOSE: The purpose of this drug review was to explore the safety and efficacy of the newly approved benzodiazepine, remimazolam, in order to evaluate its place in therapy. SUMMARY: Remimazolam has a faster onset of action and recovery time than midazolam when given as single IV doses. Additionally, it has no known CYP450 interactions that would contribute to drug-drug interactions. Patients with severe hepatic impairment may require dose titration as well as the elderly who should be closely monitored. Although remimazolam vials should be protected from light and must be reconstituted immediately before use, the reconstituted vial may be stored for later use at room temperature for up to 8 hours. Remimazolam is more expensive than current options used in practice, as such individual institutional formulary and provider preference will require review to see if its advantages are worth the additional cost and to determine its place in therapy. CONCLUSION: Remimazolam is a novel option when choosing a benzodiazepine for procedural sedation that has pharmacokinetic and pharmacodynamic advantages when compared to other commonly prescribed sedatives. Remimazolam has proved superior to midazolam when analyzing drug-drug interactions, onset, and time to alertness. Remimazolam also has a shorter elimination half-life and decreased volume of distribution when compared to midazolam.

Atypical gaze patterns in autistic adults are heterogeneous across but reliable within individuals.

BACKGROUND: Across behavioral studies, autistic individuals show greater variability than typically developing individuals. However, it remains unknown to what extent this variability arises from heterogeneity across individuals, or from unreliability within individuals. Here, we focus on eye tracking, which provides rich dependent measures that have been used extensively in studies of autism. Autistic individuals have an atypical gaze onto both static visual images and dynamic videos that could be leveraged for diagnostic purposes if the above open question could be addressed. METHODS: We tested three competing hypotheses: (1) that gaze patterns of autistic individuals are less reliable or noisier than those of controls, (2) that atypical gaze patterns are individually reliable but heterogeneous across autistic individuals, or (3) that atypical gaze patterns are individually reliable and also homogeneous among autistic individuals. We collected desktop-based eye tracking data from two different full-length television sitcom episodes, at two independent sites (Caltech and Indiana University), in a total of over 150 adult participants (N = 48 autistic individuals with IQ in the normal range, 105 controls) and quantified gaze onto features of the videos using automated computer vision-based feature extraction. RESULTS: We found support for the second of these hypotheses. Autistic people and controls showed equivalently reliable gaze onto specific features of videos, such as faces, so much so that individuals could be identified significantly above chance using a fingerprinting approach from video epochs as short as 2 min. However, classification of participants into diagnostic groups based on their eye tracking data failed to produce clear group classifications, due to heterogeneity in the autistic group. LIMITATIONS: Three limitations are the relatively small sample size, assessment across only two videos (from the same television series), and the absence of other dependent measures (e.g., neuroimaging or genetics) that might have revealed individual-level variability that was not evident with eye tracking. Future studies should expand to larger samples across longer longitudinal epochs, an aim that is now becoming feasible with Internet- and phone-based eye tracking. CONCLUSIONS: These findings pave the way for the investigation of autism subtypes, and for elucidating the specific visual features that best discriminate gaze patterns-directions that will also combine with and inform neuroimaging and genetic studies of this complex disorder.

Process-oriented analysis of dominant sources of uncertainty in the land carbon sink.

The observed global net land carbon sink is captured by current land models. All models agree that atmospheric CO2 and nitrogen deposition driven gains in carbon stocks are partially offset by climate and land-use and land-cover change (LULCC) losses. However, there is a lack of consensus in the partitioning of the sink between vegetation and soil, where models do not even agree on the direction of change in carbon stocks over the past 60 years. This uncertainty is driven by plant productivity, allocation, and turnover response to atmospheric CO2 (and to a smaller extent to LULCC), and the response of soil to LULCC (and to a lesser extent climate). Overall, differences in turnover explain ~70% of model spread in both vegetation and soil carbon changes. Further analysis of internal plant and soil (individual pools) cycling is needed to reduce uncertainty in the controlling processes behind the global land carbon sink.

Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model.

Humanized liver rodent models, in which the host liver parenchyma is repopulated by human hepatocytes, have been increasingly used for drug development and disease research. Unlike the leading humanized liver mouse model in which Fumarylacetoacetate Hydrolase (Fah), Recombination Activating Gene (Rag)-2 and Interleukin-2 Receptor Gamma (Il2rg) genes were inactivated simultaneously, generation of similar recipient rats has been challenging. Here, using Velocigene and 1-cell-embryo-targeting technologies, we generated a rat model deficient in Fah, Rag1/2 and Il2rg genes, similar to humanized liver mice. These rats were efficiently engrafted with Fah-expressing hepatocytes from rat, mouse and human. Humanized liver rats expressed human albumin and complement proteins in serum and showed a normal liver zonation pattern. Further, approaches were developed for gene delivery through viral transduction of human hepatocytes either in vivo, or in vitro prior to engraftment, providing a novel platform to study liver disease and hepatocyte-targeted therapies.

Edge-centric analysis of time-varying functional brain networks with applications in autism spectrum disorder.

The interaction between brain regions changes over time, which can be characterized using time-varying functional connectivity (tvFC). The common approach to estimate tvFC uses sliding windows and offers limited temporal resolution. An alternative method is to use the recently proposed edge-centric approach, which enables the tracking of moment-to-moment changes in co-fluctuation patterns between pairs of brain regions. Here, we first examined the dynamic features of edge time series and compared them to those in the sliding window tvFC (sw-tvFC). Then, we used edge time series to compare subjects with autism spectrum disorder (ASD) and healthy controls (CN). Our results indicate that relative to sw-tvFC, edge time series captured rapid and bursty network-level fluctuations that synchronize across subjects during movie-watching. The results from the second part of the study suggested that the magnitude of peak amplitude in the collective co-fluctuations of brain regions (estimated as root sum square (RSS) of edge time series) is similar in CN and ASD. However, the trough-to-trough duration in RSS signal is greater in ASD, compared to CN. Furthermore, an edge-wise comparison of high-amplitude co-fluctuations showed that the within-network edges exhibited greater magnitude fluctuations in CN. Our findings suggest that high-amplitude co-fluctuations captured by edge time series provide details about the disruption of functional brain dynamics that could potentially be used in developing new biomarkers of mental disorders.

Pervasive alterations to snow-dominated ecosystem functions under climate change.

Climate change projections consistently demonstrate that warming temperatures and dwindling seasonal snowpack will elicit cascading effects on ecosystem function and water resource availability. Despite this consensus, little is known about potential changes in the variability of ecohydrological conditions, which is also required to inform climate change adaptation and mitigation strategies. Considering potential changes in ecohydrological variability is critical to evaluating the emergence of trends, assessing the likelihood of extreme events such as floods and droughts, and identifying when tipping points may be reached that fundamentally alter ecohydrological function. Using a single-model Large Ensemble with sophisticated terrestrial ecosystem representation, we characterize projected changes in the mean state and variability of ecohydrological processes in historically snow-dominated regions of the Northern Hemisphere. Widespread snowpack reductions, earlier snowmelt timing, longer growing seasons, drier soils, and increased fire risk are projected for this century under a high-emissions scenario. In addition to these changes in the mean state, increased variability in winter snowmelt will increase growing-season water deficits and increase the stochasticity of runoff. Thus, with warming, declining snowpack loses its dependable buffering capacity so that runoff quantity and timing more closely reflect the episodic characteristics of precipitation. This results in a declining predictability of annual runoff from maximum snow water equivalent, which has critical implications for ecosystem stress and water resource management. Our results suggest that there is a strong likelihood of pervasive alterations to ecohydrological function that may be expected with climate change.

Children with ASD establish joint attention during free-flowing toy play without face looks.

Children's ability to share attention with another person (i.e., achieve joint attention) is critical for learning about their environments in general1-3 and supporting language and object word learning in particular.1,4-14 While joint attention (JA) as it pertains to autism spectrum disorder (ASD) is often more narrowly operationalized as arising from eye gaze or explicit pointing cues alone,2,5,10,15-19 recent evidence demonstrates that JA in natural environments can be achieved more broadly through multiple other pathways beyond gaze and gestures.2,4,20-31 Here, we use dual head-mounted eye tracking to examine pathways into and characteristics of JA episodes during free-flowing parent-child toy play, comparing children with ASD to typically developing (TD) children. Moments of JA were defined objectively as both the child's and parent's gaze directed to the same object at the same time. Consistent with previous work in TD children,4,21,25,30-32 we found that both TD and ASD children rarely look at their parent's face in this unstructured free play context. Nevertheless, both groups achieved similarly high rates of JA that far exceeded chance, suggesting the use of alternative pathways into JA. We characterize these alternate pathways, find they occur at similar levels across both groups, and achieve similar ends: namely, for both groups, targets of JA are named more frequently by parents in those moments than non-jointly attended objects. These findings broaden the conceptualization of JA abilities and impairment in ASD and raise questions regarding the mechanistic role of the face-gaze-mediated JA pathway in ASD.

Evaluation of spatial Bayesian Empirical Likelihood models in analysis of small area data.

Bayesian empirical likelihood (BEL) models are becoming increasingly popular as an attractive alternative to fully parametric models. However, they have only recently been applied to spatial data analysis for small area estimation. This study considers the development of spatial BEL models using two popular conditional autoregressive (CAR) priors, namely BYM and Leroux priors. The performance of the proposed models is compared with their parametric counterparts and with existing spatial BEL models using independent Gaussian priors and generalised Moran basis priors. The models are applied to two benchmark spatial datasets, simulation study and COVID-19 data. The results indicate promising opportunities for these models to capture new insights into spatial data. Specifically, the spatial BEL models outperform the parametric spatial models when the underlying distributional assumptions of data appear to be violated.