Clinical Data Extraction During Public Health Emergencies: A Blockchain Technology Assessment.

OBJECTIVE: We sought to explore the technical and legal readiness of healthcare institutions for novel data-sharing methods that allow clinical information to be extracted from electronic health records (EHRs) and submitted securely to the Food and Drug Administration's (FDA's) blockchain through a secure data broker (SDB). MATERIALS AND METHODS: This assessment was divided into four sections: an institutional EHR readiness assessment, legal consultation, institutional review board application submission, and a test of healthcare data transmission over a blockchain infrastructure. RESULTS: All participating institutions reported the ability to electronically extract data from EHRs for research. Formal legal agreements were deemed unnecessary to the project but would be needed in future tests of real patient data exchange. Data transmission to the FDA blockchain met the success criteria of data connection from within the four institutions' firewalls, externally to the FDA blockchain via a SDB. DISCUSSION: The readiness survey indicated advanced analytic capability in hospital institutions and highlighted inconsistency in Fast Healthcare Interoperability Resources format utilitzation across institutions, despite requirements of the 21st Century Cures Act. Further testing across more institutions and annual exercises leveraging the application of data exchange over a blockchain infrastructure are recommended actions for determining the feasibility of this approach during a public health emergency and broaden the understanding of technical requirements for multisite data extraction. CONCLUSION: The FDA's RAPID (Real-Time Application for Portable Interactive Devices) program, in collaboration with Discovery, the Critical Care Research Network's PREP (Program for Resilience and Emergency Preparedness), identified the technical and legal challenges and requirements for rapid data exchange to a government entity using the FDA blockchain infrastructure.

Citations of articles in predatory nursing journals.

BACKGROUND: Nursing journals from predatory publication outlets may look authentic and seem to be a credible source of information. However, further inspection may reveal otherwise. PURPOSE: The purpose of this study was to analyze publication and dissemination patterns of articles published in known predatory nursing journals. METHOD: Using Scopus, reference lists were searched for citations from seven identified predatory nursing journals. Bibliographic information and subsequent citation information were then collected and analyzed. FINDINGS: A total of 814 citations of articles published in predatory nursing journals were identified. Further analysis indicated that these articles were cited in 141 nonpredatory nursing journals of various types. DISCUSSION: Predatory nursing journals continue to persist, yet fewer may now be in existence. Education and information may help authors and reviewers identify predatory journals, thereby discouraging submissions to these publications and hesitancy among authors to cite articles published in them.

cl-dash: rapid configuration and deployment of Hadoop clusters for bioinformatics research in the cloud.

UNLABELLED: : One of the solutions proposed for addressing the challenge of the overwhelming abundance of genomic sequence and other biological data is the use of the Hadoop computing framework. Appropriate tools are needed to set up computational environments that facilitate research of novel bioinformatics methodology using Hadoop. Here, we present cl-dash, a complete starter kit for setting up such an environment. Configuring and deploying new Hadoop clusters can be done in minutes. Use of Amazon Web Services ensures no initial investment and minimal operation costs. Two sample bioinformatics applications help the researcher understand and learn the principles of implementing an algorithm using the MapReduce programming pattern. AVAILABILITY AND IMPLEMENTATION: Source code is available at https://bitbucket.org/booz-allen-sci-comp-team/cl-dash.git. CONTACT: hodor_paul@bah.com.

Two novel, tightly linked, and rapidly evolving genes underlie Aedes aegypti mosquito reproductive resilience during drought.

Female Aedes aegypti mosquitoes impose a severe global public health burden as vectors of multiple viral pathogens. Under optimal environmental conditions, Aedes aegypti females have access to human hosts that provide blood proteins for egg development, conspecific males that provide sperm for fertilization, and freshwater that serves as an egg-laying substrate suitable for offspring survival. As global temperatures rise, Aedes aegypti females are faced with climate challenges like intense droughts and intermittent precipitation, which create unpredictable, suboptimal conditions for egg-laying. Here, we show that under drought-like conditions simulated in the laboratory, females retain mature eggs in their ovaries for extended periods, while maintaining the viability of these eggs until they can be laid in freshwater. Using transcriptomic and proteomic profiling of Aedes aegypti ovaries, we identify two previously uncharacterized genes named tweedledee and tweedledum, each encoding a small, secreted protein that both show ovary-enriched, temporally-restricted expression during egg retention. These genes are mosquito-specific, linked within a syntenic locus, and rapidly evolving under positive selection, raising the possibility that they serve an adaptive function. CRISPR-Cas9 deletion of both tweedledee and tweedledum demonstrates that they are specifically required for extended retention of viable eggs. These results highlight an elegant example of taxon-restricted genes at the heart of an important adaptation that equips Aedes aegypti females with 'insurance' to flexibly extend their reproductive schedule without losing reproductive capacity, thus allowing this species to exploit unpredictable habitats in a changing world.

Neural activity ramps in frontal cortex signal extended motivation during learning.

Learning requires the ability to link actions to outcomes. How motivation facilitates learning is not well understood. We designed a behavioral task in which mice self-initiate trials to learn cue-reward contingencies and found that the anterior cingulate region of the prefrontal cortex (ACC) contains motivation-related signals to maximize rewards. In particular, we found that ACC neural activity was consistently tied to trial initiations where mice seek to leave unrewarded cues to reach reward-associated cues. Notably, this neural signal persisted over consecutive unrewarded cues until reward associated cues were reached, and was required for learning. To determine how ACC inherits this motivational signal we performed projection specific photometry recordings from several inputs to ACC during learning. In doing so, we identified a ramp in bulk neural activity in orbitofrontal cortex (OFC) -to-ACC projections as mice received unrewarded cues, which continued ramping across consecutive unrewarded cues, and finally peaked upon reaching a reward associated cue, thus maintaining an extended motivational state. Cellular resolution imaging of OFC confirmed these neural correlates of motivation, and further delineated separate ensembles of neurons that sequentially tiled the ramp. Together, these results identify a mechanism by which OFC maps out task structure to convey an extended motivational state to ACC to facilitate goal-directed learning.

Development, implementation, and feasibility of site-specific hepatitis C virus treatment workflows for treating vulnerable, high-risk populations: protocol of the Erase Hep C study - a prospective single-arm intervention trial.

BACKGROUND: Hepatitis C virus (HCV) is the leading indication for liver transplantation and liver-related mortality. The development of direct-acting antivirals (DAA) and a simplified treatment algorithm with a > 97% cure rate should make global elimination of HCV an achievable goal. Yet, vulnerable populations with high rates of HCV still have limited access to treatment. By designing locally contextualized site-specific HCV treatment workflows, we aim to cure HCV in vulnerable, high-risk populations, including people experiencing homelessness (PEH) and people who inject drugs (PWID), in Austin, TX, USA. METHODS: Our implementation science study will utilize a qualitative and design thinking approach to characterize patient and systemic barriers and facilitators to HCV treatment in vulnerable, high-risk populations seeking care across seven diverse primary care clinics serving PEHs and PWIDs. Qualitative interviews guided by the Practical, Robust Implementation and Sustainability Model (PRISM) framework will identify barriers and facilitators by leveraging knowledge and experience from both clinic staff and patients. Data synthesized using thematic analysis and design thinking will feed into workshops with clinic stakeholders for idea generation to design site-specific HCV treatment workflows. Providers will be trained on the use of a simplified HCV treatment algorithm with DAAs and clinic staff on the new site-specific HCV treatment workflows. These workflows will be implemented by the seven diverse primary care clinics serving vulnerable, high-risk populations. Implementation and clinical outcomes will be measured using data collected through interviews with staff as well as through medical chart review. DISCUSSION: Our study provides a model of how to contextualize and implement site-specific HCV treatment workflows targeting vulnerable, high-risk populations in other geographic locations. This model can be adopted for future implementation research programs aiming to develop and implement site-specific treatment workflows for vulnerable, high-risk populations and in primary care clinical settings for other disease states beyond just HCV. TRIAL REGISTRATION: Registered on ClinicalTrials.gov on July, 14, 2022. Identifier: NCT05460130 .

Identifying barriers and facilitators along the hepatitis C care cascade to inform human-centered design of contextualized treatment protocols for vulnerable populations in Austin, Texas: a qualitative study.

BACKGROUND: Hepatitis C virus (HCV) is a leading cause of liver-related mortality and morbidity. Despite effective direct acting antivirals and a simplified treatment algorithm, limited access to HCV treatment in vulnerable populations, including people experiencing homelessness (PEH) and people who inject drugs (PWID), hinders global elimination. Adapting the evidence-based, simplified HCV treatment algorithm to the organizational and contextual realities of non-traditional clinic settings serving vulnerable populations can help overcome specific barriers to HCV care. The first phase of the Erase Hep C study aimed to identify barriers and facilitators specific to these vulnerable populations to design the site-specific, simplified treatment protocols. METHODS: Forty-two semi-structured qualitative interviews, guided by the Practical, Robust Implementation and Sustainability Model (PRISM) framework, were conducted with clinic staff, community-based organizations providing screening and linkage to care, and patients diagnosed with HCV, to identify contextual barriers and facilitators to treatment at a local community health center's Health Care for the Homeless program in Austin, Texas. Audio-recorded interviews were systematically analyzed using thematic analysis informed by the PRISM framework and design thinking, to anchor barriers and facilitators along the HCV care cascade. Findings were fed into human-centered design workshops to co-design, with clinic staff, site-specific, simplified HCV treatment protocols. RESULTS: The specific needs of PEH and PWID patient populations informed barriers and facilitators of HCV care. Barriers included tracking patients who miss critical appointments or labs, medication access and adherence, and patient HCV knowledge. Clinical teams leveraged existing facilitators and incorporated solutions to barriers into clinic workflows to improve care coordination and medication access. Actionable solutions included augmenting existing staff roles, employing HCV care navigation throughout the cascade, and standardizing medication adherence counseling. CONCLUSIONS: Clinic staff identified HCV care facilitators to leverage, and designed actionable solutions to address barriers, to incorporate into site-specific treatment protocols to improve patient HCV outcomes. Methods used to incorporate staff and patient experiential knowledge into the design of contextualized treatment protocols in non-traditional clinic settings could serve as a model for future implementation research. The next phase of the study is protocol implementation and patient enrollment into a single-arm trial to achieve HCV cure.

A multi-method approach to modeling COVID-19 disease dynamics in the United States.

In this paper, we proposed a multi-method modeling approach to community-level spreading of COVID-19 disease. Our methodology was composed of interconnected age-stratified system dynamics models in an agent-based modeling framework that allowed for a granular examination of the scale and severity of disease spread, including metrics such as infection cases, deaths, hospitalizations, and ICU usage. Model parameters were calibrated using an optimization technique with an objective function to minimize error associated with the cumulative cases of COVID-19 during a training period between March 15 and October 31, 2020. We outlined several case studies to demonstrate the model's state- and local-level projection capabilities. We further demonstrated how model outcomes could be used to evaluate perceived levels of COVID-19 risk across different localities using a multi-criteria decision analysis framework. The model's two, three, and four week out-of-sample projection errors varied on a state-by-state basis, and generally increased as the out-of-sample projection period was extended. Additionally, the prediction error in the state-level projections was generally due to an underestimation of cases and an overestimation of deaths. The proposed modeling approach can be used as a virtual laboratory to investigate a wide range of what-if scenarios and easily adapted to future high-consequence public health threats.

Protecting providers and patients: results of an Internet survey of health care workers' risk perceptions and ethical concerns during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has generated worldwide scarcity of critical resources to protect against and treat disease. Shortages of face masks and other protective equipment place health workers, already on the frontline of the disease, at higher risk. Moral distress from making difficult decisions about allocating scarce resources and care to patients ill with COVID-19 can further add to burdens health workers face. This study investigates clinical health workers' risk perceptions and concerns about the ethics of their clinical decision-making, the actions of their institutions to address resource scarcity concerns during the COVID-19 pandemic, and their ability to voice safety concerns, as well as their own views on how scarce resources should be allocated. METHODS: An online survey was open to health care workers who provide clinical care to patients, with no specialty training or geographic location requirements, from May 19 to June 30, 2020. Participants were recruited through purposive sampling using medical association and institutional email lists, and by snowball sampling. RESULTS: Of 839 participants, a majority were physicians (540, 69.4%) working in academic medical centers (270, 35.2%) or private health systems in the community (234, 30.5%) in the USA (760, 90.7%). Most reported being concerned about their own health (494, 73.6%) and about the possibility of spreading COVID-19 to family and friends (534, 85.9%) during the pandemic. All respondents reported shortages or rationing of at least one type of medical resource (e.g., sanitizing supplies and personal protective equipment). More than half of respondents (351, 53.9%) did not feel they received sufficient training in how to allocate scarce resources in the pandemic. Many felt moral distress related to conflicts between institutional constraints and what they believed was right (459, 66.5%). Though a majority (459, 67.7%) reported feeling "comfortable" internally communicating with their administration about safety issues, far fewer reported feeling "confident" speaking publicly about safety issues without retaliation from their institution (255, 37.3%). CONCLUSIONS: In the face of limited resources, surveyed health care workers reported concern about their own and their families' health from exposure. Securing adequate protective equipment must be a high priority for pandemic management. In addition, more governmental and facility-level ethical guidance is required for allocation of resources given ongoing scarcity, and facilities must create conditions so health care workers can speak openly about safety issues without fear of retaliation.

#EEGManyLabs: Investigating the replicability of influential EEG experiments.

There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.

Effortful control of motivation, not withdrawal motivation, relates to greater right frontal asymmetry.

Past models of frontal asymmetry have associated greater relative right frontal cortical activity with greater withdrawal motivation and greater relative left frontal cortical activity with greater approach motivation. However, this traditional model of frontal asymmetry leaves little to no room for the control processes that engage and regulate these emotional and motivational systems. A growing body of literature suggests that greater relative right frontal activation may be associated with greater regulatory control (Gable et al. 2018). However, this work confounded regulatory control and motivational direction. The current studies sought to test the competing hypotheses that currently exist in the literature by examining whether greater right frontal activation is more closely associated with regulatory control or withdrawal motivation. In Study 1, participants listened to negative and neutral sounds while suppressing their emotional reactions or listening naturally. Greater relative right frontal activation during the sound clips was associated with participants' reported effort when attempting to suppress their motivational responses to negative stimuli. Greater relative right frontal activation did not relate to experiencing negative affect. In Study 2, participants could win money by looking at a negative or neutral image or escape from looking at them for no reward. Greater relative right frontal activation was associated with looking at the negative pictures longer when there was a possibility of reward, but not when the possibility of reward was absent. Together, these studies suggest that it is the affective control of emotion rather than negative affect driving greater relative right frontal asymmetry. Additionally, these studies suggest that motivational conflicts engage effortful control.

An EEG Study of Children With and Without ADHD Symptoms: Between-Group Differences and Associations With Sluggish Cognitive Tempo Symptoms.

Objective: We examined differences between those with and without ADHD symptoms on resting state electroencephalography (EEG) indices and unique relations with sluggish cognitive tempo (SCT) symptoms. Method: Children with ADHD symptoms (n = 21) and healthy controls (n = 20) were assessed using rating scales, a neuropsychological task measuring sustained attention and inhibitory control, and EEG activity during a resting state period. Between-group, correlational, and regression analyses were conducted. Results: Large differences (particularly for theta/beta ratio in frontal and frontocentral regions) were found on EEG measures between those with and without ADHD symptoms. While ADHD and SCT symptoms both related to sustained attention on a computerized task, only ADHD symptoms were related to frontal and frontocentral theta/beta ratio. Conclusion: Results support the conclusion that ADHD symptoms are strongly associated with theta/beta ratio in frontal and frontocentral regions. Future studies should explore unique neurophysiological correlates of SCT.

Community-Acquired Antimicrobial Resistant Enterobacteriaceae in Central America: A One Health Systematic Review.

Community-acquired antimicrobial resistant Enterobacteriaceae (CA-ARE) are an increasingly important issue around the world. Characterizing the distribution of regionally specific patterns of resistance is important to contextualize and develop locally relevant interventions. This systematic review adopts a One Health framework considering the health of humans, animals, and the environment to describe CA-ARE in Central America. Twenty studies were identified that focused on antimicrobial resistance (AMR) in Enterobacteriaceae. Studies on CA-ARE in Central America characterized resistance from diverse sources, including humans (n = 12), animals (n = 4), the environment (n = 2), and combinations of these categories (n = 2). A limited number of studies assessed prevalence of clinically important AMR, including carbapenem resistance (n = 3), third generation cephalosporin resistance (n = 7), colistin resistance (n = 2), extended spectrum beta-lactamase (ESBL) production (n = 4), or multidrug resistance (n = 4). This review highlights significant gaps in our current understanding of CA-ARE in Central America, most notably a general dearth of research, which requires increased investment and research on CA-ARE as well as AMR more broadly.

Ubiquitin-dependent regulation of a conserved DMRT protein controls sexually dimorphic synaptic connectivity and behavior.

Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a phylogenetically conserved, but previously uncharacterized Doublesex/Mab-3 related transcription factor (DMRT), dmd-4, is expressed in two classes of sex-shared phasmid neurons specifically in hermaphrodites but not in males. We find dmd-4 to promote hermaphrodite-specific synaptic connectivity and neuronal function of phasmid sensory neurons. Sex-specificity of DMD-4 function is conferred by a novel mode of posttranslational regulation that involves sex-specific protein stabilization through ubiquitin binding to a phylogenetically conserved but previously unstudied protein domain, the DMA domain. A human DMRT homolog of DMD-4 is controlled in a similar manner, indicating that our findings may have implications for the control of sexual differentiation in other animals as well.

Shifts in frontal asymmetry underlying impulsive and controlled decision-making.

The frontal cortices are asymmetrically activated in impulsive and inhibitory action. However, no past work has examined shifts in frontal asymmetric activation during active impulse control or risk-taking behavior. The current study examined impulsive and controlled behavior in a behavioral risk-taking task (Balloon Analogue Risk Task) under alcohol or neutral cue exposure while EEG was recorded. Results revealed activity shifted towards greater relative left frontal activation on alcohol trials with impulsive behavior (balloon explosion) driven by reduced activation of the right inferior frontal gyrus. In contrast, activity from the first half to the second half of alcohol trials with successful impulse control (cash out) localized to reduced activation of the left inferior frontal gyrus. These findings suggest that shifting of right or left frontal asymmetry in inhibitory or impulsive behaviors stem from activation of the inferior frontal gyrus and reveal the importance of examining shifts in neural activity during behavioral processes.

Suppression of Active HIV-1 Infection in CD34+ Hematopoietic Humanized NSG Mice by a Combination of Combined Antiretroviral Therapy and CCR5 Targeting Drugs.

Significant progress has been made in the diagnostics and treatment of AIDS since the discovery of the human immunodeficiency virus type 1 (HIV-1) in 1983. The remarkable effectiveness of combined antiretroviral therapy (cART) is evidenced by mortality reduction, control of peripheral blood viral load, and in a nearly normal quality of HIV patients' lives. Remaining obstacles in treatment and cure are drug toxicities and side effects, viral resistance, persistence of HIV-1 reservoirs on termination of cART treatment, the cost of lifelong antiretroviral therapy, and the stigma associated with taking antiretroviral drugs. As determined by plasma viral RNA and peripheral blood mononuclear cells (PBMC) proviral DNA, we show improved suppression of productive HIV infection in human CD34+ hematopoietic stem cell-engrafted NOD (nonobese diabetic)-SCID (severe combined immunodeficiency)-il2rg-/- (NSG) mice by combined treatment with cART and CCR5 targeting drugs, compared with cART alone, as well as an increased preservation of human CD4+ T cells (defined as CD45+ CD3+ CD4+ cells) and CD4+/CD8+ cell ratios in infected mice. The data also suggest a possible reduction in viral reservoirs. Our data confirm that this animal model is suitable for detection of productive HIV infection, replication, and establishment of viral reservoirs. The data also provide proof of principle for the utility of combining CCR5 targeting drugs, maraviroc and rapamycin, with traditional cART to improve control of viremia and reduce viral reservoirs. This study thus serves as a model for future HIV-1 studies that could lead to the clinical development of new generations of antiretroviral drugs.

Regulatory behavior and frontal activity: Considering the role of revised-BIS in relative right frontal asymmetry.

Essential to human behavior are three core personality systems: approach, avoidance, and a regulatory system governing the two motivational systems. Decades of research has linked approach motivation with greater relative left frontal-cortical asymmetry. Other research has linked avoidance motivation with greater relative right frontal-cortical asymmetry. However, past work linking withdrawal motivation with greater relative right frontal asymmetry has been mixed. The current article reviews evidence suggesting that activation of the regulatory system (revised Behavioral Inhibition System [r-BIS]) may be more strongly related to greater relative right frontal asymmetry than withdrawal motivation. Specifically, research suggests that greater activation of the r-BIS is associated with greater relative right frontal activity, and reduced r-BIS activation is associated with reduced right frontal activity (greater relative left frontal activity). We review evidence examining trait and state frontal activity using EEG, source localization, lesion studies, neuronal stimulation, and fMRI supporting the idea that r-BIS may be the core personality system related to greater relative right frontal activity. In addition, the current review seeks to disentangle avoidance motivation and r-BIS as substrates of relative right frontal asymmetry.

Regulatory control and impulsivity relate to resting frontal activity.

Gray's Reinforcement Sensitivity Theory (RST) asserts three core personality systems: the behavioral approach system (BAS), the fight-flight-freeze system (FFFS) and the revised behavioral inhibition system (r-BIS). Past models of frontal activity link greater relative left frontal activity with Carver and White's (1994) BAS scale and trait impulsivity and greater relative right frontal activity with Carver and White's (1994) BIS scale. However, the original BIS scale assesses both FFFS and r-BIS. Past work linking the BIS scale and right frontal activity does not indicate which system is related to right frontal activity. The current study (n = 182) examined frontal asymmetric activity with personality traits associated with approach (BAS), withdrawal (FFFS-Fear), behavioral inhibition (BIS-Anxiety) and impulsivity (UPPS-P). Resting frontal cortical activity was recorded using electroencephalography (EEG), and the traditional alpha band was examined. Greater BIS-Anxiety related to greater relative right frontal activity. Impulsivity related to less relative right frontal activity. BAS and FFFS-Fear (approach and withdrawal motivation) did not relate to asymmetric frontal activity. Regulatory control processes associated with r-BIS and impulsivity, rather than withdrawal motivation associated with FFFS, may be more closely related to right frontal activity.

Attenuating the alcohol allure: attentional broadening reduces rapid motivational response to alcohol pictures.

RATIONALE: Past research has found that exposure to alcohol cues causes a narrowing of attentional scope and enhances the neural responses associated with approach motivation. OBJECTIVE: The current research sought to determine if a manipulated broadened (global) attentional scope would reduce approach-motivated neural reactivity to alcohol pictures. METHODS: In the current study, participants (n = 82) were exposed to alcohol and neutral pictures following either a global or local attentional scope manipulation. Early motivated attentional processing was assessed using the N1 event-related potential (ERP), a neurophysiological marker of rapid motivated attention. RESULTS: A global attentional scope reduced N1 amplitudes to alcohol pictures as compared to a local attentional scope. Self-reported binge drinking related to larger N1 amplitudes to alcohol pictures, but not to neutral pictures. Individuals with greater binge drinking experience demonstrated increased rapid motivated attentional processing to alcohol pictures. CONCLUSIONS: These results suggest that enhancing a global (vs. local) attentional scope attenuates rapid motivated attentional processing of alcohol pictures in comparison to neutral pictures. Graphical abstract ᅟ.