Nonhuman Research Research Articles

Abstract 5903: Clinical immune and genomic profiling of STK11 mutant non-squamous non-small cell lung cancer

Abstract Background: The use of immune PD-1/PD-L1 checkpoint inhibitors (ICI) has dramatically altered the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). However, a large proportion of patients with NSCLC do not derive clinical benefit from ICI treatment. Recent studies have identified STK11 mutations leading to loss of LKB1 in NSCLC as drivers of primary resistance to ICI treatment. Using a clinical cohort of patients whose tumors underwent comprehensive genomic and immune transcriptomic analysis, we characterized the immune gene expression profile of STK11 mutant non-squamous NSCLC tumors and identified TRIM29 as a potential therapeutic target in STK11 mutant non-squamous NSCLC. Methods: We performed comprehensive analysis of the genomic and immunological landscape of 199 formalin-fixed, paraffin-embedded tumor samples (obtained prior to ICI treatment) from advanced stage non-squamous NSCLC patients treated at Roswell Park Comprehensive Cancer Center using a CLIA-certified laboratory test that included targeted NGS genomic sequencing, gene fusion analysis, and RNA-seq of 394 immune transcripts. Differential gene expression analysis was performed using R/Bioconductor package limma with Benjamini-Hochberg adjusted p-values reported. This study was approved by Roswell Park internal review board review (protocol BDR 091817) according to institutional policy for nonhuman subjects research. Results: Among the cohort of 199 cases, 32 contained truncating STK11 mutations. STK11 mutant cases showed an immunosuppressive environment with decreased PD-L1 expression (p=0.01) and decreased T-cell inflammation gene expression signature (p=0.0029) consistent with prior published cohorts. Analysis of differentially expressed immune genes signatures showed significant decreases in antigen presentation (p=0.015) and processing (p=0.044), NK cell activation (p=0.039), chemokine and cytokine signaling (p=0.044), immune checkpoint pathways (p=0.015), innate immune response (p=0.04), and interferon signaling (p=0.039). The top upregulated gene in STK11 mutant cases was TRIM29 (p=0.03). Other overexpressed targets included ID3 (p=0.009), KRT7 (p=0.02), and NOTCH3 (p=0.05). Interrogation of TCGA LUAD dataset also demonstrated elevated TRIM29 expression (p=0.006) in STK11-mutant compared to STK11-wild-type samples and we also confirmed elevated TRIM29 RNA and protein expression in a panel of STK11 mutant NSCLC human cell lines. Immunohistochemical staining of a cohort of 68 KRAS mutant NSLCLC patient samples also showed higher levels of TRIM29 protein staining in STK11 mutant samples. Knockdown of TRIM29 using shRNA inhibited growth of STK11 mutant tumor xenografts. TRIM29 is a E3 ubiquitin ligase and we evaluated known targets of TRIM29 and found decreased TAB2 expression in STK11 mutant NSCLC. Notably, TAB2 is also regulated by SIK1/3, which have been recently identified as signaling partners with STK11. TRIM29 has been implicated as a mediator of processes also involved in STK11 tumorigenesis such as cellular metabolism, DNA damage repair, innate immunity, and squamous differentiation. Conclusion: Using a large clinical cohort of non-squamous NSCLC patients we characterized the immunosuppressive environment of STK11 mutant tumors and identified the E3 ubiquitin ligase TRIM29 as a potential therapeutic target. Citation Format: Edwin Yau, Sarabjot Pabla, Sean Glenn, Antonios Papanicolau-Sengos, Mary Nesline, Grace Dy, Carl Morrison. Clinical immune and genomic profiling of STK11 mutant non-squamous non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5903.

Asynchronous pediatric caregiver simulation in a virtual setting during the COVID pandemic.

Patient simulation has been used widely in health professions education.1-3 The University of North Carolina at Chapel Hill (UNC-CH) Adams School of Dentistry has embraced patient simulations as a core component of student assessment. Students complete in-person interviews with standardized patient (SP) actors to practice interviewing skills and develop deeper diagnostic reasoning and critical thinking. Simulation exercises are treated as real-life events subject to professional codes of conduct and confidentiality regulations.4 Each SP encounter is video-recorded for student assessment and debriefing, and the videos are stored on university-approved digital storage platforms. In the spring semester of 2020, patient simulations were integrated into a pediatric dentistry course for second-year dental students. The pandemic prevented students from completing their final in-person simulation. As part of a larger evaluation of patient simulation in dental education, the UNC-CH Institutional Review Board deemed this nonhuman subjects research (IRB #20-0292). The original objective of the final encounter was to assess the student's ability to deliver oral health counseling and pediatric dental treatment plans. As an alternative to the in-person encounter, the SP encounter occurred virtually. Using secure Zoom, the course director video-recorded a simulated caregiver interview with the SP training specialist at the UNC-CH School of Medicine's Clinical Skills and Patient Simulation Center. Students responded to SP questions and delivered a prioritized list of treatment options. They had 24 hours to prepare and submit a 5–10-minute video for grading. The Clinical Skills and Patient Simulation Center provided a communication rubric template to the course director. Departmental faculty added checklists for the clinical interview, and Likert items for oral health counseling and pediatric treatment planning. Calibration occurred during weekly faculty meetings. Following the pandemic modification, the final rubric omitted all checklists, and included only 12 Likert items using a 4-point scale, with 1 = “poor” and 4 = “outstanding” (Figure 1). Originally, departmental faculty were scheduled to grade the in-person simulations remotely via video simulcast (Figure 2). Following the pandemic modification, the same faculty had 1 week to complete grading. A critical component of SP encounters is student debriefing and reflection.4 Better guidance from faculty would have standardized student attire and professionalism for their recordings. Students expressed enthusiasm for the future potential of asynchronous teledentistry; however, some were uncertain about the widespread applicability in comprehensive oral health care. Peer-to-peer reflection helped students understand alternative perspectives and integrate key concepts. As a quality improvement exercise, the consent process for recording SP encounters was revisited. Students signed a generic electronic media policy that included recording for educational purposes, which was assumed to cover SP encounters. Following the course modification, students will sign course-specific consents for recording these encounters moving forward. The main takeaway from the faculty was the general success of this modification to patient simulation in terms of providing students an opportunity to demonstrate their grasp of oral health counseling and pediatric dental treatment planning prior to entering clinic. By applying lessons learned, asynchronous teledentistry simulation may become a regular part of the student curriculum.

Level 1 Trauma Centers and OEF/OIF Emergency Departments: Comparison of Trauma Patient Populations.

Brooke Army Medical Center (BAMC), the largest military hospital and the only level 1 trauma center in the DoD, cares for active duty, retired uniformed services personnel, and beneficiaries. In addition, BAMC works in collaboration with the Southwest Texas Regional Advisory Council (STRAC) and University Hospital (UH), San Antonio's other level 1 trauma center, to provide trauma care to residents of the city and 22 counties in southwest Texas from San Antonio to Mexico (26,000 square mile area). Civilian-military partnerships are shown to benefit the training of military medical personnel; however, to date, there are no published reports specific to military personnel experiences within emergency care. The purpose of the current study was to describe and compare the emergency department trauma patient populations of two level 1 trauma centers in one metropolitan city (BAMC and UH) as well as determine if DoD level 1 trauma cases were representative of patients treated in OEF/OIF emergency department settings. We obtained a nonhuman subjects research determination for de-identified data from the US Air Force 59th Medical Wing and the University of Texas Health Science Center at San Antonio Institutional Review Boards. Data on emergency department patients treated between the years 2015 and 2017 were obtained from the two level 1 trauma centers (BAMC and UH, located in San Antonio, Texas); data included injury descriptors, ICU and hospital days, and department procedures. Two-proportion Z-tests indicated that trauma patients were similar across trauma centers on injury type, injury severity, and discharge status; yet trauma patients differed significantly in terms of mechanism of injury and regions of injury. BAMC received significantly greater proportions of patients injured from falls, firearms and with facial and head injuries than UH, which received significantly greater proportion of patients with thorax and abdominal injuries. In addition, a significantly greater proportion of patients spent more than 2days in the ICU and greater than two total hospital days at BAMC than in UH. In comparison to military emergency departments in combat zones, BAMC had significantly lower rates of blood product administration and endotracheal intubations. The trauma patients treated at a military level 1 trauma center were similar to those treated in the civilian level 1 trauma center in the same city, indicating the effectiveness of the only DoD Level 1 trauma center to provide experience comparable to that provided in civilian trauma centers. However, further research is needed to determine if the exposure rates to specific procedures are adequate to meet predeployment readiness requirements.

Dissecting the Fornix in Basic Memory Processes and Neuropsychiatric Disease: A Review.

Background: The fornix is the primary axonal tract of the hippocampus, connecting it to modulatory subcortical structures. This review reveals that fornix damage causes cognitive deficits that closely mirror those resulting from hippocampal lesions. Methods: We reviewed the literature on the fornix, spanning non-human animal lesion research, clinical case studies of human patients with fornix damage, as well as diffusion-weighted imaging (DWI) work that evaluates fornix microstructure in vivo. Results: The fornix is essential for memory formation because it serves as the conduit for theta rhythms and acetylcholine, as well as providing mnemonic representations to deep brain structures that guide motivated behavior, such as when and where to eat. In rodents and non-human primates, fornix lesions lead to deficits in conditioning, reversal learning, and navigation. In humans, damage to the fornix manifests as anterograde amnesia. DWI research reveals that the fornix plays a key role in mild cognitive impairment and Alzheimer's Disease, and can potentially predict conversion from the former to the latter. Emerging DWI findings link perturbations in this structure to schizophrenia, mood disorders, and eating disorders. Cutting-edge research has investigated how deep brain stimulation of the fornix can potentially attenuate memory loss, control epileptic seizures, and even improve mood. Conclusions: The fornix is essential to a fully functioning memory system and is implicated in nearly all neurological functions that rely on the hippocampus. Future research needs to use optimized DWI methods to study the fornix in vivo, which we discuss, given the difficult nature of fornix reconstruction. Impact Statement The fornix is a white matter tract that connects the hippocampus to several subcortical brain regions and is pivotal for episodic memory functioning. Functionally, the fornix transmits essential neurotransmitters, as well as theta rhythms, to the hippocampus. In addition, it is the conduit by which memories guide decisions. The fornix is biomedically important because lesions to this tract result in irreversible anterograde amnesia. Research using in vivo imaging methods has linked fornix pathology to cognitive aging, mild cognitive impairment, psychosis, epilepsy, and, importantly, Alzheimer's Disease.

The Emergence and Development of Animal Research Ethics: A Review with a Focus on Nonhuman Primates

The ethics of using nonhuman animals in biomedical research is usually seen as a subfield of animal ethics. In recent years, however, the ethics of animal research has increasingly become a subfield within research ethics under the term “animal research ethics”. Consequently, ethical issues have become prominent that are familiar in the context of human research ethics, such as autonomy or self-determination, harms and benefits, justice, and vulnerability. After a brief overview of the development of the field and a discussion of relevant theoretical ethical frameworks, I consider two of these issues, namely autonomy and self-determination on the one hand, and harms and benefits on the other hand. My concern is with philosophical and ethical issues, rather than animal research oversight. I focus my discussion on nonhuman primates, as the most plausible nonhuman candidates for this approach. I conclude that the approach, although promising, depends strongly on the moral status of nonhuman research subjects.

Evaluating the neurophysiological evidence for predictive processing as a model of perception.

For many years, the dominant theoretical framework guiding research into the neural origins of perceptual experience has been provided by hierarchical feedforward models, in which sensory inputs are passed through a series of increasingly complex feature detectors. However, the long‐standing orthodoxy of these accounts has recently been challenged by a radically different set of theories that contend that perception arises from a purely inferential process supported by two distinct classes of neurons: those that transmit predictions about sensory states and those that signal sensory information that deviates from those predictions. Although these predictive processing (PP) models have become increasingly influential in cognitive neuroscience, they are also criticized for lacking the empirical support to justify their status. This limited evidence base partly reflects the considerable methodological challenges that are presented when trying to test the unique predictions of these models. However, a confluence of technological and theoretical advances has prompted a recent surge in human and nonhuman neurophysiological research seeking to fill this empirical gap. Here, we will review this new research and evaluate the degree to which its findings support the key claims of PP.

Efavirenz versus Protease Inhibitors in Patients with Human Immunodeficiency Virus – A Systematic Review and Meta-Analysis

Background: Efavirenz- and protease inhibitor-based regimens remain viable options across the globe. We conducted a meta-analysis to compare the effectiveness of efavirenz-based regimens relative to protease inhibitor-based regimens (PIs). Methods: Embase, PubMed, Cochrane, and clinicaltrials.gov were searched for randomised controlled trials (RCTs) conducted between 1987 and 2018 comparing efavirenz- with PI-based regimens. This was followed by title, abstract, and full-text screens. The quality of selected studies was assessed using the Cochrane risk of bias tool. Meta-analysis of the odds of virological suppression was conducted using the robust variance estimation approach. Findings: Fifteen studies met the inclusion criteria and totaled 6,712 patients (efavirenz arm=3,339; PI arm=3,373), of which 1,610 (24.0%) were females. Follow-up ranged from 24 to 144 weeks. Mean/median age ranged from 33 to 44 years. Mean/median baseline CD4 count ranged from 32 to 557 cells/mL while mean/median baseline viral load ranged from log10 4·5 to log10 5·5 copies /mL. Meta-analysis showed that patients receiving efavirenz-based regimens had 37% higher odds of virological suppression compared to PI-based regimens (OR=1·37, 95% CI=1·06-1·77, p=0.02). The Egger test suggested the presence of publication bias (B=0·927, t=2·214, p=0·033). The main threat to the quality of evidence was attrition bias. Interpretation: Regarding virological suppression, efavirenz-based regimens were more effective than PI-based regimens and, therefore, might be ideal for the management of treatment naive patients with HIV in settings where NNRTIs and PIs are used. Funding Statement: The authors stated that there were no funding sources for the study. Declaration of Interests: The authors have no conflicts of interests to declare. Ethics Approval Statement: The study was approved by the University of Texas at Austin Institutional Review Board and determined to be non-human subjects research as it involved obtaining information from publicly available data. Hence, informed consent was not required. The study was registered with PROSPERO, an international database supported by PRISMA (ID: CRD42018100296).

Integrative personality assessment in wild Assamese macaques (Macaca assamensis).

In nonhuman animals, individuals of the same sex and age differ in their behavior patterns consistently across time, comparable with human personality differences. To draw conclusions about the adaptive value of behavior traits, it is essential to study them in the wild where animals are subject to the ecological pressures that promoted the evolution of behavior strategies. This study was conducted in the Phu Khieo Wildlife Sanctuary, Thailand, on 4 groups of habituated wild Assamese macaques by observers who had familiarized themselves with the subjects over the course of an ongoing long-term study. We used a multimethod approach enabling the most comprehensive understanding of variation in stable interindividual differences in a species-typical ecological setting. We combined trait ratings (TRs), assessed with observer-report questionnaires (54-item Hominoid Personality Questionnaire) of 107 individuals of diverse age-sex classes, with behavior codings (BCs) of 24 adult males. We found male and female personality constructs to be congruent and examined reliability and construct validity. Combining trait rating and behavioral coding, we found two solutions with five factors to best describe the personality structure of the males: one structure comprised the dimensions GregariousnessBC, AggressivenessBC, SociabilityBC and VigilanceBC, complemented by a ConfidenceTR domain and the other structure OpportunismTR, ConfidenceTR, FriendlinessTR, ActivityTR complemented with VigianceBC. We discuss our findings with regard to the importance of construct validity and reproducibility in the context of method development and standardization in nonhuman animal personality research. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Depression Predicts Prolonged Length of Hospital Stay in Pediatric Inflammatory Bowel Disease.

Few studies report the impact of depression on inflammatory bowel disease (IBD)-related hospitalizations. We evaluated the association between depression and pediatric IBD-related hospitalizations. Our primary aim was to test the hypothesis that depression is associated with hospital length of stay (LOS); our secondary goal was to evaluate if patients with depression are at higher risk for undergoing additional imaging and procedures. Data were extracted from the 2012 Kids Inpatient Database (KID), the largest nationally representative publicly available all-payer pediatric inpatient cross-sectional database in the United States. Hospitalizations for patients less than 21 years with a primary diagnosis Crohn disease (CD) or ulcerative colitis (UC) by ICD-9 code were included. Multivariable logistic regression was used to predict long LOS controlling for patient- and hospital-level variables and for potential disease confounders. For primary IBD-related hospitalizations (N = 8222), depression was associated with prolonged LOS (odds ratio [OR] 1.50; 95% confidence interval [CI] 1.19-1.90) and total parenteral nutrition use (OR 1.54; 95% CI 1.04-2.27). Depression was not associated with increased likelihood of surgery (OR 0.97; 95% CI 0.72-1.30), endoscopy (OR 0.91; 95% CI 0.74-1.14), blood transfusion (OR 0.85; 95% CI 0.58-1.23), or abdominal imaging (OR 1.15; 95% CI 0.53-2.53). Depression is associated with prolonged LOS in pediatric patients with IBD, even when controlling for gastrointestinal disease severity. Future research evaluating the efficacy of standardized depression screening and early intervention may be beneficial to improving inpatient outcomes in this population.

What smells? Gauging attention to olfaction in canine cognition research.

One of the challenges of animal cognition research is overcoming anthropocentric sensory biases-in particular, favoring visual information and cues despite the dominance of other sensory cues in many nonhuman research subjects. As such, it is particularly important for animal cognition researchers to explicitly mention steps taken to control for and attend to the sensory world of their study species. Dogs are well known for their reliance on olfaction, but the extent to which dog cognition and behavior research accounts for olfactory cues or incorporates olfactory controls is unknown. With this bibliographic study, we reviewed canine research published in the past 10years (2008-2018) in 13 scientific journals and coded the 481 resulting papers for mentions of olfactory or odor cues or controls. Our findings indicate that despite widespread acceptance of the significance of olfaction to dogs, scientific methodology rarely takes olfactory information processing into account. Finally, we propose a simple rubric of recommended reporting of olfactory information in research contexts, with the aims to help attune researchers to the umwelt of their study subjects, and to enhance the methodological reproducibility of canine cognition research.

The Will to Fight: Aversion-Induced Aggression and the Role of Motivation in Intergroup Conflicts.

Aggressive behavior is a source of many significant human problems, most notably the catastrophic loss of life and resources that can result from violent conflicts between groups. Aggressive behavior is particularly likely to arise from aversive conditions that function as motivating operations (MOs) that establish the stimulation produced by aggressive acts as reinforcing. We describe the behavior that arises from these circumstances as aversion-induced aggression (AIA) and argue that the MOs associated with AIA are important factors in initiating and sustaining violent conflicts between groups. In support of this, we survey the basic nonhuman research that has demonstrated the aggression-motivating functions of aversive stimuli. We extend our analysis of AIA to humans and describe how the special properties of verbal stimuli serve as the basis for notable differences between AIA in humans and nonhumans. We describe how aversive conditions may be exploited by leaders to establish support for aggression against another group in the pursuit of their objectives. We suggest that conflicts between groups cannot be resolved in the long term unless the motivational conditions from which conflicts arise are alleviated. Aggression is rarely effective in this regard because it exacerbates these conditions. For this reason, we advocate against the use of aggression as a tool for resolving conflicts between groups and consider how behavior science may contribute to the development and evaluation of alternative nonviolent practices.

A Method for Controlled Odor Delivery in Olfactory Field-Testing.

A widely recognized limitation in mammalian olfactory research is the lack of current methods for measuring odor availability (i.e., the quantifiable amount of odor presented and thus available for olfaction) of training or testing materials during behavioral or operational testing. This research utilized an existing technology known as Controlled Odor Mimic Permeation Systems (COMPS) to produce a reproducible, field-appropriate odor delivery method that can be analytically validated and quantified, akin to laboratory-based research methods, such as permeation devices that deliver a stable concentration of a specific chemical vapor for instrumental testing purposes. COMPS were created for 12 compounds across a range of carbon chain lengths and functional groups in such a way to produce similar permeation rates for all compounds. Using detection canines as a model, field-testing was performed to assess the efficacy of the method. Additionally headspace concentrations over time were measured as confirmation of odor availability using either externally sampled internal standard-solid phase microextraction-gas chromatography-mass spectrometry (ESIS-SPME-GC-MS) or collection onto a programmable temperature vaporizing (PTV) GC inlet with MS detection. Finally, lifetime usage was considered. An efficient method for producing and measuring reliable odor availabilities across various chemical functional groups was developed, addressing a noted gap in existing literature that will advance canine and other nonhuman mammal research testing.

Validity of Digital and Manual Refractometers for Measuring Urine Specific Gravity During Field Operations: A Brief Report.

Dehydration can have an immediate negative impact on the performance of Soldiers in training or combat environments. Field expedient methods for assessing hydration status may be valuable for service members. Measurement of urine-specific gravity (USG) via refractometer is inexpensive, simple, fast, and a validated indicator of hydration status. Manual (MAN) and digital (DIG) refractometers are commonly used in laboratory settings however, digital (DIG) devices have not been validated in the field against MAN devices. The purpose of this study was to determine the validity and feasibility of using a DIG refractometer to assess USG compared to a MAN refractometer during a military field training exercise. Fifty-six military service members provided 672 urine samples during two 10-day field training exercises in central Texas. USG was assessed using a MAN and a DIG refractometer with cutoff value of ≥1.020 indicating hypohydration. The study received a non-human research determination. The MAN measurements were strongly correlated with the DIG (r = 0.91, p < 0.0001) measurements. Bland-Altman analysis demonstrated agreement between the refractometers. The DIG displayed good sensitivity (93.9%) and specificity (85.8%) compared to the MAN. The DIG refractometer used in this study was reliable and valid compared with a MAN device and was feasible for use in a field environment; however, the DIG refractometer tended to over overestimate hypohydration.

What are we measuring? Novices agree amongst themselves (but not always with experts) in their assessment of dog behaviour

AbstractHumans differ in how they perceive, assess, and measure animal behaviour. This is problematic because strong observer bias can reduce statistical power, accuracy of scientific inference, and in the worst cases, lead to spurious results. Unfortunately, reports and studies of measurement reliability in animal behaviour studies are rare. Here, we investigated two aspects of measurement reliability in working dogs: inter‐observer agreement and criterion validity (comparing novice ratings with those given by experts). Here, we extend for the first time a powerful framework used in human psychological studies to investigate three potential aspects of (dis)agreement in nonhuman animal behaviour research: (a) that some behaviours are easier to observe than others; (b) that some subjects are easier to observe than others; and (c) that observers with different levels of experience with the subject animal give the same or different ratings. We found that novice observers with the same level of experience agreed upon measures of a wide range of behaviours. We found no evidence that age of the dogs affected agreement between these same novice observers. However, when observers with different levels of experience (i.e., novices vs. a working dog expert) assessed the same dogs, agreement appeared to be strongly affected by the measurement instrument used to assess behaviour. Given that animal behaviour research often utilizes different observers with different levels of experience, our results suggest that further tests of how different observers may measure behaviour in different ways are needed across a wider variety of organisms and measurement instruments.

Refinement techniques in non-human primate neuroscientific research.

Non-human primates (NHP) are widely considered an essential model for biomedical research because of their close genetic, anatomo-functional and cognitive similarities to humans. These same reasons also raise particular ethical concerns for the unavoidable harm caused to these animals, in particular to those involved in neuroscientific studies. Besides reducing the number of animals needed to the absolute minimum, it is therefore essential to implement procedures allowing, at the same time, to minimize the harm to the animals and maximize the quality and ecological validity of the data. Technological progresses have made possible, for example, to self-train monkeys in their home cage with positive reinforcement techniques and to adopt various types of telemetric systems for wirelessly recording neuronal activity in freely behaving animals. Example of full application of these techniques are still very limited in the literature, but different recent international projects and pioneering studies are paving the way for turning to the use of new technologies to get a more "ethically acceptable" NHP neuroscientific research.

Metabolomics for predicting fetal growth restriction: protocol for a systematic review and meta-analysis

IntroductionFetal growth restriction (FGR) is a relevant research and clinical concern since it is related to higher risks of adverse outcomes at any period of life. Current predictive tools in...

OligoPVP: Phenotype-driven analysis of individual genomic information to prioritize oligogenic disease variants

An increasing number of disorders have been identified for which two or more distinct alleles in two or more genes are required to either cause the disease or to significantly modify its onset, severity or phenotype. It is difficult to discover such interactions using existing approaches. The purpose of our work is to develop and evaluate a system that can identify combinations of alleles underlying digenic and oligogenic diseases in individual whole exome or whole genome sequences. Information that links patient phenotypes to databases of gene–phenotype associations observed in clinical or non-human model organism research can provide useful information and improve variant prioritization for genetic diseases. Additional background knowledge about interactions between genes can be utilized to identify sets of variants in different genes in the same individual which may then contribute to the overall disease phenotype. We have developed OligoPVP, an algorithm that can be used to prioritize causative combinations of variants in digenic and oligogenic diseases, using whole exome or whole genome sequences together with patient phenotypes as input. We demonstrate that OligoPVP has significantly improved performance when compared to state of the art pathogenicity detection methods in the case of digenic diseases. Our results show that OligoPVP can efficiently prioritize sets of variants in digenic diseases using a phenotype-driven approach and identify etiologically important variants in whole genomes. OligoPVP naturally extends to oligogenic disease involving interactions between variants in two or more genes. It can be applied to the identification of multiple interacting candidate variants contributing to phenotype, where the action of modifier genes is suspected from pedigree analysis or failure of traditional causative variant identification.

Memory-related hippocampal activation in the sleeping toddler

Nonhuman research has implicated developmental processes within the hippocampus in the emergence and early development of episodic memory, but methodological challenges have hindered assessments of this possibility in humans. Here, we delivered a previously learned song and a novel song to 2-year-old toddlers during natural nocturnal sleep and, using functional magnetic resonance imaging, found that hippocampal activation was stronger for the learned song compared with the novel song. This was true regardless of whether the song was presented intact or backwards. Toddlers who remembered where and in the presence of which toy character they heard the song exhibited stronger hippocampal activation for the song. The results establish that hippocampal activation in toddlers reflects past experiences, persists despite some alteration of the stimulus, and is associated with behavior. This research sheds light on early hippocampal and memory functioning and offers an approach to interrogate the neural substrates of early memory.

Impulsivity and behaviour problems in dogs: A Reinforcement Sensitivity Theory perspective

Trait impulsivity is an increasingly relevant topic for human and non-human animal personality research. There are similarities in dog and human manifestations of trait impulsivity at the behavioural, genetic, and neurobiological level. We investigated a well-validated measure of dog impulsivity and responsivity (the Dog Impulsivity Assessment Scale, DIAS) and a neuropsychological theory of human trait approach and avoidance (the Reinforcement Sensitivity Theory of personality, RST). Owners reported their dogs’ dispositional behaviour on the DIAS, an RST scale modified to describe dogs’ behaviour, and a list of common dog behaviour problems. In a sample of 730 dogs, we observed convergence between the RST and the DIAS. There was a negative correlation between RST ‘Behaviour Inhibition System’ and DIAS impulsivity factor (‘Behavioural Regulation’). RST ‘Behavioural Approach System’ correlated positively with DIAS ‘Responsiveness’. The RST ‘Fight-Flight-Freeze System’ (FFFS) and the DIAS ‘Aggression and response to novelty factor were both distinct from other factors. However, the DIAS ‘Aggression and response to novelty’ factor and the RST FFFS explained different aspects of dog behaviour problems. Importantly, whilst the DIAS factors indicated tendencies towards avoidant behaviours, the FFFS discriminated between active and passive avoidance. The findings suggest a partial overlapping between the DIAS and RST scales, and highlights the utility of personality models in investigating behaviour problems in dogs.

Using Drones to Study Human Beings: Ethical and Regulatory Issues.

Researchers have used drones to track wildlife populations, monitor forest fires, map glaciers, and measure air pollution but have only begun to consider how to use these unmanned aerial vehicles to study human beings. The potential use of drones to study public gatherings or other human activities raises novel issues of privacy, confidentiality, and consent, which this article explores in depth. It argues that drone research could fall into several different categories: non-human subjects research (HSR), exempt HSR, or non-exempt HSR. In the case of non-exempt HSR, it will be difficult for institutional review boards to approve studies unless they are designed so that informed consent can be waived. Whether drone research is non-HSR, exempt HSR, or non-exempt HSR, it is important for investigators to consult communities which could be affected by the research.