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The goal of this study was to evaluate the effect of a human observer on Rabbit Grimace Scale (RbtGS) scores. The study scored video footage taken of 28 rabbits before and after orthopedic surgery, as follows: 24 h before surgery ( baseline), 1 h after surgery ( pain), 3 h after analgesia administration ( analgesia), and 24 h after surgery ( 24h) in the presence and absence of an observer. Videos were assessed twice in random order by 3 evaluators who were blind to the collection time and the presence or absence of an observer. Responses to pain and analgesia were evaluated by comparing the 4 time points using the Friedman test, followed by the Dunn test. The influence of the presence or absence of the observer at each time point was evaluated using the Wilcoxon test. Intra- and interrater reliabilities were estimated using the intraclass correlation coefficient. The scale was responsive to pain, as the scores increased after surgery and had decreased by 24 h after surgery. The presence of the observer reduced significantly the RbtGS scores (median and range) at pain (present, 0.75, 0 to 1.75; absent, 1, 0 to 2) and increased the scores at baseline (present, 0.2, 0 to 2; absent, 0, 0 to 2) and 24h after surgery (present, 0.33, 0 to 1.75; absent, 0.2, 0 to 1.5). The intrarater reliability was good (0.69) to very good (0.82) and interrater reliability was moderate (0.49) to good (0.67). Thus, the RbtGS appeared to detect pain when scored from video footage of rabbits before and after orthopedic surgery. In the presence of the observer, the pain scores were underestimated at the time considered to be associated with the greatest pain and overestimated at the times of little or no pain.

Chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 or CD22 induce remissions in the majority of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), although relapse due to target antigen loss or downregulation has emerged as a major clinical dilemma. Accordingly, great interest exists in developing CAR T cells directed against alternative leukemia cell surface antigens that may help to overcome immunotherapeutic resistance. The fms-like tyrosine kinase 3 receptor (FLT3) is constitutively activated via FLT3 mutation in acute myeloid leukemia (AML) or wild-type FLT3 overexpression in KMT2A (lysine-specific methyltransferase 2A)-rearranged ALL, which are associated with poor clinical outcomes in children and adults. We developed monovalent FLT3-targeted CAR T cells (FLT3CART) and bispecific CD19xFLT3CART and assessed their anti-leukemia activity in preclinical models of FLT3-mutant AML and KMT2A-rearranged infant ALL. We report robust in vitro FLT3CART-induced cytokine production and cytotoxicity against AML and ALL cell lines with minimal cross-reactivity against normal hematopoietic and non-hematopoietic tissues. We also observed potent in vivo inhibition of leukemia proliferation in xenograft models of both FLT3-mutant AML and KMT2A-rearranged ALL, including a post-tisagenlecleucel ALL-to-AML lineage switch patient-derived xenograft model pairing. We further demonstrate significant in vitro and in vivo activity of bispecific CD19xFLT3CART against KMT2Arearranged ALL and posit that this additional approach might also diminish potential antigen escape in these high-risk leukemias. Our preclinical data credential FLT3CART as a highly effective immunotherapeutic strategy for both FLT3- mutant AML and KMT2A-rearranged ALL which is poised for further investigation and clinical translation.

Killing is often an unavoidable and necessary procedure for laboratory mice involved in scientific research, and providing a humane death is vital for public acceptance. Exposure to carbon dioxide (CO 2 ) gas is the most widely used methodology despite well proven welfare concerns. Consequently, the continued use of CO 2 and its globally permitted status in legislation and guidelines presents an ethical dilemma for users. We investigated whether killing with hypobaric hypoxia via gradual decompression was associated with better welfare outcomes for killing laboratory mice. We compared the spontaneous behaviour of mice exposed to CO 2 , decompression or sham conditions, and used analgesic or anxiolytic interventions to determine their relative welfare impact. Gradual decompression resulted in longer times to unconsciousness and death and the pharmacological interventions support the notion of a minimally negative animal experience, while providing further evidence for pain and anxiety associated with exposure to CO 2 . Decompression resulted in moderate ear haemorrhage, but our welfare assessment suggests this may happen when mice are unconscious. Hence, gradual decompression could be the basis of significant refinement for killing laboratory mice. Future work should corroborate behaviour with neurobiological markers of loss of consciousness to verify the conscious phase of concern for animal welfare.

Rodents are the predominant species used for scientific research and must be humanely killed upon completion of the work. In the UK this is regulated by Schedule 1 of the Animals Scientific Procedures Act 1986, which lists permitted methodologies considered capable of humane killing, including overdose of an anaesthetic, exposure to carbon dioxide (CO2) gas, dislocation of the neck and concussion of the brain by striking the cranium. Although all are permitted, operator motivations behind method selection and individual operator preference remain unknown. The views of 219 laboratory animal personnel on institutional availability and use of Schedule 1 killing methods for laboratory rodents were obtained. Only 10% of participants reported that all four methods were available at their institution with 57.5% of respondents preferring cervical dislocation. For CO2, only 18.6% of participants reported using the recommended flow rate, while 45.5% did not know the flow rate employed. We highlight the urgent requirement for the development of quality-controlled training programmes, to improve knowledge and confidence in the selection and application of killing methods. We advocate for continuous review of killing practices to ensure best practice is reflected in legislation and achieve optimal protection of the welfare of laboratory rodents during killing.

Using food rewards to motivate mice is commonplace in behavioural research. Using a reward which is highly desirable is of benefit, as it can reduce the need to food restrict animals and can encourage higher levels of consumption, allowing for changes in levels of consumption following an intervention to be easily determined. Here, we aimed to determine the preferred milk reward for adult male C57Bl/6 mice. Thirty male C57Bl/6 mice were provided with soya milk, chocolate milk, almond milk or water for a four-hour period in a cross-over design. When planning studies that involve the use of a palatable liquid reward, soya milk is the preferred option for adult male C57BL/6 mice. Providing a liquid reward of high value will give increased levels of consumption, with little or no food restriction required.

Rabbits typically undergo at least one painful procedure during their lifetime and appropriate methods of assessment are essential to reduce or alleviate pain. Various methods of assessing pain in rabbits have been investigated, with the validity of spontaneous behavior and grimace scale scoring being the most studied to date. Assessment of pain is challenging, compounded by rabbits being a prey species that display freezing behavior in the presence of unfamiliar caregivers. Here we discuss some key changes in rabbits that can be used in the assessment of pain and provide some practical suggestions to ensure that the assessment can be carried out effectively.

EEG methods offer a promising approach to study the development of attention or attention-related processes such as change-detection and attentional capture. However, the development of these attention processes from early to middle childhood is not well understood. In the current study, we utilized a passive three-stimulus oddball paradigm to examine age-related changes in auditory change-detection and attentional capture in a large sample of children across childhood (N = 475; 249 female, 226 male; M(age)=6.71; SD(age)=2.22; Range(age)= 4.01–11.5 years). Conventional ERP analyses revealed no age-related changes in change detection (mismatch negativity) and attentional capture (P3a) components, but we observed age-related reductions in late automatic processing of auditory change (late discriminative negativity). However, when utilizing time-frequency analyses, we observed developmental increases in frontocentral signal strength (power) and consistency (inter-trial phase synchrony) in delta and theta bands in response to novel sounds. Such frontocentral delta/theta responses have been linked in prior work to cognitive control. To further examine this possibility, we examined relations with inhibitory control. Results revealed that increased consistency in theta in response to novel sounds was related to improved inhibitory control. Together, our results advance our understanding of the development of attention in childhood. Moreover, they demonstrate the contributions of time-frequency approaches to studying neurocognitive development. Finally, our results highlight the utility of neuroimaging paradigms that have low cognitive and motor demands to study the development of psychological processes.

This study is the first to examine spectrum-wide (1 to 250 Hz) differences in electroencephalogram (EEG) power between eyes open (EO) and eyes closed (EC) resting state conditions in 486 children. The results extend the findings of previous studies by characterizing EEG power differences from 30 to 250 Hz between EO and EC across childhood. Developmental changes in EEG power showed spatial and frequency band differences as a function of age and EO/EC condition. A 64-electrode system was used to record EEG at 4, 5, 7, 9, and 11 years of age. Specific findings were: (1) the alpha peak shifts from 8 Hz at 4 years to 9 Hz at 11 years, (2) EC results in increased EEG power (compared to EO) at lower frequencies but decreased EEG power at higher frequencies for all ages, (3) the EEG power difference between EO and EC changes from positive to negative within a narrow frequency band which shifts toward higher frequencies with age, from 9 to 12 Hz at 4 years to 32 Hz at 11 years, (4) at all ages EC is characterized by an increase in lower frequency EEG power most prominently over posterior regions, (5) at all ages, during EC, decreases in EEG power above 30 Hz are mostly over anterior regions of the scalp. This report demonstrates that the simple challenge of opening and closing the eyes offers the potential to provide quantitative biomarkers of phenotypic variation in brain maturation by employing a brief, minimally invasive protocol throughout childhood.

Even though the fatality rate from skin cancers is low, evidence from a few cohort studies has raised the possibility that people with a personal history of skin cancer may have a higher all-cause mortality rate compared with those without a personal history of skin cancer. The purpose of the present study was to investigate the potential links between a personal history or family history of skin cancer and all-cause and cancer-specific mortality A prospective cohort (n = 8,622) was assembled within the NHANES I follow-up study. Cox Proportional Hazard Regression analysis was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association for personal and family history of skin cancer and all-cause and cancer-specific mortality. After adjustment for several potential confounding variables, a personal history of skin cancer was associated with decreased risk for all-cause mortality (HR 0.72, 95% CI 0.61–0.85), whereas the results for cancer-specific mortality were consistent with a null association (HR 0.97, 95% CI 0.74–1.27). A family history of skin cancer was not significantly associated with all-cause mortality (HR 0.97, 95% CI 0.76–1.24) or cancer-specific mortality (HR 0.69, 95% CI 0.38–1.24). The results of the present study do not support the hypothesis that a personal history or family history of skin cancer is associated with an increased risk of all-cause or cancer-specific mortality. The high prevalence of skin cancer adds to the public health significance of this question, providing a strong rationale for further research to resolve this question.

Chimeric antigen receptor (CAR) T cell immunotherapies targeting CD19 or CD22 induce remissions in the majority of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), although relapse due to target antigen loss or downregulation has emerged as a major clinical dilemma. Accordingly, great interest exists in developing CAR T cells directed against alternative leukemia cell surface antigens that may help to overcome immunotherapeutic resistance. The fms-like tyrosine kinase 3 receptor (FLT3) is constitutively activated via FLT3 mutation in acute myeloid leukemia (AML) or wild-type FLT3 overexpression in KMT2A (lysine-specific methyltransferase 2A)-rearranged B-acute lymphoblastic leukemia (ALL), which are associated with poor clinical outcomes in children and adults. We developed monovalent FLT3-targeted CAR T cells (FLT3CART) and bispecific CD19xFLT3CART and assessed their anti-leukemia activity in preclinical models of FLT3-mutant AML and KMT2Arearranged infant ALL. We report robust in vitro FLT3CART-induced cytokine production and cytotoxicity against AML and ALL cell lines with minimal cross-reactivity against normal hematopoietic and non-hematopoietic tissues. We also observed potent in vivo inhibition of leukemia proliferation in xenograft models of both FLT3-mutant AML and KMT2A-rearranged ALL, including a post-tisagenlecleucel ALL-to-AML lineage switch patient-derived xenograft model pairing. We further demonstrate significant in vitro and in vivo activity of bispecific CD19xFLT3CART against KMT2A-rearranged ALL and posit that this additional approach might also diminish potential antigen escape in these high-risk leukemias. Our preclinical data credential FLT3CART as a highly effective immunotherapeutic strategy for both FLT3-mutant AML and KMT2A-R ALL that is poised for further investigation and clinical translation.

Prevention of pain in rabbits is a priority for both welfare and validity of scientific data. We aimed to determine if the rabbit grimace scale (RbtGS) could be used as a viable, rapid assessment tool in two breeds of rabbit, Dutch belted (DB) and New Zealand white (NZW), following orchidectomy, as an adjunct to behavioral analysis. All animals received analgesia. Rabbits were filmed and their behavior was recorded at multiple time points pre- and post-orchidectomy. Observers then scored specific pain associated behaviors for analysis. Time matched footage was also scored using the rabbit grimace scale (RbtGS). Following surgery, rabbits showed significant increases in the duration spent displaying key pain associated behaviors at 1 and 5 h post-surgery. DB rabbits that received low dose meloxicam (0.2 mg/kg) showed significantly more pain behaviors at 1 and 5 h post-surgery compared to those administered a combination of higher dose meloxicam (0.6 mg/kg) and a lidocaine/bupivacaine local infusion. DB rabbits showed an increase in RbtGS score at both 1 and 5 h post-surgery. In the NZW rabbits, an increase in RbtGS score was only observed at 1 h post-surgery. Using behavioral analysis as the gold standard for comparison, the RbtGS was an effective means of determining when rabbits are painful following orchidectomy. Higher dose meloxicam (0.6 mg/kg) combined with local anesthetic was a more effective method of reducing pain, compared to lower dose meloxicam (0.2 mg/kg) alone.

Heightened novelty seeking phenotypes are associated with a range of behavioral traits including susceptibility to drug use. These relationships are recapitulated in preclinical models, where rats that exhibit increased exploratory activity in novel environments (high responders- HR) acquire self-administration of psychostimulants more rapidly compared to rats that display low novelty exploration (low responders- LR). Dopamine release dynamics in the nucleus accumbens (NAc) covaries with response to novelty and differences in dopaminergic signaling are thought to be a major underlying driver of the link between novelty seeking and drug use vulnerability. Accumbal dopamine release is controlled by local microcircuits including modulation through glutamatergic and nicotinic acetylcholine receptor (nAChR) systems, but whether these mechanisms contribute to disparate dopamine signaling across novelty phenotypes is unclear. Here, we used ex vivo voltammetry in the NAc of rats to determine if α7 nAChRs contribute to differential dopamine dynamics associated with individual differences in novelty exploration. We found that blockade of α7 nAChRs attenuates tonic dopamine release evoked by low frequency stimulations across phenotypes, but that phasic release is decreased in LRs while HRs are unaffected. These stimulation frequency- and phenotype-dependent effects result in a decreased dynamic range of release exclusively in LRs. Furthermore, we found that differential α7 modulation of dopamine release in LRs is dependent on AMPA but not NMDA receptors. These results help to form an understanding of the local NAc microcircuitry, and provides a potential mechanism for covariance of dopamine dynamics and sensitivity to the reinforcing effects of drugs of abuse.

Considering the widespread use of rabbits in research that potentially causes pain and discomfort and the limited number of pain assessment validated tools in this species, we aimed to develop and validate a scale of acute postoperative pain in rabbits (RPBS). Footage of 58 rabbits from previous studies were used, recorded at ‘baseline’(before orthopaedic and soft tissue surgeries), ‘pain’(after surgery), ‘analgesia’(after analgesic), and ‘24h post’(24 hours after surgery). The videos were randomised and assessed twice by four evaluators, within one-month interval between evaluations. After content validation, RBPS was further refined using the criteria from the validation. According to the principal component analysis, RPBS was considered unidimensional. The intra- and inter-observer reliability was excellent (ICC>0.80) for all evaluators. There was a high Spearman’s correlation of the RPBS with unidimensional scales (>0.80) and a moderate correlation with the Rabbit Grimace Scale (0.68), confirming criterion validity. According to the mixed linear model, the scale was responsive, shown by the increase in pain scores after surgery. Construct validity was confirmed by known-group approach and internal relationships among items. Adequate item-total correlation (>0.3) was observed for all items, except for the attention to the affected area (0.04). The internal consistency was very good (Cronbach’s α coefficient = 0.78; Mcdonald’s ω coefficient = 0.83). The cut-off score for rescue analgesia was ≥3, with an area under the curve >0.95, demonstrating a high discriminatory capacity of the instrument. Scores 3 and 4 were within the uncertainty diagnostic zone. Specificity was 87% and sensitivity was 90%. It was concluded that the RPBS presented content, criterion, and construct validities, responsiveness, and reliability to assess acute pain in rabbits submitted to orthopaedic and soft tissue surgeries. The cut-off for rescue analgesia serves as a basis for the administration of analgesics to rabbits submitted to painful procedures.

Past work shows that processing information in relation to the self improves memory which is known as the self‐reference effect in memory. Other work suggests that transcranial direct current stimulation (tDCS) can also improve memory. Given recent research on self‐reference context memory effects (improved memory for contextual episodic details associated with self‐referential processing), we were interested in examining the extent stimulation might increase the magnitude of the self‐reference context memory effect. In this investigation, participants studied objects superimposed on different background scenes in either a self‐reference or other‐reference condition while receiving either active or sham stimulation to the dorsal medial prefrontal cortex (dmPFC), a cortical region known to support self‐reference context memory effects. Participants then completed a memory test that assessed item memory (have you seen this object before?) and context memory (with which background scene was this object paired?). Results showed a self‐reference context memory effect driven by enhanced memory for stimuli processed in the self‐reference compared to the other‐reference condition across all participants (regardless of stimulation condition). tDCS, however, had no effect on memory. Specifically, stimulation did not increase the magnitude of the self‐reference context memory effect under active compared to sham stimulation. These results suggest that stimulation of the dmPFC at encoding may not add to the memory benefits induced by self‐referential processing suggesting a boundary condition to tDCS effects on memory., In this investigation we examined the extent transcranial direct current (tDCS) applied to the dorsal medial prefrontal cortex (dmPFC) affects memory for information processed in reference to the self. We found strong evidence that self‐referential processing improved memory (relative to a control condition), but further showed that tDCS did not have strong effects on memory. Results advance understanding of the extent tDCS affects memory.

Effective management of pain is critical to the improvement of animal welfare. For this to happen, pain must be recognised and assessed in a variety of contexts. Pain is a complex phenomenon, making reliable, valid, and feasible measurement challenging. The use of facial expressions as a technique to assess pain in non-verbal human patients has been widely utilised for many years. More recently this technique has been developed for use in a number of non-human species: rodents, rabbits, ferrets, cats, sheep, pigs and horses. Facial expression scoring has been demonstrated to provide an effective means of identifying animal pain and in assessing its severity, overcoming some of the limitations of other measures for pain assessment in animals. However, there remain limitations and challenges to the use of facial expression as a welfare assessment tool which must be investigated. This paper reviews current facial expression pain scales (“Grimace Scales”), discussing the general conceptual and methodological issues faced when assessing pain, and highlighting the advantages of using facial expression scales over other pain assessment methods. We provide guidance on how facial expression scales should be developed so as to be valid and reliable, but we also provide guidance on how they should be used in clinical practice.

Lower-density Electroencephalography (EEG) recordings (from 1 to approximately 32 electrodes) are widely-used in research and clinical practice and enable scalable brain function measurement across a variety of settings and populations. Though a number of automated pipelines have recently been proposed to standardize and optimize EEG pre-processing for high-density systems with state-of-the-art methods, few solutions have emerged that are compatible with lower-density systems. However, lower-density data often include long recording times and/or large sample sizes that would benefit from similar standardization and automation with contemporary methods. To address this need, we propose the HAPPE In Low Electrode Electroencephalography (HAPPILEE) pipeline as a standardized, automated pipeline optimized for EEG recordings with lower density channel layouts of any size. HAPPILEE processes task-free (e.g., resting-state) and task-related EEG (including event-related potential data by interfacing with the HAPPE+ER pipeline), from raw files through a series of processing steps including filtering, line noise reduction, bad channel detection, artifact correction from continuous data, segmentation, and bad segment rejection that have all been optimized for lower density data. HAPPILEE also includes post-processing reports of data and pipeline quality metrics to facilitate the evaluation and reporting of data quality and processing-related changes to the data in a standardized manner. Here the HAPPILEE steps and their optimization with both recorded and simulated EEG data are described. HAPPILEE's performance is then compared relative to other artifact correction and rejection strategies. The HAPPILEE pipeline is freely available as part of HAPPE 2.0 software under the terms of the GNU General Public License at: https://github.com/PINE-Lab/HAPPE.

Low-density Electroencephalography (EEG) recordings (e.g. fewer than 32 electrodes) are widely-used in research and clinical practice and enable scalable brain function measurement across a variety of settings and populations. Though a number of automated pipelines have recently been proposed to standardize and optimize EEG preprocessing for high-density systems with state-of-the-art methods, few solutions have emerged that are compatible with low-density systems. However, low-density data often include long recording times and/or large sample sizes that would benefit from similar standardization and automation with contemporary methods. To address this need, we propose the HAPPE In Low Electrode Electroencephalography (HAPPILEE) pipeline as a standardized, automated pipeline optimized for EEG recordings with low density channel layouts of any size. HAPPILEE processes task-free (e.g. resting-state) and task-related EEG, and event-related potential (ERP) data, from raw files through a series of processing steps including filtering, line noise reduction, bad channel detection, artifact rejection from continuous data, segmentation, and bad segment rejection that have all been optimized for low density data. HAPPILEE also includes post-processing reports of data and pipeline quality metrics to facilitate the evaluation and reporting of data quality and processing-related changes to the data in a standardized manner. We describe multiple approaches with both recorded and simulated EEG data to optimize and validate pipeline performance. The HAPPILEE pipeline is freely available as part of HAPPE 2.0 software under the terms of the GNU General Public License at: https://github.com/PINE-Lab/HAPPE.

This mini-review article offers a commentary on a singular analytical problem faced by legal scholars who use complexity theory and methods in legal research on climate change and the “Anthropocene”. It positions such research as a subset of complexity scholarship in law, which is generally faced with the methodological and analytical challenge of negotiating and reconciling empirical description with normative prescription. It argues that this challenge is particularly acute for legal scholars writing on climate change and the Anthropocene. Using examples from scholars writing about “Earth systems law,” it demonstrates how a heavy reliance on complexity-based empirical data as a source material for normative claim-making can distract scholars from important but difficult questions about normative legitimacy and how legal change happens at multiple levels. The special epistemological challenges posed by climate change and the Anthropocene should demand that scholars writing in this domain be especially mindful and explicit on how they link complexity descriptions to the normative claims they make, both for the sake of scientific credibility as well as for the legitimacy and viability of their propositions.

When we treat an animal’s welfare as an individual experience, we should consider the possibility that it may be associated with individual differences in personality. We tested for such associations in 44 socially housed rhesus macaques (Macaca mulatta) that lived at the California National Primate Research Center. For each macaque, we obtained ratings on a 16-item welfare questionnaire, a 4-item subjective well-being questionnaire, and a 54-item personality questionnaire, the last of which we used to define each macaque’s standing on six personality domains---Confidence, Openness, Dominance, Friendliness, Activity, and Anxiety---identified in an earlier study. Finally, we used focal animal sampling to obtain measures of behavior. We found evidence for interrater agreement for all the welfare items, all but one item from the subjective well-being questionnaire, and all but four items from the personality questionnaire. Using principal components analysis, we found the welfare and subjective well-being survey items loaded together onto a single component. Macaques higher on this dimension received less aggression, engaged in fewer displacement activities (e.g., scratching), and were rated as higher in Confidence, Openness, Dominance, and Friendliness. These results are consistent with reports on chimpanzees and brown capuchin monkeys and constitute further evidence that observer ratings are based on observed behavioral states, suggesting them to be a psychometrically valid way to assess primate welfare.

Error monitoring allows individuals to monitor and adapt their behavior by detecting errors. Error monitoring is thought to develop throughout childhood and adolescence. However, most of this evidence comes from studies in late childhood and adolescence utilizing ERPs. The current study utilizes time-frequency (TF) and connectivity analyses to provide a comprehensive examination of age-related changes in error monitoring processes across early childhood (N=326; 50.9% females; 4-9 years). ERP analyses indicated the presence of the error-related negativity (ERN) and error positivity (Pe) across age. Results showed no error-specific age-related changes in the ERN and the Pe. However, TF analyses suggested error-related frontocentral responses in delta and theta signal strength (power), delta consistency (inter-trial phase synchrony), and delta synchrony (inter-channel phase synchrony) between frontrocentral and frontolateral clusters–all of which increased with age. Additionally, the current study examines the reliability and effect size estimates of the ERP and TF measures. For most measures, more trials were needed to achieve acceptable reliability than what is commonly used in the psychophysiological literature. Resources to facilitate the measurement and reporting of reliability are provided. Overall, findings highlight the utility of TF analyses and provide useful information for future studies examining the development of error monitoring.

The last decade has seen increased availability of mobile electroencephalography (EEG). These mobile systems enable researchers to conduct data collection “in-context,” reducing participant burden and potentially increasing diversity and representation of research samples. Our research team completed in-home data collection from more than 400 12-month-old infants from low-income backgrounds using a mobile EEG system. In this manuscript, we provide methodological and analytic guidance for collecting high-quality, mobile EEG in infants. Specifically, we offer insights and recommendations for equipment selection, data collection, and data analysis, highlighting important considerations for selecting a mobile EEG system. Examples include the size of the recording equipment, electrode type, reference types, and available montages. We also highlight important recommendations surrounding preparing a non-standardized recording environment for EEG collection, obtaining informed consent from parents, instructions for parents during capping and recording, stimuli and task design, training researchers, and monitoring data as it comes in. Additionally, we provide access to the analysis code and demonstrate the robustness of the data from a recent study using this approach, in which 20 artifact-free epochs achieve good internal consistency reliability. Finally, we provide recommendations and publicly available resources for future studies aiming to collect mobile EEG.

Despite the importance for both animal welfare and scientific integrity of effective welfare assessment in non-human primates, there has been little or no consensus as what should be assessed. A Delphi consultation process was undertaken to identify the animal- and environment-based measures of welfare for laboratory-housed macaques and to determine their relative importance in on-site welfare assessments. One-hundred fifteen potential indictors were identified through a comprehensive literature search, followed by a two-round iterative electronic survey process to collect expert opinion. Stable group response and consensus about the validity, reliability, and feasibility of the proposed indicators (67.5% agreement) was achieved by the completion of Round Two. A substantially higher proportion of environment-based measures (72%: n = 44/61) were considered as valid, reliable, and feasible compared to the animal-based measures (22%: n = 12/54). The indicators that ranked most highly for assessing welfare were the presence of self-harm behaviours and the provision of social enrichment. This study provides an empirical basis upon which these indicators can be validated and then integrated into assessment tools developed for macaques and emphasises the need to include both animal- and environment-based indicators for accurate welfare monitoring.

Due to the natural selection pressure, certain aspects of memory may have been selected to give humans a survival advantage. Research has demonstrated that processing information for survival relevance leads to better item memory (i.e., the content of information) compared to control conditions. The current study investigates the effects of survival processing on context memory (i.e., memory for peripheral episodic details) and item memory to better understand when the survival processing memory advantage emerges. In this study, participants studied pictures of objects in either a survival or moving (control) condition. Objects were presented in either a plausible color, for example, a red apple, or in an implausible color, such as a green pie. We chose this color plausibility manipulation because color is a detail that conveys information about the fitness (and other diagnostic information) about an item. After studying items, participants made item memory judgments (did you see this item before?) and two context memory judgments: color context (in which color did you see this item?) and source context (in which condition did you see this item?). Results indicated better item memory for materials processed in the survival relative to moving condition. Critically, for color context, there was a condition by plausibility interaction, where memory was best for plausibly colored items in the survival processing condition. There was no difference, however, in source context memory between the survival and moving conditions. These results suggest the survival processing memory advantage extends to contextual details that particularly reflect the survival utility of items such as color.

Whether and to what extent animals experience emotions is crucial for understanding their decisions and behaviour, and underpins a range of scientific fields, including animal behaviour, neuroscience, evolutionary biology and animal welfare science. However, research has predominantly focused on alleviating negative emotions in animals, with the expression of positive emotions left largely unexplored. Therefore, little is known about positive emotions in animals and how their expression is mediated. We used tail handling to induce a negative mood in laboratory mice and found that while being more anxious and depressed increased their expression of a discrete negative emotion (disappointment), meaning that they were less resilient to negative events, their capacity to express a discrete positive emotion (elation) was unaffected relative to control mice. Therefore, we show not only that mice have discrete positive emotions, but that they do so regardless of their current mood state. Our findings are the first to suggest that the expression of discrete positive and negative emotions in animals is not equally affected by long-term mood state. Our results also demonstrate that repeated negative events can have a cumulative effect to reduce resilience in laboratory animals, which has significant implications for animal welfare.

The generation effect is the memory benefit for information that is self-generated compared to read. This effect is robust for both younger and older adults. Recent work with younger adults has shown that the generation effect for context memory (i.e., contextual details associated with an episode) can be increased when there are fewer rather than greater experimental constraints placed on what participants can generate. This increase in context memory is attributable to enhanced relational processing. Given older adults’ deficits in context memory the present study tested whether fewer generation constraints would similarly improve the generation effect for contextual details in older adults. In this study, we examined age differences in item and context (i.e., source and associative) memory across three different tasks comprising the encoding of cue-target pairs: a lower-constraint generation task (i.e., free response to cue, such as assist – ____), a higher-constraint generation task (i.e., solving an anagram, such as assist – hlpe), and a read task (i.e., simply reading the cue-target pair, such as assist – help). Both age groups showed improved item and context memory for materials studied during the generation tasks (both lower- and higher-constraint) compared to the read task. However, only younger adults showed increased source memory for lower-constraint compared to higher-constraint generation, whereas older adults showed equivalent source and associative memory for both lower- and higher-constraint generation tasks. These findings suggest both age groups benefit from self-generation, but older adults may benefit less from conditions that enhance relational processing (lower-constraint generation) in younger adults.

Background: Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods: We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Results: Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P =0.3), equally likely to be female (44% versus 48%, P =0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P =0.0004), prior antiarrhythmic drug use (52% versus 40%, P =0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P =0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P =0.003; cardioversion: 12.2% versus 5.9%, P =0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P =0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P =0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve ( P Conclusions: In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Dysregulation of biological rhythms plays a role in a wide range of psychiatric disorders. We report mechanistic insights into the rhythms of rapid dopamine signals and cholinergic interneurons (CINs) working in concert in the rodent striatum. These rhythms mediate diurnal variation in conditioned responses to reward-associated cues. We report that the dopamine signal-to-noise ratio varies according to the time of day and that phasic signals are magnified during the middle of the dark cycle in rats. We show that CINs provide the mechanism for diurnal variation in rapid dopamine signals by serving as a gain of function to the dopamine signal-to-noise ratio that adjusts across time of day. We also show that conditioned responses to reward-associated cues exhibit diurnal rhythms, with cue-directed behaviors observed exclusively midway through the dark cycle. We conclude that the rapid dopamine signaling rhythm is mediated by a diurnal rhythm in CIN activity, which influences learning and motivated behaviors across the time of day.

Words that can be used as both noun and verb create regions of syntactic ambiguity that could create processing challenges for listeners. However, acoustic properties, such as duration, differ between noun and verb uses of such words [1–4], and listeners may use these differences to facilitate ambiguity processing. In this study, we replaced noun uses of ambiguous words with verb uses to determine whether these manipulations affected the N400 event related potential (ERP), which is associated with semantic violations, or the P600 component, which is associated with syntactic ambiguity. The results suggest that the acoustic differences between noun/verb polysemes mitigate the extent to which these words are perceived as ambiguous, although the results do not indicate whether replacing one with the other produces a meaning violation. Durational differences in noun/verb polysemes may affect their processing in fluent speech.

Montane birds face significant threats from a warming climate, so determining the environmental factors that most strongly influence the composition of such assemblages is of critical conservation importance. Changes in temperature and other environmental conditions along elevational gradients are known to influence the species richness and abundance of bird assemblages occupying mountains. However, the role of species‐specific traits in mediating the responses of bird species to changing conditions remains poorly understood. We aimed to determine whether different bird species responded differently to changing environmental conditions in a relatively understudied biodiversity hotspot in subtropical rainforest on the east coast of Australia. We examined patterns in avian species richness and abundance along two rainforest elevational gradients using monthly point counts between September 2015 and October 2016. Environmental data on temperature, wetness, canopy cover and canopy height were collected simultaneously, and trait information on body size and feeding guild membership for each bird species was obtained from the Handbook of Australian, New Zealand and Antarctic Birds. We used a generalized linear mixed modelling (GLMM) framework to determine the drivers of species richness and abundance and to quantify species’ trait–environment interactions. GLMMs indicated that temperature alone was significantly positively correlated with species richness and abundance. Species richness declined with increasing elevation. When modelling abundance, we found that feeding guild membership did not significantly affect species’ responses to environmental conditions. In contrast, the predicted abundance of a species was found to depend on its body size, due to significant positive interactions between this trait, temperature and canopy cover. Our findings indicate that large‐bodied birds are likely to increase in abundance more rapidly than small‐bodied birds with continued climatic warming. These results underline the importance of temperature as a driving factor of avian community assembly along environmental gradients.

Objectives Older adults experience associative memory deficits relative to younger adults (Old & Naveh-Benjamin, 2008). The aim of this study was to test the effect of transcranial direct current stimulation (tDCS) on face-name associative memory in older and younger adults. Method Experimenters applied active (1.5 mA) or sham (0.1 mA) stimulation with the anode placed over the left dorsolateral prefrontal cortex (dlPFC) during a face-name encoding task, and measured both cued recall and recognition performance. Participants completed memory tests immediately after stimulation and after a 24-h delay to examine both immediate and delayed stimulation effects on memory. Results Results showed improved face-name associative memory performance for both recall and recognition measures, but only for younger adults, whereas there was no difference between active and sham stimulation for older adults. For younger adults, stimulation-induced memory improvements persisted after a 24-h delay, suggesting delayed effects of tDCS after a consolidation period. Discussion Although effective in younger adults, these results suggest that older adults may be resistant to this intervention, at least under the stimulation parameters used in the current study. This finding is inconsistent with a commonly seen trend, where tDCS effects on cognition are larger in older than younger adults.

Climate change is likely to negatively impact populations of rainforest birds along Australia’s eastern seaboard. To this end, accurate estimations of species’ current population sizes are necessary for future monitoring and conservation. Here, we used distance sampling protocols to generate abundance and density estimates for 11 species of birds occupying the Gondwanan rainforests of the Tweed Caldera on the Queensland–New South Wales border. Data were collected along two elevational gradients in subtropical rainforest between September 2015 and October 2016. Half-normal functions with cosine adjustments were used to calculate the density of each species per km 2 . We used a GIS to determine the total area of suitable habitat available in protected areas adjacent to the sampling locations (~425 km 2 ) and then extrapolated the density estimates to generate estimates of population size for each target species in the study area. Estimated population sizes ranged from 473 719 (Yellow-throated Scrubwren Sericornis citreogularis ) to 21 841 (White-throated Treecreeper Cormobates leucophaea ). The standard error (SE) associated with the population estimate of the White-throated Treecreeper was large, as was the SE associated with the Eastern Yellow Robin Eopsaltria australis (estimated population 235 084), Green Catbird Ailuroedus crassirostris (69 731) and Grey Fantail Rhipidura fuliginosa (124 534). Accurate abundance estimates (SE

Prior work demonstrates that application of transcranial direct current stimulation (tDCS) improves memory. In this study, we investigated tDCS effects on face-name associative memory using both recall and recognition tests. Participants encoded face-name pairs under either active (1.5mA) or sham (.1mA) stimulation applied to the scalp adjacent to the left dorsolateral prefrontal cortex (dlPFC), an area known to support associative memory. Participants' memory was then tested after study (day one) and then again after a 24-h delay (day two), to assess both immediate and delayed stimulation effects on memory. Results indicated that active relative to sham stimulation led to substantially improved recall (more than 50%) at both day one and day two. Recognition memory performance did not differ between stimulation groups at either time point. These results suggest that stimulation at encoding improves memory performance by enhancing memory for details that enable a rich recollective experience, but that these improvements are evident only under some testing conditions, especially those that rely on recollection. Overall, stimulation of the dlPFC could have led to recall improvement through enhanced encoding from stimulation or from carryover effects of stimulation that influenced retrieval processes, or both.

Facilities housing captive animals are full of staff who, every day, interact with the animals under their care. The expertise and familiarity of staff can be used to monitor animal welfare by means of questionnaires. It was the goal of our study to examine the association between chimpanzee (Pan troglodytes) welfare, happiness, and personality. To these ends we collected two waves of welfare and subjective well-being ratings of 18 chimpanzees housed at the Edinburgh Zoo and one set of ratings of 13 chimpanzees housed at Fundació Mona. Ratings were made on a welfare questionnaire that included 12 items related to stress, psychological stimulation, and behavioural indicators of negative and positive welfare states, and a 4-item subjective well-being questionnaire. In addition, ratings were made on the 54-item Hominoid Personality Questionnaire and an abbreviated version of this scale consisting of 37 antonym pairs. We used generalizability theory to test whether welfare ratings generalized across items, raters, chimpanzees, and time. We then assessed the validity of the welfare and subjective well-being questionnaires by examining their associations with behaviour. Finally, we tested whether the welfare and subjective well-being ratings were associated with personality. Welfare ratings generalized across items, raters, chimpanzees, and time. Principal components analysis and regularized exploratory factor analysis indicated that ten welfare items and all four subjective well-being items formed a single dimension (welfareSWB). LASSO regression found that lower welfareSWB was associated with regurgitation, coprophagy, urophagy, and decreased proximity to nearest neighbour. A linear model that adjusted for age, sex, and facility, indicated that higher Extraversion and lower Neuroticism were related to higher welfareSWB. Welfare ratings were reliable and associated with subjective well-being and personality, demonstrating that staff ratings are a valid and potentially valuable tool for chimpanzee welfare assessment.

Without the ability to effectively recognise pain and assess its severity in animals, there is no way of assessing the efficacy of analgesia administered. Therefore, we have no way of ensuring that pain is adequately managed. Despite the extensive use of rodents in medical research that often involves the assessment of pain and distress, translation of this knowledge to veterinary medicine has been relatively neglected, and original veterinary research in pain assessment in rodents is lacking. This article aims to provide a broad overview of common behaviours that could be used to assess pain in rodents.

Even though the fatality rate from skin cancers is low, evidence from a few cohort studies has raised the possibility that people with a personal history of skin cancer may have a higher all-cause mortality rate compared with those without a personal history of skin cancer. The purpose of the present study was to investigate the potential links between a personal history or family history of skin cancer and all-cause and cancer-specific mortality METHODS: A prospective cohort (n = 8,622) was assembled within the NHANES I follow-up study. Cox Proportional Hazard Regression analysis was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association for personal and family history of skin cancer and all-cause and cancer-specific mortality.After adjustment for several potential confounding variables, a personal history of skin cancer was associated with decreased risk for all-cause mortality (HR 0.72, 95% CI 0.61-0.85), whereas the results for cancer-specific mortality were consistent with a null association (HR 0.97, 95% CI 0.74-1.27). A family history of skin cancer was not significantly associated with all-cause mortality (HR 0.97, 95% CI 0.76-1.24) or cancer-specific mortality (HR 0.69, 95% CI 0.38-1.24).The results of the present study do not support the hypothesis that a personal history or family history of skin cancer is associated with an increased risk of all-cause or cancer-specific mortality. The high prevalence of skin cancer adds to the public health significance of this question, providing a strong rationale for further research to resolve this question.

Compared to adult EEG, EEG signals recorded from pediatric populations have shorter recording periods and contain more artifact contamination. Therefore, pediatric EEG data necessitate specific preprocessing approaches in order to remove environmental noise and physiological artifacts without losing large amounts of data. However, there is presently a scarcity of standard automated preprocessing pipelines suitable for pediatric EEG.In an effort to achieve greater standardization of EEG preprocessing, and in particular for the analysis of pediatric data, we developed the Maryland Analysis of Developmental EEG (MADE) pipeline as an automated preprocessing pipeline compatible with EEG data recorded with different hardware systems, different populations, levels of artifact contamination, and length of recordings. MADE uses EEGLAB and functions from some EEGLAB plugins, and includes additional customizable features particularly useful for EEG data collected from pediatric populations.MADE processes event-related and resting state EEG from raw data files through a series of preprocessing steps and outputs processed clean data ready to be analyzed in time, frequency, or time-frequency domain. MADE provides a report file at the end of the preprocessing that describes a variety of features of the processed data to facilitate the assessment of the quality of processed data. In this paper we discuss some practical issues, which are specifically relevant to pediatric EEG preprocessing. We also provide custom-written scripts to address these practical issues.MADE is freely available under the terms of the GNU General Public License at https://github.com/ChildDevLab/MADE-EEG-preprocessing-pipeline.

To determine whether participation in dog agility has an impact on canine arousal and welfare, this study aimed firstly to identify the effect of the competition context on arousal changes experienced by dogs, as distinct from purely physical participation in agility, and secondly to assess the handlers' ability to recognize this. Behaviors indicative of changes in arousal were recorded for twenty dogs immediately before completion of both a competition and a training run, whilst the accuracy of handlers' observations of their dogs' behavior was examined via questionnaire. Whilst a moderate number of behaviors presented with greater frequency or duration in competition, the total number of different arousal behaviors performed was higher for dogs in competition (

Background Failure to perform Mohs micrographic surgery (MMS) meticulously on the nose and lips can lead to larger defects and tumor recurrence, which can have aesthetic and functional repercussions for patients. Objective To review pre-, intra-, and postoperative techniques and pearls for performing MMS on the nose and lips to optimize outcomes. Materials and methods Technical nuances and pearls cultured from the authors' own practice, those acquired from mentors and colleagues, and information identified from the literature are discussed to provide a logical approach to performing effective MMS on the nose and lips. Results When performing MMS on the nose and lips, sound preoperative preparation, precise surgical technique, and particular attention to reducing false-positives and false-negatives while harvesting Mohs layers enhances the fidelity of the MMS procedure, minimizing defect sizes and reducing tumor recurrence. Conclusion Refining Mohs technique on the nose and lips allows more effective performance of tumor extirpation, improved microscopic evaluation, and more conservative reconstruction, leading to better patient outcomes.

A major challenge for electroencephalograph (EEG) studies on pediatric populations is that large amounts of data are lost due to artifacts (e.g., movement and blinks). Independent component analysis (ICA) can separate artifactual and neural activity, allowing researchers to remove such artifactual activity and retain a greater percentage of EEG data for analyses. However, manual identification of artifactual components is time-consuming and requires subjective judgment. Automated algorithms, like ADJUST and ICLabel, have been validated on adults, but to our knowledge, no such algorithms have been optimized for pediatric data. Therefore, in an attempt to automate artifact selection for pediatric data collected with geodesic nets, we modified ADJUST's algorithm. Our "adjusted-ADJUST" algorithm was compared to the "original-ADJUST" algorithm and ICLabel in adults, children, and infants on three different performance measures: respective classification agreement with expert coders, the number of trials retained following artifact removal, and the reliability of the EEG signal after preprocessing with each algorithm. Overall, the adjusted-ADJUST algorithm performed better than the original-ADJUST algorithm and no ICA correction with adult and pediatric data. Moreover, in some measures, it performed better than ICLabel for pediatric data. These results indicate that optimizing existing algorithms improves artifact classification and retains more trials, potentially facilitating EEG studies with pediatric populations. Adjusted-ADJUST is freely available under the terms of the GNU General Public License at: https://github.com/ChildDevLab/MADE-EEG-preprocessing-pipeline/tree/master/adjusted_adjust_scripts.

This study aims to identify the most valid, reliable and practicable indicators of laboratory mouse welfare using the Delphi consultation technique. The effective assessment of laboratory mouse welfare is a fundamental legal and moral requirement as it is critical part of both maintaining and improving the welfare of the most widely used laboratory animal globally. Although many different welfare indicators are routinely used to assess mouse welfare, the validity, reliability and practicability of many of these measures remains unclear. The Delphi consultation technique is designed to gauge expert opinion through multiple rounds of surveys until a consensus is reached. Participants ranked 59 welfare indicators in terms their validity, reliability and practicability for either a half-day unit audit or a daily welfare assessment and for each scenario identified 10 key indicators. The Delphi consultation reached consensus at 72% for the overall list of indicators and over 60% for each individual indicator. From this consensus the key indicators for each mouse welfare scenario (half day audit and daily welfare assessment) were identified and used to create a welfare scoring system for each scenario.

Background Opioid overprescribing is a major contributor to the opioid crisis. The lack of procedure-specific guidelines contributes to the vast differences in prescribing practices. Objective Create opioid-prescribing consensus guidelines for common dermatologic procedures. Methods We utilized a four-step modified Delphi method to conduct a systematic discussion among a panel of providers in the fields of general dermatology, dermatologic surgery, and cosmetics/phlebology to develop opioid-prescribing guidelines for some of the most common dermatologic procedural scenarios. Guidelines were developed for opioid-naive patients undergoing routine procedures. Opioid tablets were defined as oxycodone 5-mg oral equivalents. Results Postoperative pain after most uncomplicated procedures (76%) can be adequately managed with acetaminophen and/or ibuprofen. Group consensus identified no specific dermatological scenario that routinely requires more than 15 oxycodone 5-mg oral equivalents to manage postoperative pain. Group consensus found that 23 percent of the procedural scenarios routinely require 1-10 opioid tablets, while only one routinely requires 1-15 opioid tablets. Limitations These recommendations are based on expert consensus in lieu of quality evidence-based outcomes research. These recommendations must be individualized to accommodate patients’ comorbidities. Conclusions Procedure-specific opioid-prescribing guidelines may serve as a foundation to produce effective and responsible postoperative pain management strategies after dermatologic interventions.