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BACKGROUND: Unsupervised online cognitive assessments have demonstrated promise as an efficient and scalable approach for evaluating cognition in aging, and Alzheimers disease and related dementias. OBJECTIVES: The aim of this study was to evaluate the feasibility, usability, and construct validity of the Paired Associates Learning task from the Cambridge Neuropsychological Test Automated Battery® in adults enrolled in the Brain Health Registry. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: The Paired Associates Learning task was administered to Brain Health Registry participants in a remote, unsupervised, online setting. In this cross-sectional analysis, we 1) evaluated construct validity by analyzing associations between Paired Associates Learning performance and additional participant registry data, including demographics, self- and study partner-reported subjective cognitive change (Everyday Cognition scale), self-reported memory concern, and depressive symptom severity (Patient Health Questionnaire-9) using multivariable linear regression models; 2) determined the predictive value of Paired Associates Learning and other registry variables for identifying participants who self-report Mild Cognitive Impairment by employing multivariable binomial logistic regressions and calculating the area under the receiver operator curve; 3) investigated feasibility by looking at task completion rates and statistically comparing characteristics of task completers and non-completers; and 4) evaluated usability in terms of participant requests for support from BHR related to the assessment. RESULTS: In terms of construct validity, in participants who took the Paired Associates Learning for the first time (N=14,528), worse performance was associated with being older, being male, lower educational attainment, higher levels of self- and study partner-reported decline, more self-reported memory concerns, greater depressive symptom severity, and self-report of Mild Cognitive Impairment. Paired Associates Learning performance and Brain Health Registry variables together identified those with self-reported Mild Cognitive Impairment with moderate accuracy (areas under the curve: 0.66-0.68). In terms of feasibility, in a sub-sample of 29,176 participants who had the opportunity to complete Paired Associates Learning for the first time in the registry, 14,417 started the task. 11,647 (80.9% of those who started) completed the task. Compared to those who did not complete the task at their first opportunity, those who completed were older, had more years of education, more likely to self-identify as White, less likely to self-identify as Latino, less likely to have a subjective memory concern, and more likely to report a family history of Alzheimers disease. In terms of usability, out of 8,395 received requests for support from BHR staff via email, 4.4% (n=374) were related to PAL. Of those, 82% were related to technical difficulties. CONCLUSIONS: Our findings support moderate feasibility, good usability, and construct validity of cross-sectional Paired Associates Learning in an unsupervised online registry, but also highlight the need to make the assessment more inclusive and accessible to individuals from ethnoculturally and socioeconomically diverse communities. A future, improved version could be a scalable, efficient method to assess cognition in many different settings, including clinical trials, observational studies, healthcare, and public health.

Abstract The Simcyp Simulator is a software platform widely used in the pharmaceutical industry to conduct stochastic physiologically‐based pharmacokinetic (PBPK) modeling. This approach has the advantage of combining routinely generated in vitro data on drugs and drug products with knowledge of biology and physiology parameters to predict a priori potential pharmacokinetic changes in absorption, distribution, metabolism, and excretion for populations of interest. Combining such information with pharmacodynamic knowledge of drugs enables planning for potential dosage adjustment when clinical studies are feasible. Although the conduct of dedicated clinical studies in some patient groups (e.g., with hepatic or renal diseases) is part of the regulatory path for drug development, clinical studies for all permutations of covariates potentially affecting pharmacokinetics are impossible to perform. The role of PBPK in filling the latter gap is becoming more appreciated. This tutorial describes the different input parameters required for the creation of a virtual population giving robust predictions of likely changes in pharmacokinetics. It also highlights the considerations needed to qualify the models for such contexts of use. Two case studies showing the step‐by‐step development and application of population files for obese or morbidly obese patients and individuals with Crohn's disease are provided as the backbone of our tutorial to give some hands‐on and real‐world examples.

During dissertation writing, PhD candidates face challenges engaging with academic writing, among other things, which leads to their participation in writing retreats with their peers. Developing a better understanding of PhD candidates' needs to optimize engagement with writing is important for improving the overall doctoral experience and reduce attrition. We then conducted a qualitative longitudinal experimental study with PhD candidates from Canadian universities: 15 respondents who participated in a writing retreat and 15 respondents who never participated in such event. Based on our findings, this article presents a complementary perspective to the theoretical model of engagement with writing by Murray (2015). Thereon, we expand on the intersectionality of components (cognitive, physical, social) to illustrate the influence of structured writing activities. These intersections highlight the benefits of writing retreats to answer the needs of PhD candidates to engage with writing: planning dedicated writing periods, implementing effective work methods in environments enabling concentration, and engaging with collective writing activities. By way of supplementing the most recent literature on the subject, we suggest that the participation in structured writing retreats serves as a pedagogical benchmark for graduate programs to offer students comparable conditions in support of their writing requirements to enhance academic success.

Over the past twenty years, graduate studies have seen significant growth, with student numbers more than doubling worldwide. Unfortunately, the Organization for Economic Co-operation and Development continues to report dropout rates averaging 50% for PhD and 40% for master's programs, in all disciplines combined. Among the reasons quoted for abandoning study programs are deficient academic writing competencies that could not only hinder how graduate students progress through their academic journey, but also how they integrate with the scientific community as novice scholars. Accordingly, this article will present an overview of studies related to academic writing groups, which have been identified as one of the strategies to benefit graduate studies. Based on a systematic literature review, we present a chronological account of key issues and concepts that have influenced the phenomenon throughout history. Thereafter, we explain the various characteristics of academic writing groups in order to delineate this phenomenon through the description of its inherent elements and propose an all-encompassing definition. The analysis of 72 documentary sources also allows the observation of trends through the examination of geographical, disciplinary, and methodological factors drawn from scholarly publications. Finally, we highlight considerations for future exploration of academic writing groups used as a pedagogical strategy in the context of higher education, from disciplinary, sociocultural, and gender perspectives.

IntroductionNormative cognitive data can distinguish impairment from healthy cognitive function and pathological decline from normal ageing. Traditional methods for deriving normative data typically require extremely large samples of healthy participants, stratifying test variation by pre-specified age groups and key demographic features (age, sex, education). Linear regression approaches can provide normative data from more sparsely sampled datasets, but non-normal distributions of many cognitive test results may lead to violation of model assumptions, limiting generalisability.MethodThe current study proposes a novel Bayesian framework for normative data generation. Participants (n = 728; 368 male and 360 female, age 18–75 years), completed the Cambridge Neuropsychological Test Automated Battery via the research crowdsourcing website Prolific.ac. Participants completed tests of visuospatial recognition memory (Spatial Working Memory test), visual episodic memory (Paired Associate Learning test) and sustained attention (Rapid Visual Information Processing test). Test outcomes were modelled as a function of age using Bayesian Generalised Linear Models, which were able to derive posterior distributions of the authentic data, drawing from a wide family of distributions. Markov Chain Monte Carlo algorithms generated a large synthetic dataset from posterior distributions for each outcome measure, capturing normative distributions of cognition as a function of age, sex and education.ResultsComparison with stratified and linear regression methods showed converging results, with the Bayesian approach producing similar age, sex and education trends in the data, and similar categorisation of individual performance levels.ConclusionThis study documents a novel, reproducible and robust method for describing normative cognitive performance with ageing using a large dataset.

Abstract The concept of agonist-independent signalling that can be attenuated by inverse agonists is a fundamental element of the cubic ternary complex model of G protein-coupled receptor (GPCR) activation. This model shows how a GPCR can exist in two conformational states in the absence of ligands; an inactive R state and an active R* state that differ in their affinities for agonists, inverse agonists, and G-protein alpha subunits. The proportion of R* receptors that exist in the absence of agonists determines the level of constitutive receptor activity. In this study we demonstrate that mechanical stimulation can induce β2-adrenoceptor agonist-independent Gs-mediated cAMP signalling that is sensitive to inhibition by inverse agonists such as ICI-118551 and propranolol. The size of the mechano-sensitive response is dependent on the cell surface receptor expression level in HEK293G cells, is still observed in a ligand-binding deficient D113A mutant β2-adrenoceptor and can be attenuated by site-directed mutagenesis of the extracellular N-glycosylation sites on the N-terminus and second extracellular loop of the β2-adrenoceptor. Similar mechano-sensitive agonist-independent responses are observed in HEK293G cells overexpressing the A2A-adenosine receptor. These data provide new insights into how agonist-independent constitutive receptor activity can be enhanced by mechanical stimulation and regulated by inverse agonists.

Abstract Background Low-pass whole-genome sequencing and imputation offer significant cost savings, enabling substantial increases in sample size and statistical power. This approach is particularly promising in livestock breeding, providing an affordable means of screening individuals for deleterious alleles or calculating genomic breeding values. Consequently, it may also be of value in companion animal genomics to support pedigree breeding. We sought to evaluate in dogs the impact of low coverage sequencing and reference-guided imputation on genotype concordance and association analyses. Results DNA isolated from saliva of 30 Labrador retrievers was sequenced at low (0.9X and 3.8X) and high (43.5X) coverage, and down-sampled from 43.5X to 9.6X and 17.4X. Genotype imputation was performed using a diverse reference panel (1021 dogs), and two subsets of the former panel (256 dogs each) where one had an excess of Labrador retrievers relative to other breeds. We observed little difference in imputed genotype concordance between reference panels. Association analyses for a locus acting as a disease proxy were performed using single-marker (GEMMA) and haplotype-based (XP-EHH) tests. GEMMA results were highly correlated (r ≥ 0.97) between 43.5X and ≥ 3.8X depths of coverage, while for 0.9X the correlation was lower (r ≤ 0.8). XP-EHH results were less well correlated, with r ranging from 0.58 (0.9X) to 0.88 (17.4X). Across a random sample of 10,000 genomic regions averaging 17 kb in size, we observed a median of three haplotypes per dog across the sequencing depths, with 5% of the regions returning more than eight haplotypes. Inspection of one such region revealed genotype and phasing inconsistencies across sequencing depths. Conclusions We demonstrate that saliva-derived canine DNA is suitable for whole-genome sequencing, highlighting the feasibility of client-based sampling. Low-pass sequencing and imputation require caution as incorrect allele assignments result when the subject possesses alleles that are absent in the reference panel. Larger panels have the capacity for greater allelic diversity, which should reduce the potential for imputation error. Although low-pass sequencing can accurately impute allele dosage, we highlight issues with phasing accuracy that impact haplotype-based analyses. Consequently, if accurately phased genotypes are required for analyses, we advocate sequencing at high depth (> 20X).

Flooding of communities is becoming a repeated, widespread issue within the UK, and elsewhere. Small businesses are a crucial part of the UK economy; the UK Summer 2007 flood resulted in flooding of 7,000 businesses and monetary loss to local economies. There has, however, been limited research on how small businesses learn to adapt to increase their resilience. This paper shares interdisciplinary research that has developed an innovative coproduction process to engage small businesses and the stakeholders that support them in resilience building, in partnership working to develop a prototype e-learning tool to promote longer-term adaptation to flooding amongst small businesses. The research focus here is on both the processes of the co-production and their influence on the outcome - the prototype e-learning tool. The co-production processes combined workshops, virtual engagement and co-creation of learning resources that captured business knowledge and learning on flood adaptation. Data were captured through: independent observation, audio/visual recording, transcription of discussions, and the participatory production of graphic outputs. Our approach reflects current ethics and practices of stakeholder participation within research so that other equally valid forms of knowledge are recognised and drawn on. The e-learning tool is designed as a living resource to support development of a community of learning practice among small businesses to increase resilience to increased flood risk.

To overcome the assumption that dissertation writing is an anxiety-provoking process, this multi-phase mixed-method research aimed to develop a comprehensive picture of writing enjoyment in the context of doctoral studies, as well as to understand if and how writing in the company of others can enhance dissertation writing enjoyment. Firstly, we interviewed 30 PhD students to conceptualize writing enjoyment. These qualitative results revealed that dissertation writing enjoyment represents a moment of clarity when doctoral students' ideas are easily extracted from the mind to be written as a tangible text perceived to be of high quality. Then, based on a pre-experimental design, a T-test was used to compare the scores of writing enjoyment and sense of writing community for two equivalent groups in terms of sociodemographic and academic profiles: 59 PhD students participating in writing retreats (experimental group) and 59 PhD students writing alone (control group). Overall, the experimental group shows higher writing enjoyment. Lastly, 15 PhD students participating in writing retreats were interviewed to understand how writing in the company of others seems to enhance writing enjoyment, that is, by way of social flow. Finally, this article provides empirical evidence for reforming pedagogical practices to foster PhD students' positive emotions.

Technicians and technical staff are making increasingly significant contributions to the teaching and learning of undergraduate and postgraduate students in the UK. This paper reports on a survey of 1766 technical staff regarding their roles within teaching and learning environments, and a series of follow-up focus groups with 44 technical staff further exploring the roles, visibility, and recognition of technical staff. Analysis suggests many technicians' roles have transitioned to such an extent that traditional lines between academic and technical teaching responsibilities, expertise, and contributions are becoming increasingly blurred. This trend is particularly noticeable for disciplines within creative arts but is also found in other discipline areas. This is likely accelerated by a competitive higher education environment and global graduate job market which incentivise skills-based learning and graduate employability, with a general transition towards increased value of 'know-how' as well as 'know-what'. Although this can greatly enhance students' skills-based learning at the hands of experienced practitioners, there is a danger that under-valued 'cheap labour' could be used to replace under-resourced academic teaching communities, or that technical staff find expansion of their teaching responsibilities are not being matched with adjustments in value, recognition, or reward. Specific examples are explored, and the impact of COVID-19 related disruption is further used to highlight these overall themes. The authors advocate for common understanding and recognition of teaching roles throughout the higher education sector, regardless of job family.

PhD candidates face heavy workloads and lack strategies to prioritize their dissertation, resulting in limited writing opportunities and low confidence in writing capabilities. Although writing retreats are known to propel academics' writing productivity, little is known about how they may assist PhD candidates in enhancing writing self-efficacy and self-regulation. An Explanatory Sequential Mixed Method with a quasi-experimental design was used to examine the impacts of writing retreats on PhD candidates' internal factors (writing self-efficacy and self-regulation) and external factors (urgency and opportunities to write). An experimental group (n = 34) and a control group (n = 64) answered a questionnaire measuring retreat effects, after which a subsample (n = 30) was interviewed to further interpret these effects. In sum, writing retreats enhance PhD candidates' writing self-efficacy and self-regulation through goals setting and time management practices. Recommendations are provided about using socially structured writing activities to support PhD candidates' dissertation advancement.

Abstract Objectives Although antiretroviral therapy (ART) efficiently suppresses HIV viral load, immune dysregulation and dysfunction persist in people living with HIV (PLWH). γδ T cells are functionally impaired during untreated HIV infection, but the extent to which they are reconstituted upon ART is currently unclear. Methods Utilising a cohort of ART‐treated PLWH, we assessed the frequency and phenotype, characterised in vitro functional responses and defined the impact of immune checkpoint marker expression on effector functions of both Vδ1 and Vδ2 T cells. We additionally explore the in vitro expansion of Vδ2 T cells from PLWH on ART and the mechanisms by which such expanded cells may sense and kill HIV‐infected targets. Results A matured NK cell‐like phenotype was observed for Vδ1 T cells among 25 ART‐treated individuals (PLWH/ART) studied compared to 17 HIV‐uninfected controls, with heightened expression of 2B4, CD160, TIGIT and Tim‐3. Despite persistent phenotypic perturbations, Vδ1 T cells from PLWH/ART exhibited strong CD16‐mediated activation and degranulation, which were suppressed upon Tim‐3 and TIGIT crosslinking. Vδ2 T cell degranulation responses to the phosphoantigen (E)‐4‐hydroxy‐3‐methyl‐but‐2‐enyl pyrophosphate at concentrations up to 2 ng mL−1 were significantly impaired in an immune checkpoint‐independent manner among ART‐treated participants. Nonetheless, expanded Vδ2 T cells from PLWH/ART retained potent anti‐HIV effector functions, with the NKG2D receptor contributing substantially to the elimination of infected cells. Conclusion Our findings highlight that although significant perturbations remain within the γδ T cell compartment throughout ART‐treated HIV, both subsets retain the capacity for robust anti‐HIV effector functions.

The graphic design industry has moved beyond its traditional focus on printed matter to deliver multidimensional communication projects involving diverse audiences and media channels. No longer a skills and service industry, graphic design increasingly informs business strategy and innovation processes, requiring heterogeneous expertise, a rigorous design process and the ability to work in multidisciplinary teams. This shift raises the question of the relevance of a traditional design portfolio in demonstrating employability, especially when employers prioritise generic over disciplinary and technical skills. Our article reports the results of a survey of 53 Australian employers of graphic design graduates on the role of the portfolio in evidencing design-specific and more general employability skills, capacities and attributes. The article provides a deeper understanding of the role of a portfolio in the transition to work. We argue that graphic design graduates need 'portfolio literacy'--which combines insight in the curation of the portfolio and its use in interview performance--to demonstrate both core graphic design and creative skills and capacities in communication, collaboration and problem-solving. This significant know-how is best developed during graduates' tertiary studies.