Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in New England Seals, United States.

We report the spillover of highly pathogenic avian influenza A(H5N1) into marine mammals in the northeastern United States, coincident with H5N1 in sympatric wild birds. Our data indicate monitoring both wild coastal birds and marine mammals will be critical to determine pandemic potential of influenza A viruses.

Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective.

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.

Putting Youth in Charge: Exploring a Multi-Year Interagency Community Engagement Experiential Programme for Youth with Disabilities and Their Families.

This paper outlines a qualitative exploration of the experiences of Youth in Charge (YiC), a 3-year pilot programme. YiC was designed to promote early, immersive community participation for students with physical disabilities, and was co-developed/co-hosted by three agencies (hospital, community rehabilitation, school board). To better understand the experiences of the youth, parents, and staff involved in this broad intervention, observation of 10 programme sessions and annual semi-structured interviews with youth (n = 5), parents (n = 4) and staff (n = 6) were undertaken. Qualitative results comprise six themes based in the two major thematic areas of participation-related experiences and programme considerations. Results indicate the need for community-based experiences, measured risk-taking, long-term engagement, parental involvement, and greater interagency collaboration and integration.

Time of day differences in appetite and gut hormone responses to meal and stress challenges in adults with normal-weight and obesity.

BACKGROUND: Lifestyle factors like time of eating and stress exposure may impact physiology to promote excess weight gain. To understand behavioral and physiological mechanisms underlying these potential effects, we compared appetite and gut hormone responses to a series of meal and stress challenges beginning in the morning and the afternoon, in adults with normal-weight and obesity. METHOD: Thirty-two adults (16 with normal-weight, 16 with obesity) underwent the same test protocol on different days, each following an 8 h fast. On one day the protocol began in the morning (AM condition); on the other day it began in the late afternoon (PM condition). On each day they first received a standardized liquid meal (9:00am/4:00pm), then a stress test (Socially-Evaluated Cold Pressor Test, 11:10am/6:10pm), then an ad libitum buffet meal (11:40am/6:40pm). Appetite and stress ratings were obtained, and blood was drawn for measures of ghrelin, PYY, GLP-1, insulin, glucose, cortisol and leptin. Acetaminophen was administered as a tracer to assess gastric emptying of the liquid meal. RESULTS: Across all three challenges, AUC cortisol was lower in the PM vs. AM condition (all p<.001), and AUC insulin and leptin were higher in the obesity vs. normal-weight group (all p<.001). For the standardized liquid meal only, AUC hunger, desire to eat and ghrelin were greater in the PM vs. AM condition (all p<0.05), and AUC ghrelin was lower in the obesity vs. normal-weight group, even when controlling for baseline values (p<0.05). AUC glucose was higher in the evening for the normal-weight group only (condition x group interaction p<0.05). Post-liquid meal gastric emptying as indexed by AUC acetaminophen was slower in the PM vs. AM (p<.01). For the stress test, AUC cortisol was lower in the PM than the AM condition even when controlling for baseline values (p<.05). AUC leptin was lower in the evening in the obesity group only (condition x group interaction p<0.01). PYY showed an acute decrease post-stressor in the normal-weight but not the obesity group (p<.05). Post-stress ad libitum buffet meal intake was similar in the evening and morning conditions, and higher in the obesity group (p<0.05). Only among the obesity group in the evening condition, higher stressor-associated stress and cortisol were associated with greater meal-associated appetite (p<0.05). CONCLUSIONS: Normal-weight individuals and those with obesity may be at risk of evening overeating as a result of differential appetite and gut hormone responses following meal intake and stress exposure.

Including ethnic minorities in dementia research: Recommendations from a scoping review.

Introduction: Ethnicity influences dementia etiology, prognosis, and treatment, while culture shapes help-seeking and care. Despite increasing population diversity in high-income settlement countries, ethnic minorities remain underrepresented in dementia research. We investigated approaches to enhance the recruitment, and consistent collection and analysis of variables relevant to, ethnic minorities in dementia studies to make recommendations for consistent practice in dementia research. Methods: We did a scoping review, searching Embase, PsycINFO, Medline, CENTRAL, and CINAHL between January 1, 2010 and January 7, 2020. Dementia clinical and cohort studies that actively recruited ethnic minorities in high-income countries were included. A steering group of experts developed criteria through which high-quality studies were identified. Results: Sixty-six articles were retrieved (51 observational; 15 experimental). Use of interpreters and translators (n = 17) was the most common method to facilitate participant recruitment. Race and ethnicity (n = 59) were the most common variables collected, followed by information on native language (n = 14), country of birth (n = 9), and length of time in country of settlement (n = 8). Thirty-three studies translated or used a culturally validated instrument. Twenty-three articles conducted subgroup analyses based on ethnicity. Six high-quality studies facilitated inclusion through community engagement, collected information on multiple aspects of ethnic diversity, and adjusted/substratified to analyze the impact of ethnicity on dementia. Discussion: We make recommendations for consistent recruitment, collection, and reporting of variables relating to ethnic and cultural diversity in dementia research.

Ethics review of COVID-19 human challenge studies: A joint HRA/WHO workshop.

This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop discusses the ethics review of the first COVID-19 human challenge studies, undertaken in the midst of the pandemic. It reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies and create the frameworks to ensure rigorous and timely review of these studies. This report evaluates the utility of the WHO's international guidance document Key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) as a practical resource for the ethics review of COVID-19 human challenge studies. It also assesses the UK HRA's approach to these complex ethics reviews, including the formation of a Specialist Ad-Hoc Research Ethics Committee (REC) for COVID-19 Human Challenge Studies to review all current and future COVID-19 human challenge studies. In addition, the report outlines the reflections of REC members and researchers regarding the ethics review process of the first COVID-19 human challenge studies. Finally, it considers the potential ongoing scientific justification for COVID-19 human challenge studies, particularly in relation to next-generation vaccines and optimisation of vaccination schedules. Overall, there was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Workshop members suggested that the WHO Key Criteria could be practically implemented to support researchers and ethics reviewers, including in the training of ethics committee members. In future, a wider audience may be engaged by the original document and potential additional materials, informed by the experiences of those involved in the first COVID-19 human challenge studies outlined in this document.

A Comparison of Foveal and Peripheral Contour Interaction and Crowding.

SIGNIFICANCE: Performance on clinical tests of visual acuity can be influenced by the presence of nearby targets. This study compared the influence of neighboring flanking bars and letters on foveal and peripheral letter identification. PURPOSE: Contour interaction and crowding refer to an impairment of visual resolution or discrimination produced by different types of flanking stimuli. This study compared the impairment of percent correct letter identification that is produced in normal observers when a target letter is surrounded by an array of four flanking bars (contour interaction) or four flanking letters (crowding). METHODS: Performance was measured at the fovea and at eccentricities of 1.25, 2.5, and 5° for photopic (200 cd/m2) and mesopic stimuli (0.5 cd/m2) and a range of target-to-flanker separations. RESULTS: Consistent with previous reports, foveal contour interaction and crowding were more pronounced for photopic than mesopic targets. However, no statistically significant difference existed between foveal contour-interaction and crowding functions at either luminance level. On the other hand, flanking bars produced much less impairment of letter identification than letter flankers at all three peripheral locations, indicating that crowding is more severe than contour interaction in peripheral vision. In contrast to the fovea, peripheral crowding and contour-interaction functions did not differ systematically for targets of photopic and mesopic luminance. CONCLUSION: The similarity between foveal contour interaction and crowding and the dissimilarity between peripheral contour interaction and crowding suggest the involvement of different mechanisms at different retinal locations.

Effective delivery of Complex Innovative Design (CID) cancer trials-A consensus statement.

The traditional cancer drug development pathway is increasingly being superseded by trials that address multiple clinical questions. These are collectively termed Complex Innovative Design (CID) trials. CID trials not only assess the safety and toxicity of novel anticancer medicines but also their efficacy in biomarker-selected patients, specific cancer cohorts or in combination with other agents. They can be adapted to include new cohorts and test additional agents within a single protocol. Whilst CID trials can speed up the traditional route to drug licencing, they can be challenging to design, conduct and interpret. The Experimental Cancer Medicine Centres (ECMC) network, funded by the National Institute for Health Research (NIHR), Cancer Research UK (CRUK) and the Health Boards of Wales, Northern Ireland and Scotland, formed a working group with relevant stakeholders from clinical trials units, the pharmaceutical industry, funding bodies, regulators and patients to identify the main challenges of CID trials. The working group generated ten consensus recommendations. These aim to improve the conduct, quality and acceptability of oncology CID trials in clinical research and, importantly, to expedite the process by which effective treatments can reach cancer patients.

Distinct modes of cell competition shape mammalian tissue morphogenesis.

Cell competition-the sensing and elimination of less fit 'loser' cells by neighbouring 'winner' cells-was first described in Drosophila. Although cell competition has been proposed as a selection mechanism to optimize tissue and organ development, its evolutionary generality remains unclear. Here, by using live imaging, lineage tracing, single-cell transcriptomics and genetics, we identify two cell competition mechanisms that sequentially shape and maintain the architecture of stratified tissue during skin development in mice. In the single-layered epithelium of the early embryonic epidermis, winner progenitors kill and subsequently clear neighbouring loser cells by engulfment. Later, as the tissue begins to stratify, the basal layer instead expels losers through upward flux of differentiating progeny. This cell competition switch is physiologically relevant: when it is perturbed, so too is barrier formation. Our findings show that cell competition is a selective force that optimizes vertebrate tissue function, and illuminate how a tissue dynamically adjusts cell competition strategies to preserve fitness as its architectural complexity increases during morphogenesis.

A modified high-throughput analysis of PLFAs in soil.

Microbial community profiling via phospholipid fatty-acid (PLFA) analysis is an insightful technique which elucidates the phenotypic structure of microbial assemblages within soil. Previous iterations of PLFA analysis have used large quantities of chemicals and can take extended periods of time to perform. Another barrier to the implementation of this method is the cost and availability of specialised machinery. We report on a high-throughput method which reduces both the time to extract PLFAs from soil and reduces the quantity of chemicals required.

Contour interaction under photopic and scotopic conditions.

In the present study, we asked whether contour interaction undergoes significant changes for different luminance levels in the central and peripheral visual field. This study included nine normal observers at two laboratories (five at Palacky University Olomouc, Czech Republic and four at the University of Houston, USA). Observers viewed a randomly selected Sloan letter surrounded by four equally spaced bars for several separations measured edge-to-edge in min arc. Stimuli were viewed foveally under photopic and mesopic luminances and between 5° and 12° peripherally for four different background luminances of the display monitors, corresponding to photopic, mesopic, scotopic, and dim scotopic levels. The extent of the contour interaction in the fovea is approximately 20 times smaller than in the periphery. Whereas the magnitude of foveal contour interaction markedly decreases with decreasing luminance, no consistent luminance-induced change occurs in peripheral contour interaction. The extent of contour interaction does not scale with the size of the target letter, either in the fovea or peripherally. The results support a neural origin of contour interaction consistent with the properties of center-surround antagonism.

Basal Cell-Extracellular Matrix Adhesion Regulates Force Transmission during Tissue Morphogenesis.

Tissue morphogenesis requires force-generating mechanisms to organize cells into complex structures. Although many such mechanisms have been characterized, we know little about how forces are integrated across developing tissues. We provide evidence that integrin-mediated cell-extracellular matrix (ECM) adhesion modulates the transmission of apically generated tension during dorsal closure (DC) in Drosophila. Integrin-containing adhesive structures resembling focal adhesions were identified on the basal surface of the amnioserosa (AS), an extraembryonic epithelium essential for DC. Genetic modulation of integrin-mediated adhesion results in defective DC. Quantitative image analysis and laser ablation experiments reveal that basal cell-ECM adhesions provide resistance to apical cell displacements and force transmission between neighboring cells in the AS. Finally, we provide evidence for integrin-dependent force transmission to the AS substrate. Overall, we find that integrins regulate force transmission within and between cells, thereby playing an essential role in transmitting tension in developing tissues.

The talin head domain reinforces integrin-mediated adhesion by promoting adhesion complex stability and clustering.

Talin serves an essential function during integrin-mediated adhesion in linking integrins to actin via the intracellular adhesion complex. In addition, the N-terminal head domain of talin regulates the affinity of integrins for their ECM-ligands, a process known as inside-out activation. We previously showed that in Drosophila, mutating the integrin binding site in the talin head domain resulted in weakened adhesion to the ECM. Intriguingly, subsequent studies showed that canonical inside-out activation of integrin might not take place in flies. Consistent with this, a mutation in talin that specifically blocks its ability to activate mammalian integrins does not significantly impinge on talin function during fly development. Here, we describe results suggesting that the talin head domain reinforces and stabilizes the integrin adhesion complex by promoting integrin clustering distinct from its ability to support inside-out activation. Specifically, we show that an allele of talin containing a mutation that disrupts intramolecular interactions within the talin head attenuates the assembly and reinforcement of the integrin adhesion complex. Importantly, we provide evidence that this mutation blocks integrin clustering in vivo. We propose that the talin head domain is essential for regulating integrin avidity in Drosophila and that this is crucial for integrin-mediated adhesion during animal development.

The relationship between self-reported sleep quality and reading comprehension skills.

Inadequate sleep undermines many cognitive functions, including memory, concentration, and attention, which are vital in everyday activities. We hypothesized that poor quality or shorter sleep length may impair reading-related skills, resources, and outcomes, specifically verbal working memory span, verbal efficiency, and reading comprehension. Contrary to the hypotheses, neither short sleep length nor self-reported sleep quality were related to reading skills performance. However, longer sleep times were significantly related to lower verbal efficiency, and participants with the poorest sleep quality fared significantly better on the reading comprehension task than participants with moderate sleep quality. Given the paucity of research examining sleep and reading specifically, as well as these surprising data, more research in this area is warranted.

Talin autoinhibition is required for morphogenesis.

The establishment of a multicellular body plan requires coordinating changes in cell adhesion and the cytoskeleton to ensure proper cell shape and position within a tissue. Cell adhesion to the extracellular matrix (ECM) via integrins plays diverse, essential roles during animal embryogenesis and therefore must be precisely regulated. Talin, a FERM-domain containing protein, forms a direct link between integrin adhesion receptors and the actin cytoskeleton and is an important regulator of integrin function. Similar to other FERM proteins, talin makes an intramolecular interaction that could autoinhibit its activity. However, the functional consequence of such an interaction has not been previously explored in vivo. Here, we demonstrate that targeted disruption of talin autoinhibition gives rise to morphogenetic defects during fly development and specifically that dorsal closure (DC), a process that resembles wound healing, is delayed. Impairment of autoinhibition leads to reduced talin turnover at and increased talin and integrin recruitment to sites of integrin-ECM attachment. Finally, we present evidence that talin autoinhibition is regulated by Rap1-dependent signaling. Based on our data, we propose that talin autoinhibition provides a switch for modulating adhesion turnover and adhesion stability that is essential for morphogenesis.

Zasp regulates integrin activation.

Integrins are heterodimeric adhesion receptors that link the extracellular matrix (ECM) to the cytoskeleton. Binding of the scaffold protein, talin, to the cytoplasmic tail of ß-integrin causes a conformational change of the extracellular domains of the integrin heterodimer, thus allowing high-affinity binding of ECM ligands. This essential process is called integrin activation. Here we report that the Z-band alternatively spliced PDZ-motif-containing protein (Zasp) cooperates with talin to activate α5ß1 integrins in mammalian tissue culture and αPS2ßPS integrins in Drosophila. Zasp is a PDZ-LIM-domain-containing protein mutated in human cardiomyopathies previously thought to function primarily in assembly and maintenance of the muscle contractile machinery. Notably, Zasp is the first protein shown to co-activate α5ß1 integrins with talin and appears to do so in a manner distinct from known αIIbß3 integrin co-activators.

Mechanical force regulates integrin turnover in Drosophila in vivo.

Regulated assembly and disassembly, or turnover, of integrin-mediated cell-extracellular matrix (ECM) adhesions is essential for dynamic cell movements and long-term tissue maintenance. For example, in Drosophila, misregulation of integrin turnover disrupts muscle-tendon attachment at myotendinous junctions (MTJs). We demonstrate that mechanical force, which modulates integrin activity, also regulates integrin and intracellular adhesion complex (IAC) turnover in vivo. Using conditional mutants to alter the tensile force on MTJs, we found that the proportion of IAC components undergoing turnover inversely correlated with the force applied on MTJs. This effect was disrupted by point mutations in ß-integrin that interfere with ECM-induced conformational changes and activation of ß-integrin or integrin-mediated cytoplasmic signalling. These mutants also disrupted integrin dynamics at MTJs during larval development. Together, these data suggest that specific ß-integrin-mediated signals regulate adhesion turnover in response to tension during tissue formation. We propose that integrin-ECM adhesive stability is continuously controlled by force in vivo through integrin-dependent auto-regulatory feedback mechanisms so that tissues can quickly adapt to and withstand mechanical stresses.

In vivo functional analysis reveals specific roles for the integrin-binding sites of talin.

Adhesion receptors play diverse roles during animal development and require precise spatiotemporal regulation, which is achieved through the activity of their binding partners. Integrins, adhesion receptors that mediate cell attachment to the extracellular matrix (ECM), connect to the intracellular environment through the cytoplasmic adapter protein talin. Talin has two essential functions: orchestrating the assembly of the intracellular adhesion complex (IAC), which associates with integrin, and regulating the affinity of integrins for the ECM. Talin can bind to integrins through two different integrin-binding sites (IBS-1 and IBS-2, respectively). Here, we have investigated the roles of each in the context of Drosophila development. We find that although IBS-1 and IBS-2 are partially redundant, they each have specialized roles during development: IBS-1 reinforces integrin attachment to the ECM, whereas IBS-2 reinforces the link between integrins and the IAC. Disruption of each IBS has different developmental consequences, illustrating how the functional diversity of integrin-mediated adhesion is achieved.