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Background SARS-CoV-2 remains rapidly evolving, and many biologically important genomic substitutions/indels have characterised novel SARS-CoV-2 lineages, which have emerged during successive global waves of the pandemic. Worldwide genomic sequencing has been able to monitor these waves, track transmission clusters, and examine viral evolution in real time to help inform healthcare policy. One school of thought is that an apparent greater than average divergence in an emerging lineage from contemporary variants may require persistent infection, for example in an immunocompromised host. Due to the nature of the COVID-19 pandemic and sampling, there were few studies that examined the evolutionary trajectory of SARS-CoV-2 in healthy individuals. Methods We investigated viral evolutionary trends and participant symptomatology within a cluster of 16 SARS-CoV-2 infected, immunocompetent individuals with no co-morbidities in a closed transmission chain. Longitudinal nasopharyngeal swab sampling allowed characterisation of SARS-CoV-2 intra-host variation over time at both the dominant and minor genomic variant levels through Nimagen-Illumina sequencing. Results A change in viral lineage assignment was observed in individual infections; however, there was only one indel and no evidence of recombination over the period of an acute infection. Minor and dominant genomic modifications varied between participants, with some minor genomic modifications increasing in abundance to become the dominant viral sequence during infection. Conclusions Data from this cohort of SARS-CoV-2-infected participants demonstrated that long-term persistent infection in an immunocompromised host was not necessarily a prerequisite for generating a greater than average frequency of amino acid substitutions. Amino acid substitutions at both the dominant and minor genomic sequence level were observed in immunocompetent individuals during infection showing that viral lineage changes can occur generating viral diversity.

There is an enduring requirement to develop animal models of COVID-19 to assess the efficacy of vaccines and therapeutics that can be used to treat the disease in humans. In this study, six marmosets were exposed to a small particle aerosol (1–3 µm) of SARS-CoV-2 VIC01 that delivered the virus directly to the lower respiratory tract. Following the challenge, marmosets did not develop clinical signs, although a disruption to the normal diurnal temperature rhythm was observed in three out of six animals. Early weight loss and changes to respiratory pattern and activity were also observed, yet there was limited evidence of viral replication or lung pathology associated with infection. There was a robust innate immunological response to infection, which included an early increase in circulating neutrophils and monocytes and a reduction in the proportion of circulating T-cells. Expression of the ACE2 receptor in respiratory tissues was almost absent, but there was ubiquitous expression of TMPRSS2. The results of this study indicate that exposure of marmosets to high concentrations of aerosolised SARS-CoV-2 did not result in the development of clear, reproducible signs of COVID-19.

Background Recruiting frail older adults is challenging, resulting in underpowered trials, wasted resources, and unexpected costs. Researchers rarely report transparently and comprehensively on recruitment. However, sharing recruitment experiences could improve future efforts. This study tracks recruitment efforts and assesses their impact on recruitment outcomes in the ACTIVE-AGE@home trial to develop effective strategies for engaging community-dwelling frail older adults in long-term trials.  Methods A mixed-method study assessed recruitment partner contacts and their respective influence on recruitment outcomes at three levels: macro-, meso-, and micro-level contacts. Quantitative data were used to measure strategy efficiency. Qualitative data consisted of field notes, personal annotations recorded by the researchers during 15 months recruitment for ACTIVE-AGE@home. These notes were analyzed thematically following Braun and Clarke’s approach: deductively, guided by the TIBaR model for recruiting hard-to-reach older adults (emphasizing building Trust, offering Incentives, identifying Barriers, and being Responsive), and inductively to explore themes related to prolonged engagement, adherence and maintenance.  Results Over 15 months, 49 macro-level, 112 meso-level, and 1001 micro-level recruitment partners were contacted. Of these, 30 meso-level and 44 micro-level partners referred frail older adults. Micro-level referrals yielded the greatest number of eligible participants, with 6 (meso-level) and 23 ( micro-level) included. The study introduced the “BRIDGe recruitment model” with the following themes: (1) being appealing (2), fostering reciprocal relationships (3), understanding the recruitment partner and target group identity, and (4) gear trial requirements. The BRIDGe model serves as a reflective tool to balance recruitment and identity needs with trial requirements.  Conclusions Micro-level recruitment strategies are crucial for reaching frail older adults through warm referrals and personal contact. A bottom-up approach targeting local healthcare and welfare workers is recommended, with macro- and meso-level contacts supporting these connections. Rigid study designs hinder recruitment and translating research into practice requires flexible methods. Therefore, balancing rigor and feasibility is essential when designing context-specific studies. By transparently sharing recruitment successes and challenges, we aim to build collective knowledge to overcome recruitment barriers for frail older adults in intervention trials. Trial registration The ACTIVEAGE@home trial was registered on ClinicalTrials.gov on July 6, 2023, and published July 14, 2023. Trial registration NCT05946109.

Between 2020 and 2050, the world’s population aged 80 years and over will triple, drastically increasing the prevalence of frailty and associated healthcare costs. Multimodal exercise programmes have proven to be an ideal countermeasure for frailty, but the current Flemish standard of care does not include them. The purpose of this study is to investigate the effect of the home-based exercise programme for frail community-dwelling older adults (>70 years), ACTIVE-AGE@home, on frailty-associated outcomes, when delivered by professionals or volunteers, as well as its cost-effectiveness. A pragmatic randomised controlled trial will be conducted. Participants will be randomised into three parallel groups using permuted block randomisation. There will be two intervention groups: in one group, the intervention is delivered by professionals with a bachelor or masters’ degree in physiotherapy, occupational therapy and/or physical education, and in the other by trained volunteers. Both groups will be compared with a control group receiving usual care. Participants (n=195) are community-dwelling physically frail older adults (>70 years), as defined by Fried et al. (2001). The intervention is a 24 week programme that consists of three 1 hour visits per week and contains aerobic, strength, balance, flexibility, coordination and dual tasking exercises, accompanied by goal-setting and motivational interviewing. The Timed Chair Stand (TCS) test is the primary outcome. Functional ability, cognition, loneliness, self-management, health-related quality of life, healthcare utilisation and meaningful activities will be measured in all groups at 0, 24 and 48 weeks. Time and expenses invested by professionals or volunteers will be kept in diaries for trial and model-based cost-effectiveness analyses, expressed in incremental cost per QALY (quality-adjusted life year). The model will be designed to associate the frailty at the end of follow-up with further expected healthcare expenses beyond the duration of the trial. Statistical analysis will be blinded to group allocation, and outcome assessors will be blinded to the maximal extent possible.Ethics and disseminationEthics approval has been obtained from the Medical Ethics Committee of UZ Brussel (O.G. 016), Peer reflection group Biomedical Ethics, Laarbeeklaan 101, 1090 Brussels. Results will be disseminated in publications and other relevant platforms. This study was registered at Clinicaltrials.gov on 6 July 2023 and posted on 14 July 2023 after National Library of Medicine quality control review. Registration details: NCT05946109Trial registration numberNCT05946109.

With the rise of antimicrobial resistance, novel ways to treat bacterial infections are required and the use of predatory bacteria may be one such approach. Bdellovibrio species have been shown in vitro to predate on a wide range of other Gram-negative bacteria, including CDC category A/B pathogens such as Yersinia pestis . The data reported here show that treatment of SKH-1 mice with Bdellovibrio bacteriovorus HD100 provided significant protection from a lethal challenge of Yersinia pestis CO92. This is the first report of protection conferred by predation in vivo against a systemic pathogen challenge. However, this protective effect was not observed in a preliminary study with Balb/c mice. Therefore the effects of the predatory bacteria are complex and may be dependent on immune status/genetics of the host. Overall, predatory bacteria may have utility as a therapeutic modality but further work is required to understand the predator-host interaction.

Purpose The world population is ageing rapidly because of longer life expectancy and shrinking fertility rates. Not all older adults age in a healthy way. Evidence-based estimates indicate that 35-40% of the older adults are in a frail or prefrail state. Multi-component physical activity (PA) programs have shown to be effective to tackle frailty. However, only a scarce amount of the older adults succeed to overcome barriers towards PA. This pilot study aimed to examine the feasibility and acceptability of a home-based, functional PA program, ACTIVE-AGE@home, in frail community dwelling older adults. Methods In a mixed method design, a single-blind pragmatic randomized trial with two intervention groups (light (n = 29) and intensive (n = 18) version of ACTIVE-AGE@home) and one control group (n = 23) was conducted. In addition, qualitative data was collected through in-depth interviews, pre-and post-intervention, to reveal the participant’s subjective experience regarding the program. Results The arm curl test (p = 0.03), balance and gate (p = 0.052) and also independence, participation and health related quality of life (borderline significant) showed positive effects in favor for the most intensive version of ACTIVE-AGE@home compared to the control group. Nearly all participants in both intervention groups experienced positive effects regarding: fitness (90%), stability (80%), agility (70%), confidence (63%), resilient (90%) and 63% had less fear of falling. The training program was considered acceptable (95%). Conclusion Literature showed clear impact of PA on the physical, mental, emotional and social wellbeing of older adults. These findings were confirmed in this pilot study. ACTIVE-AGE@home shows great potential for further research. Therefore, starting 2023, the effectiveness and cost-effectiveness of the updated ACTIVE-AGE@home program will be tested on a bigger scale. Support/funding source The pilot study was developed by funding of the Flemish Government at Artevelde University of Applied Sciences. The updated version of ACTIVE-AGE@home (2022-2026) is funded by The Research Foundation – Flanders (FWO) as a Applied Biomedical Research with a Primary Social finality.

This article illustrates how designing schools with Indigenous systems of relationality can be life giving for a healthier post-COVID world. Indigenous systems of relationality—the worldviews, beliefs and practices, and moral precepts of being in relation with the rest of the living world—are the cornerstone of Indigenous knowledges, and the cornerstone of Indigenous families and communities. We consider the ways in which Indigenous systems of relationality can offer strategies for educators, families, and communities to redesign approaches to learning in schools in ways that sustain and promote life. Drawing on three case studies of schools in Thailand, México, and Colombia, we show how educators might respond to the specific needs within their communities, repair the fracturing of humans from nature, and orient us to life-giving forms of activity that are beneficial beyond our current crises and into the future.

Companion dogs have emerged as a valuable model in the study of cognitive aging, but assessments of cognitive function in large, diverse, and geographically distributed samples of dogs are challenging to obtain. We developed two novel functional assessments of short-term spatial memory that were administered by community science participants in a sample of 6,753 dogs through the Dog Aging Project. We compared data generated by community scientists to those gathered by research professionals, estimated relationships between age and task performance, and tested the hypothesis that associations between age and cognitive performance vary by dog body mass, as a proxy for expected lifespan. Community scientists generated similar data to research professionals and both cognitive tasks were sensitive to age-related deficits, beginning in midlife. Relationships between age and cognitive function were highly similar across small and large dogs and, for both tasks, comparison of models with and without an interaction between age and body mass yielded decisive evidence for the model without the interaction. Large dogs exhibit accelerated aging across many traits, and so the lack of evidence for accelerated cognitive aging raises the possibility that their large size confers a neuroprotective advantage. We consider possible mechanisms underlying this effect and address how experimental studies of dog cognition using community science methods can support future research on mechanisms of brain and cognitive aging.

Endothelial cells lining the blood vessel wall communicate intricately with the surrounding extracellular matrix, translating mechanical cues into biochemical signals. Moreover, vessels require the capability to enzymatically degrade the matrix surrounding them, to facilitate vascular expansion. c-Src plays a key role in blood vessel growth, with its loss in the endothelium reducing vessel sprouting and focal adhesion signalling. Here, we show that constitutive activation of c-Src in endothelial cells results in rapid vascular expansion, operating independently of growth factor stimulation or fluid shear stress forces. This is driven by an increase in focal adhesion signalling and size, with enhancement of localised secretion of matrix metalloproteinases responsible for extracellular matrix remodelling. Inhibition of matrix metalloproteinase activity results in a robust rescue of the vascular expansion elicited by heightened c-Src activity. This supports the premise that moderating focal adhesion-related events and matrix degradation can counteract abnormal vascular expansion, with implications for pathologies driven by unusual vascular morphologies.

Sequences that can form DNA secondary structures, such as G-quadruplexes (G4s) and intercalated-Motifs (iMs), are abundant in the human genome and play a range of physiological roles. However, they can also pose a challenge to the replication machinery and in turn threaten genome stability. Multiple lines of evidence suggest G4s interfere with replication, but the underlying mechanism remains unclear. Moreover, there is a lack of evidence of how iMs affect the replisome. Here, we reconstitute replication of physiologically derived structure-forming sequences to find that a single G4 or iM is sufficient to arrest DNA replication. Direct single molecule structure detection within solid-state nanopores reveals structures form as a consequence of replication. A combination of genetic and biophysical characterisation establishes that structure forming capacity is a key determinant of replisome arrest. Mechanistically, replication fork arrest is caused by impaired synthesis, resulting in helicase-polymerase uncoupling. Significantly, iMs also induce breakage of nascent DNA. Finally, stalled forks are only rescued by a specialised helicase, Pif1, but not Sgs1 or Chl1. Altogether, this study provides a potential mechanism for quadruplex structure formation and resolution during replication and highlights G4s and iMs as endogenous sources of replication stress, which may explain their genomic instability and mutation frequencies in cancer.