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Abstract Background The Active Connected Engaged [ACE] study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial [RCT] with an internal pilot phase. The ACE study incorporates a multi-level mixed methods process evaluation including a systems mapping approach and an economic evaluation. ACE aims to test the effectiveness and cost-effectiveness of a peer-volunteer led active ageing intervention designed to support older adults at risk of mobility disability to become more physically and socially active within their communities and to reduce or reverse, the progression of functional limitations associated with ageing. Methods/design Community-dwelling, older adults aged 65 years and older (n = 515), at risk of mobility disability due to reduced lower limb physical functioning (Short Physical Performance Battery (SPPB) score of 4–9 inclusive) will be recruited. Participants will be randomised to receive either a minimal control intervention or ACE, a 6-month programme underpinned by behaviour change theory, whereby peer volunteers are paired with participants and offer them individually tailored support to engage them in local physical and social activities to improve lower limb mobility and increase their physical activity. Outcome data will be collected at baseline, 6, 12 and 18 months. The primary outcome analysis (difference in SPPB score at 18 months) will be undertaken blinded to group allocation. Primary comparative analyses will be on an intention-to-treat (ITT) basis with due emphasis placed on confidence intervals. Discussion ACE is the largest, pragmatic, community-based randomised controlled trial in the UK to target this high-risk segment of the older population by mobilising community resources (peer volunteers). A programme that can successfully engage this population in sufficient activity to improve strength, coordination, balance and social connections would have a major impact on sustaining health and independence. ACE is also the first study of its kind to conduct a full economic and comprehensive process evaluation of this type of community-based intervention. If effective and cost-effective, the ACE intervention has strong potential to be implemented widely in the UK and elsewhere. Trial registration ISRCTN, ISRCTN17660493. Registered on 30 September 2021. Trial Sponsor: University of Birmingham, Contact: Dr Birgit Whitman, Head of Research Governance and Integrity; Email: researchgovernance@contacts.bham.ac.uk. Protocol Version 5 22/07/22.

The heart is composed of muscle cells called cardiomyocytes, including a specialized population named pacemaker cells that form the cardiac conduction system (CCS), which is responsible for generating the action potential dictating heart contractions. Failure of the CCS system leads to cardiac arrhythmias, which require complicated therapies and often the surgical implantation of electrical pacemakers. However, recent research has focused on the development of novel therapies using biological pacemakers that aim to substitute electrical devices. While most signaling pathways and transcription factors involved in the development of the pacemaker cells are known, the upstream regulatory networks need to be predicted through computer-based databases, mathematical modeling, as well as the functional testing of the regulatory elements in vivo, indicating the need for further research. Here, we summarize the current knowledge about the vertebrate myocardial CCS system and the development of the pacemaker cells, as well as emphasize the areas of future research to clarify the regulation of muscle pacemaker cells and the ease of development of biological therapies.

Societal Impact Statement The world faces major changes in rainfall patterns and water availability, posing a significant threat to plant productions systems and food security. The arbuscular mycorrhizal (AM) fungi associate with most major crops and can support plant nutrient and water uptake. Here, AM fungi were shown to mitigate the negative effects of low water availability on sorghum growth and phosphorus uptake, an effect that was associated with shifts in the fungal community structure. To realise the potential of AM fungi in sustainable agriculture requires more examination of their interactions with edaphic stresses in crop systems.

Background: The prevalence of hidradenitis suppurativa (HS) is 0.00033% to 4.10% globally. Few epidemiological studies derive from Asia, with social stigmatization postulated to result in under-diagnosis. Objective: This study aimed to assess the self-reported prevalence of HS, and the knowledge, attitudes, and perceptions towards HS among Singaporean young-adults. Methods: A cross-sectional study (n = 158) was conducted by anonymous online questionnaire. The association between demographic factors and risk of potentially undiagnosed HS was evaluated using multivariable logistic regression. Differences between attitude-perception scores by demographic factors and knowledge of HS were tested using two-sample t-tests. Results: The prevalence of diagnosed and potentially undiagnosed HS was 0.63% and 8.9%, respectively. Non-Chinese had significantly higher social attitude-perception scores than Chinese (P = .029). Females had significantly higher social (P = .048) as well as economic and work (P = .037) attitude-perception scores than males. Those with knowledge of HS had significantly higher attitude-perception scores for interpersonal (P = .031) and social (P = .0052) subsections. Limitations: Small sample size, low frequency of HS cases, and self-reported prevalence may not generalize to the broader population in Singapore. Conclusion: Our results suggest a potential underdiagnosis of HS. Non-Chinese stigmatize HS less than Chinese, and females less than males. Individuals with knowledge of HS might be more open to interpersonal and social interactions with HS sufferers.

Gastrointestinal (GI) parasites cause significant production losses in grazing ruminants which can be mitigated by breeding animals resistant to disease. Lymphocyte cytokine production and parasite-specific Immunoglobulin A (IgA) are adaptive immune traits associated with immunity to GI parasites. To explore the utility of these traits for selective breeding purposes, this study estimated the genetic parameters of the immune traits in sheep and assessed their relationship with disease and productivity traits. Whole blood stimulation assays were performed on 1 040 Scottish Blackface lambs at two months of age in 2016–2017. Blood was stimulated with either pokeweed mitogen (PWM), a non-specific activator of lymphocytes, and Teladorsagia circumcincta (T-ci) larval antigen to activate parasite-specific T lymphocytes. The type of adaptive immune response was determined by quantifying production of cytokines interferon-gamma (IFN-γ), interleukin (IL)-4, and IL-10, which relate to T-helper type (Th) 1, Th2 and regulatory T cell responses, respectively. Serum T-ci specific IgA was also quantified. Heritabilities were estimated for each immune trait by univariate analyses. Genetic and phenotypic correlations were estimated between different immune traits, and between immune traits vs. disease and productivity traits that were recorded at three months of age. Disease phenotypes were expressed as faecal egg counts (FEC) of nematode parasites (Strongyles and Nematodirus), faecal oocyst counts (FOC) of coccidian parasites, and faecal soiling score; production was measured as lamb live weight. Significant genetic variation was observed in all immune response traits. Heritabilities of cytokine production varied from low (0.14 ± 0.06) to very high (0.77 ± 0.09) and were always significantly greater than zero (P

Transient and frequency-dependent conductivity measurements on excised brain-tissue lesions from epilepsy patients indicate that sodium cations are the predominant charge carriers. The transient conductivity ultimately vanishes as ions encounter blockages. The initial and final values of the transient conductivity correspond to the high-frequency and low-frequency limits of the frequency-dependent conductivity, respectively. Carrier dynamics determines the conductivity between these limits. Typically, the conductivity rises monotonically with increasing frequency. By contrast, when pathology examinations found exceptionally disorganized excised tissue, the conductivity falls with increasing frequency as it approaches its high-frequency limit. To analyze these measurements, excised tissues are modeled as mixtures of "normal" tissue within which sodium cations can diffuse and "abnormal" tissue within which sodium cations are trapped. The decrease in the conductivity with increasing frequency indicates the predominance of trapping. The high-frequency conductivity decreases as the rate with which carriers are liberated from traps decreases. A relatively low conductivity results when most sodium cations remain trapped in "abnormal" brain tissue, while few move within "normal" brain tissue. Thus, the high densities of sodium nuclei observed by 23Na-MRI in epilepsy patients' lesions are consistent with the low densities of diffusing sodium cations inferred from conductivity measurements of excised lesions.

Physician rating of cutaneous erythema is central to clinical dermatological assessment as well as quantification of outcome measures in clinical trials in a number of dermatologic conditions. However, issues with inter-rater reliability and variability in the setting of higher Fitzpatrick skin types make visual erythema assessment unreliable. We developed and validated a computer-assisted image-processing algorithm (EQscore) to reliably quantify erythema (across a range of skin types) in the dermatology clinical setting. Our image processing algorithm evaluated erythema based upon green light suppression differentials between affected and unaffected skin. A group of four dermatologists used a 4-point Likert scale as a human evaluation of similar erythematous patch tests. The algorithm and dermatologist scores were compared across 164 positive patch test reactions. The intra-class correlation coefficient of groups and the correlation coefficient between groups were calculated. The EQscore was validated on and independent image set of psoriasis, minimal erythema dose testing and steroid-induced blanching images. The reliability of the erythema quantification method produced an intra-class correlation coefficient of 0.84 for the algorithm and 0.67 for dermatologists. The correlation coefficient between groups was 0.85. The EQscore demonstrated high agreement with clinical scoring and superior reliability compared with clinical scoring, avoiding the pitfalls of erythema underrating in the setting of pigmentation. The EQscore is easily accessible (http://lab.rockefeller.edu/krueger/EQscore), user-friendly, and may allow dermatologists to more readily and accurately rate the severity of dermatological conditions and the response to therapeutic treatments.

Abstract The soil bacterium Pseudomonas putida KT2440 has been shown to produce selenium nanoparticles aerobically from selenite; however, the molecular actors involved in this process are unknown. Here, through a combination of genetic and analytical techniques, we report the first insights into selenite metabolism in this bacterium. Our results suggest that the reduction of selenite occurs through an interconnected metabolic network involving central metabolic reactions, sulphur metabolism, and the response to oxidative stress. Genes such as sucA, D2HGDH and PP_3148 revealed that the 2‐ketoglutarate and glutamate metabolism is important to convert selenite into selenium. On the other hand, mutations affecting the activity of the sulphite reductase decreased the bacteria's ability to transform selenite. Other genes related to sulphur metabolism (ssuEF, sfnCE, sqrR, sqr and pdo2) and stress response (gqr, lsfA, ahpCF and sadI) were also identified as involved in selenite transformation. Interestingly, suppression of genes sqrR, sqr and pdo2 resulted in the production of selenium nanoparticles at a higher rate than the wild‐type strain, which is of biotechnological interest. The data provided in this study brings us closer to understanding the metabolism of selenium in bacteria and offers new targets for the development of biotechnological tools for the production of selenium nanoparticles.

Abstract Background The prevalence of excess weight has been increasing globally in the last decades, affecting disproportionally adults from low socio-economic backgrounds and putting undue pressure on health systems and societal resources. In England, tackling unfair and unjust health inequalities is at the heart of national public health policy, and a prerequisite for enabling these decision makers to set policy priorities is an understanding of the prevalence and determinants of excess weight inequalities in their local population. Methods We conducted both pooled (England) and regional-level (nine regions: North-East, North-West, Yorkshire and Humber, East Midlands, West Midlands, East of England, London, South East and South West) analyses of individual level data from a nationally representative sample of adults (N = 6,387). We used the Corrected Concentration Index (CCI) to measure absolute inequalities in excess weight across three dimensions of socio-economic deprivation: neighbourhood-level deprivation, occupational status and educational qualification. We used a Shapley decomposition method to evaluate their relative contribution to inequality. Results At a national level, all three dimensions of socio-economic deprivation were found to be positively associated with excess weight across the adult population, as measured by the CCI, with educational qualification ranking first [CCI: -0.090, p

Abstract Background Many people do not regularly participate in physical activity, which may negatively impact their health. Current physical activity guidelines are focused on promoting weekly accumulation of at least 150 min of moderate to vigorous intensity physical activity (MVPA). Whilst revised guidance now recognises the importance of making small changes to physical activity behaviour, guidance still focuses on adults needing to achieve at least 150 min of MVPA per week. An alternative ‘whole day’ approach that could motivate the public to be more physically active, is a concept called Snacktivity™. Instead of focusing on achieving 150 min per week of physical activity, for example 30 min of MVPA over 5 days, Snacktivity™ encourages the public to achieve this through small, but frequent, 2–5 min ‘snacks’ of MVPA throughout the whole day. Methods The primary aim is to undertake a feasibility trial with nested qualitative interviews to assess the feasibility and acceptability of the Snacktivity™ intervention to inform the design of a subsequent phase III randomised trial. A two-arm randomised controlled feasibility trial aiming to recruit 80 inactive adults will be conducted. Recruitment will be from health and community settings and social media. Participants will be individually randomised (1:1 ratio) to receive either the Snacktivity™ intervention or usual care. The intervention will last 12 weeks with assessment of outcomes completed before and after the intervention in all participants. We are interested in whether the Snacktivity™ trial is appealing to participants (assessed by the recruitment rate) and if the Snacktivity™ intervention and trial methods are acceptable to participants (assessed by Snacktivity™/physical activity adherence and retention rates). The intervention will be delivered by health care providers within health care consultations or by researchers. Participants’ experiences of the trial and intervention, and health care providers’ views of delivering the intervention within health consultations will be explored. Discussion The development of physical activity interventions that can be delivered at scale are needed. The findings from this study will inform the viability and design of a phase III trial to assess the effectiveness and cost-effectiveness of Snacktivity™ to increase physical activity. Trial registration ISRCTN: 64851242.

BackgroundFrontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.MethodsWe studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X-/- KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD-GRN. To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X.ResultsThe R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X-/- KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X-/- KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X-/- KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV-GRN-R493X-V5 mice.ConclusionsTaken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.

OBJECTIVES/GOALS: Full Spectrum Town Halls (FSTH) were organized to bring together patients, scientists, clinicians, advocates and others interested in Hidradenitis Suppurative (HS) – stakeholders across the spectrum of translational research – to infuse patient experiences and voices into designing HS research METHODS/STUDY POPULATION: The Rockefeller University (RU), Clinical Directors Network (CDN), and the HS Foundation organized three hybrid in-person/online HS FSTHs (2018-2023). The 2018 event focused on patients, describing the current state of HS knowledge and new research into HS biology (T2, T3). Patients shared lived experiences in testimonials and a panel discussion. Advocates described community and mental health resources (T4). The 2021 event returned research results (T2, T3) to the community and updates about treatments in the pipeline (T4). The 2023 FSTH targeted clinicians (T4) addressing a critical translational gap in HS care and presenting best practices in diagnosis, surgical, and medical treatments. RESULTS/ANTICIPATED RESULTS: Impact on science: FSTH attendees joined a Community Engagement Studio providing feedback used to refine study variables/procedures. Attendees joined research studies that advanced understanding HS mechanisms of disease, clinical course and treatment.Impact on patient experience: Participants appreciated having a forum to hear/share experiences of shame, mistrust, misdiagnosis and hope. Feedback improved practices for privacy, consenting, and returning study results. Impact on clinical practice and care: FSTH raised awareness of stigma, need for respect and empathy, and advanced learning about in disease mechanisms, effective biologics, importance of epithelial tunnels and surgical care. DISCUSSION/SIGNIFICANCE: HS is a stigmatizing, poorly understood disease. FSTHs fostered bidirectional learning among scientists, clinicians, patients and other stakeholders. Patients engaged with researchers to improve research design and participate in mechanistic and therapeutic clinical research, advancing the field.