Landscape transcriptomics as a tool for addressing global change effects across diverse species

Landscape transcriptomics is an emerging field studying how genome-wide expression patterns reflect dynamic landscape-scale environmental drivers, including habitat, weather, climate, and contaminants, and the subsequent effects on organismal function. This field is benefitting from advancing and increasingly accessible molecular technologies, which in turn are allowing the necessary characterization of transcriptomes from wild individuals distributed across natural landscapes. This research is especially important given the rapid pace of anthropogenic environmental change and potential impacts that span levels of biological organization. We discuss three major themes in landscape transcriptomic research: connecting transcriptome variation across landscapes to environmental variation, generating and testing hypotheses about the mechanisms and evolution of transcriptomic responses to the environment, and applying this knowledge to species conservation and management. We discuss challenges associated with this approach and suggest potential solutions. We conclude that landscape transcriptomics has great promise for addressing fundamental questions in organismal biology, ecology, and evolution, while providing tools needed for conservation and management of species

Relations between Home Literacy Environment, Child Characteristics, and Print Knowledge for Preschool Children with Language Impairment

To contribute to the modest body of work examining the home literacy environment (HLE) and emergent literacy outcomes for children with disabilities, this study addressed two aims: (a) to determine the unique contributions of the HLE on print knowledge of preschool children with language impairment (LI); and (b) to identify whether specific child characteristics (oral language ability, print interest) moderated these relations. The sample consisted of 119 preschool children with LI. HLE was conceptualized as frequency of storybook reading and literacy teaching during book reading. Frequency of storybook reading was a unique predictor of print knowledge, which is consistent with research on children with typical language. Literacy teaching did not predict print knowledge, which diverges from research on children with typical language. No interactions between the HLE and child characteristics were significant, but language ability and print interest play a role in understanding individual differences in literacy development

Development and optimisation of a multi-component workplace intervention to increase cycling for the Cycle Nation Project

The Cycle Nation Project (CNP) aimed to develop, test the feasibility of and optimize a multi-component individual-/social-level workplace-based intervention to increase cycling among office staff at a multinational bank (HSBC UK). To do this, we first explored barriers to cycling in a nationally-representative survey of UK adults, then undertook focus groups with bank employees to understand any context-specific barriers and ways in which these might be overcome. These activities led to identification of 10 individual-level, two social-level, and five organizational-level modifiable factors, which were mapped to candidate intervention components previously identified in a scoping review of cycling initiatives. Interviews with HSBC UK managers then explored the practicality of implementing the candidate intervention components in bank offices. The resultant pilot CNP intervention included 32 core components across six intervention functions (education, persuasion, incentivisation, training, environmental restructuring, enablement). Participants received a loan bike for 12-weeks (or their own bike serviced), and a 9-week cycle training course (condensed to 6 weeks for those already confident in basic cycling skills), including interactive information sharing activities, behavior change techniques (e.g., weekly goal setting), bike maintenance training, practical off-road cycling skill games and on-road group rides. Sessions were delivered by trained bank staff members who were experienced cyclists. The CNP pilot intervention was delivered across three sites with 68 participants. It was completed in two sites (the third site was stopped due to COVID-19) and was feasible and acceptable to both women and men and across different ethnicities. In addition, the CNP intervention was successful (at least in the short term) in increasing cycling by 3 rides/week on average, and improving perceptions of safety, vitality, confidence, and motivation to cycle. Following minor modifications, the long-term effectiveness and cost-effectiveness of the CNP intervention should be tested in a full-scale randomized controlled trial

A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer. Experimental design: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements. Results: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 microg/kg (group A) or 100, 1,000, or 2,000 microg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, and IL-18-binding protein were observed following dosing. Conclusions: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined

Beyond cycle lanes and large-scale infrastructure: a scoping review of initiatives that groups and organisations can implement to promote cycling for the Cycle Nation Project

Background/objectives: Cycling has well-established positive relationships with health. Evidence suggests that large-scale infrastructure and built-environment initiatives to promote cycling are likely to be necessary but not sufficient to maximise cycling participation. Smaller-scale initiatives that can be implemented by organisations (eg, employers) and groups (eg, community groups) are therefore also important, but the full range of feasible activities to promote cycling is not known. We aimed to scope the literature and map organisational, social and individual level activities to increase cycling.MethodsDesign: Scoping review following an established five-stage process.Eligibility criteria: Studies or publicly available reports describing cycling promotion initiatives deemed feasible for organisations or groups to implement.Sources of evidence and selection: (i) online databases (Ovid (Medline), Ovid (Embase), SportDISCUS (Ebscohost), ProQuest, Web of Science), (ii) existing systematic reviews, (iii) expert stakeholder consultation.Results: We extracted data from 129 studies and reports, from 20 different countries, identifying 145 cycling promotion initiatives. From these initiatives we identified 484 actions within 93 action types within 33 action categories under the nine intervention functions described by Michie et al. Environmental restructuring (micro-level), enablement, education and persuasion were the functions with the most action types, while coercion, modelling and restriction had the fewest action types.Conclusion: This is the first comprehensive map to summarise the broad range of action types feasible for implementation within organisation/group-based cycling promotion initiatives. The map will be a critical tool for communities, employers, practitioners and researchers in designing interventions to increase cycling

Clinical and cost-effectiveness of a personalised health promotion intervention enabling independence in older people with mild frailty (‘HomeHealth’) compared to treatment as usual: study protocol for a randomised controlled trial

Background: Frailty is clinically associated with multiple adverse outcomes, including reduced quality of life and functioning, falls, hospitalisations, moves to long-term care and mortality. Health services commonly focus on the frailest, with highest levels of need. However, evidence suggests that frailty is likely to be more reversible in people who are less frail. Evidence is emerging on what interventions may help prevent or reduce frailty, such as resistance exercises and multi-component interventions, but few interventions are based on behaviour change theory. There is little evidence of cost-effectiveness. Previously, we co-designed a new behaviour change health promotion intervention (“HomeHealth”) to support people with mild frailty. HomeHealth is delivered by trained voluntary sector support workers over six months who support older people to work on self-identified goals to maintain their independence, such as strength and balance exercises, nutrition, mood and enhancing social engagement. The service was well received in our feasibility randomised controlled trial and showed promising effects upon outcomes. Aim: To test the clinical and cost-effectiveness of the HomeHealth intervention on maintaining independence in older people with mild frailty in comparison to treatment as usual (TAU).Methods: Single-blind individually randomised controlled trial comparing the HomeHealth intervention to TAU. We will recruit 386 participants from general practices and the community across three English regions. Participants are included if they are community-dwelling, aged 65+, with mild frailty according to the Clinical Frailty Scale. Participants will be randomised 1:1 to receive HomeHealth or TAU for 6 months. The primary outcome is independence in activities of daily living (modified Barthel Index) at 12 months. Secondary outcomes include instrumental activities of daily living, quality of life, frailty, wellbeing, psychological distress, loneliness, cognition, capability, falls, carer burden, service use, costs and mortality. Outcomes will be analysed using linear mixed models, controlling for baseline Barthel score and site. A health economic analysis and embedded mixed-methods process evaluation will be conducted. Discussion: This trial will provide definitive evidence on the effectiveness and cost-effectiveness of a home-based, individualised intervention to maintain independence in older people with mild frailty in comparison to TAU, that could be implemented at scale if effective

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins