Genetic Testing for Familial Hypercholesterolemia in Clinical Practice.

PURPOSE OF REVIEW: Genetic testing has proven utility in identifying and diagnosing individuals with FH. Here we outline the current landscape of genetic testing for FH, recommendations for testing practices and the efforts underway to improve access, availability, and uptake. RECENT FINDINGS: Alternatives to the traditional genetic testing and counseling paradigm for FH are being explored including expanding screening programs, testing in primary care and/or cardiology clinics, leveraging electronic communication tools like chatbots, and implementing direct contact approaches to facilitate genetic testing of both probands and at-risk relatives. There is no consensus on if, when, and how genetic testing or accompanying genetic counseling should be provided for FH, though traditional genetic counseling and/or testing in specialty lipid clinics is often recommended in expert statements and professional guidelines. More evidence is needed to determine whether alternative approaches to the implementation of genetic testing for FH may be more effective.

Rituximab treatment for systemic sclerosis-associated interstitial lung disease: a case series of 13 patients.

BACKGROUND: Systemic sclerosis (SSc) associated interstitial lung disease (ILD) is a common complication of SSc, with a high mortality, despite current available treatments. Rituximab has shown some promising, although varied, results for the treatment of SSc-ILD. AIMS: To determine whether rituximab stabilised or improved pulmonary function at 12 months, in patients with SSc-ILD. METHODS: A retrospective analysis of patients with SSc-ILD who progressed despite conventional therapy and received rituximab between 2008 and 2019 was performed at two tertiary centres. Baseline percentage forced vital capacity (FVC) and percentage diffusing capacity of carbon monoxide (DLCO) were compared with 1-year post the first dose of rituximab. Mean and median change in FVC (%) and DLCO (%) were calculated. For those with available data, the FVC (%) and DLCO (%) 2 years and 1 year prior to rituximab were compared with the change 12-months post-rituximab. RESULTS: Thirteen patients were included in the analysis. All patients demonstrated stability in their pulmonary function testing at 1-year post-rituximab. The mean FVC (%) was 57.18 (±16.93 standard deviation (SD)) prior to rituximab and 59.75 (±18.83 SD) 12-month post-rituximab, demonstrating an increase of 2.57 (±4.70 SD; P-value 0.07). The mean DLCO (%) increased from 37.10 (±18.41 SD) prior to rituximab to 38.03 (±19.83) post-rituximab. The mean change in DLCO (%) was 0.93 (±5.05 SD; P-value 0.53). In the 2 years preceding rituximab, the mean FVC (%) and DLCO (%) declined by 9.25 and 9.66 respectively. CONCLUSION: This case series suggests that rituximab might stabilise pulmonary function tests, and delay deterioration in patients with progressive SSc-ILD. These findings add to the growing body of evidence suggesting a role for rituximab in the treatment of SSc-ILD.

A mixed-methods process evaluation of the feasibility and acceptability of involving community and peer role models within a physical activity intervention for primary-school-aged girls (the CHARMING study).

BACKGROUND: Role models have been identified as a potential means to tackle the persisting low levels of physical activity among young girls. The aim of this research was to explore the involvement of community- and peer role models within the CHARMING (CHoosing Active Role Models to INspire Girls) intervention, an intervention which aims to increase and sustain physical activity among 9-10-year-old girls. The research questions were, is it feasible and acceptable to recruit role models? and what are the perceived barriers and facilitators to the inclusion of peer role models within the intervention? METHODS: A mixed methods process evaluation was embedded within a larger feasibility study, involving three secondary schools and four adjoining primary schools in South Wales, United Kingdom. One-to-one interviews were conducted with teachers (N = 10) across the seven schools and community role models (N = 10). Focus groups were conducted with 18 peer role models (older girls from adjoining secondary schools) and 18 girls aged 9-10-years who had participated in the intervention. Primary school teachers kept observation logs of each intervention session. A researcher completed observation logs of two random sessions per school. Qualitative data were analysed using thematic analysis with a combined deductive and inductive coding approach. Observation data were analysed using descriptive statistics. Data were triangulated and comparative analyses conducted across schools. RESULTS: Twenty-three peer role models (aged 12-16-years) and 16 community role models participated in intervention delivery. Overall, the inclusion of both types of role models was shown as acceptable and feasible within the CHARMING intervention. Observation data highlighted key areas (i.e., intervention components delivered inconsistently) for further qualitative exploration. Six themes were identified during analyses; reach and access, communication, logistics, existing systems, interpersonal relationships, and perceived impacts. Themes were intertwined across the barriers and facilitators of recruitment and implementation. Areas for future improvement were highlighted. CONCLUSIONS: Findings can be used to optimise the CHARMING intervention and inform wider interventions or policies employing several role models across settings to promote physical activity among children.

Optimizing communication strategies and designing a comprehensive program to facilitate cascade testing for familial hypercholesterolemia.

BACKGROUND: This project aimed to optimize communication strategies to support family communication about familial hypercholesterolemia (FH) and improve cascade testing uptake among at-risk relatives. Individuals and families with FH provided feedback on multiple strategies including: a family letter, digital tools, and direct contact. METHODS: Feedback from participants was collected via dyadic interviews (n = 11) and surveys (n = 98) on communication strategies and their proposed implementation to improve cascade testing uptake. We conducted a thematic analysis to identify how to optimize each strategy. We categorized optimizations and their implementation within the project's healthcare system using a Traffic Light approach. RESULTS: Thematic analysis resulted in four distinct suggested optimizations for each communication strategy and seven suggested optimizations that were suitable across all strategies. Four suggestions for developing a comprehensive cascade testing program, which would offer all optimized communication strategies also emerged. All optimized suggestions coded green (n = 21) were incorporated. Suggestions coded yellow (n = 12) were partially incorporated. Only two suggestions were coded red and could not be incorporated. CONCLUSIONS: This project demonstrates how to collect and analyze stakeholder feedback for program design. We identified feasible suggested optimizations, resulting in communication strategies that are patient-informed and patient-centered. Optimized strategies were implemented in a comprehensive cascade testing program.

Self-harm, in-person bullying and cyberbullying in secondary school-aged children: A data linkage study in Wales.

INTRODUCTION: Although the evidence base on bullying victimization and self-harm in young people has been growing, most studies were cross-sectional, relied on self-reported non-validated measures of self-harm, and did not separate effects of in-person and cyberbullying. This study aimed to assess associations of self-harm following in-person bullying at school and cyberbullying victimization controlling for covariates. METHODS: School survey data from 11 to 16 years pupils collected in 2017 from 39 Welsh secondary schools were linked to routinely collected data. Inverse probability weighting was performed to circumvent selection bias. Survival analyses for recurrent events were conducted to evaluate relative risks (adjusted hazard ratios [AHR]) of self-harm among bullying groups within 2 years following survey completion. RESULTS: A total of 35.0% (weighted N = 6813) of pupils reported being bullied, with 18.1%, 6.4% and 10.5% being victims of in-person bullying at school only, cyberbullying only and both in-person bullying at school and cyberbullying respectively. Adjusting for covariates, effect sizes for self-harm were significant after being in-person bullied at school only (AHR = 2.2 [1.1-4.3]) and being both in-person bullied at school and cyberbullied (AHR = 2.2 [1.0-4.7]) but not being cyberbullied only (AHR = 1.2 [0.4-3.3]). Feeling lonely during recent summer holidays was also a robust predictor (AHR = 2.2 [1.2-4.0]). CONCLUSIONS: We reaffirm the role of in-person bullying victimization on self-harm. Pupils were twice as likely to self-harm following in-person bullying as their nonvictimised peers. Interventions for young people that minimize the potential impacts of bullying on self-harm should also include strategies to prevent loneliness.

Targeted BRCA1/2 population screening among Ashkenazi Jewish individuals using a web-enabled medical model: An observational cohort study.

PURPOSE: This study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs). METHODS: Across 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years. RESULTS: A total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing. CONCLUSION: Although continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated.

Challenges and Opportunities in Engaging Primary Care Providers in BRCA Testing: Results from the BFOR Study.

PURPOSE: Engaging primary care providers (PCPs) in BRCA1/2 testing and results disclosure would increase testing access. The BRCA Founder OutReach (BFOR) study is a prospective study of BRCA1/2 founder mutation screening among individuals of Ashkenazi Jewish descent that sought to involve participants' PCPs in results disclosure. We used quantitative and qualitative methods to evaluate PCPs' perspectives, knowledge, and experience disclosing results in BFOR. METHODS: Among PCPs nominated by BFOR participants to disclose BRCA1/2 results, we assessed the proportion agreeing to disclose. To examine PCP's perspectives, knowledge, and willingness to disclose results, we surveyed 501 nominated PCPs. To examine PCPs' experiences disclosing results in BFOR, we surveyed 101 PCPs and conducted 10 semi-structured interviews. RESULTS: In the BFOR study overall, PCPs agreed to disclose their patient's results 40.5% of the time. Two hundred thirty-four PCPs (46.7%) responded to the initial survey. Responding PCPs were more likely to agree to disclose patients' results than non-responders (57.3% vs. 28.6%, p<0.001). Among all respondents, most felt very (19.7%) or somewhat (39.1%) qualified to share results. Among PCPs declining to disclose, insufficient knowledge was the most common reason. In multivariable logistic regression, feeling qualified was the only variable significantly associated with agreeing to disclose results (OR 6.53, 95% CI 3.31, 12.88). In post-disclosure surveys (response rate=55%), PCPs reported largely positive experiences. Interview findings suggested that although PCPs valued the study-provided educational materials, they desired better integration of results and decision support into workflows. CONCLUSION: Barriers exist to incorporating BRCA1/2 testing into primary care. Most PCPs declined to disclose their patients' BFOR results, although survey respondents were motivated and had positive disclosure experiences. PCP training and integrated decision support could be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03351803), November 24, 2017.

Mental health and life satisfaction among 10-11-year-olds in Wales, before and one year after onset of the COVID-19 pandemic.

BACKGROUND: In many countries, including in the United Kingdom (UK), COVID-19 social distancing measures placed substantial restrictions on children's lives in 2020 and 2021, including closure of schools and limitations on play. Many children faced milestones such as transition to secondary school having missed several months of face-to-face schooling in the previous academic years. METHODS: This paper examines change in mental health difficulties, life satisfaction, school connectedness, and feelings about transition to secondary school among 10-11-year-olds in Wales, UK, using data from repeat cross-sectional surveys before and after the onset of the COVID-19 pandemic. Participants were 4032 10-11-year-old schoolchildren. The first cohort completed a school-based survey in 2019 (prior to introduction of social distancing measures), and the second in 2021 (following full return to school after two rounds of school closure). RESULTS: The percentage of children reporting elevated emotional difficulties rose from 17% in 2019 to 27% in 2021 (Odds Ratio = 1.65; 95%CI = 1.23 to 2.20). There was no evidence of increased behavioural difficulties (OR = 1.04; 95%CI = 0.73 to 1.46). There was a tendency toward declines in life satisfaction in all analyses, but this intersected the null (OR = 0.86; 95%CI = 0.70 to 1.07). Children reported a high degree of school connectedness before and after the pandemic, with no evidence of change in ratings of teacher relationships, pupil relationships or pupil involvement in school life. There was no evidence of impacts of the pandemic on children's feelings about the transition to secondary school, with feelings becoming more positive as transition neared. Most findings were robust to a range of sensitivity analyses. CONCLUSIONS: Supporting children's emotional recovery from the COVID-19 pandemic is a public health priority requiring urgent and effective action at multiple levels of society. Maintaining connectedness to school through the pandemic may have played a role in preventing a steeper increase in child mental health difficulties.

The effectiveness of digital interventions for increasing physical activity in individuals of low socioeconomic status: a systematic review and meta-analysis.

BACKGROUND: Digital technologies such as wearables, websites and mobile applications are increasingly used in interventions targeting physical activity (PA). Increasing access to such technologies makes an attractive prospect for helping individuals of low socioeconomic status (SES) in becoming more active and healthier. However, little is known about their effectiveness in such populations. The aim of this systematic review was to explore whether digital interventions were effective in promoting PA in low SES populations, whether interventions are of equal benefit to higher SES individuals and whether the number or type of behaviour change techniques (BCTs) used in digital PA interventions was associated with intervention effects. METHODS: A systematic search strategy was used to identify eligible studies from MEDLINE, Embase, PsycINFO, Web of Science, Scopus and The Cochrane Library, published between January 1990 and March 2020. Randomised controlled trials, using digital technology as the primary intervention tool, and a control group that did not receive any digital technology-based intervention were included, provided they had a measure of PA as an outcome. Lastly, studies that did not have any measure of SES were excluded from the review. Risk of Bias was assessed using the Cochrane Risk of Bias tool version 2. RESULTS: Of the 14,589 records initially identified, 19 studies were included in the final meta-analysis. Using random-effects models, in low SES there was a standardised mean difference (SMD (95%CI)) in PA between intervention and control groups of 0.06 (- 0.08,0.20). In high SES the SMD was 0.34 (0.22,0.45). Heterogeneity was modest in both low (I2 = 0.18) and high (I2 = 0) SES groups. The studies used a range of digital technologies and BCTs in their interventions, but the main findings were consistent across all of the sub-group analyses (digital interventions with a PA only focus, country, chronic disease, and duration of intervention) and there was no association with the number or type of BCTs. DISCUSSION: Digital interventions targeting PA do not show equivalent efficacy for people of low and high SES. For people of low SES, there is no evidence that digital PA interventions are effective, irrespective of the behaviour change techniques used. In contrast, the same interventions in high SES participants do indicate effectiveness. To reduce inequalities and improve effectiveness, future development of digital interventions aimed at improving PA must make more effort to meet the needs of low SES people within the target population.

From a research trial to routine practice: stakeholders' perceptions and experiences of referrals to the National Exercise Referral Scheme (NERS) in Wales.

BACKGROUND: Over ten years on from a randomised controlled trial and subsequent national roll-out, the National Exercise Referral Scheme (NERS) continues to be routinely delivered in primary care across Wales, UK. Few studies have revisited effective interventions years into their delivery in routine practice to understand how implementation, and perceived effects, have been maintained over time. This study explores perceptions and experiences of referral to NERS among referrers, scheme deliverers and patients. METHODS: Individual, semi-structured interviews were conducted with 50 stakeholders: scheme referrers (n = 9); scheme deliverers (n = 22); and referred patients (n = 19). Convenience sampling techniques were used to recruit scheme referrers and purposive sampling to recruit scheme deliverers and patients. Thematic analysis was employed. RESULTS: Analyses resulted in five key themes; referrer characteristics, geographical disparities in referral and scheme access, reinforcements for awareness of the scheme, patient characteristics and processes and context underpinning a referral. Overall there was a high concordance of views between all three stakeholder groups and barriers and facilitators were found to be entwined within and across themes. Referral barriers persisting since the earlier trial included a lack of consultation time and a lack of referral feedback. Newly identified barriers included a lack of scheme awareness and a referral system perceived to be time intensive and disjointed. Key referral facilitators included patient self-referrals, a growing scheme reputation and promotional activities of scheme deliverers. CONCLUSIONS: Findings provide evidence that could inform the further development of NERS and wider exercise referral schemes to ensure the referral process is timely, efficient and equitable.

Does Receiving a Text Message Reminder Increase Follow-up Compliance After Discharge From a Pediatric Emergency Department?

OBJECTIVES: Compliance with recommended follow-up from the pediatric emergency department (PED) has been shown to be poor. This study evaluated whether a text message reminder to the caregivers after discharge from the PED improved compliance with recommended primary care follow-up. METHODS: This was a blinded randomized control trial conducted at a level 1 pediatric trauma center. The intervention was a text message sent to the caregiver within 24 hours of discharge from the PED reminding them to follow up with their primary care doctor. Patients were eligible if the caregiver had text message capability on their cellular phones, they were currently established patients of the organization's Pediatric Faculty Practice, they were discharged home from the PED, and they were referred for follow-up within 1 week of discharge by the pediatric emergency physician. After informed consent, pediatric patients were randomized to either an intervention group (text message appointment reminder) or a control group (standard scheduling with no reminder). The patient, treating physician, and primary care outpatient center were blinded to the group assignment. Enrollment occurred 24 hours per day and 7 days per week. RESULTS: There were 123 patients enrolled in the study, 62 patients randomized to the control group (standard scheduling) and 61 randomized to the intervention group (text message appointment reminder). Of the patients, 58% were male and 42% were female, with the average age of the patients being 2.2 years (SD, 2.8). The majority of patients were seen in the PED on a weekday, with 24% presenting on a weekend. Only 28% of patients completed the recommended follow-up, and the average time from PED discharge to follow-up was 6 days (SD, 4.2; range, 0-17 days). There was no significant difference in follow-up in the standard treatment group (19/62, 31%) versus the text message intervention group (16/61, 26%) (P = 0.69; rate ratio, 0.94; 95% confidence interval, 0.75-1.18). When we assessed other variables, we found that parents of younger children were more likely to follow up as recommended by the pediatric ED physician. Of those who were compliant with follow-up, we found a mean age of 1.3 years (SD, 2.0; range, 0.8-9.1) versus 2.6 years (SD, 3.0; range, 0.08-15.3) for those who were not compliant with follow-up (P = 0.02). CONCLUSIONS: In this randomized controlled study, a text message reminder to caregivers did not improve compliance for PED patients. However, caregivers of younger children were more likely to complete follow-up as recommended by the PED physician compared with caregivers of older children.

Sources of potential bias when combining routine data linkage and a national survey of secondary school-aged children: a record linkage study.

BACKGROUND: Linking survey data to administrative records requires informed participant consent. When linkage includes child data, this includes parental and child consent. Little is known of the potential impacts of introducing consent to data linkage on response rates and biases in school-based surveys. This paper assessed: i) the impact on overall parental consent rates and sample representativeness when consent for linkage was introduced and ii) the quality of identifiable data provided to facilitate linkage. METHODS: Including an option for data linkage was piloted in a sub-sample of schools participating in the Student Health and Wellbeing survey, a national survey of adolescents in Wales, UK. Schools agreeing to participate were randomized 2:1 to receive versus not receive the data linkage question. Survey responses from consenting students were anonymised and linked to routine datasets (e.g. general practice, inpatient, and outpatient records). Parental withdrawal rates were calculated for linkage and non-linkage samples. Multilevel logistic regression models were used to compare characteristics between: i) consenters and non-consenters; ii) successfully and unsuccessfully linked students; and iii) the linked cohort and peers within the general population, with additional comparisons of mental health diagnoses and health service contacts. RESULTS: The sub-sample comprised 64 eligible schools (out of 193), with data linkage piloted in 39. Parental consent was comparable across linkage and non-linkage schools. 48.7% (n = 9232) of students consented to data linkage. Modelling showed these students were more likely to be younger, more affluent, have higher positive mental wellbeing, and report fewer risk-related behaviours compared to non-consenters. Overall, 69.8% of consenting students were successfully linked, with higher rates of success among younger students. The linked cohort had lower rates of mental health diagnoses (5.8% vs. 8.8%) and specialist contacts (5.2% vs. 7.7%) than general population peers. CONCLUSIONS: Introducing data linkage within a national survey of adolescents had no impact on study completion rates. However, students consenting to data linkage, and those successfully linked, differed from non-consenting students on several key characteristics, raising questions concerning the representativeness of linked cohorts. Further research is needed to better understand decision-making processes around providing consent to data linkage in adolescent populations.

Comparison of up-front cash cards and checks as incentives for participation in a clinician survey: a study within a trial.

BACKGROUND: Evidence is needed regarding effective incentive strategies to increase clinician survey response rates. Cash cards are increasingly used as survey incentives; they are appealing because of their convenience and because in some cases their value can be reclaimed by investigators if not used. However, their effectiveness in clinician surveys is not known. In this study within the BRCA Founder OutReach (BFOR) study, a clinical trial of population-based BRCA1/2 mutation screening, we compared the use of upfront cash cards requiring email activation versus checks as clinician survey incentives. METHODS: Participants receiving BRCA1/2 testing in the BFOR study could elect to receive their results from their primary care provider (PCP, named by the patient) or from a geneticist associated with the study. In order to understand PCPs' knowledge, attitudes, experiences and willingness to disclose results we mailed paper surveys to the first 501 primary care providers (PCPs) in New York, Boston, Los Angeles and Philadelphia who were nominated by study participants to disclose their BRCA1/2 mutation results obtained through the study. We used alternating assignment stratified by city to assign the first 303 clinicians to receive a $50 up-front incentive as a cash card (N = 155) or check (N = 148). The cash card required PCPs to send an activation email in order to be used. We compared response rates by incentive type, adjusting for PCP characteristics and study site. RESULTS: In unadjusted analyses, PCPs who received checks were more likely to respond to the survey than those who received cash cards (54.1% versus 41.9%, p = 0.046); this remained true when we adjusted for provider characteristics (OR for checks 1.61, 95% CI 1.01, 2.59). No other clinician characteristics had a statistically significant association with response rates in adjusted analyses. When we included an interaction term for incentive type and city, the favorable impact of checks on response rates was evident only in Los Angeles and Philadelphia. CONCLUSIONS: An up-front cash card incentive requiring email activation may be less effective in eliciting clinician responses than up-front checks. However, the benefit of checks for clinician response rates may depend on clinicians' geographic location. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03351803 ), November 24, 2017.

Parent recommendations to support physical activity for families with young children: Results of interviews in deprived and affluent communities in South Wales (United Kingdom).

BACKGROUND: Physical inactivity is the fourth leading cause of mortality worldwide. Early childhood is a critical period when healthy behaviours can be instilled for a future active lifestyle. We explored community, societal and environmental factors affecting child and family physical activity and sought parent recommendations to support physical activity in families with young children. METHODS: We interviewed 61 parents expecting a child or with a baby ≤12 months (35 mother and father paired interviews and 26 interviews with mothers only). We purposively sampled families for neighbourhood deprivation status (Townsend Index; 26 affluent; 35 deprived). We conducted thematic analysis of interview transcripts using Bronfenbrenner's socio-ecological framework to guide interpretation. RESULTS: We identified four themes: work family-life balance; spaces for activity; beliefs and attitudes; and physical activity facilitators. We found that parents from deprived neighbourhoods were more likely to be underactive because of a complex web of community, social and personal factors which reduced motivation and hindered opportunity for physical activity. To increase knowledge and opportunity, respondents suggested 'help not tell' messages covering 'why', 'how' and 'where' information about physical activity, and using physical activity to support community engagement and social interaction. CONCLUSIONS: Recommendations from parents highlight effective communication about the importance of early child and family physical activity and improved community access to safe facilities and opportunities. Both parents need to be engaged in designing interventions to support greater physical activity and healthy behaviours which are relevant and achievable in individuals' lives.

Formative research to develop a school-based, community-linked physical activity role model programme for girls: CHoosing Active Role Models to INspire Girls (CHARMING).

BACKGROUND: Physical inactivity is a persistent challenge among girls. School-based physical activity (PA) interventions have shown mixed effects on girl's activity levels, with multi-component approaches involving both school and community links appearing more effective for sustainable change. The purpose of the current research was to gather views from preadolescent girls, parents, teachers and stakeholders in order to co-produce a multi-component school-based, community linked PA intervention programme. METHODS: Focus groups were conducted in two primary schools with 34 girls aged 9-11 years and 11 parents (10 female, 1 male). In-depth interviews were conducted with four female teachers (including two head teachers). Focus groups and interviews focused on programme design (structure, content and delivery) and potential factors affecting intervention uptake and continued PA participation. A series of stakeholder engagement events occurred throughout the study period. All data were transcribed verbatim and thematically analysed in NVivo 11. RESULTS: Girls reported that fun taster sessions delivered by role models would encourage them to participate in a school-based role model programme, with tailored taster sessions each week to enhance continued PA participation. Parents and teachers identified a number of barriers to uptake and continued PA participation, and active involvement of stakeholders facilitated the development of intervention strategies. Strategies included; single-sex after-school sessions, use of female role models, low-cost activity options and mapping community provision. Analyses revealed the importance of tailoring the programme to align with local needs, demands and provision. CONCLUSIONS: Data show numerous barriers to intervention uptake and continued PA participation when designing a school-based, community-linked intervention. Adopting a co-production approach, this formative work highlights a number of potential strategies for overcoming these barriers. Findings from the research directed the development and implementation of the CHARMING role model intervention and informed the creation of an intervention logic model.

Acceptability and Feasibility of Implementing Accelorometry-Based Activity Monitors and a Linked Web Portal in an Exercise Referral Scheme: Feasibility Randomized Controlled Trial.

BACKGROUND: Exercise referral schemes (ERSs) are recommended for patients with health conditions or risk factors. Evidence points to the initial effectiveness and cost-effectiveness of such schemes for increasing physical activity, but effects often diminish over time. Techniques such as goal setting, self-monitoring, and personalized feedback may support motivation for physical activity and maintenance of effects. Wearable technologies could provide an opportunity to integrate motivational techniques into exercise schemes. However, little is known about acceptability to exercise referral populations or implementation feasibility within exercise referral services. OBJECTIVE: To determine the feasibility and acceptability of implementing an activity-monitoring device within the Welsh National ERS to inform a decision on whether and how to proceed to an effectiveness trial. METHODS: We conducted a feasability randomized controlled trial with embedded mixed-methods process evaluation and an exploratory economic analysis. Adults (N=156) were randomized to intervention (plus usual practice; n=88) or usual practice only (n=68). Usual practice was a 16-week structured exercise program. The intervention group additionally received an accelerometry-based activity monitor (MyWellnessKey) and associated Web platform (MyWellnessCloud). The primary outcomes were predefined progression criteria assessing acceptability and feasibility of the intervention and proposed evaluation. Postal questionnaires were completed at baseline (time 0:T0), 16 weeks (T1), and 12 months after T0 (T2). Routine data were accessed at the same time-points. A subsample of intervention participants and scheme staff were interviewed following the initiation of intervention delivery and at T2. RESULTS: Participants were on average aged 56.6 (SD 16.3) years and mostly female (101/156, 64.7%) and white (150/156, 96.2%). Only 2 of 5 progression criteria were met; recruitment and randomization methods were acceptable to participants, and contamination was low. However, recruitment and retention rates (11.3% and 67.3%, respectively) fell substantially short of target criteria (20% and 80%, respectively), and disproportionally recruited from the least deprived quintile. Only 57.4% of intervention participants reported receipt of the intervention (below the 80% progression threshold). Less than half reported the intervention to be acceptable at T2. Participant and staff interviews revealed barriers to intervention delivery and engagement related to the device design as well as context-specific technological challenges, all of which made it difficult to integrate the technology into the service. Routinely collected health economic measures had substantial missing data, suggesting that other methods for collecting these should be used in future. CONCLUSIONS: To our knowledge, this is the first study to evaluate short- and long-term feasibility and acceptability of integrating wearable technologies into community-based ERSs. The findings highlight device- and context-specific barriers to doing this in routine practice, with typical exercise referral populations. Key criteria for progression to a full-scale evaluation were not met. TRIAL REGISTRATION: ISRCTN Registry ISRCTN85785652; http://www.isrctn.com/ISRCTN85785652.

Modeling Water and Nutrient Movement in Sandy Soils Using HYDRUS-2D.

Models help to describe and predict complex processes and scenarios that are difficult to understand or measure in environmental management systems. Thus, model simulations were performed (i) to calibrate HYDRUS-2D for water and solute movement as a possible decision support system for Candler and Immokalee fine sand using data from microsprinkler and drip irrigation methods, (ii) to validate the performance of HYDRUS-2D using field data of microsprinkler and drip irrigation methods, and (iii) to investigate Br, NO, and water movement using annual or seasonal weather data and variable fertigation scenarios. The model showed reasonably good agreement between measured and simulated values for soil water content ( = 0.87-1.00), Br ( = 0.63-0.96), NO-N ( = 0.66-0.98), P ( = 0.25-0.78), and K ( = 0.44-0.99) movement. The model could be successfully used for scheduling irrigation and predicting nutrient leaching for both microsprinkler and drip irrigation systems on Florida's sandy soils.

Impact of early conversion from cyclosporin to everolimus on left ventricular mass index: A randomized controlled trial.

This is an 18-month prospective, randomized controlled trial (RCT) designed to compare the effect of early conversion from cyclosporin to everolimus/mycophenolic acid (E-MPA) between 3 and 4 months post-transplant to cyclosporin/mycophenolic acid (CsA-MPA) on left ventricular mass index (LVMI) at 3 and 18 months post-transplant (primary outcome). Secondary outcomes included estimated glomerular filtration rate (eGFR), viral infection, and adverse events. Twenty-four patients were randomized in a 1:1 ratio to E-MPA or CsA-MPA groups. There were no significant differences in mean (SD) LVMI at 3 (51.6±18.5 vs 53.7±15.7 g/m2.7 ) and 18 months (52.7±16.3 vs 51.7±16.8 g/m2.7 ) between CsA-MPA and E-MPA groups. The incidence of viral infections was reduced in E-MPA compared to CsA-MPA treatment groups (8% vs 50%, P=.02), but the incidences of acute rejection, adverse events, and drug discontinuation were similar between groups. There was an overall increase in eGFR with time (0.04 log- mL/min/1.73 m2 per 6 months, P=.012) but no significant difference between the two groups across time (0.11 log- mL/min/1.73 m2 , P=.311). Immunosuppressive regimen comprising early conversion from cyclosporine to everolimus was not associated with a regression of LVMI, but a lower risk of viral infections was observed.

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency.

Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the NF1 gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in NF1 and have a 200- to 500-fold increased risk of juvenile myelomonocytic leukemia. Leukemia cells from patients with juvenile myelomonocytic leukemia display hypersensitivity to certain cytokines, such as granulocyte-macrophage colony-stimulating factor. The granulocyte-macrophage colony-stimulating factor receptor utilizes pre-associated JAK2 to initiate signals after ligand binding. JAK2 subsequently activates STAT5, among other downstream effectors. Although STAT5 is gaining recognition as an important mediator of growth factor signaling in myeloid leukemias, the contribution of STAT5 to the development of hyperactive RAS-initiated myeloproliferative disease has not been well described. In this study, we investigated the consequence of STAT5 attenuation via genetic and pharmacological approaches in Nf1-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous Stat5 deficiency extended the lifespan of Nf1-deficient mice and eliminated the development of myeloproliferative neoplasm associated with Nf1 gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in Nf1-deficient mice. Finally, we found that primary cells from a patient with KRAS-mutant juvenile myelomonocytic leukemia displayed reduced colony formation in response to JAK2 inhibition. Our findings establish a central role for STAT5 activation in the pathogenesis of juvenile myelomonocytic leukemia and suggest that targeting this pathway may be of clinical utility in these patients.

Predictors of physical activity and sedentary behaviours among 11-16 year olds: Multilevel analysis of the 2013 Health Behaviour in School-aged Children (HBSC) study in Wales.

BACKGROUND: The present study investigated associations between individual- and school-level predictors and young people's self-reported physical activity (total activity and moderate-to-vigorous activity) and sedentary behaviours. METHODS: Individual-level data provided by the 2013/14 cross-sectional survey 'Health Behaviour in School-aged Children (HBSC) study in Wales' were linked to school-level data within the 'HBSC School Environment Questionnaire'. The final sample comprised 7,376 young people aged 11-16 years across 67 schools. Multilevel modelling was used to examine predictors of total physical activity, moderate-to-vigorous physical activity (MVPA) and sedentary behaviours (screen-based behaviours). RESULTS: Taking more physical activity (less than 5 days vs. 5 or more days per week), engaging in higher levels of MVPA (less than 4 hours vs. 4 or more hours per week) and reporting 2 or less hours of sedentary time were predicted by several individual level variables. Active travel to school positively predicted high levels of physical activity, however, gender stratified models revealed active travel as a predictor amongst girls only (OR:1.25 (95 % CI:1.05 - 1.49)). No school-level factors were shown to predict physical activity levels, however, a lower school socio-economic status was associated with a higher level of MVPA (OR:1.02 (95 % CI:1.01 - 1.03)) and a lower risk of sedentary behaviour (OR:0.97 (95 % CI:0.96 - 0.99)). A shorter lunch break (OR:1.33 (95 % CI:1.11 - 1.49)) and greater provision of facilities (OR:1.02 (95 % CI:1.00 - 1.05)) were associated with increased sedentary activity. Gender stratified models revealed that PE lesson duration (OR:1.18 (95 % CI:1.01 - 1.37)) and the provision of sports facilities (OR:1.03 (95 % CI:1.00 - 1.06)) were predictors of boy's sedentary behaviours only. CONCLUSION: Shorter lunch breaks were associated with increased sedentary time. Therefore, while further research is needed to better understand the causal nature of this association, extending lunch breaks could have a positive impact on sedentary behaviour through the provision of more time for physical activity. The findings also suggest that active travel could offer a mechanism for increasing physical activity levels particularly amongst girls. Particularly, the design and evaluation of interventions to promote physical activity during school hours should employ a comprehensive approach, including a focus on school policies and behaviours both in and out of school hours.