Information and Risk Modification Trial (INFORM): design of a randomised controlled trial of communicating different types of information about coronary heart disease risk, alongside lifestyle advice, to achieve change in health-related behaviour.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of death globally. Primary prevention of CVD requires cost-effective strategies to identify individuals at high risk in order to help target preventive interventions. An integral part of this approach is the use of CVD risk scores. Limitations in previous studies have prevented reliable inference about the potential advantages and the potential harms of using CVD risk scores as part of preventive strategies. We aim to evaluate short-term effects of providing different types of information about coronary heart disease (CHD) risk, alongside lifestyle advice, on health-related behaviours. METHODS/DESIGN: In a parallel-group, open randomised trial, we are allocating 932 male and female blood donors with no previous history of CVD aged 40-84 years in England to either no intervention (control group) or to one of three active intervention groups: i) lifestyle advice only; ii) lifestyle advice plus information on estimated 10-year CHD risk based on phenotypic characteristics; and iii) lifestyle advice plus information on estimated 10-year CHD risk based on phenotypic and genetic characteristics. The primary outcome is change in objectively measured physical activity. Secondary outcomes include: objectively measured dietary behaviours; cardiovascular risk factors; current medication and healthcare usage; perceived risk; cognitive evaluation of provision of CHD risk scores; and psychological outcomes. The follow-up assessment takes place 12 weeks after randomisation. The experiences, attitudes and concerns of a subset of participants will be also studied using individual interviews and focus groups. DISCUSSION: The INFORM study has been designed to provide robust findings about the short-term effects of providing different types of information on estimated 10-year CHD risk and lifestyle advice on health-related behaviours. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17721237 . Registered 12 January 2015.

Rewriting regulatory DNA to dissect and reprogram gene expression.

Regulatory DNA sequences within enhancers and promoters bind transcription factors to encode cell type-specific patterns of gene expression. However, the regulatory effects and programmability of such DNA sequences remain difficult to map or predict because we have lacked scalable methods to precisely edit regulatory DNA and quantify the effects in an endogenous genomic context. Here we present an approach to measure the quantitative effects of hundreds of designed DNA sequence variants on gene expression, by combining pooled CRISPR prime editing with RNA fluorescence in situ hybridization and cell sorting (Variant-FlowFISH). We apply this method to mutagenize and rewrite regulatory DNA sequences in an enhancer and the promoter of PPIF in two immune cell lines. Of 672 variant-cell type pairs, we identify 497 that affect PPIF expression. These variants appear to act through a variety of mechanisms including disruption or optimization of existing transcription factor binding sites, as well as creation of de novo sites. Disrupting a single endogenous transcription factor binding site often led to large changes in expression (up to -40% in the enhancer, and -50% in the promoter). The same variant often had different effects across cell types and states, demonstrating a highly tunable regulatory landscape. We use these data to benchmark performance of sequence-based predictive models of gene regulation, and find that certain types of variants are not accurately predicted by existing models. Finally, we computationally design 185 small sequence variants (≤10 bp) and optimize them for specific effects on expression in silico. 84% of these rationally designed edits showed the intended direction of effect, and some had dramatic effects on expression (-100% to +202%). Variant-FlowFISH thus provides a powerful tool to map the effects of variants and transcription factor binding sites on gene expression, test and improve computational models of gene regulation, and reprogram regulatory DNA.

Effect of communicating phenotypic and genetic risk of coronary heart disease alongside web-based lifestyle advice: the INFORM Randomised Controlled Trial.

OBJECTIVE: To determine whether provision of web-based lifestyle advice and coronary heart disease risk information either based on phenotypic characteristics or phenotypic plus genetic characteristics affects changes in objectively measured health behaviours. METHODS: A parallel-group, open randomised trial including 956 male and female blood donors with no history of cardiovascular disease (mean [SD] age=56.7 [8.8] years) randomised to four study groups: control group (no information provided); web-based lifestyle advice only (lifestyle group); lifestyle advice plus information on estimated 10-year coronary heart disease risk based on phenotypic characteristics (phenotypic risk estimate) (phenotypic group) and lifestyle advice plus information on estimated 10-year coronary heart disease risk based on phenotypic (phenotypic risk estimate) and genetic characteristics (genetic risk estimate) (genetic group). The primary outcome was change in physical activity from baseline to 12 weeks assessed by wrist-worn accelerometer. RESULTS: 928 (97.1%) participants completed the trial. There was no evidence of intervention effects on physical activity (difference in adjusted mean change from baseline): lifestyle group vs control group 0.09 milligravity (mg) (95% CI -1.15 to 1.33); genetic group vs phenotypic group -0.33 mg (95% CI -1.55 to 0.90); phenotypic group and genetic group vs control group -0.52 mg (95% CI -1.59 to 0.55) and vs lifestyle group -0.61 mg (95% CI -1.67 to 0.46). There was no evidence of intervention effects on secondary biological, emotional and health-related behavioural outcomes except self-reported fruit and vegetable intake. CONCLUSIONS: Provision of risk information, whether based on phenotypic or genotypic characteristics, alongside web-based lifestyle advice did not importantly affect objectively measured levels of physical activity, other health-related behaviours, biological risk factors or emotional well-being. TRIAL REGISTRATION NUMBER: ISRCTN17721237; Pre-results.

Influence of Palliative Care on Medical Treatment of Pediatric Patients with Complex Chronic Diseases at Cook Children's Medical Center.

BACKGROUND: Literature in adult palliative care (PC) boasts fewer invasive procedures, shorter lengths of stay, and decreased cost of care. Benefits of pediatric PC are under-researched and are important to identify to optimize care. OBJECTIVE: Our aim was to estimate the influence and utilization of PC on pediatric patient care. DESIGN: We evaluated the electronic medical record of 43 patients at Cook Children's Medical Center (CCMC) with complex chronic conditions, who died between January 1, 2013, and December 31, 2014, comparing the length and frequency of hospitalizations, number of medications administered and procedures performed, and established limits of resuscitation between patients who received PC and those who did not. MEASUREMENTS: Data analyses were performed using SAS Enterprise (version 6.1; SAS Institute, Inc., Cary, NC). Continuous variables were described as medians and ranges and analyzed with Wilcoxon rank-sum test for ordinal data. Categorical variables were described as percentages and analyzed with chi-square test of independence. Repeated-measures analyses were performed utilizing multilevel linear modeling, which examined the data at the level of the 236 visits rather than the 43 patients. RESULTS: Twelve (28%) eligible patients were seen by PC. PC patients had more hospitalizations, longer lengths of stay, and fewer medications and procedures than those patients without PC services. PC patients were also more likely to have a medical orders for scope of treatment in place. CONCLUSION: These data demonstrate that PC services at CCMC are underutilized and support the need for PC services by decreased medications and procedures and identified family wishes for medical treatment.

A case report of coronary-subclavian steal syndrome treated with carotid to axillary artery bypass.

Coronary-subclavian steal syndrome results from atherosclerotic disease of the proximal subclavian artery causing reversal of flow in an internal mammary artery used as conduit for coronary artery bypass. This rare complication of cardiac revascularisation leads to recurrence of myocardial ischaemia. When feasible, subclavian angioplasty and/or stent placement can provide acceptable result for these patients. Vascular reconstruction through carotid to subclavian artery bypass has been the standard procedure of choice. Other interventions in literature include axilloaxillary bypass and subclavian carotid transposition. This case report describes the use of carotid axillary artery bypass for the treatment of coronary-subclavian steal syndrome.

Survey of current prenatal screening for Down syndrome in Australian hospitals providing maternity care.

BACKGROUND: The present study assessed the screening tests for Down syndrome available to women within Australian hospitals. METHODS: Postal questionnaires. RESULTS: A total of 282 (57%) hospitals responded with over two-thirds offering some form of screening test which varied by geographical region and level of institution. First trimester maternal serum screening was offered by 11% of hospitals. Nuchal translucency screening was offered by 52% of hospitals with higher use in Australian Capital Territory and New South Wales than in the other regions. Second trimester maternal serum screening was offered by 75% of hospitals with higher rates in Australian Capital Territory, South Australia and the lowest rate in Queensland. CONCLUSIONS: A high proportion of women are offered screening but with wide variation in the tests used.