A novel, multidomain, primary care nurse-led and mHealth-assisted intervention for dementia risk reduction in middle-aged adults (HAPPI MIND): study protocol for a cluster randomised controlled trial.

INTRODUCTION: Middle-aged multidomain risk reduction interventions targeting modifiable risk factors for dementia may delay or prevent a third of dementia cases in later life. We describe the protocol of a cluster randomised controlled trial (cRCT), HAPPI MIND (Holistic Approach in Primary care for PreventIng Memory Impairment aNd Dementia). HAPPI MIND will evaluate the efficacy of a multidomain, nurse-led, mHealth supported intervention for assessing dementia risk and reducing associated risk factors in middle-aged adults in the Australian primary care setting. METHODS AND ANALYSIS: General practice clinics (n≥26) across Victoria and New South Wales, Australia, will be recruited and randomised. Practice nurses will be trained to implement the HAPPI MIND intervention or a brief intervention. Patients of participating practices aged 45-65 years with ≥2 potential dementia risk factors will be identified and recruited (approximately 15 patients/clinic). Brief intervention participants receive a personalised report outlining their risk factors for dementia based on Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) scores, education booklet and referral to their general practitioner as appropriate. HAPPI MIND participants receive the brief intervention as well as six individualised dementia risk reduction sessions with a nurse trained in motivational interviewing and principles of behaviour change, a personalised risk reduction action plan and access to the purpose-built HAPPI MIND smartphone app for risk factor self-management. Follow-up data collection will occur at 12, 24 and 36 months. Primary outcome is ANU-ADRI score change at 12 months from baseline. Secondary outcomes include change in cognition, quality of life and individual risk factors of dementia. ETHICS AND DISSEMINATION: Project approved by Monash University Human Research Ethics Committee (ID: 28273). Results will be disseminated in peer-reviewed journals and at healthcare conferences. If effective in reducing dementia risk, the HAPPI MIND intervention could be integrated into primary care, scaled up nationally and sustained over time. TRIAL REGISTRATION NUMBER: ACTRN12621001168842.

Pregnancy Nutrition Core Outcome Set (PRENCOS): A core outcome set development study.

OBJECTIVE: To develop a core outcome set for pregnancy nutrition. DESIGN: Mixed-methods core outcome set development study. SETTING: Online. POPULATION: Healthcare professionals, researchers and women with experience of pregnancy. METHODS: Candidate outcomes were identified from a systematic review of intervention and observational studies. One-to-one semi-structured interviews with women with experience of pregnancy (n = 26) were transcribed and analysed using inductive thematic analysis. Outcomes were consolidated, organised into domains and categorised using the Core Outcome Measures in Effectiveness Trials taxonomy. A two-round, modified Delphi survey (May-August 2021) was conducted. Participants voted on how critical each outcome was to include using a nine-point Likert scale. All outcomes that did not reach consensus were discussed at a consensus meeting. MAIN OUTCOME MEASURES: Critical outcomes to include in the core outcome set. RESULTS: A total of 53 091 articles were identified. Outcomes were extracted from 427 articles. The qualitative data yielded 45 outcomes. An additional 24 outcomes came from the literature. In round one, 82 participants ranked 30 outcomes. One new outcome was included in round two, during which participants (n = 60) voted 12/31 outcomes as critical to include. The remaining 20 outcomes were discussed at the consensus meeting and two outcomes were included. Maternal outcomes included: pregnancy complications; delivery complications; maternal wellbeing; gestational weight change; maternal vitamin and mineral status; mental health; diet quality; nutritional intakes; need for treatments, interventions, medications and supplements; pregnancy loss or perinatal death; birth defects or congenital anomalies; neonatal complications; and newborn anthropometry and body composition. CONCLUSIONS: The use of the Pregnancy Nutrition Core Outcome Set (PRENCOS) will ensure researchers measure what matters most from the perspective of key stakeholders.

Folic Acid Supplementation in Postpolypectomy Patients in a Randomized Controlled Trial Increases Tissue Folate Concentrations and Reduces Aberrant DNA Biomarkers in Colonic Tissues Adjacent to the Former Polyp Site.

BACKGROUND: Low folate status is associated with an increased risk of colorectal carcinogenesis. Optimal folate status may be genoprotective by preventing uracil misincorporation into DNA and DNA hypomethylation. Adenomatous polyps have low folate status compared with normal colonic mucosa, and they are surrounded by histologically normal mucosa that also is of low folate status. OBJECTIVE: In a randomized controlled trial conducted at a single Dublin hospital between April 2002 and March 2004, we assessed the effect of folic acid supplementation on tissue folate, uracil misincorporation into DNA, and global DNA hypomethylation in colonocytes isolated from sites of adenomatous polyps and from histologically normal tissue adjacent and 10-15 cm distal to them. METHODS: Twenty patients with adenomatous polyps on initial colonoscopy and polypectomy were randomly assigned to receive either 600 µg folic acid/d [n = 12, 38% men, mean age 64.3 y, and body mass index (BMI, in kg/m(2)) 26.6] or placebo (n = 8, 50% men, mean age 68.4 y, and BMI 27.2) for 6 mo, and then repeat the colonoscopy. Blood and colonocyte tissue folate concentrations were measured with the use of a microbiological assay. Uracil misincorporation and global DNA hypomethylation were measured in colonocytes with the use of modified comet assays. RESULTS: Over time, folic acid supplementation, compared with placebo, increased tissue folate (mean ± SEM) from 15.6 ± 2.62 pg/10(5) cells to 18.1 ± 2.12 pg/10(5) cells (P < 0.001) and decreased the global DNA hypomethylation ratio from 1.7 ± 0.1 to 1.0 ± 0.1 (P < 0.001). The uracil misincorporation ratio decreased by 0.5 ± 0.1 for the site adjacent to the polyp over time (P = 0.05). CONCLUSION: A response to folic acid supplementation, which increased colonocyte folate and improved folate-related DNA biomarkers of cancer risk, was seen in the participants studied. Exploratory analysis points toward the area formerly adjacent to polyps as possibly driving the response. That these areas persist after polypectomy in the absence of folate supplementation is consistent with a potentially carcinogenic field's causing the appearance of the polyp.

Low colonocyte folate is associated with uracil misincorporation and global DNA hypomethylation in human colorectum.

Low folate status is a risk factor for colon carcinogenesis; mechanisms proposed to account for this relationship include uracil misincorporation into DNA and global DNA hypomethylation. We investigated whether such biomarkers are related to folate status in isolated colonocytes from colonoscopy patients. In cases with adenomatous polyps (n = 40) or hyperplastic polyps (n = 16), colonocytes were isolated from biopsies from the polyp, from a site adjacent to the polyp, and from normal mucosa 10-15 cm distal to the polyp. In polyp-free controls (n = 53), biopsies were taken from ascending, transverse, and descending areas of colon. Within adenoma cases, there was a trend (P-trend < 0.001) of decreasing colonocyte folate (pg/105 cells, mean ± CI) from the site distal to the polyp (16.9 ± 2.4), to the site adjacent to the polyp (14.7 ± 2.3), to the polyp (12.8 ± 2.0). Correspondingly, there were increases in uracil misincorporation (P-trend < 0.001) and global DNA hypomethylation (P-trend = 0.012) across the 3 sites. Colonocyte folate concentrations were significantly correlated with RBC folate concentrations, but only in individuals with generally lower (≤484 µg/L) RBC folate status (r = 0.54; P = 0.006; n = 24), and were also significantly lower in normal mucosa of cases with adenomatous polyps than in controls matched for colonic segment. In conclusion, localized folate deficiency in specific areas of colon might create carcinogenic fields and affect the development of colorectal polyps through uracil misincorporation and DNA hypomethylation; alternatively, the polyp itself might deplete folate in the surrounding tissue. Folate supplementation trials aimed at colon cancer prevention should target individuals with suboptimal folate status.

Engaging community pharmacists in the primary prevention of cardiovascular disease: protocol for the Pharmacist Assessment of Adherence, Risk and Treatment in Cardiovascular Disease (PAART CVD) pilot study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death globally. Community pharmacist intervention studies have demonstrated clinical effectiveness for improving several leading individual CVD risk factors. Primary prevention strategies increasingly emphasise the need for consideration of overall cardiovascular risk and concurrent management of multiple risk factors. It is therefore important to demonstrate the feasibility of multiple risk factor management by community pharmacists to ensure continued currency of their role. METHODS/DESIGN: This study will be a longitudinal pre- and post-test pilot study with a single cohort of up to 100 patients in ten pharmacies. Patients aged 50-74 years with no history of heart disease or diabetes, and taking antihypertensive or lipid-lowering medicines, will be approached for participation. Assessment of cardiovascular risk, medicines use and health behaviours will be undertaken by a research assistant at baseline and following the intervention (6 months). Validated interview scales will be used where available. Baseline data will be used by accredited medicines management pharmacists to generate a report for the treating community pharmacist. This report will highlight individual patients' overall CVD risk and individual risk factors, as well as identifying modifiable health behaviours for risk improvement and suggesting treatment and behavioural goals. The treating community pharmacist will use this information to finalise and implement a treatment plan in conjunction with the patient and their doctor. Community pharmacists will facilitate patient improvements in lifestyle, medicines adherence, and medicines management over the course of five counselling sessions with monthly intervals. The primary outcome will be the change to average overall cardiovascular risk, assessed using the Framingham risk equation. DISCUSSION: This study will assess the feasibility of implementing holistic primary CVD prevention programs into community pharmacy, one of the most accessible health services in most developed countries. TRIAL REGISTRATION: Australia and New Zealand Clinical Trial Registry Number: ACTRN12609000677202.

Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation.

There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 micromol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.