A randomized controlled trial evaluating a theory driven, complex intervention centered on task sharing and mobile health to improve selfcare and outcomes in heart failure - The PANACEA-HF RCT: Design and rationale.

Background: We developed a three-pronged complex intervention to improve selfcare and deliver whole person care for patients with heart failure, underpinned by the 'extant cycle' theory - a theory based on our formative work. Methods: This is a 3 centre, 2-arm, 1:1, open, adaptive stratified, randomized controlled trial. We included patients aged ≥ 18 years with heart failure, taking any of the key guideline directed medical treatments, with a history of or currently on a high ceiling diuretic. We excluded end stage renal disease, clinically diagnosed severe mental illness or cognitive dysfunction and having no caregivers. Interventions included, (i) trained hospital based lay health worker mediated assessment of patients' current selfcare behaviour, documenting barriers and facilitators and implementing a plan to 'transition' the patient toward optimal selfcare. (ii) m-health mediated remote monitoring and (iii) dose optimization through a 'physician supervisor'. Results: We recruited 301 patients between Jan 2021 and Jan 2022. Mean age was 59.8 (±11.7) years, with 195 (64.8 %) from rural or semi-urban areas and 67.1 % having intermediate to low health literacy. 190 (63.1 %) had an underlying ischemic cardiomyopathy. In the intervention arm, 142 (94.1 %) had a Selfcare in Heart Failure Index (SCHFI) score of ≤70, with significant barriers being 'lack of knowledge' 105 (34.5 %) and 'behavioural passivity' 23 (7.5 %). Conclusion: This is the first South Asian trial evaluating a complex intervention underpinned by behaviour change theory for whole person heart failure care. These learnings can be applied to heart failure patient care in other resource constrained health systems.

Principles Governing DNA Methylation during Neuronal Lineage and Subtype Specification.

Although comprehensively described during early neuronal development, the role of DNA methylation/demethylation in neuronal lineage and subtype specification is not well understood. By studying two distinct neuronal progenitors as they differentiate to principal neurons in mouse hippocampus and striatum, we uncovered several principles governing neuronal DNA methylation during brain development. (1) The program consists of three stages: an initial genome-wide methylation during progenitor proliferation is followed by loss of methylation during the transition of regional progenitors to "young" hippocampal/striatal neurons, which is then reversed by gain in methylation during maturation to subtype-specific neurons. (2) At the first two stages, gain and loss of methylation are limited to CpGs, whereas during the third maturation stage, methylation also occurs at non-CpG sites in both lineages. (3) Methylation/demethylation, similar to transcription, are initially highly similar in the two lineages, whereas diversification in methylation and transcription during maturation creates subtype-specific methylation differences. (4) Initially, methylation targets all genomic locations, whereas later, during early and late differentiation, the preferred targets are intronic/intergenic sequences with enhancer-like activity. (5) Differentially methylated genes are enriched in sequential neurodevelopmental functions (such as progenitor proliferation, migration, neuritogenesis, and synaptic transmission); upregulated genes represent current and consecutive stage-specific functions, and downregulated genes represent preceding functions that are no longer required. The main conclusion of our work is that the neuronal methylation/demethylation program is predominantly developmental with minimal lineage specificity, except in the final stage of development when neuron subtype-specific differences also emerge. SIGNIFICANCE STATEMENT: Our work is the first to describe a set of relatively simple rules that govern DNA methylation and demethylation in neuronal development in vivo. By dividing neurodevelopment to three major stages and applying rules to each of them, we created a matrix that comprehensively describes DNA methylation/demethylation events in two neuronal lineages, with a total of 10 cell types spanning the entire neurodevelopment. Beyond increasing our understanding of the epigenetic regulation of normal development, our work will be useful in deciphering how environmental perturbations, such as gestational toxins, drugs, stress, infection, and offspring neglect/maltreatment, interfere with the developmental methylation program.

The need for routine pre-operative coagulation screening tests (prothrombin time PT/partial thromboplastin time PTT) for healthy children undergoing elective tonsillectomy and/or adenoidectomy.

In some medical centers, the routine pre-operative evaluation of healthy children undergoing elective tonsillectomy and/or adenoidectomy (T and A) includes coagulation screening tests (PT, prothrombin Time; PTT, partial thromboplastin time; and INR, international normalized ratio). In this retrospective study, we determined whether there is a positive correlation between prolonged PT/PTT/INR tests in healthy children, with no prior medical history of coagulation problems, and bleeding during surgery and/or bleeding in the month following surgery. We reviewed the records of 416 elective T and A surgeries performed at the Soroka University Medical Center in Beer-Sheva, Israel, over the course of 1999. One hundred and twenty-one (29.1%) patients had preoperative prolonged PT values but only four (3.3%) of these patients experienced light bleeding during surgery. Seven (5.8%) of the 121 patients with prolonged PT tests experienced bleeding episodes during the 1st month subsequent to the surgery. Of the 65 (15.6%) patients who had prolonged pre-operative INR values, only three (4.6%) experienced light bleeding during surgery. Two (3.1%) patients with prolonged INR values experienced light bleeding during the 1st month subsequent to surgery. Sixty-one (14.7%) patients had prolonged first preoperative PTT values, only five of whom (8.2%) experienced light bleeding during surgery. Two (3.3%) of the 61 with prolonged PTT values experienced light bleeding during the 1st month subsequent to surgery. We therefore concluded that pre-operative coagulation screening tests provide low sensitivity and low bleeding predictive value. As such, routine coagulation tests before T &A are not indicated unless a medical history of bleeding tendency is suspected.