Implementation strategies to enhance the implementation of eHealth programs for patients with chronic illnesses: realist systematic review

Background: There is growing evidence of the positive effects of electronic health (eHealth) interventions for patients with chronic illness, but implementation of such interventions into practice is challenging. Implementation strategies that potentially impact implementation outcomes and implementation success have been identified. Which strategies are actually used in the implementation of eHealth interventions for patients with chronic illness and which ones are the most effective is unclear. Objective: This systematic realist review aimed to summarize evidence from empirical studies regarding (1) which implementation strategies are used when implementing eHealth interventions for patients with chronic illnesses living at home, (2) implementation outcomes, and (3) the relationship between implementation strategies, implementation outcomes, and degree of implementation success. Methods: A systematic literature search was performed in the electronic databases MEDLINE, Embase, PsycINFO, Scopus, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library. Studies were included if they described implementation strategies used to support the integration of eHealth interventions into practice. Implementation strategies were categorized according to 9 categories defined by the Expert Recommendations for Implementing Change project: (1) engage consumers, (2) use evaluative and iterative strategies, (3) change infrastructure, (4) adapt and tailor to the context, (5) develop stakeholder interrelationships, (6) use financial strategies, (7) support clinicians, (8) provide interactive assistance, and (9) train and educate stakeholders. Implementation outcomes were extracted according to the implementation outcome framework by Proctor and colleagues: (1) acceptability, (2) adoption, (3) appropriateness, (4) cost, (5) feasibility, (6) fidelity, (7) penetration, and (8) sustainability. Implementation success was extracted according to the study authors’ own evaluation of implementation success in relation to the used implementation strategies. Results: The implementation strategies management support and engagement, internal and external facilitation, training, and audit and feedback were directly related to implementation success in several studies. No clear relationship was found between the number of implementation strategies used and implementation success. Conclusions: This is the first review examining implementation strategies, implementation outcomes, and implementation success of studies reporting the implementation of eHealth programs for patients with chronic illnesses living at home. The review indicates that internal and external facilitation, audit and feedback, management support, and training of clinicians are of importance for eHealth implementation. The review also points to the lack of eHealth studies that report implementation strategies in a comprehensive way and highlights the need to design robust studies focusing on implementation strategies in the future.publishedVersio

The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer

Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping