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Therapeutic Area: Heart Failure - Quality Improvement Background: Sodium glucose transport inhibitors (SGLT2i) have been shown to reduce the risk of hospitalizations and Cardiovascular (CV) death in patients with heart failure (HF). However, residents may be under prescribing SGLT2i for patients with HF in the outpatient setting possibly due to being unaware of newest guidelines or lack of comfort with prescribing SGLT2i for HF. The aim of this resident-led quality improvement project is to increase the rate of SGLT2i prescribed in patients with HF in the UT Tyler Internal Medicine (IM) Resident Clinic by 10% from a baseline of 16% within one month. Methods: Using a fish-bone diagram, root-cause analysis was performed for different reasons SGLT2i are under prescribed by residents. A Pick Chart was used for intervention planning which involved reminders on conference tables aimed at the preceptor and resident during report out.The intervention was implemented for one month and data was pulled using built EMR data analysis tool after this initial run to evaluate the percentage of SGLT2i prescriptions. Results: Pre-intervention data was pulled and revealed 16% of patients at the IM clinic with ICD codes indicating HF diagnosis were on SGLT2i (Figure 1). Post-intervention data analysis that used the same ICD codes showed a 10.7% increase to 26.7% of HF patients on SGLT2i (Figure 2). Conclusions: At the IM clinic, our goal was to improve SGLT2i prescription by 10% among the IM residents by educating and reminding residents on their indications. SGLT-2i have emerged as a staple in improving mortality and hospital readmission of patients with HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) as seen in Emperor Reduced and Emperor Preserved Trials. Despite the proven benefits of SGLT-2i in HF, their use in clinical practice remains suboptimal due to lack of awareness, concerns about side effects, and high cost.We intend to continue to assess rates of SGLT2i prescription by analyzing SGLT2i prescription rates every six months and improving current interventions further by implementing more robust signs that are updated periodically with changing guidelines. This project can be further expanded and replicated at other associated clinics and in the inpatient setting in the future.

Summary: To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder. : In this report, Lowry and colleagues found that loss of MECP2 has a more profound effect as pluripotent stem cells are terminally differentiated toward neurons. The loss of MECP2 leads to induction of P53 protein and subsequent senescence pathways including an SASP gene program, which appears to be a cause of diminished dendritic branching in Rett neurons. Keywords: MECP2, Rett syndrome, disease in a dish, senescence

Nature Communications 6: Article number: 10005 (2015); Published: 24 November 2015; Updated: 7 June 2016 In the original version of this Article the chemical structures of 2-ketoisovaleric acid and isobutanal in Fig. 3a were incorrect. The correct version of Fig. 3 appears below. Figure 3