Inhibition of endothelial histone deacetylase 2 shifts endothelial-mesenchymal transitions in cerebral arteriovenous malformation models.

Cerebral arteriovenous malformations (AVMs) are the most common vascular malformations worldwide and the leading cause of hemorrhagic strokes that may result in crippling neurological deficits. Here, using newly generated mouse models, we uncovered that cerebral endothelial cells (ECs) acquired mesenchymal markers and caused vascular malformations. Interestingly, we found that limiting endothelial histone deacetylase 2 (HDAC2) prevented cerebral ECs from undergoing mesenchymal differentiation and reduced cerebral AVMs. We found that endothelial expression of HDAC2 and enhancer of zeste homolog 1 (EZH1) was altered in cerebral AVMs. These alterations changed the abundance of H4K8ac and H3K27me in the genes regulating endothelial and mesenchymal differentiation, which caused the ECs to acquire mesenchymal characteristics and form AVMs. Together, this investigation demonstrated that the induction of HDAC2 altered specific histone modifications, which resulted in mesenchymal characteristics in the ECs and cerebral AVMs. The results provided insight into the epigenetic impact on AVMs.

CDK1 inhibition reduces osteogenesis in endothelial cells in vascular calcification.

Vascular calcification is a severe complication of cardiovascular diseases. Previous studies demonstrated that endothelial lineage cells transitioned into osteoblast-like cells and contributed to vascular calcification. Here, we found that inhibition of cyclin-dependent kinase (CDK) prevented endothelial lineage cells from transitioning to osteoblast-like cells and reduced vascular calcification. We identified a robust induction of CDK1 in endothelial cells (ECs) in calcified arteries and showed that EC-specific gene deletion of CDK1 decreased the calcification. We found that limiting CDK1 induced E-twenty-six specific sequence variant 2 (ETV2), which was responsible for blocking endothelial lineage cells from undergoing osteoblast differentiation. We also found that inhibition of CDK1 reduced vascular calcification in a diabetic mouse model. Together, the results highlight the importance of CDK1 suppression and suggest CDK1 inhibition as a potential option for treating vascular calcification.

Developing a User-Centered Digital Clinical Decision Support App for Evidence-Based Medication Recommendations for Type 2 Diabetes Mellitus: Prototype User Testing and Validation Study.

BACKGROUND: Closing the gap between care recommended by evidence-based guidelines and care delivered in practice is an ongoing challenge across systems and delivery models. Clinical decision support systems (CDSSs) are widely deployed to augment clinicians in their complex decision-making processes. Despite published success stories, the poor usability of many CDSSs has contributed to fragmented workflows and alert fatigue. OBJECTIVE: This study aimed to validate the application of a user-centered design (UCD) process in the development of a standards-based medication recommender for type 2 diabetes mellitus in a simulated setting. The prototype app was evaluated for effectiveness, efficiency, and user satisfaction. METHODS: We conducted interviews with 8 clinical leaders with 8 rounds of iterative user testing with 2-8 prescribers in each round to inform app development. With the resulting prototype app, we conducted a validation study with 43 participants. The participants were assigned to one of two groups and completed a 2-hour remote user testing session. Both groups reviewed mock patient facts and ordered diabetes medications for the patients. The Traditional group used a mock electronic health record (EHR) for the review in Period 1 and used the prototype app in Period 2, while the Tool group used the prototype app during both time periods. The perceived cognitive load associated with task performance during each period was assessed with the National Aeronautics and Space Administration Task Load Index. Participants also completed the System Usability Scale (SUS) questionnaire and Kano Survey. RESULTS: Average SUS scores from the questionnaire, taken at the end of 5 of the 8 user testing sessions, ranged from 68-86. The results of the validation study are as follows: percent adherence to evidence-based guidelines was greater with the use of the prototype app than with the EHR across time periods with the Traditional group (prototype app mean 96.2 vs EHR mean 72.0, P<.001) and between groups during Period 1 (Tool group mean 92.6 vs Traditional group mean 72.0, P<.001). Task completion times did not differ between groups (P=.23), but the Tool group completed medication ordering more quickly in Period 2 (Period 1 mean 130.7 seconds vs Period 2 mean 107.7 seconds, P<.001). Based on an adjusted α level owing to violation of the assumption of homogeneity of variance (Ps>.03), there was no effect on screens viewed and on perceived cognitive load (all Ps>.14). CONCLUSIONS: Through deployment of the UCD process, a point-of-care medication recommender app holds promise of improving adherence to evidence-based guidelines; in this case, those from the American Diabetes Association. Task-time performance suggests that with practice the T2DM app may support a more efficient ordering process for providers, and SUS scores indicate provider satisfaction with the app.

Elevation of serum creatine phosphokinase in hospitalized patients.

BACKGROUND: The clinical characteristics and outcomes of patients with significant noncardiac and cardiac serum creatine phosphokinase (CPK) elevations are not well described. METHODS: One hundred fifty-eight inpatients who had CPK elevation of >1000 IU/L were identified. One hundred thirty-seven patients whose CPK elevations could be attributed to either noncardiac or cardiac etiologies were included and analyzed for clinical characteristics, 30-day, 3-month, and 1-year all-cause mortality rates. Twenty-one patients were excluded, in whom noncardiac and cardiac CPK (CCPK) elevations coexisted, or etiologies were unclear. RESULTS: Of the 137 patients, 43 (31%) patients had CCPK elevation and 94 (69%) patients had noncardiac CPK (NCCPK) elevation. One-year mortality rate was 26.6% (25 of 94 patients) in NCCPK elevation group. Decedents were older (P < 0.05), had higher blood urea nitrogen (P < 0.01) and creatinine (P < 0.05) levels, and had higher white blood cell counts (P < 0.05) compared with survivors. In CCPK elevation group, 37.2% (16 of 43 patients) died within 1 year after admission. Decedents were also older (P < 0.01) and had higher blood urea nitrogen (P < 0.01) and creatinine (P < 0.01) levels. CONCLUSION: The incidence of NCCPK elevation is greater than that of CCPK elevation in a veteran, mostly male, population. One-year mortality rate in patients with NCCPK elevation is comparable to that in patients with CCPK elevation (26.6% versus 37.2%, P = 0.290). Age and renal insufficiency are 2 major predictors for increased mortality in both groups.

New onset atrial fibrillation developing in medical inpatients.

BACKGROUND: The outcome of patients who develop new onset atrial fibrillation (AF) after admission to an Internal Medicine service for acute medical illnesses is unknown. METHODS: In a retrospective review, we compared patients in the study group: patients who were admitted to hospital for acute medical illnesses and subsequently developed new onset AF during hospitalization, with a control group 1: patients whose admitting diagnosis was new onset AF and a control group 2: patients who were admitted for acute medical illnesses and never developed AF. We analyzed clinical characteristics and all-cause mortality rate during the first 30 days, 6 months, and 1 year after admission. RESULTS: The 1-year mortality rates in study group were significantly higher than control group 1 (62% versus 8%, P < 0.001) and control group 2 (62% versus 29%, P < 0.05). These results suggest that AF and acute medical illness both are risk factors for increased mortality. The odds ratios were 4.05 (P = 0.023) and 18.33 (P = 0.001) for AF and acute medical illnesses, respectively, indicating that acute medical illness is the better predictor for mortality. Troponin I levels were elevated in 46% of patients in study group versus 12% in control group 1 and 42% in control group 2 (P < 0.05). CONCLUSIONS: Medical inpatients who develop new onset AF during hospitalization for acute medical illnesses have an increased mortality when compared with patients who were admitted solely for new onset AF. Acute medical illness rather than AF plays a more important role on the increased mortality in this subset of patient population.