Right ventricular energetic biomarkers from 4D Flow CMR are associated with exertional capacity in pulmonary arterial hypertension

Background: Cardiovascular magnetic resonance (CMR) offers comprehensive right ventricular (RV) evaluation in pulmonary arterial hypertension (PAH). Emerging four-dimensional (4D) flow CMR allows visualization and quantification of intracardiac flow components and calculation of phasic blood kinetic energy (KE) parameters but it is unknown whether these parameters are associated with cardiopulmonary exercise test (CPET)-assessed exercise capacity, which is a surrogate measure of survival in PAH. We compared 4D flow CMR parameters in PAH with healthy controls, and investigated the association of these parameters with RV remodelling, RV functional and CPET outcomes. Methods: PAH patients and healthy controls from two centers were prospectively enrolled to undergo on-site cine and 4D flow CMR, and CPET within one week. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes (EDV). Phasic (peak systolic, average systolic, and peak E-wave) LV and RV blood flow KE indexed to EDV (KEIEDV) and ventricular LV and RV flow components (direct flow, retained inflow, delayed ejection flow, and residual volume) were calculated. Oxygen uptake (VO2), carbon dioxide production (VCO2) and minute ventilation (VE) were measured and recorded. Results: 45 PAH patients (46 ± 11 years; 7 M) and 51 healthy subjects (46 ± 14 years; 17 M) with no significant differences in age and gender were analyzed. Compared with healthy controls, PAH had significantly lower median RV direct flow, RV delayed ejection flow, RV peak E-wave KEIEDV, peak VO2, and percentage (%) predicted peak VO2, while significantly higher median RV residual volume and VE/VCO2 slope. RV direct flow and RV residual volume were significantly associated with RV remodelling, function, peak VO2, % predicted peak VO2 and VE/VCO2 slope (all P < 0.01). Multiple linear regression analyses showed RV direct flow to be an independent marker of RV function, remodelling and exercise capacity. Conclusion: In this 4D flow CMR and CPET study, RV direct flow provided incremental value over RVEF for discriminating adverse RV remodelling, impaired exercise capacity, and PAH with intermediate and high risk based on risk score. These data suggest that CMR with 4D flow CMR can provide comprehensive assessment of PAH severity, and may be used to monitor disease progression and therapeutic response

SYNTHESIS OF SMALL MOLECULES FOR STEM CELL DIFFERENTIATION AND CELLULAR REPROGRAMMING

Ph.DDOCTOR OF PHILOSOPH

Transitional care for the highest risk patients: findings of a randomised control study

Background: Interventions to prevent readmissions of patients at highest risk have not been rigorously evaluated. We conducted a randomised controlled trial to determine if a post-discharge transitional care programme can reduce readmissions of such patients in Singapore.Methods: We randomised 840 patients with two or more unscheduled readmissions in the prior 90 days and Length of stay, Acuity of admission, Comorbidity of patient, Emergency department utilisation score ≥10 to the intervention programme (n = 419) or control (n = 421). Patients allocated to the intervention group received post-discharge surveillance by a multidisciplinary integrated care team and early review in the clinic. The primary outcome was the proportion of patients with at least one unscheduled readmission within 30 days after discharge.Results: We found no statistically significant reduction in readmissions or emergency department visits in patients on the intervention group compared to usual care. However, patients in the intervention group reported greater patient satisfaction (p &lt; 0.001).Conclusion: Any beneficial effect of interventions initiated after discharge is small for high-risk patients with multiple comorbidity and complex care needs. Future transitional care interventions should focus on providing the entire cycle of care for such patients starting from time of admission to final transition to the primary care setting.Trial Registration: Clinicaltrials.gov, no NCT0232575

Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling

10.1016/j.yjmcc.2014.12.003Journal of Molecular and Cellular Cardiology8056-7

Molecular docking-aided identification of small molecule inhibitors targeting β-catenin-TCF4 interaction

Summary: Here we report a molecular docking-based approach to identify small molecules that can target the β-catenin (β-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of β-cat using publicly available β-cat protein crystal structures, and existing β-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to β-cat, of which 3 were identified to be effective against a Wnt-responsive luciferase reporter. In vitro functional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the β-cat-TCF4 PPI. GB1874 also affected the proliferation and stemness of Wnt-addicted colorectal cancer (CRC) cells in vitro. Encouragingly, GB1874 inhibited the growth of CRC tumor xenografts in vivo, thus demonstrating its potential for further development into therapeutics against Wnt-associated cancer indications

Risk of malignancies in patients with spondyloarthritis treated with biologics compared with those treated with non-biologics:a systematic review and meta-analysis

Background: The aim of our study was to synthesize evidence on the occurrence of malignancy in spondyloarthritis (SpA), from randomized controlled trials (RCTs) comparing biologics with non-biologics and biologics to each other. Methods: We systematically searched Medline, Cochrane Library, EMBASE, Scopus and ClinicalTrials.gov from inception until 31 October 2018. RCTs with ⩾24-week follow-up were included. We extracted data using standardized forms and assessed the risk of bias using the Cochrane Risk of Bias Tool. We performed pair-wise meta-analyses and network meta-analyses to compare the risk of malignancy for each biologics class and SpA type. We reported the Peto odds ratio (OR) of any malignancy along with 95% confidence intervals (95% CI). Bayesian posterior probabilities comparing risk of malignancy of each biologic class with non-biologics were computed as supplementary measures. Results: Fifty-four trials were included; most (44/54) had follow-up 1, they had wide 95% CI and p  >0.05. The overall Peto OR comparing biologics with non-biologics was 1.42 (95% CI 0.80–2.53). Only interleukin-17 inhibitors in peripheral SpA had p  <0.05 (Peto OR 2.77, 95% CI 1.07–7.13); the posterior probability that the risk was higher than non-biologics was 98%. Stratified analyses revealed no consistent trend by prior exposure to biologics, duration of follow-up, study quality, study-arm crossover, analytical approaches and type of malignancy. Conclusions: Our findings indicate no overall elevated risk of malignancy with biologics in SpA. As our meta-analyses are unable to conclude on the long-term risk, long-term pharmacovigilance of biologics in SpA may still be warranted

Applying the Integrated Practice Unit Concept to a Modified Virtual Ward Model of Care for Patients at Highest Risk of Readmission: A Randomized Controlled Trial

<div><p>Background</p><p>Emerging evidence from the virtual ward care model showed that multidisciplinary case management are inadequate to reduce readmissions or death for high risk patients. There is consensus that interventions should encompass both pre-hospital discharge and post-discharge transitional care to be effective. Integrated practice units (IPU) had been proposed as an approach of restructuring the organization and work processes of multidisciplinary teams to achieve value in healthcare. Our primary objective is to evaluate if the novel application of the IPU concept to organize a modified virtual ward model incorporating pre-hospital discharge transitional care can reduce readmissions of patients at highest risk for readmission.</p><p>Methods</p><p>We conducted an open label, assessor blinded randomized controlled trial on patients with one or more unscheduled readmissions in the prior 90 days and LACE score ≥ 10. 840 patients were randomized in 1:1 ratio and blocks of 6 to the intervention program (n = 420) or control (n = 420). Allocation concealment was effected via an off-site telephone service maintained by a hospital administrator. Intervention patients received discharge planning, medication reconciliation, coaching on self-management of chronic diseases using standardized action plans and an individualized care plan complete with written discharge instructions, appointments schedule, medication changes and the contact information of the outpatient VW nurse before discharge. At discharge, care is handed over to the outpatient VW team. Patients were closely monitored in the VW for three months that included a telephone review within 72 hours of discharge, home assessment, regular telephone reviews to identify early complications and early review clinics for patients who destabilize. The VW meet daily to discuss new patients and review care plans for patients. Control patients received standard hospital care that included a standardized patient copy of the hospital discharge summary listing their medical diagnoses and medications; and follow up is arranged with a primary care provider or specialist as considered necessary. The primary outcome was the unplanned readmission rate to any hospital within 30 days of discharge. Secondary outcomes included the unplanned readmission rate, emergency department (ED) attendance rate to any hospital and the probability without readmission or death up to 180 days of discharge. Length of stay and mortality rate at 90-day were compared between the two groups. Outcome data were objectively retrieved from the hospital and National Electronic Health Records by a blinded outcome assessor.</p><p>Findings</p><p>All patients’ outcomes were included in an intention-to-treat analysis. The characteristics of both study groups were similar. Patients in the intervention group had a significant reduction in the number of 30-day readmissions, IRR 0.67 (95% CI, 0.52 to 0.86, p = 0.001) and the number of 30-day emergency department attendances, IRR 0.60 (95% CI, 0.46 to 0.79, p<0.001) compared to those receiving standard hospital care. The effectiveness was sustained at 90 and 180 days. The intervention group utilized 1164 fewer hospital bed days at 90-day post discharge. No adverse events were reported.</p><p>Conclusion</p><p>Applying the integrated practice unit concept to the virtual ward program resulted in reduced readmissions in patients who are at highest risk of readmission.</p></div

10 Attributes of Integrated Practice Units (IPUs) as applied to our modified Virtual Ward Model.

<p>10 Attributes of Integrated Practice Units (IPUs) as applied to our modified Virtual Ward Model.</p

Analysis of Outpatient Specialist Clinic Visits.

<p>Analysis of Outpatient Specialist Clinic Visits.</p

Baseline Characteristics of Participants.

<p>Baseline Characteristics of Participants.</p