Statistical modeling of extracellular vesicle cargo to predict clinical trial outcomes for hypoplastic left heart syndrome.

Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). To understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevant in vitro experiments to build a predictive model. We isolated CPCs from cardiac biopsies of patients with congenital heart disease (n = 29) and the lead-in patients with HLHS in the CHILD trial (n = 5). We sequenced CPC-EVs, and measured EV inflammatory, fibrotic, angiogeneic, and migratory responses. Overall, CPC-EV RNAs involved in pro-reparative outcomes had a significant fit to cardiac development and signaling pathways. Using a model trained on previously collected CPC-EVs, we predicted in vitro outcomes for the CHILD clinical samples. Finally, CPC-EV angiogenic performance correlated to clinical improvements in right ventricle performance.

Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome (CHILD Study).

Mortality in infants with hypoplastic left heart syndrome (HLHS) is strongly correlated with right ventricle (RV) dysfunction. Cell therapy has demonstrated potential improvements of RV dysfunction in animal models related to HLHS, and neonatal human derived c-kit+ cardiac-derived progenitor cells (CPCs) show superior efficacy when compared to adult human cardiac-derived CPCs (aCPCs). Neonatal CPCs (nCPCs) have yet to be investigated in humans. The CHILD trial (Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome) is a Phase I/II trial aimed at investigating intramyocardial administration of autologous nCPCs in HLHS infants by assessing the feasibility, safety, and potential efficacy of CPC therapy. Using an open-label, multicenter design, CHILD investigates nCPC safety and feasibility in the first enrollment group (Group A/Phase I). In the second enrollment group, CHILD uses a randomized, double-blinded, multicenter design (Group B/Phase II), to assess nCPC efficacy based on RV functional and structural characteristics. The study plans to enroll 32 patients across 4 institutions: Group A will enroll 10 patients, and Group B will enroll 22 patients. CHILD will provide important insights into the therapeutic potential of nCPCs in patients with HLHS.Clinical Trial Registration https://clinicaltrials.gov/ct2/home NCT03406884, First posted January 23, 2018.

Risk of hospitalized and non-hospitalized gastrointestinal bleeding in ALLHAT trial participants receiving diuretic, ACE-inhibitor, or calcium-channel blocker.

OBJECTIVES: This post-trial data linkage analysis was to utilize the data of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants linked with their Medicare data to examine the risk of hospitalized and non-hospitalized gastrointestinal (GI) bleeding associated with antihypertensives. SETTINGS: ALLHAT was a multicenter, randomized, double-blind, active-controlled trial conducted in a total of 42,418 participants aged ≥55 years with hypertension in 623 North American centers. Data for ALLHAT participants who were aged at ≥65 have been linked with their Medicare claims data. PARTICIPANTS: A total of 16,676 patients (4,480 for lisinopril, 4,537 for amlodipine, and 7,659 for chlorthalidone) with complete Medicare claims data were available for the final analysis. RESULTS: The cumulative incidences through March 31, 2002 of hospitalized GI bleeding were 5.4%, 5.8% and 5.4% for amlodipine, lisinopril, and chlorthalidone arms, respectively, but were not statistically significant among the 3 arms after adjusting for confounders in Cox regression models. The cumulative incidences of non-hospitalized GI bleeding were also similar across the 3 arms (12.0%, 12.2% and 12.0% for amlodipine, lisinopril, and chlorthalidone, respectively). The increased risk of GI bleeding by age was statistically significant after adjusting for confounders (HR = 1.04 per year, 95% CI: 1.03-1.05). Smokers also had a significantly higher risk of having hospitalized GI bleeding (1.45, 1.19-1.76). Hispanics, those who used aspirin or atenolol in-trial, had diabetes, more education, and a history of stroke had a significantly lower risk of having GI bleeding than their counterparts. Other factors such as gender, history of CHD, prior antihypertensive use, use of estrogen in women, and obesity did not have significant effects on the risk of GI bleeding. CONCLUSION: There were no statistically significant differences on the risk of hospitalized or non-hospitalized GI bleeding among the 3 ALLHAT trial arms (amlodipine, lisinopril, and chlorthalidone) during the entire in-trial follow-up.

Behind closed doors: physician-patient discussions about colorectal cancer screening.

BACKGROUND: Despite the availability of multiple effective screening tests for colorectal cancer, screening rates remain suboptimal. The literature documents patient preferences for different test types and recommends a shared decision-making approach for physician-patient colorectal cancer screening (CRCS) discussions, but it is unknown whether such communication about CRCS preferences and options actually occurs in busy primary-care settings. OBJECTIVE: Describe physician-patient CRCS discussions during a wellness visit. DESIGN: Cross-sectional; patients audio-recorded with physicians. PARTICIPANTS: A subset of patients (N = 64) participating in a behavioral intervention trial designed to increase CRCS who completed a wellness visit during the trial with a participating physician (N = 8). APPROACH: Transcripts were analyzed using qualitative methods. RESULTS: Physicians in this sample consistently recommended CRCS, but focused on colonoscopy. Physicians did not offer a fecal occult blood test alone as a screening choice, which may have created missed opportunities for some patients to get screened. In this single visit, physicians' communication processes generally precluded discussion of patients' test preferences and did not facilitate shared decision-making. Patients' questions indicated their interest in different CRCS test types and appeared to elicit more information from physicians. Some patients remained resistant to CRCS after discussing it with a physician. CONCLUSION: If a preference for colonoscopy is widespread among primary-care physicians, the implications for intervention are either to prepare patients for this preference or to train physicians to offer options when recommending screening to patients.

Estimating development cost for a tailored interactive computer program to enhance colorectal cancer screening compliance.

The authors used an actual-work estimate method to estimate the cost of developing a tailored interactive computer education program to improve compliance with colorectal cancer screening guidelines in a large multi-specialty group medical practice. Resource use was prospectively collected from time logs, administrative records, and a design and computing subcontract. Sensitivity analysis was performed to examine the uncertainty of the overhead cost rate and other parameters. The cost of developing the system was Dollars 328,866. The development cost was Dollars 52.79 per patient when amortized over a 7-year period with a cohort of 1,000 persons. About 20% of the cost was incurred in defining the theoretic framework and supporting literature, constructing the variables and survey, and conducting focus groups. About 41% of the cost was for developing the messages, algorithms, and constructing program elements, and the remaining cost was to create and test the computer education program. About 69% of the cost was attributable to personnel expenses. Development cost is rarely estimated but is important for feasibility studies and ex-ante economic evaluations of alternative interventions. The findings from this study may aid decision makers in planning, assessing, budgeting, and pricing development of tailored interactive computer-based interventions.