ABSTRACT
Recent advances in the understanding and use of pluripotent stem cells have produced major changes in approaches to the diagnosis and treatment of human disease. An obstacle to the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for regenerative medicine, disease modeling and drug discovery is their immature state relative to adult myocardium. We show the effects of a combination of biochemical factors, thyroid hormone, dexamethasone, and insulin-like growth factor-1 (TDI) on the maturation of hiPSC-CMs in 3D cardiac microtissues (CMTs) that recapitulate aspects of the native myocardium. Based on a comparison of the gene expression profiles and the structural, ultrastructural, and electrophysiological properties of hiPSC-CMs in monolayers and CMTs, and measurements of the mechanical and pharmacological properties of CMTs, we find that TDI treatment in a 3D tissue context yields a higher fidelity adult cardiac phenotype, including sarcoplasmic reticulum function and contractile properties consistent with promotion of the maturation of hiPSC derived cardiomyocytes.
Subject(s)
Cell Differentiation , Induced Pluripotent Stem Cells/cytology , Myocytes, Cardiac/cytology , Action Potentials , Biomechanical Phenomena , Calcium Signaling , Cell Shape , Gene Expression Regulation , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/ultrastructure , Myocardial Contraction , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/ultrastructure , Proteome/metabolism , Tissue Engineering , Transcriptome/geneticsABSTRACT
BACKGROUND: The Patient Health Questionnaire-2 (PHQ-2) is an ultra-brief questionnaire widely used by researchers and clinicians to detect major depressive disorder (MDD). Despite its individual and societal impact, MDD is often undetected and untreated particularly among sub-Saharan Africans. We conducted this study to evaluate the reliability and validity of using the PHQ-2 as a screen for MDD among Ethiopian adults. METHODS: A total of 926 adults attending outpatient departments in a major referral hospital in Addis Ababa, Ethiopia participated in this study. Construct validity was assessed by examining associations of PHQ-2 scores with World Health Organization Quality of Life (WHO-QOL) domains. We assessed criterion validity and performance characteristics against an independent, blinded, and psychiatrist administered semi-structured Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview using measures of sensitivity, specificity and receiver operating characteristics (ROC) curves. RESULTS: The PHQ-2 items showed good reliability (intraclass correlation coefficient=0.92). Quality of life, as reflected by subscale scores for four WHO-QOL domains, was significantly lower among patients with increasing PHQ-2 scores demonstrating good construct validity. ROC analysis and Youden Index showed that a PHQ-2 threshold score of 3 offered optimal discriminatory power with respect to the diagnosis of MDD via the clinical interview (sensitivity=74% and specificity=60%). CONCLUSION: The Amharic language version of the PHQ-2 had good sensitivity and fair specificity for detecting MDD compared against a psychiatrist administered SCAN diagnosis. This study provides evidence for the PHQ-2 as a reliable and valid ultra-brief screening tool for initial identification of MDD.
