Cardiac tissues generated from human induced pluripotent stem (iPS) cells can serve as platforms for patient-specific studies of physiology and disease1–6. The predictive power of these models remains limited by their immature state1,2,5,6. We show that this fundamental limitation could be overcome if cardiac tissues are formed from early iPS-derived cardiomyocytes (iPS-CM), soon after the initiation of spontaneous contractions, and subjected to physical conditioning of an increasing intensity. After only 4 weeks of culture, these tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiologic sarcomere length (2.2 μm) and density of mitochondria (30%), the presence of transverse tubules (t-tubules), oxidative metabolism, positive force-frequency relationship, and functional calcium handling for all iPS cell lines studied. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiologic responses to isoproterenol and recapitulating pathological hypertrophy, in support of the utility of this tissue model for studies of cardiac development and disease.

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Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders.

ObjectiveTo explore medication-related burden (MRB) and patients’ lived experience with medicines (PLEM) without regard to particular medication therapies or medical conditions.DesignSystematic review and metasynthesis of qualitative studies.Data sourcesMEDLINE, EMBASE, International Pharmaceutical Abstracts, PsycINFO, Global health, CINAHL and Web of Science were searched from January 2000 to August 2014 using medication burden and patients’ lived experience terms.Synthesis methodsSynthesis was undertaken following metaethnography methods and a comparative thematic analysis technique.Results34 articles from 12 countries with a total of 1144 participants were included. 3 major inter-related themes emerged central to PLEM: MRB, medication related beliefs and medication taking practice. The negative impact of MRB, due to its interference on patients’ daily lives and effects on well-being, its influence on patients’ beliefs and behaviours, and a potential risk for drug-related problems (DRPs) was evident. This resulted in non-adherence and poorer outcomes (unachieved therapeutic goals and damage to patients’ health). Patients who experienced MRB interference in their life over time begin to juggle their medicines. Others continue their medicines despite experiencing MRB resulting in compromised physical, social or psychological well-being.ConclusionsThere is a shared commonality of PLEM among the studies. MRB plays a central role in influencing patients’ health and well-being, beliefs and behaviour towards medicines. Given the complexity of MRB and its impact evident from this review, there is a need for healthcare practitioners to have insight into PLEM in therapeutic care plans. Understanding PLEM is an opportunity for practitioners to identify particular MRBs that patients encounter, and provide individualised care through selection of therapeutic care plans that suit a patient's life. This may assist in helping to achieve patients’ medication-related needs, and improve medication therapy and health outcomes.