Cardiac Transthyretin-derived Amyloidosis:An Emerging Target in Heart Failure with Preserved Ejection Fraction?

Heart failure with preserved ejection fraction (HFpEF) comprises half of the heart failure population. A specific, but underdiagnosed, cause for HFpEF is transthyretin-derived (ATTR) amyloidosis. This article reviews the clinical characteristics of cardiac ATTR amyloidosis. The clinical suspicion of cardiac ATTR amyloidosis is strong if pronounced left ventricular hypertrophy is present in the absence of hypertension. Scintigraphy with a diphosphonate tracer is a diagnostic tool for the early detection of cardiac ATTR amyloidosis with high sensitivity and specificity. First treatment options for ATTR amyloidosis recently emerged, and showed a reduction in morbidity and mortality, especially if treatment was started in the early stages of disease. In light of these results, screening for ATTR amyloidosis in the general HFpEF population with left ventricular hypertrophy might be useful

Organs-on-Chips in Drug Development: The Importance of Involving Stakeholders in Early Health Technology Assessment

Organs-on-chips are three-dimensional, microfluidic cell culture systems that simulate the function of tissues and organ subunits. Organ-on-chip systems are expected to contribute to drug candidate screening and the reduction of animal tests in preclinical drug development and may increase efficiency of these processes. To maximize the future impact of the technology on drug development, it is important to make informed decisions regarding the attributes and features of organs-on-chips even though the technology is still in a stage of early development. It is likely that different stakeholders in organ-on-chip development, such as engineers, biologists, regulatory scientists, and pharmaceutical researchers, will have different perspectives on how to maximize the future impact of the technology. Various aspects of organ-on-chip development, such as cost, materials, features, cell source, read-out technology, types of data, and compatibility with existing technology, will likely be judged differently by different stakeholders. Early health technology assessment (HTA) is needed in order to facilitate the essential integration of such potentially conflicting views in the process of technology development. In this critical review we discuss the potential impact of organs-on-chips on the drug development process, and we use a pilot study to give examples of how different stakeholders have different perspectives on attributes of organ-on-chip technology. As a future tool in early HTA of organs-on-chips, we suggest the use of multicriteria decision analysis (MCDA), which is a formal method to deal with multiple and conflicting criteria in technology development. We argue that it is essential to design and perform a comprehensive MCDA for organ-on-chip development, and so the future impact of this technology in the pharmaceutical industry can be maximized

Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes:The Importance of Functional Studies above Prediction

Genetic variants in gene-encoding proteins involved in cell-cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype-phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype-phenotype correlations, we separate variants into 'protein reducing' or 'altered protein' variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation

Comparative genetic and physiological characterisation of Pectinatus species reveals shared tolerance to beer-associated stressors but halotolerance specific to pickle-associated strains

This work was supported by Heineken Supply Chain B.V. PL, SD & HJF receive support from the Scottish Government Rural and Environment Sciences and Analytical Services (RESAS). We would like to express thanks to Nicola Smith for her help formatting Fig. 1, Dr Paul Sheridan for bioinformatics-based advice and help with troubleshooting scripts, Dr Kenneth Forbes for his advice on core and pan genome analysis, Sandro Cocuzza for providing the hop extract and Marine Freyereisen for supplying Lactobacillus brevis MB521.Peer reviewedPostprin