The evolving paradigm and current perception of hypertrophic cardiomyopathy: Implications for management.

Recent evidence from imaging and genetic screening studies has clearly shown that hypertrophic cardiomyopathy (HCM) is more common than initially perceived, emphasizing the need to reassess its associated clinical and social burden. While clinical and academic efforts have long been focused on stratification of arrhythmic risk and management of intraventricular obstruction, progression of cardiac dysfunction and heart failure-related complications have emerged as most relevant from the epidemiological standpoint, delineating a major unmet need. Furthermore, a broader perspective of our patients' needs has become central in the care of individuals with HCM, addressing issues that are not strictly clinical but equally important to their wellbeing, such as quality of life, athletic participation, lifestyle and reproductive choices and psychological adaptation to a chronic condition often detected at a young age. The appropriate evaluation and objective assessment of disease burden associated with HCM are increasingly relevant not only to management but also to trial design and evaluation of the efficacy of emerging, targeted treatments. In this review, we discuss the evolving perception of HCM prevalence and natural history, as well as recent acquisitions regarding its true, often under-appreciated socio-economic and clinical burden.

Expression Dysregulation as a Mediator of Fitness Costs in Antibiotic Resistance.

Antimicrobial resistance (AMR) poses a threat to global health and the economy. Rifampicin-resistant Mycobacterium tuberculosis accounts for a third of the global AMR burden. Gaining the upper hand on AMR requires a deeper understanding of the physiology of resistance. AMR often results in a fitness cost in the absence of drug. Identifying the molecular mechanisms underpinning this cost could help strengthen future treatment regimens. Here, we used a collection of M. tuberculosis strains that provide an evolutionary and phylogenetic snapshot of rifampicin resistance and subjected them to genome-wide transcriptomic and proteomic profiling to identify key perturbations of normal physiology. We found that the clinically most common rifampicin resistance-conferring mutation, RpoB Ser450Leu, imparts considerable gene expression changes, many of which are mitigated by the compensatory mutation in RpoC Leu516Pro. However, our data also provide evidence for pervasive epistasis-the same resistance mutation imposed a different fitness cost and functionally distinct changes to gene expression in genetically unrelated clinical strains. Finally, we report a likely posttranscriptional modulation of gene expression that is shared in most of the tested strains carrying RpoB Ser450Leu, resulting in an increased abundance of proteins involved in central carbon metabolism. These changes contribute to a more general trend in which the disruption of the composition of the proteome correlates with the fitness cost of the RpoB Ser450Leu mutation in different strains.

Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis.

BACKGROUND: Amyloid transthyretin (ATTR) amyloidosis is caused by the systemic deposition of transthyretin molecules, either normal (wild-type ATTR, ATTRwt) or mutated (variant ATTR, ATTRv). ATTR amyloidosis is a disease with a severe impact on patients' quality of life (QoL). Nonetheless, limited attention has been paid to QoL so far, and no specific tools for QoL assessment in ATTR amyloidosis currently exist. QoL can be evaluated through patient-reported outcome measures (PROMs), which are completed by patients, or through scales, which are compiled by clinicians. The scales investigate QoL either directly or indirectly, i.e., by assessing the degree of functional impairment and limitations imposed by the disease. DESIGN: Search for the measures of QoL evaluated in phase 2 and phase 3 clinical trials on ATTR amyloidosis. RESULTS: Clinical trials on ATTR amyloidosis have used measures of general health status, such as the Short Form 36 Health Survey (SF-36), or tools developed in other disease settings such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or adaptations of other scales such as the modified Neuropathy Impairment Score +7 (mNIS+7). CONCLUSIONS: Scales or PROMs for ATTR amyloidosis would be useful to better characterize newly diagnosed patients and to assess disease progression and response to treatment. The ongoing ITALY (Impact of Transthyretin Amyloidosis on Life qualitY) study aims to develop and validate 2 PROMs encompassing the whole phenotypic spectrum of ATTRwt and ATTRv amyloidosis, that might be helpful for patient management and may serve as surrogate endpoints for clinical trials.

Model-based media selection to minimize the cost of metabolic cooperation in microbial ecosystems.

MOTIVATION: Simple forms of mutualism between microorganisms are widespread in nature. Nevertheless, the role played by the environmental nutrient composition in mediating cross-feeding in microbial ecosystems is still poorly understood. RESULTS: Here, we use mixed-integer bilevel linear programming to investigate the cost of sharing metabolic resources in microbial communities. The algorithm infers an optimal combination of nutrients that can selectively sustain synergistic growth for a pair of species and guarantees minimum cost of cross-fed metabolites. To test model-based predictions, we selected a pair of Escherichia coli single gene knockouts auxotrophic, respectively, for arginine and leucine: ΔargB and ΔleuB and we experimentally verified that model-predicted medium composition significantly favors mutualism. Moreover, mass spectrometry profiling of exchanged metabolites confirmed the predicted cross-fed metabolites, supporting our constraint based modeling approach as a promising tool for engineering microbial consortia. AVAILABILITY AND IMPLEMENTATION: The software is freely available as a matlab script in the Supplementary materials. CONTACT: zampieri@imsb.biol.ethz.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.