Carcinoid heart disease: Two clinical cases and a review

We present two cases of metastatic carcinoid tumours, complicated by carcinoid syndrome and by cardiac valve involvement, a well-known, but infrequent, complication. Carcinoid tumours are generally more indolent than other cancers and may have a long asymptomatic phase. The symptoms of carcinoid syndrome generally manifest only once metastases to the liver have occurred. Cardiac involvement occurs in up to 50% of patients, and heralds a poor prognosis. However, a multidisciplinary team approach has improved the prognosis and quality of life for patients with carcinoid heart disease. Therapy includes somatostatin analogues and treatment for heart failure, removal of primary or metastatic tumour deposits, valve replacement in the presence of valvular involvement, and radioisotopes therapy

Robustness and epistasis in mutation-selection models

We investigate the fitness advantage associated with the robustness of a phenotype against deleterious mutations using deterministic mutation-selection models of quasispecies type equipped with a mesa shaped fitness landscape. We obtain analytic results for the robustness effect which become exact in the limit of infinite sequence length. Thereby, we are able to clarify a seeming contradiction between recent rigorous work and an earlier heuristic treatment based on a mapping to a Schr\"odinger equation. We exploit the quantum mechanical analogy to calculate a correction term for finite sequence lengths and verify our analytic results by numerical studies. In addition, we investigate the occurrence of an error threshold for a general class of epistatic landscape and show that diminishing epistasis is a necessary but not sufficient condition for error threshold behavior.Comment: 20 pages, 14 figure

Effect of host species on the topography of fitness landscape for a plant RNA virus

[EN] Adaptive fitness landscapes are a fundamental concept in evolutionary biology that relate the genotype of individuals with their fitness. At the end, the evolutionary fate of evolving populations depends on the topography of the landscape, that is, the number of accessible mutational pathways and of possible fitness peaks (i.e, adaptive solutions). For long time, fitness landscapes were only theoretical constructions due to a lack of precise information on the mapping between genotypes and phenotypes. In recent years, however, efforts have been devoted to characterize the properties of empirical fitness landscapes for individual proteins or for microbes adapting to artificial environments. In a previous study, we had characterized the properties of the empirical fitness landscape defined by the first five mutations fixed during adaptation of tobacco etch potyvirus (TEV) to a new experimental host, Arabidopsis thaliana. Here we evaluate the topography of this landscape in the ancestral host Nicotiana tabacum. Comparing the topographies of the landscape in the two hosts, we found that some features remain similar, such as the existence of fitness holes and the prevalence of epistasis, including cases of sign and of reciprocal sign that create rugged, uncorrelated and highly random topographies. However, we also observed significant differences in the fine grained details among both landscapes due to changes in the fitness and epistatic interactions of some genotypes. Our results support the idea that not only fitness tradeoffs between hosts but also topographical incongruences among fitness landscapes in alternative hosts may contribute to virus specialization.This project was funded by grants BFU2012-30805 and BFU2015-65037P from the Spanish Ministry of Economy and Competitiveness (MINECO), PROMETEOII/2014/021 from the Generalitat Valenciana, and EvoEvo (ICT610427) from the European Commission 7th Framework Program to S.F.E. H.C. was supported by contract BES2013-065595 from MINECO. J.L. was supported by a JAE-pre contract from CSIC.Cervera-Benet, H.; Lalic, J.; Elena Fito, SF. (2016). Effect of host species on the topography of fitness landscape for a plant RNA virus. Journal of Virology. 90(22):10160-10169. https://doi.org/10.1128/JVI.01243-16S1016010169902

Newborn screening for pompe disease? A qualitative study exploring professional views

Background: Developments in enzyme replacement therapy have kindled discussions on adding Pompe disease, characterized by progressive muscle weakness and wasting, to neonatal screening. Pompe disease does not fit traditional screening criteria as it is a broad-spectrum phenotype disorder that may occur in lethal form in early infancy or manifest in less severe forms from infancy to late adulthood. Current screening tests cannot differentiate between these forms. Normally, expanding screening is discussed among experts in advisory bodies. While advisory reports usually mention the procedures and outcome of deliberations, little is known of the importance attached to different arguments and the actual weighing processes involved. In this research we aim to explore the views of a wide range of relevant professionals to gain more insight into the process of weighing pros and cons of neonatal screening for Pompe disease, as an example of the dilemmas involved in screening for broad-spectrum phenotype disorders.Methods: We conducted 24 semi-structured interviews with medical, lab, insurance and screening professionals, and executive staff of patient organisations. They were asked about their first reaction to neonatal screening for Pompe disease, after which benefits and harms and requirements for screening were explored in more detail.Results: Advantages included health gain by timely intervention, avoiding a diagnostic quest, having a reproductive choice and gaining more knowledge about the natural course and treatment. Being prepared was mentioned as an advantage for the later manifesting cases. Disadvantages included treatment costs and uncertainties about its effect, the timing of treatment in later manifesting cases, the psychological burden for the patient-in-waiting and the family. Also the downsides of having prior knowledge as well as having to consider a reproductive option were mentioned as disadvantages.Conclusion: When weighing pros and cons, interviewees attach different importance to different arguments, based on personal and professional views. Professionals expect benefits from neonatal screening for Pompe disease, especially for early-onset cases. Some interviewees valued screening in later manifesting cases as well, while stressing the need for adequate support of pre-symptomatic patients and their families. Others considered the psychological burden and uncertainties regarding treatment as reasons not to screen

Influenza vaccine effectiveness in adults 65 years and older, Denmark, 2015/16:a rapid epidemiological and virological assessment

In Denmark, both influenza A(H1N1)pdm09 and influenza B co-circulated in the 2015/16 season. We estimated the vaccine effectiveness (VE) of the trivalent influenza vaccine in patients 65 years and older using the test-negative case–control design. The adjusted VE against influenza A(H1N1)pdm09 was 35.0% (95% confidence interval (CI): 11.1–52.4) and against influenza B 4.1% (95% CI: −22.0 to 24.7). The majority of influenza A(H1N1)pdm09 circulating in 2015/16 belonged to the new genetic subgroup subclade 6B.1.</jats:p

All-cause admissions following a first-ever exacerbation-related hospitalization in COPD

Background Hospital admissions are important contributors to the overall burden of chronic obstructive pulmonary disease (COPD). Understanding the patterns and causes of hospital admissions will help to identify targets for preventive interventions. This study aimed to determine the 5-year all-cause hospital admission trajectories of patients with COPD following their first ever exacerbation-related hospitalisation. Methods Patients with COPD were identified from the Danish national registries. Patients experiencing their first ever exacerbation-related hospitalisation, defined as the index event, between 2000 and 2014 were included. All-cause hospital admissions were examined during a subsequent 5-year follow-up period, and categorised using the International Classification of Diseases, 10th revision. Results In total, 82 964 patients with COPD were included. The mean±sd age was 72±10 years and 48% were male. Comorbidities were present in 58%, and 65% of the patients collected inhalation medication ≤6 months prior to the index event. In total, 337 066 all-cause hospital admissions were identified, resulting in a 5-year admission rate of 82%. Most admissions were due to nonrespiratory causes (59%), amongst which cardiac events were most common (19%). Conclusion Hospital admissions following a first exacerbation-related hospitalisation are common; nonrespiratory events constitute the majority of admissions. Besides the respiratory causes, treatment targeting the nonrespiratory causes of hospital admission should be considered to effectively decrease the burden of hospitalisation in COPD

Predictability of evolutionary trajectories in fitness landscapes

Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.Comment: 14 pages, 7 figure

Canalization of the evolutionary trajectory of the human influenza virus

Since its emergence in 1968, influenza A (H3N2) has evolved extensively in genotype and antigenic phenotype. Antigenic evolution occurs in the context of a two-dimensional 'antigenic map', while genetic evolution shows a characteristic ladder-like genealogical tree. Here, we use a large-scale individual-based model to show that evolution in a Euclidean antigenic space provides a remarkable correspondence between model behavior and the epidemiological, antigenic, genealogical and geographic patterns observed in influenza virus. We find that evolution away from existing human immunity results in rapid population turnover in the influenza virus and that this population turnover occurs primarily along a single antigenic axis. Thus, selective dynamics induce a canalized evolutionary trajectory, in which the evolutionary fate of the influenza population is surprisingly repeatable and hence, in theory, predictable.Comment: 29 pages, 5 figures, 10 supporting figure