Emerging therapeutic targets in the short QT syndrome

Introduction: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable.

Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome.

Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K⁺ channel inhibitors. A combination of K⁺ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K⁺ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.     

First detection of Theileria parva in cattle from Cameroon in the absence of the main tick vector Rhipicephalus appendiculatus

A major risk factor for the spread of livestock diseases and their vectors is the uncontrolled transboundary movement of live animals for trade and grazing. Such movements constrain effective control of tick‐transmitted pathogens, including Theileria parva. Only limited studies have been undertaken to identify ticks and tick‐borne diseases (TTBDs) affecting cattle in central African countries, including Cameroon. We hereby report the collection of baseline data on the prevalence of T. parva in Cameroon through a countrywide cross‐sectional survey, conducted in 2016, involving collection of blood samples from cattle from 63 sites across the five agro‐ecological zones (AEZs) of the country. ELISA‐based surveillance of infected cattle was performed on 479 randomly selected samples and revealed specific antibodies to T. parva in 22.7% and T. mutans in 41.1% of cattle. Screening of 1,340 representative DNA samples for the presence of T. parva identified 25 (1.86%) positives using a p104 antigen gene‐based nested PCR assay. The positives were distributed across agro‐ecological zones I, II, III and V. None of the p104 positive cattle exhibited clinical symptoms of East Coast fever (ECF). Using reverse line blot (RLB), 58 (4.3%) and 1,139 (85%) of the samples reacted with the T. parva and T. mutans oligonucleotide probes, respectively. This represents the first report of T. parva from Cameroon. Surprisingly, no Rhipicephalus appendiculatus ticks, the main vector of T. parva, were identified in a parallel study involving comprehensive morphological and molecular survey of tick species present in the country. Only two of the 25 p104 positive cattle were PCR‐positive for the CD8+ T‐cell target schizont‐expressed antigen gene Tp1. Cloning and sequencing of Tp1 amplicons revealed sequence identity with the reference T. parva Muguga. This new finding raises serious concerns of a potential spread of ECF into the central African region.     

Unraveling postoperative alterations after mitral valve replacement with three-dimensional printing

Mitral valve (MV) surgery is the second most performed valve operation in Europe. MV pathology is associated with atrial fibrillation, and, therefore, frequently combined with rhythm surgery and left atrial appendage exclusion (LAAE). Currently, no guidelines exist regarding the follow up after LAAE postoperative. Postoperative imaging with computed tomography (CT), in the absence of complaints, will inherently reveal unsuspected cardiac and noncardiac findings with potential clinical significance. However, poststernotomy alterations are nonspecific and often overlap with normal postoperative changes and could, therefore, not directly be recognized. Virtual three-dimensional (3D) CT reconstructions can help us to visualize 2D structures, especially in areas where structures overlap like coronary arteries or when devices (atrial clip, MV prosthesis) cause scattering artifacts. Advanced imaging reconstructions and 3D printing can enhance understanding of the cardiac anatomy in the postoperative phase and help us to determine follow-up strategies.     

Genetic specificity of a plant–insect food web: Implications for linking genetic variation to network complexity

Theory predicts that intraspecific genetic variation can increase the complexity of an ecological network. To date, however, we are lacking empirical knowledge of the extent to which genetic variation determines the assembly of ecological networks, as well as how the gain or loss of genetic variation will affect network structure. To address this knowledge gap, we used a common garden experiment to quantify the extent to which heritable trait variation in a host plant determines the assembly of its associated insect food web (network of trophic interactions). We then used a resampling procedure to simulate the additive effects of genetic variation on overall food-web complexity. We found that trait variation among host-plant genotypes was associated with resistance to insect herbivores, which indirectly affected interactions between herbivores and their insect parasitoids. Direct and indirect genetic effects resulted in distinct compositions of trophic interactions associated with each host-plant genotype. Moreover, our simulations suggest that food-web complexity would increase by 20% over the range of genetic variation in the experimental population of host plants. Taken together, our results indicate that intraspecific genetic variation can play a key role in structuring ecological networks, which may in turn affect network persistence.Network theory has provided both a conceptual and a quantitative approach for mapping interactions between species and making predictions about how the gain or loss of species will affect the structure and dynamics of ecological networks (1–3). Representing a network at the species level, however, makes the implicit assumption that each species consists of a homogenous population of individuals, all of which interact equally with individuals of different species. However, most populations are heterogeneous mixtures of individuals that vary in their phenotypes, and there is growing evidence that this intraspecific variation is an important factor governing the assembly of ecological communities (4–6). Consequently, there is a clear need to account for the role of intraspecific variation in structuring ecological networks (7).Genetic variation is a key driver of intraspecific variation and many studies have now demonstrated direct and indirect genetic effects on species interactions (8–10) and the composition of communities across multiple trophic levels (11–14). This prior work forms a clear expectation that intraspecific genetic variation is capable of scaling up to affect the structure of an ecological network. In particular, we expect that network structure will be affected by genetic variation through at least two different mechanisms. For a food web (network of trophic interactions), genetic variation in the quality of a basal resource may alter the (i) abundances or (ii) phenotypes of consumer species or both (15). These direct genetic effects on consumers may then have cascading effects on the strength of trophic interactions between consumers and their predators (15), resulting in distinct compositions of trophic interactions associated with different genotypes of the basal resource (Fig. 1). If such genetic specificity in the composition of trophic interactions occurs, then theory predicts that increasing genetic variation will result in more interactions per species (6, 16) and therefore greater food-web complexity (Fig. 2). Moreover, greater complexity may in turn affect food-web dynamics, as more complex food webs are predicted to be more robust to species extinctions (3, 17). However, whether genetic variation is capable of scaling up to affect food-web complexity is currently unclear.Open in a separate windowFig. 1.Genetic specificity of trophic interactions in a plant–insect food web. The species comprising the food web in this study include a host plant (coastal willow, S. hookeriana), four herbivorous galling insects, and six insect parasitoids (species details in Materials and Methods). The plant–insect food web consists of 16 trophic interactions (4 willow–gall and 12 gall–parasitoid) aggregated from all plant individuals sampled in this common garden experiment, whereas each genotype subweb represents the trophic interactions aggregated from all plant individuals of the corresponding genotype. We depicted three genotype subwebs (of 26) to illustrate the differences in trophic interactions associated with each willow genotype. The width of each gray segment is proportional to the number of individuals associated with each trophic interaction. Note that we scaled the width of trophic interactions to be comparable among genotype subwebs, but not between subwebs and the aggregated food web, to emphasize the differences among subwebs.Open in a separate windowFig. 2.Conceptual model of how increasing genetic variation (number of shades of green circles) results in greater food-web complexity (number of interactions per species). If different genotypes of a basal resource are associated with distinct compositions of trophic interactions (i.e., genetic specificity of trophic interactions), then increasing genetic variation in the resource will result in a more complex food web because of the increase in the number of interactions per species at all three trophic levels. Colors correspond to different trophic levels (green, basal resource; blue, primary consumer; orange, secondary consumer), whereas different shapes within each trophic level correspond to different species.In this study, we quantify the genetic specificity of trophic interactions and use these data to simulate the additive effects of genetic variation on food-web complexity. To do this, we used a common garden experiment of a host plant (26 genotypes of coastal willow, Salix hookeriana) and its associated food web of insect galls and parasitoids (Fig. 1). We focused on this plant–insect food web for three reasons. First, we have demonstrated in previous work that S. hookeriana (hereafter, willow) displays heritable variation in traits associated with leaf quality (36 traits, mean H² = 0.72) and plant architecture (4 traits, mean H² = 0.27), some of which are also associated with resistance to its community of galling herbivores (18). Second, the unique biology of galling insects makes them ideal for building quantitative food webs. In particular, galls provide a refuge for larva from attack by most generalist predators (19); therefore, galls and their natural enemies often form a distinct subset of the larger food web associated with host plants. In our system, all of the natural enemies are insect parasitoids that complete their development within the gall after parasitizing larva, making it easy to identify and quantify all of the trophic interactions within this food web. Third, the biology of galls is also ideal for identifying the mechanisms mediating trophic interactions. In particular, gall size is a key trait that affects the ability of parasitoids to successfully oviposit through the gall wall and into the larva within the gall (i.e., larger galls provide a refuge from parasitism) (20). Moreover, gall size is determined, in part, by the genotype of the plant (20), so we have a clear mechanism by which genetic variation can affect the strength of trophic interactions. Taken together, our study seeks to examine how intraspecific genetic variation influences the structure of ecological networks. In doing so, our study takes a crucial step toward a more predictive understanding of how the gain or loss of genetic variation will affect the dynamics of ecological networks.     

Analysis of factors contributing to long-term success among graduates of aresidential weight management program for women

This study evaluated several components of a residential weight loss program for adult women and compared the characteristics of successful and nonsuccessful participants. Program components included a 1000–1200-kcal daily diet, nutrition counseling, behavior modification, and regular exercise. Weight loss averaged 7 kg during an average 35-day stay. Thirty-eight percent of participants (n = 226) responded to questionnaires that were mailed 6 months to 5 years after participation. Respondents did not differ on any baseline measure of body composition or characteristics from nonrespondents including degree of overweight, rate of weight loss, etc. Nineteen percent reported weight increment since initial attendance. Fifty-two percent of the respondents reported maintenance of all weight loss with 18% losing an additional 5 kg and 8% losing an additional 9 kg. Duration of time since attendance and repeated visits were not related to successful weight maintenance. No behavioral profile discriminated between successful and unsuccessful respondents. However, continued success was related to increased and regular exercise and later age of onset of obesity.     

In Vitro Confirmation of Artemisinin Resistance in Plasmodium falciparum from Patient Isolates,Southern Rwanda, 2019

Artemisinin resistance in Plasmodium falciparum is conferred by mutations in the kelch 13 (K13) gene. In Rwanda, K13 mutations have increased over the past decade, including mutations associated with delayed parasite clearance. We document artemisinin resistance in P. falciparum patient isolates from Rwanda carrying K13 R561H, A675V, and C469F mutations.     

Applying Zinc Nutrient Reference Values as Proposed by Different Authorities Results in Large Differences in the Estimated Prevalence of Inadequate Zinc Intake by Young Children and Women and in Cameroon

Nutrient reference values (NRVs) for zinc set by several expert groups differ widely and may affect the predicted prevalence of inadequate zinc intake. We examined this possibility using NRVs published by four different authorities and nationally representative dietary intake data collected among children aged 12–59 months and women in Cameroon. Usual zinc intake was estimated from 24 h recall data using the National Cancer Institute method. Prevalences of total zinc intake below the dietary requirement and of “absorbable zinc intake” below the physiological requirement were estimated using NRVs published by the World Health Organization (WHO), US Institute of Medicine (IOM), International Zinc Nutrition Consultative Group (IZiNCG), and European Food Safety Authority (EFSA). The prevalence of inadequate zinc intake ranged from 10% (IZiNCG—physiological requirement, 95% CI 7–13%) to 81% (EFSA—physiological requirement, 95% CI 78–84%) among children and 9% (WHO—physiological requirement, 95% CI 8–11.0%) to 94% (IOM—physiological requirement, 95% CI 92–95%) among women These differences in the prevalence of inadequate intake translated into sizeable differences in the predicted benefit and cost-effectiveness of zinc fortification programs. Depending on the NRVs applied, assessments differ regarding the need for and design of zinc fortification programs. Efforts are needed to harmonize NRVs for zinc.