Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.

BACKGROUND: Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated. METHODS: We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing. RESULTS: Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different. CONCLUSIONS: In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.).

Corrigendum: Mega-evolutionary dynamics of the adaptive radiation of birds.

This corrects the article DOI: 10.1038/nature21074.

Mega-evolutionary dynamics of the adaptive radiation of birds.

The origin and expansion of biological diversity is regulated by both developmental trajectories and limits on available ecological niches. As lineages diversify, an early and often rapid phase of species and trait proliferation gives way to evolutionary slow-downs as new species pack into ever more densely occupied regions of ecological niche space. Small clades such as Darwin's finches demonstrate that natural selection is the driving force of adaptive radiations, but how microevolutionary processes scale up to shape the expansion of phenotypic diversity over much longer evolutionary timescales is unclear. Here we address this problem on a global scale by analysing a crowdsourced dataset of three-dimensional scanned bill morphology from more than 2,000 species. We find that bill diversity expanded early in extant avian evolutionary history, before transitioning to a phase dominated by packing of morphological space. However, this early phenotypic diversification is decoupled from temporal variation in evolutionary rate: rates of bill evolution vary among lineages but are comparatively stable through time. We find that rare, but major, discontinuities in phenotype emerge from rapid increases in rate along single branches, sometimes leading to depauperate clades with unusual bill morphologies. Despite these jumps between groups, the major axes of within-group bill-shape evolution are remarkably consistent across birds. We reveal that macroevolutionary processes underlying global-scale adaptive radiations support Darwinian and Simpsonian ideas of microevolution within adaptive zones and accelerated evolution between distinct adaptive peaks.

Piperaquine-Induced QTc Prolongation Decreases With Repeated Monthly Dihydroartemisinin-Piperaquine Dosing in Pregnant Ugandan Women.

BACKGROUND: Intermittent preventive treatment with monthly dihydroartemisinin-piperaquine (DHA-PQ) is highly effective at preventing both malaria during pregnancy and placental malaria. Piperaquine prolongs the corrected QT interval (QTc), and it is possible that repeated monthly dosing could lead to progressive QTc prolongation. Intensive characterization of the relationship between piperaquine concentration and QTc interval throughout pregnancy can inform effective, safe prevention guidelines. METHODS: Data were collected from a randomized controlled trial, where pregnant Ugandan women received malaria chemoprevention with monthly DHA-PQ (120/960 mg DHA/PQ; n = 373) or sulfadoxine-pyrimethamine (SP; 1500/75 mg; n = 375) during the second and third trimesters of pregnancy. Monthly trough piperaquine samples were collected throughout pregnancy, and pre- and postdose electrocardiograms were recorded at 20, 28, and 36 weeks' gestation in each woman. The pharmacokinetics-QTc relationship for piperaquine and QTc for SP were assessed using nonlinear mixed-effects modeling. RESULTS: A positive linear relationship between piperaquine concentration and Fridericia corrected QTc interval was identified. This relationship progressively decreased from a 4.42 to 3.28 to 2.13 millisecond increase per 100 ng/mL increase in piperaquine concentration at 20, 28, and 36 weeks' gestation, respectively. Furthermore, 61% (n = 183) of women had a smaller change in QTc at week 36 than week 20. Nine women given DHA-PQ had grade 3-4 cardiac adverse events. SP was not associated with any change in QTc. CONCLUSIONS: Repeated DHA-PQ dosing did not result in increased risk of QTc prolongation and the postdose QTc intervals progressively decreased. Monthly dosing of DHA-PQ in pregnant women carries minimal risk of QTc prolongation. CLINICAL TRIALS REGISTRATION: NCT02793622.

Global biogeographic patterns of avian morphological diversity.

Understanding the biogeographical patterns, and evolutionary and environmental drivers, underpinning morphological diversity are key for determining its origins and conservation. Using a comprehensive set of continuous morphological traits extracted from museum collections of 8353 bird species, including geometric morphometric beak shape data, we find that avian morphological diversity is unevenly distributed globally, even after controlling for species richness, with exceptionally dense packing of species in hyper-diverse tropical hotspots. At the regional level, these areas also have high morphological variance, with species exhibiting high phenotypic diversity. Evolutionary history likely plays a key role in shaping these patterns, with evolutionarily old species contributing to niche expansion, and young species contributing to niche packing. Taken together, these results imply that the tropics are both 'cradles' and 'museums' of phenotypic diversity.

AVONET: morphological, ecological and geographical data for all birds.

Functional traits offer a rich quantitative framework for developing and testing theories in evolutionary biology, ecology and ecosystem science. However, the potential of functional traits to drive theoretical advances and refine models of global change can only be fully realised when species-level information is complete. Here we present the AVONET dataset containing comprehensive functional trait data for all birds, including six ecological variables, 11 continuous morphological traits, and information on range size and location. Raw morphological measurements are presented from 90,020 individuals of 11,009 extant bird species sampled from 181 countries. These data are also summarised as species averages in three taxonomic formats, allowing integration with a global phylogeny, geographical range maps, IUCN Red List data and the eBird citizen science database. The AVONET dataset provides the most detailed picture of continuous trait variation for any major radiation of organisms, offering a global template for testing hypotheses and exploring the evolutionary origins, structure and functioning of biodiversity.

The evolution of the traplining pollinator role in hummingbirds: specialization is not an evolutionary dead end.

Trapliners are pollinators that visit widely dispersed flowers along circuitous foraging routes. The evolution of traplining in hummingbirds is thought to entail morphological specialization through the reciprocal coevolution of longer bills with the long-tubed flowers of widely dispersed plant species. Specialization, such as that exhibited by traplining hummingbirds, is often viewed as both irreversible and an evolutionary dead end. We tested these predictions in a macroevolutionary framework. Specifically, we assessed the relationship between beak morphology and foraging and tested whether transitions to traplining are irreversible and lead to lower rates of diversification as predicted by the hypothesis that specialization is an evolutionary dead end. We find that there have been multiple independent transitions to traplining across the hummingbird phylogeny, but reversals have been rare or incomplete at best. Multiple independent lineages of trapliners have become morphologically specialized, convergently evolving relatively large bills for their body size. Traplining is not an evolutionary dead end however, since trapliners continue to give rise to new traplining species at a rate comparable to non-trapliners.

Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women.

Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations of >10.3 ng/ml have been associated with reduced maternal parasitemia, placental malaria, and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks. The effects of covariates such as pregnancy, nutritional status (body mass index [BMI]), and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2,218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to postpartum and HIV-uninfected pregnant women, respectively. Low BMI at 28 weeks of gestation was associated with increased clearance (2% increase per unit decrease in BMI). Low-BMI women given DHA-PQ every 8 weeks had a higher prevalence of parasitemia, malaria infection, and placental malaria compared to women with higher BMIs. The reduced piperaquine exposure in women with low BMI as well as during EFV coadministration, compared to pregnant women with higher BMIs and not taking EFV, suggests that these populations could benefit from weekly instead of monthly dosing for prevention of malaria parasitemia. Simulations indicated that because of the BMI-clearance relationship, weight-based regimens would not improve protection compared to a 2,880 mg fixed-dose regimen when provided monthly. (The clinical trials described in this paper have been registered at ClinicalTrials.gov under identifiers NCT02163447 and NCT02282293.).

Real-Time in Situ Monitoring of Nitrogen Dynamics in Wastewater Treatment Processes using Wireless, Solid-State, and Ion-Selective Membrane Sensors.

Real-time, in situ accurate monitoring of nitrogen contaminants in wastewater over a long-term period is critical for swift feedback control, enhanced nitrogen removal efficiency, and reduced energy consumption of wastewater treatment processes. Existing nitrogen sensors suffer from high cost, low stability, and short life times, posing hurdles for their mass deployment to capture a complete picture within heterogeneous systems. Tackling this challenge, this study presents solid-state ion-selective membrane (S-ISM) nitrogen sensors for ammonium (NH4+) and nitrate (NO3-) in wastewater that were coupled to a wireless data transmission gateway for real-time remote data access. Lab-scale test and continuous-flow field tests using real municipal wastewater indicated that the S-ISM nitrogen sensors possessed excellent accuracy and precision, high selectivity, and multiday stability. Importantly, autocorrections of the sensor readings on the cloud minimized temperature influences and assured accurate nitrogen concentration readings in remote-sensing applications. It was estimated that real-time, in situ monitoring using wireless S-ISM nitrogen sensors could save 25% of electric energy under normal operational conditions and reduce 22% of nitrogen discharge under shock conditions.

Preclinical Pharmacological Development of Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection.

Hepatitis C virus (HCV) is a small, single-stranded, positive-sense RNA virus that infects more than an estimated 70 million people worldwide. Untreated, persistent HCV infection often results in chronic hepatitis, cirrhosis, or liver failure, with progression to hepatocellular carcinoma. Current anti-HCV regimens comprising direct acting antivirals (DAAs) can provide curative treatment; however, due to high costs there remains a need for effective, shorter-duration, and affordable treatments. Recently, we disclosed anti-HCV activity of the cheap antihistamine chlorcyclizine, targeting viral entry. Following our hit-to-lead optimization campaign, we report evaluation of preclinical in vitro absorption, distribution, metabolism, and excretion properties, and in vivo pharmacokinetic profiles of lead compounds. This led to selection of a new lead compound and evaluation of efficacy in chimeric mice engrafted with primary human hepatocytes infected with HCV. Further development and incorporation of this compound into DAA regimens has the potential to improve treatment efficacy, affordability, and accessibility.

Can Twitter improve your health? An analysis of alcohol consumption guidelines on Twitter.

This article is the first in the feature to highlight the social network site Twitter as a tool for health information and it reports on a study by Emma Hughes, who completed an MSc in information and library studies at Aberystwyth University in 2014. Emma's research investigated the quality of health information available on Twitter, in particular the information available on UK alcohol consumption guidelines. Her research suggests that users searching for this information would need certain literacy skills to interpret it correctly. However, there is no doubt that Twitter is an increasingly popular resource for information dissemination and health professionals, and organisations should be encouraged to use it frequently as a tool for sharing information. AM.

Interplay among malnutrition, chemoprevention, and the risk of malaria in young Ugandan children: Longitudinal pharmacodynamic and growth analysis.

African children are at risk of malaria and malnutrition. We quantified relationships between malaria and malnutrition among young Ugandan children in a high malaria transmission region. Data were used from a randomized controlled trial where Ugandan HIV-unexposed (n = 393) and HIV-exposed (n = 186) children were randomized to receive no malaria chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole, or monthly dihydroartemisinin-piperaquine (DP) from age 6-24 months, and then were followed off chemoprevention until age 36 months. Monthly height and weight, and time of incident malaria episodes were obtained; 89 children who received DP contributed piperaquine (PQ) concentrations. Malaria hazard was modeled using parametric survival analysis adjusted for repeated events, and height and weight were modeled using a Brody growth model. Among 579 children, stunting (height-for-age z-score [ZHA] < -2) was associated with a 17% increased malaria hazard (95% confidence interval [CI] 10-23%) compared with children with a ZHA of zero. DP was associated with a 35% lower malaria hazard (hazard ratio [HR] [95% CI], 0.65 [0.41-0.97]), compared to no chemoprevention. After accounting for PQ levels, stunted children who received DP had 2.1 times the hazard of malaria (HR [95% CI] 2.1 [1.6-3.0]) compared with children with a ZHA of zero who received DP. Each additional malaria episode was associated with a 0.4% reduced growth rate for height. Better dosing regimens are needed to optimize malaria prevention in malnourished populations, but, importantly, malaria chemoprevention may reduce the burden of malnutrition in early childhood.

Competencies and standards in nurse education: The irresolvable tensions.

This paper explores the inherent contradiction between the purpose of nurse education - to produce critical thinking, autonomous and accountable future nurses - and the prescription of standards and competencies to realize this goal. Drawing on examples from the United Kingdom's Nursing and Midwifery Council's (NMC) 'Future Nurse' standards, we argue that standards and competencies offer little more than a veneer of protection to the public and that, fundamentally, educational approaches based on 'dot point' formulations are antithetical to conditions in which genuinely critical-thinking, autonomous and accountable practitioners can develop. The purpose of this paper is to raise debate about the hegemony of competencies and standards. For the sake of academic health and the future of the nursing profession, the ubiquity of competency-based education must be critiqued and challenged.

Innovation and elaboration on the avian tree of life.

Widely documented, megaevolutionary jumps in phenotypic diversity continue to perplex researchers because it remains unclear whether these marked changes can emerge from microevolutionary processes. Here, we tackle this question using new approaches for modeling multivariate traits to evaluate the magnitude and distribution of elaboration and innovation in the evolution of bird beaks. We find that elaboration, evolution along the major axis of phenotypic change, is common at both macro- and megaevolutionary scales, whereas innovation, evolution away from the major axis of phenotypic change, is more prominent at megaevolutionary scales. The major axis of phenotypic change among species beak shapes at megaevolutionary scales is an emergent property of innovation across clades. Our analyses suggest that the reorientation of phenotypes via innovation is a ubiquitous route for divergence that can arise through gradual change alone, opening up further avenues for evolution to explore.

Fluctuating power: an exploration of refugee health nursing within the resettlement context in Victoria, Australia.

Background: The Refugee Health Program (RHP) is a nurse-led community initiative, introduced in 2005 with the aim of responding to complex health issues of refugees arriving in Victoria, Australia. Little is known about refugee health nursing in the resettlement context and the impact of dedicated refugee healthcare. Aim: To explore the experiences and perspectives of Refugee Health Nurses (RHNs), Refugee Health Managers (managers) and refugees, gaining insight into professional relationships and the complexities of offering a specialised refugee health service. Method: A focused ethnographic approach incorporated semi-structured interviews with five RHNs, two managers and eight refugees, two focus groups with refugees and participant observation within the RHP during April 2017 to December 2017. Data collection was undertaken across two sites and interviews, focus groups and observations were transcribed and thematically analysed. Social constructionism asserts that the focus of enquiry should be on interaction, group processes and social practices. Emphasis is placed upon relationships between RHNs, managers and refugees, with knowledge viewed as relational and interactional. Results: Professional relationships between RHNs and refugees are complex, with power oscillating between them. Contrary to discourses of 'vulnerability' of refugees, both RHNs and refugees demonstrated power in their relationships with each other. Nurses also suggested that these relationships were stressful and could lead to burnout. Key themes were developed: (1) nursing autonomy and gatekeeping; (2) vicarious trauma and burnout; and (3) refugee negotiation of care. Conclusions: The balance of power is central to therapeutic relationships. In relationships between RHNs and refugees, power fluctuates as RHNs are exposed to vicarious trauma and symptoms of burnout, while refugees exercise agency by recognising benefits to specialised care. In developing effective therapeutic relationships between RHNs and refugees, attention should be paid to how care is delivered to protect RHNs from burnout while ensuring that refugees receive appropriate care.

The homogenization of avian morphological and phylogenetic diversity under the global extinction crisis.

Biodiversity is facing a global extinction crisis that will reduce ecological trait diversity, evolutionary history, and ultimately ecosystem functioning and services.1-4 A key challenge is understanding how species losses will impact morphological and phylogenetic diversity at global scales.5,6 Here, we test whether the loss of species threatened with extinction according to the International Union for Conservation of Nature (IUCN) leads to morphological and phylogenetic homogenization7,8 across both the whole avian class and within each biome and ecoregion globally. We use a comprehensive set of continuous morphological traits extracted from museum collections of 8,455 bird species, including geometric morphometric beak shape data,9 and sequentially remove species from those at most to least threat of extinction. We find evidence of morphological, but not phylogenetic, homogenization across the avian class, with species becoming more alike in terms of their morphology. We find that most biome and ecoregions are expected to lose morphological diversity at a greater rate than predicted by species loss alone, with the most imperiled regions found in East Asia and the Himalayan uplands and foothills. Only a small proportion of assemblages are threatened with phylogenetic homogenization, in particular parts of Indochina. Species extinctions will lead to a major loss of avian ecological strategies, but not a comparable loss of phylogenetic diversity. As the decline of species with unique traits and their replacement with more widespread generalist species continues, the protection of assemblages at most risk of morphological and phylogenetic homogenization should be a key conservation priority.

Allometric conservatism in the evolution of bird beaks.

Evolution can involve periods of rapid divergent adaptation and expansion in the range of diversity, but evolution can also be relatively conservative over certain timescales due to functional, genetic-developmental, and ecological constraints. One way in which evolution may be conservative is in terms of allometry, the scaling relationship between the traits of organisms and body size. Here, we investigate patterns of allometric conservatism in the evolution of bird beaks with beak size and body size data for a representative sample of over 5000 extant bird species within a phylogenetic framework. We identify clades in which the allometric relationship between beak size and body size has remained relatively conserved across species over millions to tens of millions of years. We find that allometric conservatism is nonetheless punctuated by occasional shifts in the slopes and intercepts of allometric relationships. A steady accumulation of such shifts through time has given rise to the tremendous diversity of beak size relative to body size across birds today. Our findings are consistent with the Simpsonian vision of macroevolution, with evolutionary conservatism being the rule but with occasional shifts to new adaptive zones.

Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction.

Numerous studies have established the involvement of lysosomal and mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson diseases. Building on our previous studies of the neurodegenerative lysosomal lipidosis Niemann-Pick C1 (NPC1), we have unexpectedly discovered that activation of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) leads to the correction of the lysosomal storage phenotype in patient cells from multiple lysosomal storage disorders including NPC1. Using small compound activators specific for TRAP1, we find that activation of this chaperone leads to a generalized restoration of lysosomal and mitochondrial health. Mechanistically, we show that this process includes inhibition of oxidative phosphorylation and reduction of oxidative stress, which results in activation of AMPK and ultimately stimulates lysosome recycling. Thus, TRAP1 participates in lysosomal-mitochondrial crosstalk to maintain cellular homeostasis and could represent a potential therapeutic target for multiple disorders.

Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations.

Malaria is an infectious disease which disproportionately effects children and pregnant women. These vulnerable populations are often excluded from clinical trials resulting in one-size-fits-all treatment regimens based on those established for a nonpregnant adult population. Pharmacokinetic/pharmacodynamic (PK/PD) models can be used to optimize dose selection as they define the drug exposure-response relationship. Additionally, these models are able to identify patient characteristics that cause alterations in the expected PK/PD profiles and through simulations can recommend changes to dosing which compensate for the differences. In this review, we examine how PK/PD models have been applied to optimize antimalarial dosing recommendations for young children, including those who are malnourished, pregnant women, and individuals receiving concomitant therapies such as those for HIV treatment. The malaria field has had great success in utilizing PK/PD models as a foundation to update treatment guidelines and propose the next generation of dosing regimens to investigate in clinical trials. We propose how the malaria field can continue to use modeling to improve therapies by further integrating PK data into clinical studies and including data on drug resistance and host immunity in PK/PD models. Finally, we suggest that other disease areas can achieve similar success in applying pharmacometrics to improve outcomes by implementing three key principals.