The burden of proof: the current state of atrial fibrillation prevention and treatment trials

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3–5, 2015

Vertical foraging shifts in Hawaiian forest birds in response to invasive rat removal

Worldwide, native species increasingly contend with the interacting stressors of habitat fragmentation and invasive species, yet their combined effects have rarely been examined. Direct negative effects of invasive omnivores are well documented, but the indirect effects of resource competition or those caused by predator avoidance are unknown. Here we isolated and examined the independent and interactive effects of invasive omnivorous Black rats (Rattus rattus) and forest fragment size on the interactions between avian predators and their arthropod prey. Our study examines whether invasive omnivores and ecosystem fragment size impact: 1) the vertical distribution of arthropod species composition and abundance, and 2) the vertical profile of foraging behaviors of five native and two non-native bird species found in our study system. We predicted that the reduced edge effects and greater structural complexity and canopy height of larger fragments would limit the total and proportional habitat space frequented by rats and thus limit their impact on both arthropod biomass and birds’ foraging behavior. We experimentally removed invasive omnivorous Black rats across a 100-fold (0.1 to 12 ha) size gradient of forest fragments on Hawai‘i Island, and paired foraging observations of forest passerines with arthropod sampling in the 16 rat-removed and 18 control fragments. Rat removal was associated with shifts in the vertical distribution of arthropod biomass, irrespective of fragment size. Bird foraging behavior mirrored this shift, and the impact of rat removal was greater for birds that primarily eat fruit and insects compared with those that consume nectar. Evidence from this model study system indicates that invasive rats indirectly alter the feeding behavior of native birds, and consequently impact multiple trophic levels. This study suggests that native species can modify their foraging behavior in response to invasive species removal and presumably arrival through behavioral plasticity

Donor aid mentioning newborns and stillbirths, 2002-19: an analysis of levels, trends, and equity.

BACKGROUND: Global aid for reproductive, maternal, newborn, and child health has stagnated in recent years, and aid mentioning newborns or stillbirths has previously represented a very small proportion of aid for reproductive, maternal, newborn, and child health. Neonatal survival targets have been set by 78 countries, and stillbirth prevention targets have been set by 30 countries, to address the 4·4 million newborn deaths and stillbirths globally. We aimed to generate novel estimates of current levels of, and trends in, aid mentioning newborns and stillbirths over 2002-19, and to assess whether the amount of aid disbursed aligns with the associated mortality burden. METHODS: For this analysis, we did a manual review and coding of the Organisation for Economic Co-operation and Development (OECD)'s Creditor Reporting System database from 2002 to 2019 using key search terms for aid mentioning newborns and stillbirths. We compared these findings with estimates of aid for reproductive, maternal, newborn, and child health for 2002-19 based on the Muskoka2 method. Findings are presented in 2019 US$according to the OECD's Development Assistance Committee deflators, which account for variation in exchange rates and inflation in donor countries. FINDINGS: We identified 21 957 unique records in the 2002-19 period. Aid mentioning newborns and stillbirths comprised approximately 10$1·6 billion) of reproductive, maternal, newborn, and child health funding overall in 2019 ($15·9 billion), with a small decrease in value between 2015 and 2019. 1284 (6$535 million) of their total value mentioned aid focused only on newborn health. Ten donors contributed 87% ($13·7 billion) of the total value of aid mentioning newborns and stillbirths during 2002-19. Aid mentioning newborns and stillbirths was inequitably allocated in the least developed countries (as defined by the UN), ranging from$18 per death in Angola to $1389 per death in Timor-Leste. Stillbirths were not mentioned in any funding in 2002-09, and they were only mentioned in 46 of 21 957 records in 2010-19, comprising$44·4 million of aid disbursed during this period. INTERPRETATION: Aid mentioning newborns and stillbirths is poorly matched to their corresponding mortality burden (representing 10% of aid for reproductive, maternal, newborn, and child health overall, yet accounting for approximately 50% of mortality in children <5 years) and across recipient countries (with substantial variation in the amount of aid received per newborn death and stillbirth between countries with similar health and economic needs). Our findings indicate that aid needs to be better targeted to populations with the highest mortality burdens, creating greater potential for impact. FUNDING: John D and Catherine T MacArthur Foundation, Bill & Melinda Gates Foundation, ELMA Philanthropies, Children's Investment Fund Foundation UK, Lemelson Foundation, and Ting Tsung and Wei Fong Chao Foundation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

A distinct, high-affinity, alkaline phosphatase facilitates occupation of P-depleted environments by marine picocyanobacteria

Marine picocyanobacteria of the genera Prochlorococcus and Synechococcus, the two most abundant phototrophs on Earth, thrive in oligotrophic oceanic regions. While it is well known that specific lineages are exquisitely adapted to prevailing in situ light and temperature regimes, much less is known of the molecular machinery required to facilitate occupancy of these low-nutrient environments. Here, we describe a hitherto unknown alkaline phosphatase, Psip1, that has a substantially higher affinity for phosphomonoesters than other well-known phosphatases like PhoA, PhoX, or PhoD and is restricted to clade III Synechococcus and a subset of high light I-adapted Prochlorococcus strains, suggesting niche specificity. We demonstrate that Psip1 has undergone convergent evolution with PhoX, requiring both iron and calcium for activity and likely possessing identical key residues around the active site, despite generally very low sequence homology. Interrogation of metagenomes and transcriptomes from TARA oceans and an Atlantic Meridional transect shows that psip1 is abundant and highly expressed in picocyanobacterial populations from the Mediterranean Sea and north Atlantic gyre, regions well recognized to be phosphorus (P)-deplete. Together, this identifies psip1 as an important oligotrophy-specific gene for P recycling in these organisms. Furthermore, psip1 is not restricted to picocyanobacteria and is abundant and highly transcribed in some α-proteobacteria and eukaryotic algae, suggesting that such a high-affinity phosphatase is important across the microbial taxonomic world to occupy low-P environments.</p

Aspergillus hancockii sp. Nov., a biosynthetically talented fungus endemic to southeastern Australian soils

Aspergillus hancockii sp. nov., classified in Aspergillus subgenus Circumdati section Flavi, was originally isolated from soil in peanut fields near Kumbia, in the South Burnett region of southeast Queensland, Australia, and has since been found occasionally from other substrates and locations in southeast Australia. It is phylogenetically and phenotypically related most closely to A. leporis States and M. Chr., but differs in conidial colour, other minor features and particularly in metabolite profile. When cultivated on rice as an optimal substrate, A. hancockii produced an extensive array of 69 secondary metabolites. Eleven of the 15 most abundant secondary metabolites, constituting 90% of the total area under the curve of the HPLC trace of the crude extract, were novel. The genome of A. hancockii, approximately 40 Mbp, was sequenced and mined for genes encoding carbohydrate degrading enzymes identified the presence of more than 370 genes in 114 gene clusters, demonstrating that A. hancockii has the capacity to degrade cellulose, hemicellulose, lignin, pectin, starch, chitin, cutin and fructan as nutrient sources. Like most Aspergillus species, A. hancockii exhibited a diverse secondary metabolite gene profile, encoding 26 polyketide synthase, 16 nonribosomal peptide synthase and 15 nonribosomal peptide synthase-like enzymes

Successful management of invasive rats across a fragmented landscape

Summary Introduced mammalian predators are responsible for the decline and extinction of many native species, with rats (genus Rattus) being among the most widespread and damaging invaders worldwide. In a naturally fragmented landscape, we demonstrate the multi-year effectiveness of snap traps in the removal of Rattus rattus and Rattus exulans from lava-surrounded forest fragments ranging in size from 10 ha. Relative to other studies, we observed low levels of fragment recolonization. Larger rats were the first to be trapped, with the average size of trapped rats decreasing over time. Rat removal led to distinct shifts in the foraging height and location of mongooses and mice, emphasizing the need to focus control efforts on multiple invasive species at once. Furthermore, because of a specially designed trap casing, we observed low non-target capture rates, suggesting that on Hawai\u27i and similar islands lacking native rodents the risk of killing non-target species in snap traps may be lower than the application of rodenticides, which have the potential to contaminate food webs. These efforts demonstrate that targeted snap-trapping is an effective removal method for invasive rats in fragmented habitats and that, where used, monitoring of recolonization should be included as part of a comprehensive biodiversity management strategy

Aspergillus Genomes and the Aspergillus Cloud

Aspergillus Genomes is a public resource for viewing annotated genes predicted by various Aspergillus sequencing projects. It has arisen from the union of two significant resources: the Aspergillus/Aspergillosis website and the Central Aspergillus Data REpository (CADRE). The former has primarily served the medical community, providing information about Aspergillus and associated diseases to medics, patients and scientists; the latter has focused on the fungal genomic community, providing a central repository for sequences and annotation extracted from Aspergillus Genomes. By merging these databases, genomes benefit from extensive cross-linking with medical information to create a unique resource, spanning genomics and clinical aspects of the genus. Aspergillus Genomes is accessible from http://www.aspergillus-genomes.org.uk

Chaste: an open source C++ library for computational physiology and biology

Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to "re-invent the wheel" with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials

Ten Simple Rules for Effective Computational Research

<p>Ten Simple Rules for Effective Computational Research</p