Real-world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice

The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host-parasite interaction

Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5′ ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct

Design and Implementation of Degenerate Microsatellite Primers for the Mammalian Clade

Microsatellites are popular genetic markers in molecular ecology, genetic mapping and forensics. Unfortunately, despite recent advances, the isolation of de novo polymorphic microsatellite loci often requires expensive and intensive groundwork. Primers developed for a focal species are commonly tested in a related, non-focal species of interest for the amplification of orthologous polymorphic loci; when successful, this approach significantly reduces cost and time of microsatellite development. However, transferability of polymorphic microsatellite loci decreases rapidly with increasing evolutionary distance, and this approach has shown its limits. Whole genome sequences represent an under-exploited resource to develop cross-species primers for microsatellites. Here we describe a three-step method that combines a novel in silico pipeline that we use to (1) identify conserved microsatellite loci from a multiple genome alignments, (2) design degenerate primer pairs, with (3) a simple PCR protocol used to implement these primers across species. Using this approach we developed a set of primers for the mammalian clade. We found 126,306 human microsatellites conserved in mammalian aligned sequences, and isolated 5,596 loci using criteria based on wide conservation. From a random subset of ∼1000 dinucleotide repeats, we designed degenerate primer pairs for 19 loci, of which five produced polymorphic fragments in up to 18 mammalian species, including the distinctly related marsupials and monotremes, groups that diverged from other mammals 120–160 million years ago. Using our method, many more cross-clade microsatellite loci can be harvested from the currently available genomic data, and this ability is set to improve exponentially as further genomes are sequenced

High Quality Care and Ethical Pay-for-Performance: A Society of General Internal Medicine Policy Analysis

BACKGROUND: Pay-for-performance is proliferating, yet its impact on key stakeholders remains uncertain. OBJECTIVE: The Society of General Internal Medicine systematically evaluated ethical issues raised by performance-based physician compensation. RESULTS: We conclude that current arrangements are based on fundamentally acceptable ethical principles, but are guided by an incomplete understanding of health-care quality. Furthermore, their implementation without evidence of safety and efficacy is ethically precarious because of potential risks to stakeholders, especially vulnerable patients. CONCLUSION: We propose four major strategies to transition from risky pay-for-performance systems to ethical performance-based physician compensation and high quality care. These include implementing safeguards within current pay-for-performance systems, reaching consensus regarding the obligations of key stakeholders in improving health-care quality, developing valid and comprehensive measures of health-care quality, and utilizing a cautious evaluative approach in creating the next generation of compensation systems that reward genuine quality

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF and supported by grant U01 DK062418 from the US National Institutes of Health. Further support was provided by grants from the NIDDK (DK046635 and DK085678) to P.C. and by a joint JDRF and Wellcome Trust grant (WT061858/09115) to the Diabetes and Inflammation Laboratory at Cambridge University, which also received support from the NIHR Cambridge Biomedical Research Centre. ImmunoBase receives support from Eli Lilly and Company. C.W. and H.G. are funded by the Wellcome Trust (089989). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council and the Wellcome Trust. We acknowledge use of DNA samples from the NIHR Cambridge BioResource. We thank volunteers for their support and participation in the Cambridge BioResource and members of the Cambridge BioResource Scientific Advisory Board (SAB) and Management Committee for their support of our study. We acknowledge the NIHR Cambridge Biomedical Research Centre for funding. Access to Cambridge BioResource volunteers and to their data and samples are governed by the Cambridge BioResource SAB. Documents describing access arrangements and contact details are available at http://www.cambridgebioresource.org.uk/. We thank the Avon Longitudinal Study of Parents and Children laboratory in Bristol, UK, and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton, for preparing and providing the control DNA samples. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113; a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/.This is the author accepted manuscript. The final version is available via NPG at http://www.nature.com/ng/journal/v47/n4/full/ng.3245.html

Social Perceptions of Forest Ecosystem Services in the Democratic Republic of Congo

The forests of the Albertine Rift are known for their high biodiversity and the important ecosystem services they provide to millions of inhabitants. However, their conservation and the maintenance of ecosystem service delivery is a challenge, particularly in the Democratic Republic of the Congo. Our research investigates how livelihood strategy and ethnicity affects local perceptions of forest ecosystem services. We collected data through 25 focus-group discussions in villages from distinct ethnic groups, including farmers (Tembo, Shi, and Nyindu) and hunter-gatherers (Twa). Twa identify more food-provisioning services and rank bush meat and honey as the most important. They also show stronger place attachment to the forest than the farmers, who value other ecosystem services, but all rank microclimate regulation as the most important. Our findings help assess ecosystem services trade-offs, highlight the important impacts of restricted access to forests resources for Twa, and point to the need for developing alternative livelihood strategies for these communities

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe