Does intensive management improve remission rates in patients with intermediate rheumatoid arthritis? (the TITRATE trial): study protocol for a randomised controlled trial.

BACKGROUND: Uncontrolled active rheumatoid arthritis can lead to increasing disability and reduced quality of life over time. 'Treating to target' has been shown to be effective in active established disease and also in early disease. However, there is a lack of nationally agreed treatment protocols for patients with established rheumatoid arthritis who have intermediate disease activity. This trial is designed to investigate whether intensive management of disease leads to a greater number of remissions at 12 months. Levels of disability and quality of life, and acceptability and cost-effectiveness of the intervention will also be examined. METHODS: The trial is a 12-month, pragmatic, randomised, open-label, two-arm, parallel-group, multicentre trial undertaken at specialist rheumatology centres across England. Three hundred and ninety-eight patients with established rheumatoid arthritis will be recruited. They will currently have intermediate disease activity (disease activity score for 28 joints assessed using an erythrocyte sedimentation rate of 3.2 to 5.1 with at least three active joints) and will be taking at least one disease-modifying anti-rheumatic drug. Participants will be randomly selected to receive intensive management or standard care. Intensive management will involve monthly clinical reviews with a specialist health practitioner, where drug treatment will be optimised and an individualised treatment support programme delivered based on several principles of motivational interviewing to address identified problem areas, such as pain, fatigue and adherence. Standard care will follow standard local pathways and will be in line with current English guidelines from the National Institute for Health and Clinical Excellence. Patients will be assessed initially and at 6 and 12 months through self-completed questionnaires and clinical evaluation. DISCUSSION: The trial will establish whether the known benefits of intensive treatment strategies in active rheumatoid arthritis are also seen in patients with established rheumatoid arthritis who have moderately active disease. It will evaluate both the clinical and cost-effectiveness of intensive treatment. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN70160382 . Registered on 16 January 2014.MRC Funding: MC_UP_1302/3 NIHR Funding: RP-PG-0610-1006

A connectome and analysis of the adult Drosophila central brain.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy

BACKGROUND Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439. opens in new tab.

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Kenneth Grahame’s The Wind in the Willows: A Children’s Classic at 100

In 1908, Kenneth Grahame\u27s The Wind in the Willows was published to surprisingly little critical fanfare. But readers championed its cause, and Grahame\u27s novel of a riverbank life soon proved both a commercial_and ultimately critical_success. One hundred years after its first publication, Grahame\u27s book and its memorable characters continue their hold on the public imagination and have taken their place in the canon of children\u27s literature. However, little academic criticism emerged in the wake of the book\u27s initial publication. Only after the appearance of Peter Green\u27s biocritical study did the academy begin to wrestle with Grahame\u27s complex work, though many read it in terms of Grahame\u27s often unhappy personal life. The essays in Kenneth Grahame\u27s The Wind in the Willows: A Children\u27s Classic at 100 focus on recent discussions of the book in regards to class, gender, and nationality but also examine issues previously not addressed by Grahame criticism, such as the construction of heteronormative masculinity, the appeal of this very English novel to Chinese readers, and the meaning of a text in which animals can be human-like, pets, servants, and even food. This volume also revisits some of the issues that have engaged critics from the start, including the book\u27s dual-strand narrative structure, the function of home, and the psychological connections between Toad and Grahame. Scholars of fantasy and children\u27s literature will find great value in this collection that sheds new light on this enduring classic.https://orc.library.atu.edu/atu_faculty_books/1044/thumbnail.jp

Annotated mitochondrial genome assemblies for two sand lances (genus: Ammodytes) from the northwest Atlantic

Complete mitochondrial genomes of two northwest Atlantic sand lances (Ammodytes americanus and Ammodytes dubius) were sequenced, assembled, and annotated. Both genomes were 16 519 bp in length and were differentiated by a genetic distance of only 0.01. Furthermore, mitochondrial gene annotations were identical for both species. Phylogenetic analysis revealed that divergence between the two species was shallow, relative to other members of the genus

A connectome and analysis of the adult Drosophila central brain.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain

A connectome and analysis of the adult Drosophila central brain

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain