Rational's experience using Ada for very large systems

The experience using the Rational Environment has confirmed the advantages forseen when the project was started. Interactive syntatic and semantic information makes a tremendous difference in the ease of constructing programs and making changes to them. The ability to follow semantic references makes it easier to understand exisiting programs and the impact of changes. The integrated debugger makes it much easier to find bugs and test fixes quickly. Taken together, these facilites have helped greatly in reducing the impact of ongoing maintenance of the ability to produce a new code. Similar improvements are anticipated as the same level of integration and interactivity are achieved for configuration management and version control. The environment has also proven useful in introducing personnel to the project and existing personnel to new parts of the system. Personnel benefit from the assistance with syntax and semantics; everyone benefits from the ability to traverse and understand the structure of unfamiliar software. It is often possible for someone completely unfamiliar with a body of code to use these facilities, to understand it well enough to successfully with a body of code to use these facilities to understand it well enough to successfully diagnose and fix bugs in a matter of minutes

Sulfur-bearing phases detected by evolved gas analysis of the Rocknest aeolian deposit, Gale Crater, Mars

The Sample Analysis at Mars (SAM) instrument suite detected SO_2, H_(2)S, OCS, and CS_2 from ~450 to 800°C during evolved gas analysis (EGA) of materials from the Rocknest aeolian deposit in Gale Crater, Mars. This was the first detection of evolved sulfur species from a Martian surface sample during in situ EGA. SO_2 (~3–22 µmol) is consistent with the thermal decomposition of Fe sulfates or Ca sulfites, or evolution/desorption from sulfur-bearing amorphous phases. Reactions between reduced sulfur phases such as sulfides and evolved O_2 or H_(2)O in the SAM oven are another candidate SO_2 source. H_(2)S (~41–109 nmol) is consistent with interactions of H_(2)O, H_2 and/or HCl with reduced sulfur phases and/or SO2 in the SAM oven. OCS (~1–5 nmol) and CS2 (~0.2–1 nmol) are likely derived from reactions between carbon-bearing compounds and reduced sulfur. Sulfates and sulfites indicate some aqueous interactions, although not necessarily at the Rocknest site; Fe sulfates imply interaction with acid solutions whereas Ca sulfites can form from acidic to near-neutral solutions. Sulfides in the Rocknest materials suggest input from materials originally deposited in a reducing environment or from detrital sulfides from an igneous source. The presence of sulfides also suggests that the materials have not been extensively altered by oxidative aqueous weathering. The possibility of both reduced and oxidized sulfur compounds in the deposit indicates a nonequilibrium assemblage. Understanding the sulfur mineralogy in Rocknest materials, which exhibit chemical similarities to basaltic fines analyzed elsewhere on Mars, can provide insight in to the origin and alteration history of Martian surface materials

A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma

Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses.A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.ClinicalTrials.gov NCT00626015

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

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

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

A computational framework for complex disease stratification from multiple large-scale datasets.

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)