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

Public Deliberations in Technology Policy Making: a Report on Two Danish-Style Consensus Conferences in the U.S.

Role of democracy in the making of science & technology policy In an age that has seen the expansion of democracy throughout regions of the world that have experienced only authoritarian, tyrannical governance for generations is one of the great achievements of the last decade of the 20th century. But within the celebrations of democratic expansion, there are aspects of our own democracies that beg for attention. Of particular importance to me is the challenge of developing policies about sci..

Public health clinical demonstration project for smoking cessation in veterans with posttraumatic stress disorder

Veterans with post traumatic stress disorder are at high risk for smoking and experience difficulty with smoking cessation. We designed this clinical demonstration project to provide a low-cost, feasibly implemented smoking cessation intervention that would maximize the number of smokers who accessed the intervention. Five hundred eighty-four veteran smokers were contacted by invitational letters. Interested veterans received follow-up telephone calls using standardized scripts offering three intervention resources: 1) a referral to the National Cancer Institute\u27s Smoking Quitline, 2) web-based counseling, and 3) local Veteran Affairs pharmacologic treatment for smoking cessation. Twenty-three percent of survey recipients participated in the clinical program. Two months after these resources were offered by phone, follow-up phone calls indicated that 25% of participants providing follow-up information reported maintaining smoking abstinence. This clinical demonstration project was associated with a 2.6% impact (i.e., reach [31.1% of smokers accessed intervention] by efficacy [8.4% of those accessing intervention quit]), meaning that 2.6% of the total number of targeted smokers reported 8 week abstinence. Results suggested that this brief, low cost intervention was feasible and promoted smoking cessation in veterans with post-traumatic stress disorder

Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis

On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing–remitting multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study. Freedom from disease activity is composed of three components that are commonly used individually as endpoints in clinical trials; it is defined as the patient having no relapse, no 3-month sustained change in expanded disability status scale (EDSS) score, and no new MRI lesions (no T1 gadolinium-enhancing or active T2 lesions) over a specified period. We assessed the effect of two doses of cladribine tablets versus placebo on the proportion of patients who were free from disease activity based on the individual components, all pair-wise combinations, and the composite of the three components (freedom from disease activity). Freedom from disease activity was analysed at 24, 48, and 96 weeks, and in subgroups of patients stratified according to baseline demographic and disease characteristics (age, disease duration, previous treatment with disease-modifying therapy, T1 gadolinium-enhancing lesion number, T2 lesion volume, EDSS score, number of previous relapses, and highly active disease). Of the 1326 patients randomly assigned to treatment in the CLARITY study, 1192 were assessable for freedom from disease activity at 96 weeks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3·5 mg/kg group and 283 (70%) of 406 in the cladribine 5·25 mg/kg group were free from disease activity, versus 145 (39%) of 373 in the placebo group (odds ratio [OR] 3·31, 95% CI 2·46–4·46 for the 3·5 mg/kg group; and 3·68, 2·73–4·97 for the 5·25 mg/kg group; both p<0·0001). Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3·5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 86 (24%) of 360 patients in the placebo group (OR 3·80, 2·77–5·22 for the 3·5 mg/kg group; 4·13, 3·02–5·66 for the 5·25 mg/kg group; both p<0·0001). Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3·5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 60 (16%) of 379 patients in the placebo group (OR 4·28, 3·05–6·02 for the 3·5 mg/kg group; 4·62, 3·29–6·48 for the 5·25 mg/kg group; both p<0·0001). The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups. Treatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS. Merck Serono SA–Geneva, Switzerland; an affiliate of Merck, Darmstadt, Germany

MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study

We herein provide a comprehensive assessment of magnetic resonance imaging (MRI) outcomes from CLARITY, a 96-week, double-blind study demonstrating significant clinical and MRI improvements in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets. Patients with RRMS were randomized 1:1:1 to annual short-course therapy with cladribine tablets cumulative dose 3.5 or 5.25 mg/kg or placebo. MRI endpoints included mean number of T1 gadolinium-enhancing (Gd+), active T2 and combined unique (CU) lesions/patient/scan. MRI-measured disease activity was significantly reduced in both cladribine tablets groups versus placebo. The proportion of patients with no active lesions at study end was: T1 Gd+ lesions: 86.8 and 91.0 versus 48.3 % (p < 0.001); active T2 lesions: 61.7 and 62.5 versus 28.4 % (p < 0.001); CU lesions: 59.6 and 60.7 versus 26.1 % (p < 0.001). Clinically meaningful and significant reductions in active lesion counts and increases in proportions of active lesion-free patients were achieved consistently in cladribine tablet groups when data were stratified by baseline disease characteristics. For example, the percentage of patients who remained lesion-free over the study was significantly greater in cladribine tablet groups than in the placebo group for all lesion types regardless of relapse category at baseline (p < 0.001 for all analyses of patients with ≤1 or 2 relapses; p ≤ 0.022 for analyses of patients with ≥3 relapses). MRI-measured disease activity was greatly reduced by both doses of cladribine tablets, with consistent effect across clinically relevant patient populations. These findings add to our scientific understanding of the neurological impact of this therapeutic modality in patients with RRMS

A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis

Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis. We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients). Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135.