Impact of high-throughput screening in biomedical research Macarron, Ricardo; Banks, Martyn N; Bojanic, Dejan ...
Nature reviews. Drug discovery,
201103, 2011-03-00, 2011-3-1, 20110301, Letnik:
10, Številka:
3
Journal Article, Book Review
Recenzirano
High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for ...stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.
Antithrombotic therapy for intracranial arterial stenosis was recently evaluated in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. A prespecified aim of WASID was to ...identify patients at highest risk for stroke in the territory of the stenotic artery who would be the target group for a subsequent trial comparing intracranial stenting with medical therapy.
WASID was a randomized, double-blinded, multicenter trial involving 569 patients with transient ischemic attack or ischemic stroke due to 50% to 99% stenosis of a major intracranial artery. Median time from qualifying event to randomization was 17 days, and mean follow-up was 1.8 years. Multivariable Cox proportional hazards models were used to identify factors associated with subsequent ischemic stroke in the territory of the stenotic artery. Subsequent ischemic stroke occurred in 106 patients (19.0%); 77 (73%) of these strokes were in the territory of the stenotic artery. Risk of stroke in the territory of the stenotic artery was highest with severe stenosis > or =70% (hazard ratio 2.03; 95% confidence interval 1.29 to 3.22; P=0.0025) and in patients enrolled early (< or =17 days) after the qualifying event (hazard ratio 1.69; 95% confidence interval 1.06 to 2.72; P=0.028). Women were also at increased risk, although this was of borderline significance (hazard ratio 1.59; 95% confidence interval 1.00 to 2.55; P=0.051). Location of stenosis, type of qualifying event, and prior use of antithrombotic medications were not associated with increased risk.
Among patients with symptomatic intracranial stenosis, the risk of subsequent stroke in the territory of the stenotic artery is greatest with stenosis > or =70%, after recent symptoms, and in women.
The WASID trial showed no advantage of warfarin over aspirin for preventing the primary endpoint of ischemic stroke, brain hemorrhage, or vascular death. In analyses of selected subgroups, there was ...no definite benefit from warfarin. Warfarin reduced the risk of the primary endpoint among patients with basilar artery stenosis, but there was no reduction in stroke in the basilar artery territory or benefit for vertebral artery stenosis or posterior circulation disease in general.
African American adolescent girls are at high risk for human immunodeficiency virus (HIV) infection, but interventions specifically designed for this population have not reduced HIV risk behaviors.
...To evaluate the efficacy of an intervention to reduce sexual risk behaviors, sexually transmitted diseases (STDs), and pregnancy and enhance mediators of HIV-preventive behaviors.
Randomized controlled trial of 522 sexually experienced African American girls aged 14 to 18 years screened from December 1996 through April 1999 at 4 community health agencies. Participants completed a self-administered questionnaire and an interview, demonstrated condom application skills, and provided specimens for STD testing. Outcome assessments were made at 6- and 12-month follow-up.
All participants received four 4-hour group sessions. The intervention emphasized ethnic and gender pride, HIV knowledge, communication, condom use skills, and healthy relationships. The comparison condition emphasized exercise and nutrition.
The primary outcome measure was consistent condom use, defined as condom use during every episode of vaginal intercourse; other outcome measures were sexual behaviors, observed condom application skills, incident STD infection, self-reported pregnancy, and mediators of HIV-preventive behaviors.
Relative to the comparison condition, participants in the intervention reported using condoms more consistently in the 30 days preceding the 6-month assessment (unadjusted analysis, intervention, 75.3% vs comparison, 58.2%) and the 12-month assessment (unadjusted analysis, intervention, 73.3% vs comparison, 56.5%) and over the entire 12-month period (adjusted odds ratio, 2.01; 95% confidence interval CI, 1.28-3.17; P =.003). Participants in the intervention reported using condoms more consistently in the 6 months preceding the 6-month assessment (unadjusted analysis, intervention, 61.3% vs comparison, 42.6%), at the 12-month assessment (unadjusted analysis, intervention, 58.1% vs comparison, 45.3%), and over the entire 12-month period (adjusted odds ratio, 2.30; 95% CI, 1.51-3.50; P<.001). Using generalized estimating equation analyses over the 12-month follow-up, adolescents in the intervention were more likely to use a condom at last intercourse, less likely to have a new vaginal sex partner in the past 30 days, and more likely to apply condoms to sex partners and had better condom application skills, a higher percentage of condom-protected sex acts, fewer unprotected vaginal sex acts, and higher scores on measures of mediators. Promising effects were also observed for chlamydia infections and self-reported pregnancy.
Interventions for African American adolescent girls that are gender-tailored and culturally congruent can enhance HIV-preventive behaviors, skills, and mediators and may reduce pregnancy and chlamydia infection.
Atherosclerotic intracranial arterial stenosis is an important cause of stroke. Warfarin is commonly used in preference to aspirin for this disorder, but these therapies have not been compared in a ...randomized trial.
We randomly assigned patients with transient ischemic attack or stroke caused by angiographically verified 50 to 99 percent stenosis of a major intracranial artery to receive warfarin (target international normalized ratio, 2.0 to 3.0) or aspirin (1300 mg per day) in a double-blind, multicenter clinical trial. The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.
After 569 patients had undergone randomization, enrollment was stopped because of concerns about the safety of the patients who had been assigned to receive warfarin. During a mean follow-up period of 1.8 years, adverse events in the two groups included death (4.3 percent in the aspirin group vs. 9.7 percent in the warfarin group; hazard ratio for aspirin relative to warfarin, 0.46; 95 percent confidence interval, 0.23 to 0.90; P=0.02), major hemorrhage (3.2 percent vs. 8.3 percent, respectively; hazard ratio, 0.39; 95 percent confidence interval, 0.18 to 0.84; P=0.01), and myocardial infarction or sudden death (2.9 percent vs. 7.3 percent, respectively; hazard ratio, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.02). The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group (P=0.16); the rate of death from nonvascular causes was 1.1 percent and 3.8 percent, respectively (P=0.05). The primary end point occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent of those in the warfarin group (hazard ratio, 1.04; 95 percent confidence interval, 0.73 to 1.48; P=0.83).
Warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin in this trial. Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.
Accidental contamination of the Michigan food chain with polybrominated biphenyls (PBBs) led to the exposure of more than 4,000 individuals in 1973. Because PBB exposure is suspected to disrupt ...endocrine function, we assessed pubertal development in females 5-24 years of age (N = 327) who were exposed to PBB in utero and, in many cases, through breast-feeding. We estimated in utero PBB exposure using maternal serum PBB measurements taken after exposure (1976-1979) and extrapolated to time of pregnancy using a model of PBB decay. We found that breastfed girls exposed to high levels of PBB in utero (≥7 parts per billion) had an earlier age at menarche (mean age = 11.6 years) than breastfed girls exposed to lower levels of PBB in utero (mean age = 12.2-12.6 years) or girls who were not breastfed (mean age = 12.7 years). This association persisted after adjustment for potential confounders (menarche ratio = 3.4, 95% confidence interval = 1.3-9.0). Perinatal PBB exposure was associated with earlier pubic hair stage in breastfed girls, but little association was found with breast development. The associations observed here lend support to the hypothesis that pubertal events may be affected by pre- and postnatal exposure to organohalogens.
Abstract
Introduction
A BMI increase, in men and women, is associated with an increased severity and progression of OSA. This study will examine the impact of BMI on varying levels of OSA severity ...and progression.
Methods
Participants, divided by sex, included 2728 (47%) men and 3076 (53%) women over the age of 40 that were in the Sleep Heart Health Study (SHHS). Participants were separated into 1 of 10 groups based on initial OSA levels at SHHS time point 1 (SHHS1) and ending OSA levels at SHHS time point 2 (SHHS2) as measured by RDI. A Kruskall-Wallis test examined the BMI median differences in the groups. Post-hoc tests, including pairwise comparisons and Wilcoxon rank sum test with Holm adjustment, were conducted to further examine results.
Results
Significant differences existed between certain groups (Men: Chi-Square=146.87, p<.001, df=9; Women: Chi-Square=128.59, p<.001, df=9). For men and women, those in the group with normal OSA levels at SHHS1 and SHHS2 had significant BMI differences compared to those in all 9 other groups where mild, moderate, or severe OSA levels exist at SHHS1 or SHHS2. Additionally, in men, BMI is significantly different for those with normal or mild OSA levels at SHHS2 compared to those with moderate or severe OSA levels at SHHS2. Also, a significant BMI difference exists in men maintaining mild OSA levels throughout SHHS compared to those maintaining severe OSA levels.
Conclusion
Although BMI is a known influential factor in OSA progression, this study demonstrated that those maintaining normal OSA levels over time have a significant BMI difference compared to those reaching even mild OSA levels over time. Additional implications were also found for men. These findings may coincide with recent research suggesting that one needs to progress only to moderate OSA levels to reach a tipping point of significantly increasing and impacting many health risks.
Support
Robert Wood Johnson Foundation Future of Nursing Scholars Program
Following publication of concerns about the results of the National Institute of Neurological Disorders and Stroke (NINDS) intravenous tissue plasminogen activator (t-PA) in acute stroke treatment ...trial, NINDS commissioned an independent committee "to address whether there is concern that eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials and, whether the subgroup imbalance (in baseline stroke severity) invalidates the entire trial."
The original NINDS trial data were reanalyzed to assess the t-PA treatment effect, the effect of the baseline imbalance in stroke severity between the treatment groups on the t-PA treatment effect, and whether subgroups of patients did not benefit from receiving t-PA.
A clinically important and statistically significant benefit of t-PA therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-PA treated patients. The adjusted t-PA to placebo odds ratio (OR) of a favorable outcome was 2.1 (95% CI, 1.5 to 2.9). Although these exploratory analyses found no statistical evidence that the t-PA treatment effect differed among patient subgroups, the study was not powered to detect subgroup treatment differences.
These findings support the use of t-PA to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-PA trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-PA in acute ischemic stroke patients.
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