8 research outputs found
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.
Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications
Superparamagnetic iron oxide nanoparticles
can providemultiple benefits for biomedical applications
in aqueous environments such asmagnetic separation or
magnetic resonance imaging. To increase the colloidal
stability and allow subsequent reactions, the introduction
of hydrophilic functional groups onto the particles’
surface is essential. During this process, the original
coating is exchanged by preferably covalently bonded
ligands such as trialkoxysilanes. The duration of the
silane exchange reaction, which commonly takes more
than 24 h, is an important drawback for this approach. In
this paper, we present a novel method, which introduces
ultrasonication as an energy source to dramatically
accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove
the generic character, different functional groups were
introduced on the surface including polyethylene glycol
chains, carboxylic acid, amine, and thiol groups. Their
colloidal stability in various aqueous buffer solutions as
well as human plasma and serum was investigated to
allow implementation in biomedical and sensing
applications.status: publishe
Succession of Ephemeral Secondary Forests and Their Limited Role for the Conservation of Floristic Diversity in a Human-Modified Tropical Landscape
Enhanced interpretation of newborn screening results without analyte cutoff values.
PURPOSE: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries.
METHODS: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors.
RESULTS: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events.
CONCLUSION: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project.
Purpose: To achieve clinical validation of cutoff values for newborn screening by tandem mass
215 spectrometry through a worldwide collaboration. Methods: Cumulative percentiles of amino
216 acids and acylcarnitines in dried blood spots of approximately 30 million normal newborns and
217 10,615 true positive cases are compared to assign clinical significance, which is achieved when
218 the median of a disease range is either >99%ile or <1%ile of the normal population. The cutoff
219 target ranges of analytes and ratios are then defined as the interval between the limits of the two
220 populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity
221 taking in consideration all available factors. Results: As of December 1, 2010, 129 sites in 45
222 countries have uploaded to the project website a total of 23,970 percentile data points, 558,168
223 analyte results of 10,615 true positive cases with 64 conditions, and 5,088 cutoff values. The
224 average rate of submission of true positive cases between December 1, 2008 and December 1,
225 2010 was 4.7 cases per day (3,418 cases). This cumulative evidence generated 91 and 23 high
226 and low target cutoff ranges, respectively. The overall proportion of cutoff values within the
227 respective target range was 43% (2,176/5,088). Conclusions: An unprecedented level of
228 cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114
229 markers applied to newborn screening of rare metabolic disorders. This set of data could be used
230 as baseline for monitoring of future performance
Polymorphisms in early neurodevelopmental genes affect natural variation in alcohol sensitivity in adult drosophila
Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients
Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin- kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients