In this paper we evaluate the three main methods for correcting the susceptibility-induced artefact in diffusion-weighted magnetic-resonance (DW-MR) data, and assess how correction is affected by the ...susceptibility field's interaction with motion. The susceptibility artefact adversely impacts analysis performed on the data and is typically corrected in post-processing. Correction strategies involve either registration to a structural image, the application of an acquired field-map or the use of additional images acquired with different phase-encoding. Unfortunately, the choice of which method to use is made difficult by the absence of any systematic comparisons of them. In this work we quantitatively evaluate these methods, by extending and employing a recently proposed framework that allows for the simulation of realistic DW-MR datasets with artefacts. Our analysis separately evaluates the ability for methods to correct for geometric distortions and to recover lost information in regions of signal compression. In terms of geometric distortions, we find that registration-based methods offer the poorest correction. Field-mapping techniques are better, but are influenced by noise and partial volume effects, whilst multiple phase-encode methods performed best. We use our simulations to validate a popular surrogate metric of correction quality, the comparison of corrected data acquired with AP and LR phase-encoding, and apply this surrogate to real datasets. Furthermore, we demonstrate that failing to account for the interaction of the susceptibility field with head movement leads to increased errors when analysing DW-MR data. None of the commonly used post-processing methods account for this interaction, and we suggest this may be a valuable area for future methods development.
In this paper we demonstrate a simulation framework that enables the direct and quantitative comparison of post-processing methods for diffusion weighted magnetic resonance (DW-MR) images. DW-MR ...datasets are employed in a range of techniques that enable estimates of local microstructure and global connectivity in the brain. These techniques require full alignment of images across the dataset, but this is rarely the case. Artefacts such as eddy-current (EC) distortion and motion lead to misalignment between images, which compromise the quality of the microstructural measures obtained from them. Numerous methods and software packages exist to correct these artefacts, some of which have become de-facto standards, but none have been subject to rigorous validation. In the literature, improved alignment is assessed using either qualitative visual measures or quantitative surrogate metrics. Here we introduce a simulation framework that allows for the direct, quantitative assessment of techniques, enabling objective comparisons of existing and future methods. DW-MR datasets are generated using a process that is based on the physics of MRI acquisition, which allows for the salient features of the images and their artefacts to be reproduced. We apply this framework in three ways. Firstly we assess the most commonly used method for artefact correction, FSL's eddy_correct, and compare it to a recently proposed alternative, eddy. We demonstrate quantitatively that using eddy_correct leads to significant errors in the corrected data, whilst eddy is able to provide much improved correction. Secondly we investigate the datasets required to achieve good correction with eddy, by looking at the minimum number of directions required and comparing the recommended full-sphere acquisitions to equivalent half-sphere protocols. Finally, we investigate the impact of correction quality by examining the fits from microstructure models to real and simulated data.
•We propose a framework for assessing artefact correction techniques in diffusion MRI.•The proposed framework simulates realistic diffusion MRI data, with artefacts.•We apply the framework to assess two widely-used FSL tools: eddy_correct and eddy.•Eddy outperforms eddy_correct in correcting motion and eddy-current distortion.•We show that poor correction adversely impacts the estimation of microstructure.
Increasing Persistence of College Students in STEM Graham, Mark J.; Frederick, Jennifer; Byars-Winston, Angela ...
Science (American Association for the Advancement of Science),
09/2013, Letnik:
341, Številka:
6153
Journal Article
Recenzirano
An evidence-based framework offers a guide for efforts to increase student persistence in STEM majors.
A 2012 report by the President's Council of Advisors on Science and Technology (PCAST) predicts ...that the U.S. workforce will suffer a deficit of one million college graduates in science, technology, engineering, and mathematics (STEM) over the next decade (
1
). The report calls for addressing the shortfall by increasing retention of college students in STEM. But many academic leaders have not responded aggressively to workforce needs by implementing measures that increase retention. Some of this nonaction is likely due to lack of knowledge about proven retention strategies.
The Pfizer-BioNTech (BNT162b2) and the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in phase 3 trials. We aimed to investigate the safety and ...effectiveness of these vaccines in a UK community setting.
In this prospective observational study, we examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine. We also compared infection rates in a subset of vaccinated individuals subsequently tested for SARS-CoV-2 with PCR or lateral flow tests with infection rates in unvaccinated controls. All analyses were adjusted by age (≤55 years vs >55 years), sex, health-care worker status (binary variable), obesity (BMI <30 kg/m2vs ≥30 kg/m2), and comorbidities (binary variable, with or without comorbidities).
Between Dec 8, and March 10, 2021, 627 383 individuals reported being vaccinated with 655 590 doses: 282 103 received one dose of BNT162b2, of whom 28 207 received a second dose, and 345 280 received one dose of ChAdOx1 nCoV-19. Systemic side-effects were reported by 13·5% (38 155 of 282 103) of individuals after the first dose of BNT162b2, by 22·0% (6216 of 28 207) after the second dose of BNT162b2, and by 33·7% (116 473 of 345 280) after the first dose of ChAdOx1 nCoV-19. Local side-effects were reported by 71·9% (150 023 of 208 767) of individuals after the first dose of BNT162b2, by 68·5% (9025 of 13 179) after the second dose of BNT162b2, and by 58·7% (104 282 of 177 655) after the first dose of ChAdOx1 nCoV-19. Systemic side-effects were more common (1·6 times after the first dose of ChAdOx1 nCoV-19 and 2·9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection than among those without known past infection. Local effects were similarly higher in individuals previously infected than in those without known past infection (1·4 times after the first dose of ChAdOx1 nCoV-19 and 1·2 times after the first dose of BNT162b2). 3106 of 103 622 vaccinated individuals and 50 340 of 464 356 unvaccinated controls tested positive for SARS-CoV-2 infection. Significant reductions in infection risk were seen starting at 12 days after the first dose, reaching 60% (95% CI 49–68) for ChAdOx1 nCoV-19 and 69% (66–72) for BNT162b2 at 21–44 days and 72% (63–79) for BNT162b2 after 45–59 days.
Systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination occur at frequencies lower than reported in phase 3 trials. Both vaccines decrease the risk of SARS-CoV-2 infection after 12 days.
ZOE Global, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, UK Medical Research Council, Wellcome Trust, UK Research and Innovation, American Gastroenterological Association.
Despite efforts to recruit and retain more women, a stark gender disparity persists within academic science. Abundant research has demonstrated gender bias in many demographic groups, but has yet to ...experimentally investigate whether science faculty exhibit a bias against female students that could contribute to the gender disparity in academic science. In a randomized double-blind study (n = 127), science faculty from research-intensive universities rated the application materials of a student—who was randomly assigned either a male or female name—for a laboratory manager position. Faculty participants rated the male applicant as significantly more competent and hireable than the (identical) female applicant. These participants also selected a higher starting salary and offered more career mentoring to the male applicant. The gender of the faculty participants did not affect responses, such that female and male faculty were equally likely to exhibit bias against the female student. Mediation analyses indicated that the female student was less likely to be hired because she was viewed as less competent. We also assessed faculty participants’ preexisting subtle bias against women using a standard instrument and found that preexisting subtle bias against women played a moderating role, such that subtle bias against women was associated with less support for the female student, but was unrelated to reactions to the male student. These results suggest that interventions addressing faculty gender bias might advance the goal of increasing the participation of women in science.
Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins.
We evaluated antisense ...oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter 1.0 to 1.7 mmol per liter or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins.
The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events.
Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).
Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) Lp(a) is an independent causal risk factor for CVD, including myocardial ...infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis. Lp(a) levels >50 mg/dl are highly prevalent (20% of the general population) and are overrepresented in patients with CVD and aortic stenosis. These data support the notion that Lp(a) should be a target of therapy for CVD event reduction and to reduce progression of aortic stenosis. However, effective therapies to specifically reduce plasma Lp(a) levels are lacking. Recent animal and human studies have shown that Lp(a) can be specifically targeted with second generation antisense oligonucleotides (ASOs) that inhibit apo(a) mRNA translation. In apo(a) transgenic mice, an apo(a) ASO reduced plasma apo(a)/Lp(a) levels and their associated oxidized phospholipid (OxPL) levels by 86 and 93%, respectively. In cynomolgus monkeys, a second generation apo(a) ASO, ISIS-APO(a)Rx, significantly reduced hepatic apo(a) mRNA expression and plasma Lp(a) levels by >80%. Finally, in a phase I study in normal volunteers, ISIS-APO(a)Rx ASO reduced Lp(a) levels and their associated OxPL levels up to 89 and 93%, respectively, with minimal effects on other lipoproteins. ISIS-APO(a)Rx represents the first specific and potent drug in clinical development to lower Lp(a) levels and may be beneficial in reducing CVD events and progression of calcific aortic valve stenosis.
Summary Background Elevated lipoprotein(a) (Lpa) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved ...specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations. Methods We did two randomised, double-blind, placebo-controlled trials. In a phase 2 trial (done in 13 study centres in Canada, the Netherlands, Germany, Denmark, and the UK), we assessed the effect of IONIS-APO(a)Rx , an oligonucleotide targeting apolipoprotein(a). Participants with elevated Lp(a) concentrations (125–437 nmol/L in cohort A; ≥438 nmol/L in cohort B) were randomly assigned (in a 1:1 ratio in cohort A and in a 4:1 ratio in cohort B) with an interactive response system to escalating-dose subcutaneous IONIS-APO(a)Rx (100 mg, 200 mg, and then 300 mg, once a week for 4 weeks each) or injections of saline placebo, once a week, for 12 weeks. Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration at day 85 or 99 in the per-protocol population (participants who received more than six doses of study drug) and safety and tolerability in the safety population. In a phase 1/2a first-in-man trial, we assessed the effect of IONIS-APO(a)-LRx , a ligand-conjugated antisense oligonucleotide designed to be highly and selectively taken up by hepatocytes, at the BioPharma Services phase 1 unit (Toronto, ON, Canada). Healthy volunteers (Lpa ≥75 nmol/L) were randomly assigned to receive a single dose of 10–120 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo (in a 3:1 ratio; single-ascending-dose phase), or multiple doses of 10 mg, 20 mg, or 40 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo (in an 8:2 ratio) at day 1, 3, 5, 8, 15, and 22 (multiple-ascending-dose phase). Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration, safety, and tolerability at day 30 in the single-ascending-dose phase and day 36 in the multiple-ascending-dose phase in participants who were randomised and received at least one dose of study drug. In both trials, the randomised allocation sequence was generated by Ionis Biometrics or external vendor with a permuted-block randomisation method. Participants, investigators, sponsor personnel, and clinical research organisation staff who analysed the data were all masked to the treatment assignments. Both trials are registered with ClinicalTrials.gov , numbers NCT02160899 and NCT02414594. Findings From June 25, 2014, to Nov 18, 2015, we enrolled 64 participants to the phase 2 trial (51 in cohort A and 13 in cohort B). 35 were randomly assigned to IONIS-APO(a)Rx and 29 to placebo. At day 85/99, participants assigned to IONIS-APO(a)Rx had mean Lp(a) reductions of 66·8% (SD 20·6) in cohort A and 71·6% (13·0) in cohort B (both p<0·0001 vs pooled placebo). From April 15, 2015, to Jan 11, 2016, we enrolled 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-LRx . Of 28 participants in the single-ascending-dose phase, three were randomly assigned to 10 mg, three to 20 mg, three to 40 mg, six to 80 mg, six to 120 mg, and seven to placebo. Of 30 participants in the multiple-ascending-dose phase, eight were randomly assigned to 10 mg, eight to 20 mg, eight to 40 mg, and six to placebo. Significant dose-dependent reductions in mean Lp(a) concentrations were noted in all single-dose IONIS-APO(a)-LRx groups at day 30. In the multidose groups, IONIS-APO(a)-LRx resulted in mean reductions in Lp(a) of 66% (SD 21·8) in the 10 mg group, 80% (SD 13·7%) in the 20 mg group, and 92% (6·5) in the 40 mg group (p=0·0007 for all vs placebo) at day 36. Both antisense oligonucleotides were safe. There were two serious adverse events (myocardial infarctions) in the IONIS-APO(a)Rx phase 2 trial, one in the IONIS-APO(a)Rx and one in the placebo group, but neither were thought to be treatment related. 12% of injections with IONIS-APO(a)Rx were associated with injection-site reactions. IONIS-APO(a)-LRx was associated with no injection-site reactions. Interpretation IONIS-APO(a)-LRx is a novel, tolerable, potent therapy to reduce Lp(a) concentrations. IONIS-APO(a)-LRx might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a) concentrations with existing cardiovascular disease or calcific aortic valve stenosis. Funding Ionis Pharmaceuticals.
Summary Background Lipoprotein(a) (Lpa) is a risk factor for cardiovascular disease and calcific aortic valve stenosis. No effective therapies to lower plasma Lp(a) concentrations exist. We have ...assessed the safety, pharmacokinetics, and pharmacodynamics of ISIS-APO(a)Rx , a second-generation antisense drug designed to reduce the synthesis of apolipoprotein(a) (apoa) in the liver. Methods In this randomised, double-blind, placebo-controlled, phase 1 study at the PAREXEL Clinical Pharmacology Research Unit (Harrow, Middlesex, UK), we screened for healthy adults aged 18–65 years, with a body-mass index less than 32·0 kg/m2 , and Lp(a) concentration of 25 nmol/L (100 mg/L) or more. Via a randomisation technique, we randomly assigned participants to receive a single subcutaneous injection of ISIS-APO(a)Rx (50 mg, 100 mg, 200 mg, or 400 mg) or placebo (3:1) in the single-dose part of the study or to receive six subcutaneous injections of ISIS-APO(a)Rx (100 mg, 200 mg, or 300 mg, for a total dose exposure of 600 mg, 1200 mg, or 1800 mg) or placebo (4:1) during a 4 week period in the multi-dose part of the study. Participants, investigators, and study staff were masked to the treatment assignment, except for the pharmacist who prepared the ISIS-APO(a)Rx or placebo. The primary efficacy endpoint was the percentage change from baseline in Lp(a) concentration at 30 days in the single-dose cohorts and at 36 days for the multi-dose cohorts. Safety and tolerability was assessed 1 week after last dose and included determination of the incidence, severity, and dose relation of adverse events and changes in laboratory variables, including lipid panel, routine haematology, blood chemistry, urinalysis, coagulation, and complement variables. Other assessments included vital signs, a physical examination, and 12-lead electrocardiograph. This trial is registered with European Clinical Trials Database, number 2012-004909-27. Findings Between Feb 27, 2013, and July 15, 2013, 47 (23%) of 206 screened volunteers were randomly assigned to receive ISIS-APO(a)Rx as a single-dose or multi-dose of ascending concentrations or placebo. In the single-dose study, we assigned three participants to receive 50 mg ISIS-APO(a)Rx , three participants to receive 100 mg ISIS-APO(a)Rx , three participants to receive 200 mg ISIS-APO(a)Rx , three participants to receive 400 mg ISIS-APO(a)Rx , and four participants to receive placebo. All 16 participants completed treatment and follow-up and were included in the pharmacodynamics, pharmacokinetics, and safety analyses. For the multi-dose study, we assigned eight participants to receive six doses of 100 mg ISIS-APO(a)Rx , nine participants to receive six doses of 200 mg ISIS-APO(a)Rx , eight participants to receive six doses of 300 mg ISIS-APO(a)Rx , and six participants to receive six doses of placebo. Whereas single doses of ISIS-APO(a)Rx (50–400 mg) did not decrease Lp(a) concentrations at day 30, six doses of ISIS-APO(a)Rx (100–300 mg) resulted in dose-dependent, mean percentage decreases in plasma Lp(a) concentration of 39·6% from baseline in the 100 mg group (p=0·005), 59·0% in the 200 mg group (p=0·001), and 77·8% in the 300 mg group (p=0·001). Similar reductions were observed in the amount of oxidized phospholipids associated with apolipoprotein B-100 and apolipoprotein(a). Mild injection site reactions were the most common adverse events. Interpretation ISIS-APO(a)Rx results in potent, dose-dependent, selective reductions of plasma Lp(a). The safety and tolerability support continued clinical development of ISIS-APO(a)Rx as a potential therapeutic drug to reduce the risk of cardiovascular disease and calcific aortic valve stenosis in patients with elevated Lp(a) concentration. Funding Isis Pharmaceuticals.
Despite its great potential in studying brain anatomy and structure, diffusion magnetic resonance imaging (dMRI) is marred by artefacts more than any other commonly used MRI technique. In this paper ...we present a non-parametric framework for detecting and correcting dMRI outliers (signal loss) caused by subject motion.
Signal loss (dropout) affecting a whole slice, or a large connected region of a slice, is frequently observed in diffusion weighted images, leading to a set of unusable measurements. This is caused by bulk (subject or physiological) motion during the diffusion encoding part of the imaging sequence. We suggest a method to detect slices affected by signal loss and replace them by a non-parametric prediction, in order to minimise their impact on subsequent analysis. The outlier detection and replacement, as well as correction of other dMRI distortions (susceptibility-induced distortions, eddy currents (EC) and subject motion) are performed within a single framework, allowing the use of an integrated approach for distortion correction. Highly realistic simulations have been used to evaluate the method with respect to its ability to detect outliers (types 1 and 2 errors), the impact of outliers on retrospective correction of movement and distortion and the impact on estimation of commonly used diffusion tensor metrics, such as fractional anisotropy (FA) and mean diffusivity (MD). Data from a large imaging project studying older adults (the Whitehall Imaging sub-study) was used to demonstrate the utility of the method when applied to datasets with severe subject movement.
The results indicate high sensitivity and specificity for detecting outliers and that their deleterious effects on FA and MD can be almost completely corrected.
•We present a framework for correction of distortions, subject movement and signal dropout in diffusion weighted images.•It has been validated on realistic simulated data.•One can reliably correct for signal dropout as long as the affected slices constitute no more than 10% of the total.
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