For environmental studies assessing uptake of orally ingested engineered nanoparticles (ENPs), a key step in ensuring accurate quantification of ingested ENPs is efficient separation of the organism ...from ENPs that are either nonspecifically adsorbed to the organism and/or suspended in the dispersion following exposure. Here, we measure the uptake of 30 and 60 nm gold nanoparticles (AuNPs) by the nematode, Caenorhabditis elegans, using a sucrose density gradient centrifugation protocol to remove noningested AuNPs. Both conventional inductively coupled plasma mass spectrometry (ICP-MS) and single particle (sp)ICP-MS are utilized to measure the total mass and size distribution, respectively, of ingested AuNPs. Scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDS) imaging confirmed that traditional nematode washing procedures were ineffective at removing excess suspended and/or adsorbed AuNPs after exposure. Water rinsing procedures had AuNP removal efficiencies ranging from 57 to 97% and 22 to 83%, while the sucrose density gradient procedure had removal efficiencies of 100 and 93 to 98%, respectively, for the 30 and 60 nm AuNP exposure conditions. Quantification of total Au uptake was performed following acidic digestion of nonexposed and Au-exposed nematodes, whereas an alkaline digestion procedure was optimized for the liberation of ingested AuNPs for spICP-MS characterization. Size distributions and particle number concentrations were determined for AuNPs ingested by nematodes with corresponding confirmation of nematode uptake via high-pressure freezing/freeze substitution resin preparation and large-area SEM imaging. Methods for the separation and in vivo quantification of ENPs in multicellular organisms will facilitate robust studies of ENP uptake, biotransformation, and hazard assessment in the environment.
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IJS, KILJ, NUK, PNG, UL, UM
In polypharmacy patients under home health management, pharmacogenetic testing coupled with guidance from a clinical decision support tool (CDST) on reducing drug, gene, and cumulative interaction ...risk may provide valuable insights in prescription drug treatment, reducing re-hospitalization and emergency department (ED) visits. We assessed the clinical impact of pharmacogenetic profiling integrating binary and cumulative drug and gene interaction warnings on home health polypharmacy patients.
This prospective, open-label, randomized controlled trial was conducted at one hospital-based home health agency between February 2015 and February 2016. Recruitment came from patient referrals to home health at hospital discharge. Eligible patients were aged 50 years and older and taking or initiating treatment with medications with potential or significant drug-gene-based interactions. Subjects (n = 110) were randomized to pharmacogenetic profiling (n = 57). The study pharmacist reviewed drug-drug, drug-gene, and cumulative drug and/or gene interactions using the YouScript® CDST to provide drug therapy recommendations to clinicians. The control group (n = 53) received treatment as usual including pharmacist guided medication management using a standard drug information resource. The primary outcome measure was the number of re-hospitalizations and ED visits at 30 and 60 days after discharge from the hospital. The mean number of re-hospitalizations per patient in the tested vs. untested group was 0.25 vs. 0.38 at 30 days (relative risk (RR), 0.65; 95% confidence interval (CI), 0.32-1.28; P = 0.21) and 0.33 vs. 0.70 at 60 days following enrollment (RR, 0.48; 95% CI, 0.27-0.82; P = 0.007). The mean number of ED visits per patient in the tested vs. untested group was 0.25 vs. 0.40 at 30 days (RR, 0.62; 95% CI, 0.31-1.21; P = 0.16) and 0.39 vs. 0.66 at 60 days (RR, 0.58; 95% CI, 0.34-0.99; P = 0.045). Differences in composite outcomes at 60 days (exploratory endpoints) were also found. Of the total 124 drug therapy recommendations passed on to clinicians, 96 (77%) were followed. These findings should be verified with additional prospective confirmatory studies involving real-world applications in larger populations to broaden acceptance in routine clinical practice.
Pharmacogenetic testing of polypharmacy patients aged 50 and older, supported by an appropriate CDST, considerably reduced re-hospitalizations and ED visits at 60 days following enrollment resulting in potential health resource utilization savings and improved healthcare.
ClinicalTrials.gov NCT02378220.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Carbon nanotubes (CNTs) have numerous exciting potential applications and some that have reached commercialization. As such, quantitative measurements of CNTs in key environmental matrices (water, ...soil, sediment, and biological tissues) are needed to address concerns about their potential environmental and human health risks and to inform application development. However, standard methods for CNT quantification are not yet available. We systematically and critically review each component of the current methods for CNT quantification including CNT extraction approaches, potential biases, limits of detection, and potential for standardization. This review reveals that many of the techniques with the lowest detection limits require uncommon equipment or expertise, and thus, they are not frequently accessible. Additionally, changes to the CNTs (e.g., agglomeration) after environmental release and matrix effects can cause biases for many of the techniques, and biasing factors vary among the techniques. Five case studies are provided to illustrate how to use this information to inform responses to real-world scenarios such as monitoring potential CNT discharge into a river or ecotoxicity testing by a testing laboratory. Overall, substantial progress has been made in improving CNT quantification during the past ten years, but additional work is needed for standardization, development of extraction techniques from complex matrices, and multimethod comparisons of standard samples to reveal the comparability of techniques.
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IJS, KILJ, NUK, PNG, UL, UM
Gravimetry typically lacks the resolution to measure single microdroplets, whereas microscopy is often inaccurate beyond the resolution limit. To address these issues, we advance and integrate these ...complementary methods, introducing simultaneous measurements of the same microdroplets, comprehensive calibrations that are independently traceable to the International System of Units (SI), and Monte-Carlo evaluations of volumetric uncertainty. We achieve sub-picoliter agreement of measurements of microdroplets in flight with volumes of approximately 70 pL, with ensemble gravimetry and optical microscopy both yielding 95% coverage intervals of ±0.6 pL, or relative uncertainties of ±0.9%, and root-mean-square deviations of mean values between the two methods of 0.2 pL or 0.3%. These uncertainties match previous gravimetry results and improve upon previous microscopy results by an order of magnitude. Gravimetry precision depends on the continuity of droplet formation, whereas microscopy accuracy requires that optical diffraction from an edge reference matches that from a microdroplet. Applying our microscopy method, we jet and image water microdroplets suspending fluorescent nanoplastics, count nanoplastic particles after deposition and evaporation, and transfer volumetric traceability to the number concentrations of single microdroplets. We expect that our methods will impact diverse fields involving dimensional metrology and volumetric analysis of microdroplets, including inkjet microfabrication, disease transmission, and industrial sprays.
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IJS, KILJ, NUK, PNG, UL, UM
Four techniques for analyzing single molecule tracking data--confinement level analysis, time series analysis and statistical analysis of lateral diffusion, multistate kinetics, and a newly developed ...method, radius of gyration evolution analysis--are compared using a set of sample fluorophore trajectories obtained from the lipophilic carbocyanine dye 1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine, DiIC(18), partitioned into surface tethered poly(n-isopropylacrylamide). The purpose here is two-fold: first to test that these techniques can be applied to single molecules trajectories, which typically contain a smaller total number of frames than those obtained from other particles, e.g. quantum dots or gold nanoparticles; and second to critically compare the information obtained from each method against the others. A set of five SMT trajectories, ranging in length from 41 to 273 steps with a 30 ms frame transfer exposure, were all successfully analyzed by all four techniques, provided two important criteria were met: enough steps to define the motion were acquired in the trajectory, generally on the order of 50 steps, and the fast and slow diffusion coefficients differ by at least a factor of 5. Beyond that the four trajectory analysis methods studied provide partially confirmatory and partially complementary information. SMT data resulting from more complex physical behavior may well benefit from using these techniques in succession to identify and sort populations.
•We explored the reliability, validity, and measurement error of rapid scans.•Rapid scans produced high-quality morphometrics in ∼1/5th of a traditional scan.•For many current uses, rapid scans can ...replace standard structural scans.•Rapid scans can reduce costs, limit participant burden and allow for scan repeats.
T1-weighted structural MRI is widely used to measure brain morphometry (e.g., cortical thickness and subcortical volumes). Accelerated scans as fast as one minute or less are now available but it is unclear if they are adequate for quantitative morphometry. Here we compared the measurement properties of a widely adopted 1.0 mm resolution scan from the Alzheimer's Disease Neuroimaging Initiative (ADNI = 5′12’’) with two variants of highly accelerated 1.0 mm scans (compressed-sensing, CSx6 = 1′12’’; and wave-controlled aliasing in parallel imaging, WAVEx9 = 1′09’’) in a test-retest study of 37 older adults aged 54 to 86 (including 19 individuals diagnosed with a neurodegenerative dementia). Rapid scans produced highly reliable morphometric measures that largely matched the quality of morphometrics derived from the ADNI scan. Regions of lower reliability and relative divergence between ADNI and rapid scan alternatives tended to occur in midline regions and regions with susceptibility-induced artifacts. Critically, the rapid scans yielded morphometric measures similar to the ADNI scan in regions of high atrophy. The results converge to suggest that, for many current uses, extremely rapid scans can replace longer scans. As a final test, we explored the possibility of a 0′49’’ 1.2 mm CSx6 structural scan, which also showed promise. Rapid structural scans may benefit MRI studies by shortening the scan session and reducing cost, minimizing opportunity for movement, creating room for additional scan sequences, and allowing for the repetition of structural scans to increase precision of the estimates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Spatial and temporal heterogeneities in expanded and collapsed surface bound poly(N-isopropylacrylamide), pNIPAAm, films are studied by single molecule tracking (SMT) experiments. Tracking data are ...analyzed using both radius of gyration (R g) evolution and confinement level calculations to elucidate the range of behaviors displayed by single Rhodamine6G (R6G) molecules. Confined diffusion that is dictated by the free volume within surface tethered chains is observed with considerable dispersion among individual R6G molecules. Thus, the distribution of probe behavior reflects nanometer-scale information about the behavior of the probe–polymer system at temperatures above (T > T LCST) and below (T < T LCST) the lower critical solution temperature (LCST). In this context, confinement-level analysis and R g evolution both show a larger degree of confinement of the probe in pNIPAAm at T > T LCST. Temperature-dependent changes in confinement are evidenced at T > T LCST by a higher percentage of confined steps, longer periods of confined events, and smaller area of confined zones, as well as a shift in the overall distribution of R g evolution paths and final R g distributions.
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IJS, KILJ, NUK, PNG, UL, UM
The structure of a hydrated poly(N-isopropylacrylamide) brush loaded with 5 vol % Isoniazid is studied as a function of temperature using neutron reflectometry (NR) and atomic force microscopy (AFM). ...NR measurements show that Isoniazid increases the thickness of the brush before, during and after the polymer collapse, and it is retained inside the brush at all measured temperatures. The Isoniazid concentration in the expanded brush is ∼14% higher than in the bulk solution, and the concentration nearly doubles in the collapsed polymer, suggesting stronger binding between Isoniazid and the polymer compared to water, even at temperatures below the lower critical solution temperature (LCST) where the polymer is hydrophilic. Typically, additives that bind strongly to the polymer backbone and increase the hydrophilicity of the polymer will delay the onset of the LCST, which is suggested by AFM and NR measurements. The extent of small-molecule loading and distribution throughout a thermo-responsive polymer brush, such as pNIPAAm, will have important consequences for applications such as drug delivery and gating.
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IJS, KILJ, NUK, PNG, UL, UM
Parent chronic illness may increase somatic symptomology risk in children. The current study examines this association in relation to a variety of chronic illnesses and also considers possible ...related parental and adolescent background factors.
Secondary analyses used longitudinal data from the University of North Carolina National Longitudinal Study of Adolescent to Adult Health. Interviews were used to assess demographics, adolescent somatic symptoms, living situation, and parental illness and general physical health. Somatic symptoms in adolescents with no ill parents (n = 2302 adolescents; Mage = 15.3) were compared with adolescents with ill mothers (n = 2336; Mage = 15.3), ill fathers (n = 1304; Mage = 15.3), or two ill parents (n = 3768; Mage = 15.3) using Poisson regression models. We also examined the role of living status, adolescent sex, and parent general physical health on somatic symptom outcomes.
Elevated somatic symptoms were observed in adolescents with ill mothers (mean ratio MR = 1.15, p = .015) and with both parents ill (MR = 1.10, p < .001). Among adolescents with ill parents, females had more symptoms than males (ill mother: MR = 1.12, p < .001; ill father: MR = 1.23, p < .001; and both parents ill: MR = 1.23, p < .001). Poorer maternal physical health also increased somatic symptom risk (MR = 1.12, p = .02). Longitudinally, adolescents with ill mothers (MR = 1.14, p < .001), ill fathers (MR = 1.13, p < .001), or both parents ill (MR = 1.16, p < .001) had increased somatic symptom risk. Wave I somatic symptoms also increased future risk: ill mother (MR = 1.19, p < .001), ill father (MR = 1.22, p < .001), or both parents ill (MR = 1.20, p < .001).
The results highlight that having an ill parent is a risk factor for adolescent somatic symptoms. In addition, other factors such as adolescent sex play an additional role in adolescent somatic symptoms.
Background. Amplified copy number in the plasmepsin II/III genes within Plasmodium falciparum has been associated with decreased sensitivity to piperaquine. To examine this association and test ...whether additional loci might also contribute, we performed a genome-wide association study of ex vivo P. falciparum susceptibility to piperaquine. Methods. Plasmodium falciparum DNA from 183 samples collected primarily from Cambodia was genotyped at 33716 genome-wide single nucleotide polymorphisms (SNPs). Linear mixed models and random forests were used to estimate associations between parasite genotypes and piperaquine susceptibility. Candidate polymorphisms were evaluated for their association with dihydroartemisinin-piperaquine treatment outcomes in an independent dataset. Results. Single nucleotide polymorphisms on multiple chromosomes were associated with piperaquine 90% inhibitory concentrations (IC90) in a genome-wide analysis. Fine-mapping of genomic regions implicated in genome-wide analyses identified multiple SNPs in linkage disequilibrium with each other that were significantly associated with piperaquine IC90' including a novel mutation within the gene encoding the P. falciparum chloroquine resistance transporter, PfCRT. This mutation (F145I) was associated with dihydroartemisinin-piperaquine treatment failure after adjusting for the presence of amplified plasmepsin II/III, which was also associated with decreased piperaquine sensitivity. Conclusions. Our data suggest that, in addition to plasmepsin II/III copy number, other loci, including pfcrt, may also be involved in piperaquine resistance.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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