The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and ...recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing examples of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Prescription opioid misuse has become a leading cause of unintentional injury and death among adolescents and young adults in the United States. However, there is limited information on how ...adolescents and young adults obtain prescription opioids. There are also inadequate recent data on the prevalence of additional drug abuse among those misusing prescription opioids. In this study, we evaluated past-year prevalence of prescription opioid use and misuse, sources of prescription opioids, and additional substance use among adolescents and young adults.
This was a retrospective analysis of the National Survey on Drug Use and Health (NSDUH) for the years 2015 and 2016. Prevalence of opioid use, misuse, use disorder, and additional substance use were calculated with 95% confidence intervals (CIs), stratified by age group and other demographic variables. Sources of prescription opioids were determined for respondents reporting opioid misuse. We calculated past-year prevalence of opioid use and misuse with or without use disorder, sources of prescription opioids, and prevalence of additional substance use. We included 27,857 adolescents (12-17 years of age) and 28,213 young adults (18-25 years of age) in our analyses, corresponding to 119.3 million individuals in the extrapolated national population. There were 15,143 respondents (27.5% 95% CI 27.0-28.0, corresponding to 32.8 million individuals) who used prescription opioids in the previous year, including 21.0% (95% CI 20.4-21.6) of adolescents and 32.2% (95% CI 31.4-33.0) of young adults. Significantly more females than males reported using any prescription opioid (30.3% versus 24.8%, P < 0.001), and non-Hispanic whites and blacks were more likely to have had any opioid use compared to Hispanics (28.9%, 28.1%, and 25.8%, respectively; P < 0.001). Opioid misuse was reported by 1,050 adolescents (3.8%; 95% CI 3.5-4.0) and 2,207 young adults (7.8%; 95% CI 7.3-8.2; P < 0.001). Male respondents using opioids were more likely to have opioid misuse without use disorder compared with females (23.2% versus 15.8%, respectively; P < 0.001), with similar prevalence by race/ethnicity. Among those misusing opioids, 55.7% obtained them from friends or relatives, 25.4% from the healthcare system, and 18.9% through other means. Obtaining opioids free from friends or relatives was the most common source for both adolescents (33.5%) and young adults (41.4%). Those with opioid misuse reported high prevalence of prior cocaine (35.5%), hallucinogen (49.4%), heroin (8.7%), and inhalant (30.4%) use. In addition, at least half had used tobacco (55.5%), alcohol (66.9%), or cannabis (49.9%) in the past month. Potential limitations of the study are that we cannot exclude selection bias in the study design or socially desirable reporting among participants, and that longitudinal data are not available for long-term follow-up of individuals.
Results from this study suggest that the prevalence of prescription opioid use among adolescents and young adults in the US is high despite known risks for future opioid and other drug use disorders. Reported prescription opioid misuse is common among adolescents and young adults and often associated with additional substance abuse, underscoring the importance of drug and alcohol screening programs in this population. Prevention and treatment efforts should take into account that greater than half of youths misusing prescription opioids obtain these medications through friends and relatives.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tablets have much to offer children with learning difficulties, but evidence of their effectiveness to teach academic skills is limited and cannot be easily separated from the quality of the ...software. This paper analyses data from 3 iterative cycles of designing an app for children with Down syndrome to support their awareness of quantity through an inclusive game. Research with neurotypical children suggests that representation of quantity (or magnitude) is an area with considerable potential in supporting the foundations for children's mathematical learning. It has received little attention as an aspect for intervention for children with Down syndrome. Data collected in this study illustrate the need to carefully align the game mechanic to the target skills, strengthen levels of access, and introduce gradations of attentional demand. They also signal the interrelationship between children's cognitive and affective responses to the game, making it essential to find the optimal level of challenge. Children's strategies in response to mistakes indicate the importance of creating an agile responsive system. The data also suggest that developers routinely extend the number of features that are optional, enabling a greater level of personalization and a more inclusive game.
Lay Description
What is already known about this topic:
A number of children with Down syndrome experience particular difficulties with counting, placing constraints on their mathematical development.
There is an overreliance on early years software for children with Down syndrome with limited research concerning the development of bespoke apps.
Structured approaches, using small steps, characterize successful mathematics teaching for children with moderate and severe intellectual disability.
There is an important role for educational researchers, drawing on this pedagogic evidence to work alongside creative and software designers to develop engaging and accessible instructional tools.
What this paper adds:
New insights from the collection of qualitative as well as quantitative data from the first bespoke app designed to support magnitude representation in children with Down syndrome;
better understanding of the design challenges with respect to building in different kinds of progression and support and a range of types of feedback; and
illustration of the ways in which children respond to mistakes and the impact this has on engagement with the game.
Implications for practice:
Attending to the clarity of the visual display and careful choice of icons;
analysis of progression in the task together with cognitive load in the presentation of the game;
building in a system that is responsive to children's error patterns; and
widening the nature of optional features for personalizing the game, including rewards that range in sophistication.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major.
We analyzed cardiac and liver T2* magnetic ...resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia.
Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.
Studying the interactions between nanoengineered materials and biological systems plays a vital role in the development of biological applications of nanotechnology and the improvement of our ...fundamental understanding of the bio-nano interface. A significant barrier to progress in this multidisciplinary area is the variability of published literature with regards to characterizations performed and experimental details reported. Here, we suggest a 'minimum information standard' for experimental literature investigating bio-nano interactions. This standard consists of specific components to be reported, divided into three categories: material characterization, biological characterization and details of experimental protocols. Our intention is for these proposed standards to improve reproducibility, increase quantitative comparisons of bio-nano materials, and facilitate meta analyses and in silico modelling.
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IJS, NUK, SBMB, UL, UM, UPUK
Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue ...of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Synthetic polymer membranes are enabling components in key technologies at the water–energy nexus, including desalination and energy conversion, because of their high water/salt selectivity or ionic ...conductivity. However, many applications at the water–energy nexus require ion selectivity, or separation of specific ionic species from other similar species. Here, the ion selectivity of conventional polymeric membrane materials is assessed and recent progress in enhancing selective transport via tailored free volume elements and ion–membrane interactions is described. In view of the limitations of polymeric membranes, three material classes—porous crystalline materials, 2D materials, and discrete biomimetic channels—are highlighted as possible candidates for ion‐selective membranes owing to their molecular‐level control over physical and chemical properties. Lastly, research directions and critical challenges for developing bioinspired membranes with molecular recognition are provided.
Emerging water and energy technologies often require membranes that selectively separate an ion from similar species. Progress in enhancing selective ion transport in polymeric membranes is described, followed by analysis of three advanced material classes that are possible candidates for ion‐selective membranes owing to their molecular‐level control over physicochemical properties. Research directions and challenges for developing ion‐selective membranes are discussed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Oral lipid-based drug delivery systems may include a broad range of oils, surfactants, and cosolvents. This diversity makes comparison of lipid-based formulations difficult. Although the relationship ...between formulation and drug absorption is understood at a conceptual level, performance
in vivo cannot be predicted with confidence at present. The Lipid Formulation Classification System (LFCS) identifies the factors which are likely to affect performance
in vivo. There is now a need to establish performance criteria which will facilitate
in vitro–
in vivo correlation studies. In this review we discuss the properties of excipients, and identify criteria for selection of excipients for lipid-based formulations. Excipients are discussed in the context of the LFCS, our existing knowledge of the fate of these materials during dispersion and digestion, and the likely consequences of their use in formulations. We outline the formulation strategies that can be used for each type of lipid formulation, and suggest a framework for the
in vitro testing of each type. Finally we address the choice of lipid formulations in relation to the physicochemical properties of the drug.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In the study of equity in public transit service distribution to disadvantaged groups, there is often a desire for a concise and relatable quantitative measure of equity. This ambition has often ...pushed researchers to develop methods for combining (or aggregating) various dimensions of disadvantage into a single, multi-faceted metric of potential transit demand (or need) among the disadvantaged population. These metrics then enable a somewhat straightforward analysis of the transit needs of the aggregate disadvantaged population to the transit service supplied in order to arrive at a measure of transit equity.
More recently, it has been proposed that such aggregated transit equity analysis may introduce veiled judgments or bias through the specific interpretation of key definitions and through the particular choices in the construction of a combined metric. It may also be the case that such an aggregate metric may mask or convolute important disparities in transit equity experienced by the various disadvantaged populations aggregated into a combined metric.
This research studies these issues through a clear discussion of the ambiguity and implied judgments often found in transit equity literature and then provides recommendations to mitigate these issues. Also, two common equity analysis methods are compared through a case study of public transit service in the city of Corvallis, Oregon, and a new transit service metric construction is introduced. By comparing the results of both the aggregated and disaggregated forms of disadvantaged group transit need within each analysis method, this study provides further evidence that important information may be concealed or easily misinterpreted when using aggregated descriptions of transit need.
•Clearly defining equity is essential for interpreting equity analysis results.•Implicit judgement and bias in metric construction is explored.•A new construction for a transit supply metric using road length is proposed.•The common Lorenz curve and Needs gap methods are compared.•Aggregated disadvantaged group metrics may mask or convolute transit inequity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Histone deacetylases (HDACs) regulate myriad cellular processes by catalyzing the hydrolysis of acetyl–L-lysine residues in histone and nonhistone proteins. The Zn2+-dependent class IIb enzyme HDAC6 ...regulates microtubule function by deacetylating α-tubulin, which suppresses microtubule dynamics and leads to cell cycle arrest and apoptosis. Accordingly, HDAC6 is a target for the development of selective inhibitors that might be useful in new therapeutic approaches for the treatment of cancer, neurodegenerative diseases, and other disorders. Here, we present high-resolution structures of catalytic domain 2 from Danio rerio HDAC6 (henceforth simply “HDAC6”) complexed with compounds that selectively inhibit HDAC6 while maintaining nanomolar inhibitory potency: N-hydroxy-4-(N(2-hydroxyethyl)-2-phenylacetamido)methyl)-benzamide) (HPB), ACY-1215 (Ricolinostat), and ACY-1083. These structures reveal that an unusual monodentate Zn2+ coordination mode is exploited by sterically bulky HDAC6-selective phenylhydroxamate inhibitors. We additionally report the ultrahigh-resolution structure of the HDAC6–trichostatin A complex, which reveals two Zn2+-binding conformers for the inhibitor: a major conformer (70%) with canonical bidentate hydroxamate-Zn2+ coordination geometry and a minor conformer (30%) with monodentate hydroxamate-Zn2+ coordination geometry, reflecting a free energy difference of only 0.5 kcal/mol. The minor conformer is not visible in lower resolution structure determinations. Structural comparisons of HDAC6-inhibitor complexes with class I HDACs suggest active site features that contribute to the isozyme selectivity observed in biochemical assays.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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