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A cognitive aid is a tool used to help people accurately and efficiently perform actions. Similarly themed cognitive aids may be collated into a manual to provide relevant information for a specific context (eg, operating room emergencies). Expert content and design are paramount to facilitate the utility of a cognitive aid, especially during a crisis when accessible memory may be limited and distractions may impair task completion. A cognitive aid does not represent a rigid approach to problem-solving or a replacement for decision-making. Successful cognitive aid implementation requires dedicated training, access, and culture integration. Here the authors present a set of evidence-based cognitive aids for thoracic anesthesia emergencies developed by a Canadian thoracic taskforce. [ABSTRACT FROM AUTHOR]

Perioperative organ injury is a frequent and major complication for the ∼240 million people undergoing surgery worldwide annually. Ischaemic preconditioning is a powerful technique that reduces organ injury in experimental models of heart, lung, gut, brain, and kidney ischaemia–reperfusion injury. However, ischaemic preconditioning has been a challenge to translate into clinical practice. We describe how utilising isolated pre-conditioned exosomes (secreted vesicles containing many cell-survival mediators), some of the translational hurdles of ischaemic preconditioning can be overcome. Delivery of exosomes in the perioperative period could become a promising new therapeutic strategy to prevent perioperative organ injury. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2006.03.017 Byline: Andrew Owen Abstract: The survival of patients with chronic heart failure is typically reported as a comparison of different groups of patients using the hazard ratio from a Cox proportional hazards analysis. The absolute survival is generally neglected. Furthermore, attention is often focused on relatively young patients although chronic heart failure largely affects older patients. The present study was undertaken to determine the life expectancy (a measure of absolute survival) of older patients with chronic heart failure. Author Affiliation: Department of Cardiology, Kent and Canterbury Hospital, Canterbury, UK Article History: Received 6 November 2005; Accepted 20 March 2006

Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits. [ABSTRACT FROM AUTHOR]

This paper presents the results of an accessibility-based model of aggregate commute mode share, focusing on the share of transit relative to auto. It demonstrates the use of continuous accessibility – calculated continuously in time, rather than at a single of a few departure times – for the evaluation of transit systems. These accessibility calculations are accomplished using only publicly-available data sources. A binomial logic model is estimated which predicts the likelihood that a commuter will choose transit rather than auto for a commute trip based on aggregate characteristics of the surrounding area. Variables in this model include demographic factors as well as detailed accessibility calculations for both transit and auto. The mode achieves a ρ 2 value of 0.597, and analysis of the results suggests that continuous accessibility of transit systems may be a valuable tool for use in modeling and forecasting. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Patients with severe, but asymptomatic aortic stenosis (AS) present a difficult clinical challenge. The conventional strategy is ‘wait for symptoms’ approach. However, some observational studies have suggested early aortic valve replacement (AVR) results in better outcome compared to late surgery. There are no randomised controlled trials comparing clinical outcome of early and late AVR. This meta-analysis is to examine the effect of the two approaches on clinical outcome in such patients. Methods: We searched the PubMed for published studies on asymptomatic AS and treatment. Four observational studies (N=976 patients) were suitable for inclusion in the analysis. Results: All four studies provided sufficient details. Using the subgroup of asymptomatic patients who underwent early surgery together or separately from the subgroup who had surgery after developing symptoms resulted in ORs of 0.17 and 0.16 respectively (p<0.00001) in favour of early AVR compared with conservational or late surgery. Conclusion: Meta-analysis of the available observational studies has demonstrated highly significant clinical outcome in favour of early AVR compared with late surgery, suggesting that early surgical approach offers substantial survival benefit for severe asymptomatic AS patients. [Copyright &y& Elsevier]

Abstract: The mechanisms that underpin the passage of lamotrigine at the blood–brain barrier to its site of action in the brain is poorly understood. Lamotrigine has been postulated to be delivered to its site of action in the brain favourably despite its physicochemical properties. The aim of this study was to investigate the transport of lamotrigine in an in-vitro model of the BBB. In this study, lamotrigine was found to have a distribution coefficient of 0 at pH 7.4 indicating that it was not highly lipophilic. Human brain endothelial cells (hCMEC/D3) were used to probe the interaction of lamotrigine with drug transporters. The uptake of lamotrigine into hCMEC/D3 cells was found to be an active process (K m =62±14μM; V max =385±30pmol/min/million cells). Furthermore, use of a panel of transporter inhibitors indicated that this active uptake was mediated by organic cation transporter 1 (OCT1). OCT1 mRNA and protein were shown to be expressed in hCMEC/D3 cells. KCL22 cells overexpressing OCT1 were then used to validate these findings. Lamotrigine was confirmed to be a substrate and inhibitor in OCT1-transfected KCL22 cells. A putative pharmacokinetic drug–drug interaction (DDI) between quetiapine and lamotrigine was recently reported in patients and we show here that quetiapine is a potent inhibitor of the OCT1-mediated transport of lamotrigine. This is the first time that a specific influx transporter has been shown to transport lamotrigine. The clinical implications of these findings with respect to the efficacy of lamotrigine and its potential for DDI require further investigation. [Copyright &y& Elsevier]

Abstract: Introduction: Coronary artery stenoses have been shown in various trials to be moderated by treatment with statins. A similar effect on coronary artery calcification has not been demonstrated. We therefore undertook meta-analyses of trials examining the effect of statin treatment on coronary artery stenoses and coronary artery calcification. Methods: Literature searches identified five controlled trials suitable for inclusion in the analysis of the effect of statins (high dose versus either low dose or placebo) on coronary artery calcification and six trials suitable for inclusion in the analysis of the effect of statins on coronary artery stenoses. Results: All trials reported substantial and significant reductions in LDL-C with statin treatment which results in net reductions of LDL-C in the CAC and coronary stenoses trials of 1.0mmol/L and 0.9mmol/L, respectively. Analysis of the CAC trials did not demonstrate any effect of statins on the progression of calcification. In contrast, in the coronary stenoses trials there was a consistent moderation of stenosis severity progression with statins (p <0.0001). Conclusions: Meta-analyses of the available trials have demonstrated a significant moderation of coronary stenoses associated with the statin-induced reduction in LDL-C. In contrast, there was no effect on coronary calcification despite a similar reduction in LDL-C levels. This suggests that the pathogenesis of the two conditions may be different, if not in aetiology, then certainly in their development. It further suggests that statin use to moderate arterial calcification is not effective. [Copyright &y& Elsevier]

Abstract: The role of aspirin for the primary prevention of stroke in patients with non valvular atrial fibrillation is critically reviewed. It is shown that the currently held belief that aspirin (at doses of 75 to 325mg daily) is an effective treatment is based on a flawed interpretation of the data. A Bayesian network meta analysis is presented that demonstrates that aspirin at 325mg daily is superior to control and similar to warfarin for the reduction of the risk of both stroke and death. In contrast for lower daily doses of aspirin there is no evidence of any efficacy over control for the reduction of the risk of stroke. The data are inconclusive as to whether lower doses of aspirin may have some benefit in reducing the risk of death. [Copyright &y& Elsevier]

Abstract: Using survey data from three Polish parliamentary elections, we provide the first systematic micro-level test contrasting a standard incumbency-based model of economic voting with a transitional economic voting model in the post-communist context. To do so, we introduce a novel temporal component to micro-level studies of economic voting that supplements standard short-term retrospective economic evaluations (e.g., “do you feel the economy has improved in the past 12 months?”) with longer “transitional” retrospective economic evaluations (e.g., “do you feel the economy has improved since the collapse of communism?”). Our analyses reveal a nuanced picture suggesting multiple paths for economic influences on voting in Poland. We find evidence consistent with the standard incumbency-based approach, but only for the specific set of evaluations to which the theory is most appropriately applied: short-term retrospective economic evaluations and the vote for incumbent parties. By contrast, the transitional model is strongly supported by evidence that evaluations of changes in economic conditions since the collapse of communism (“long-term economic evaluations”) have an effect on the vote for a range of parties. We demonstrate as well that these results are robust to model specification and generational effects. [Copyright &y& Elsevier]

Purpose: To prospectively compare contrast-enhanced (CE) magnetic resonance (MR) angiography against digital subtraction angiography (DSA) in patients with critical lower-limb ischemia. Materials and Methods: Thirty patients with critical lower limb ischemia underwent both CE MR angiography and DSA. CE MR angiography commenced with a dedicated high-resolution study of the below-knee arteries followed by a three-station bolus-chase examination. Two blinded observers recorded the severity of the most significant stenosis within each arterial segment. Interobserver agreement was calculated and, with DSA as the reference standard, the sensitivity and specificity of CE MR angiography for the detection of significant stenosis (≥50% luminal narrowing) or occlusion was calculated. Results: All 390 arterial segments were scored by both observers. Sensitivity was higher in the distal segments (92%–96%) compared with the proximal segments (69%–79%). Specificity was similar in distal (90%–91%) and more proximal segments (86%–96%). Overall, interobserver agreement was excellent (κ = 0.95 for CE MR angiography and DSA) and was superior within the distal segments. Twenty-eight segments that were considered occluded on DSA were shown to be patent on CE MR angiography and 16 segments that were considered occluded on CE MR angiography were shown to be patent on DSA. Conclusions: In patients with critical lower-limb ischemia, CE MR angiography with high-resolution distal imaging is highly accurate for assessment of the below-knee arteries. Both DSA and CE MR angiography may identify patent vessels that are considered occluded based on the other modality. [Copyright &y& Elsevier]

Abstract: For decades, wind tunnel testing has been conducted in test section environments that have not been adequately or consistently documented. Since wind tunnel flow quality can adversely affect test results, accurate and consistent flow quality measurements are required, along with an understanding of the sources, characteristics, and management of flow turbulence. This paper will review turbulence measurement techniques and data obtained in subsonic, transonic, and supersonic test facilities as they relate to the determination and assessment of wind tunnel flow quality. The principles and practical application of instrumentation used in the measurement and characterization of wind tunnel turbulence will be described. Techniques used for the identification of the sources of wind tunnel disturbances, and the performance of turbulence suppression devices will be outlined. These test techniques will be illustrated with extensive measurements obtained in a number of test facilities. The measurements will provide comprehensive turbulence data that are vital to the assessment and management of flow quality. Procedures designed to assess the potential influence of adverse flow quality on wind tunnel model test performance will also be discussed. [Copyright &y& Elsevier]

Summary: If tuberculosis therapy is to be shortened it is imperative that the sterilising activity of current and future anti-tuberculosis drugs is enhanced. Intracellular Mycobacterium tuberculosis (MTB) phagocytosed by macrophages may be a key subpopulation of bacteria that are less readily eliminated by therapy. Here we investigate whether macrophages provide MTB with a pharmacological sanctuary site, making them less susceptible to chemotherapy than extracellular bacilli. Intracellular drug activity was determined by a novel colorimetric method that measures the ability of a drug to protect A-THP1 cells from infection-mediated cell death by H37Rv. Extracellular bactericidal activity was determined by the microplate alamar blue assay (MABA). Further, the effect of P-glycoprotein (P-gp) expressed on macrophages on the intracellular kill of H37Rv was assessed. To screen the anti-tuberculosis drugs for P-gp substrate specificity, their toxicity and cellular accumulation were determined in CEM and CEMVBL100 cells. Intracellular and extracellular anti-tuberculosis drug activity following 7-day treatment with isoniazid (mean EC50±SD: 36.7±2.2 and 57.2±2.5ng/mL, respectively) and ethambutol (243±95 and 263±12ng/mL, respectively) were similar. However, for rifampicin a higher concentration was required to kill intracellular (148±32ng/mL) versus extracellular (1.27±0.02ng/mL) bacilli. The P-gp inhibitor tariquidar, significantly increased intracellular kill of H37Rv by ethambutol and rifampicin and both of these drugs were shown to be substrates for P-gp using the P-gp overexpressing CEMVBL100 cells. We observed a large discrepancy between intracellular and extracellular activity of rifampicin (but not with isoniazid or ethambutol). Several factors could have accounted for this including inoculum size, media and cell-mediated metabolism. These factors make the comparison of intracellular and extracellular drug activity complex. However, the intracellular assay described here has potential for studying the impact of host proteins (such as drug transporters) on the intracellular activity of drugs, and has been used successfully here to demonstrate that both rifampicin and ethambutol are substrates for P-gp. [Copyright &y& Elsevier]

Abstract: Calcareous soils are frequently characterized by the low bioavailability of plant nutrients. Consequently, many vascular plant species are unable to successfully colonize calcareous sites and the floristic composition of calcareous and acid silicate soils has been shown to differ markedly. The root exudation of oxalate and citrate has been suggested to play a pivotal role in same nutrient acquisition mechanisms operating in calcareous soils. The aim of this study was therefore to investigate the nutrient extraction efficiency of three individual organic acids commonly identified in root exudates, i.e. citric, malic and oxalic acid. Our results clearly demonstrate the context dependent nature of nutrient release by organic acids. The degree of P extraction was highly dependent on which organic acid was added, their concentration and pH, and their contact time with the soil. P is generally more efficiently extracted by organic acids at a high pH and follows the series oxalate>citrate>malate. The opposite relationship between pH and extraction efficiency was apparent for most other cations examined (e.g. Zn, Fe), which are more efficiently extracted by organic acids at low pH. A serious constraint to the ecological importance of organic acid exudation in response to P deficiency is, however, their very low P mobilization efficiency. For every mol of soil P mobilized, 1000mol of organic acid has to be added. It can, however, be speculated that in a calcareous soil with extremely low P concentrations it is still beneficial to the plants to exude organic acids in spite of the seemingly high costs in terms of carbon. [Copyright &y& Elsevier]

Background: Echocardiography of endurance athletes has demonstrated a substantial increase in left ventricular mass with no disturbance of diastolic function as assessed by the e:a ratio. Few studies have examined the right ventricle of athletes. The present study evaluated diastolic function of both right and left ventricles of endurance athletes through use of measurements of the motion of the atrioventricular (AV) plane. Methods: Endurance athletes (runners) and sedentary subjects were studied. All subjects were male, aged 30–45 years and were free of cardiovascular disease. There were 21 runners and 40 sedentary subjects. The diastolic motion of the AV plane was assessed by measurement of total displacement and peak early velocity. Results: The runners had a greater peak oxygen consumption (ml kg-1 min-1) (59.5 vs. 33.5, P<10-3) and left ventricular mass (g) (281 vs. 202, P<10-3). The e:a ratio for both groups was similar (1.41 vs. 1.45, P=0.8). Both total displacement and peak early velocity for both ventricles were similar between groups, P>0.3. No correlation with age was found for total displacement or peak early velocity for either group in either ventricle, with the exception of peak early velocity for the right ventricle in the runners, where a highly significant correlation was found: peak early velocity=24.0-0.4 age, r2=0.75, P=10-5. Conclusion: Chronic endurance training is associated with a greater LV mass than in comparable sedentary subjects. Despite this, no effect on AV plane motion was found. A decline in right ventricular peak early velocity of the AV plane with increasing age was identified in the runners. This was an unexpected finding and requires further study. [Copyright &y& Elsevier]

Amino acids, either in a free or polymeric state, represent a significant addition of N to most ecosystems and therefore comprise a key pool in the soil nitrogen cycle. The ability of some plants to take up amino acids directly from soil may confer a competitive advantage particularly in N-limited environments. Whilst measurements of inorganic N concentrations (NH4+ and NO3−) are routinely undertaken on either soil solutions or soil water/KCl extracts, there is a need for a supplementary procedure to determine free amino acids and enable determination of all plant-available pools. The aim of this study is to develop and test a procedure for the rapid and sensitive determination of total free amino acids in soil solutions and soil extracts (water or 2 M KCl) and to compare this with the standard ninhydrin method of . The spectrofluorometric procedure relies on the reaction of free amino acids with o-phthaldialdehyde and β-mercaptoethanol. The fluorometric method is much more sensitive (working range 0.1–50 μM) than typical spectrophotometric analysis procedures for free amino acids which employs the ninhydrin reagent (working range 10–500 μM). In addition, the method only requires small sample volumes (1–50 μl), is rapid (1 min sample−1), simple to perform, and linear over a concentration range of three orders of magnitude (0.1–100 μM). The method was used to determine free amino acid concentrations across a range of ecosystem types (upland and lowland grasslands, forest, heathland and coastal saltmarsh). Generally, the concentration of free amino acids in soil solution was low and relatively independent of soil type. The average soluble N concentrations across all sites (n=7) were 24±8 μM for amino acids, 39±14 μM for NH4+ and 67±42 μM for NO3−. Free amino acids typically constituted 10–40% of the total soluble N in the soil solution and therefore comprise a significant soluble N and plant available pool in soil. [Copyright &y& Elsevier]

The exudation of organic acids into the rhizosphere by plant roots has been hypothesized to be one potential mechanism by which plants can enhance the mobilization of poorly soluble nutrients in the soil. The experiments undertaken in this study were aimed at determining whether the organic acids, citrate and oxalate, could enhance the uptake of 33P from a calcareous soil with a high P fixation capacity (Typic rendoll). Soil-filled rhizosphere microcosms were constructed which allowed the growth of a single maize root axis through a KH233PO4-labelled patch of soil. After passage of the root through the 33P-labelled soil, organic acids or distilled water (control) were added to the patch at concentrations of 1 and 10 mM over a subsequent 4-day period. While oxalate resulted in an approximately two-fold enhancement in shoot 33P accumulation, citrate did not result in a significant enhancement of 33P uptake above controls to which only distilled water were added. No synergistic effect on shoot 33P accumulation was observed when both oxalate and citrate were added to the soil simultaneously. We hypothesize that the observed differences in shoot 33P accumulation by the two organic acids were due primarily to the differences in their biodegradation rate and P mobilization reactions. This study demonstrates that in vivo, organic acids can cause a significant enhancement of plant P uptake, however, the magnitude of the P mobilization response is likely to be highly context dependent. [Copyright &y& Elsevier]

• Long-acting injectable or implantable antiretrovirals are an alternative to oral drugs. • Long-acting cabotegravir and rilpivirine should be approved shortly. • Extended-release polymer implants are in development. • Transcutaneous microarray patches are a novel drug delivery system. Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long-acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early- and late-stage clinical trials. Strategies to manage toxicity and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated and efficacious in large randomised phase 3 studies. Regulatory approval for this two-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the USA during 2021. 4ʹ-Ethynyl-2-fluoro-2′-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long-acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly-neutralising monoclonal antibodies have potent antiviral activity in early human trials, however there is substantial baseline resistance and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include management of toxicities and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well tolerated and economical, they are likely to gain broader appeal. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Chest compressions performed correctly have the potential to increase survival post cardiac arrest. The 2005 European Resuscitation Council (ERC) guidelines altered and simplified instructions for hand position placement to increase the number of chest compressions performed. This randomised controlled trial compares chest compression efficacy (hand position and number of effective chest compressions) after training using the 2005 guidelines or the 2005 guidelines with a hand position modification based on 2000 ERC guidelines. Methods: First year healthcare students at the University of Birmingham, United Kingdom, were randomly allocated to either ‘2005’ or ‘intervention’ group immediately after passing a Basic Life Support (BLS) assessment to ERC standards. The 2005 group performed 2min of BLS on a SkillReporter™ manikin (Laerdal Medical, Stavanger, Norway). The intervention group received training on hand placement using landmark techniques from the 2000 ERC guidelines; emphasising rapid hand positioning. This group also performed 2min of BLS on a SkillReporter™ manikin. Results: 82 students were assessed; 41 in the 2005 group and 41 in the intervention group. Average compression rate was 102 in the 2005 group and 104 in the intervention group (p =0.29). Average number of incorrect hand placements was 24 in the 2005 group and 9 in the intervention group (p =0.03). Conclusions: The use of landmark measurement techniques in hand placement for external chest compressions does not have a detrimental effect on the number of chest compressions performed during BLS and increases correct hand positioning. [Copyright &y& Elsevier]

Abstract: The importance of immediate cardiopulmonary resuscitation (CPR) and defibrillation after cardiac arrest is established. The 2005 European Resuscitation Council (ERC) guidelines were altered to try to improve survival after cardiac arrest. This observational study compares the errors in basic life support (BLS) performance after training using the 2000 or 2005 guidelines. First-year healthcare students at the University of Birmingham, United Kingdom, were taught adult BLS in a standardised 8-h course: an historical group with previous ERC guidelines (Old), the other with 2005 ERC guidelines (New). 2537 (Old 1773; New 764) students were trained and assessed in BLS. There was no difference in overall error rate between Old and New (5.53% vs. 6.70% (p >0.05)) or adherence to the sequence of the respective BLS algorithm. The New group (“hands in centre of the chest”) had significantly more erroneous hand positions compared to the Old group (5.23% vs. 1.64%, p <0.001). The 2005 ERC guidelines do not significantly improve correct BLS performance. Removal of hand placement measurement results in a significant increase in hand position errors. The clinical benefit of an increased number of compressions impaired by worsened hand positioning is unknown and requires further study. [Copyright &y& Elsevier]

Summary: Nanomedicine offers many benefits for the future treatment of disease conditions. The development of a nanomedicine may take different approaches but considerations of the disease, clinical practice, patient compliance and risk/benefit profiles are key to selecting the appropriate technologies. [Copyright &y& Elsevier]

Calcium carbonate nanoparticles loaded with curcumin were modified by layer-by-layer to form stimuli responsive nanocapsules. In-vitro drug release at different pH conditions mimicking gastrointestinal transit showed that the design of the structures of the layers in the nanocapsules can be used to protect the drug in the stomach and release it in the intestine. Stimuli-responsive layer-by-layer (LbL) capsules are appealing drug carriers for oral drug delivery owing to their abilities to utilize environmental differences to trigger changes in particles properties. LbL capsules typically have micrometer diameter ranging between 1 and 5 µm. The opportunity to use LbL for the modification of particles in the nanorange may provide enhanced benefits and properties for drug delivery. In this work, we used multiple polyelectrolytes to prepare novel stimuli-responsive multi-layered nanocapsules with submicron diameters. A systematic study was conducted to investigate the influence of various experimental parameters on the formation of calcium carbonate nanoparticles (CaCO 3) as nanocores. The resultant nanocores were then used for the assembly of LbL nanocapsules and the variables that influenced the diameter of capsules were investigated. Finally, novel stimuli-responsive multi-layered nanocapsules made of four polyelectrolytes including Eudragit L100, chitosan, sodium alginate, and poly-L-arginine were prepared and characterized. The stimuli-responsive multi-layered nanocapsules loaded with a model drug, curcumin, were assessed for drug release under pH conditions that mimic the gastrointestinal tract. These data demonstrate the potential for nanocapsules to be designed to protect the drug in the stomach and release it in the lower gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Layer-by-layer (LbL) modification is an effective way to tune the properties of particles. However, the traditional LbL process involves repeated washing steps which are not compatible with nanoparticles with a partial solubility. In this work, we demonstrate the use of a titration method for producing LbL coatings onto a nanosuspension of curcumin (a compound with a limited aqueous solubility). The aim of the work was to show how LbL can be used to enhance the release behaviour and stability of the curcumin in a nanosuspension form. Coated nanosuspension samples were produced using biocompatible and biodegradable polyelectrolytes, poly- l -arginine, and sodium alginate and was sizes approximately 500 nm. A stimuli-responsive nanosuspension was prepared by coating the nanosuspension with 5 layers of poly- l -arginine and alginate and Eudragit L100 as an outmost layer. The in vitro release of these nanosuspensions revealed that the use of a pH-responsive layer (Eudragit L100) as an outermost shell resulted in delay the release of curcumin (5%) in acidic pH and facilities its release in neutral pH (11%) over 72 h. Additionally, the bioaccessibility study showed that increasing the number of layers resulted in increasing the stability curcumin in nanosuspension when exposed to conditions that mimic the gastrointestinal tract from 20% for uncoated nanosuspension to 40% and 90% for 4-layered coated nanosuspension and stimuli-responsive (6-layered) coated nanosuspension, respectively. The cytotoxicity of LbL-coating of nanosuspension revealed a reduction in the toxicity of curcumin. This work shows how a titrated LbL modification approach could be used to tailor the stability and the release behaviour of nanosuspensions for oral drug delivery applications. [Display omitted] • Titration method is a simple and wash-less approach for tuning the nanostructures properties. • Optimization of the titration method enabled the production of 4-layered and 6-layered coated curcumin nanosuspensions. • A stimuli-responsive nanosuspension was coated by 5-layers of poly-l-arginine and alginate, with Eudragit L100. • The stimuli-responsive nanosuspension revealed a delay in the release under neutral pH compared to acidic pH. • The titrated LbL approach could be used to tailor the release behavior of nanosuspensions for oral drug delivery. [ABSTRACT FROM AUTHOR]

Background & Aims There is growing interest in the use of bone marrow cells to treat liver fibrosis, however, little is known about their antifibrotic efficacy or the identity of their effector cell(s). Sphingosine-1-phosphate (S1P) mediates egress of immune cells from the lymphoid organs into the lymphatic vessels; we investigated its role in the response of hematopoietic stem cells (HSCs) to liver fibrosis in mice. Methods Purified (c-kit+/sca1+/lin-) HSCs were infused repeatedly into mice undergoing fibrotic liver injury. Chronic liver injury was induced in BoyJ mice by injection of carbon tetrachloride (CCl 4 ) or placement on a methionine-choline–deficient diet. Some mice were irradiated and given transplants of bone marrow cells from C57BL6 mice, with or without the S1P antagonist FTY720; we then studied HSC mobilization and localization. Migration of HSC lines was quantified in Transwell assays. Levels of S1P in liver, bone marrow, and lymph fluid were measured using an enzyme-linked immunosorbent assay. Liver tissues were collected and analyzed by immunohistochemical quantitative polymerase chain reaction and sphingosine kinase activity assays. We performed quantitative polymerase chain reaction analyses of the expression of sphingosine kinase 1 and 2, sphingosine-1-phosphate lyase 1, and sphingosine-1-phosphate phosphatase 1 in normal human liver and cirrhotic liver from patients with alcohol-related liver disease (n = 6). Results Infusions of HSCs into mice with liver injury reduced liver scarring based on picrosirius red staining (49.7% reduction in mice given HSCs vs control mice; P < .001), and hepatic hydroxyproline content (328 mg/g in mice given HSCs vs 428 mg/g in control mice; P < .01). HSC infusion also reduced hepatic expression of α-smooth muscle actin (0.19 ± 0.007-fold compared with controls; P < .0001) and collagen type I α 1 chain (0.29 ± 0.17-fold compared with controls; P < .0001). These antifibrotic effects were maintained with infusion of lymphoid progenitors that lack myeloid potential and were associated with increased numbers of recipient neutrophils and macrophages in liver. In studies of HSC cell lines, we found HSCs to recruit monocytes, and this process to require C-C motif chemokine receptor 2. In fibrotic liver tissue from mice and patients, hepatic S1P levels increased owing to increased hepatic sphingosine kinase-1 expression, which contributed to a reduced liver:lymph S1P gradient and limited HSC egress from the liver. Mice given the S1P antagonist (FTY720) with HSCs had increased hepatic retention of HSCs (1697 ± 247 cells in mice given FTY720 vs 982 ± 110 cells in controls; P < .05), and further reductions in fibrosis. Conclusions In studies of mice with chronic liver injury, we showed the antifibrotic effects of repeated infusions of purified HSCs. We found that HSCs promote recruitment of endogenous macrophages and neutrophils. Strategies to reduce SIP signaling and increase retention of HSCs in the liver could increase their antifibrotic activities and be developed for treatment of patients with liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract The use of solid drug nanoparticles (SDN) has become an established approach to improve drug delivery, supporting enhancement of oral absorption and long-acting administration strategies. A broad range of SDNs have been successfully utilised for multiple products and several development programmes are currently underway across different therapeutic areas. With some approaches, a large range of material space is available with diversity in physical characteristics, excipient choice and pharmacological behaviour. The selection of SDN lead candidates is a complex process including a broad range of in vitro and in vivo data, and a better understanding of how physical characteristics relate to performance is required. Physiologically-based pharmacokinetic (PBPK) modelling is based upon a comprehensive integration of experimental data into a mathematical description of drug distribution, allowing simulation of SDN pharmacokinetics that can be qualified in vivo prior to human prediction. This review aims to provide a description of how PBPK can find application into the development of SDN. Integration of predictive PBPK modelling into SDN development allows a better understanding of the SDN dose-response relationship, supporting a framework for rational optimisation while reducing the risk of failure in developing safe and effective nanomedicines. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Assessment of collision risk between pedestrians and automobiles offers a powerful and informative tool in urban planning applications, and can be leveraged to inform proper placement of improvements and treatment projects to improve pedestrian safety. Such assessment can be performed using existing datasets of crashes, pedestrian counts, and automobile traffic flows to identify intersections or corridors characterized by elevated collision risks to pedestrians. The Safety In Numbers phenomenon, which refers to the observable effect that pedestrian safety is positively correlated with increased pedestrian traffic in a given area (i.e. that the individual per-pedestrian risk of a collision decreases with additional pedestrians), is a readily observed phenomenon that has been studied previously, though its directional causality is not yet known. A sample of 488 intersections in Minneapolis were analyzed, and statistically-significant log-linear relationships between pedestrian traffic flows and the per-pedestrian crash risk were found, indicating the Safety In Numbers effect. Potential planning applications of this analysis framework towards improving pedestrian safety in urban environments are discussed. [ABSTRACT FROM AUTHOR]

This study measures accessibility by automobile for the Minneapolis - Saint Paul (Twin Cities) region from 1995 to 2005. In contrast to most previous analyses of accessibility, this study uses travel time estimates derived, to the extent possible, from actual observations of network performance by time of day. A set of cumulative opportunity measures are computed with transport analysis zones (TAZs) as the unit of analysis for 1995 and 2005. Analysis of the changes in accessibility by location over the period of study reveals that, for the majority of locations in the region, accessibility increased over this period, though the increases were not uniform. A “flattening” or convergence of levels of accessibility across locations was observed over time, with faster-growing suburban locations gaining the most in terms of employment accessibility. An effort to decompose the causes of changes in accessibility into components related to transport network structure and land use (opportunity location) reveals that both causes make a contribution to increasing accessibility, though the effects of changes to the transportation network tend to be more location-specific. Overall, the results of the study demonstrate the feasibility and relevance of using accessibility as a key performance measure to describe the regional transport system. [ABSTRACT FROM AUTHOR]

Abstract: Despite the economic turmoil of the time, a typical study of vote choice in the 2008 US Presidential Election would (falsely) find little evidence that voters’ opinions about the future state of the economy affected their vote choice. We argue that this misleading conclusion results from serious measurement error in the standard prospective economic evaluations survey question. Relying instead on a revised question, included for the first time in the 2008 American National Election Study, we find that most respondents condition their prospective economic evaluations on potential election outcomes, and that these evaluations are an important determinant of vote choice. A replication in a very different political context – the 2008 Ghanaian election – yields similar results. [Copyright &y& Elsevier]

Curcumin is widely used as a nutraceutical ingredient in food and beverage products. It has been reported that curcumin has a broad spectrum of biological activities such as anticancer, anti-inflammatory, antioxidant, and antibacterial effects. Despite the potent therapeutic effect of curcumin, its low aqueous solubility, stability, and oral bioavailability limits its effectiveness. In order to improve the physical and chemical properties of curcumin, we have formulated curcumin as a nanosuspension by using the emulsion templated freeze-drying technique. This approach produces a solid that can be dispersed as required to form a nanosuspension. The formulations were investigated in a screening process using various excipients, resulting in the identification of one curcumin nanosuspension sample which contained only polyethylene glycol (PEG) as the excipient. This formulation exhibited a small diameter (211 nm), low polydispersity (0.06) and zeta potential of −25 mV and was therefore chosen for further in vitro investigations. Various experimental parameters such as active agent and excipient concentrations, and sonication time were varied to tune the size and polydispersity of the chosen formulation. The resulting nanosuspension showed an improved chemical stability at pH values that mimic the gastrointestinal tract. An in vitro bioaccessibility experiment showed that the nanosuspension formulation resulted in more dissolution of the curcumin but this was also coupled with reduced stability. Cytotoxicity studies showed that the nanosuspension offered a reduced cytotoxicity profile compared to the solubilised curcumin on both cell lines investigated. This redispersible curcumin nanosuspension formulation may provide new opportunities for the oral dosing of curcumin. Curcumin was formulated as a nanosuspension by an emulsion-templated freeze-drying technique. The curcumin formulation could be redispersed to form a nanosuspension and demonstrated favourable colloidal and chemical stability. [Display omitted] • A simple formulation of curcumin that uses a single excipient and forms nanosuspension with an average diameter of ~200 nm. • The formulation is produced as a dry solid that can be dispersed on-demand to form the nanoparticles. • The nanosuspension show improved chemical stability compared to solubilised curcumin. • The cytotoxicity of the curcumin nanosuspension is similar to the solubilised curcumin but does not require solvent. [ABSTRACT FROM AUTHOR]