Mechanisms of burst release from pH-responsive polymeric microparticles.

Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of the prepared microparticles and investigated the underlying mechanisms responsible for the “burst release” effect. Using two different pH-responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS-MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. Although, spray drying is an attractive approach due to rapid particle production and relatively low solvent waste, the oil-in-oil microencapsulation method is superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil-in-oil emulsification process allows adequate time for drug and polymer redistribution in the microparticles and reduces uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated non-porous particles whereas thermal analysis and X-ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release

APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice

Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202–210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157–162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that adenomatous polyposis coli (APC) mutations found in human colorectal cancers dominantly inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and, thus, blocking initiation of the cytokinetic furrow. We find that dividing crypt cells in the small intestines of APCMin/+ mice exhibit similar mitotic defects, including misoriented spindles and misaligned chromosomes. These defects are observed in normal crypt cells with wild-type levels of β-catenin and, importantly, are associated with tetraploid genotypes. We provide direct evidence that the dominant activity of APC mutants induces aneuploidy in vivo. Our data support a model whereby tetraploid cells represent a first step in the onset of genomic instability and colorectal cancer

Using pH abnormalities in diseased skin to trigger and target topical therapy

Abstract Purpose: The pH discrepancy between healthy and atopic dermatitis skin was identified as a site specific trigger for delivering hydrocortisone from microcapsules. Methods: Using Eudragit L100, a pH-responsive polymer which dissolves at pH 6, hydrocortisone-loaded microparticles were produced by oil-in-oil microencapsulation or spray drying. Release and permeation of hydrocortisone from microparticles alone or in gels was assessed and preliminary stability data was determined. Results: Drug release from microparticles was pH-dependent though the particles produced by spray drying also gave significant non-pH dependent burst release, resulting from their porous nature or from drug enrichment on the surface of these particles. This pH-responsive release was maintained upon incorporation of the oil-in-oil microparticles into Carbopol- and HPMC-based gel formulations. In-vitro studies showed 4 to 5-fold higher drug permeation through porcine skin from the gels at pH 7 compared to pH 5. Conclusions: Permeation studies showed that the oil-in-oil generated particles deliver essentially no drug at normal (intact) skin pH (5.0 – 5.5) but that delivery can be triggered and targeted to atopic dermatitis skin where the pH is elevated. The incorporation of these microparticles into Carbopol- and HPMC-based aqueous gel formulations demonstrated good stability and pH-responsive permeation into porcine skin

Pathways linking car transport for young adults and the public health in Northern Ireland: a qualitative study to inform the evaluation of graduated driver licensing.

BACKGROUND: Novice drivers are at relatively high risk of road traffic injury. There is good evidence that Graduated Driving Licensing (GDL) schemes reduce collisions rates, by reducing exposure to risk and by extending learning periods. Legislation for a proposed scheme in Northern Ireland was passed in 2016, providing an opportunity for future evaluation of the full public health impacts of a scheme in a European context within a natural experiment. This qualitative study was designed to inform the logic model for such an evaluation, and provide baseline qualitative data on the role of private cars in health and wellbeing. METHODS: Nine group interviews with young people aged 16-23 (N = 43) and two group interviews with parents of young people (N = 8) were conducted in a range of settings in Northern Ireland in 2015. Data were analysed using thematic content analysis. RESULTS: Informal car-pooling within and beyond households led to routine expectations of lift provision and uptake. Experiences of risky driving situations were widespread. In rural areas, extensive use of farm vehicles for transport needs meant many learner drivers had both early driving experience and expectations that legislation may have to be locally adapted to meet social needs. Cars were used as a site for socialising, as well as essential means of transport. Alternative modes (public transport, walking and cycling) were held in low esteem, even where available. Recall of other transport-related public health messages and parents' existing use of GDL-type restrictions suggested GDL schemes were acceptable in principle. There was growing awareness and use of in-car technologies (telematics) used by insurance companies to reward good driving. CONCLUSIONS: Key issues to consider in evaluating the broader public health impact of GDL will include: changes in injury rates for licensed car occupants and other populations and modes; changes in exposure to risk in the licensed and general population; and impact on transport exclusion. We suggest an important pathway will be change in social norms around offering and accepting lifts and to risk-taking. The growing adoption of in-car telematics will have implications for future GDL programmes and for evaluation

Small domain estimation of census coverage: A case study in Bayesian analysis of complex survey data

Many countries conduct a full census survey to report official population statistics. As no census survey ever achieves 100 per cent response rate, a post-enumeration survey (PES) is usually conducted and analysed to assess census coverage and produce official population estimates by geographic area and demographic attributes. Considering the usually small size of PES, direct estimation at the desired level of disaggregation is not feasible. Design-based estimation with sampling weight adjustment is a commonly used method but is difficult to implement when survey non-response patterns cannot be fully documented and population benchmarks are not available. We overcome these limitations with a fully model-based Bayesian approach applied to the New Zealand PES. Although theory for the Bayesian treatment of complex surveys has been described, published applications of individual level Bayesian models for complex survey data remain scarce. We provide such an application through a case study of the 2018 census and PES surveys. We implement a multilevel model that accounts for the complex design of PES. We then illustrate how mixed posterior predictive checking and cross-validation can assist with model building and model selection. Finally, we discuss potential methodological improvements to the model and potential solutions to mitigate dependence between the two surveys.Comment: 35 pages, 5 figures This is an author version of a paper accepted for publication in the Journal of Official Statistics. Once published by the Journal of Official Statistics use the Journal citation. This version includes supplementary material and corrected version of Figure

Relationship between serum B12 concentrations and mortality:experience in NHANES

BACKGROUND: There is conflicting evidence in the literature on the association between (elevated) serum B12 concentrations and subsequent disease or mortality. We evaluated in the NHANES general population the association of serum B12 concentrations as well as vitamin B12 supplement intake with all-cause, cardiovascular, and cancer-related mortality, while taking into account demographic and lifestyle factors and significant other diseases which are known to be associated with poorer outcome. METHODS: The main outcomes of our study were all-cause mortality, cardiovascular mortality, and cancer-related mortality. Mortality status and cause of death were determined by NHANES-linked National Death Index public access files through December 31, 2015. The association of serum B12 concentrations and vitamin B12 supplement intake with mortality was assessed with Cox proportional hazard (PH) models, with adjustment for a number of relevant demographic and lifestyle factors and comorbidity. RESULTS: The final study population of 24,262 participants had a mean age of 48 (SD 19) years; 50.1% were males. The median follow-up duration was 109 months (range 1-201 months). On the census day of December 31, 2015, 3023 participants were determined as deceased (12.5%). The fully adjusted Cox PH model indicated that low serum B12 concentrations  700 pmol/l were associated with an increase in cardiovascular mortality only (HR 1.45, 95% CI 1.01-2.06, p = 0.042). Participants with a diagnosis of hypertension, dyslipidemia, CVD, and cancer more frequently used vitamin B12-containing supplements than those without these diagnoses. We could not demonstrate an association between vitamin B12 supplement intake and mortality, when adjusted for comorbidity. CONCLUSIONS: In the general population of NHANES, low serum B12 concentrations were associated with a moderate increase in all-cause mortality. There was a small but significant increase in cardiovascular mortality in the groups with low or high serum B12. High intake of vitamin B12 in the form of supplements was not associated with any adverse effect on mortality and therefore can be regarded as safe

Crossover of Organizational Commitment

Spousal commitment toward an employee\u27s organization is a little-studied construct that deserves attention because his or her spouse may influence the employee\u27s assessments of organizational commitment and turnover intentions. Using 186 couples, this study investigated spousal influence on U.S. military members’ organizational commitment and their decisions to reenlist. Results of a structural equation model analysis indicate that indirect mechanisms of crossover (e.g., positive emotions displayed by the spouse during discussions of reenlistment) facilitated the positive relationships between the organizational commitment of military spouses and members. Findings and discussion contribute to the fields of organizational commitment and crossover, and we conclude our analysis by offering practical implications for nonmilitary occupations

Perovskite-perovskite tandem photovoltaics with optimized bandgaps

We demonstrate four and two-terminal perovskite-perovskite tandem solar cells with ideally matched bandgaps. We develop an infrared absorbing 1.2eV bandgap perovskite, $FA_{0.75}Cs_{0.25}Sn_{0.5}Pb_{0.5}I_3$, that can deliver 14.8 % efficiency. By combining this material with a wider bandgap $FA_{0.83}Cs_{0.17}Pb(I_{0.5}Br_{0.5})_3$ material, we reach monolithic two terminal tandem efficiencies of 17.0 % with over 1.65 volts open-circuit voltage. We also make mechanically stacked four terminal tandem cells and obtain 20.3 % efficiency. Crucially, we find that our infrared absorbing perovskite cells exhibit excellent thermal and atmospheric stability, unprecedented for Sn based perovskites. This device architecture and materials set will enable 'all perovskite' thin film solar cells to reach the highest efficiencies in the long term at the lowest costs

“We can all just get on a bus and go” : Rethinking independent mobility in the context of the universal provision of free bus travel to young Londoners

This paper uses qualitative data from interviews with 118 young Londoners (age 12-18) to examine how the universal provision of free bus travel has affected young people’s independent mobility. Drawing on Sen’s ‘capabilities approach’, we argue that free bus travel enhanced young Londoners’ capability to shape their daily mobility, both directly by increasing financial access and indirectly by facilitating the acquisition of the necessary skills, travelling companions and confidence. These capabilities in turn extended both opportunity freedoms (e.g. facilitating non-“necessary” recreational and social trips) and process freedoms (e.g. feeling more independent by decreasing reliance on parents). Moreover, the universal nature of the entitlement rendered buses a socially inclusive way for groups to travel and spend time together, thereby enhancing group-level capabilities. We believe this attention to individual and group capabilities for self-determination provides the basis for a broader and more child-centred view of ‘independent mobility’ than the typical research focus upon ‘travelling without an adult’ and acquiring parental permissions.Peer reviewe

The Process of Organ Donation from Non-Living Donors: A Case-Based Journey from Potential Donor Identification to Organ Procurement

Each year, thousands of people worldwide succumb to end-organ failure while awaiting life-saving transplantation procedures. The shortage of organs continues with no signs of easing in the foreseeable future. The availability of organs from living donors continues to be constrained. At the same time, the cumulative knowledge of organ preservation is advancing steadily resulting in an enhanced ability to utilize a growing number of previously unsuitable tissue and organ gifts. Our ability to procure and preserve more organs is accompanied by the increasing use of so-called “expanded criteria” donors, or those whose organs may not have been suitable without modern advances in organ preservation science. Within the overall context of organ donation from non-living donors, the importance of physiologic and end-organ optimization cannot be understated. This chapter discusses our current state of understanding of optimized organ procurement approaches derived from practical experiences and “lessons learned” at a high-performing, community-based tertiary referral hospital