Use of programme budgeting and marginal analysis to set priorities for local NHS dental services: learning from the north east of England

Background - Priority setting is necessary where competing demands exceed the finite resources available. The aim of the study was to develop and test a prioritization framework based upon programme budgeting and marginal analysis (PBMA) as a tool to assist National Health Service (NHS) commissioners in their management of resources for local NHS dental services. Methods - Twenty-seven stakeholders (5 dentists, 8 commissioners and 14 patients) participated in a case-study based in a former NHS commissioning organization in the north of England. Stakeholders modified local decision-making criteria and applied them to a number of different scenarios. Results - The majority of financial resources for NHS dental services in the commissioning organization studied were allocated to primary care dental practitioners’ contracts in perpetuity, potentially constraining commissioners’ abilities to shift resources. Compiling the programme budget was successful, but organizational flux and difficulties engaging local NHS commissioners significantly impacted upon the marginal analysis phase. Conclusions - NHS dental practitioners’ contracts resemble budget-silos which do not facilitate local resource reallocation. ‘Context-specific’ factors significantly challenged the successful implementation and impact of PBMA. A local PBMA champion embedded within commissioning organizations should be considered. Participants found visual depiction of the cost-value ratio helpful during their initial priority setting deliberations

Callose-associated silica deposition in Arabidopsis

The mechanism of biological silicification in plants remains to be elucidated. There are strong arguments supporting a role for the plant extracellular matrix and the β-1-3-glucan, callose, has been identified as a possible template for silica deposition in the common horsetail, Equisetum arvense. The model plant Arabidopsis thaliana, which is not known as a silica accumulator, can be engineered to produce mutants in which, following a pathogen-associated molecular pattern challenge, callose production in leaves is either induced (35S:PMR4-GFP) or not (pmr4). We have grown these mutants hydroponically in the presence of added silicon to test if the induction of callose results in greater silica deposition in the leaves. Callose induction was identified throughout leaf tissue of wild type Arabidopsis and the mutant 35S:PMR4-GFP but not in the mutant pmr4. Similarly both wild type Arabidopsis and the mutant 35S:PMR4-GFP showed extensive silicification of leaf tissue while the pmr4 mutant deposited very little silica in its leaf tissues. Wild type Arabidopsis and the mutant 35S:PMR4-GFP responded to a pathogen-like challenge by producing both callose and biogenic silica coincidently in their leaf tissues. Trichomes in particular showed both callose deposition and extensive silicification. The lack of both induced callose deposition and subsequent silicification in the pmr4 mutant strongly suggested that the biochemistry of callose formation and deposition were allied to biological silicification in Arabidopsis

Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations

Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al3+ in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, potentially generating a greater inflammatory response at the site of simulated injection. The cellular uptake of aluminium based adjuvants (ABAs) used in clinically approved vaccinations are compared to a commonly used experimental ABA, in an in vitro THP-1 cell model. Using lumogallion as a direct-fluorescent molecular probe for aluminium, complemented with transmission electron microscopy provides further insight into the morphology of internalised particulates, driven by the physicochemical variations of the ABAs investigated. We demonstrate that not all aluminium adjuvants are equal neither in terms of their physical properties nor their biological reactivity and potential toxicities both at the injection site and beyond. High loading of aluminium oxyhydroxide in the cytoplasm of THP-1 cells without immediate cytotoxicity might predispose this form of aluminium adjuvant to its subsequent transport throughout the body including access to the brain

From Stock Bottle to Vaccine: Elucidating the Particle Size Distributions of Aluminum Adjuvants Using Dynamic Light Scattering.

The physicochemical properties of aluminum salts are key determinants of their resultant adjuvanticity in vivo when administered as part of a vaccine. While there are links between particle size and the efficacy of the immune response, the limited literature directly characterizing the PSD of aluminum adjuvants has stymied the elucidation of such a relationship for these materials. Hence, this comparative study was undertaken to monitor the PSD of aluminum adjuvants throughout the process of vaccine formulation using DLS. A significant proportion of the stock suspensions was highly agglomerated (>9 μm) and Alhydrogel® exhibited the smallest median size (2677 ± 120 nm) in comparison to Adju-Phos® or Imject alum® (7152 ± 308 and 7294 ± 146 nm respectively) despite its large polydispersity index (PDI). Dilution of these materials induced some degree of disaggregation within all samples with Adju-Phos® being the most significantly affected. The presence of BSA caused the median size of Alhydrogel® to increase but these trends were not evident when model vaccines were formulated with either Adju-Phos® or Imject alum®. Nevertheless, Alhydrogel® and Adju-Phos® exhibited comparable median sizes in the presence of this protein (4194 ± 466 and 4850 ± 501 nm respectively) with Imject alum® being considerably smaller (2155 ± 485 nm). These results suggest that the PSD of aluminum adjuvants is greatly influenced by dilution and the degree of protein adsorption experienced within the vaccine itself. The size of the resultant antigen-adjuvant complex may be important for its immunological recognition and subsequent clearance from the injection site

The Identification of Aluminum in Human Brain Tissue Using Lumogallion and Fluorescence Microscopy.

Aluminum in human brain tissue is implicated in the etiologies of neurodegenerative diseases including Alzheimer's disease. While methods for the accurate and precise measurement of aluminum in human brain tissue are widely acknowledged, the same cannot be said for the visualization of aluminum. Herein we have used transversely-heated graphite furnace atomic absorption spectrometry to measure aluminum in the brain of a donor with Alzheimer's disease, and we have developed and validated fluorescence microscopy and the fluor lumogallion to show the presence of aluminum in the same tissue. Aluminum is observed as characteristic orange fluorescence that is neither reproduced by other metals nor explained by autofluorescence. This new and relatively simple method to visualize aluminum in human brain tissue should enable more rigorous testing of the aluminum hypothesis of Alzheimer's disease (and other neurological conditions) in the future

How is silicic acid transported in plants?

Plants accumulate silicon in their tissues as amorphous silica. The form of silicon taken up by plants is silicic acid, a neutral molecule that passes through membrane channels with water. After seminal work on rice identified an aquaporin that appeared to mediate the passage of silicic acid, several papers followed and classified similar channels (referred to as “transporters”) in a number of plant species. These channels have been described as essential for silicon uptake and specific for the metalloid. Herein, we critically review the published data on the characterisation of one channel in particular, Lsi1, and identify possible caveats in results and limitations in methods used. Our analysis does not support the suggestion that the identified channels are specific for silicic acid. Computational analyses of the size of the Lsi1 pore additionally suggest that it may not play a significant role in mediating the movement of silicic acid in planta. We suggest that to avoid further confusion, channels currently implicated in the transport of silicic acid in planta are not referred to as silicon-specific transporters. Future research including the use of molecular dynamics simulations will enable the unequivocal identification of channels involved in silicon transport in plants