Methylene Blue-Loaded Dissolving Microneedles: Potential Use in Photodynamic Antimicrobial Chemotherapy of Infected Wounds

Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has been termed "photodynamic antimicrobial chemotherapy" (PACT). In the treatment of chronic wounds, the delivery of photosensitising agents is often impeded by the presence of a thick hyperkeratotic/necrotic tissue layer, reducing their therapeutic efficacy. Microneedles (MNs) are an emerging drug delivery technology that have been demonstrated to successfully penetrate the outer layers of the skin, whilst minimising damage to skin barrier function. Delivering photosensitising drugs using this platform has been demonstrated to have several advantages over conventional photodynamic therapy, such as, painless application, reduced erythema, enhanced cosmetic results and improved intradermal delivery. The aim of this study was to physically characterise dissolving MNs loaded with the photosensitising agent, methylene blue and assess their photodynamic antimicrobial activity. Dissolving MNs were fabricated from aqueous blends of Gantrez(®) AN-139 co-polymer containing varying loadings of methylene blue. A height reduction of 29.8% was observed for MNs prepared from blends containing 0.5% w/w methylene blue following application of a total force of 70.56 N/array. A previously validated insertion test was used to assess the effect of drug loading on MN insertion into a wound model. Staphylococcus aureus, Escherichia coli and Candida albicans biofilms were incubated with various methylene blue concentrations within the range delivered by MNs in vitro (0.1-2.5 mg/mL) and either irradiated at 635 nm using a Paterson Lamp or subjected to a dark period. Microbial susceptibility to PACT was determined by assessing the total viable count. Kill rates of >96%, were achieved for S. aureus and >99% for E. coli and C. albicans with the combination of PACT and methylene blue concentrations between 0.1 and 2.5 mg/mL. A reduction in the colony count was also observed when incorporating the photosensitiser without irradiation, this reduction was more notable in S. aureus and E. coli strains than in C. albicans.

Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention

Breast cancer screening has led to a dramatic increase in the detection of pre-invasive breast lesions. While mastectomy is almost guaranteed to treat the disease, more conservative approaches could be as effective if patients can be stratified based on risk of co-existing or recurrent invasive disease.Here we use a range of biomarkers to interrogate and classify purely non-invasive lesions (PNL) and those with co-existing invasive breast cancer (CEIN). Apart from Ductal Carcinoma In Situ (DCIS), relative homogeneity is observed. DCIS contained a greater spread of molecular subtypes. Interestingly, high expression of p-mTOR was observed in all PNL with lower expression in DCIS and invasive carcinoma while the opposite expression pattern was observed for TOP2A.Comparing PNL with CEIN, we have identified p53 and Ki67 as predictors of CEIN with a combined PPV and NPV of 90.48% and 43.3% respectively. Furthermore, HER2 expression showed the best concordance between DCIS and its invasive counterpart.We propose that these biomarkers can be used to improve the management of patients with pre-invasive breast lesions following further validation and clinical trials. p53 and Ki67 could be used to stratify patients into low and high-risk groups for co-existing disease. Knowledge of expression of more actionable targets such as HER2 or TOP2A can be used to design chemoprevention or neo-adjuvant strategies. Increased knowledge of the molecular profile of pre-invasive lesions can only serve to enhance our understanding of the disease and, in the era of personalised medicine, bring us closer to improving breast cancer care.

Gramsci, austerity common sense and the attacks on the welfare state: The need to understand and resist the imposition of the global neoliberal agenda and the role of the social work profession.

During the last 30 years governments almost everywhere in the world are furthering a global neoliberal agenda by withdrawing the state from the delivery of services, decreasing social spending and lowering corporate taxation etc. This restructuring has led to a massive transfer of wealth from the welfare state and working class people into capital. In order to legitimize this restructuring conservative governments engage in collective blaming towards their denizens. This presentation will examine some of the well circulated phrases that have been used by the dominant elite in some countries during the last year to legitimize the imposition of austerity measures. Phrases such as, ‘We all partied’ used by the Irish finance minister, Brian Lenihan, to explain the Irish crisis and collectively blame all Irish people, ‘We must all share the pain’, deployed by another Irish Minister Gilmore and the UK coalition administration’s sound bite ‘We are all in this together’, legitimize the imposition of austerity measures. Utilizing the Gramscian concept of common sense (Gramsci, 1971), I call these phrases ‘austerity common sense’. They are austerity common sense because they both reflect and legitimate the austerity agenda. By deploying these phrases, the ruling economic and political elite seek to influence the perception of the people and pre-empt any intention of resistance. The dominant theme of these phrases is that there is no alternative and that austerity measures are somehow self-inflicted and, as such, should not be challenged because we are all to blame. The purpose of this presentation is to explore the “austerity common sense” theme from a Gramscian approach, focus on its implications for the social work profession and discuss the ways to resist the imposition of the global neoliberal agenda.

Magnitude, form and bioavailability of fluvial carbon exports from Irish organic soils under pasture

Organic soils are widespread in Ireland and vulnerable to degradation via drainage for agriculture. The soil-landuse combination of pasture on organic soils may play a disproportionate role in regional C dynamics but is yet to receive study. Fluvial C fluxes and labile organic fractions were determined for two such sites at nested field (c.4 ha) and subcatchment scales (>40 ha); one relatively dry and nutrient rich, the other wetter and nutrient poor. Field scale flux from the nutrient poor site over 2 years was 38.9 ± 6.6 g C m⁻² yr⁻¹ with DIC > DOC > POC at 57, 32 and 11 % respectively, and 72 % DIC was comprised of above equilibrium CO₂. At the nutrient rich site, which overlies limestone geology, field scale export over an individual year was 90.4 g C m⁻² with DIC > DOC > POC at 49, 42 and 9 %, but with 90 % DIC as bicarbonate. By comparison with the nutrient poor site, the magnitude and composition of inorganic C exports from the nutrient rich site implied considerable export of soil-respiratory C as bicarbonate, and lower evasion losses due to carbonate system buffering. Labile DOC determined using dark incubations indicated small fractions (5–10 %) available for remineralisation over typical downstream transit times of days to weeks. These fractions are probably conservative as photolysis in the environment can increase the proportion of labile compounds via photocleavage and directly remineralise organic matter. This study demonstrates that monitoring at soil–water interfaces can aid capture of total landscape fluvial fluxes by precluding the need to incorporate prior C evasion, although rapid runoff responses at field scales can necessitate high resolution flow proportional, and hydrograph sampling to constrain uncertainty of flux estimates.

Length matters:Keeping atomic wires in check

Dynamical effects of non-conservative forces in long, defect free atomic wires are investigated. Current flow through these wires is simulated and we find that during the initial transient, the kinetic energies of the ions are contained in a small number of phonon modes, closely clustered in frequency. These phonon modes correspond to the waterwheel modes determined from preliminary static calculations. The static calculations allow one to predict the appearance of non-conservative effects in advance of the more expensive real-time simulations. The ion kinetic energy redistributes across the band as non-conservative forces reach a steady state with electronic factional forces. The typical ion kinetic energy is found to decrease with system length, increase with atomic mass, and its dependence on bias, mass and length is supported with a pen and paper model. This paper highlights the importance of non-conservative forces in current carrying devices and provides criteria for the design of stable atomic wires.

Relationships Between Deprivation and the Self-reported Health of Older People in Northern Ireland

Objectives: There are few studies on relationships between deprivation and the self-reported health of people aged over 64 years, and no studies fully representative of Northern Ireland’s older population. This paper addresses this gap. Methods: Deprivation of older people as reported in the 2001 and 2011 Censuses and the relationship with self-reported health are analyzed over a ten-year span using multilevel modeling. The data are from the Northern Ireland Longitudinal Study (NILS) linked to 2001-11 Census returns. Deprivation measures include housing tenure, property-value, access to a car, educational, employment and area-level income-deprivation. Results: Older people suffering deprivation face a significant health disadvantage over a ten-year time span. Discussion: This health disadvantage is stronger in men than in women, likely due to conservative gender roles prevalent among Northern Ireland’s older population, leading to psychological distress among deprived men. The analysis found strongly significant area-level effects, aggravating the health impact of deprivation.

Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial

BACKGROUND: In sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9-10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.

METHODS/DESIGN: TRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children. The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4-6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity (haematological correction, nutritional and infectious), safety and cost-effectiveness.

DISCUSSION: If confirmed by the trial, a cheap and widely available 'bundle' of effective interventions, directed at immediate and downstream consequences of severe anaemia, could lead to substantial reductions in mortality in a substantial number of African children hospitalised with severe anaemia every year, if widely implemented.

The Exclusive Brethren ‘Doctrine of Separation’: An Anthropology of Theology

Why do the Exclusive Brethren attend church ten times a week? Why do they shun excommunicated members, including immediate family? Why do they refuse to eat with outsiders? Why will they employ outsiders in their businesses, but never be employed by them? Why do they reject modern media as “pipelines of filth”? Why do they refuse to vote, while simultaneously campaigning for Conservative Party candidates? Why do they only live in detached houses, and build churches entirely without windows? How, in other words, do the Exclusive Brethren try to live good lives? And what can we learn anthropologically from these models of ‘the good’, and from the objections they provoke? Drawing inspiration from Keane’s (2014) suggestion that ‘we shouldn’t decide in advance what ethics will look like’, this paper seeks to critically contribute to new scholarship within the anthropology of morality and detachment by constructing, in a very literal sense, an anthropology of theology via an analysis of the Exclusive Brethren ‘doctrine of separation’.

Dimensionality of Policy Space in Consociational Northern Ireland

A criticism of consociational power sharing as an institutional response to violent conflict is that it buttresses rather than ameliorates the underlying (linguistic, religious or ethno-national) divide, hence prohibiting the emergence of new dimensions of political competition (such as economic left-right or moral liberal-conservative dimensions) that are characteristic of 'normal' societies. We test this argument in the context of the illustrative Northern Ireland case, using data from expert coding of party policy documents and opinion data derived from two Voter Advice Applications (VAAs). We find evidence for a moral liberal-conservative dimension of politics in addition to the ethno-national dimension. Hence, we caution against assuming that consociational polities are uni-dimensional.

Monitoring ocular hypertension, how much and how often? A cost-effectiveness perspective

OBJECTIVE: To assess the efficiency of alternative monitoring services for people with ocular hypertension (OHT), a glaucoma risk factor.

DESIGN: Discrete event simulation model comparing five alternative care pathways: treatment at OHT diagnosis with minimal monitoring; biennial monitoring (primary and secondary care) with treatment if baseline predicted 5-year glaucoma risk is ≥6%; monitoring and treatment aligned to National Institute for Health and Care Excellence (NICE) glaucoma guidance (conservative and intensive).

SETTING: UK health services perspective.

PARTICIPANTS: Simulated cohort of 10 000 adults with OHT (mean intraocular pressure (IOP) 24.9 mm Hg (SD 2.4).

MAIN OUTCOME MEASURES: Costs, glaucoma detected, quality-adjusted life years (QALYs).

RESULTS: Treating at diagnosis was the least costly and least effective in avoiding glaucoma and progression. Intensive monitoring following NICE guidance was the most costly and effective. However, considering a wider cost-utility perspective, biennial monitoring was less costly and provided more QALYs than NICE pathways, but was unlikely to be cost-effective compared with treating at diagnosis (£86 717 per additional QALY gained). The findings were robust to risk thresholds for initiating monitoring but were sensitive to treatment threshold, National Health Service costs and treatment adherence.

CONCLUSIONS: For confirmed OHT, glaucoma monitoring more frequently than every 2 years is unlikely to be efficient. Primary treatment and minimal monitoring (assessing treatment responsiveness (IOP)) could be considered; however, further data to refine glaucoma risk prediction models and value patient preferences for treatment are needed. Consideration to innovative and affordable service redesign focused on treatment responsiveness rather than more glaucoma testing is recommended.

How do clinicians become teachers? A communities of practice perspective.

There is widespread acceptance that clinical educators should be trained to teach, but faculty development for clinicians is undermined by poor attendance and inadequate learning transfer. As a result there has been growing interest in situating teacher development initiatives in clinical workplaces. The relationship between becoming a teacher and clinical workplace contexts is under theorised. In response, this qualitative research set out to explore how clinicians become teachers in relation to clinical communities and institutions. Using communities of practice (CoP) as a conceptual framework this research employed the sensitising concepts of regimes of competence and vertical (managerial) and horizontal (professional) planes of accountability to elucidate structural influences on teacher development. Fourteen hospital physicians completed developmental timelines and underwent semi-structured interviews, exploring their development as teachers. Despite having very different developmental pathways, participants’ descriptions of their teacher identities and practice that were remarkably congruent. Two types of CoP occupied the horizontal plane of accountability i.e. clinical teams (Firms) and communities of junior doctors (Fraternities). Participants reproduced teacher identities and practice that were congruent with CoPs’ regimes of competence in order to gain recognition and legitimacy. Participants also constructed their teacher identities in relation to institutions in the vertical plane of accountability (i.e. hospitals and medical schools). Institutions that valued teaching supported the development of teacher identities along institutionally defined lines. Where teaching was less valued, clinicians adapted their teacher identities and practices to suit institutional norms. Becoming a clinical educator entails continually negotiating one’s identity and practice between two potentially conflicting planes of accountability. Clinical CoPs are largely conservative and reproductive of teaching practice whereas accountability to institutions is potentially disruptive of teacher identity and practice.