PLT practitioners : soldiers For “vocationalism”, or double agents?

This presentation extends on some previous work around my PhD research.
I question ways in which social structures are inscribed into legal education practices, and conversely, whether practices can modify those structures. I argue PLT practitioners are not simply soldiers for a “vocationalist” strategy. Instead, I re-imagine PLT practitioners as “double agents” or “resistance fighters”, lamplighters in a still emergent professional trajectory. It is a trajectory catalysed by the 1970s introduction of institutional PLT; just a baby really, in the context of English common law.

In Bourdieu’s terms it is possible, by revisiting past struggles in Australian legal education, to conceptualise institutional PLT as the product of judicial, professional, and academic struggles to produce a vocationalised, non-academic, and critique-free sub-field within the juridical field. Those struggles succeeded, to some extent, in the extra-individual dimension of structures, regulation, and institutions, to collectively inculcate preferred dispositions within individuals about legal education and professional identity.

That account, however, ignores the potential for agency and alterity – the ways in which individuals might appropriate, in Certeau’s terms, the resources of the legal field to explore new professional trajectories. For some, these trajectories involve struggles to enrich, and add texture to, legal education. Drawing on interviews with PLT practitioners, I identify multi-vocal and multi-perspectival themes, including notions of social justice, equality, professional ethics, personal improvement, and indeed, interest in scholarship of teaching and learning.

It is in this sense I re-imagine PLT practitioners as “double agents”, operating betwixt and between dominant domains in law. In my view, PLT practitioners can participate in conceptualising and developing emergent approaches in legal education, and to theorise “practice” as lawyers and educators. Scholarship of teaching and learning has its part to play in this. It provides a means, as lawyers and as educators, to discover information, to reflect, critique, communicate, and conceptualise, insights about “practice” and practices.

Differentiation of cultured epithelial cells : response to toxic agents

Cell culture systems are instrumental in elucidating regulation of normal function and mechanisms of its perturbation by toxic substances. To this end, three applications of epithelial cells cultured with 3T3 feeder layer support are described. First, treatment of the premalignant human epidermal keratinocyte line SCC-12F2 with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate suppressed cell growth and differentiation. This agent produced a biphasic growth response greatly inhibiting cell growth at 1 to 10 nM, but much less above 100 nM. Expression of the differentiated functions involucrin and transglutaminase was found to be inhibited markedly at concentrations above 10 nM. Second, 3-methylcholanthrene toxicity was surveyed in a variety of rat epithelial cell types. The two most sensitive to growth inhibition were epidermal and mammary epithelial cells, while those from bladder, prostate, thyroid, and endometrium were insensitive to growth inhibition. Great differences were evident even among those cells derived from stratified squamous epithelia (epidermal, esophageal, vaginal, forestomach) despite their expression of aryl hydrocarbon hydroxylase activities to similar degrees. Finally, expression of estrogen receptors in rat endometrial cells was shown to be stimulated by the cAMP-elevating agent forskolin. Maximal stimulation of 3- to 6-fold occurred in 6 hr, compatible with a requirement for protein synthesis. Although expressing keratinocyte character (transglutaminase activity and envelope forming ability), the cells thus retain some hormonal character that may be modulated by cAMP-dependent kinase activity. Pursuit of such results will aid in understanding differences in response among cell types and species, in elucidating mechanisms of action of known toxic substances and, ultimately, in predicting toxicity of less well understood agents.

Atypical antipsychotic agents; peas in a pod or chalk and cheese?

With escalating health expenditure and a shrinking purse, there is increased focus on the cost efficacy of still patented versus generic medications in general, and for atypical antipsychotics in particular. In a recent BMC Medicine article, Godman and colleagues presented data indicating poor uptake of the off patent atypical antipsychotic risperidone, arguing for authorities to mandate its greater use. This is under the assumption of clinical equivalence of atypical antipsychotics. This commentary argues that there are clinically meaningful differences between atypical antipsychotics and important inter-individual heterogeneity in clinical response and tolerability. Access to a broad range of atypical antipsychotics enables clinicians to tailor care, taking consideration of differential efficacy and adverse effects profile in order to meet the needs of individual patients with improved real world effectiveness of treatment. Restriction of agent choice risks detracting from optimal clinical care, with possible poorer outcomes and greater costs of care. A balance between encouraging use of cheapest in class agent and allowing access to various atypical agents for tailored care is likely to produce optimal health outcomes.Please see related article: http://www.biomedcentral.com/1741-7015/12/98.

Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression

Objective: Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder. Methods: This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase. Results: The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment. Conclusion: This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression. Trial registration: Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.

Re-Imagining Practical Legal Training Practitioners – Soldiers for ‘Vocationalism’, or Double Agents?

I adopt a constructivist approach in order to study Australian PLT practitioners’ engagement with scholarship of teaching and learning (SoTL) in institutional practical legal training (PLT). Drawing on Bourdieu’s reflexive sociology and Certeau’s heterological science, I argue PLT is enclosed by discursive operations that constrain PLT practitioners’ engagement with SoTL. I contend SoTL could address a knowledge gap in practice research in law and legal education. I propose to re-imagine PLT teaching work by conceptualising it as an emergent professional trajectory, engaged in practice research, teaching and learning. By considering ways in which structures are inscribed into legal education practice, and conversely, whether practice can modify such structures, I re-imagine PLT practitioners as double agents or resistance fighters, enriching legal education through SoTL as practice research.

Mobile Agents Security Protocols

Mobile agents are expected to run in partially unknown and untrustworthy environments. They transport from one host to another host through insecure channels and may execute on non-trusted hosts. Thus, they are vulnerable to direct security attacks of intruders and non-trusted hosts. The security of information the agents collect is a fundamental requirement for a trusted implementation of electronic business applications and trade negotiations. This chapter discusses the security protocols presented in the literature that aim to secure the data mobile agents gather while searching the Internet, and identifies the security flaws revealed in the protocols. The protocols are analyzed with respect to the security properties, and the security flaws are identified. Two recent promising protocols that fulfill the various security properties are described. The chapter also introduces common notations used in describing security protocols and describes the security properties of the data that mobile agents gather.

A critical ethnography of communication processes involving the management of oral chemotherapeutic agents by patients with a primary diagnosis of colorectal cancer: study protocol.

AIM: To describe the protocol used to examine the processes of communication between health professionals, patients and informal carers during the management of oral chemotherapeutic medicines to identify factors that promote or inhibit medicine concordance. BACKGROUND: Ideally communication practices about oral medicines should incorporate shared decision-making, two-way dialogue and an equality of role between practitioner and patient. While there is evidence that healthcare professionals are adopting these concordant elements in general practice there are still some patients who have a passive role during consultations. Considering oral chemotherapeutic medications, there is a paucity of research about communication practices which is surprising given the high risk of toxicity associated with chemotherapy. DESIGN: A critical ethnographic design will be used, incorporating non-participant observations, individual semi-structured and focus-group interviews as several collecting methods. METHODS: Observations will be carried out on the interactions between healthcare professionals (physicians, nurses and pharmacists) and patients in the outpatient departments where prescriptions are explained and supplied and on follow-up consultations where treatment regimens are monitored. Interviews will be conducted with patients and their informal carers. Focus-groups will be carried out with healthcare professionals at the conclusion of the study. These several will be analysed using thematic analysis. This research is funded by the Department for Employment and Learning in Northern Ireland (Awarded February 2012). DISCUSSION: Dissemination of these findings will contribute to the understanding of issues involved when communicating with people about oral chemotherapy. It is anticipated that findings will inform education, practice and policy.

Novel 1,4-substituted-1,2,3-triazoles as antitubercular agents

Tuberculosis (TB) remains a pressing unmet medical need, particularly with the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. Here, a series of 1,4-substituted-1,2,3-triazoles have been synthesized and evaluated as potential antitubercular agents. These compounds were assembled via click chemistry in high crude purity and in moderate to high yield. Of the compounds tested, 12 compounds showed promising antitubercular activity with six possessing minimum inhibitory concentration (MIC) values <10 μg mL^-1, and total selectivity for Mycobacterium tuberculosis (Mtb) growth inhibition. A second set of 21 compounds bearing variations on ring C were synthesized and evaluated. This second library gave an additional six compounds displaying MIC values ≤10 μg mL^-1 and total selectivity for Mtb growth inhibition. These compounds serve as an excellent starting point for further development of antitubercular therapies.

Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents

Background Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians. Objective To describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents. Design, setting, and participants We report on a cohort of 59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of whom had received prior enzalutamide. Outcome measurements and statistical analysis Changes in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy. Results and limitations The post-endocrine-therapy patients received abiraterone (n = 32), sequential abiraterone and enzalutamide (n = 5) or enzalutamide (n = 4). These patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median of six cabazitaxel cycles (range: 1-10 cycles) were delivered, with ≥50% PSA declines in 16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naïve cohort (n = 18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis. Conclusions This is the first report of cabazitaxel activity in CRPC progressing after treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant cabazitaxel activity in this setting. Patient summary We looked at the antitumour activity of the chemotherapy drug cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after these novel endocrine treatments. © 2013 European Association of Urology.

Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study

Background & Aims Use of dabigatran, an inhibitor of thrombin, increases the risk of gastrointestinal bleeding (GIB). However, it is not clear whether gastroprotective agents (GPAs) prevent GIB in dabigatran users. We investigated the risk of GIB and the role of gastroprotective agents (including proton pump inhibitors and histamine type-2-receptor antagonists) in patients using dabigatran. Methods We performed a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly prescribed dabigatran from 2010 through 2013 were included in the analysis. Poisson regression was used to assess the risk of GIB in dabigatran users by incidence rate ratio (IRR), adjusted for patient characteristics, comorbidities, and concurrent medications. Results Among the 5041 patients newly prescribed dabigatran, 124 (2.5%) developed GIB during follow-up evaluation (4.2/100 patient-years). The risk of GIB in this population increased among patients 75 years and older (IRR, 2.47; 95% confidence interval [CI], 1.66-3.68), patients with a history of peptic ulcers or GIB (IRR, 2.31; 95% CI, 1.54-3.46), and patients who used aspirin (IRR, 1.52; 95% CI, 1.03-2.24). Concomitant use of gastroprotective agents was associated with a reduced risk of GIB (IRR, 0.52; 95% CI, 0.35-0.77). Subcategory analysis showed that use of proton pump inhibitors (IRR, 0.53; 95% CI, 0.31-0.91) or histamine type-2-receptor antagonists (IRR, 0.61; 95% CI, 0.40-0.94) were associated with a lower risk of GIB. Further analysis showed that the risk reduction by gastroprotective agents was significant for only upper GIB (IRR, 0.29; 95% CI, 0.15-0.54), and only for patients with a prior history of peptic ulcers or GIB (IRR, 0.14; 95% CI, 0.06-0.30). Conclusions In the Hong Kong population, use of gastroprotective agents was associated with a reduced risk of GIB in patients taking dabigatran. The association was stronger for upper GIB than lower GIB, and in patients with a prior history of peptic ulcers or GIB.

Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents

A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL(-1) against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.

Synthesis and in vivo evaluation of [123I]melanin-targeted agents

This study reports the synthesis, [(123)I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41, and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [(123)I]41 and [(123)I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [(123)I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [(131)I] therapeutic evaluation.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

Norbornane-based peptidomimetics as antibacterial agents

 A library of norbornane-based peptide mimetics have been synthesised and shown to exhibit antibacterial activity against a range of troublesome Gram-positive and Gram-negative bacterial pathogens.