High-resolution loss of heterozygosity screening implicates PTPRJ as a potential tumor suppressor gene that affects susceptibility to non-Hodgkin's Lymphoma

We employed a Hidden-Markov-Model (HMM) algorithm in loss of heterozygosity (LOH) analysis of high-density single nucleotide polymorphism (SNP) array data from Non-Hodgkin’s lymphoma (NHL) entities, follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region 11p11.2, containing the gene encoding the protein tyrosine phosphatase receptor type J (PTPRJ). Although PTPRJ regulates components of key survival pathways in B-cells (i.e., BCR, MAPK, and PI3K signaling), its role in B-cell development is poorly understood. LOH of PTPRJ has been described in several types of cancer but not in any hematological malignancy. Interestingly, FL cases with LOH exhibited down-regulation of PTPRJ, in contrast no significant variation of expression was shown in DLBCLs. In addition, sequence screening in Exons 5 and 13 of PTPRJ identified the G973A (rs2270993), T1054C (rs2270992), A1182C (rs1566734), and G2971C (rs4752904) coding SNPs (cSNPs). The A1182 allele was significantly more frequent in FLs and in NHLs with LOH. Significant over-representation of the C1054 (rs2270992) and the C2971 (rs4752904) alleles were also observed in LOH cases. A haplotype analysis also revealed a significant lower frequency of haplotype GTCG in NHL cases, but it was only detected in cases with retention. Conversely, haplotype GCAC was over-representated in cases with LOH. Altogether, these results indicate that the inactivation of PTPRJ may be a common lymphomagenic mechanism in these NHL subtypes and that haplotypes in PTPRJ gene may play a role in susceptibility to NHL, by affecting activation of PTPRJ in these B-cell lymphomas.

High levels of BACH2 associated with lower levels of BCL2 transcript abundance in t(14;18)(q21;q34) translocation positive non-Hodgkin’s lymphoma

The t(14;18)(q21;q34) BCL2 translocation is a common genetic alteration in follicular and diffuse large B-cell lymphoma. However, it is not invariably associated with BCL2 gene overexpression due to undefined mechanisms that regulate expression from the proximal immunoglobulin heavy-chain (IgH) promoter. The BACH2 transcriptional repressor is able to modulate activity of this promoter. Here we have shown that, in tumor samples with BCL2 translocation, those with high levels of BACH2 had significantly lower BCL2 transcript abundance compared to those with low levels of BACH2. This indicates that BACH2 may be partially responsible for regulation of BCL2 expression from the t(14;18)(q21;q34) translocation.

Validity and reliability of nutrition screening administered by nurses

Background: Nutrition screening is usually administered by nurses. However, most studies on nutrition screening tools have not used nurses to validate the tools. The 3-Minute Nutrition Screening (3-MinNS) assesses weight loss, dietary intake and muscle wastage, with the composite score of each used to determine risk of malnutrition. The aim of the study was to determine the validity and reliability of 3-MinNS administered by nurses, who are the intended assessors. Methods: In this cross sectional study, three ward-based nurses screened 121 patients aged 21 years and over using 3-MinNS in three wards within 24 hours of admission. A dietitian then assessed the patients’ nutritional status using Subjective Global Assessment within 48 hours of admission, whilst blinded to the results of the screening. To assess the reliability of 3-MinNS, 37 patients screened by the first nurse were re-screened by a second nurse within 24 hours, who was blinded to the results of the first nurse. The sensitivity, specificity and best cutoff score for 3-MinNS were determined using the Receiver Operator Characteristics Curve. Results: The best cutoff score to identify all patients at risk of malnutrition using 3-MinNS was three, with sensitivity of 89% and specificity of 88%. This cutoff point also identified all (100%) severely malnourished patients. There was strong correlation between 3-MinNS and SGA (r=0.78, p<0.001). The agreement between two nurses conducting the 3-MinNS tool was 78.3%. Conclusion: 3-Minute Nutrition Screening is a valid and reliable tool for nurses to identify patients at risk of malnutrition.

Design LED innovation to rejuvenate local food systems and healthy communities : an emerging research agenda

Food Sovereignty (food freedom) is about empowering people to develop their own local food system. Food Sovereignty challenges designers to enable people to innovate the local food system, rather than having a food system which is dictated by corporate interests and failed business ethics. Communities are realising the potential for design to assist in the innovation process, and add strategic value to potentially localise the food system. Design Led Innovation (DLI) offers a strategic framework to address large-scale cultural, systemic and economic changes. The DLI approach empowers communities to take organised action to achieve a healthy, prosperous and happy way of life. DLI can assist with business models in the business world and it is evident this approach can assist with creating social change too. This paper presents on an emerging research agenda aimed to assist designer’s focus from individuals and systems to communities and urban problems. This paper also presents the research proposition that DLI and service design coupled with social entrepreneurial ventures such as local food projects and creative community inventions, have the potential to enable social innovation for healthy and happy communities.

Genetic susceptibility to complex traits : moving towards informed analysis of whole-genome screens

Susceptibility to complex traits, by definition, involves aetiological polymorphisms at multiple genetic loci combined with variable contributions by environmental factors. However, the approaches taken to identifying genetic loci implicated in susceptibility to complex traits frequently overlooks the compounding contribution of multiple loci in favour of highlighting a single gene solely responsible for predisposition. It is only in a small minority of cases that this has resulted in clear disease heritability associated with polymorphisms in a single gene. More often, this approach has led to an accumulation of single-gene associations with minor contributions to disease susceptibility. As the genomic era advances and genome-wide screens become higher in resolution and throughput, the need for simultaneous consideration of multiple loci is becoming more important. With special reference to non-Hodgkin’s lymphoma (NHL), this chapter will overview the current progress made in elucidating genetic polymorphisms associated with disease susceptibility. We also present novel data from a high-resolution single nucleotide polymorphism (SNP) microarray screen for susceptibility loci that are involved in NHL. Using an ‘informed approach’, the findings are highlighted within the context of cellular pathways, and provide insight and new ideas for methods of analysis for genome-wide screens for susceptibility.

Validity and reliability of 3-minute nutrition screening (3-MinNS)performed by nurses on oncology and surgical patients

Background Nutrition screening is usually administered by nurses. However, most studies on nutrition screening tools have not used nurses to validate the tools. The 3-Minute Nutrition Screening (3-MinNS) assesses weight loss, dietary intake and muscle wastage, with the composite score of each used to determine risk of malnutrition. The aim of the study was to determine the validity and reliability of 3-MinNS administered by nurses, who are the intended assessors. Methods In this cross sectional study, three ward-based nurses screened 121 patients aged 21 years and over using 3-MinNS in three wards within 24 hours of admission. A dietitian then assessed the patients’ nutritional status using Subjective Global Assessment within 48 hours of admission, whilst blinded to the results of the screening. To assess the reliability of 3-MinNS, 37 patients screened by the first nurse were re-screened by a second nurse within 24 hours, who was blinded to the results of the first nurse. The sensitivity, specificity and best cutoff score for 3-MinNS were determined using the Receiver Operator Characteristics Curve. Results The best cutoff score to identify all patients at risk of malnutrition using 3-MinNS was three, with sensitivity of 89% and specificity of 88%. This cutoff point also identified all (100%) severely malnourished patients. There was strong correlation between 3-MinNS and SGA (r=0.78, p<0.001). The agreement between two nurses conducting the 3-MinNS tool was 78.3%. Conclusion 3-Minute Nutrition Screening is a valid and reliable tool for nurses to identify patients at risk of malnutrition.

Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial

Background Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. Methods We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. Discussion Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel.

A point prevalence study of cancer nursing practices for managing intravascular devices in an Australian tertiary cancer center

Purpose The use of intravascular devices is associated with a number of potential complications. Despite a number of evidence-based clinical guidelines in this area, there continues to be nursing practice discrepancies. This study aims to examine nursing practice in a cancer care setting to identify nursing practice and areas for improvement respective to best available evidence. Methods A point prevalence survey was undertaken in a tertiary cancer care centre in Queensland, Australia. On a randomly selected day, four nurses assessed intravascular device related nursing practices and collected data using a standardized survey tool. Results 58 inpatients (100%) were assessed. Forty-eight (83%) had a device in situ, comprising 14 Peripheral Intravenous Catheters (29.2%), 14 Peripherally Inserted Central Catheters (29.2%), 14 Hickman catheters (29.2%) and six Port-a-Caths (12.4%). Suboptimal outcomes such as incidences of local site complications, incorrect/inadequate documentation, lack of flushing orders, and unclean/non intact dressings were observed. Conclusions This study has highlighted a number of intravascular device related nursing practice discrepancies compared with current hospital policy. Education and other implementation strategies can be applied to improve nursing practice. Following education strategies, it will be valuable to repeat this survey on a regular basis to provide feedback to nursing staff and implement strategies to improve practice. More research is required to provide evidence to clinical practice with regards to intravascular device related consumables, flushing technique and protocols.

Developing cultural responsiveness in environmental design students through digital storytelling and photovoice

As the Latino population in the United States grows, it will become increasingly important for undergraduate students in environmental design and related disciplines to become more culturally responsive and learn how to understand and address challenges faced by population groups, such as Latino youth. To this end, we involved environmental design undergraduate students at the University of Colorado in a service-learning class to mentor Latino youth in the creation of multimedia narratives using photovoice and digital storytelling techniques. The introduction of technology was used as a bridge between the two groups and to provide a platform for the Latino youth to reveal their community experiences. Based on focus group results, we describe the impact on the undergraduate students and provide recommendations for similar programs that can promote cultural responsiveness through the use of digital technology and prepare environmental design students to work successfully in increasingly diverse communities.

A pre-clinical functional assessment of an acellular scaffold intended for the treatment of hard-to-heal wounds

Dermal wound healing is a biochemical and cellular process critical to life. While the majority of the population will only ever experience successful wound healing outcomes, some 1-3 % of those aged over 65 years will experience wound healing delay or perpetuation. These hard-to-heal wounds are comprised of degraded and dysfunctional extracellular matrix, yet the integrity of this structure is critical in the processes of normal wound healing. As such, extracellular matrix replacements have been devised that can replace dysfunctional extracellular matrix in hard-to-heal wounds with the aim of restoring normal wound healing processes. Here we evaluated a novel synthetic matrix protein for its ability to act as an acellular scaffold that can replace dysfunctional extracellular matrix. In this regard the synthetic protein demonstrated an ability to rapidly adsorb to the dermal surface, permit cell attachment and facilitate the cellular functions essential to wound healing. When applied to deep partial thickness wounds in a porcine animal model the matrix protein also demonstrated the ability to reduce wound duration. These data provide evidence that the synthetic matrix protein has the ability to function as an acellular scaffold for wound healing purposes.

Effectiveness of an acellular synthetic matrix in the treatment of hard-to-heal leg ulcers

Hard-to-heal leg ulcers are a major cause of morbidity in the elderly population. Despite improvements in wound care, some wounds will not heal and they present a significant challenge for patients and health care providers. A multi-centre cohort study was conducted to evaluate the effectiveness and safety of a synthetic, extracellular matrix protein as an adjunct to standard care in the treatment of hard-to-heal venous or mixed leg ulcers. Primary effectiveness criteria were (i) reduction in wound size evaluated by percentage change in wound area and (ii) healing assessed by number of patients healed by end of the 12 week study. Pain reduction was assessed as a secondary effectiveness criteria using VAS. A total of 45 patients completed the study and no difference was observed between cohorts for treatment frequency. Healing was achieved in 35·6% and wound size decreased in 93·3% of patients. Median wound area percentage reduction was 70·8%. Over 50% of patients reported pain on first visit and 87·0% of these reported no pain at the end of the study. Median time to first reporting of no pain was 14 days after treatment initiation. The authors consider the extracellular synthetic matrix protein an effective and safe adjunct to standard care in the treatment of hard-to-heal leg ulcers.

Regulating integrated advertising

This chapter approaches integrated advertising as a practice that is continuous with advertising history, rather than a phenomenon associated with new technologies. Competition for technology-enabled audiences in expanding media and entertainment markets is nonetheless an important factor in the turn to integrated advertising and marketing strategies in recent years. While integrated advertising provides solutions for advertisers, it is problematic for media consumers because it is not always distinguishable from surrounding program content and clearly identifiable as advertising. It creates opportunities for advertisers to fly below the radar of citizen and consumer awareness of commercial and political influences in media content, and for this reason has been constrained by regulation. Media regulators have come to play an important role in striking a balance between public and private interests in commercial media by setting and adjudicating the limits of integrated advertising practices. This chapter looks at how broadcasting regulators have responded to the challenges of regulating integrated advertising in commercial radio in three different territories (United States, United Kingdom and Australia). It draws attention to the ways in which integrated advertising simultaneously drives innovation in media genres and forms, as well as de-regulation of the influence exercised by advertisers in commercial media content.

Physiotherapists have accurate expectations of their patients’ future health-related quality of life after first assessment in a subacute rehabilitation setting

BACKGROUND Expectations held by health professionals and their patients are likely to affect treatment choices in subacute inpatient rehabilitation settings for older adults. There is a scarcity of empirical evidence evaluating whether health professionals expectations of the quality of their patients' future health states are accurate. METHODS A prospective longitudinal cohort investigation was implemented to examine agreement (kappa coefficients, exact agreement, limits-of-agreement, and intraclass-correlation coefficients) between physiotherapists' (n = 23) prediction of patients' discharge health-related quality of life (reported on the EQ-5D-3L) and the actual health-related quality of life self-reported by patients (n = 272) at their discharge assessment (using the EQ-5D-3L). The mini-mental state examination was used as an indicator of patients' cognitive ability. RESULTS Overall, 232 (85%) patients had all assessment data completed and were included in analysis. Kappa coefficients (exact agreement) ranged between 0.37-0.57 (58%-83%) across EQ-5D-3L domains in the lower cognition group and 0.53-0.68 (81%-85%) in the better cognition group. CONCLUSIONS Physiotherapists in this subacute rehabilitation setting predicted their patients' discharge health-related quality of life with substantial accuracy. Physiotherapists are likely able to provide their patients with sound information regarding potential recovery and health-related quality of life on discharge. The prediction accuracy was higher among patients with better cognition than patients with poorer cognition.

Phenytoin metabolism by human cytochrome P450 : involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation

The anticonvulsant phenytoin (5,5-diphenylhydantoin) provokes a skin rash in 5 to 10% of patients, which heralds the start of an idiosyncratic reaction that may result from covalent modification of normal self proteins by reactive drug metabolites. Phenytoin is metabolized by cytochrome P450 (P450) enzymes primarily to 5-(p-hydroxyphenyl-),5-phenylhydantoin (HPPH), which may be further metabolized to a catechol that spontaneously oxidizes to semiquinone and quinone species that covalently modify proteins. The aim of this study was to determine which P450s catalyze HPPH metabolism to the catechol, proposed to be the final enzymatic step in phenytoin bioactivation. Recombinant human P450s were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. Novel bicistronic expression vectors were constructed for P450 2C19 and the three major variants of P450 2C9, i.e., 2C9*1, 2C9*2, and 2C9*3. HPPH metabolism and covalent adduct formation were assessed in parallel. P450 2C19 was the most effective catalyst of HPPH oxidation to the catechol metabolite and was also associated with the highest levels of covalent adduct formation. P450 3A4, 3A5, 3A7, 2C9*1, and 2C9*2 also catalyzed bioactivation of HPPH, but to a lesser extent. Fluorographic analysis showed that the major targets of adduct formation in bacterial membranes were the catalytic P450 forms, as suggested from experiments with human liver microsomes. These results suggest that P450 2C19 and other forms from the 2C and 3A subfamilies may be targets as well as catalysts of drug-protein adduct formation from phenytoin.