Exploring the Limits of Cyanobactin Macrocyclase PatGmac: Cyclization of PawS-Derived Peptide Sunflower Trypsin Inhibitor-1 and Cyclotide Kalata B1.

The subtilisin-like macrocyclase PatGmac is produced by the marine cyanobacterium Prochloron didemni. This enzyme is involved in the last step of the biosynthesis of patellamides, a cyanobactin type of ribosomally expressed and post-translationally modified cyclic peptides. PatGmac recognizes, cleaves, and cyclizes precursor peptides after a specific recognition motif comprised of a C-terminal tail with the sequence motif -AYDG. The result is the native macrocyclic patellamide, which has eight amino acid residues. Macrocyclase activity can be exploited by incorporating that motif in other short linear peptide precursors, which then are formed into head-to-tail cyclized peptides. Here, we explore the possibility of using PatGmac in the cyclization of peptides larger than the patellamides, namely, the PawS-derived peptide sunflower trypsin inhibitor-1 (SFTI-1) and the cyclotide kalata B1. These peptides fall under two distinct families of disulfide constrained macrocyclic plant peptides. They are both implicated as scaffolds for drug design due to their structures and unusual stability. We show that PatGmac can be used to efficiently cyclize the 14 amino acid residue long SFTI-1, but less so the 29 amino acid residue long kalata B1.

Cell death of Acanthamoeba castellanii following exposure to antimicrobial agents commonly included in contact lens disinfecting solutions.

Several antimicrobial agents are commonly included in contact lens disinfectant solutions including chlorhexidine diacetate (CHX), polyhexamethylene biguanide (PHMB) or myristamidopropyl dimethylamine (MAPD); however, their mode of action, i.e. necrosis versus apoptosis is incompletely understood. Here, we determined whether a mechanism of cell death resembling that of apoptosis was present in Acanthamoeba castellanii of the T4 genotype (NEFF) following exposure to the aforementioned antimicrobials using the anticoagulant annexin V that undergoes rapid high affinity binding to phosphatidylserine in the presence of calcium, making it a sensitive probe for phosphatidylserine exposure. The results revealed that under the conditions employed in this study, an apoptotic pathway of cell death in this organism at the tested conditions does not occur. Our findings suggest that necrosis is the likely mode of action; however, future mechanistic studies should be accomplished in additional experimental conditions to further comprehend the molecular mechanisms of cell death in Acanthamoeba.

The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease.

The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non-alcoholic fatty liver disease (NAFLD). Eighteen adults were randomized to receive 20 g/d of an inulin-propionate ester (IPE), designed to deliver propionate to the colon, or an inulin control for 42 days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between the groups (P = 0.082), however, IHCL significantly increased within the inulin-control group (20.9% ± 2.9% to 26.8% ± 3.9%; P = 0.012; n = 9), which was not observed within the IPE group (22.6% ± 6.9% to 23.5% ± 6.8%; P = 0.635; n = 9). The predominant SCFA from colonic fermentation of inulin is acetate, which, in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate-mediated increase in IHCL.

Health service brokerage to improve primary care access for populations experiencing vulnerability or disadvantage: a systematic review and realist synthesis.

BACKGROUND: Individuals experiencing disadvantage or marginalisation often face difficulty accessing primary health care. Overcoming access barriers is important for improving the health of these populations. Brokers can empower and enable people to access resources; however, their role in increasing access to health services has not been well-defined or researched in the literature. This review aims to identify whether a health service broker working with health and social service providers in the community can (a) identify individuals experiencing vulnerability who may benefit from improved access to quality primary care, and (b) link these individuals with an appropriate primary care provider for enduring, appropriate primary care. METHODS: Six databases were searched for studies published between January 2008 and August 2015 that evaluated a health service broker intervention linking adults experiencing vulnerability to primary care. Relevant websites were also searched. Included studies were analysed using candidacy theory and a realist matrix was developed to identify mechanisms that may have contributed to changes in response to the interventions in different contexts. RESULTS: Eleven studies were included in the review. Of the eight studies judged to provide detailed description of the programs, the interventions predominately addressed two domains of candidacy (identification of candidacy and navigation), with limited applicability to the third and fourth dimensions (permeability of services and appearances at health services). Six of the eight studies were judged to have successfully linked their target group to primary care. The majority of the interventions focused on assisting patients to reach services and did not look at ways that providers or health services could alter the way they deliver care to improve access. CONCLUSIONS: While specific mechanisms behind the interventions could not be identified, it is suggested that individual advocacy may be a key element in the success of these types of interventions. The interventions were found to address some dimensions of candidacy, with health service brokers able to help people to identify their need for care and to access, navigate and interact with services. More consideration should be given to the influence of providers on patient candidacy, rather than placing the onus on patients.

Manual wheelchair downhill stability: an analysis of factors affecting tip probability.

BACKGROUND: For people who use manual wheelchairs, tips and falls can result in serious injuries including bone fractures, concussions, and traumatic brain injury. We aimed to characterize how wheelchair configuration changes (including on-the-fly adjustments), user variables, and usage conditions affected dynamic tip probability while rolling down a slope and contacting a small block. METHODS: Rigid body dynamic models of a manual wheelchair and test dummy were created using multi-body software (Madymo, TASS International, Livonia, MI), and validated with 189 experiments. Dynamic stability was assessed for a range of seat angles (0 to 20° below horizontal), backrest angles (0 to 20°), rear axle positions (0 to 20 cm from base of backrest), ground slopes (0 to 15°), bump heights (0 to 4 cm), wheelchair speeds (0 to 20 km/hr), user masses (50 to 115 kg), and user positions (0 to 10 cm from base of backrest). The tip classifications (forward tip, backward tip, rolled over bump, or stopped by bump) were investigated using a nominal logistic regression analysis. RESULTS: Faster wheelchair speeds significantly increased the probability of tipping either forward or backward rather than stopping, but also increased the probability of rolling over the bump (p < 0.001). When the rear axle was positioned forward, this increased the risk of a backward tip compared to all other outcomes (p < 0.001), but also reduced the probability of being stopped by the bump (p < 0.001 compared to forward tip, p < 0.02 compared to rolling over). Reclining the backrest reduced the probability of a forward tip compared to all other outcomes (p < 0.001), and lowering the seat increased the probability of either rolling over the bump or tipping backwards rather than tipping forward (p < 0.001). In general, the wheelchair rolled over bumps < 1.5 cm, and forwards tipping was avoided by reducing the speed to 1 km/hr. CONCLUSIONS: The probability of forward tipping, corresponding to the greatest risk of injury, was significantly reduced for decreased speeds, smaller bumps, a reclined backrest, and a lower rear seat height. For wheelchairs with dynamic seating adjustability, when travelling downhill, on-the-fly adjustments to the seat or backrest can increase the likelihood of safely rolling over a bump.

Accurate quantification of modified cyclic peptides without the need for authentic standards.

There is a growing interest in the use of cyclic peptides as therapeutics, but their efficient production is often the bottleneck in taking them forward in the development pipeline. We have recently developed a method to synthesise azole-containing cyclic peptides using enzymes derived from different cyanobactin biosynthetic pathways. Accurate quantification is crucial for calculation of the reaction yield and for the downstream biological testing of the products. In this study, we demonstrate the development and validation of two methods to accurately quantify these compounds in the reaction mixture and after purification. The first method involves the use of a HPLC coupled in parallel to an ESMS and an ICPMS, hence correlating the calculated sulfur content to the amount of cyclic peptide. The second method is an NMR ERETIC method for quantifying the solution concentration of cyclic peptides. These methods make the quantification of new compounds much easier as there is no need for the use of authentic standards when they are not available.

Metabolic switches and adaptations deduced from the proteomes of Streptomyces coelicolor wild type and phoP mutant grown in batch culture.

Bacteria in the genus Streptomyces are soil-dwelling oligotrophs and important producers of secondary metabolites. Previously, we showed that global messenger RNA expression was subject to a series of metabolic and regulatory switches during the lifetime of a fermentor batch culture of Streptomyces coelicolor M145. Here we analyze the proteome from eight time points from the same fermentor culture and, because phosphate availability is an important regulator of secondary metabolite production, compare this to the proteome of a similar time course from an S. coelicolor mutant, INB201 (ΔphoP), defective in the control of phosphate utilization. The proteomes provide a detailed view of enzymes involved in central carbon and nitrogen metabolism. Trends in protein expression over the time courses were deduced from a protein abundance index, which also revealed the importance of stress pathway proteins in both cultures. As expected, the ΔphoP mutant was deficient in expression of PhoP-dependent genes, and several putatively compensatory metabolic and regulatory pathways for phosphate scavenging were detected. Notably there is a succession of switches that coordinately induce the production of enzymes for five different secondary metabolite biosynthesis pathways over the course of the batch cultures.

Pathology image of the month. Black esophagus detected at autopsy in a patient with abdominal pain and bloody diarrhea. DIAGNOSIS: Acute esophageal necrosis, ischemic and pseudomembranous colitis.

A 73-year-old African-American male was transported to the emergency department due to what emergency personnel described as "coffee ground emesis." He was pronounced dead shortly after arrival. An unlimited autopsy examination was conducted under authorization of the coroner's office. Medical record review revealed that the decedent had been discharged from the hospital just one day prior to his death following a three-day admission for abdominal pain, bloody diarrhea, and a 22-lb unintentional weight loss. Medical history documented hypertension, chronic obstructive lung disease, and a 57-pack-year smoking history. Alcohol abuse was also endorsed, but cessation of use was reported six months prior. During that admit, he was treated for volume-depletion, a urinary tract infection, and suspected infective colitis with antibiotics. Symptoms had resolved on hospital day three, and the patient was discharged home with a two-week course of ciprofloxacin and metronidazole and a follow-up colonoscopy appointment in one month. At the time of autopsy, the decedent was described as cachectic. Figure 1a shows the decedent's esophagus, opened longitudinally. Figure 1b shows the corresponding histology from the esophagus. Other findings documented at autopsy included ischemic bowel disease in the descending colon with patchy superimposed pseudomembranous colitis, emphysematous change, papillary renal cell carcinoma of the right kidney, microscopic prostatic adenocarcinoma, hepatic fibrosis, and intact hepatic hemangiomata.

An efficient method for the in vitro production of azol(in)e-based cyclic peptides.

Heterocycle-containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine-derived enzymes and substrates obtained from a family of ribosomally produced and post-translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non-native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6-9 residues representing 11 out of the 20 canonical amino acids.

The association of cardiometabolic, diet and lifestyle parameters with plasma glucagon-like peptide-1: An IMI DIRECT study.

CONTEXT: The role of glucagon-like peptide-1(GLP-1) in Type 2 diabetes (T2D) and obesity is not fully understood. OBJECTIVE: We investigate the association of cardiometabolic, diet and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. METHOD: We analysed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1(n=2127) individuals at risk of diabetes; cohort 2 (n=789) individuals with new-onset of T2D. RESULTS: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin resistant phenotype and observe a strong independent relationship with male sex, increased adiposity and liver fat particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycaemia, higher adiposity, liver fat, male sex and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit and vegetables inpeople with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. CONCLUSION: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.

Accuracy and efficiency define Bxb1 integrase as the best of fifteen candidate serine recombinases for the integration of DNA into the human genome.

BACKGROUND: Phage-encoded serine integrases, such as φC31 integrase, are widely used for genome engineering. Fifteen such integrases have been described but their utility for genome engineering has not been compared in uniform assays. RESULTS: We have compared fifteen serine integrases for their utility for DNA manipulations in mammalian cells after first demonstrating that all were functional in E. coli. Chromosomal recombination reporters were used to show that seven integrases were active on chromosomally integrated DNA in human fibroblasts and mouse embryonic stem cells. Five of the remaining eight enzymes were active on extra-chromosomal substrates thereby demonstrating that the ability to mediate extra-chromosomal recombination is no guide to ability to mediate site-specific recombination on integrated DNA. All the integrases that were active on integrated DNA also promoted DNA integration reactions that were not mediated through conservative site-specific recombination or damaged the recombination sites but the extent of these aberrant reactions varied over at least an order of magnitude. Bxb1 integrase yielded approximately two-fold more recombinants and displayed about two fold less damage to the recombination sites than the next best recombinase; φC31 integrase. CONCLUSIONS: We conclude that the Bxb1 and φC31 integrases are the reagents of choice for genome engineering in vertebrate cells and that DNA damage repair is a major limitation upon the utility of this class of site-specific recombinase.

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study.

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired ß cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments.

The dynamic architecture of the metabolic switch in Streptomyces coelicolor.

BACKGROUND: During the lifetime of a fermenter culture, the soil bacterium S. coelicolor undergoes a major metabolic switch from exponential growth to antibiotic production. We have studied gene expression patterns during this switch, using a specifically designed Affymetrix genechip and a high-resolution time-series of fermenter-grown samples. RESULTS: Surprisingly, we find that the metabolic switch actually consists of multiple finely orchestrated switching events. Strongly coherent clusters of genes show drastic changes in gene expression already many hours before the classically defined transition phase where the switch from primary to secondary metabolism was expected. The main switch in gene expression takes only 2 hours, and changes in antibiotic biosynthesis genes are delayed relative to the metabolic rearrangements. Furthermore, global variation in morphogenesis genes indicates an involvement of cell differentiation pathways in the decision phase leading up to the commitment to antibiotic biosynthesis. CONCLUSIONS: Our study provides the first detailed insights into the complex sequence of early regulatory events during and preceding the major metabolic switch in S. coelicolor, which will form the starting point for future attempts at engineering antibiotic production in a biotechnological setting.

Dietary metabolite profiling brings new insight into the relationship between nutrition and metabolic risk: An IMI DIRECT study.

BACKGROUND: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D. METHODS: We analysed data from plasma collected at baseline and 18-month follow-up in individuals from the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohort 1 n = 403 individuals with normal or impaired glucose regulation (prediabetic) and cohort 2 n = 458 individuals with new onset of T2D. A dietary metabolite profile model (Tpred) was constructed using multivariable regression of 113 plasma metabolites obtained from targeted metabolomics assays. The continuous Tpred score was used to explore the relationships between diet, glycaemic deterioration and cardio-metabolic risk via multiple linear regression models. FINDINGS: A higher Tpred score was associated with healthier diets high in wholegrain (ß=3.36 g, 95% CI 0.31, 6.40 and ß=2.82 g, 95% CI 0.06, 5.57) and lower energy intake (ß=-75.53 kcal, 95% CI -144.71, -2.35 and ß=-122.51 kcal, 95% CI -186.56, -38.46), and saturated fat (ß=-0.92 g, 95% CI -1.56, -0.28 and ß=-0.98 g, 95% CI -1.53, -0.42 g), respectively for cohort 1 and 2. In both cohorts a higher Tpred score was also associated with lower total body adiposity and favourable lipid profiles HDL-cholesterol (ß=0.07 mmol/L, 95% CI 0.03, 0.1), (ß=0.08 mmol/L, 95% CI 0.04, 0.1), and triglycerides (ß=-0.1 mmol/L, 95% CI -0.2, -0.03), (ß=-0.2 mmol/L, 95% CI -0.3, -0.09), respectively for cohort 1 and 2. In cohort 2, the Tpred score was negatively associated with liver fat (ß=-0.74%, 95% CI -0.67, -0.81), and lower fasting concentrations of HbA1c (ß=-0.9 mmol/mol, 95% CI -1.5, -0.1), glucose (ß=-0.2 mmol/L, 95% CI -0.4, -0.05) and insulin (ß=-11.0 pmol/mol, 95% CI -19.5, -2.6). Longitudinal analysis showed at 18-month follow up a higher Tpred score was also associated lower total body adiposity in both cohorts and lower fasting glucose (ß=-0.2 mmol/L, 95% CI -0.3, -0.01) and insulin (ß=-9.2 pmol/mol, 95% CI -17.9, -0.4) concentrations in cohort 2. INTERPRETATION: Plasma dietary metabolite profiling provides objective measures of diet intake, showing a relationship to glycaemic deterioration and cardiometabolic health. FUNDING: This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115,317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies.

Primary health care provider-focused interventions for improving outcomes for people with type 2 diabetes: a rapid review.

Objectives and importance of the study: The bulk of care for people with type 2 diabetes occurs in primary health care. This rapid review evaluated the effectiveness of primary health care provider-focused interventions in improving biochemical, clinical, psychological and health-related quality-of-life outcomes in people with type 2 diabetes. METHODS: We searched Medline, Embase, All EBM Reviews, CINAHL, PsycINFO and grey literature focusing on the Organisation for Economic Co-operation and Development (OECD) member countries. We selected studies that targeted adults with type 2 diabetes, described a provider-focused intervention conducted in primary health care, and included an evaluation component. Four researchers extracted data and each included study was assessed for quality by two researchers. RESULTS: Of the 15 studies identified, there was one systematic review (high quality), four randomised controlled trials (RCTs) (two strong quality, one each moderate and weak) and 10 cluster RCTs (two strong quality, five moderate, three weak). The range of follow-up periods was 3-32 months. In all but one study, the intervention was compared against usual care. The applied interventions included: computerised and noncomputerised decision support; culturally tailored interventions; feedback to the healthcare provider on quality of diabetes care; practice nurse involvement; and integrated primary and specialist care. All interventions aimed to improve the biochemical outcomes of interest; 13 studies also included clinical, psychological and/or health-related quality-of-life outcomes. Outcome results were mixed. CONCLUSIONS: All interventions had mixed impacts on the outcomes of interest except the one study testing a decision aid, which did not show any improvement. A number of interventions are already available in Australia but need wider adoption. Other effective interventions are yet to be broadly adopted, and need to be evaluated for their applicability, feasibility and sustainability in the Australian context.

Electronic, mobile and telehealth tools for vulnerable patients with chronic disease: a systematic review and realist synthesis.

OBJECTIVES: The objective of this review was to assess the benefit of using electronic, mobile and telehealth tools for vulnerable patients with chronic disease and explore the mechanisms by which these impact patient self-efficacy and self-management. DESIGN: We searched MEDLINE, all evidence-based medicine, CINAHL, Embase and PsychINFO covering the period 2009 to 2018 for electronic, mobile or telehealth interventions. Quality was assessed according to rigour and relevance. Those studies providing a richer description ('thick') were synthesised using a realist matrix. SETTING AND PARTICIPANTS: Studies of any design conducted in community-based primary care involving adults with one or more diagnosed chronic health condition and vulnerability due to demographic, geographic, economic and/or cultural characteristics. RESULTS: Eighteen trials were identified targeting a range of chronic conditions and vulnerabilities. The data provided limited insight into the mechanisms underpinning these interventions, most of which sought to persuade vulnerable patients into believing they could self-manage their conditions through improved symptom monitoring, education and support and goal setting. Patients were relatively passive in the interaction, and the level of patient response attributed to their intrinsic level of motivation. Health literacy, which may be confounded with motivation, was only measured in one study, and eHealth literacy was not assessed. CONCLUSIONS: Research incorporating these tools with vulnerable groups is not comprehensive. Apart from intrinsic motivation, health literacy may also influence the reaction of vulnerable groups to technology. Social persuasion was the main way interventions sought to achieve better self-management. Efforts to engage patients by healthcare providers were lower than expected. Use of social networks or other eHealth mechanisms to link patients and provide opportunities for vicarious experience could be further explored in relation to vulnerable groups. Future research could also assess health and eHealth literacy and differentiate the specific needs for vulnerable groups when implementing health technologies.

How can communities and organisations improve their health literacy?

Definitions of health literacy have tended to focus on the abilities of patients and communities, rather than on the ability of the health system and its services to respond to patients' different levels of health literacy. However, health literacy is increasingly being recognised as part of a dynamic, two-way relationship, affected by both organisational factors (e.g. tailoring of communication and care to patients' needs) and community factors (e.g. individuals' ability to perceive and seek care). Developing a more comprehensive understanding of health literacy is an important step towards improving health literacy. Most health literacy interventions described in the literature tend to be small and focused on either organisational or community aspects of health literacy rather than addressing both sides. However, some good examples can be found in Local Health Districts and Primary Health Networks in New South Wales (NSW), Australia, of health literacy interventions that are multidimensional and address both organisational and community health literacy. Although progress is being made, gaps in knowledge remain. A deeper understanding of the intersection between health literacy, culture and language is needed, as well as identification of effective communication strategies after patient comprehension has been assessed using strategies such as 'teach-back'. The teach-back method can be used to check patient understanding, but it is not a communication strategy in itself. If teach-back shows that the patient has not understood, clinicians can employ communication strategies such as limiting discussion to two or three points, or using visual aids. If these are not effective, extended family networks and the use of patient navigators may be required. These health literacy interventions address both organisational and community aspects. More work is needed to evaluate such interventions, in particular their impact on health literacy and appropriate and timely access to healthcare.

Preventing chronic disease in patients with low health literacy using eHealth and teamwork in primary healthcare: protocol for a cluster randomised controlled trial.

INTRODUCTION: Adults with lower levels of health literacy are less likely to engage in health-promoting behaviours. Our trial evaluates the impacts and outcomes of a mobile health-enhanced preventive intervention in primary care for people who are overweight or obese. METHODS AND ANALYSIS: A two-arm pragmatic practice-level cluster randomised trial will be conducted in 40 practices in low socioeconomic areas in Sydney and Adelaide, Australia. Forty patients aged 40-70 years with a body mass index ≥28 kg/m2 will be enrolled per practice. The HeLP-general practitioner (GP) intervention includes a practice-level quality improvement intervention (medical record audit and feedback, staff training and practice facilitation visits) to support practices to implement the clinical intervention for patients. The clinical intervention involves a health check visit with a practice nurse based on the 5As framework (assess, advise, agree, assist and arrange), the use of a purpose-built patient-facing app, my snapp, and referral for telephone coaching. The primary outcomes are change in health literacy, lifestyle behaviours, weight, waist circumference and blood pressure. The study will also evaluate changes in quality of life and health service use to determine the cost-effectiveness of the intervention and examine the experiences of practices in implementing the programme. ETHICS AND DISSEMINATION: The study has been approved by the University of New South Wales (UNSW) Human Research Ethics Committee (HC17474) and ratified by the University of Adelaide Human Research Ethics committee. There are no restrictions on publication, and findings of the study will be made available to the public via the Centre for Primary Health Care and Equity website and through conference presentations and research publications. Deidentified data and meta-data will be stored in a repository at UNSW and made available subject to ethics committee approval. TRIAL REGISTRATIONREGISTRATION NUMBER: ACTRN12617001508369; Pre-results.

Quantifying the effects of on-the-fly changes of seating configuration on the stability of a manual wheelchair.

In general, manual wheelchairs are designed with a fixed frame, which is not optimal for every situation. Adjustable on the fly seating allow users to rapidly adapt their wheelchair configuration to suit different tasks. These changes move the center of gravity (CoG) of the system, altering the wheelchair stability and maneuverability. To assess these changes, a computer simulation of a manual wheelchair was created with adjustable seat, backrest, rear axle position and user position, and validated with experimental testing. The stability of the wheelchair was most affected by the position of the rear axle, but adjustments to the backrest and seat angles also result in stability improvements that could be used when wheeling in the community. These findings describe the most influential parameters for wheelchair stability and maneuverability, as well as provide quantitative guidelines for the use of manual wheelchairs with on the fly adjustable seats.

Partner status and mental and physical health of independently living men aged 70 years and older.

AIM: To describe and compare the mental health and physical functioning of community-dwelling men aged 70 years and over who live alone, and those who live with their partner/spouse. METHOD: Data were obtained from the baseline survey of the New South Wales 45 and Up Study. Mental health was measured using the Kessler Psychological Distress Scale and physical health was measured using the Medical Outcome Short Form 36 physical functioning scale. RESULTS: 37 690 community-dwelling men aged 70 years or over were included in the analyses. Men living alone were more likely to have high psychological distress scores and lower physical functioning scores compared to men living with a spouse/partner within each age group, except those 85 and over. CONCLUSIONS: Specific health and welfare programs targeted to the increasing number of older men living alone may be needed to address their higher levels of psychological distress and lower levels of physical functioning.