GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior.

The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development of peptide YY (PYY)-based approaches to treat obesity are no exception, as PYY receptor agonism is often accompanied by nausea and vomiting. Here, we sought to determine whether glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist reduced conditioned taste avoidance (CTA) without affecting hypophagia mediated by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were found to be expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in detecting aversive stimuli. Peripheral administration of a GIPR agonist induced neuronal activation (cFos) in the AP. Further, whole-brain cFos analyses indicated that PYY-induced CTA was associated with augmented neuronal activity in the parabrachial nucleus (PBN), a brainstem nucleus that relays aversive/emetic signals to brain regions that control feeding behavior. Importantly, GIPR agonism reduced PYY-mediated neuronal activity in the PBN, providing a potential mechanistic explanation for how GIPR agonist treatment reduces PYY-induced nausea-like behavior. Together, the results of our study indicate a novel mechanism by which GIP-based therapeutics may have benefit in improving the tolerability of weight loss agents.

Implementing primary care diabetes prevention for women with previous gestational diabetes: a mixed-methods study.

BACKGROUND: The implementation of diabetes prevention for women with previous gestational diabetes (GDM) has been stymied by many barriers that are located within routine general practice (GP). We aimed to unpack the GP factors and understand the mechanisms that explain why a diabetes prevention intervention for this population succeeds or fails. METHODS: We performed a mixed-methods study with a Normalization Process Theory framework that included clinical audits, semistructured interviews, and focus groups within mixed urban and rural primary care practices in Victoria, Australia. Staff of primary care practices and external support staff who provide services to women with previous GDM participated in a 12-month quality improvement collaborative intervention. We compared diabetes screening and prevention activity planning with the strategies and factors identified through a process evaluation of full-, moderate-, and low-active participating practices. RESULTS: The intervention doubled screening rates (26%-61%) and 1-in-10 women received a diabetes prevention planning consultation. Critical improvement factors were: mothers being seen as participants in the quality improvement work; staff collectively building care strategies; staff taking a long-term care of a community perspective rather than episodic service delivery; and feedback processes being provided and acted on across the practice. The observable factors from the external perspective were: leadership by identified practice staff, reminder systems in action and practice staff driving the process collectively. CONCLUSIONS: Successful engagement in diabetes prevention for women with previous GDM requires proactive building of the critical improvement factors and audit feedback into routine GP.

Structural determinants of dual incretin receptor agonism by tirzepatide.

SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.

Barriers to and enablers of type 2 diabetes screening among women with prior gestational diabetes: A systematic review update and qualitative synthesis applying the Theoretical Domains Framework.

AIMS: Women with prior gestational diabetes have nearly 10 times the risk of developing type 2 diabetes. Postpartum screening for type 2 diabetes is recommended for early diagnosis and management, yet uptake is low. This work updates a previous systematic review and advances it through the application of the Theoretical Domains Framework (TDF) to synthesise personal-level factors impacting type 2 diabetes screening and the Capability, Opportunity, Motivation-Behaviour model (COM-B), to develop messaging recommendations for use in clinical practice and screening promotion interventions. METHODS: We searched seven academic databases from September 2017 (prior review) to April 2021, reference lists and grey literature. Two reviewers independently screened articles against inclusion criteria (qualitative studies exploring factors impacting postpartum diabetes screening, any language) and extracted data. Using an inductive-deductive model, we coded determinants to the TDF and mapped onto the COM-B model. RESULTS: We identified 38 eligible papers from 34 studies (N = 1291 participants). Most (71%) reported sample sizes of N ≥ 16. The ratio of barriers to enablers was three to one. Eight key TDF domains were identified. Evidence-based recommendations include addressing knowledge, risk perception, fear of diabetes diagnosis, low prioritisation of personal health and fatalism. The risk of bias was low and confidence in findings was moderate to high. A limitation was conceptual overlap between TDF domains, which we addressed via the study procedure. CONCLUSIONS: The theoretical categorisation of determinants enables the development of messaging and interventions at the personal level, to promote women's uptake of postpartum type 2 diabetes screening.

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling.

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRALAP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.

Implementing screening interventions in community pharmacy to promote interprofessional coordination of primary care - A mixed methods evaluation.

BACKGROUND: Screening is a critical component of efforts to reduce the population burden of cardiovascular disease (CVD), by facilitating early use of cost-effective prevention and treatment strategies. While international evidence suggests that screening in community pharmacies improves screening access and identifies at-risk individuals, concerns from medical organisations about the absence of interdisciplinary coordination and related lack of continuity of care with general practice have significantly contributed to reluctance from some stakeholders to endorse, and engage with, pharmacy-based screening initiatives. The Cardiovascular Absolute Risk Screening (CARS) study was designed to address these challenges and promote an interprofessional approach to screening for cardiovascular disease risk by pharmacists. This study describes the impact of the CARS implementation model on interdisciplinary coordination and continuity of care. METHODS: In addition to clinical training, pharmacists at eleven participating pharmacies were provided with implementation training, resources and support to promote interprofessional coordination. Completion of training and pharmacy implementation plans, both of which highlighted GP engagement strategies, were pre-requisites for screening commencement. Using mixed methods approaches, data were analyzed from screening records (n = 388), researcher interviews with patients at 6-10 weeks post-screening (n = 248, 64%), and pharmacist interviews (n = 10). RESULTS: Screening records suggested that 94% of screened individuals were advised to seek formal GP assessment, and 98% consented to sharing of results. Among interviewed participants, 81% recalled direct pharmacist action to facilitate GP engagement. Among interviewees who had seen their GP already (n = 70), 79% reported that their GP was aware of the results (another 16% were uncertain). Pharmacists reported positive GP feedback stemming from efforts at early engagement, but an absence of ongoing collaboration. CONCLUSIONS: Use of implementation planning by pharmacists, alongside clinical training, can effectively promote an interdisciplinary coordination focus by pharmacists.

Updates to Binding MOAD (Mother of All Databases): Polypharmacology Tools and Their Utility in Drug Repurposing.

The goal of Binding MOAD is to provide users with a data set focused on high-quality x-ray crystal structures that have been solved with biologically relevant ligands bound. Where available, experimental binding affinities (Ka, Kd, Ki, IC50) are provided from the primary literature of the crystal structure. The database has been updated regularly since 2005, and this most recent update has added nearly 7000 new structures (growth of 21%). MOAD currently contains 32,747 structures, composed of 9117 protein families and 16,044 unique ligands. The data are freely available on www.BindingMOAD.org. This paper outlines updates to the data in Binding MOAD as well as improvements made to both the website and its contents. The NGL viewer has been added to improve visualization of the ligands and protein structures. MarvinJS has been implemented, over the outdated MarvinView, to work with JChem for small molecule searching in the database. To add tools for predicting polypharmacology, we have added information about sequence, binding-site, and ligand similarity between entries in the database. A main premise behind polypharmacology is that similar binding sites will bind similar ligands. The large amount of protein-ligand information available in Binding MOAD allows us to compute pairwise ligand and binding-site similarities. Lists of similar ligands and similar binding sites have been added to allow users to identify potential polypharmacology pairs. To show the utility of the polypharmacology data, we detail a few examples from Binding MOAD of drug repurposing targets with their respective similarities.

Results of the first recorded evaluation of a national gestational diabetes mellitus register: Challenges in screening, registration, and follow-up for diabetes risk.

OBJECTIVE: Gestational Diabetes Mellitus (GDM) increases the risk of type 2 diabetes. A register can be used to follow-up high risk women for early intervention to prevent progression to type 2 diabetes. We evaluate the performance of the world's first national gestational diabetes register. RESEARCH DESIGN AND METHODS: Observational study that used data linkage to merge: (1) pathology data from the Australian states of Victoria (VIC) and South Australia (SA); (2) birth records from the Consultative Council on Obstetric and Paediatric Mortality and Morbidity (CCOPMM, VIC) and the South Australian Perinatal Statistics Collection (SAPSC, SA); (3) GDM and type 2 diabetes register data from the National Gestational Diabetes Register (NGDR). All pregnancies registered on CCOPMM and SAPSC for 2012 and 2013 were included-other data back to 2008 were used to support the analyses. Rates of screening for GDM, rates of registration on the NGDR, and rates of follow-up laboratory screening for type 2 diabetes are reported. RESULTS: Estimated GDM screening rates were 86% in SA and 97% in VIC. Rates of registration on the NGDR ranged from 73% in SA (2013) to 91% in VIC (2013). During the study period rates of screening at six weeks postpartum ranged from 43% in SA (2012) to 58% in VIC (2013). There was little evidence of recall letters resulting in screening 12 months follow-up. CONCLUSIONS: GDM Screening and NGDR registration was effective in Australia. Recall by mail-out to young mothers and their GP's for type 2 diabetes follow-up testing proved ineffective.

Screening for diabetes prevention with diabetes risk scores - A balancing act.

AIMS: To compare the diabetes prevention impact and cost of several screening scenarios for diabetes prevention programs with the scenario which included an oral glucose tolerance test (OGTT). METHODS: We included 4864 participants of the Australian Diabetes, Obesity and Lifestyle study who were aged ≥40 years, did not have known diabetes at baseline, and attended the five year follow-up. The proportions of participants eligible or ineligible for diabetes prevention program were estimated for each scenario. The costs of screening and diabetes prevention programs were also estimated. RESULTS: Screening with OGTT alone identified 21% of participants as eligible for diabetes prevention. While 3.1% of the cohort were identified as high risk and developed diabetes after five years, 1.0% of the cohort were identified as low risk and developed diabetes. The population prevention potential (i.e. sensitivity) for OGTT alone was 76.5%. Screening all Australian adults aged ≥40 years in 2015 by OGTT would have cost a total of AU$2025 million (AU$1031 million on screening and AU$994 million on prevention programs). The total costs of screening and prevention were substantially lower when AUSDRISK was used alone or in combination with a blood test. However, the population prevention potentials were also lower (ranged from 20.1% to 50.7%). CONCLUSIONS: A blood test post non-invasive risk assessment is a worthwhile step in the process of enrolling participants in a diabetes prevention program. Nevertheless, there will be ineligible individuals who proceed to diabetes.

Health professional perspectives on the management of multimorbidity and polypharmacy for older patients in Australia.

Background: delivering appropriate care for patients with multimorbidity and polypharmacy is increasingly challenging. Challenges for individual healthcare professions are known, but only little is known about overall healthcare team implementation of best practice for these patients. Objective: to explore current approaches to multimorbidity management, and perceived barriers and enablers to deliver appropriate medications management for community-dwelling patients with multimorbidity and polypharmacy, from a broad range of healthcare professional (HCP) perspectives in Australia. Methods: this qualitative study used semi-structured interviews to gain in-depth understanding of HCPs' perspectives on the management of multimorbidity and polypharmacy. The interview guide was based on established principles for the management of multimorbidity in older patients. HCPs in rural and metropolitan Victoria and South Australia were purposefully selected to obtain a maximum variation sample. Twenty-six HCPs, from relevant medical, dentistry, nursing, pharmacy and allied health backgrounds, were interviewed between October 2013 and February 2014. Fourteen were prescribers and 12 practiced in primary care. Interviews were digitally audio-taped, transcribed verbatim and analysed using a constant comparison approach. Results: most participants did not routinely use structured approaches to incorporate patients' preferences in clinical decision-making, address conflicting prescriber advice, assess patients' adherence to treatment plans or seek to optimise care plans. Most HCPs were either unaware of medical decision aids and measurements tools to support these processes or disregarded them as not being user-friendly. Challenges with coordination and continuity of care, pressures of workload and poorly defined individual responsibilities for care, all contributed to participants' avoiding ownership of multimorbidity management. Potential facilitators of improved care related to improved culture, implementation of electronic health records, greater engagement of pharmacists, nurses and patients, families in care provision, and the use of care coordinators. Conclusion: extensive shortcomings exist in team-based care for the management of multimorbidity. Delegating coordination and review responsibilities to specified HCPs may support improved overall care.

Patient and carer identified factors which contribute to safety incidents in primary care: a qualitative study.

BACKGROUND: Patients can have an important role in reducing harm in primary-care settings. Learning from patient experience and feedback could improve patient safety. Evidence that captures patients' views of the various contributory factors to creating safe primary care is largely absent. The aim of this study was to address this evidence gap. METHODS: Four focus groups and eight semistructured interviews were conducted with 34 patients and carers from south-east Australia. Participants were asked to describe their experiences of primary care. Audio recordings were transcribed verbatim and specific factors that contribute to safety incidents were identified in the analysis using the Yorkshire Contributory Factors Framework (YCFF). Other factors emerging from the data were also ascertained and added to the analytical framework. RESULTS: Thirteen factors that contribute to safety incidents in primary care were ascertained. Five unique factors for the primary-care setting were discovered in conjunction with eight factors present in the YCFF from hospital settings. The five unique primary care contributing factors to safety incidents represented a range of levels within the primary-care system from local working conditions to the upstream organisational level and the external policy context. The 13 factors included communication, access, patient factors, external policy context, dignity and respect, primary-secondary interface, continuity of care, task performance, task characteristics, time in the consultation, safety culture, team factors and the physical environment. DISCUSSION: Patient and carer feedback of this type could help primary-care professionals better understand and identify potential safety concerns and make appropriate service improvements. The comprehensive range of factors identified provides the groundwork for developing tools that systematically capture the multiple contributory factors to patient safety.

Waste the waist: a pilot randomised controlled trial of a primary care based intervention to support lifestyle change in people with high cardiovascular risk.

BACKGROUND: In the UK, thousands of people with high cardiovascular risk are being identified by a national risk-assessment programme (NHS Health Checks). Waste the Waist is an evidence-informed, theory-driven (modified Health Action Process Approach), group-based intervention designed to promote healthy eating and physical activity for people with high cardiovascular risk. This pilot randomised controlled trial aimed to assess the feasibility of delivering the Waste the Waist intervention in UK primary care and of conducting a full-scale randomised controlled trial. We also conducted exploratory analyses of changes in weight. METHODS: Patients aged 40-74 with a Body Mass Index of 28 or more and high cardiovascular risk were identified from risk-assessment data or from practice database searches. Participants were randomised, using an online computerised randomisation algorithm, to receive usual care and standardised information on cardiovascular risk and lifestyle (Controls) or nine sessions of the Waste the Waist programme (Intervention). Group allocation was concealed until the point of randomisation. Thereafter, the statistician, but not participants or data collectors were blinded to group allocation. Weight, physical activity (accelerometry) and cardiovascular risk markers (blood tests) were measured at 0, 4 and 12 months. RESULTS: 108 participants (22% of those approached) were recruited (55 intervention, 53 controls) from 6 practices and 89% provided data at both 4 and 12 months. Participants had a mean age of 65 and 70% were male. Intervention participants attended 72% of group sessions. Based on last observations carried forward, the intervention group did not lose significantly more weight than controls at 12 months, although the difference was significant when co-interventions and co-morbidities that could affect weight were taken into account (Mean Diff 2.6Kg. 95%CI: -4.8 to -0.3, p = 0.025). No significant differences were found in physical activity. CONCLUSIONS: The Waste the Waist intervention is deliverable in UK primary care, has acceptable recruitment and retention rates and produces promising preliminary weight loss results. Subject to refinement of the physical activity component, it is now ready for evaluation in a full-scale trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10707899 .

Processes of behavior change and weight loss in a theory-based weight loss intervention program: a test of the process model for lifestyle behavior change.

BACKGROUND: Process evaluation is important for improving theories of behavior change and behavioral intervention methods. The present study reports on the process outcomes of a pilot test of the theoretical model (the Process Model for Lifestyle Behavior Change; PMLBC) underpinning an evidence-informed, theory-driven, group-based intervention designed to promote healthy eating and physical activity for people with high cardiovascular risk. METHODS: 108 people at high risk of diabetes or heart disease were randomized to a group-based weight management intervention targeting diet and physical activity plus usual care, or to usual care. The intervention comprised nine group based sessions designed to promote motivation, social support, self-regulation and understanding of the behavior change process. Weight loss, diet, physical activity and theoretically defined mediators of change were measured pre-intervention, and after four and 12 months. RESULTS: The intervention resulted in significant improvements in fiber intake (M between-group difference = 5.7 g/day, p < .001) but not fat consumption (-2.3 g/day, p = 0.13), that were predictive of weight loss at both four months (M between-group difference = -1.98 kg, p < .01; R(2) = 0.2, p < 0.005), and 12 months (M difference = -1.85 kg, p = 0.1; R(2) = 0.1, p < 0.01). The intervention was successful in improving the majority of specified mediators of behavior change, and the predicted mechanisms of change specified in the PMBLC were largely supported. Improvements in self-efficacy and understanding of the behavior change process were associated with engagement in coping planning and self-monitoring activities, and successful dietary change at four and 12 months. While participants reported improvements in motivational and social support variables, there was no effect of these, or of the intervention overall, on physical activity. CONCLUSIONS: The data broadly support the theoretical model for supporting some dietary changes, but not for physical activity. Systematic intervention design allowed us to identify where improvements to the intervention may be implemented to promote change in all proposed mediators. More work is needed to explore effective mechanisms within interventions to promote physical activity behavior.

Large scale characterization of the LC13 TCR and HLA-B8 structural landscape in reaction to 172 altered peptide ligands: a molecular dynamics simulation study.

The interplay between T cell receptors (TCRs) and peptides bound by major histocompatibility complexes (MHCs) is one of the most important interactions in the adaptive immune system. Several previous studies have computationally investigated their structural dynamics. On the basis of these simulations several structural and dynamical properties have been proposed as effectors of the immunogenicity. Here we present the results of a large scale Molecular Dynamics simulation study consisting of 100 ns simulations of 172 different complexes. These complexes consisted of all possible point mutations of the Epstein Barr Virus peptide FLRGRAYGL bound by HLA-B*08:01 and presented to the LC13 TCR. We compare the results of these 172 structural simulations with experimental immunogenicity data. We found that simulations with more immunogenic peptides and those with less immunogenic peptides are in fact highly similar and on average only minor differences in the hydrogen binding footprints, interface distances, and the relative orientation between the TCR chains are present. Thus our large scale data analysis shows that many previously suggested dynamical and structural properties of the TCR/peptide/MHC interface are unlikely to be conserved causal factors for peptide immunogenicity.

Patients' and carers' perceptions of safety in rural general practice.

OBJECTIVES: To explore patients' and carers' experiences of rural general practice to identify their perceptions of safety of care. DESIGN, PARTICIPANTS AND SETTING: Four focus group interviews were conducted with 26 rural patients and carers in south-west Victoria between September and December 2012. Frequent users of general practice were recruited from local allied health self-management programs and a mothers' group. Focus groups were audio recorded, transcripts were independently analysed and interpreted using narrative methodologies. RESULTS: Participants who had experienced some level of harm were able to comment more extensively on safety aspects of care. Several key themes related to safety were identified from the analysis of all participant narratives. An assumed sense of safety in general practice was predominant, and was influenced by participants' level of risk awareness and trust in their general practitioner. Additional unique themes included feelings of vulnerability, desire for an explanation and apology, a forgiving view of mistakes, and preference for GP interpersonal skills over competence. CONCLUSIONS: This study revealed new insights into the factors that influence patients' and carers' perspectives of safety, and demonstrated the value of incorporating the patient voice into safety research. An assumed sense of safety due to a default position of trust, coupled with limited risk perception, directly contests the current literature on patient involvement in safety. Further exploration is required to determine how patients and carers can effectively engage in and assist with improving safety in general practice.

Who's responsible for the care of women during and after a pregnancy affected by gestational diabetes?

Despite its increasing incidence and high conferred risk to women and their children, gestational diabetes mellitus (GDM) is managed inconsistently during and after pregnancy due to an absence of a systemic approach to managing these women. New guidelines for GDM testing and diagnosis are based on stronger evidence, but raise concerns about increased workloads and confusion in a landscape of multiple, conflicting guidelines. Postnatal care and long-term preventive measures are particularly fragmented, with no professional group taking responsibility for this crucial role. Clearer guidelines and assistance from existing frameworks, such as the National Gestational Diabetes Register, could enable general practitioners to take ownership of the management of women at risk of type 2 diabetes following GDM, applying the principles of chronic disease management long term.

Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319.

Fibroblast growth factor 21 is a novel hormonal regulator with the potential to treat a broad variety of metabolic abnormalities, such as type 2 diabetes, obesity, hepatic steatosis, and cardiovascular disease. Human recombinant wild type FGF21 (FGF21) has been shown to ameliorate metabolic disorders in rodents and non-human primates. However, development of FGF21 as a drug is challenging and requires re-engineering of its amino acid sequence to improve protein expression and formulation stability. Here we report the design and characterization of a novel FGF21 variant, LY2405319. To enable the development of a potential drug product with a once-daily dosing profile, in a preserved, multi-use formulation, an additional disulfide bond was introduced in FGF21 through Leu118Cys and Ala134Cys mutations. FGF21 was further optimized by deleting the four N-terminal amino acids, His-Pro-Ile-Pro (HPIP), which was subject to proteolytic cleavage. In addition, to eliminate an O-linked glycosylation site in yeast a Ser167Ala mutation was introduced, thus allowing large-scale, homogenous protein production in Pichia pastoris. Altogether re-engineering of FGF21 led to significant improvements in its biopharmaceutical properties. The impact of these changes was assessed in a panel of in vitro and in vivo assays, which confirmed that biological properties of LY2405319 were essentially identical to FGF21. Specifically, subcutaneous administration of LY2405319 in ob/ob and diet-induced obese (DIO) mice over 7-14 days resulted in a 25-50% lowering of plasma glucose coupled with a 10-30% reduction in body weight. Thus, LY2405319 exhibited all the biopharmaceutical and biological properties required for initiation of a clinical program designed to test the hypothesis that administration of exogenous FGF21 would result in effects on disease-related metabolic parameters in humans.

Predicting changes in lifestyle and clinical outcomes in preventing diabetes: the Greater Green Triangle Diabetes Prevention Project.

OBJECTIVES: To analyse how psychosocial determinants of lifestyle changes targeted in the Greater Green Triangle Diabetes Prevention Project conducted in Southeast Australia in 2004-2006 predict changes in dietary behaviour and clinical risk factors. METHODS: A longitudinal pre-test and post-test study design was used. The group program was completed by 237 people at high risk of type 2 diabetes. Associations between changes in the variables were examined by structural equation modelling using a path model in which changes in psychological determinants for lifestyle predicted changes in dietary behaviours (fat and fibre intake), which subsequently predicted changes in waist circumference and other clinical outcomes. Standardised regression weights are presented, with ß=±0.1 and ß=±0.3 representing small and medium associations, respectively. RESULTS: Improvements in coping self-efficacy and planning predicted improvements in fat (ß=-0.15, p<0.05 and ß=-0.32, p<0.001, respectively) and fibre intake (ß=0.15, p<0.05 and ß=0.23, p<0.001, respectively) which in turn predicted improvements in waist circumference (ß=0.18, p<0.01 and ß=-0.16, p<0.05, respectively). Improvements in waist circumference predicted improvements in diastolic blood pressure (ß=0.13, p<0.05), HDL (ß=-0.16, p<0.05), triglycerides (ß=0.17, p<0.01), and fasting glucose (ß=0.15, p<0.05). CONCLUSIONS: Psychological changes predicted behaviour changes, resulting in 12-month biophysical changes. The findings support the theoretical basis of the interventions.

When big isn't beautiful: lessons from England and Scotland on primary health care organisations.

United Kingdom primary care trusts resembled the primary health care organisations (PHCOs) that have been proposed for Australia--for example, Medicare Locals. They resulted in a loss of innovation, creativity, motivation and morale among general practitioners and other front-line staff. English primary care trusts are being abolished and £80 billion will be handed over to GP commissioners. Management theory and practical experience shows repeatedly the dangers of reorganising into larger units. Lessons for Australia are to defer deciding on the size of PHCOs until their purposes are clear, to enshrine the principle of subsidiarity, and to opt for networking of the current Divisions of General Practice over mergers. So far, debate on the functions and structures of PHCOs has been muted. It is now time for vigorous debate.

Rural smokers - a prevention opportunity.

BACKGROUND: Smoking is the largest single cause of preventable death and disease in Australia. This study describes smoking prevalence and the characteristics of rural smokers to guide general practitioners in targeting particular groups. METHODS: Cross sectional surveys in the Greater Green Triangle region of southeast Australia using a random population sample (n=1563, participation rate 48.7%) aged 25-74 years. Smoking information was assessed by a self administered questionnaire. RESULTS: Complete smoking data were available for 1494 participants. Overall age adjusted current smoking prevalence was 14.9% (95% CI: 13.1-16.7). In both genders, current smoking prevalence decreased with age. Those aged 25-44 years were more likely to want to stop smoking and to have attempted cessation, but less likely to have received cessation advice than older smokers. DISCUSSION: This study provides baseline smoking data for rural health monitoring and identifies intervention opportunities. General practice is suited to implement interventions for smoking prevention and cessation at every patient encounter, particularly in younger individuals.royal, australian, college, general, practitioner, gp, doctor, medical, practice, racgp, health, care, medication, information, practitioners, family, physician, 2009, AFP, May, sleep, rural, smokers, prevention