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We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer–small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF–TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein–protein interactions., TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.

DNA methylation regulates cell type-specific gene expression. Here, in a transgenic mouse model, we show that deletion of the gene encoding DNA methyltransferase Dnmt3a in hypothalamic AgRP neurons causes a sedentary phenotype characterized by reduced voluntary exercise and increased adiposity. Whole-genome bisulfite sequencing (WGBS) and transcriptional profiling in neuronal nuclei from the arcuate nucleus of the hypothalamus (ARH) reveal differentially methylated genomic regions and reduced expression of AgRP neuron-associated genes in knockout mice. We use read-level analysis of WGBS data to infer putative ARH neural cell types affected by the knockout, and to localize promoter hypomethylation and increased expression of the growth factor Bmp7 to AgRP neurons, suggesting a role for aberrant TGF-β signaling in the development of this phenotype. Together, these data demonstrate that DNA methylation in AgRP neurons is required for their normal epigenetic development and neuron-specific gene expression profiles, and regulates voluntary exercise behavior., AgRP neurons in the hypothalamic arcuate nucleus (ARH) are involved in regulating hunger and energy balance. Here the authors show that knockout of the DNA methyltransferase Dnmt3a in AgRP neurons of the ARH leads to a reduction in voluntary exercise along with numerous epigenetic and gene expression changes in ARH neurons.

Background DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific. Results For each of 10 donors from the NIH Genotype-Tissue Expression (GTEx) program, CpG methylation is measured by deep whole-genome bisulfite sequencing of genomic DNA from tissues representing the three germ layer lineages: thyroid (endoderm), heart (mesoderm), and brain (ectoderm). We develop a computational algorithm to identify genomic regions at which interindividual variation in DNA methylation is consistent across all three lineages. This approach identifies 9926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, are inter-correlated over long genomic distances, associated with transposable elements and subtelomeric regions, conserved across diverse human ethnic groups, sensitive to periconceptional environment, and associated with genes implicated in a broad range of human disorders and phenotypes. CoRSIV methylation in one tissue can predict expression of associated genes in other tissues. Conclusions In addition to charting a previously unexplored molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease. Electronic supplementary material The online version of this article (10.1186/s13059-019-1708-1) contains supplementary material, which is available to authorized users.

Background The geographic distribution of health workers is a pervasive policy concern. Many governments are responding by introducing financial incentives to attract health care workers to locate in areas that are underserved. However, clear evidence of the effectiveness of such financial incentives is lacking. Methods This paper examines General Practitioners’ (GPs) relocation choices in Australia and proposes a dynamic location choice model accounting for both source and destination factors associated with a choice to relocate, thereby accounting for push and pull factors associated with job separation. The model is used to simulate financial incentive policies and assess potential for such policies to redistribute GPs. This paper examines the role of financial factors in relocating established GPs into neighbourhoods with relatively low socioeconomic status. The paper uses a discrete choice model and panel data on GPs’ actual changes in location from one year to the next. Results This paper finds that established GPs are not very mobile, even when a financial incentive is offered. Policy simulation predicts that 93.2% of GPs would remain at their current practice and that an additional 0.8% would be retained or would relocate in a low-socioeconomic status (SES) neighbourhood in response to a hypothetical financial incentive of a 10% increase in the earnings of all metropolitan GPs practising in low-SES neighbourhoods. Conclusion With current evidence on the effectiveness of redistribution programmes limited to newly entering GPs, the policy simulations in this paper provide an insight into the potential effectiveness of financial incentives as a redistribution policy targeting the entire GP population. Overall, the results suggest that financial considerations are part of many factors influencing the location choice of GPs. For instance, GP practice ownership played almost as important a role in mobility as earnings.

Background We investigate factors affecting Australian general practitioners’ decisions to adopt novel oral anticoagulants (NOACs) for the prevention of stroke/systemic embolism among patients with atrial fibrillation. Australia has a national homogeneous review and coverage system, which enables us to distinguish physician level factors while maintaining system level factors and patient coverage information constant. Methods We conduct a cohort analyses by using longitudinal physician survey data from the Medicine in Australia: Balancing Employment and Life panel survey of Australian physicians (MABEL). MABEL data contain rich physician-level information such as age, gender, education, risk preferences, personality, physicians’ communications with other medical professionals, and other practice characteristics. Importantly, the survey data were linked, with physician’s consent, to actual utilization data from the Australian Pharmaceutical Benefits Scheme and the Medicare Benefits Schedule between January 1, 2012 and December 31, 2015. We measure speed (days until first time prescribing) of adopting NOACs. We estimate a Cox proportional hazard model to estimate factors affecting the adoption speed. Results Several factors predict earlier adoption of NOACs: being male, more likely to take clinical risk, higher prescribing volume, being a principal or partner in the practice instead of an employee, spending less time in a typical consultation, and practicing in more affluent areas or areas with a higher proportion of older patients. GPs in Queensland are more likely to adopt NOACs and more likely to be extensive early adopters compared to other GPs. Other characteristics including physician personality, family circumstances, their involvement with public hospitals and teaching activities, and the distance between physician practice location to other clinics in the area are not statistically associated with earlier adoption. Conclusions Our paper is one of the first to study the relationship between GPs’ risk preferences, personality and their decisions to adopt new prescription drugs. Because NOACs are commonly prescribed and considered more cost-effective than their older counterpart, understanding factors affecting physicians’ decisions to adopt NOACs has direct policy implications. Our results also highlight that even with universal coverage for prescription drugs, access to new drugs is different among patients, partially because who their doctors are and where they practice.

Background The capacity for high-income countries to supply enough locally trained doctors to minimise their reliance on overseas-trained doctors (OTDs) is important for equitable global workforce distribution. However, the ability to achieve self-sufficiency of individual countries is poorly evaluated. This review draws on a decade of research evidence and applies additional stratified analyses from a unique longitudinal medical workforce research program (the Medicine in Australia: Balancing Employment and Life survey (MABEL)) to explore Australia’s rural medical workforce self-sufficiency and inform rural workforce planning. Australia is a country with a strong medical education system and extensive rural workforce policies, including a requirement that newly arrived OTDs work up to 10 years in underserved, mostly rural, communities to access reimbursement for clinical services through Australia’s universal health insurance scheme, called Medicare. Findings Despite increases in the number of Australian-trained doctors, more than doubling since the late 1990s, recent locally trained graduates are less likely to work either as general practitioners (GPs) or in rural communities compared to local graduates of the 1970s–1980s. The proportion of OTDs among rural GPs and other medical specialists increases for each cohort of doctors entering the medical workforce since the 1970, peaking for entrants in 2005–2009. Rural self-sufficiency will be enhanced with policies of selecting rural-origin students, increasing the balance of generalist doctors, enhancing opportunities for remaining in rural areas for training, ensuring sustainable rural working conditions and using innovative service models. However, these policies need to be strongly integrated across the long medical workforce training pathway for successful rural workforce supply and distribution outcomes by locally trained doctors. Meanwhile, OTDs substantially continue to underpin Australia’s rural medical service capacity. The training pathways and social support for OTDs in rural areas is critical given their ongoing contribution to Australia’s rural medical workforce. Conclusion It is essential for Australia to monitor its ongoing reliance on OTDs in rural areas and be considerate of the potential impact on global workforce distribution.

The generic health-related quality-of-life (HR-QOL) utility measures the EQ-5D and SF-6D are both commonly used to inform healthcare policy developments. However, their application to pharmacy practice is limited and the optimal method to inform policy developments is unknown. Our objective was to test the sensitivity of the EQ-5D and SF-6D within pharmacy when measuring whether changes in health status or other co-variates at baseline affect the effectiveness of the intervention at follow-up. A further objective was to consider the implications of the findings for pharmacy research and policy. The EQ-5D and SF-6D utility measures were employed within a randomized controlled trial (RCT) of community pharmacy-led medicines management for patients with coronary heart disease. The intervention covered a baseline visit with the potential for follow-up. Simultaneous quantile regression assessed the impact of the intervention on both EQ-5D and SF-6D measures at follow-up, controlling for baseline health, appropriateness of treatment, personal characteristics and self-reported satisfaction. No statistically significant difference in HR-QOL across the intervention and control groups at follow-up was reported for either measure. Increased health gain was however associated with the baseline utility score (with the EQ-5D more sensitive for those in worse health) and the appropriateness of treatment, but not patient characteristics or self-reported satisfaction. Neither generic measure detected a gain in HR-QOL as a result of the introduction of an innovative pharmacy-based service. This finding supports other work in the area of pharmacy, where health gains have not changed following interventions. Disease-specific utility measures should be investigated as an alternative to generic approaches such as the EQ-5D and SF-6D. Given that the RCT found an increase in self-reported satisfaction, broader measures of benefit that value patient experiences, such as contingent valuation and discrete-choice experiments, should also be considered in pharmacy.

The folding of transmembrane proteins into the outer membrane presents formidable challenges to Gram-negative bacteria. These proteins must migrate from the cytoplasm, through the inner membrane and into the periplasm, before being recognized by the beta-barrel assembly machinery, which mediates efficient insertion of folded beta-barrels into the outer membrane. Recent discoveries of component structures and accessory interactions of this complex are yielding insights into how cells fold membrane proteins. Here, we discuss how these structures illuminate the mechanisms responsible for the biogenesis of outer membrane proteins.

Coronary heart disease (CHD) is the most common cause of death in the UK. CHD cost the UK National Health Service (NHS) pound 3.5 billion in 2003. The economic impact of community pharmacists providing a medicines management service for patients with CHD has not been rigorously evaluated; the full economic costs of such interventions are rarely presented in the literature.To examine the incremental costs of a 1-year community pharmacist-led medicines management service for patients with CHD in the UK, from a healthcare system and patient perspective.A cost-minimisation analysis was conducted alongside a multicentre randomised controlled trial. The primary study participants were patients with CHD identified from general practice computer records. Patients (intervention, n = 980; control, n = 500) from 38 general practices in nine geographical areas in the UK were included in the study. INTERVENTION AND OUTCOMES MEASURES: The intervention consisted of a review of pharmaceuticals and lifestyle advice by pharmacists in their premises, with recommendations communicated to the patient's GP. The main outcome measure was the incremental cost per patient in the intervention group compared with the control group. Annual costs ( pound, 2003/4 values) included the costs of the intervention (training and delivery costs), the usual costs of NHS treatment (costs of pharmaceuticals, GP and hospital visits) and costs borne by patients. Data were collected in the 12 months before and 12 months after the intervention.The total NHS cost increased between baseline and follow-up in both groups (from pound 1243 to pound 1286 [3%] in the control group and from pound 1410 to pound 1433 [2%] in the intervention group). The greater cost in the intervention group largely reflects the additional cost of the pharmacist training and the time taken to deliver the intervention; the difference in costs between the intervention and control groups, after controlling for differences in costs at baseline at follow-up, was statistically significant (p = 0.001). The costs of pharmaceuticals was higher in the intervention group ( pound 769.20 vs pound 742.3; p = 0.04). According to the sensitivity analysis, the intervention cost would need to decrease by 35% to achieve equivalence between costs in each arm of the trial. Difference to costs of patients and their carers at follow-up were not statistically significant.The introduction of a 1-year pharmacist-led medicines management service is likely to increase the total cost of CHD treatment and prevention from the healthcare perspective, as the cost of the intervention outweighed the observed reduction in the cost of drugs in the intervention group. No changes in costs from the patient perspective were found.

Background: Major changes in the roles and responsibilities of pharmacists across the world are occurring. A new Scottish Community Pharmacy contract was introduced in April 2006, following the introduction of a similar contract in England in 2005. This contract encourages greater involvement in medicines management and other clinical cognitive roles, whilst retaining a supply function. Objective: To use a discrete choice experiment (DCE) to examine the strength of preference of community pharmacists for existing and potential new roles, prior to the introduction of the new contract. Study design: The DCE was a component of a larger questionnaire, which assessed demography, workload, attitudes to, and satisfaction with, proposed new roles, and current levels of activity. Attributes and levels for the DCE were based on the recent policy document for Scotland, The Right Medicine, and informed consensus, respectively. Scenarios were organised into pairs, and pharmacists were asked “Which job would you prefer?” The questionnaire was mailed to all pharmacists working in the community setting in Scotland (n = 1621), as identified from a telephone survey. The questionnaire was totally anonymous, and two reminders were sent. Results: There was an overall response rate of 56.4% (914/1621). Community pharmacists preferred to work in an extended pharmacy team, to have strong integration with secondary care, and to provide a minor illness advice service. In 2003, they would forgo an annual income of £3443, £2183 and £2798, respectively to achieve this. However, overall, the pharmacists preferred more income to less. Repeat dispensing, chronic disease management, offering health promotion services, and the number of prescriptions dispensed per month were not significant predictors of job choice. Conclusion: Community pharmacists placed the highest value on organisational aspects of their work, and having a first contact primary care role. Although total income was important, there were indications that they would be prepared to forgo income to attain their preferred job.

To evaluate the in vitro and in vivo characteristics of hypromellose (HPMC) capsules prepared using a gellan gum and potassium gelling system compared to conventional hard gelatin capsules.The in vitro dissolution of ibuprofen gelatin and HPMC capsules was determined using the USP and TRIS buffers at pH 7.2. The effect of pH and composition of the media was determined using a model drug that is soluble throughout the pH range 1.2 to 7.2. In an 11 subject four-way crossover study, the gastrointestinal performance of ibuprofen gelatin and HPMC capsule formulations was evaluated using scintigraphy and pharmacokinetics following fasted and fed dosing.Acid conditions and the presence of K+ cations hinder HPMC capsule opening, whereas in water, dissolution is identical to that of gelatin. These effects are related to the nature of the gel network that is formed in the presence of cations. No significant difference in esophageal transit was observed. Although the in vivo opening times of HPMC capsules were longer than for their gelatin counterparts, no significant difference in the regulatory important pharmacokinetic metrics of C(max) and AUC was found between ibuprofen, gelatin and HPMC capsules.The in vitro performance of HPMC capsules differ from gelatin, which will require modification to dissolution testing methodology for certain drugs. However, for the class II BCS drug ibuprofen, the two capsule types were not statistically different when comparing AUC and C(max) values, which suggests that the in vitro differences have reduced in vivo relevance.

Background Smoking during pregnancy is harmful to the unborn child. Few smoking cessation interventions have been successfully incorporated into standard antenatal care. The main aim of this study is to determine the feasibility of a personal financial incentive scheme for encouraging smoking cessation among pregnant women. Design A pilot randomised control trial will be conducted to assess the feasibility and potential effectiveness of two varying financial incentives that increase incrementally in magnitude ($20 vs. $40AUD), compared to no incentive in reducing smoking in pregnant women attending an Australian public hospital antenatal clinic. Method Ninety (90) pregnant women who self-report smoking in the last 7 days and whose smoking status is biochemically verified, will be block randomised into one of three groups: a. No incentive control group (n=30), b. $20 incremental incentive group (n=30), and c. $40 incremental incentive group (n=30). Smoking status will be assessed via a self-report computer based survey in nine study sessions with saliva cotinine analysis used as biochemical validation. Women in the two incentive groups will be eligible to receive a cash reward at each of eight measurement points during pregnancy if 7-day smoking cessation is achieved. Cash rewards will increase incrementally for each period of smoking abstinence. Discussion Identifying strategies that are effective in reducing the number of women smoking during pregnancy and are easily adopted into standard antenatal practice is of utmost importance. A personal financial incentive scheme is a potential antenatal smoking cessation strategy that warrants further investigation. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12612000399897

Background Dental caries (decay) is the most prevalent disease of childhood. It is often left untreated and can impact negatively on general health, and physical, developmental, social and learning outcomes. Similar to other health issues, the greatest burden of dental caries is seen in those of low socio-economic position. In addition, a number of diet-related risk factors for dental caries are shared risk factors for the development of childhood obesity. These include high and frequent consumption of refined carbohydrates (predominately sugars), and soft drinks and other sweetened beverages, and low intake of (fluoridated) water. The prevalence of childhood obesity is also at a concerning level in most countries and there is an opportunity to determine interventions for addressing both of these largely preventable conditions through sustainable and equitable solutions. This study aims to prospectively examine the impact of drink choices on child obesity risk and oral health status. Methods/Design This is a two-stage study using a mixed methods research approach. The first stage involves qualitative interviews of a sub-sample of recruited parents to develop an understanding of the processes involved in drink choice, and inform the development of the Discrete Choice Experiment analysis and the measurement instruments to be used in the second stage. The second stage involves the establishment of a prospective birth cohort of 500 children from disadvantaged communities in rural and regional Victoria, Australia (with and without water fluoridation). This longitudinal design allows measurement of changes in the child's diet over time, exposure to fluoride sources including water, dental caries progression, and the risk of childhood obesity. Discussion This research will provide a unique contribution to integrated health, education and social policy and program directions, by providing clearer policy relevant evidence on strategies to counter social and environmental factors which predispose infants and children to poor health, wellbeing and social outcomes; and evidence-based strategies to promote health and prevent disease through the adoption of healthier lifestyles and diet. Further, given the absence of evidence on the processes and effectiveness of contemporary policy implementation, such as community water fluoridation in rural and regional communities it's approach and findings will be extremely informative.

Background While there is considerable research on medical workforce supply trends, there is little research examining the determinants of labour supply decisions for the medical workforce. The "Medicine in Australia: Balancing Employment and Life (MABEL)" study investigates workforce participation patterns and their determinants using a longitudinal survey of Australian doctors. It aims to generate evidence to support developing effective policy responses to workforce issues such as shortages and maldistribution. This paper describes the study protocol and baseline cohort, including an analysis of response rates and response bias. Methods/Design MABEL is a prospective cohort study. All Australian doctors undertaking clinical work in 2008 (n = 54,750) were invited to participate, and annual waves of data collections will be undertaken until at least 2011. Data are collected by paper or optional online version of a questionnaire, with content tailored to four sub-groups of clinicians: general practitioners, specialists, specialists in training, and hospital non-specialists. In the baseline wave, data were collected on: job satisfaction, attitudes to work and intentions to quit or change hours worked; a discrete choice experiment examining preferences and trade-offs for different types of jobs; work setting; workload; finances; geographic location; demographics; and family circumstances. Discussion The baseline cohort includes 10,498 Australian doctors, representing an overall response rate of 19.36%. This includes 3,906 general practitioners, 4,596 specialists, 1,072 specialists in training, and 924 hospital non-specialists. Respondents were more likely to be younger, female, and to come from non-metropolitan areas, the latter partly reflecting the effect of a financial incentive on response for doctors in remote and rural areas. Specialists and specialists in training were more likely to respond, whilst hospital non-specialists were less likely to respond. The distribution of hours worked was similar between respondents and data from national medical labour force statistics. The MABEL survey provides a large, representative cohort of Australian doctors. It enables investigation of the determinants of doctors' decisions about how much, where and in what circumstances they practice, and of changes in these over time. MABEL is intended to provide an important resource for policy makers and other stakeholders in the Australian medical workforce.