High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases.

Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

A Polynesian-specific copy number variant encompassing the MICA gene associates with gout.

Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

Association between routine cell salvage use for lower segment caesarean section and post-operative iron infusion and anemia.

PURPOSE: Intraoperative cell salvage is central to Patient Blood Management including for lower segment caesarean section. Prior to April 2020, we initiated intraoperative cell salvage during caesarean section based on risk assessment for hemorrhage and patient factors. As the pandemic broadened, we mandated intraoperative cell salvage to prevent peri-partum anemia and potentially reduce blood product usage. We examined the association of routine intraoperative cell salvage on maternal outcomes. METHODS: We conducted a single-center non-overlapping before-after study of obstetric patients undergoing lower segment caesarean section in the 2 months prior to a change in practice ('usual care = selective intraoperative cell salvage', n = 203) and the 2 months following ('mandated intraoperative cell salvage', n = 228). Recovered blood was processed when a minimal autologous reinfusion volume of 100 ml was expected. Post-operative iron infusion and length of stay were modelled using logistic or linear regression, using inverse probability weighting to account for confounding. RESULTS: More emergency lower-segment caesarean sections occurred in the Usual Care group. Compared to the Usual Care group, post-operative hemoglobin was higher and anemia cases fewer in the Mandated intraoperative cell salvage group. Rates of post-partum iron infusion were significantly lower in the Mandated intraoperative cell salvage group (OR = 0.31, 95% CI = 0.12 to 0.80, P = 0.016). No difference was found for length of stay. CONCLUSION: Routine cell salvage provision during lower segment caesarean section was associated with a significant reduction in post-partum iron infusions, increased post-operative hemoglobin and reduced anemia prevalence.

Association of rs9939609 in FTO with BMI among Polynesian peoples living in Aotearoa New Zealand and other Pacific nations.

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Maori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.

An allopurinol adherence tool using plasma oxypurinol concentrations.

AIMS: This study aimed to develop and evaluate an allopurinol adherence tool based on steady-state oxypurinol plasma concentrations, allopurinol's active metabolite. METHODS: Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100-800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD-FIX). RESULTS: The allopurinol adherence tool produced S&S values for trough thresholds of 89-98% and 76-84%, respectively, and 90%-98% and 76-83% for peak thresholds. PPV and NPV were 79-84% and 88-94%, respectively, for trough and 80-85% and 89-98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113. CONCLUSION: A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings.

Engaging the collective voice of physicians: Optimizing participation in research and policy development in the context of COVID-19 and physician burnout.

Physicians and governments work collaboratively to determine optimal healthcare policy options. Physicians are also engaged by health researchers to participate in studies. Physician engagement can be impeded by limits on physician time and remuneration for engagement, and the impact of physician burnout (exacerbated by COVID-19). Doctors Nova Scotia engaged physicians on various research and policy items throughout the pandemic. Strategies included integrating physicians into research teams, remunerating engagement activities, and leveraging existing tools and networks. Health researchers and policy-makers can improve physician engagement through physician champions, reduction of research duplication, valuing of physician contributions, and integrating networks.

Telephone and Web-Based Delivery of Healthy Eating and Active Living Interventions for Parents of Children Aged 2 to 6 Years: Mixed Methods Process Evaluation of the Time for Healthy Habits Translation Trial.

BACKGROUND: Few translational trials have provided detailed reports of process evaluation results. OBJECTIVE: This study reported on findings from a mixed methods process evaluation of a large translational trial comparing 2 remotely delivered healthy eating and active living interventions with an active control, targeting parents of young children. METHODS: Mixed methods process evaluation data were collected as part of a 3-arm, partially randomized preference trial targeting parents of children aged 2 to 6 years from New South Wales, Australia. Recruitment strategies were assessed through the participant baseline questionnaire and a questionnaire completed by the health promotion staff involved in recruitment. Data on participants' intervention preferences were collected at baseline and after the intervention. Intervention acceptability and demographic data were collected via a postintervention questionnaire (approximately 3 months after baseline), which was supplemented by qualitative participant interviews. Implementation data on intervention fidelity and withdrawal were also recorded. Differences in intervention acceptability, fidelity, and withdrawal rates between telephone and web-based interventions and between randomized and nonrandomized participants were analyzed. The significance level was set at P<.05 for all tests. The interview content was analyzed, key themes were drawn from participant responses, and findings were described narratively. RESULTS: Data were collected from 458 participants in the baseline survey and 144 (31.4%) participants in the 3-month postintervention survey. A total of 30 participants completed the qualitative interviews. A total of 6 health promotion staff members participated in the survey on recruitment strategies. Most participants were recruited from Early Childhood Education and Care services. There was a broad reach of the study; however, better take-up rates were observed in regional and rural areas compared with metropolitan areas. Parents with a university education were overrepresented. Most participants preferred the web-based medium of delivery at baseline. There was high acceptability of the web-based and telephone interventions. Participants found the healthy eating content to be the most useful component of the modules (web-based) and calls (telephone). They regarded text (web-based) or verbal (telephone) information as the most useful component. A high proportion of participants completed the telephone intervention compared with the web-based intervention; however, more participants actively withdrew from the telephone intervention. CONCLUSIONS: This is one of the first studies to comprehensively report on process evaluation data from a translation trial, which demonstrated high acceptability of all interventions but a strong participant preference for the web-based intervention. This detailed process evaluation is critical to inform further implementation and be considered alongside the effectiveness outcomes.

Mid-pass whole genome sequencing enables biomedical genetic studies of diverse populations.

BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.

Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects.

Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.

Venous thromboembolism (VTE) risk stratification in general medical patients at an academic medical center.

Hospital-acquired venous thromboembolism (VTE) is still a concern for general medical patients. Pharmacologic prophylaxis can reduce VTE incidence, but there is the potential for adverse effects. Therefore, determining which patients should receive VTE prophylaxis via risk scoring tools is essential. Limited evidence exists for the ideal venous thromboembolism risk assessment model (RAM) in hospitalized medical patients, as compared to other hospitalized patient subgroups such as surgical patients. The primary objective was to investigate the utilization and appropriateness of our institution-based VTE RAM and comparison to the Padua Prediction Score (PPS). This would allow for a gauge of provider risk assessment accuracy as well as appropriate predictive potential of the PPS or whether an alternative to the PPS should be considered. A total of 330 adult general medicine patients were included in this retrospective chart review. When compared to our institution-based VTE RAM, providers predominately stratified patients at a higher VTE risk than the institution-based VTE RAM. VTE incidence was 0.3%, which was lower than predicted. Significant discordance exists between providers' VTE risk assessment and that predicted by RAMs. Our institution-based VTE RAM appears comparable to PPS; however, it was not being utilized by providers, resulting in potentially unnecessary use of pharmacologic prophylaxis. The most appropriate venous thromboembolism risk assessment model for general medicine patients is undetermined. Our providers generally assess patients as moderate or high VTE risk, despite our institution-based RAM which typically recommends a lower risk category than provider selection. Because of provider risk assessment, more patients received pharmacologic VTE prophylaxis than would have been recommended by the RAM, which might correlate to the low incidence of VTE which was < 0.5%, although bleeding complications were not assessed in this study. A prospective study utilizing the Padua Prediction Score (or similar RAM) in general medicine patients is warranted in order to decipher the best method of predicting VTE risk.

The Weight of Words: Co-Analysis of Thick Ethnographic Description and "Friction" as Methodological Strategies in a Health Policy Research Partnership.

Co-production partnerships between policymakers, practitioners, and researchers are designed to facilitate production of relevant and readily usable research in health policy and practice contexts. We describe methodological strategies for in-depth collaborative analysis based on a co-produced ethnography of health promotion practice, involving ethnographic researchers and government-based research partners. We draw on a co-production dialogue to reflect critically on the role and value of co-analyzing research findings using thick ethnographic descriptions. The ambiguity of ethnographic imagery allowed flexibility in interpretation of findings and also generated friction. Specific ethnographic images became focal points for productive friction that crystallized ethical and analytical imperatives underpinning the diverse expertise in the team. To make the most of co-analysis of thick ethnographic descriptions, we assert that friction points must be reflexively considered as key learning opportunities for (a) higher order analysis informed by diverse analytical perspectives and (b) more cohesive and useful interpretations of research findings.

A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression.

The precise molecular mechanisms by which urate-associated genetic variants affect urate levels are unknown. Here, we tested for functional linkage of the maximally associated genetic variant rs1967017 at the PDZK1 locus to elevated PDZK1 expression. We performed expression quantitative trait loci (eQTL) and likelihood analyses and gene expression assays. Zebrafish were used to evaluate tissue-specific gene expression. Luciferase assays in HEK293 and HepG2 cells measured the effect of rs1967017 on transcription amplitude. Probabilistic Annotation Integrator analysis revealed rs1967017 as most likely to be causal and rs1967017 was an eQTL for PDZK1 in the intestine. The region harboring rs1967017 was capable of directly driving green fluorescent protein expression in the kidney, liver and intestine of zebrafish embryos, consistent with a conserved ability to confer tissue-specific expression. Small interfering RNA depletion of HNF4A reduced endogenous PDZK1 expression in HepG2 cells. Luciferase assays showed that the T allele of rs1967017 gains enhancer activity relative to the urate-decreasing C allele, with T allele enhancer activity abrogated by HNF4A depletion. HNF4A physically binds the rs1967017 region, suggesting direct transcriptional regulation of PDZK1 by HNF4A. Computational prediction of increased motif strength, together with our functional assays, suggests that the urate-increasing T allele of rs1967017 strengthens a binding site for the transcription factor HNF4A. Our and other data predict that the urate-raising T allele of rs1967017 enhances HNF4A binding to the PDZK1 promoter, thereby increasing PDZK1 expression. As PDZK1 is a scaffold protein for many ion channel transporters, increased expression can be predicted to increase activity of urate transporters and alter excretion of urate.

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Granulomatous Mastitis: Comparison of Novel Treatment of Steroid Injection and Current Management.

BACKGROUND: Granulomatous mastitis (GM) is a rare entity of benign origin. Multiple treatment strategies, including surgical procedures, can have sequelae of recurrence, nonhealing wounds, and protracted pain. Even after GM is diagnosed, the best management strategy remains controversial. We sought to evaluate intralesional steroid injection as a potential treatment for GM. MATERIALS AND METHODS: Electronic medical records from 2003 to 2017 of patients diagnosed with benign breast lesions were retrospectively reviewed. Patients with pathologically confirmed GM were identified. All treatment methods were documented, which included observation, oral steroids, methotrexate, steroid injection, and surgical excision. Primary outcome was time to resolution. Effectiveness was based on relief of symptoms along with duration of symptoms from initial time of diagnosis to full relief. Analysis of variance was used to compare outcomes between groups. RESULTS: Of the 49 patients with confirmed GM diagnoses, 57% had observation only, 24% had steroid injection, and 19% had surgical resection. The average time to resolution differed significantly among the three groups (11.5 mo from the start of observation, 2.0 mo from the time of steroid injection, and 0.5 mo from the time of surgical excision, P < 0.001). CONCLUSIONS: Intralesional steroid injection is an effective treatment of GM. Selective management is appropriate for patients with GM, and surgical resection is not required for most patients.

Can an electronic monitoring system capture implementation of health promotion programs? A focussed ethnographic exploration of the story behind program monitoring data.

BACKGROUND: There is a pressing need for policy makers to demonstrate progress made on investments in prevention, but few examples of monitoring systems capable of tracking population-level prevention policies and programs and their implementation. In New South Wales, Australia, the scale up of childhood obesity prevention programs to over 6000 childcare centres and primary schools is monitored via an electronic monitoring system, "PHIMS". METHODS: Via a focussed ethnography with all 14 health promotion implementation teams in the state, we set out to explore what aspects of program implementation are captured via PHIMS, what aspects are not, and the implications for future IT implementation monitoring systems as a result. RESULTS: Practitioners perform a range of activities in the context of delivering obesity prevention programs, but only specific activities are captured via PHIMS. PHIMS thereby defines and standardises certain activities, while non-captured activities can be considered as "extra" work by practitioners. The achievement of implementation targets is influenced by multi-level contextual factors, with only some of the factors accounted for in PHIMS. This evidences incongruencies between work done, recorded and, therefore, recognised. CONCLUSIONS: While monitoring systems cannot and should not capture every aspect of implementation, better accounting for aspects of context and "extra" work involved in program implementation could help illuminate why implementation succeeds or fails. Failure to do so may result in policy makers drawing false conclusions about what is required to achieve implementation targets. Practitioners, as experts of context, are well placed to assist policy makers to develop accurate and meaningful implementation targets and approaches to monitoring.

Translation of two healthy eating and active living support programs for parents of 2-6 year old children: a parallel partially randomised preference trial protocol (the 'time for healthy habits' trial).

BACKGROUND: Parents are key decision makers and role models in establishing and maintaining healthy behaviours in their children. Interventions involving parents have been shown to be more effective than those that do not, but there are barriers to participation. Efficacy trials have previously been conducted on two such parent-focussed healthy eating and active living interventions with the potential to overcome these barriers - Healthy Habits (telephone-based) and Time2bHealthy (online) with promising results. Further research is now required to determine the effectiveness of these interventions in a real-world context. The Time for Healthy Habits study is a 3-arm partially randomised preference trial which aims to evaluate the effectiveness and cost-effectiveness of two theory-based programs to promote healthy eating and appropriate levels of movement behaviours (physical activity, sedentary behaviour and sleep) for parents of 2- to 6-year-old children (Healthy Habits Plus telephone-based program and Time2bHealthy online program), when compared to a comparison group receiving written materials. METHODS: Participants will be recruited across five Local Health Districts in New South Wales, Australia. The partially randomised preference design initially allows for participants to decide if they wish to be randomised or opt to select their preferred intervention and has been recommended for use to test effectiveness in a real-world setting. Both interventions incorporate multiple behaviour change techniques and support parents to improve their children's healthy eating, and movement behaviours (physical activity, sedentary behaviour and sleep) and run for 12 weeks, followed by a 3-month and 9-month post-baseline follow-up. Participants will also be asked to complete a process evaluation questionnaire at the completion of the intervention (3-months post-baseline). Outcomes include fruit and vegetable intake (primary outcome), non-core food intake, weight status, physical activity, sedentary behaviour, and sleep habits. DISCUSSION: To our knowledge, this is the first translational research trial evaluating the effectiveness and cost-effectiveness of a healthy eating and active living intervention in the 2- to 6-years age group. The results will build the evidence base in regard to translation of effective childhood obesity prevention interventions and inform the implementation and delivery of community based childhood obesity prevention programs. TRIAL REGISTRATION: UTN: U1111-1228-9748, ACTRN: 12619000396123p.

Key Performance Indicators for program scale-up and divergent practice styles: a study from NSW, Australia.

Implementing programs at scale has become a vital part of the government response to the continuing childhood obesity epidemic. We are studying the largest ever scale-up of school and child care obesity prevention programs in Australia. Health promotion teams support primary schools and early childhood services in their area to achieve a number of specified, evidence-based practices aimed at organizational changes to improve healthy eating and physical activity. Key performance indicators (KPIs) were devised to track program uptake across different areas-measuring both the proportion of schools and early childhood services reached and the proportion of practices achieved in each setting (i.e. the proportion of sites implementing programs as planned). Using a 'tight-loose-tight' model, all local health districts receive funding and are held accountable to reaching KPI implementation targets. However, local teams have independent discretion over how to best use funds to reach targets. Based on 12 months of ethnographic fieldwork and interviews across all districts, this study examines variations in the decision making and strategizing processes of the health promotion teams. We identified three distinct styles of practice: KPI-driven practice (strategic, focussed on targets); relationship-driven practice (focussed on long-term goals); and equity-driven practice (directing resources to sites most in need). In adapting to KPIs, teams make trade-offs and choices. Some teams struggled to balance a moral imperative to attend to equity issues, with a practical need to meet implementation targets. We discuss how models of program scale-up and tracking could possibly evolve to recognize this complexity.

mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy?

OBJECTIVE: Gout is the most common inflammatory arthritis worldwide, and patients experience a heavy burden of cardiovascular and metabolic diseases. The inflammation is caused by the deposition of monosodium urate (MSU) crystals in tissues, especially in the joints, triggering immune cells to mount an inflammatory reaction. Recently, it was shown that MSU crystals can induce mechanistic target of rapamycin (mTOR) signalling in monocytes encountering these crystals in vitro. The mTOR pathway is strongly implicated in cardiovascular and metabolic disease. We hypothesised that inhibiting this pathway in gout might be a novel avenue of treatment in these patients, targeting both inflammation and comorbidities. METHODS: We used a translational approach starting from ex vivo to in vitro and back to in vivo. RESULTS: We show that ex vivo immune cells from patients with gout exhibit higher expression of the mTOR pathway, which we can mimic in vitro by stimulating healthy immune cells (B lymphocytes, monocytes, T lymphocytes) with MSU crystals. Monocytes are the most prominent mTOR expressers. By using live imaging, we demonstrate that monocytes, on encountering MSU crystals, initiate cell death and release a wide array of proinflammatory cytokines. By inhibiting mTOR signalling with metformin or rapamycin, a reduction of cell death and release of inflammatory mediators was observed. Consistent with this, we show that patients with gout who are treated with the mTOR inhibitor metformin have a lower frequency of gout attacks. CONCLUSIONS: We propose mTOR inhibition as a novel therapeutic target of interest in gout treatment.

Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis.

OBJECTIVES: To provide estimates of the cumulative incidence of gout according to baseline serum urate. METHODS: Using individual participant data from four publicly available cohorts (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, and both the Original and Offspring cohorts of the Framingham Heart Study), the cumulative incidence of clinically evident gout was calculated according to baseline serum urate category. Cox proportional hazards modelling was used to evaluate the relation of baseline urate categories to risk of incident gout. RESULTS: This analysis included 18 889 participants who were gout-free at baseline, with mean (SD) 11.2 (4.2) years and 212 363 total patient-years of follow-up. The cumulative incidence at each time point varied according to baseline serum urate concentrations, with 15-year cumulative incidence (95% CI) ranging from 1.1% (0.9 to 1.4) for <6 mg/dL to 49% (31 to 67) for ≥10 mg/dL. Compared with baseline serum urate <6 mg/dL, the adjusted HR for baseline serum urate 6.0-6.9 mg/dL was 2.7, for 7.0-7.9 mg/dL was 6.6, for 8.0-8.9 mg/dL was 15, for 9.0-9.9 mg/dL was 30, and for ≥10 mg/dL was 64. CONCLUSIONS: Serum urate level is a strong non-linear concentration-dependent predictor of incident gout. Nonetheless, only about half of those with serum urate concentrations ≥10mg/dL develop clinically evident gout over 15 years, implying a role for prolonged hyperuricaemia and additional factors in the pathogenesis of gout.