An across breed, diet and tissue analysis reveals the transcription factor NR1H3 as a key mediator of residual feed intake in beef cattle.

BACKGROUND: Provision of feed is a major determinant of overall profitability in beef production systems, accounting for up to 75% of the variable costs. Thus, improving cattle feed efficiency, by way of determining the underlying genomic control and subsequently selecting for feed efficient cattle, provides a method through which feed input costs may be reduced. The objective of this study was to undertake gene co-expression network analysis using RNA-Sequence data generated from Longissimus dorsi and liver tissue samples collected from steers of two contrasting breeds (Charolais and Holstein-Friesian) divergent for residual feed intake (RFI), across two consecutive distinct dietary phases (zero-grazed grass and high-concentrate). Categories including differentially expressed genes (DEGs) based on the contrasts of RFI phenotype, breed and dietary source, as well as key transcription factors and proteins secreted in plasma were utilised as nodes of the gene co-expression network. RESULTS: Of the 2,929 DEGs within the network analysis, 1,604 were reported to have statistically significant correlations (≥ 0.80), resulting in a total of 43,876 significant connections between genes. Pathway analysis of clusters of co-expressed genes revealed enrichment of processes related to lipid metabolism (fatty acid biosynthesis, fatty acid ß-oxidation, cholesterol biosynthesis), immune function, (complement cascade, coagulation system, acute phase response signalling), and energy production (oxidative phosphorylation, mitochondrial L-carnitine shuttle pathway) based on genes related to RFI, breed and dietary source contrasts. CONCLUSIONS: Although similar biological processes were evident across the three factors examined, no one gene node was evident across RFI, breed and diet contrasts in both liver and muscle tissues. However within the liver tissue, the IRX4, NR1H3, HOXA13 and ZNF648 gene nodes, which all encode transcription factors displayed significant connections across the RFI, diet and breed comparisons, indicating a role for these transcription factors towards the RFI phenotype irrespective of diet and breed. Moreover, the NR1H3 gene encodes a protein secreted into plasma from the hepatocytes of the liver, highlighting the potential for this gene to be explored as a robust biomarker for the RFI trait in beef cattle.

Review: Early and late determinants of puberty in ruminants and the role of nutrition.

This article reviews the scientific literature on puberty with a focus on ruminants and draws inference, where appropriate, from recent findings in transgenic mouse models and human pathology. Early genetic determinants of puberty have been discovered in humans suffering from hypogonadotropic hypogonadism or central precocious puberty. Transgenic mouse models selected on the basis of the causative defective genes helped in discovering the cellular and molecular mechanisms involved. Most of the genes found are involved in the development of neuroendocrine networks during embryo development and early postnatal life. Notwithstanding that the development of neuroendocrine networks takes place early in puberty, a delay or acceleration in the development of Gonadotropin Releasing Hormone (GnRH) neurons has an impact on puberty onset inducing a delay or an advance, respectively. Among the genes discovered in humans and laboratory models, only a few of them displayed polymorphisms associated with advanced sexual maturity, but also marbling, growth traits and callipygian conformation. This could be related to the fact that rather than puberty onset, most research monitored sexual maturity. Sexual maturity occurs after puberty onset and involves factors regulating the maturation of gonads and in the expression of sexual behaviour. The association with growth and metabolic traits is not surprising since nutrition is the major environmental factor that will act on late genetic determinants of puberty onset. However, a recent hypothesis emerged suggesting that it is the postnatal activation of the GnRH neuronal network that induces the acceleration of growth and weight gain. Hence, nutritional factors need the activation of GnRH neurons first before acting on late genetic determinants. Moreover, nutritional factors can also affect the epigenetic landscape of parental gamete's genome with the consequence of specific methylation of genes involved in GnRH neuron development in the embryo. Season is another important regulator of puberty onset in seasonal small ruminants and appears to involve the same mechanisms that are involved in seasonal transition in adults. The social environment is also an underestimated factor affecting puberty onset in domestic ruminants, most research studies focused on olfactory cues, but the genetic basis has not heretofore been adequately tackled by the scientific community. Additionally, there is some evidence to suggest transgenerational effects exist, in that nutritional and social cues to which parents were exposed, could affect the epigenetic landscape of parental gametes resulting in the epigenetic regulation of early genetic determinants of puberty onset in their offspring.

Review: Role of early life nutrition in regulating sexual development in bulls.

The availability of high-quality semen from genetically elite bulls is essential to support continued genetic gain and the sustainability of cattle production worldwide. While reducing the age at which usable semen is available also reduces the generation interval, it is dependent on timely onset of puberty in young bulls. There is now good evidence that hastened sexual development in bulls is achieved through enhancing nutrition in early life. This review will cover the physiological and molecular-based response to prevailing diet in key organs that orchestrate the ontogeny of sexual development in the bull calf. Given the central importance of the interaction between metabolic status and neuronal function to the progression of sexual development, we will discuss how communication between metabolic organs, reproductive organs and the brain are mediated via molecular and physiological processes. The availability of high-throughput nucleic acid and protein sequencing technologies and innovative data analytics have allowed us to improve our understanding of molecular regulation of puberty and sexual development. Analysing data from a number of organs, simultaneously, allows for a better understanding of the underlying biology and biochemical interactions that are influencing sexual development. Specifically, we can determine how early life nutritional interventions augment changes in potential key molecules regulating sexual development. Ultimately, a greater understanding of the inherent regulation of postnatal sexual development in the bull calf and how strategically targeted nutritional management can advance the ontogeny of this process, will facilitate the timely availability of high-quality semen from genetically elite animals, thus supporting more economically and environmentally sustainable beef and dairy production systems.

ForWhen Australian perinatal and infant mental health navigation programme: evaluation protocol.

INTRODUCTION: Many parents and carers experience mental health challenges during pregnancy and early postpartum years, and there are cumulative shortfalls in the identification, follow-up, and treatment of those experiencing perinatal and infant mental health (PIMH) challenges. ForWhen is a new national navigation programme in Australia that aims to improve outcomes for families by supporting parents and carers to access PIMH services that best meet their needs. This paper presents the protocol of an evaluation of the ForWhen programme, to be conducted over the first 3 years of its implementation. The specific objectives of the evaluation include examining the characteristics of navigation service delivery, its implementation and clinical impact, and identifying potential moderators of change. METHODS AND ANALYSIS: Utilising a mixed-methods design, this evaluation will incorporate three phases that reflect the stages of the programme life-cycle: (1) programme description, (2) implementation evaluation and (3) outcomes evaluation. The evaluation will use a mix of quantitative and qualitative data including deidentified routinely collected service data, participant observations, semistructured interviews, surveys and questionnaires, and a resource audit. DISCUSSION: Evaluation findings will be used to inform the development of a refined clinical navigation model, identify barriers and facilitators to successful navigation programme implementation, examine the impact of the ForWhen programme on client clinical outcomes and health service utilisation, understand how the programme is/can be best embedded in the evolving service system, and assess the cost-effectiveness and sustainability of a national navigation programme in improving health outcomes for PIMH in Australia. ETHICS AND DISSEMINATION: This research was approved by South Western Sydney Local Health District Human Research Ethics Committee (2021/ETH11611). This study was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12622001443785). Results will be disseminated at conferences, in scientific journals, and in a final evaluation report.

Congenital heart disease: addressing the need for novel lower-risk percutaneous interventional strategies.

INTRODUCTION: With the advent of improved neonatal care, increasingly vulnerable higher-risk patients with complex congenital heart anomalies are presenting for intervention. This group of patients will always have a higher risk of an adverse event during a procedure but by recognizing this risk and with the introduction of risk scoring systems and thus the development of novel lower risk procedures, the rate of adverse events can be reduced. AREA COVERED: This article reviews risk scoring systems for congenital catheterization and demonstrates how they can be used to reduce the rate of adverse events. Then, novel low risk strategies are discussed for low-weight infants e.g. patent ductus arteriosus (PDA) stent insertion; premature infants e.g. PDA device closure; and transcatheter pulmonary valve replacement. Finally, how risk is assessed and managed within the inherent bias of an institution is discussed. EXPERT OPINION: There has been a remarkable improvement in the rate of adverse events in congenital cardiac interventions, but now, as the benchmark of mortality rate is switched to morbidity and quality of life, continued innovation into lower risk strategies and understanding the inherent bias when assessing risk will be key to continuing this improvement.

Evolution in the management of aorta to left ventricular tunnel in a national congenital cardiology centre.

An aorto-ventricular tunnel is a rare congenital cardiac defect, where a channel connects the lumen of the ascending aorta to the left or right ventricle. Four patients presented with an aorto-left ventricular tunnel over two decades at a median age of 8 months (range 0.1-10 months). Two patients (50%) had associated cardiac anomalies including hypoplastic left heart syndrome and left ventricular noncompaction/hypertrophic cardiomyopathy with aortic/pulmonary valve dysplasia in one patient each. Although traditionally surgical treatment has addressed this problem, management has evolved to transcatheter closure with excellent outcomes in appropriately selected patients at our national centre.

Incidence, Predictors, and Outcomes of Cardiac Perforation During Pediatric Cardiac Catheterization: a Retrospective Observational Study from the Congenital Cardiac Interventional Study Consortium (CCISC).

INTRODUCTION: Cardiac perforation is a rare life-threatening complication of cardiac catheterization. There is very little published literature detailing risk factors for cardiac perforation and outcomes from this complication in children. MATERIALS AND METHODS: This was a retrospective study analyzing the cardiac catheterization case registry of the Congenital Cardiovascular Interventional Study Consortium. Children aged < 18 years were included during the study period of 9 years (January 2009-December 2017). The primary outcome measures were incidence of cardiac perforation, risk factors for and outcomes of patients who experience cardiac perforation during cardiac catheterization. RESULTS: Cardiac perforation occurred in 50 patients from a total of 36,986 (0.14%). Cardiac perforation was more likely to occur in younger, smaller patients undergoing urgent/emergent and interventional procedures (p < 0.01). Cardiac peroration risk was significantly different across diagnostic and procedure categories (p < 0.01). Higher CRISP score (Area Under Curve [AUC] = 0.87), lower age, and procedure category (radiofrequency perforation of pulmonary valve, AUC = 0.84) were independent predictors of cardiac perforation. Cardiac perforation was associated with a significantly higher rate of mortality (14%), further emergency procedure (42%), ECMO (14%), and cardiac arrest (6%), p < 0.01. CONCLUSIONS: Cardiac perforation during cardiac catheterization is a life-threatening complication with a range of associated secondary complications. Higher CRISP score, lower age, and radiofrequency perforation of pulmonary valve are independent predictors.

Identification of sperm proteins as biomarkers of field fertility in Holstein-Friesian bulls used for artificial insemination.

Despite passing stringent quality control, bulls used in artificial insemination can vary significantly in their fertility, emphasizing the need for reliable markers of sperm quality. This study aimed to identify sperm proteins acting as biomarkers of fertility in 2 different populations of dairy bulls classified based on their field fertility. Semen was collected and cryopreserved from: 54 Holstein bulls located in Ireland, classified according to fertility indexes as low fertility (LF, n = 23), medium fertility (n = 14), or high fertility (HF, n = 17); and 18 Holstein bulls located in Denmark, classified as LF (n = 8) or HF (n = 10). The proteome was measured through liquid chromatography-mass spectrometry and data were analyzed with the R software. Differentially abundant proteins between HF and LF bulls and biomarker proteins were determined through a modified t-test and random forest, respectively, selecting 301 differentially abundant proteins and 34 biomarker proteins. The predictive ability of the 34 biomarkers was evaluated employing support vector machine as the classifier, using their abundance levels in the Irish bulls to train the model and in the Danish bulls for validation. The prediction accuracy was 94.4%, with only one HF bull misclassified, corresponding to the lowest fertility index bull in the HF group. The biomarkers more abundant in sperm of HF bulls enriched axoneme assembly and sperm motility (false discovery rate <0.05), according to functional analysis. In conclusion, a robust model coupled with the application of appropriate bioinformatic tools allowed the identification of functionally relevant sperm proteins predictive of the fertility of Holstein bulls used in artificial insemination.

Influence of sire fertility status on conceptus-induced transcriptomic response of the bovine endometrium.

The aim was to examine the effect of sire fertility status on conceptus-induced changes in the bovine endometrial transcriptome. To generate elongated conceptuses, Day 7 blastocysts produced in vitro using frozen-thawed sperm from Holstein Friesian bulls (3 High fertility, HF and 3 Low fertility, LF) were transferred in groups of 5-10 into synchronized heifers (n = 7 heifers per bull) and recovered following slaughter on Day 15. Day 15 endometrial explants recovered from the uterine horn ipsilateral to the corpus luteum were recovered from synchronized cyclic heifers (n = 4). Explants from each heifer were co-cultured for 6 h in RPMI medium alone (Control) or with 100 ng/ml ovine recombinant interferon tau (IFNT) or with a single conceptus from each HF or LF bull. After 6 h, explants were snap frozen and stored at -80°C. Extracted mRNA was subjected to RNA-seq and the resulting data were analyzed with R software. The numbers of differentially expressed genes (DEG; FDR<0.05) were: HF vs. Control: 956; LF vs. Control: 1021; IFNT vs. Control: 1301; HF vs. LF: 2. Unsurprisingly, the majority of DEG (658) were common to all comparisons and were related to IFNT-induced changes in the endometrium. Prior to applying the adjusted p-value, there were 700 DEG between HF and LF, with 191 and 509 genes more expressed in HF or LF, respectively (p < 0.05). Overrepresentation analysis of KEGG pathways (FDR<0.05), revealed that DEG with higher expression in LF were involved in cell cycle and proteolysis, while those upregulated DEG by HF conceptuses were strongly associated with immune process pathways, such as TNF, NF-kappa B, cytokine-cytokine receptor interaction, and TLR signaling. These pathways were also enriched by DEG upregulated by IFNT compared to the Control. Furthermore, only the HF, and not the LF group, affected the expression of most genes in these pathways (p < 0.05) according to a negative binomial regression model. Finally, a weighted gene co-expression network analysis revealed two clusters of co-expressed genes associated with the HF conceptuses (p < 0.05), which were also enriched for the aforementioned pathways. In conclusion, HF conceptuses, similar to IFNT treatment, stimulated multiple pathways involved in immune response, which were apparently not affected by LF conceptuses.

Enhancing early life nutrition alters the hepatic transcriptome of Angus × Holstein-Friesian heifer calves.

Early life nutrition has a major influence on subsequent lifetime performance in cattle. The aim of this experiment was to investigate the effect of plane of nutrition from 3 to 21 weeks of age on the liver transcriptome. Holstein-Friesian × Angus heifer calves with a mean (±SD) age and BW of 19 (±5) days and 51.2 (±7.8) kg, respectively, were assigned to either a high-energy diet to support a mean average daily gain (ADG) of 1.2 kg/day (HI; n = 15) or a moderate diet (MOD; n = 15) to support a mean ADG of 0.5 kg/day. At 145 ±â€¯3 days of age, all calves were euthanised, liver tissue samples collected and flash-frozen in liquid nitrogen. Following RNA sequence analysis, the total number of differentially expressed genes (DEGs) (at false discovery rate (FDR) > 0.05) was 537; 308 upregulated and 229 downregulated in HI compared to MOD. The number of DEGs mapped to IPA (at FDR > 0.05) was 460; 264 upregulated and 196 downregulated. There was greater expression of genes associated with cellular development and metabolism in heifers on the HI compared to the MOD diet. The genes (fold change) of the somatotrophic axis; IGF1 (3.7), IGFALS (2.6) and GHR (1.5) were upregulated in the HI compared to MOD diet. The cytokine receptor genes, IL17RB (1.7) and IL20RA (3.3), were upregulated in the HI heifers, which were detected in a network interacting with metabolically regulated genes. The potential enhanced cell-to-cell communication evident from DEGs would increase the calves' ability to combat health challenges. The findings of this study indicate that enhancing the early life plane of nutrition in heifer calves results in the upregulation of genes that are associated with increased metabolic activity and thus metabolic capacity. Moreover, the interaction between metabolic and immune communication genes indicates that enhanced nutrition has the potential to improve the immune response in the liver which will play a central role in ensuring optimal lifetime performance.

The effect of natural and induced calving of beef heifers on stress-related gene expression and maternal health and immunity.

The peri-partum processes can exert stress on a cow on many levels. There is little evidence about acute stress around the calving event and subsequent potential effects for the cows' immunological status or subsequent reproductive health. To investigate this, 55 crossbred recipient beef heifers carrying purebred Simmental embryos were assigned to one of three groups on day 285 of gestation: (i) control (no parturition induction treatment; n = 19); (ii) induction of parturition with corticosteroid (n = 20) and (iii) induction of parturition with corticosteroid plus prostaglandin (n = 16). Interval from induction of parturition to calving and calving ease was recorded. Reproductive tract examinations were conducted on Day 21 (D21) and Day 42, and a sample was obtained for the determination of uterine cytology on D21. Blood samples were taken from the dams two weeks before parturition, one day after parturition (D1) and two weeks after parturition (D14) for gene expression and cortisol and calcium concentration determination. Calves were weighed at birth and subsequently every week until they were 10 weeks of age. A colostrum sample was taken immediately after calving and stored for subsequent Immunoglobin G (IgG) concentration analysis. Data were analysed using ANOVA with posthoc Tukey, Spearman correlation and stepwise backwards linear regression using SAS. Quantitative reverse transcription PCR was performed on the following immune genes: Interleukins IL1a and b, IL2, IL4, IL8, Tumour Necrosis Factor Alpha, Interferon-gamma, Lymphotoxin, Toll-Like Receptor, Nuclear factor of kappa light polypeptide gene enhancer in B cells 1 and 2, glucocorticoid receptor alpha, as well as the neutrophil genes that regulate inflammation: Fas, L-selectin, MMP-9 and BPI. The results show that compared with non-induced contemporaries, induction has no negative effect on dystocia or subsequent calf weight gain but can have a positive effect on colostral IgG concentration. Blood calcium concentrations on both D1 and D14 postcalving are associated with subsequent uterine health. Parturition events were reflected in temporal changes in the expression of the cytokines IFNγ, TNFα, IL1b, IL4, IL8 and Haptoglobin in the dams' blood, all of which are associated with the immune competence of the cow during this period. The conclusion is that induction of calving can have a positive effect on colostral IgG concentration. Calcium concentrations postcalving are associated with subsequent reproductive tract health. Events associated with the peri- and postpartum period are all reflected in temporal changes in immune function-related cytokines.

A Dynamic Approach to Economic Priority Setting to Invest in Youth Mental Health and Guide Local Implementation: Economic Protocol for Eight System Dynamics Policy Models.

Background: Mental illness costs the world economy over US2.5 Bn each year, including premature mortality, morbidity, and productivity losses. Multisector approaches are required to address the systemic drivers of mental health and ensure adequate service provision. There is an important role for economics to support priority setting, identify best value investments and inform optimal implementation. Mental health can be defined as a complex dynamic system where decision makers are challenged to prospectively manage the system over time. This protocol describes the approach to equip eight system dynamics (SD) models across Australia to support priority setting and guide portfolio investment decisions, tailored to local implementation context. Methods: As part of a multidisciplinary team, three interlinked protocols are developed; (i) the participatory process to codesign the models with local stakeholders and identify interventions for implementation, (ii) the technical protocol to develop the SD models to simulate the dynamics of the local population, drivers of mental health, the service system and clinical outcomes, and (iii) the economic protocol to detail how the SD models will be equipped to undertake a suite of economic analysis, incorporating health and societal perspectives. Models will estimate the cost of mental illness, inclusive of service costs (health and other sectors, where necessary), quality-adjusted life years (QALYs) lost, productivity costs and carer costs. To assess the value of investing (disinvesting) in interventions, economic analysis will include return-on-investment, cost-utility, cost benefit, and budget impact to inform affordability. Economic metrics are expected to be dynamic, conditional upon changing population demographics, service system capacities and the mix of interventions when synergetic or antagonistic interactions. To support priority setting, a portfolio approach will identify best value combinations of interventions, relative to a defined budget(s). User friendly dashboards will guide decision makers to use the SD models to inform resource allocation and generate business cases for funding. Discussion: Equipping SD models to undertake economic analysis is intended to support local priority setting and help optimise implementation regarding the best value mix of investments, timing and scale. The objectives are to improve allocative efficiency, increase mental health and economic productivity.

Gene co-expression networks contributing to reproductive development in Holstein-Friesian bull calves.

Enhanced early life nutrition stimulates the functionality of the hypothalamic-pituitary-testicular (HPT) biochemical signalling axis, resulting in precocious reproductive development in bull calves. Additionally, there is evidence that peptides and hormones produced within adipose tissue depots are also central in mediating the effect of metabolic status with reproductive development. The objective of this study was to undertake gene co-expression analyses on transcriptional data of the HPT and adipose tissues derived from bull calves fed contrasting planes of nutrition up to 18 weeks of life. The relationship between networks of co-expressed genes in each tissue dataset with calf phenotypic data was also assessed using a Pearson correlation analysis. Phenotypic data were related to metabolic status (systemic concentrations of insulin, leptin, adiponectin and IGF-1) reproductive development (systemic concentrations of testosterone, FSH and LH) and markers of testicular development (seminiferous tubule diameter, seminiferous tubule lumen score, spermatogenic cells and Sertoli cells). In the hypothalamus, gene co-expression networks involved in biochemical signalling processes related to gonadotropin-releasing hormone (GnRH) secretion were positively associated (P < 0.05) with systemic concentrations of IGF-1 and insulin. Similarly, a network of gene transcripts involved in GnRH signalling in the anterior pituitary was positively associated (P < 0.05) with systemic concentrations of LH. In the testes and adipose tissues, networks of co-expressed genes implicated in cholesterol and fatty acid biosynthesis were positively associated (P < 0.05) with lumen score, Sertoli cell number, and stage of spermatogenesis. Additionally, gene co-expression networks significantly associated (P < 0.05) with both metabolic and reproductive trait data were found to be enriched (P < 0.05) for biological pathways related to energy production, cellular growth and proliferation, GnRH signalling and cholesterol biosynthesis across multiple tissues examined. Results from this study highlight networks of co-expressed genes directly associated with markers of enhanced metabolic status and subsequent earlier reproductive development. Furthermore, genes involved in biological processes mentioned above may hold potential for informing genomic selection breeding programmes for the selection of calves capable of displaying earlier reproductive development as a consequence of enhanced dietary intake.

From Spreadsheets to Script: Experiences From Converting a Scottish Cardiovascular Disease Policy Model into R.

Given the advantages in transparency, reproducibility, adaptability and computational efficiency in R, there is a growing interest in converting existing spreadsheet-based models into an R script for model re-use and upskilling training among health economic modellers. The objective of this exercise was to convert the Scottish Cardiovascular Disease (CVD) Policy Model from Excel to R and discuss the lessons learnt throughout this process. The CVD model is a competing risk state transition cohort model. Four health economists, with varied experience of R, attempted to replicate an identical model structure in R based on the model in Excel and reproduce the intermediate and final results. Replications varied in their use of specialist health economics packages in addition to standard data management packages. Two versions of the CVD model were created in R along with a Shiny app. Version 1 was developed without health economics specialist packages and produced identical results to the Excel version. Version 2 used the heemod package and did not achieve the same results, possibly due to the non-standard elements of the model and limited time to adapt the functions. The R model requires less than half the computational time than the Excel model. Conversion of the spreadsheet models to script models is feasible for health economists. A step-by-step guide for the conversion process is provided and modellers' experience is discussed. Coding without specialist packages allows full flexibility, while specialist packages may add convenience if the model structure is suitable. Whichever approach is taken, transparency and replicability remain the key criteria in model programming. Model conversions must maintain standards in these areas regardless of the choice of software.

Use of the Electronic Health Record to Optimize Antimicrobial Prescribing.

PURPOSE: This review summarizes how interventions in the electronic health record (EHR) can optimize antimicrobial stewardship across the continuum of antimicrobial decision making, from diagnosis of infection to discontinuation of therapy. In addition, opportunities to optimize provider communication and patient education are identified. METHODS: A narrative review was conducted to identify how interventions in the EHR can influence antimicrobial prescribing behavior. Examples from pediatrics were specifically identified. Interventions were then categorized into high-impact/low-effort, high-impact/high-effort, and low-impact/low-effort groupings based on historical experience. FINDINGS: EHR-based interventions can be used for stratifying patients at risk for infection and are useful in identifying patients with new-onset infections. Additional tools include automatically updated antibiograms tailored to specific patient populations, timely authorization of restricted antimicrobials, and more accurate allergy labeling. Medical errors can be reduced and communication between providers can be improved by standardized data fields. Clinical decision support tools can guide appropriate selection of therapy, and visual prompts can reduce unnecessarily prolonged therapy. Benchmarking of antimicrobial use, tailored patient education, and improved communication during transitions of care are enhanced through EHR-based interventions. IMPLICATIONS: Prescribing behavior can be modified through a range of interventions in the EHR, including tailored education, alerts, prompts, and restrictions on provider behavior. Further studies are needed to compare the effectiveness of various strategies.

Gazing through time and beyond the health sector: Insights from a system dynamics model of cardiovascular disease in Australia.

OBJECTIVE: To construct a whole-of-system model to inform strategies that reduce the burden of cardiovascular disease (CVD) in Australia. METHODS: A system dynamics model was developed with a multidisciplinary modelling consortium. The model population comprised Australians aged 40 years and over, and the scope encompassed acute and chronic CVD as well as primary and secondary prevention. Health outcomes were CVD-related deaths and hospitalisations, and economic outcomes were the net benefit from both the healthcare system and societal perspectives. The eight strategies broadly included creating social and physical environments supportive of a healthy lifestyle, increasing the use of preventive treatments, and improving systems response to acute CVD events. The effects of strategies were estimated as relative differences to the business-as-usual between 2019-2039. Probabilistic sensitivity analysis produced uncertainty intervals of interquartile ranges (IQR). FINDINGS: The greatest reduction in CVD-related deaths was seen in strategies that improve systems response to acute CVD events (8.9%, IQR: 7.7-10.2%), yet they resulted in an increase in CVD-related hospitalisations due to future recurrent admissions (1.6%, IQR: 0.1-2.3%). This flow-on effect highlighted the importance of addressing underlying CVD risks. On the other hand, strategies targeting the broad environment that supports a healthy lifestyle were effective in reducing both hospitalisations (7.1%; IQR: 5.0-9.5%) and deaths (8.1% reduction; IQR: 7.1-8.9%). They also produced an economic net benefit of AU$43.3 billion (IQR: 37.7-48.7) using a societal perspective, largely driven by productivity gains. Overall, strategic planning to reduce the burden of CVD should consider the varying effects of strategies over time and beyond the health sector.

Pediatric Head and Neck Tumors Associated with Li-Fraumeni Syndrome.

INTRODUCTION: Cancer predisposition syndromes are germline pathogenic variants in genes that greatly raise the risk of developing neoplastic diseases. One of the most well-known is Li-Fraumeni syndrome (LFS), which is due to pathogenic variants in the TP53 gene. Children with LFS have higher risks for multiple malignancies before adulthood, often with rare and aggressive subtypes. OBJECTIVE: To examine head and neck manifestations of LFS in children treated at a tertiary children's hospital over a 20-year period. METHODS: A retrospective review of LFS children with neoplastic disease presenting in traditional Otolaryngologic head and neck subsites from 2000 to 2019, with patient charts reviewed for relevant clinical, imaging, and operative data. RESULTS: Of the 40 LFS patients initially identified, 27 neoplastic tumors were identified in 20 children within this cohort (20 primary, 7 second primary). Head and neck subsites aside from the brain or orbit were involved in 22% (6/27) of these tumors, representing 20% (4/20) of primary tumors and 29% (2/7) of second primary tumors. Both second primaries within the head and neck were within the radiation fields of the first primary tumor. The mean ages at primary and second primary diagnosis were 4.6 years (SD 3.5) and 12 years (SD 1.4), respectively. The male/female ratio was 1:6 among all patients with head and neck tumors. All 6 head and neck tumors were sarcomas. Rhabdomyosarcoma (N = 3, 50%) was the most common pathology, and the other 3 demonstrated rare tumor pathological subtypes (synovial cell sarcoma, pleomorphic myxoid liposarcoma, mandibular osteosarcoma). The neck was the most common subsite (75%) within this group for primary tumor presentation. CONCLUSION: This study identifies a high potential for head and neck involvement in children with LFS, which has not been previously described in the literature. Otolaryngological care should be included in a multidisciplinary care team surveilling these patients.

Study protocol for the Healthier Wealthier Families (HWF) pilot randomised controlled trial: testing the feasibility of delivering financial counselling to families with young children who are identified as experiencing financial hardship by community-based nurses.

INTRODUCTION: Poverty and deprivation can harm children's future health, learning, economic productivity and societal participation. The Australian Healthier Wealthier Families project seeks to reduce the childhood inequities caused by poverty and deprivation by creating a systematic referral pathway between two free, community-based services: universal, well-child nursing services, which provide health and development support to families with children from birth to school entry, and financial counselling. By adapting the successful Scottish 'Healthier Wealthier Children' model, the objectives of this Australian pilot are to test the (1) feasibility of systematising the referral pathway, and (2) short-term impacts on household finances, caregiver health, parenting efficacy and financial service use. METHODS AND ANALYSIS: This pilot randomised controlled trial will run in three sites across two Australian states (Victoria and New South Wales), recruiting a total of 180 participants. Nurses identify eligible caregivers with a 6-item, study-designed screening survey for financial hardship. Caregivers who report one or more risk factors and consent are randomised. The intervention is financial counselling. The comparator is usual care plus information from a government money advice website. Feasibility will be evaluated using the number/proportion of caregivers who complete screening, consent and research measures, and access financial counselling. Though powered to assess feasibility, impacts will be measured 6 months post-enrolment with qualitative interviews and questionnaires about caregiver-reported income, loans and costs (adapted from national surveys, for example, the Household, Income and Labour Dynamics in Australia Survey); health (General Health Questionnaire 1, EuroQol five-dimensional questionnaire, Depression, Anxiety, Stress Scale short-form); efficacy (from the Longitudinal Study of Australian Children); and financial service use (study-designed) compared between arms. ETHICS AND DISSEMINATION: Ethics committees of the Royal Children's Hospital (HREC/57372/RCHM-2019) and South West Sydney Local Health District (2019/ETH13455) have approved the study. Participants and stakeholders will receive results through regular communication channels comprising meetings, presentations and publications. TRIAL REGISTRATION NUMBER: ACTRN12620000154909; prospectively registered. Pre-results.