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Refereed/Peer-reviewed Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Refereed/Peer-reviewed The identification of a somatic mutation associated with myeloid malignancy is of diagnostic importance in myeloproliferative neoplasms (MPNs). Individuals with no mutation detected in common screening tests for variants in JAK2, CALR, and MPL are described as ‘triple-negative’ and pose a diagnostic challenge if there is no other evidence of a clonal disorder. To identify potential drivers that might explain the clinical phenotype, we used an extended sequencing panel to characterise a cohort of 44 previously diagnosed triple-negative MPN patients for canonical mutations in JAK2, MPL and CALR at low variant allele frequency (found in 4/44 patients), less common variants in the JAK-STAT signalling pathway (12 patients), or other variants in recurrently mutated genes from myeloid malignancies (18 patients), including hotspot variants of potential clinical relevance in eight patients. In one patient with thrombocytosis we identified biallelic germline MPL variants. Neither MPL variant was activating in cell proliferation assays, and one of the variants was not expressed on the cell surface, yet co-expression of both variants led to thrombopoietin hypersensitivity. Our results highlight the clinical value of extended sequencing including germline variant analysis and illustrate the need for detailed functional assays to determine whether rare variants in JAK2 or MPL are pathogenic.

There is growing recognition that reproductive factors are associated with increased risk of future cardiovascular disease. Infertility has been less well studied, although emerging data support its association with increased risk of cardiovascular disease. Whether infertility is associated with future risk of heart failure (HF) is not known.This study sought to examine the development of HF and HF subtypes in women with and without history of infertility.We followed postmenopausal women from the Women's Health Initiative prospectively for the development of HF. Infertility was self-reported at study baseline. Multivariable cause-specific Cox models were used to evaluate the association of infertility with incident overall HF and HF subtypes (heart failure with preserved ejection fraction [HFpEF]: left ventricular ejection fraction of ≥50% vs heart failure with reduced ejection fraction [HFrEF]: left ventricular ejection fraction of 50%]).Among 38,528 postmenopausal women (mean age: 63 ± 7 years), 5,399 (14%) participants reported a history of infertility. Over a median follow-up of 15 years, 2,373 developed incident HF, including 807 with HFrEF and 1,133 with HFpEF. Infertility was independently associated with future risk of overall HF (HR: 1.16; 95% CI: 1.04-1.30; P = 0.006). Notably, when examining HF subtypes, infertility was associated with future risk of HFpEF (HR: 1.27; 95% CI: 1.09-1.48; P = 0.002) but not HFrEF (HR: 0.97; 95% CI: 0.80-1.18).Infertility was significantly associated with incident HF. This was driven by increased risk of HFpEF, but not HFrEF, and appeared independent of traditional cardiovascular risk factors and other infertility-related conditions. Future research should investigate mechanisms that underlie the link between infertility and HFpEF.

Summary Objectives To evaluate adherence after treatment switch from a multiple-tablet regimen (MTR) to a single-tablet regimen (STR) in a national cohort of human immunodeficiency virus (HIV) patients. Methods This retrospective observational cohort, with data spanning January 1, 2000 to March 1, 2019, consisted of HIV infected patients receiving treatment from the Veterans Affairs (VA) health system. Patients were required to have a complete MTR regimen after January 1, 2006 and before December 31, 2018 with at least 60 days of treatment. Medical and pharmacy data were analyzed from the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database. Statistical analyses examined differences in adherence when patients switched to a STR. Patients who switched to a STR were propensity score matched to those who never switched. Descriptive statistics and multivariable linear mixed effects models were utilized to evaluate differences in adherence between MTR and STR treatment in both the matched and unmatched samples. Results A total of 5021 patients met the study criteria, 3906 patients in the MTR only cohort and 1115 patients in the switch to STR cohort. The unmatched cohorts were similar in terms of sex, index year, drug/alcohol abuse, and viral load but differed in terms of race, Charlson comorbidity and mental health conditions. The one to one propensity score matched cohort included 2230 patients, 1115 patients in each cohort. Among patients that switched from a MTR to STR, adherence increased on average from 65.9% to 78.12%. We find overall adherence is higher with STRs than with MTR HIV regimens in both the matched and unmatched sample and adherence declines with time for both STR and MTR regimens. Conclusions Switching to a STR is associated with higher adherence compared to MTR among patients with HIV treated with antiretrovirals. However, adherence declines over time with both STR and MTR regimens.

Advance care planning (ACP) informs future medical decision-making, especially for patients with advanced age or serious illness. For clinicians to act on these preferences, or continue the ACP conversation as illness progresses, documentation of ACP discussions must be readily accessible within the electronic health record (EHR).Develop an intervention to improve accessible ACP documentation for hospitalized patients and assess its impact on viewing and documentation of ACP conversations within a specific EHR location.Adult patients age 75 or older or with serious illness discharged during a two-year period were included. The EHR's ACP Navigator was targeted as the intended location for documenting ACP-related activities. We implemented a hospital-wide, multipronged intervention that included increased ACP Navigator visibility and a process for workflow-congruent ACP documentation. Accessible ACP documentation was measured by documentation within the ACP Navigator and was analyzed by interrupted time-series analysis. ACP Navigator access was measured by user audit logs.After the intervention, 6703 of 16,117 (41.6%) patient encounters had accessible ACP documentation, compared to 3689 of 13,143 (28.1%) preintervention (P.001). In the intervention's first month, accessible ACP documentation increased 5.3% (P.001, CI 2.9%-7.6%), followed by a 1.3% monthly increase relative to the preintervention period (P.001, CI 1.0%-1.6%). ACP Navigator access for patients with ACP documentation increased in the intervention period (52.2% vs. 39.8%, P.001).An institution-wide intervention significantly increased accessible ACP documentation within a centralized location of the EHR. EHR usability changes improved rates of accessible ACP documentation and subsequent views of this documentation.

Background Evidence supports that PhD doctoral students experience conceptually difficult knowledge, or troublesome knowledge, during their studies. These areas of troublesome knowledge are often associated with threshold concepts, those ideas specific to a discipline that must be understood to advance ways of thinking and making knowledge in the discipline. Purpose To examine troublesome knowledge identified by a group of PhD nursing students during an introductory course and to consider threshold concepts related to that knowledge. Method Design: Case study research methodology. Sample: 18 entry-level PhD nursing students recruited with convenience sampling. Data collection: Content analysis was used to analyze data collected from student reflective learning journals. Journal data was triangulated with formative and summative faculty assessments of student learning. Results Three essential threshold concepts for entry-level PhD nursing students were identified: developing new ways of knowing, constructing researcher and writer identity, and positioning within the nursing research community. Analysis indicates that entry-level students found the threshold concept of constructing researcher and writer identity most troublesome. Conclusion A PhD introductory nursing course which includes metacognitive activities, scaffolding of assignments, and early positioning within the research community can assist students with mastery of threshold concepts for the research-focused doctorate.

Atrial fibrillation (AF) occurrence and maintenance is associated with progressive remodeling of electrophysiological (repolarization and conduction) and 3D structural (fibrosis, fiber orientations, and wall thickness) features of the human atria. Significant diversity in AF etiology leads to heterogeneous arrhythmogenic electrophysiological and structural substrates within the 3D structure of the human atria. Since current clinical methods have yet to fully resolve the patient-specific arrhythmogenic substrates, mechanism-based AF treatments remain underdeveloped. Here, we review current knowledge from in-vivo, ex-vivo, and in-vitro human heart studies, and discuss how these studies may provide new insights on the synergy of atrial electrophysiological and 3D structural features in AF maintenance. In-vitro studies on surgically acquired human atrial samples provide a great opportunity to study a wide spectrum of AF pathology, including functional changes in single-cell action potentials, ion channels, and gene/protein expression. However, limited size of the samples prevents evaluation of heterogeneous AF substrates and reentrant mechanisms. In contrast, coronary-perfused ex-vivo human hearts can be studied with state-of-the-art functional and structural technologies, such as high-resolution near-infrared optical mapping and contrast-enhanced MRI. These imaging modalities can resolve atrial arrhythmogenic substrates and their role in reentrant mechanisms maintaining AF and validate clinical approaches. Nonetheless, longitudinal studies are not feasible in explanted human hearts. As no approach is perfect, we suggest that combining the strengths of direct human atrial studies with the high fidelity approaches available in the laboratory and in realistic patient-specific computer models would elucidate deeper knowledge of AF mechanisms. We propose that a comprehensive translational pipeline from ex-vivo human heart studies to longitudinal clinically relevant AF animal studies and finally to clinical trials is necessary to identify patient-specific arrhythmogenic substrates and develop novel AF treatments.

The objective of this study was to evaluate the impact of a video-assisted thoracoscopic (VATS) approach on outcomes in patients who underwent sleeve lobectomy for non-small-cell lung cancer (NSCLC). Outcomes of patients with cT1-T3, N0-N2, M0 NSCLC who underwent sleeve lobectomy in the National Cancer Data Base (NCDB) from 2010-2015 were assessed using Kaplan-Meier, propensity score-matching, and Cox proportional hazards analyses. An "intent-to-treat" analysis was performed. In the NCDB, 210 sleeve lobectomy patients met inclusion criteria (VATS 44 [21%], thoracotomy 166 [79%]). Nine (20%) of the VATS cases were converted to open. Compared to an open approach, VATS was associated with no significant differences in lymph nodes examined (median 9.5 vs 9.0; p = 0.72), length of stay (median 6 days vs 6 days; p = 0.36), 30-day mortality (4.5% vs 1.8%; p = 0.28), and 90-day mortality (6.8% vs 4.8%; p = 0.70). There were no significant differences in 5-year survival between the VATS and open groups in both the entire cohort (VATS [85%] vs open [79%]; log-rank p = 0.91) and in a propensity score-matched analysis of 86 patients (log-rank p = 0.75). Furthermore, a VATS approach was also not associated with worse survival in multivariable analysis (HR = 0.64; 95% CI [0.23-1.78]; p = 0.39). In this national analysis, a VATS approach for sleeve lobectomy for NSCLC was not associated with worse short-term or long-term outcomes when compared to an open approach.

C2–C4 alcohols are advantageous blendstocks identified by many research groups, including the U.S. Department of Energy Co-Optima Initiative, towards enabling efficient, boosted Spark-Ignition (SI) engines. Their use in advanced engine applications requires a comprehensive understanding of their intermediate-temperature autoignition behavior. This work reports an experimental and modeling study covering their fundamental autoignition characteristics in a twin-piston rapid compression machine at pressures of 20 and 40 bar, intermediate temperatures from 750 to 980 K, and two fuel loading conditions representative of boosted SI engines. Direct comparison between these alcohols is made, where the order of reactivity is established across different thermodynamic and fuel loading conditions. Changes in preliminary exothermicity (or intermediate-temperature heat release) displayed in single-stage autoignition across different alcohols and conditions are also quantified. This provides insight into fuel-to-fuel differences, and how these could affect advanced combustion concepts such as spark-assisted compression ignition. Kinetic models are used to simulate the experiments, and reasonable agreement is obtained. The sensitivity analysis results demonstrate the importance of accurately capturing the autoignition kinetics, particularly H-abstraction reactions on the parent fuels by OH and HO2, and the branching ratio associated with these.

Alcohols, and particularly isoalcohols, are potentially advantageous blendstocks towards achieving efficient, low-carbon intensity internal combustion engines. Their use in advanced configurations, such as boosted spark-ignition or spark-assisted compression ignition, requires a comprehensive understanding of their blending effects on the low- and intermediate-temperature autoignition behavior of petroleum-derived gasoline. This work reports an experimental and modeling study of such autoignition characteristics quantified in a twin-piston rapid compression machine. Isopropanol and isobutanol are blended into a research-grade gasoline (FACE-F) at oxygenate blend levels of 0 to 30% vol/vol, with tests conducted at pressures of 20 and 40 bar, temperatures from 700 to 1000 K, and dilute stoichiometric fuel loadings. Changes to overall reactivity, including first-stage and main ignition times, and preliminary exothermicity are established, with comparisons made to previous measurements with ethanol-blended FACE-F gasoline. It is found that at low-temperature/NTC conditions (700–860 K) the isoalcohols suppress first-stage reactivity and associated heat release while main ignition times are extended. At NTC/intermediate-temperature (860–1000 K) conditions changes to fuel reactivity are less significant with isopropanol slightly suppressing reactivity and isobutanol promoting ignition. Detailed chemical kinetic modeling is used to interpret the experimental measurements. Overall trends of suppression or promotion in the blending behavior are reasonably captured by the model. Sensitivity and rate of production analyses indicate that at lower temperatures H-atom abstraction reactions from the surrogate fuel molecules (e.g., cyclopentane, isooctane) and the isoalcohols via ȮH are important leading to TC3H6OH and IC4H8OH–C radicals, for isopropanol and isobutanol respectively, which act as scavengers in the system. At higher temperatures, similar chemistries are dominant, but there is an increasing importance of abstraction by HO2. The kinetic modeling also indicates that the promoting effect of isobutanol at higher temperatures is due to the increased abstractions at the γ-sites, while at lower temperatures abstraction at the α-site leads to greater reactivity suppression.

The submitted manuscript has been created in part by UChicago Argonne, LLC, Operator of Argonne National Laboratory (“Argonne”). Argonne, a U.S. Department of Energy Office of Science laboratory, is operated under Contract No. DE-AC02-06CH11357. The U.S. Government retains for itself, and others acting on its behalf, a paid-up nonexclusive, irrevocable worldwide license in said article to reproduce, prepare derivative works, distribute copies to the public, and perform publicly and display publicly, by or on behalf of the Government. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan. http://energy.gov/downloads/doe-public-access-plan. This work is performed under the auspices of the Office of Energy Efficiency and Renewable Energy, Office of Vehicle Technology, U.S. Department of Energy, under contract number DE-AC02-06CH11357, as part of the Co-Optimization of Fuels & Engines (Co-Optima).

Propanol and butanol isomers have received significant research attention as promising fuel additives or neat biofuels. Robust chemical kinetic models are needed that can provide accurate and efficient predictions of combustion performance across a wide range of engine relevant conditions. This study seeks to improve the understanding of ignition and combustion behavior of pure C3-C4 linear and iso-alcohols, and their blends with gasoline at engine-relevant conditions. In this work, a kinetic model with improved thermochemistry and reaction kinetics was developed based on recent theoretical calculations of H-atom abstraction and peroxy radical reaction rates. Kinetic model validations are reported, and the current model reproduces the ignition delay times of the C3 and C4 alcohols well. Variations in reactivity over a wide range of temperatures and other operating conditions are also well predicted by the current model. Recent ignition delay time measurements from a rapid compression machine of neat iso-propanol and iso-butanol [Cheng et al., Proc. Combust Inst. (2020)] and blends with a research grade gasoline [Goldsborough et al., Proc. Combust Inst. (2020)] at elevated pressure (20–40 bar) and intermediate temperatures (780–950 K) were used to demonstrate the accuracy of the current kinetic model at conditions relevant to boosted spark-ignition engines. The effects of alcohol blending with gasoline on the autoignition behavior are discussed. The current model captures the suppression of reactivity in the low-temperature and negative-temperature-coefficient (NTC) region when either isopropanol and isobutanol are added to a research grade gasoline. Sensitivity and reaction flux analysis were performed to provide insights into the relevant fuel chemistry of the C3-C4 alcohols.

Even though delaying Social Security is equivalent to purchasing a very favorably priced annuity, almost everyone takes Social Security at or before their full retirement age. Many who take Social Security early simultaneously report additional annuity income. This combination can create an arbitrage opportunity where an individual could explicitly or implicitly sell their relatively high priced annuity, use the proceeds to delay Social Security and secure higher income for life. Several hundred thousand, perhaps millions, of households fail to take advantage of this arbitrage opportunity, with a resulting loss that ranges up to $250,000.

Ethanol is an attractive oxygenate increasingly used for blending with petroleum-derived gasoline yielding beneficial combustion and emissions behavior for a range of internal combustion engine schemes, including stoichiometric spark-ignition and low temperature combustion (LTC). As such, it is important to fundamentally understand the autoignition behavior of gasoline/ethanol blends. This work utilizes a rapid compression machine (RCM) and a homogeneous charge compression ignition (HCCI) engine to experimentally quantify changes in fuel reactivity, through ignition delay times and preliminary heat release, for blends of 0 to 30% vol./vol. into a full boiling range research gasoline (FACE-F). Diluted/stoichiometric and undiluted/fuel-lean conditions are explored covering a wide range of compressed temperatures and pressures relevant to conventional and advanced, gasoline combustion engines. Detailed chemical kinetic modeling is undertaken using a recently updated gasoline surrogate model in conjunction with a five-component surrogate to model the RCM experiments and provide chemical insight into the perturbative effects of ethanol on the autoignition process. The diluted/stoichiometric RCM measurements reveal that within the low-temperature regime ethanol retards first-stage and main ignition delay times, and suppresses both the rates and extents of low-temperature heat release (LTHR), while within the intermediate-temperature regime ethanol only causes slight changes. Good agreement of ignition delay time and preliminary heat release prediction is found between model and experimental results. Sensitivity and flux analyses further show that ethanol blending effects are dominated by the competition between the H-atom abstraction from ethanol and other fuel components by OH radical at low temperatures, and by HO2 radical at intermediate temperatures. These findings are consistent across both fuel loading conditions explored in this study. In addition, when HCCI engine experiments are mapped onto undiluted/lean RCM measurements under a constant combustion phasing scenario, good correspondence between the two apparatuses is observed for LTHR and start of high-temperature heat release. The current study highlights the importance of characterizing LTHR in predicting fuel behaviors in high-boost/low-temperature engines, and demonstrates that RCM experiments can provide an alternative, and more-efficient avenue for such characterization.

Ethanol oxidation was studied by measuring CO time-histories and ignition delay times behind reflected shockwaves at elevated pressures. In this study, experimental conditions included a temperature range of 960–1580 K, pressure range of 17.8–23.9 atm, and initial fuel concentrations of 6.54% and 0.25% with nitrogen and argon used as bath gasses, respectively. The equivalence ratio for high fuel loading was kept constant at 1.0, and for low fuel loading equivalence ratios were 1.0 and 0.5. For high fuel loading, early heat/energy release was observed in nearly all ignition delay time measurements, indicative of preignition; however, data collected are in good agreement with model predictions. These events are interpreted as a transition from mild to strong ignition. For the low fuel loading cases (ϕ = 1.0 and 0.5), no early heat/energy release was observed. Comparisons of measured CO concentration profiles with the predictions from kinetic mechanisms of Metcalfe et al. (2013), Mittal et al. (2014), and Zhang et al. (2018) were made assuming constant internal energy and volume for the test gas. Such comparisons in addition with performed sensitivity and pathway analyses for CO formation revealed lower temperature sensitivity to the bimolecular reaction of methyl and hydroperoxyl radicals given by CH3 + HO2 CH3O + OH, and H-atom abstraction by the hydroperoxyl radical at the alpha site on ethanol given by elementary reaction C2H5OH + HO2 sC2H4OH + H2O2. The current study provides important validation targets for ethanol chemical kinetic mechanisms and highlights the benefits of time-history measurements at various temperatures and pressures in a shock tube, which are scare in the literature.