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The National Clinical Cohort Collaborative (N3C) uses privacy-preserving record linkage (PPRL) to formulate longitudinal patient histories and for de-duplication across disparate data including electronic health records, administrative claims, and mortality data. The N3C employs a linkage honest broker implementation model which separates the entity holding de-identified PPRL tokens, from the entity holding the substantive data payloads. As a result of this data governance structure, linkage quality assessments are necessarily distributed into 2 distinct processes: 1) Linkage Honest Broker receipt and processing of linkages, 2) Data Aggregation entity assembling data based on received linkage crosswalks. Data is released on a weekly basis. This presentation will focus on Step 2 for the Mortality data linkages where the downstream data linkage pipelines must assess linkage quality across several dimensions of quality, focused on plausibility. There are 4 types of mortality data spanning the electronic health record, government Social Security Administration death master files, third-party obituary data, and administrative claims. Each of these sources has different levels of authoritativeness and data latency, compounding the challenges of reconciling fact of death including accurate death reporting dates. To address these challenges, we implemented an automated linkage quality pipeline which generates reports that assess linkage plausibility across the various data types, classifying concordance and discordance between data sources including age, dates of death, surfacing plausible and non-plausible activities post-death. Sharing our real-world implementation will aid conference attendees in understanding how to plan for such activities when considering specific implementation models for privacy-preserving linkages.

Data centralization is increasingly non-viable in the changing landscape of data privacy and data governance. New models of data sharing are needed, in particular when privacy-preserving record linkages (PPRL) are being used to connect data within restricted data enclaves and public open enclaves. We share a privacy-preserving data-sharing infrastructure that employs a linkage honest broker implementation of PPRL connecting structured electronic health record data between the National Center for Advancing Translational Science (NCATS) National Clinical Cohort Collaborative (N3C), a restricted data enclave, with the National Cancer Institute (NCI) Cancer Imaging Archive (TCIA), a public open enclave. In particular we will address: • Data governance models needed when linking data from restricted vs. public enclaves • Specific privacy-preserving consideration when linking to imaging data which contain specific structured data and imaging considerations • Privacy-preserving data aggregation when combining multi-modal data from restricted data enclaves with publicly discoverable imaging data

Transepithelial electrical resistance (TEER) is a widely used technique for quantifying the permeability of epithelial and endothelial cell layers. However, traditional methods of measuring TEER are limited to single timepoint measurements and can subject cells to an altered environment during the measurement. Here, we assessed the validity of TEER measurements by the ECIS TEER96 device, which is designed to take continuous TEER measurements of a cell culture system in a standard laboratory incubator. We found that the instrument accurately measures TEER across TEER values ranging from 10 to 2050 Ω*cm2 and is more accurate than the manual epithelial voltohmmeter electrode at high TEER values. Furthermore, the high-resolution measurements provided by the device allowed for a unique insight into the mechanisms and kinetics of cells in vitro. To demonstrate the continuous measurement capability of the device, we tracked the formation of an MDCKI cell monolayer until TEER plateaued. Furthermore, we treated Caco-2 monolayers with different concentrations of DMSO and the antimicrobial and surfactant compound benzethonium chloride to measure disruptions to barrier integrity. Treatment of both compounds resulted in concentration-dependent loss of barrier integrity. Our results suggest that the ECIS TEER96 device is a reliable and convenient option for measuring TEER in cell cultures and can provide valuable insights into the behavior of cells in vitro. This technology will be especially useful for increasing throughput of drug permeability assays, inflammation studies, and gaining better understanding of disease states in a cell culture system.

Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction.

Abstract Background Multi-institution electronic health records (EHR) are a rich source of real world data (RWD) for generating real world evidence (RWE) regarding the utilization, benefits and harms of medical interventions. They provide access to clinical data from large pooled patient populations in addition to laboratory measurements unavailable in insurance claims-based data. However, secondary use of these data for research requires specialized knowledge and careful evaluation of data quality and completeness. We discuss data quality assessments undertaken during the conduct of prep-to-research, focusing on the investigation of treatment safety and effectiveness. Methods Using the National COVID Cohort Collaborative (N3C) enclave, we defined a patient population using criteria typical in non-interventional inpatient drug effectiveness studies. We present the challenges encountered when constructing this dataset, beginning with an examination of data quality across data partners. We then discuss the methods and best practices used to operationalize several important study elements: exposure to treatment, baseline health comorbidities, and key outcomes of interest. Results We share our experiences and lessons learned when working with heterogeneous EHR data from over 65 healthcare institutions and 4 common data models. We discuss six key areas of data variability and quality. (1) The specific EHR data elements captured from a site can vary depending on source data model and practice. (2) Data missingness remains a significant issue. (3) Drug exposures can be recorded at different levels and may not contain route of administration or dosage information. (4) Reconstruction of continuous drug exposure intervals may not always be possible. (5) EHR discontinuity is a major concern for capturing history of prior treatment and comorbidities. Lastly, (6) access to EHR data alone limits the potential outcomes which can be used in studies. Conclusions The creation of large scale centralized multi-site EHR databases such as N3C enables a wide range of research aimed at better understanding treatments and health impacts of many conditions including COVID-19. As with all observational research, it is important that research teams engage with appropriate domain experts to understand the data in order to define research questions that are both clinically important and feasible to address using these real world data.

Effective small molecule therapies to combat the SARS-CoV-2 infection are still lacking as the COVID-19 pandemic continues globally. High throughput screening assays are needed for lead discovery and optimization of small molecule SARS-CoV-2 inhibitors. In this work, we have applied viral pseudotyping to establish a cell-based SARS-CoV-2 entry assay. Here, the pseudotyped particles (PP) contain SARS-CoV-2 spike in a membrane enveloping both the murine leukemia virus (MLV) gag-pol polyprotein and luciferase reporter RNA. Upon addition of PP to HEK293-ACE2 cells, the SARS-CoV-2 spike protein binds to the ACE2 receptor on the cell surface, resulting in priming by host proteases to trigger endocytosis of these particles, and membrane fusion between the particle envelope and the cell membrane. The internalized luciferase reporter gene is then expressed in cells, resulting in a luminescent readout as a surrogate for spike-mediated entry into cells. This SARS-CoV-2 PP entry assay can be executed in a biosafety level 2 containment lab for high throughput screening. From a collection of 5,158 approved drugs and drug candidates, our screening efforts identified 7 active compounds that inhibited the SARS-CoV-2-S PP entry. Of these seven, six compounds were active against live replicating SARS-CoV-2 virus in a cytopathic effect assay. Our results demonstrated the utility of this assay in the discovery and development of SARS-CoV-2 entry inhibitors as well as the mechanistic study of anti-SARS-CoV-2 compounds. Additionally, particles pseudotyped with spike proteins from SARS-CoV-2 B.1.1.7 and B.1.351 variants were prepared and used to evaluate the therapeutic effects of viral entry inhibitors.

Wellbeing has firmly established itself within contemporary practice, politics and policy. Indeed, the cultural, commercial, and terrestrial landscape of the concept is staggering and manifests within popular discourse and across global organisations and institutions, national governments, workplaces, and consumer lifestyle products and services. Notably, the field of sport, exercise, and physical activity has been identified by the World Health Organisation (WHO), the United Nations, and the OECD as a key sector with the potential to contribute to people's wellbeing. This should not be surprising given that there is a large body of literature espousing the benefits of regular physical activity (in myriad forms) as part of a healthy lifestyle. However, there are increasing concerns that wellbeing's global ubiquity may be leading to a range of unintended consequences and/or unscrupulous practices within both international organisations and nation-states. This largely conceptual essay focuses on the concept and process of wellbeing washing by (1) tracing the historical roots and evolution of wellbeing; (2) exploring its reconceptualization within the framework of neoliberalism; (3) offering a preliminary outline of the concept of wellbeing washing; and (4) briefly describing how wellbeing washing is manifesting within the context of sport in Aotearoa/New Zealand. Overall, this analysis explores wellbeing as a contested terrain of interests marked by a range of complexities and contradictions. [ABSTRACT FROM AUTHOR]

Athlete maltreatment in organized sport has attracted considerable attention from governing bodies, stakeholders and the general public. Despite numerous studies and policy proposals from various countries, the problem remains unresolved due to its inherent complexity. Drawing upon the concept of 'a wicked problem' widely utilized in policy analysis, this study first identifies the wicked features of maltreatment, focusing on: (1) the difficulty of establishing a definition of maltreatment; (2) the challenges of identifying its causes; and (3) the impediments to identifying solutions in a context of embedded stakeholders and unintended consequences. To provide further analysis, we compare athlete maltreatment with other issues in sport such as doping and match-fixing, to suggest that lessons can be drawn from other wicked problems in the same contested terrain. Overall, given the complex interplay between maltreatment and the maintenance/legitimization of sport systems, this paper calls for continuing attention and evaluation of existing research/policies and advocates for a more multidimensional view that acknowledges maltreatment as a wicked problem. [ABSTRACT FROM AUTHOR]

Understanding the infection parameters and host responses against SARS-CoV-2 require data from large cohorts using standardized methods. Here, the authors optimize a serum ELISA protocol that has minimal cross-reactivity and flexible sample collection workflow in an attempt to standardize data generation and help inform on COVID-19 pandemic and immunity.

On 17th May 2020, the New Zealand Government announced a $265 million investment to support sport and recreation amid the country's first COVID-19 lockdown. The Sport NZ Recovery Package (RP) focused on three investment outcomes for the sector: 'Reset and Rebuild', 'Strengthen and Adapt', and [become] 'Different and Better' (Sport NZ 2020a). This study examines the overall design features and funding initiatives of the RP as a novel policy response to 'turbulence'. Of particular interest is whether this instrument was 'system changing' (McDonnell and Elmore 1987) and how it might enable future transformation or stability in the sports sector. Drawing from documents and interviews with officials from Sport NZ, one National Sports Organisation (NSO), and six Regional Sports Trusts (RSTs), three key findings relate to 1) the characteristics of the RP as policy instrument; 2) the novelty of Tū Manawa relative to Sport NZ's shifting strategy; and 3) the way in which organisations coped with the administration of new funds. The findings suggest that Sport NZ's funding strategies were multidimensional (targeting a wider array of activities and organisations than those pre-COVID-19) and could themselves be 'turbulent-inducing'. Future studies should examine the long-term legacy of the package and its associated goals to interpret if Sport NZ's initiatives are sustained for the [promised] readjustment and strengthening of the New Zealand sports sector. [ABSTRACT FROM AUTHOR]

In the fall of 2014, an international news agency reported that patients suffering from Ebola virus disease (EVD) in Liberia were treated successfully with lamivudine, an antiviral drug used to treat human immunodeficiency virus-1 and hepatitis B virus infections. According to the report, 13 out of 15 patients treated with lamivudine survived and were declared free from Ebola virus disease. In this study, the anti-Ebola virus (EBOV) activity of lamivudine and another antiretroviral, zidovudine, were evaluated in a diverse set of cell lines against two variants of wild-type EBOV. Variable assay parameters were assessed to include different multiplicities of infection, lengths of inoculation times, and durations of dosing. At a multiplicity of infection of 1, lamivudine and zidovudine had no effect on EBOV propagation in Vero E6, Hep G2, or HeLa cells, or in primary human monocyte-derived macrophages. At a multiplicity of infection of 0.1, zidovudine demonstrated limited anti-EBOV activity in Huh 7 cells. Under certain conditions, lamivudine had low anti-EBOV activity at the maximum concentration tested (320 μM). However, lamivudine never achieved greater than 30% viral inhibition, and the activity was not consistently reproducible. Combination of lamivudine and zidovudine showed no synergistic antiviral activity. Independently, a set of in vitro experiments testing lamivudine and zidovudine for antiviral activity against an Ebola-enhanced green fluorescent protein reporter virus was performed at the Centers for Disease Control and Prevention. No antiviral activity was observed for either compound. A study evaluating the efficacy of lamivudine in a guinea pig model of EVD found no survival benefit. This lack of benefit was observed despite plasma lamivudine concentrations in guinea pig of about 4 μg/ml obtained in a separately conducted pharmacokinetics study. These studies found no evidence to support the therapeutic use of lamivudine for the treatment of EVD.

The global expansion of sports betting has resulted in the formation of (inter)national governing regimes aimed at sustaining revenue and regulating attendant issues, including match-fixing. This article explores the workings of these regimes vis-à-vis the management of match-fixing issues in sport. More particularly, this article focuses on betting monitoring programmes as countermeasures against match-fixing and conceptualises these as social instruments that ultimately define issues and influence the wider integrity agenda of anti-match-fixing campaigns. Analysing documentary, observation and interview data from two disparate monitoring programmes, the results show that betting monitoring is a technical extension of corporate risk management, invariably reflecting the business interests of the betting industry. Therefore, the operating logic of betting monitoring defines match-fixing as an act of sabotaging the competitive edge of betting companies. Moreover, this interest-laden paradigm reigns within the broader policy agenda of sport integrity by equating the betting industry's interest with that of sport. From this, the article suggests that betting monitoring plays a part in the legitimation of commercial gambling by reframing the issue of match-fixing as a common enemy that gambling and sport join forces to combat, not a risk that gambling brings to sport. [ABSTRACT FROM AUTHOR]

The concern for athlete maltreatment in elite sport emerged in response to a wide range of high-profile cases. While diverse theories and concepts have been used to explore the subject, there is a need for non-Western analyses that can attend to the cultures, practices and narratives of Asian states. Drawing on the case of South Korea's elite sport system, this paper scrutinises the mix of institutional practices and narratives that may variously converge to enable maltreatment or diverge, to prompt calls for systemic change. Grounded in ‘new institutionalism’ and a qualitative approach that incorporates document analysis and semi-structured interviews, this research examines maltreatment within a unique Korean Confucian hierarchical socio-cultural context. The results indicate that complementary practices and narratives enable maltreatment and facilitate the continuation of the system. Conversely, this study also investigated instances of divergence highlighting the impetus for change. However, there is some evidence to suggest that accommodating reforms, which remain essentially shaped by existing practices and narratives, often lead to resistance against substantial change. In sum, the combination of convergent and divergent practices and narratives, within the complex and unique cultural and structural context of Korea, signals that while policy changes to address athlete maltreatment are emerging, barriers to fundamental, sustained change remain. [ABSTRACT FROM AUTHOR]

Phosphoinositide kinases regulate diverse cellular functions and are important targets for therapeutic development for diseases, such as diabetes and cancer. Preparation of the lipid substrate is crucial for the development of a robust and miniaturizable lipid kinase assay. Enzymatic assays for phosphoinositide kinases often use lipid substrates prepared from lyophilized lipid preparations by sonication, which result in variability in the liposome size from preparation to preparation. Herein, we report a homogeneous 1536-well luciferase-coupled bioluminescence assay for PI5P4Kα. The substrate preparation is novel and allows the rapid production of a DMSO-containing substrate solution without the need for lengthy liposome preparation protocols, thus enabling the scale-up of this traditionally difficult type of assay. The Z'-factor value was greater than 0.7 for the PI5P4Kα assay, indicating its suitability for high-throughput screening applications. Tyrphostin AG-82 had been identified as an inhibitor of PI5P4Kα by assessing the degree of phospho transfer of γ-(32)P-ATP to PI5P; its inhibitory activity against PI5P4Kα was confirmed in the present miniaturized assay. From a pilot screen of a library of bioactive compounds, another tyrphostin, I-OMe tyrphostin AG-538 (I-OMe-AG-538), was identified as an ATP-competitive inhibitor of PI5P4Kα with an IC(50) of 1 µM, affirming the suitability of the assay for inhibitor discovery campaigns. This homogeneous assay may apply to other lipid kinases and should help in the identification of leads for this class of enzymes by enabling high-throughput screening efforts.

With growing governmental involvement in sport, there has been a corresponding demand on national sport organizations (NSOs) to operate within performance measurement systems. In this study, we analyze data from New Zealand to determine NSO officials’ perceptions of (a) their reporting relationship with the central agency (Sport and Recreation New Zealand), and (b) the system of performance contracts (or “investment schedules”). Following Norman (2002), we found differing perceptions regarding the legitimacy of performance systems and three tensions emerged. First, the clarity of focus enabled by performance measurement was tempered by the perception of an ever-changing political environment. Second, NSO officials acted strategically and opportunistically at times, marshalling arguments around performance measures to “capture” their principal. Third, neither trust nor distrust in the system necessarily translated into compliance; some NSOs sought independence from the system. This research speaks to the legitimacy of performance systems, a significant but tenuous element to their sustainability. [ABSTRACT FROM AUTHOR]

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Despite growing calls from activists and sport scholars for public consultation over the expenditure of public funds for stadium developments, there remains a lack of empirical research that examines the politics of these practices. This study critically examines the power relations and tensions present in the public-consultation processes and debates over the use of public funds to renovate or rebuild Carisbrook stadium. Specifically, we engage the enabling and constraining institutional mechanisms that structured five public meetings, which emerged as discursive political spaces in the policy-making process. In doing so, we critically examine the discourses that were actively shaped by stadium proponents to fit the mandates of neoliberal growth and resisted by concerned citizens who opposed: (a) the use of public funds to renovate or rebuild the stadium, and (b) a consultation process driven by a public-private partnership of business, civic, and rugby interests that had perplexing consequences for democratic politics in local governance. [ABSTRACT FROM AUTHOR]

This study illustrates how the rules and practices of a task force inquiry shaped the formulation of its policy. Adopting an institutional approach, it analyzes New Zealand's Ministerial Taskforce on Sport, Fitness and Leisure (2001). Specifically, this article investigates the role of institutional arrangements (including public consultation and submission procedures) in shaping, delimiting, and circumscribing that task forces findings and recommendations. The investigation consists of a critical analysis of available texts—including recorded observations of public consultations, written submissions, committee notes—and interviews with task force members. Two features of this task force are described and analyzed: (1) its terms of reference and operative assumptions and (2) its rules and procedures that guided the public participation processes. It is shown that the institutional arrangements can channel debates and thereby recast political relations among interests. [ABSTRACT FROM AUTHOR]

Taskforces, commissions of inquiry, and advisory committees are significant institutional features in the development of government sport policy. This study analyzes New Zealand's Ministerial Taskforce on Sport, Fitness, and Leisure (2001) and uses empirical data gathered from observations of consultations, interviews with committee members, and available documents. It is argued that procedural, organizational, and political considerations significantly shaped and constrained the Taskforce's findings and recommendations. Two fundamental contradictions are discussed. The first concerns the expectations for these bodies to develop both innovative and pragmatic recommendations in light of their ad hoc nature, their broad mandates, and short time lines. The second contradiction speaks to the paradoxical nature of taskforces in developing sport policy, noting in particular their dual roles as both advocates for the sport sector and investigators responsible for addressing problems and issues. [ABSTRACT FROM AUTHOR]

National taskforces and inquiries are used extensively by governments wishing to review their involvement in sport. Underpinning these reviews are dominant ideas like "national unity," or "excellence." Ideas matter in public policy because they form the basis for framing political judgments and because their meanings are continually translated into future plans and actions (Hoppe, 1993. This study investigates the role of ideas in shaping and circumscribing the findings and recommendations emanating from a national taskforce in New Zealand. Information was gathered through interviews with Taskforce members, observations of public consultations, and analysis of submitted documents. Key ideas included notions of efficiency, competitiveness, and leadership. These ideas are discussed, focusing in particular on their contradictory/paradoxical nature and their role in (re)producing power relations. The paper concludes with future research questions and a call for more critical investigations into sport policy-making. [ABSTRACT FROM AUTHOR]