Antecedent and persistent symptoms in COVID-19 and other respiratory illnesses: insights from prospectively collected data in the BRACE trial.

BACKGROUND: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospective data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illnesses, identify factors associated with the risk of PACS, and explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses. METHODS: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms. FINDINGS: Participants with COVID-19 had significantly more severe illness compared to those with non-COVID-19 respiratory illnesses (OR 7·4, 95%CI 5·6-9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4-18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4-4·3). When considering only participants with COVID-19, age (aOR 2·8, 95%CI 1·3-6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3-23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4-6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath). INTERPRETATION: Healthcare workers with COVID-19 experienced more severe and longer-lasting symptoms than those with non-COVID-19 respiratory illnesses, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19. FUNDING: Bill & Melinda Gates Foundation [INV-017302] and others (see Acknowledgements).

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Does basic physician trainee selection predict successful progression in the Royal Australasian College of Physicians adult medicine training programme? A retrospective cohort study.

BACKGROUND: The optimal selection process for basic physician trainees (BPTs) is unclear. AIMS: To assess an adult BPT selection process, including a standardised recruitment interview assessing clinical decision-making and situational judgement. METHODS: A retrospective multi-year cohort study of applicants who were selected for interview during the annual recruitment for 2011-2015 clinical years in an adult basic physician training network in NSW. The predictive capacity of the final recruitment assessment score was compared with success in the Royal Australasian College of Physicians (RACP) adult medicine clinical examination within 2 years. RESULTS: Four hundred thirty-six applicants were selected for interview (84-91 in each year). Summary mean post-interview scores ranged from 1.25 to 10, with the median ranging between 7 and 8. Median scores were higher in those who passed the examination than those who did not (7.75 vs 6.43, P < 0.0001). Those who did not sit for the examination in the relevant year or never sat for the examination had similar median scores (7 vs 6.75, P = 0.11). Those not deemed eligible for recruitment were less likely to pass the clinical examination within 2 years than those on the eligibility list (odds ratio (OR) = 0.38, 95% confidence interval (CI) = 0.25-0.57). Applicants with mean scores lower than 8 were less likely to pass than those in the top band (8.1-10); scores between 6.1 and 8 OR 0.42 (95% CI = 0.26-0.68), 4.1-6 OR 0.23 (95% CI = 0.13-0.41) and 2.1-4 OR 0.24 (95% CI = 0.10-0.60). CONCLUSION(S): The predictive capacity of the selection process for success in the RACP clinical examination within the minimum time period is high.

Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.

Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Regulating antimicrobial use within hospitals: A qualitative study.

OBJECTIVES: To examine how regulatory structures and processes focused on antimicrobial stewardship and antimicrobial resistance are experienced by hospital managers and clinicians. METHODS: Forty-two hospital managers and clinicians working within accreditation and antimicrobial stewardship teams in three Australian hospitals participated in individual in-depth interviews. Thematic analysis was performed. RESULTS: Thematic analysis revealed participants' experiences of hospital antimicrobial regulation and their perceptions of what would be required for meaningful antimicrobial optimisation. Theme 1: Experience of regulation of antimicrobials within hospitals: Participants described an increased profile of antimicrobial resistance with inclusion in regulatory requirements, but also the risks of bureaucratic manoeuvring to meet standards rather than governance-inducing systemic changes. Theme 2: Growth of accreditation processes and hospitals over time: Both regulatory requirements and hospitals were described as evolving over time, each manoeuvring in response to each other (e.g. development of short notice accreditation). Theme 3: Perceived requirements for change: Participants perceived a need for top-down buy-in, resource prioritisation, complex understanding of power and influence on clinician behaviour, and a critical need for medical engagement. CONCLUSIONS: This study around antimicrobials shows the tension and dynamic relationship between regulatory processes and hospital responses, bringing to light the enduring balance of a system that positions itself to meet regulatory requirements and emerging "demands", without necessarily addressing the key underlying concerns. Antimicrobial resistance-related solutions are perceived as likely to require further resourcing and buy-in across multiple levels, engagement across professional streams and require strategies that consider complex systems change in order for regulatory structures to have potency.

A unique cytotoxic CD4+ T cell-signature defines critical COVID-19.

Objectives: SARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T-cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T-cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines. Methods: Immunophenotyping of T-cell responses in unvaccinated individuals was performed, representing the full spectrum of COVID-19 clinical presentation. Computational and manual analyses were used to identify T-cell populations associated with distinct disease states. Results: Critical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+ lymphocytes (CTL). These CD4+ CTLs were largely absent in asymptomatic to severe disease states. In contrast, non-critical COVID-19 was associated with high frequencies of naïve T cells and lack of activation marker expression. Conclusion: Highly activated and cytotoxic CD4+ T-cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Induction of these potentially detrimental T-cell responses should be considered when developing and implementing effective COVID-19 control strategies.

Comparative Longitudinal Serological Study of Anti-SARS-CoV-2 Antibody Profiles in People with COVID-19.

Serological diagnostic assays are essential tools for determining an individual's protection against viruses like SARS-CoV-2, tracking the spread of the virus in the community, and evaluating population immunity. To assess the diversity and quality of the anti-SARS-CoV-2 antibody response, we have compared the antibody profiles of people with mild, moderate, and severe COVID-19 using a dot blot assay. The test targeted the four major structural proteins of SARS-CoV-2, namely the nucleocapsid (N), spike (S) protein domains S1 and S2, and receptor-binding domain (RBD). Serum samples were collected from 63 participants at various time points for up to 300 days after disease onset. The dot blot assay revealed patient-specific differences in the anti-SARS-CoV-2 antibody profiles. Out of the 63 participants with confirmed SARS-CoV-2 infections and clinical COVID-19, 35/63 participants exhibited diverse and robust responses against the tested antigens, while 14/63 participants displayed either limited responses to a subset of antigens or no detectable antibody response to any of the antigens. Anti-N-specific antibody levels decreased within 300 days after disease onset, whereas anti-S-specific antibodies persisted. The dynamics of the antibody response did not change during the test period, indicating stable antibody profiles. Among the participants, 28/63 patients with restricted anti-S antibody profiles or undetectable anti-S antibody levels in the dot blot assay also exhibited weak neutralization activity, as measured by a surrogate virus neutralization test (sVNT) and a microneutralization test. These results indicate that in some cases, natural infections do not lead to the production of neutralizing antibodies. Furthermore, the study revealed significant serological variability among patients, regardless of the severity of their COVID-19 illness. These differences need to be carefully considered when evaluating the protective antibody status of individuals who have experienced primary SARS-CoV-2 infections.

Clinical variation in the early assessment and management of suspected community-acquired meningitis: a multicentre retrospective study.

BACKGROUND: Bacterial meningitis is a medical emergency and timely management has been shown to improve outcomes. The aim of this study was to compare the early assessment and management of adults with suspected community-onset meningitis between hospitals and identify opportunities for clinical practice improvement. METHODS: This retrospective cohort study was conducted at three principal referral hospitals in Sydney, Australia. Adult patients with suspected meningitis undergoing cerebrospinal fluid sampling between 1 July 2018 and 31 June 2019 were included. Relevant clinical and laboratory data were extracted from the medical record. Differences between sites were analysed and factors associated with time to antimicrobial therapy were assessed by Cox regression. RESULTS: In 260 patients, the median time from triage to antibiotic administration was 332 min with a difference of up to 147 min between hospitals. Median time from triage to lumbar puncture (LP) was 366 min with an inter-hospital difference of up to 198 min. Seventy per cent of patients had neuroimaging prior to LP, and this group had a significantly longer median time to antibiotic administration (367 vs 231 min; P = 0.001). Guideline concordant antibiotics were administered in 84% of patients, with only 39% of those administered adjunctive corticosteroids. Seven (3%) patients had confirmed bacterial meningitis. Modifiable factors associated with earlier antimicrobial administration included infectious diseases involvement (adjusted hazard ratio [aHR], 1.50 [95% confidence interval (CI), 1.01-2.24]) and computed tomography (CT) scanning (aHR, 0.67 [95% CI, 0.46-0.98]). CONCLUSION: Opportunities for improvement include reducing the time to LP and antibiotic administration, improving coadministration of corticosteroids and avoiding potentially unnecessary CT scanning.

Broadly neutralizing SARS-CoV-2 antibodies through epitope-based selection from convalescent patients.

Emerging variants of concern (VOCs) are threatening to limit the effectiveness of SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing antibodies and strategies for their identification are therefore urgently required. Here we demonstrate that broadly neutralizing antibodies can be isolated from peripheral blood mononuclear cells of convalescent patients using SARS-CoV-2 receptor binding domains carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, binding to epitope class 1, and GAR12, binding to a new epitope class 6 (located between class 3 and 5). Both antibodies broadly neutralize VOCs, exceeding the potency of the clinical monoclonal sotrovimab (S309) by orders of magnitude. They also provide prophylactic and therapeutic in vivo protection of female hACE2 mice against viral challenge. Our results indicate that exposure to SARS-CoV-2 induces antibodies that maintain broad neutralization against emerging VOCs using two unique strategies: either by targeting the divergent class 1 epitope in a manner resistant to VOCs (ACE2 mimicry, as illustrated by GAR05 and mAbs P2C-1F11/S2K14); or alternatively, by targeting rare and highly conserved epitopes, such as the new class 6 epitope identified here (as illustrated by GAR12). Our results provide guidance for next generation monoclonal antibody development and vaccine design.

High activation levels maintained in receptor-binding domain-specific memory B cells in people with severe coronavirus disease 2019.

The long-term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are still being understood. The molecular and phenotypic properties of SARS-CoV-2 antigen-specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen-specific memory B-cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID-19). Here, we performed single-cell molecular analysis of the SARS-CoV-2 receptor-binding domain (RBD)-specific MBC population in three patients after severe COVID-19 and four patients after mild/moderate COVID-19. We analyzed the transcriptomic and B-cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor-alpha (TNF-α) signaling via nuclear factor-kappa B in the severe group, involving CD80, FOS, CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80hi TNFAIP3hi and CD11chi CD95hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long-term RBD-specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID-19 severity.

Longitudinal Characterization of Phagocytic and Neutralization Functions of Anti-Spike Antibodies in Plasma of Patients after Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Phagocytic responses by effector cells to opsonized viruses have been recognized to play a key role in antiviral immunity. Limited data on coronavirus disease 2019 suggest that the role of Ab-dependent and -independent phagocytosis may contribute to the observed immunological and inflammatory responses; however, their development, duration, and role remain to be fully elucidated. In this study of 62 acute and convalescent patients, we found that patients with acute coronavirus disease 2019 can mount a phagocytic response to autologous plasma-opsonized Spike protein-coated microbeads as early as 10 d after symptom onset, while heat inactivation of this plasma caused 77-95% abrogation of the phagocytic response and preblocking of Fc receptors showed variable 18-60% inhibition. In convalescent patients, phagocytic response significantly correlated with anti-Spike IgG titers and older patients, while patients with severe disease had significantly higher phagocytosis and neutralization functions compared with patients with asymptomatic, mild, or moderate disease. A longitudinal subset of the convalescent patients over 12 mo showed an increase in plasma Ab affinity toward Spike Ag and preservation of phagocytic and neutralization functions, despite a decline in the anti-Spike IgG titers by >90%. Our data suggest that early phagocytosis is primarily driven by heat-liable components of the plasma, such as activated complements, while anti-Spike IgG titers account for the majority of observed phagocytosis at convalescence. Longitudinally, a significant increase in the affinity of the anti-Spike Abs was observed that correlated with the maintenance of both the phagocytic and neutralization functions, suggesting an improvement in the quality of the Abs.

Patterns and correlates of hepatitis C virus phylogenetic clustering among people living with HIV in Australia in the direct-acting antiviral era: A molecular epidemiology study among participants in the CEASE cohort.

Background and Aims: In moving towards the elimination of hepatitis C virus (HCV) infection among people living with HIV, understanding HCV transmission patterns may provide insights to guide and evaluate interventions. In this study, we evaluated patterns of, and factors associated with HCV phylogenetic clustering among people living with HIV/HCV co-infection in Australia in the direct-acting antiviral era. Methods: HCV RNA was extracted from dried blood spot (DBS) samples collected between 2014 and 2018 in the CEASE cohort study. The HCV Core-E2 region was amplified by a polymerase chain reaction and Sanger sequenced. Maximum likelihood phylogenetic trees (1000 bootstrap replicates) were used to identify patterns of clustering (3% genetic distance threshold). Mixed-effects logistic regression was used to determine correlates of phylogenetic clustering. Factors assessed were sexual risk behavior, education, injecting drug use, housing, employment, HIV viral load, age, sex, and sexuality. Results: Phylogenetic trees were reconstructed for HCV subtype 1a (n = 139) and 3a (n = 63) sequences, with 29% (58/202) in a pair or cluster. Overall (n = 202), phylogenetic clustering was positively associated with younger age (under 40; adjusted odds ratio [aOR] 2.52, 95% confidence interval [CI] 1.20-5.29), and among gay and bisexual men (n = 168), was positively associated with younger age (aOR 2.61, 95% CI 1.10-6.19), higher education (aOR 2.58, 95% CI 1.09-6.13), and reporting high-risk sexual behavior (aOR 3.94, 95% CI 1.31-11.84). During follow-up, five reinfections were observed, but none were in phylogenetic clusters. Conclusion: This study found a high proportion of phylogenetic relatedness, predominantly among younger people and gay and bisexual men reporting high-risk sexual behavior. Despite this, few reinfections were observed, and reinfections demonstrated little relationship with known clusters. These findings highlight the importance of rapid HCV treatment initiation, together with monitoring of the phylogeny.

Maintenance of broad neutralizing antibodies and memory B cells 1 year post-infection is predicted by SARS-CoV-2-specific CD4+ T cell responses.

Understanding the long-term maintenance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity is critical for predicting protection against reinfection. In an age- and gender-matched cohort of 24 participants, the association of disease severity and early immune responses on the maintenance of humoral immunity 12 months post-infection is examined. All severely affected participants maintain a stable subset of SARS-CoV-2 receptor-binding domain (RBD)-specific memory B cells (MBCs) and good neutralizing antibody breadth against the majority of the variants of concern, including the Delta variant. Modeling these immune responses against vaccine efficacy data indicate a 45%-76% protection against symptomatic infection (variant dependent). Overall, these findings indicate durable humoral responses in most participants after infection, reasonable protection against reinfection, and implicate baseline antigen-specific CD4+ T cell responses as a predictor of maintenance of antibody neutralization breadth and RBD-specific MBC levels at 12 months post-infection.

The impact of re-opening the international border on COVID-19 hospitalisations in Australia: a modelling study.

OBJECTIVE: To estimate the numbers of COVID-19-related hospitalisations in Australia after re-opening the international border. DESIGN: Population-level deterministic compartmental epidemic modelling of eight scenarios applying various assumptions regarding SARS-CoV-2 transmissibility (baseline R0 = 3.5 or 7.0), vaccine rollout speed (slow or fast), and scale of border re-opening (mean of 2500 or 13 000 overseas arrivals per day). SETTING: Simulation population size, age structure, and age-based contact rates based on recent estimates for the Australian population. We assumed that 80% vaccination coverage of people aged 16 years or more was reached in mid-October 2021 (fast rollout) or early January 2022 (slow rollout). MAIN OUTCOME MEASURES: Numbers of people admitted to hospital with COVID-19, December 2021 - December 2022. RESULTS: In scenarios assuming a highly transmissible SARS-CoV-2 variant (R0  = 7.0), opening the international border on either scale was followed by surges in both infections and hospitalisations that would require public health measures beyond mask wearing and social distancing to avoid overwhelming the health system. Reducing the number of hospitalisations to manageable levels required several cycles of additional social and mobility restrictions. CONCLUSIONS: If highly transmissible SARS-CoV-2 variants are circulating locally or overseas, large and disruptive COVID-19 outbreaks will still be possible in Australia after 80% of people aged 16 years or more have been vaccinated. Continuing public health measures to restrict the spread of disease are likely to be necessary throughout 2022.

Institutional governance and responsiveness to antimicrobial resistance: a qualitative study of Australian hospital executives.

OBJECTIVES: Despite escalating antimicrobial resistance (AMR), implementing effective antimicrobial optimisation within healthcare settings has been hampered by institutional impediments. This study sought to examine, from a hospital management and governance perspective, why healthcare providers may find it challenging to enact changes needed to address rising AMR. DESIGN: Semistructured qualitative interviews around their experiences of antimicrobial stewardship (AMS) and responsiveness to the requirement for optimisation. Data were analysed using the framework approach. SETTING: Two metropolitan tertiary-referral hospitals in Australia. PARTICIPANTS: Twenty hospital managers and executives from the organisational level of department head and above, spanning a range of professional backgrounds and in both clinical and non-clinical roles, and different professional streams were represented. RESULTS: Thematic analysis demonstrated three key domains which managers and executives describe, and which might function to delimit institutional responsiveness to present and future AMR solutions. First, the primacy of 'political' priorities. AMR was perceived as a secondary priority, overshadowed by political priorities determined beyond the hospital by state health departments/ministries and election cycles. Second, the limits of accreditation as a mechanism for change. Hospital accreditation processes and regulatory structures were not sufficient to induce efficacious AMS. Third, a culture of acute problem 'solving' rather than future proofing. A culture of reactivity was described across government and healthcare institutions, precluding longer term objectives, like addressing the AMR crisis. CONCLUSION: There are dynamics between political and health service institutions, as well as enduring governance norms, that may significantly shape capacity to enact AMS and respond to AMR. Until these issues are addressed, and the field moves beyond individual behaviour modification models, antimicrobial misuse will likely continue, and stewardship is likely to have a limited impact.

Diagnostic Informatics-The Role of Digital Health in Diagnostic Stewardship and the Achievement of Excellence, Safety, and Value.

Diagnostic investigations (pathology laboratory and medical imaging) aim to: increase certainty of the presence or absence of disease by supporting the process of differential diagnosis; support clinical management; and monitor a patient's trajectory (e. g., disease progression or response to treatment). Digital health can be defined as the collection, storage, retrieval, transmission, and utilization of data, information, and knowledge to support healthcare. Digital health has become an essential component of the diagnostic process, helping to facilitate the accuracy and timeliness of information transfer and enhance the effectiveness of decision-making processes. Digital health is also important to diagnostic stewardship, which involves coordinated guidance and interventions to ensure the appropriate utilization of diagnostic tests for therapeutic decision-making. Diagnostic stewardship and informatics are thus important in efforts to establish shared decision-making. This is because they contribute to the establishment of shared information platforms (enabling patients to read, comment on, and share in decisions about their care) based on timely and meaningful communication. This paper will outline key diagnostic informatics and stewardship initiatives across three interrelated fields: (1) diagnostic error and the establishment of outcomes-based diagnostic research; (2) the safety and effectiveness of test result management and follow-up; and (3) digitally enhanced decision support systems.

Evaluation of the accuracy of diagnostic coding for influenza compared to laboratory results: the availability of test results before hospital discharge facilitates improved coding accuracy.

BACKGROUND: Assessing the accuracy of diagnostic coding is essential to ensure the validity and reliability of administrative coded data. The aim of the study was to evaluate the accuracy of assigned International Classification of Diseases version 10-Australian Modification (ICD-10-AM) codes for influenza by comparing with patients' results of their polymerase chain reaction (PCR)-based laboratory tests. METHOD: A retrospective study was conducted across seven public hospitals in New South Wales, Australia. A total of 16,439 patients who were admitted and tested by either cartridge-based rapid PCR or batched multiplex PCR between January 2016 and December 2017 met the inclusion criteria. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of ICD-10-AM coding using laboratory results as a gold standard. Separate analyses were conducted to determine whether the availability of test results at the time of hospital discharge influenced diagnostic coding accuracy. RESULTS: Laboratory results revealed 2759 positive influenza cases, while ICD-10-AM coding identified 2527 patients. Overall, 13.7% (n = 378) of test positive patients were not assigned an ICD-10-AM code for influenza. A further 5.8% (n = 146) patients with negative test results were incorrectly assigned an ICD-10-AM code for influenza. The sensitivity, specificity, PPV and NPV of ICD-10-AM coding were 93.1%; 98.9%; 94.5% and 98.6% respectively when test results were received before discharge and 32.7%; 99.2%; 87.8% and 89.8% respectively when test results were not available at discharge. The sensitivity of ICD-10-AM coding varied significantly across hospitals. The use of rapid PCR or hospitalisation during the influenza season were associated with greater coding accuracy. CONCLUSION: Although ICD-10-AM coding for influenza demonstrated high accuracy when laboratory results were received before discharge, its sensitivity was substantially lower for patients whose test results were not available at discharge. The timely availability of laboratory test results during the episode of care could contribute to improved coding accuracy.

Differences in antibiotic and antiviral use in people with confirmed influenza: a retrospective comparison of rapid influenza PCR and multiplex respiratory virus PCR tests.

BACKGROUND: Influenza is a highly contagious respiratory virus with clinical impacts on patient morbidity, mortality and hospital bed management. The effect of rapid nucleic acid testing (RPCR) in comparison to standard multiplex PCR (MPCR) diagnosis in treatment decisions is unclear. This study aimed to determine whether RPCR influenza testing in comparison to standard MPCR testing was associated with differences in antibiotic and antiviral (oseltamivir) utilisation and hospital length of stay in emergency department and inpatient hospital settings. METHODS: A retrospective cohort study of positive influenza RPCR and MPCR patients was performed utilising data from the 2017 influenza season. Medical records of correlating patient presentations were reviewed for data collection. An analysis of RPCR versus MPCR patient outcomes was performed examining test turnaround time, antibiotic initiation, oseltamivir initiation and hospital length of stay for both emergency department and inpatient hospital stay. Subgroup analysis was performed to assess oseltamivir use in high risk populations for influenza complications. Statistical significance was assessed using Mann-Whitney test for numerical data and Chi-squared test for categorical data. Odds ratio with 95% confidence intervals were calculated where appropriate. RESULTS: Overall, 122 RPCR and 362 MPCR positive influenza patients were included in this study. Commencement of antibiotics was less frequent in the RPCR than MPCR cohorts (51% vs 67%; p < 0.01, OR 0.52; 95% CI 0.34-0.79). People at high risk of complications from influenza who were tested with the RPCR were more likely to be treated with oseltamivir compared to those tested with the MPCR (76% vs 63%; p = 0.03, OR 1.81; 95% CI 1.07-3.08). Hospital length of stay was not impacted when either test was used in the emergency department and inpatient settings. CONCLUSIONS: These findings suggest utilisation of RPCR testing in influenza management can improve antibiotic stewardship through reduction in antibiotic use and improvement in oseltamivir initiation in those at higher risk of complications. Further research is required to determine other factors that may have influenced hospital length of stay and a cost-benefit analysis should be undertaken to determine the financial impact of the RPCR test.