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Background: Future Health Today (FHT) is a program integrated with electronic medical record (EMR) systems in general practice and comprises (1) a practice dashboard to identify people at risk of, or with, chronic disease who may benefit from intervention; (2) active clinical decision support (CDS) at the point of care; and (3) quality improvement activities. One module within FHT aims to facilitate cardiovascular disease (CVD) risk reduction in people with chronic kidney disease (CKD) through the recommendation of angiotensin-converting enzyme inhibitor inhibitors (ACEI), angiotensin receptor blockers (ARB), or statins according to Australian guidelines (defined as appropriate pharmacological therapy)., Objective: This study aimed to determine if the FHT program increases the proportion of general practice patients with CKD receiving appropriate pharmacological therapy (statins alone, ACEI or ARB alone, or both) to reduce CVD risk at 12 months postrandomization compared with active control (primary outcome)., Methods: General practices recruited through practice-based research networks in Victoria and Tasmania were randomly allocated 1:1 to the FHT CKD module or active control. The intervention was delivered to practices between October 4, 2021, and September 30, 2022. Data extracted from EMRs for eligible patients identified at baseline were used to evaluate the trial outcomes at the completion of the intervention period. The primary analysis used an intention-to-treat approach. The intervention effect for the primary outcome was estimated with a marginal logistic model using generalized estimating equations with robust SE., Results: Overall, of the 734 eligible patients from 19 intervention practices and 715 from 21 control practices, 82 (11.2%) and 70 (9.8%), respectively, had received appropriate pharmacological therapy (statins alone, ACEI or ARB alone, or both) at 12 months postintervention to reduce CVD risk, with an estimated between-trial group difference (Diff) of 2.0% (95% CI -1.6% to 5.7%) and odds ratio of 1.24 (95% CI 0.85 to 1.81; P=.26). Of the 470 intervention patients and 425 control patients that received a recommendation for statins, 61 (13%) and 38 (9%) were prescribed statins at follow-up (Diff 4.3%, 95% CI 0 to 8.6%; odds ratio 1.55, 95% CI 1.02 to 2.35; P=.04). There was no statistical evidence to support between-group differences in other secondary outcomes and general practice health care use., Conclusions: FHT harnesses the data stored within EMRs to translate guidelines into practice through quality improvement activities and active clinical decision support. In this instance, it did not result in a difference in prescribing or clinical outcomes except for small changes in statin prescribing. This may relate to COVID-19-related disruptions, technical implementation challenges, and recruiting higher performing practices to the trial. A separate process evaluation will further explore factors impacting implementation and engagement with FHT., Trial Registration: ACTRN12620000993998; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380119., (©Jo-Anne Manski-Nankervis, Barbara Hunter, Natalie Lumsden, Adrian Laughlin, Rita McMorrow, Douglas Boyle, Patty Chondros, Shilpanjali Jesudason, Jan Radford, Megan Prictor, Jon Emery, Paul Amores, An Tran-Duy, Craig Nelson. Originally published in JMIR Formative Research (https://formative.jmir.org), 03.02.2025.)

Background: This study explored the feasibility of integrating a clinical decision support tool into general practice clinical management software in Australia to prompt for alcohol screening among patients who are pregnant or planning a pregnancy. The study aimed to increase understanding of what is an appropriate and acceptable clinical decision support tool, the circumstances when a prompt to use such a screening tool should occur, and the barriers and enablers of successful implementation., Methods: This feasibility study employed a mixed methods approach and purposive sampling to identify key stakeholders to interview. Participants included vendors of clinical software used in Australian general practice, clinicians in general practice, and relevant others. Data from a literature review and 23 interviews were analysed leading to recommendations which were 'sense-tested' by an additional 22 stakeholders., Results: Although there are at least 18 clinical software packages used in Australian general practice, it is feasible to integrate an alcohol screening tool for pregnancy into software for the majority of general practices in Australia. The AUDIT-C alcohol screening tool for pregnancy was widely accepted as suitable for such a purpose. Clinicians suggested the greatest barriers to screening were lack of time within antenatal consultations and insufficient remuneration for longer consultations. Many clinicians saw opportunity for introducing a multifunctional antenatal tool that could incorporate screening and clinical decision support for alcohol, tobacco and other substance use, mental health, domestic and family violence and potentially other areas informing healthy pregnancy. It could also be used opportunistically for preconception screening and counselling. Deployment of the tool could be supported by an education campaign from professional associations., Conclusion: The integration of a tool for screening for alcohol use among women who are pregnant or planning pregnancy into general practice clinical software is feasible; however, a multifunctional antenatal screening tool, incorporating other psychosocial elements, was considered more useful than a stand-alone alcohol screening tool. Codesign is needed with vendors and end-users to develop an acceptable tool that can be widely implemented. Issues with GP renumeration need also to be addressed to encourage alcohol screening pre-pregnancy and in the early months of pregnancy., Competing Interests: Declarations. Ethics approval and consent to participate: The research was performed in accordance with the relevant guidelines and regulations, e.g. the Australian National Statement on Ethical Conduct in Human Research which is in accordance with the National Health and Medical Research Council Act 1992 and the Declaration of Helsinki. Ethics approval for the study was obtained from The University of Melbourne Human Research Ethics Committee: ID No. 2022–25585-35607–3. The GP interviews were conducted as part of a linked study also approved by The University of Melbourne Human Research Ethics Committee: ID No. 2022–24433-34787–6. All interviewed participants were given plain language information statement and provided written informed consent. The online feedback questionnaire contained a summary of consent and statement that submission of the questionnaire implied consent to participate. Consent for publication: No individual person’s identifiable information is used in this manuscript. The consent form, however, contained the following statement: “I understand that given the small number of participants involved in the study, it may not be possible to guarantee my anonymity.” Competing interests: Authors D.B., R.C. and C.H. are part of the HaBIC Research Information Technology Unit (HaBIC R2) unit in The University of Melbourne Department of General Practice and Primary Care; HaBIC R2 works with general practice clinical software vendors around data acquisition and clinical decision support tools., (© 2024. The Author(s).)

Background: Diagnosing cancer in general practice is complex, given the non-specific nature of many presenting symptoms and the overlap of potential diagnoses. This trial evaluated the effectiveness of a technology, Future Health Today (FHT), which provides clinical decision support, auditing, and quality improvement monitoring, on the appropriate follow-up of patients at risk of undiagnosed cancer., Methods: Pragmatic, cluster randomised trial in Australian general practice. Practices were randomly assigned to receive recommendations for follow-up investigations for cancer (FHT cancer module) or the active control. Algorithms were applied to the electronic medical record and used demographic information and abnormal test results that are associated with risk of undiagnosed cancer (anaemia/iron-deficiency, thrombocytosis and raised PSA) to identify patients requiring further investigation and provide recommendations for care. The intervention consisted of the FHT cancer module, a case-based learning series and ongoing practice support. Using intention-to-treat approach, between arms difference in the proportion of patients with abnormal test results followed-up according to guidelines was determined at 12-months., Results: 7555 patients were identified as at risk of undiagnosed cancer. At 12-months post-randomisation, 76.2% of patients in the intervention arm had received recommended follow-up (21 practices, n=2820/3709), compared to 70% in the control arm (19 practices, n=2693/3846; estimated between arm difference in percentages=2.6%, 95% CI -2.8% to 7.9%; odds ratio=1.15, 95% CI 0.87-1.53; p=0.332)., Conclusions: The FHT cancer module intervention did not increase the proportion of patients receiving guideline-concordant care. The proportion of patients receiving recommended followed-up was high, suggesting a possible ceiling effect for the intervention., (Copyright © 2024, The Authors.)

Background: Future Health Today (FHT) is a technology program that integrates with general practice clinical software to provide point of care (PoC) clinical decision support and a quality improvement dashboard. This qualitative study looks at the use of FHT in the context of cardiovascular disease risk in chronic kidney disease (CKD)., Objective: This study aims to explore factors influencing clinical implementation of the FHT module focusing on cardiovascular risk in CKD, from the perspectives of participating general practitioner staff., Methods: Practices in Victoria were recruited to participate in a pragmatic cluster randomized controlled trial using FHT, of which 19 practices were randomly assigned to use FHT's cardiovascular risk in CKD program. A total of 13 semistructured interviews were undertaken with a nominated general practitioner (n=7) or practice nurse (n=6) from 10 participating practices. Interview questions focused on the clinical usefulness of the tool and its place in clinical workflows. Qualitative data were coded by 2 researchers and analyzed using framework analysis and Clinical Performance Feedback Intervention Theory., Results: All 13 interviewees had used the FHT PoC tool, and feedback was largely positive. Overall, clinicians described engaging with the tool as a "prompt" or "reminder" system. Themes reflected that the tool's goals and clinical content were aligned with clinician's existing priorities and knowledge, and the tool's design facilitated easy integration into existing workflows. The main barrier to implementation identified by 2 clinicians was notification fatigue. A total of 7 interviewees had used the FHT dashboard tool. The main barriers to use were its limited integration into clinical workflows, such that some participants did not know of its existence; clinicians' competing clinical priorities; and limited time to learn and use the tool., Conclusions: This study identified many facilitators for the successful use of the FHT PoC program, in the context of cardiovascular risk in CKD, and barriers to the use of the dashboard program. This work will be used to inform the wider implementation of FHT, as well as the development of future modules of FHT for other risk or disease states., (© Caroline McBride, Barbara Hunter, Natalie Lumsden, Kaleswari Somasundaram, Rita McMorrow, Douglas Boyle, Jon Emery, Craig Nelson, Jo-Anne Manski-Nankervis. Originally published in JMIR Human Factors (https://humanfactors.jmir.org).)

The fixed-frequency and frequency-modulated continuous-wave (FM-CW) reflectometers on LTX-β (Lithium Tokamak eXperiment-β) have been configured to use the same transmission lines and antenna arrays for coincident views of the core and edge plasma. The fixed-frequency channels (13.1-20.5 and 20-40 GHz, tunable between discharges) provide time-resolved measurements of density fluctuations, while the FM-CW channels (13.1-20.2 and 19.5-33.5 GHz) measure the density profile and fluctuations, with high spatial resolution and a sampling rate determined by the frequency sweep interval (5 μs). Data from both reflectometers are synchronously acquired to simultaneously leverage the wide bandwidth and high spatial resolution of the respective systems. Experiments showed that mutual crosstalk interference is momentary and does not diminish the capability of either system. Spectral analysis indicated broad power spectra (several hundreds of kHz) and suggests that the signals from the FM-CW system are consistent with under-sampled fixed-frequency signals. Radial correlations were explored using data from the two reflectometers, as well as from the FM-CW system alone. The core channels showed high levels of agreement between these two comparisons, suggesting that the data from the reflectometers are interchangeable for statistical estimates. For the edge channels, comparisons using data from the FM-CW reflectometer alone showed significant decorrelation due to time lag caused by the finite frequency up-sweep duration. Alternatively, this effect is eliminated when cross-correlating data from the different reflectometers. These results highlight the advantages of operating the fixed-frequency and FM-CW reflectometers in this manner, where the combined system can overcome the limitations of each separate system., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Salmonella forms biofilms, and persist on food contact surfaces. Once a biofilm is formed cleaning and sanitation protocols may be inadequate for effective removal. This study evaluated attachment characteristics, surface properties, and structure of Salmonella biofilms on food contact surfaces commonly used in the tree-fruit industry. Multi-strain Salmonella biofilms were grown in a Centers for Disease Control and Prevention (CDC) biofilm reactor at 22 ± 2 °C and sampling was conducted at 2, 24 and 96-h. After each incubation period, coupons weregently rinsed and the remaining cells enumerated. Biofilms were analyzed with Laser Scanning Confocal Microscopy (LSCM). Hydrophobicity was evaluated by measuring the contact angles of reference liquids method using a drop tensiometer instrument. Material type and biofilm age significantly influenced attachment and biofilm hydrophobicity (P < 0.05). The strength of attachment, across all time points, was highest on nylon followed by wood and high-density polyethylene. The highest contact angle measurements were observed after 96-h of biofilm formation for each material. All the results and observations from this study contribute to a better understanding of the attachment and hydrophobicity characteristics of Salmonella and might help producers make informed decisions when selecting containers for harvesting and storing in order to minimize biofilm formation and potential for cross-contamination., (© 2024. The Author(s).)

Large-scale climatic fluctuations, such as the El Niño-Southern Oscillation, can have dramatic effects on ocean ecosystem productivity. Many mobile species breeding in temperate or higher latitudes escape the extremes of seasonal climate variation through long-distance, even trans-global migration, but how they deal with, or are affected by, such longer phased climate fluctuations is less understood. To investigate how a long-lived migratory species might respond to such periodic environmental change we collected and analysed a 13 year biologging dataset for a trans-equatorial migrant, the Manx shearwater ( Puffinus puffinus ). Our primary finding was that in El Niño years, non-breeding birds were at more northerly (lower) latitudes than in La Niña years, a response attributable to individual flexibility in migratory destinations. Daily time spent foraging varied in concert with this latitudinal shift, with birds foraging less in El Niño years. Secondarily, we found that in subsequent breeding, a hemisphere away, El Niño years saw a reduction in foraging time and chick provisioning rates: effects that could not be attributed to conditions at their breeding grounds in the North Atlantic. Thus, in a highly migratory animal, individuals may adjust to fluctuating non-breeding conditions but still experience cascading carry over effects on subsequent behaviour.

The National Ignition Facility produced the first nuclear fusion experiment demonstrating net positive energy gain on December 5, 2022. The x-ray streak camera that measures the bang time and burn-width from this landmark experiment had an electronic failure and did not record data. The CCD sensor was replaced with a radiation hardened CMOS sensor that has since demonstrated successful operation on repeat ignition shots. Concurrently, an instrument artifact was identified that occurs when the signal consists primarily of energetic x rays >15 keV (common on burning plasma experiments). This artifact, which appears as a background pedestal, arises from the x-ray back-fluorescence generated by the solid metal accelerating mesh behind the photocathode in the streak tube. We have mitigated this background signal by limiting the sensitive area of the photocathode. Herein, the details of the modifications and the results are presented., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Identifying protected health identifiers (PHIs) in free text is core to anonymising clinical notes for research. There is no standard metric for the quality of a PHI detection algorithm, resulting in papers reporting heterogeneous results. CensorCheck is presented, which computes specialised metrics for evaluating PHI detection taking into account the peculiarities of anonymisation tasks.

Background and Objectives: Anxiety related school avoidance can affect up to 5% of a country's students each year. VRET (Virtual Reality Exposure Therapy) is a novel therapy proven to be as effective as conventional approaches for treating many anxiety disorders. The aim of this research is to co-design and evaluate a VRET intervention for students experiencing school related anxiety., Method: Eighteen adolescents participated in design thinking workshops where they developed a script and storyboard for the VRET. Using an iterative approach, a VRET prototype was developed based on this work. Eighteen teenagers were subsequently recruited to engage with the VRET for one session each and provide feedback on their experience via a structured questionnaire (supervised by a study coordinator) particularly focusing on the ability of the VR experience to reduce school related anxiety., Results: Exposure therapy needs to produce an anxiety response to be effective. The VRET was effective in producing an anxiety response in 89% of participants. Results demonstrated that 93% of participants found the simulations immersive, 94% found the scenarios believable, and 83% could relate to 'Dala', the avatar in the videos. 100% of participants believed that VRET would help with school anxiety., Conclusion: This proof-of-concept study demonstrates favourable face validity indicating promise for this mode of intervention for delivering targeted support to anxious students. VRET could be used as a scalable, cost effective early intervention to reduce the severity of anxiety associated with school avoidance.

Background In Australia, syphilis notifications increased 2.5-fold during 2013-2022 and 83 congenital syphilis cases were reported. Timely diagnosis and management are crucial. We developed a tool to promote syphilis testing into our existing 'Future Health Today' (FHT) software and explored its acceptability in general practice. Methods Our tool (FHT-syphilis) scans electronic medical record data to identify and prompt testing for pregnant women, and, people recently tested for sexually transmissible infection (STI) or HIV, but not syphilis. It links to relevant guidelines and patient resources. We implemented FHT-syphilis in 52 general practices using FHT for other conditions and interviewed practice clinicians (n =9) to explore it's acceptability. Data were analysed deductively guided by the Theoretical Framework of Acceptability. Results Interviewees considered syphilis an important infection to focus on and broadly viewed FHT-syphilis as acceptable for identifying patients and giving clinicians authority to discuss syphilis testing. Time constraints and unrelated reasons for a patient's visit were barriers to initiating syphilis testing discussions. Australian STI guidelines were considered appropriate to link to. Some interviewees considered prompts should be based on sexual behaviour, however this is not well captured in the electonic medical record. Two interviewees were alerted to updated Australian STI guidelines via their interaction with FHT-syphilis and expanded their syphilis testing practices. Expertise to initiate discussions about syphilis and risk was deemed important. Conclusions A digital tool for prompting syphilis testing was acceptable to clinicians already using FHT. Linkage to STI guidelines alerted some end-users to updated guidelines, informing STI testing practices.

Vulval lichen sclerosus (VLS) is an inflammatory skin disease characterised by itching, apareunia, loss of vulval architecture and scarring. Heterogeneity in outcome reporting precludes comparison between treatments. This study aimed to systematically review outcome measures used to evaluate the efficacy of VLS treatments and present patients' treatment priorities. This review followed the PRISMA guidelines using a registered protocol (PROSPERO: CRD42022356738). Multiple databases were searched, along with grey literature on Clinicaltrials.gov, European Union Clinical Trials and International Standard Randomised controlled trial (RCT) registries. All RCTs assessing any treatment for VLS were eligible for inclusion. A total of 775 patients were assessed across 21 RCTs. The assessment tools reported outcomes in the following domains: patient-reported symptoms assessed with one validated scale in 12 studies and seven non-validated scales in nine studies; sexual function with validated female sexual function index and female sexual distress scale in two studies and two non-validated scales in two studies; quality of life with three validated scales in three studies and clinician-reported objective outcomes with two validated scales in three studies and six non-validated scales in fourteen studies. Histological changes were assessed in 10 studies and tissue biomechanics in one study. We also carried out an online survey completed by 809 women with VLS to assess their research and disease treatment priorities and identified validated outcome measures to assess these. There is high variability in assessing treatment outcomes for VLS. We identified validated assessment tools which could be implemented in VLS studies to evaluate the effectiveness of treatments., Competing Interests: None to declare., (© 2024 The Author(s). Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The Flexible Imaging Diffraction Diagnostic for Laser Experiments (FIDDLE) is a newly developed diagnostic for imaging time resolved diffraction in experiments at the National Ignition Facility (NIF). It builds on the successes of its predecessor, the Gated Diffraction Development Diagnostic (G3D). The FIDDLE was designed to support eight Daedalus version 2 sensors (six more hCMOS sensors than any other hCMOS-based diagnostic in NIF to date) and an integrated streak camera. We will review the electrical requirements, design, and performance of the electrical subsystems that were created to support this large number of cameras in the FIDDLE. The analysis of the data that the FIDDLE is intended to collect relies heavily on the accurate and well-understood timing of each sensor. We report camera-to-camera timing jitter of less than 100 ps rms and sensor integration times of 2.2 ns FWHM in 2-2 timing mode. Additionally, diffraction experiments on the NIF produce electric fields (EMI) on the order of 1 kV/m, which have been observed to negatively impact the performance of some electrical components of the FIDDLE. We report on the results of testing hCMOS camera electronics in a similar EMI environment generated in an offline lab. We also summarize the use of a novel approach to using a vector network analyzer as an EMI leak detector to understand and reduce the negative impacts of EMI on the FIDDLE., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific fibroblast-like synoviocyte (FLS) biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated transcriptomic and chromatin accessibility data from FLS to identify the transcription factors and pathways. Networks were constructed by integration of chromatin accessibility and gene expression data. Analysis revealed joint-specific patterns of FLS phenotype, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an "activated" state relative to the "resting" state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

Background: The use of routinely collected health data for secondary research purposes is increasingly recognised as a methodology that advances medical research, improves patient outcomes, and guides policy. This secondary data, as found in electronic medical records (EMRs), can be optimised through conversion into a uniform data structure to enable analysis alongside other comparable health metric datasets. This can be achieved with the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM), which employs a standardised vocabulary to facilitate systematic analysis across various observational databases. The concept behind the OMOP-CDM is the conversion of data into a common format through the harmonisation of terminologies, vocabularies, and coding schemes within a unique repository. The OMOP model enhances research capacity through the development of shared analytic and prediction techniques; pharmacovigilance for the active surveillance of drug safety; and 'validation' analyses across multiple institutions across Australia, the United States, Europe, and the Asia Pacific. In this research, we aim to investigate the use of the open-source OMOP-CDM in the PATRON primary care data repository., Methods: We used standard structured query language (SQL) to construct, extract, transform, and load scripts to convert the data to the OMOP-CDM. The process of mapping distinct free-text terms extracted from various EMRs presented a substantial challenge, as many terms could not be automatically matched to standard vocabularies through direct text comparison. This resulted in a number of terms that required manual assignment. To address this issue, we implemented a strategy where our clinical mappers were instructed to focus only on terms that appeared with sufficient frequency. We established a specific threshold value for each domain, ensuring that more than 95% of all records were linked to an approved vocabulary like SNOMED once appropriate mapping was completed. To assess the data quality of the resultant OMOP dataset we utilised the OHDSI Data Quality Dashboard (DQD) to evaluate the plausibility, conformity, and comprehensiveness of the data in the PATRON repository according to the Kahn framework., Results: Across three primary care EMR systems we converted data on 2.03 million active patients to version 5.4 of the OMOP common data model. The DQD assessment involved a total of 3,570 individual evaluations. Each evaluation compared the outcome against a predefined threshold. A 'FAIL' occurred when the percentage of non-compliant rows exceeded the specified threshold value. In this assessment of the primary care OMOP database described here, we achieved an overall pass rate of 97%., Conclusion: The OMOP CDM's widespread international use, support, and training provides a well-established pathway for data standardisation in collaborative research. Its compatibility allows the sharing of analysis packages across local and international research groups, which facilitates rapid and reproducible data comparisons. A suite of open-source tools, including the OHDSI Data Quality Dashboard (Version 1.4.1), supports the model. Its simplicity and standards-based approach facilitates adoption and integration into existing data processes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ward et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To define the relationship between chronic chikungunya post-viral arthritis disease severity, cytokine response and T cell subsets in order to identify potential targets for therapy., Methods: Participants with chikungunya arthritis were recruited from Colombia from 2019-2021. Arthritis disease severity was quantified using the Disease Activity Score-28 and an Arthritis-Flare Questionnaire adapted for chikungunya arthritis. Plasma cytokine concentrations (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ and tumor necrosis factor (TNF)) were measured using a Meso Scale Diagnostics assay. Peripheral blood T cell subsets were measured using flow cytometry., Results: Among participants with chikungunya arthritis (N = 158), IL-2 levels and frequency of regulatory T cells (Tregs) were low. Increased arthritis disease activity was associated with higher levels of inflammatory cytokines (IL-6, TNF and CRP) and immunoregulatory cytokine IL-10 (p<0.05). Increased arthritis flare activity was associated with higher Treg frequencies (p<0.05) without affecting T effector (Teff) frequencies, Treg/Teff ratios and Treg subsets. Finally, elevated levels of IL-2 were correlated with increased Treg frequency, percent Tregs out of CD4+ T cells, and Treg subsets expressing immunosuppressive markers, while also correlating with an increased percent Teff out of live lymphocytes (p<0.05)., Conclusion: Chikungunya arthritis is characterized by increased inflammatory cytokines and deficient IL-2 and Treg responses. Greater levels of IL-2 were associated with improved Treg numbers and immunosuppressive markers. Future research may consider targeting these pathways for therapy., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AYC reports consulting for Valneva. RLA reports stock ownership of Abbvie, Pfizer, Johnson & Johnson, & Briston Myers Squibb. GSF reports consulting for Eli Lilly. Other authors report no commercial interest or conflicts of interest in relation to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Objectives In this overview, we describe theObservational Medical Outcomes Partnership Common Data Model (OMOP-CDM), the established governance processes employed in EMR data repositories, and demonstrate how OMOP transformed data provides a lever for more efficient and secure access to electronic medical record (EMR) data by health service providers and researchers. Methods Through pseudonymisation and common data quality assessments, the OMOP-CDM provides a robust framework for converting complex EMR data into a standardised format. This allows for the creation of shared end-to-end analysis packages without the need for direct data exchange, thereby enhancing data security and privacy. By securely sharing de-identified and aggregated data and conducting analyses across multiple OMOP-converted databases, patient-level data is securely firewalled within its respective local site. Results By simplifying data management processes and governance, and through the promotion of interoperability, the OMOP-CDM supports a wide range of clinical, epidemiological, and translational research projects, as well as health service operational reporting. Discussion Adoption of the OMOP-CDM internationally and locally enables conversion of vast amounts of complex, and heterogeneous EMR data into a standardised structured data model, simplifies governance processes, and facilitates rapid repeatable cross-institution analysis through shared end-to-end analysis packages, without the sharing of data. Conclusion The adoption of the OMOP-CDM has the potential to transform health data analytics by providing a common platform for analysing EMR data across diverse healthcare settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G&#95;{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G&#95;{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Objectives: This study aimed to perform a meta-analysis of the short-term impact of ischaemic postconditioning (IPoC) on myocardial injury in ST elevation myocardial infarction (STEMI) using surrogate cardiac biomarkers., Methods: Eligible studies were identified using several article databases. Randomised controlled trials published between 1 January 2000 and 1 December 2021 comparing IPoC to standard of therapy in STEMI patients were included in the search. Outcomes included surrogates of myocardial injury, specifically peak troponin, creatine-kinase (CK) and CK myoglobin binding (CK-MB) enzyme levels., Results: 11 articles involving 1273 patients reported on CK-MB and 8 studies involving 505 patients reported on CK. Few studies used troponin as an outcome, thus, a subanalysis of troponin dynamics was not performed. Meta-regression analysis demonstrated no significant effect of IPoC on peak CK-MB (effect size -0.41, 95% CI -1.15 to 0.34) or peak CK (effect size -0.42, 95% CI -1.20 to 0.36). Linear regression analysis demonstrated a significant correlation between a history of smoking and CK-MB in the IPoC group (p=0.038)., Conclusions: IPoC does not seem to protect against myocardial injury in STEMI, except possibly in smokers. These results resonate with some studies using imaging techniques to ascertain myocardial damage. More research using troponin and cardiac imaging should be pursued to better assess the effects of IPoC on cardiovascular outcomes in STEMI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific FLS biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated transcriptomic and chromatin accessibility data from FLS to identify the transcription factors (TFs) and pathways. Networks were constructed by integration of chromatin accessibility and gene expression data. Analysis revealed joint-specific patterns of FLS phenotype, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF-stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an 'activated' state relative to the 'resting' state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

Ischemic postconditioning (IPoC) is a technique suggested to reduce reperfusion injury in patients suffering acute ST-elevation myocardial infarction (STEMI), although its use is highly controversial. This meta-analysis aimed to evaluate the effect of IPoC with percutaneous coronary intervention in patients with acute STEMI, as measured by follow-up left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging. The investigators searched PubMed, Embase, and Web of Science for all randomized controlled trials published during the last 2 decades. After the removal of duplicates, 2,021 articles from online databases had been identified using relevant search criteria. The included randomized controlled trials had studied patients with acute STEMI and Thrombolysis in Myocardial Infarction flow 0 to 1 at presentation and had measured follow-up LVEF using cardiac magnetic resonance imaging. Overall, 11 studies (n = 1,339 patients) qualified for inclusion. In each study, the control group did not differ significantly from the experimental group. The pooled data from included studies were analyzed using standardized mean difference between IPoC and control groups, and the 95% confidence interval for LVEF; the results were visualized using a forest plot. Bivariate regression analyses and 1-way analyses of LVEF coefficient ratios were done to isolate for various clinical and procedural parameters. An analysis of pooled data of the IPoC (n = 674) and control (n = 665) groups showed that IPoC did not significantly impact follow-up LVEF (using standardized mean difference 0.10, 95% confidence interval 0.00 to 0.21). Further analysis showed that IPoC did not improve follow-up LVEF when isolating for relevant clinical and procedural parameters. In conclusion, the use of IPoC as an adjunctive therapy to percutaneous coronary intervention seemingly provides no benefit to left ventricular systolic function, as quantified with cardiac magnetic resonance imaging, in patients with acute STEMI with Thrombolysis in Myocardial Infarction flow 0 to 1., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) is a relative contraindication to heart transplantation (HT). Multiple studies showed increased mortality in patients with PH. Advances in care may have led to improved outcomes in the modern era. We analyzed patients who underwent HT at our institution between 2014 and 2018. We divided patients into 2 groups based on the presence of high-risk PH defined as either pulmonary vascular resistance >3 Wood units or transpulmonary gradient >15 mm Hg. The primary outcome was survival. Secondary outcomes were post-HT morbidity and changes in hemodynamics. Subsequently, we analyzed national trends of single organ HT recipients with a high-risk PH between 1994 and 2018 from the United Network for Organ Sharing registry. Of 98 patients who underwent HT at our center, 32% had PH. In patients without and with PH, the survival was 100% at 30 days, 87%, and 81% at 3 years (p = 0.96). In both groups, pulmonary vascular resistance and trans-pulmonary gradient decreased after HT. Nationwide data revealed 30-day survival without and with PH at 97% and 98% (p = 0.47) and 3-year survival at 86% and 87% (p = 0.84), respectively, in 2018. The proportion of recipients with PH decreased from 25% in 1994 to 19% in 2018. Recipients of HT with and without high-risk PH had similar early and late mortality in a single-center and nationwide analysis. PH improved immediately after transplant. The United Network for Organ Sharing registry analysis demonstrates continued improvement in survival in patients with PH in the modern era, whereas the relative percentage of recipients with PH decreased over time., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The mechanisms of toxicity of engineered nanomaterials (ENMs) to the early life stages of freshwater fish, and the relative hazard compared to dissolved metals, is only partially understood. In the present study, zebrafish (Danio rerio) embryos were exposed to lethal concentrations of silver nitrate (AgNO 3 ) or silver (Ag) ENMs (primary size 42.5 ± 10.2 nm). The 96 h-LC 50 for AgNO 3 was 32.8 ± 0.72 μg Ag L -1 (mean ± 95% CI) compared to 6.5 ± 0.4 mg L -1 of the whole material for Ag ENMs; with the ENMs being orders of magnitude less toxic than the metal salt. The EC 50 for hatching success was 30.5 ± 1.4 μg Ag L -1 and 6.04 ± 0.4 mg L -1 for AgNO 3 and Ag ENMs, respectively. Further sub-lethal exposures were performed with the estimated LC 10 concentrations for both AgNO 3 or Ag ENMs over 96 h, where about 3.7% of the total Ag as AgNO 3 was internalised, as measured by Ag accumulation in the dechorionated embryos. However, for the ENM exposures, nearly all (99.8%) of the total Ag was associated with chorion; indicating the chorion as an effective barrier to protect the embryo in the short term. Calcium (Ca 2+ ) and sodium (Na + ) depletion was induced in embryos by both forms of Ag, but hyponatremia was more pronounced in the nano form. Total glutathione (tGSH) levels declined in embryos exposed to both Ag forms, but a superior depletion occurred with the nano form. Nevertheless, oxidative stress was mild as superoxide dismutase (SOD) activity stayed uniform and the sodium pump (Na + /K + -ATPase) activity had no appreciable inhibition compared to the control. In conclusion, AgNO 3 was more toxic to the early life stage zebrafish than the Ag ENMs, still differences were found in the exposure and toxic mechanisms of both Ag forms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Adolescence is a period of major transition in physical, cognitive, social and emotional development, and the peak time for the onset of mental health conditions, substance use disorders and sexual and reproductive health risks. Prevention and treatment during this time can improve health and well-being now and into the future. However, despite clinical guidelines recommending annual preventive health assessments for young people, health professionals cite lack of consultation time and adequate funding as key barriers. This trial aims to determine whether a specific fee-for-service ('rebate payment') for a young person's health assessment, is effective and cost-effective at increasing the detection and management of health risk behaviours and conditions among young people., Methods and Analysis: This cluster randomised controlled trial will be conducted in Australian general practice. 42 general practices (clusters) will be randomly allocated 1:1 to either an intervention arm where general practitioners receive a rebate payment for each annual health assessment undertaken for 14-24-year-olds during a 2 year study period, or a control arm (no rebate). The rebate amount will be based on the Medical Benefits Schedule (Australia's list of health professional services subsidised by the Australian Government) currently available for similar age-based assessments. Our primary outcome will be the annual rate of risk behaviours and health conditions recorded in the patient electronic health record (eg, alcohol/drug use, sexual activity and mental health issues). Secondary outcomes include the annual rate of patient management activities related to health risks and conditions identified (eg, contraception prescribed, sexually transmitted infection tests ordered). A process evaluation will assess acceptability, adoption, fidelity and sustainability of the rebate; an economic evaluation will assess its cost-effectiveness. Analyses will be intention-to-treat., Ethics and Dissemination: Ethics approval has been obtained from University of Melbourne Human and Research Ethics Committee (2022-23435-29990-3). Findings will be published in peer-reviewed journals., Trial Registration Number: ACTRN12622000114741., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Listeria monocytogenes can adapt, persist, and form biofilms on food premises surfaces, representing a challenge for food safety, since they led to disease transmission, food contamination and spoilage during production. Physical interventions (scrubbing and wiping) can help controlling formation, nevertheless when biofilms are formed, they are usually very resistant to current control strategies used in the food industry. Biofilm attachment and formation is influenced by environment characteristics, substrate properties and microbial motility. The purpose of this study was to evaluate the ability of L. monocytogenes to attach and form biofilms on different surfaces (wood, nylon, and polycarbonate) representative of the materials used during produce harvesting and storage. Multi-strain L. monocytogenes biofilms were grown in a CDC Biofilm reactor at 20 ± 2 °C up to 96-h and characterized for: a) attachment strength by enumerating cells after rinsing; b) hydrophobicity and interfacial tension by contact angle measurements; c) biofilm architecture by Laser Scanning Confocal Microscopy. All experiments were done in triplicate. Material, incubation, and solvent significantly affected the hydrophobicity and wetting properties of L. monocytogenes biofilms (P < 0.05). The type of material and incubation time significantly influenced hydrophobicity and wetting properties of L. monocytogenes biofilms (P < 0.05). Highest contact angle and lowest interfacial tension were observed on polycarbonate coupons. The data presented contributes to understanding Listeria biofilms grow on different surfaces commonly used in produce harvesting and storage. The data obtained in this study can be used when evaluating intervention strategies to control this pathogen in food premises., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Despite the availability of effective, subsidised hepatitis B treatment, linkage to care and treatment rates remain very low globally. In Australia, specially trained primary care physicians (general practitioner, GPs) can prescribe hepatitis B treatment, however, most hepatitis B care occurs in specialist clinics. Increasing hepatitis B management by GPs in primary care clinics is essential to achieve national hepatitis B linkage to care and treatment targets by 2030.This pilot study determines the feasibility, acceptability and effectiveness of Simply B, a novel GP hepatitis B e-support package designed to increase hepatitis B management by GPs in primary care clinics., Methods and Analysis: This study will be conducted in three parts:Part A: A prospective open-label pilot intervention study, comparing the proportion of people with hepatitis B who are managed by their GP in primary care clinics before, 12 months and 24 months after implementation of the Simply B electronic hepatitis B support package.Part B: A nested qualitative health services feasibility study using semistructured interviews and thematic analysisPart C: Cost-effectiveness analysis., Ethics and Dissemination: This study has received ethics approval by St Vincent's Hospital. Data management and analysis will be centralised through the Department of Gastroenterology, St Vincent's Hospital., Trial Registration Number: NCT05614466., Competing Interests: Competing interests: JH has received investigator-initiated research funding (Gilead Australia Fellowship 2017, 2019) and speaker fees (2017) from Gilead Sciences, and speaker fees and investigator-initiated research funding from Eisai (2020, 2021)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The mechanisms of toxicity of engineered nanomaterials (ENMs) to the early life stages of freshwater fish, and the relative hazard compared to dissolved metals, is only partially understood. In the present study, zebrafish embryos were exposed to lethal concentrations of copper sulphate (CuSO 4 ) or copper oxide (CuO) ENMs (primary size ∼15 nm), and then the sub-lethal effects investigated at the LC 10 concentrations over 96 h. The 96 h-LC 50 (mean ± 95% CI) for CuSO 4 was 303 ± 14 µg Cu L -1 compared to 53 ± 9.9 mg L -1 of the whole material for CuO ENMs; with the ENMs being orders of magnitude less toxic than the metal salt. The EC 50 for hatching success was 76 ± 11 µg Cu L -1 and 0.34 ± 0.78 mg L -1 for CuSO 4 and CuO ENMs respectively. Failure to hatch was associated with bubbles and foam-looking perivitelline fluid (CuSO 4 ), or particulate material smothering the chorion (CuO ENMs). In the sub-lethal exposures, about 42% of the total Cu as CuSO 4 was internalised, as measured by Cu accumulation in the de-chorionated embryos, but for the ENMs exposures, nearly all (94%) of the total Cu was associated with chorion; indicating the chorion as an effective barrier to protect the embryo from the ENMs in the short term. Both forms of Cu exposure caused sodium (Na + ) and calcium (Ca 2+ ), but not magnesium (Mg 2+ ), depletion from the embryos; and CuSO 4 caused some inhibition of the sodium pump (Na + /K + -ATPase) activity. Both forms of Cu exposure caused some loss of total glutathione (tGSH) in the embryos, but without induction of superoxide dismutase (SOD) activity. In conclusion, CuSO 4 was much more toxic than CuO ENMs to early life stage zebrafish, but there are subtle differences in the exposure and toxic mechanisms for each substance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Trapped electron mode (TEM) is the main source of turbulence predicted for the unique operation regime of a flat temperature profile under low-recycling conditions in the LTX-β tokamak, while ion temperature gradient driven turbulence may also occur with gas fueling from the edge. To investigate mainly TEM scale density fluctuations, a high spatial and time resolution 2D beam emission spectroscopy (BES) diagnostic is being developed. Apart from spatially localized density turbulence measurement, BES can provide turbulence flow and flow shear dynamics. This BES system will be realized using an avalanche photodiode-based camera and narrow band interference filter. The system can acquire data at 2 MHz. Simulations with the Simulation of Spectra (SOS) code indicate that a high signal to noise ratio can be achieved with the proposed system. This will enable sampling the density fluctuations at this high time resolution. The design considerations and system optimization using the SOS code are presented.

Introduction: Australia's current healthcare system for children is neither sustainable nor equitable. As children (0-4 years) comprise the largest proportion of all primary care-type emergency department presentations, general practitioners (GPs) report feeling undervalued as an integral member of a child's care, and lacking in opportunities for support and training in paediatric conditions. This Strengthening Care for Children (SC4C) randomised trial aims to evaluate a novel, integrated GP-paediatrician model of care, that, if effective, will improve GP quality of care, reduce burden to hospital services and ensure children receive the right care, at the right time, closer to home., Methods and Analysis: SC4C is a stepped wedge cluster randomised controlled trial (RCT) of 22 general practice clinics in Victoria and New South Wales, Australia. General practice clinics will provide control period data before being exposed to the 12-month intervention which will be rolled out sequentially each month (one clinic per state) until all 22 clinics receive the intervention. The intervention comprises weekly GP-paediatrician co-consultation sessions; monthly case discussions; and phone and email paediatrician support, focusing on common paediatric conditions. The primary outcome of the trial is to assess the impact of the intervention as measured by the proportion of children's (0-<18 years) GP appointments that result in a hospital referral, compared with the control period. Secondary outcomes include GP quality of care; GP experience and confidence in providing paediatric care; family trust in and preference for GP care; and the sustainability of the intervention. An implementation evaluation will assess the model to inform acceptability, adaptability, scalability and sustainability, while a health economic evaluation will measure the cost-effectiveness of the intervention., Ethics and Dissemination: Human research ethics committee (HREC) approval was granted by The Royal Children's Hospital Ethics Committee in August 2020 (Project ID: 65955) and site-specific HRECs. The investigators (including Primary Health Network partners) will communicate trial results to stakeholders and participating GPs and general practice clinics via presentations and publications., Trial Registration Number: Australia New Zealand Clinical Trials Registry 12620001299998., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Electron tubes continue to provide the highest speeds possible for recording dynamics of hot high-energy density plasmas. Standard streak camera drive electronics and CCD readout are not compatible with the radiation environment associated with high DT fusion yield inertial confinement fusion experiments >10 13 14 MeV DT neutrons or >10 9  n cm -2  ns -1 . We describe a hardened x-ray streak camera developed for the National Ignition Facility and present preliminary results from the first experiment on which it has participated, recording the time-resolved bremsstrahlung spectrum from the core of an inertial confinement fusion implosion at more than 40× the operational neutron yield limit of the previous National Ignition Facility x-ray streak cameras.

Background: Most people receive most of their health care in in Australia in primary care, yet researchers and policymakers have limited access to resulting clinical data. Widening access to primary care data and linking it with hospital or other data can contribute to research informing policy and provision of services and care; however, limitations of primary care data and barriers to access curtail its use. The Australian Health Research Alliance (AHRA) is seeking to build capacity in data-driven healthcare improvement; this study formed part of its workplan., Methods: The study aimed to build capacity for data driven healthcare improvement through identifying primary care datasets in Australia available for secondary use and understand data quality frameworks being applied to them, and factors affecting national capacity for secondary use of primary care data from the perspectives of data custodians and users. Purposive and snowball sampling were used to disseminate a questionnaire and respondents were invited to contribute additional information via semi-structured interviews., Results: Sixty-two respondents collectively named 106 datasets from eclectic sources, indicating a broad conceptualisation of what a primary care dataset available for secondary use is. The datasets were generated from multiple clinical software systems, using different data extraction tools, resulting in non-standardised data structures. Use of non-standard data quality frameworks were described by two-thirds of data custodians. Building trust between citizens, clinicians, third party data custodians and data end-users was considered by many to be a key enabler to improve primary care data quality and efficiencies related to secondary use. Trust building qualities included meaningful stakeholder engagement, transparency, strong leadership, shared vision, robust data security and data privacy protection. Resources to improve capacity for primary care data access and use were sought for data collection tool improvements, workforce upskilling and education, incentivising data collection and making data access more affordable., Conclusions: The large number of identified Australian primary care related datasets suggests duplication of labour related to data collection, preparation and utilisation. Benefits of secondary use of primary care data were many, and strong national leadership is required to reach consensus on how to address limitations and barriers, for example accreditation of EMR clinical software systems and the adoption of agreed data and quality standards at all stages of the clinical and research data-use lifecycle. The study informed the workplan of AHRA's Transformational Data Collaboration to improve partner engagement and use of clinical data for research., (© 2022. The Author(s).)

Cobalt occurs naturally in the earth's crust, is essential to some microorganisms and forms the core of vitamin B12. Cobalt substances are used in numerous technologies, such as catalysts or batteries. Some of these substances are classified as Carcinogens, while other cobalt compounds have a hazard profile that is less understood and are missing long term studies like cancer bioassays. There is a strong interest by society and industry to reduce and -where possible- eliminate animal testing, yet a necessity by industry and authorities to have sufficient data for hazard conclusions and risk assessments. The present paper introduces a strategy for a mode of action-informed tiered testing, aimed at full inclusion of existing hazard data and selection of relevant biological events towards a certain adverse outcome, i.e. inhalation carcinogenicity. The occurrence of these events following exposure to various cobalt substances is investigated with in vitro and with limited in vivo testing. The tiers of testing are described in the companion papers of this RTP special issue. This approach has given rise to the formulation of two distinct groups, containing substances with similar properties, that can be addressed with limited higher tier animal testing and read across of in vivo results., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Current HIV antiretroviral therapy (ART) or pre-exposure prophylaxis (PrEP) therapy adherence monitoring relies on either patient self-reported adherence or monitored drug dispensing, which are not reliable. We report a proof-of-concept adherence monitoring assay which directly measures nucleotide reverse transcriptase inhibitor (NRTI) concentration using a reverse transcription isothermal amplification inhibition assay. We measure the concentration of Tenofovir diphosphate (TFV-DP) - an NRTI that functions as a deoxyadenosine triphosphate (dATP) analog and long-term adherence marker for PrEP - by measuring the inhibition of the reverse transcription of an RNA template. The completion or inhibition of reverse transcription is evaluated by recombinase polymerase amplification (RPA), an isothermal nucleic acid amplification assay commonly used for point-of-care diagnostics. We present and validate a model that predicts the amplification probability as a function of dATP and TFV-DP concentrations, nucleotide insertion sites on the RNA template, and RNA template concentration. The model can be used to rationally design and optimize the assay to operate at clinically relevant TFV-DP concentrations. We provide statistical analysis that demonstrates how the assay may be used as a qualitative or semi-quantitative tool for measuring adherence to NRTI drugs and used to support patient compliance. Due to its simple instrumentation and short runtime (<1 hour), this assay has the potential for implementation in low-complexity laboratories or point-of-care settings, which may improve access to ART and PrEP adherence monitoring.

Fish are widely reported to ingest microplastics with low levels accumulating in the tissues, but owing to analytical constraints, much less is known about the potential accumulation of nanoplastics via the gut. Recently, the labelling of plastics with inorganic metals (e.g., palladium) has allowed measurements of nanoplastic uptake. The aim of the current study was to quantitatively assess the uptake of nanoplastics by the fish gut using palladium-doped nanoplastics (with a mean hydrodynamic radius of 202 ± 7 nm). By using an ex vivo gut sac exposure system, we show that in 4 h between 200 and 700 million nanoplastics (representing 2.5-9.4% of the administered nanoplastics dose) can enter the mucosa and muscularis layers of the intestine of salmon. Of the particles taken up, up to 700,000 (representing 0.6% of that taken into the tissue) of the nanoplastics passed across the gut epithelium of the anterior intestine and exit into the serosal saline. These data, generated in highly controlled conditions provide a proof-of-concept study, suggesting the potential for nanoplastics to distribute throughout the body, indicating the potential for systemic exposure in fish., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Understanding the points in a species breeding cycle when they are most vulnerable to environmental fluctuations is key to understanding interannual demography and guiding effective conservation and management. Seabirds represent one of the most threatened groups of birds in the world, and climate change and severe weather is a prominent and increasing threat to this group. We used a multi-state capture-recapture model to examine how the demographic rates of a long-lived trans-oceanic migrant seabird, the Manx shearwater Puffinus puffinus, are influenced by environmental conditions experienced at different stages of the annual breeding cycle and whether these relationships vary with an individual's breeding state in the previous year (i.e., successful breeder, failed breeder and non-breeder). Our results imply that populations of Manx shearwaters are comprised of individuals with different demographic profiles, whereby more successful reproduction is associated with higher rates of survival and breeding propensity. However, we found that all birds experienced the same negative relationship between rates of survival and wind force during the breeding season, indicating a cost of reproduction (or central place constraint for non-breeders) during years with severe weather conditions. We also found that environmental effects differentially influence the breeding propensity of individuals in different breeding states. This suggests individual spatio-temporal variation in habitat use during the annual cycle, such that climate change could alter the frequency that individuals with different demographic profiles breed thereby driving a complex and less predictable population response. More broadly, our study highlights the importance of considering individual-level factors when examining population demography and predicting how species may respond to climate change., Competing Interests: The authors have declared that no competing interests exist.

Background: The research of theory of mind (ToM) and emotion perception (EP) in adolescents with major depressive disorder (MDD) is scarce, and no study to date has investigated the association between EP and long-term outcomes of adolescents with MDD. The aim of the current study was to evaluate ToM and EP in adolescents with MDD, as compared to healthy controls (HCs). In addition, we aimed to assess the association between impairment in ToM and EP, depressive symptom severity, and long-term outcome in the MDD group., Methods: We compared the performance of 14 adolescents with MDD and 25 HC in the Facial Expression Recognition Task (FERT) and the Interpersonal Perception Task. We followed up with the MDD group 2 years later to assess the level of their depressive symptoms using the Children's Depression Rating Scale-Revised (CDRS-R)., Results: No differences were found between adolescents with MDD and HC in the ToM and FERT tasks. Also, within the MDD group, there was no association between the severity of depressive symptoms and task performance. In the MDD group, there was a significant correlation between lower levels of accuracy in the FERT during the index depressive episode and lower CDRS-R scores on follow-up 2 years later (r2 = 0.35, p = 0.021)., Conclusions: EP impairments in adolescents with MDD might predict worse long-term outcome. Further research is needed to verify our findings and to assess for a possible neurobiological underpinning for the state and trait impairments in EP in adolescents with MDD.

Impairments in the reactivity of Oxytocin (OT) system were associated with interpersonal difficulties in children with ADHD. The current study aimed to explore the correlation between symptoms severity and salivary OT levels at different time-points in children with ADHD. Symptoms severity was assessed in 50 children with ADHD (28 males, mean age 9.42 ± 1.65) using the Swanson, Nolan and Pelham Questionnaire-IV (SNAP-IV) and the Strengths and Difficulties Questionnaire (SDQ). Salivary OT levels were measured at baseline, as well as 15 min after positive social interaction. There was no statistical correlation between severity of ADHD and salivary OT levels in each of the time points. We conclude that impairments in the reactivity of the OT system in children with ADHD, associated with interpersonal impairments, might be a distinct aspect of the clinical picture, differentiated from the levels of inattentive, hyperactive/impulsive or behavioral symptoms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim was to investigate the correlation between ADHD symptom severity and impairments in "theory of mind" (ToM) and empathy, and the improvement in these functions following the administration of methylphenidate (MPH). Fifty children aged 6-12 years with ADHD participated in the study. Symptom severity was assessed using the Swanson, Nolan and Pelham Questionnaire-IV (SNAP-IV). ToM performance was assessed using the "ToM test" and the "Faux-Pas Recognition Test". A significant negative correlation was found between the SNAP-IV Conners index, the oppositional and deportment subscales, and ToM test scores. MPH administration improved ToM scores in a magnitude that was negatively correlated with baseline performance. Additionally, Children with more severe behavioral problems showed greater improvement in ToM following administration of MPH. We conclude that severity of ADHD symptoms, most notably behavioral symptoms, is correlated with deficits in ToM. Administration of MPH improves ToM performance, with the greatest improvement occurring in children with more severe behavioral symptoms., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Domestic violence and abuse (DVA) is prevalent, harmful and more dangerous among diaspora communities because of the difficulty accessing DVA services, language and migration issues. Consequently, migrant/refugee women are common among primary care populations, but evidence for culturally competent DVA primary care practice is negligible. This pragmatic cluster randomised controlled trial aims to increase DVA identification and referral (primary outcomes) threefold and safety planning (secondary outcome) among diverse women attending intervention vs comparison primary care clinics. Additionally, the study plans to improve recording of DVA, ethnicity, and conduct process and economic evaluations., Methods and Analysis: Recruitment of ≤28 primary care clinics in Melbourne, Australia with high migrant/refugee communities. Eligible clinics need ≥1 South Asian general practitioner (GP) and one of two common software programmes to enable aggregated routine data extraction by GrHanite. Intervention staff undertake three DVA training sessions from a GP educator and bilingual DVA advocate/educator. Following training, clinic staff and DVA affected women 18+ will be supported for 12 months by the advocate/educator. Comparison clinics are trained in ethnicity and DVA data entry and offer routine DVA care. Data extraction of DV identification, safety planning and referral from routine GP data in both arms. Adjusted regression analysis by intention-to-treat by staff blinded to arm. Economic evaluation will estimate cost-effectiveness and cost-utility. Process evaluation interviews and analysis with primary care staff and women will be framed by Normalisation Process Theory to maximise understanding of sustainability. Harmony will be the first primary care trial to test a culturally competent model for the care of diverse women experiencing DVA., Ethics and Dissemination: Ethical approval from La Trobe University Human Ethics Committee (HEC18413) and dissemination by policy briefs, journal articles and conference and community presentations., Trial Registration Number: ANZCTR- ACTRN12618001845224; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) can be caused by viral, bacterial, or environmental factors. Recent studies have suggested that procalcitonin serum levels may help reduce unnecessary antibiotic use without statistically significant differences in rates of treatment failure for AECOPD. The purpose of this quality improvement project was to create a procalcitonin-based algorithm to aid emergency department (ED) clinicians in the management of patients with AECOPD who do not require hospitalization and to evaluate its efficacy and practicality. The primary outcome of this project was the rate of antibiotic prescriptions before and after the initiation of the algorithm., Methods: This study used an observational, retrospective, pre-and posteducation/intervention design. Clinicians were educated individually on the use of procalcitonin, and a copy of the algorithm was made available to each clinician and posted in the ED. Patients who were discharged from the ED with a diagnosis of an AECOPD were identified using International Classification of Diseases , Tenth Revision codes. Patient charts were reviewed from November 2018 to March 2019 for the preimplementation period and November 2019 to March 2020 for the postimplementation period. The rate of antibiotic prescriptions and the number of procalcitonin tests ordered before and after the introduction of the algorithm were analyzed. In addition, information on COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) grouping and 30-, 60-, and 90-day reexacerbation rates were collected. It was estimated that a sample size of 146 patients (73 patients/group) would provide 80% power to detect a between-group difference of 10% in the percentage of patients who were prescribed antibiotics. Categorical variables were expressed using estimates of their frequency and percentages. Percentages were compared using Fisher exact tests. For all tests, the significance level was set at 0.05., Results: Seventy-three patients were included in the preintervention group, and 77 patients were included in the postintervention group. Patients in the preintervention and postintervention groups had similar representation in GOLD categories: 52% and 51% for D, 17.8% and 23.4% for C, 21.9% and 16.8% for B, and 8.2% and 7.8% for A, respectively. The rate of antibiotic prescriptions decreased by 20% after implementation from 83.6% before to 63.6% after implementation ( P = .01). The differences in reexacerbation rates between the preintervention and postintervention groups were similar: 19.2% vs 23.4% at 30 days, 12.3% vs 11.7% at 60 days, and 4.1% vs 9.1% at 90 days, respectively. Prior to education and introduction of the procalcitonin algorithm, procalcitonin was ordered for 1.4% of AECOPD cases. Postimplementation, procalcitonin was ordered for 28.6% of AECOPD cases and used in clinical decision making 81.8% of the time., Conclusions: In this study of the implementation of a treatment algorithm for patients with mild and moderate AECOPD who present to the ED, procalcitonin was shown to reduce the rate of antibiotic prescriptions without an observable difference in reexacerbation rates 30, 60, and 90 days after presentation., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest with regard to this article., (Copyright © 2021 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Objective: Few teenagers and young adults (TYA) with cancer participate in clinical trials. Lack of opportunity has been identified as a major barrier. We canvassed health professionals' views on how TYA's access to trials might be improved., Methods: We interviewed 35 professionals with responsibility for delivering or facilitating cancer care and/or clinical trials. We analysed data using a qualitative descriptive approach., Results: Interviewees viewed improving TYA's access to trials as challenging, but possible. They reframed the problem as one of rare disease and surmised that modifying the organisation, administration and resourcing of research (and care) might expand opportunities for both TYA and other patients with low volume conditions. Proposals coalesced around four themes: consolidating the pool of patients; streamlining bureaucratic requirements; investing in the research workforce; and promoting pragmatism in trial design., Conclusion: Accounts suggest there is scope to improve access to trials by TYA with cancer and other patients with rare diseases. Though re-configuring care, research and resource frameworks would present substantial challenges, doing nothing would also have costs. Change will require the support of a range of stakeholders, and agreement as to the best way forward. Further work, such as priority setting exercises, may be necessary to reach a consensus., (© 2021 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Worldwide, Chronic Kidney Disease (CKD), directly or indirectly, causes more than 2.4 million deaths annually with symptoms generally presenting late in the disease course. Clinical guidelines support the early identification and treatment of CKD to delay progression and improve clinical outcomes. This paper reports the protocol for the codesign, implementation and evaluation of a technological platform called Future Health Today (FHT), a software program that aims to optimise early detection and management of CKD in general practice. FHT aims to optimise clinical decision making and reduce practice variation by translating evidence into practice in real time and as a part of quality improvement activities. This protocol describes the co-design and plans for implementation and evaluation of FHT in two general practices invited to test the prototype over 12 months. Service design thinking has informed the design phase and mixed methods will evaluate outcomes following implementation of FHT. Through systematic application of co-design with service users, clinicians and digital technologists, FHT attempts to avoid the pitfalls of past studies that have failed to accommodate the complex requirements and dynamics that can arise between researchers and service users and improve chronic disease management through use of health information technology.

Aims: This study compared the bag-mediated filtration system (BMFS) and standard WHO two-phase separation methods for poliovirus (PV) environmental surveillance, examined factors impacting PV detection and monitored Sabin-like (SL) PV type 2 presence with withdrawal of oral polio vaccine type 2 (OPV2) in April 2016., Methods and Results: Environmental samples were collected in Nairobi, Kenya (Sept 2015-Feb 2017), concentrated via BMFS and two-phase separation methods, then assayed using the WHO PV isolation algorithm and intratypic differentiation diagnostic screening kit. SL1, SL2 and SL3 were detected at higher rates in BMFS than two-phase samples (P < 0·05). In BMFS samples, SL PV detection did not significantly differ with volume filtered, filtration time or filter shipment time (P > 0·05), while SL3 was detected less frequently with higher shipment temperatures (P = 0·027). SL2 was detected more frequently before OPV2 withdrawal in BMFS and two-phase samples (P < 1 × 10 -5 )., Conclusions: Poliovirus was detected at higher rates with the BMFS, a method that includes a secondary concentration step, than using the standard WHO two-phase method. SL2 disappearance from the environment was commensurate with OPV2 withdrawal., Significance and Impact of the Study: The BMFS offers comparable or improved PV detection under the conditions in this study, relative to the two-phase method., (© 2020 The Authors. Journal of Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology.)

The objective of this study was to identify the relative contribution of tenderness factors for three beef muscles with similar tenderness ratings. Longissimus lumborum (LL), tensor fascia latae (TF) and gastrocnemius (GC) were collected from 10 USDA low Choice beef carcasses and assigned to a 5 or 21 days aging period (n = 60). Sarcomere length, troponin-T degradation, collagen content, mature collagen crosslink density, intramuscular lipid content and trained panel analysis were measured. Correlation and multivariate regression analysis indicated each muscle has a specific tenderness factor that contributed to the overall tenderness evaluated by trained panelists. The equations indicated LL tenderness was driven by lipid content (P < .05); TF tenderness was driven by collagen content (P < .05). GC tenderness was driven by proteolysis (P < .01), and only collagen content can be casually used as an overall tenderness predictor for all three cuts., Competing Interests: Declaration of Competing Interest To the best of our knowledge, the named authors have no conflict of interest, financial or otherwise., (Copyright © 2020 Elsevier Ltd. All rights reserved.)