BatchFLEX: feature-level equalization of X-batch.

MOTIVATION: Integrative analysis of heterogeneous expression data remains challenging due to variations in platform, RNA quality, sample processing, and other unknown technical effects. Selecting the approach for removing unwanted batch effects can be a time-consuming and tedious process, especially for more biologically focused investigators. RESULTS: Here, we present BatchFLEX, a Shiny app that can facilitate visualization and correction of batch effects using several established methods. BatchFLEX can visualize the variance contribution of a factor before and after correction. As an example, we have analyzed ImmGen microarray data and enhanced its expression signals that distinguishes each immune cell type. Moreover, our analysis revealed the impact of the batch correction in altering the gene expression rank and single-sample GSEA pathway scores in immune cell types, highlighting the importance of real-time assessment of the batch correction for optimal downstream analysis. AVAILABILITY AND IMPLEMENTATION: Our tool is available through Github https://github.com/shawlab-moffitt/BATCH-FLEX-ShinyApp with an online example on Shiny.io https://shawlab-moffitt.shinyapps.io/batch_flex/.

Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes.

New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100-150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical-genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery.

Does Adjunctive Clindamycin Have a Role in Staphylococcus aureus Bacteremia? A Protocol for the Adjunctive Treatment Domain of the Staphylococcus aureus Network Adaptive Platform (SNAP) Randomized Controlled Trial.

BACKGROUND: The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and it is recommended in many guidelines, but this is based on limited evidence. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leukocidins (eg, Panton-Valentine leukocidin, toxic shock syndrome toxin 1, exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. METHODS AND ANALYSIS: The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multicenter adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality rates. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either 5 days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard-of-care antibiotics. Most participants with SAB (within 72 hours of index blood culture and with no contraindications) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol, and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and Panton-Valentine leukocidin-positive isolate.

Genomic investigation and clinical correlates of the in vitro ß-lactam: NaHCO3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial.

NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to ß-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with ß-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal ß-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a ß-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a ß-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro ß-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a ß-lactam.

Determination of Factors Associated with Upstage in Atypical Ductal Hyperplasia to Identify Low-Risk Patients Where Active Surveillance May be an Alternative.

BACKGROUND: Excision is routinely recommended for atypical ductal hyperplasia (ADH) found on core biopsy given cancer upstage rates of near 20%. Identifying a cohort at low-risk for upstage may avoid low-value surgery. Objectives were to elucidate factors predictive of upstage in ADH, specifically near-complete core sampling, to potentially define a group at low upstage risk. PATIENTS AND METHODS: This retrospective, cross-sectional, multi-institutional study from 2015 to 2019 of 221 ADH lesions in 216 patients who underwent excision or active observation (≥ 12 months imaging surveillance, mean follow-up 32.6 months) evaluated clinical, radiologic, pathologic, and procedural factors for association with upstage. Radiologists prospectively examined imaging for lesional size and sampling proportion. RESULTS: Upstage occurred in 37 (16.7%) lesions, 25 (67.6%) to ductal carcinoma in situ (DCIS) and 12 (32.4%) to invasive cancer. Factors independently predictive of upstage were lesion size ≥ 10 mm (OR 5.47, 95% CI 2.03-14.77, p < 0.001), pathologic suspicion for DCIS (OR 12.29, 95% CI 3.24-46.56, p < 0.001), and calcification distribution pattern (OR 8.08, 95% CI 2.04-32.00, p = 0.003, "regional"; OR 19.28, 95% CI 3.47-106.97, p < 0.001, "linear"). Near-complete sampling was not correlated with upstage (p = 0.64). All three significant predictors were absent in 65 (29.4%) cases, with a 1.5% upstage rate. CONCLUSIONS: The upstage rate among 221 ADH lesions was 16.7%, highest in lesions ≥ 10 mm, with pathologic suspicion of DCIS, and linear/regional calcifications on mammography. Conversely, 30% of the cohort exhibited all low-risk factors, with an upstage rate < 2%, suggesting that active surveillance may be permissible in lieu of surgery.

Predicting response to neoadjuvant chemotherapy for colorectal liver metastasis using deep learning on prechemotherapy cross-sectional imaging.

BACKGROUND AND OBJECTIVES: Deep learning models (DLMs) are applied across domains of health sciences to generate meaningful predictions. DLMs make use of neural networks to generate predictions from discrete data inputs. This study employs DLM on prechemotherapy cross-sectional imaging to predict patients' response to neoadjuvant chemotherapy. METHODS: Adult patients with colorectal liver metastasis who underwent surgery after neoadjuvant chemotherapy were included. A DLM was trained on computed tomography images using attention-based multiple-instance learning. A logistic regression model incorporating clinical parameters of the Fong clinical risk score was used for comparison. Both model performances were benchmarked against the Response Evaluation Criteria in Solid Tumors criteria. A receiver operating curve was created and resulting area under the curve (AUC) was determined. RESULTS: Ninety-five patients were included, with 33,619 images available for study inclusion. Ninety-five percent of patients underwent 5-fluorouracil-based chemotherapy with oxaliplatin and/or irinotecan. Sixty percent of the patients were categorized as chemotherapy responders (30% reduction in tumor diameter). The DLM had an AUC of 0.77. The AUC for the clinical model was 0.41. CONCLUSIONS: Image-based DLM for prediction of response to neoadjuvant chemotherapy in patients with colorectal cancer liver metastases was superior to a clinical-based model. These results demonstrate potential to identify nonresponders to chemotherapy and guide select patients toward earlier curative resection.

Surgical microwave ablation of 397 neuroendocrine liver metastases: a retrospective cohort analysis of 16 years of experience.

BACKGROUND: Neuroendocrine tumors (NET) constitute a heterogeneous group of malignancies whose incidence has been on the rise over the past two decades, currently documented at 5.25 per 100,000. Liver metastasis develops in over 60% of NET patients. Even after resection recurrence rates are high, underscoring the importance of parenchymal-sparing interventions. In this study, we conducted 105 surgical microwave ablations and examined outcomes related to survival and local recurrence. METHODS: Retrospective review of patients who underwent a surgical microwave ablation (MWA) at a single-center, high-volume institution from September 2007 through December 2022 using a prospective database. Primary outcome was overall survival. RESULTS: A total of 105 operations were performed on 94 patients, with 397 tumors undergoing MWA. Median tumor size was 1.3 cm (range 0.3-8.0), and the median number of tumors ablated was 2 (range 1-12). Laparoscopic approach was utilized 69.5% of the time. The most common concomitant procedure performed was hepatectomy (33.3%) and cholecystectomy (23.8%). Clavien-Dindo grade III or IV complications occurred in 9 patients (9.6%). Mortality within 30 days occurred in 1 patient (1.1%). The rate of incomplete ablation was 0.3% per tumor. Local recurrence occurred in 2.8% of tumors. Median OS was 9.43 years [95% CI 4.23-14.63 years], with a 5- and 10-year survival probability of 70.2% and 48.2%, respectively. CONCLUSION: Surgical MWA offers an efficacious, parenchymal-sparing treatment of hepatic metastasis of NET, with low rates of incomplete ablation and local recurrence per tumor.

Hepatitis B genotypes in Aboriginal and Torres Strait Islander Australians: correlation with clinical course and implications for management.

BACKGROUND: The prevalence of chronic hepatitis B (CHB) in Aboriginal and Torres Strait Islander Australians in Far North Queensland (FNQ) is greater than twice that of the general Australian population. CHB is common in Torres Strait Islanders diagnosed with hepatocellular carcinoma (HCC) - and in Aboriginals with HCC living in the Northern Territory - however, Aboriginals diagnosed with HCC in FNQ very rarely have CHB. The explanation for this apparent disparity is uncertain. AIMS: To determine the HBV genotypes in the FNQ Aboriginal and Torres Strait Islander population and their correlation with clinical phenotype. METHODS: We determined the HBV genotype of Aboriginal and Torres Strait Islander Australians living with CHB in FNQ and correlated this with demographic and clinical findings. RESULTS: 134/197 (68%) enrolled individuals had a sufficient viral load for genotyping. All 40 people with HBV/D genotype had Aboriginal heritage, whereas 85/93 (91%) with HBV/C had Torres Strait Islander heritage (P < 0.0001). Individuals with HBV/D were younger than those with HBV/C (median (interquartile range) age: 43 (39-48) vs 53 (42-66) years, P = 0.0002). However, they were less likely to be HBeAg positive (1/40 (3%) vs 23/93 (25%), P = 0.001). All three HCCs developed in Torres Strait Islanders; two-thirds were infected with HBV/C14; genotyping was not possible in the other individual. All 10 diagnoses of cirrhosis occurred in Torres Strait Islanders, 6/10 were infected with HBV/C14, genotyping was not possible in the other four individuals. CONCLUSIONS: HBV genotypes in Aboriginal and Torres Strait Islander Australians in FNQ differ markedly, which could explain the significant differences in the clinical phenotype in the two populations and might be used to inform cost-effective CHB care in the region.

Avoiding misclassification of acute kidney injury: Timing is everything.

Accurate detection of acute kidney injury (AKI) in clinical trials is important. Using a 'baseline' creatinine from trial enrolment may not be ideal for understanding a participant's true baseline kidney function. We aimed to determine if a 'pre-trial baseline creatinine' resulted in comparable creatinine concentrations to a 'trial baseline creatinine', and how the timing of baseline creatinine affected the incidence of AKI in the Combination Antibiotic therapy for MEthicillin Resistant Staphylococcus aureus (CAMERA2) randomised trial. Study sites retrospectively collected a pre-trial baseline creatinine from up to 1 year before CAMERA2 trial enrolment ideally when the patient was medically stable. Baseline creatinine from CAMERA2 (the 'trial baseline creatinine'), was the highest creatinine measurement in the 24 h preceding trial randomisation. We used Wilcoxon sign rank test to compare pre-trial and trial baseline creatinine concentrations. We included 217 patients. The median pre-trial baseline creatinine was significantly lower than the median trial baseline creatinine (82 µmol/L [IQR 65-104 µmol/L] versus 86 µmol/L [IQR 66-152 µmol/L] p = <0.001). Using pre-trial baseline creatinine, 48 of 217 patients (22%) met criteria for an AKI at CAMERA2 enrolment and only 5 of these patients met criteria for an AKI using the CAMERA2 study protocol (using baseline creatinine from trial entry). Using a baseline creatinine from the time of trial enrolment failed to detect many patients with AKI. Trial protocols should consider the optimal timing of baseline creatinine and the limitations of using a baseline creatinine during an acute illness.

An evaluation and refinement of the "Hep B Story" app, tailored to meet the community's cultural needs.

BACKGROUND: Hepatitis B is endemic amongst the Australian Aboriginal population in the Northern Territory. A participatory action research project identified the lack of culturally appropriate education tools and led to the development of the "Hep B Story" app in the Aboriginal language Yolŋu Matha. This paper describes a formal evaluation of the app's first version, which informed improvements and translation into a further ten Aboriginal languages. METHODS: The evaluation employed Participatory Action Research (PAR) principles to work within Indigenous research methodologies and prioritise Indigenous knowledge to improve the app iteratively. Semi-structured interviews and focus groups were conducted across the Northern Territory with 11 different language groups. Local Community Based Researchers and Aboriginal Research team members coordinated sessions. The recorded, translated conversations were transcribed verbatim and thematically analysed using an inductive and deductive approach. RESULTS: Between November 2018 and September 2020, 94 individuals from 11 language groups participated in 25 semi-structured interviews and 10 focus groups. All participants identified as Aboriginal. Most participants felt the app would be culturally appropriate for Aboriginal communities in the Northern Territory and improve knowledge surrounding hepatitis B. The information gathered from these interviews allowed for identifying five main themes: support for app, relationships, concept versus language, shame, and perceptions of images, along with errors that required modification. CONCLUSIONS: A "real-life" evaluation of the app was comprehensively completed using a PAR approach blended with Indigenous research methods. This evaluation allowed us to develop an updated and enhanced version of the app before creating the additional ten language versions. An iterative approach alongside strong community engagement was pivotal in ensuring the app's cultural safety and appropriateness. We recommend avoiding the use of knowledge-based evaluations in an Aboriginal setting to ensure relevant and culturally appropriate feedback is obtained.

External Validation of the Joint-Specific Bone Involvement, Antimicrobial Options, Coverage of the Soft Tissues, and Host Status (JS-BACH) Classification for Predicting Outcome in Periprosthetic Joint Infections: A Cohort of 653 Patients.

BACKGROUND: Periprosthetic joint infection (PJI) is a devastating complication in hip and knee joint arthroplasty. The "Joint-Specific Bone Involvement, Antimicrobial Options, Coverage of the Soft Tissues, and Host Status (JS-BACH)" classification system was developed in 2021 to stratify the complexity of PJI, and more importantly, to act as a tool to guide referrals to specialist centers. The "JS-BACH" classification has not been validated in an external cohort. This study aimed to do so using a large prospective cohort from Australia and New Zealand. METHODS: We applied the JS-BACH classification to the Prosthetic Joint Infection in Australia and New Zealand Observational (PIANO) cohort. This prospective study of newly diagnosed PJI collected 2-year outcome data from 653 participants enrolled in 27 hospitals. The definition of PJI treatment failure at 24 months was any of the following: death, clinical or microbiological signs of infection, destination prosthesis removed, or ongoing antibiotic use. Individual cases were classified as per JS-BACH into "1: uncomplicated" (n = 268), "2: complex" (n = 330), and "3: limited options" (n = 55). This cohort was similar to the original JS-BACH population in terms of baseline characteristics. However, there was a difference in complexity, with more debridement, antibiotics, and implant retention procedures, fewer revision procedures, and a higher proportion of uncomplicated patients in the PIANO cohort. RESULTS: The risk of treatment failure correlated strongly with the JS-BACH category, with odds ratios (95% confidence interval) for category 2 versus 1 of 1.75 (1.24 to 2.47) and for category 3 versus 1 of 7.12 (3.42 to 16.02). CONCLUSIONS: Despite the PIANO study population being less complicated than the original derivation cohort, the JS-BACH classification showed a clear association with treatment failure in this large external cohort.

Reverse Fragility Index: Comparing Revision Rates Between Direct Anterior and Other Approaches in Total Hip Arthroplasty. A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Despite increasing adoption of the direct anterior (DA) approach in total hip arthroplasty (THA), uncertainty persists regarding its outcomes beyond the 1-year mark in comparison to other approaches. We used the reverse fragility index (RFI) to evaluate the robustness of reported findings in the literature. METHODS: We conducted a systematic review of randomized controlled trials (RCTs) comparing implant revision rates between DA and other approaches in THA, defined as all those different from DA. Our primary outcome was the RFI, which gauges the number of events needed for a nonsignificant result to become significant, in the revision rate between DA and other approaches. We also calculated the reverse fragility quotient by dividing the RFI by each study's sample size. Median values and interquartile ranges (IQRs) were displayed. RESULTS: A total of 10 RCTs with a total of 971 patients were included. The median RFI was 5 (IQR, 4 to 5), indicating the study's results would be statistically significant if the outcomes of 5 patients in 1 treatment arm were reversed. The median reverse fragility quotient was 0.049 (IQR, 0.04 to 0.057), indicating that a change of outcome in 4.9% of patients would render the revision rate significant. The median number of patients lost to follow-up was 4 (IQR, 0 to 7). Of the 10 RCTs, 6 had more patients lost to follow-up than their respective RFI values. CONCLUSIONS: Notable fragility was evidenced in most studies comparing DA to other approaches for THA. Surgeons should not solely rely on the P value to determine clinical significance and instead use multiple metrics. LEVEL OF EVIDENCE: II.

Information-Theoretical Analysis of the Cycle of Creation of Knowledge and Meaning in Brains under Multiple Cognitive Modalities.

It is of great interest to develop advanced sensory technologies allowing non-invasive monitoring of neural correlates of cognitive processing in people performing everyday tasks. A lot of progress has been reported in recent years in this research area using scalp EEG arrays, but the high level of noise in the electrode signals poses a lot of challenges. This study presents results of detailed statistical analysis of experimental data on the cycle of creation of knowledge and meaning in human brains under multiple cognitive modalities. We measure brain dynamics using a HydroCel Geodesic Sensor Net, 128-electrode dense-array electroencephalography (EEG). We compute a pragmatic information (PI) index derived from analytic amplitude and phase, by Hilbert transforming the EEG signals of 20 participants in six modalities, which combine various audiovisual stimuli, leading to different mental states, including relaxed and cognitively engaged conditions. We derive several relevant measures to classify different brain states based on the PI indices. We demonstrate significant differences between engaged brain states that require sensory information processing to create meaning and knowledge for intentional action, and relaxed-meditative brain states with less demand on psychophysiological resources. We also point out that different kinds of meanings may lead to different brain dynamics and behavioral responses.

Continuous vs Intermittent ß-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial.

Importance: Whether ß-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective: To evaluate whether continuous vs intermittent infusion of a ß-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a ß-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of ß-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03213990.

Familiarity preferences in zebrafish (Danio rerio) depend on shoal proximity.

Individuals of many species prefer to associate with familiar conspecifics from their established social group over unfamiliar conspecifics. Such familiarity preferences are thought to be adaptive and have been documented widely in many social fishes. Zebrafish (Danio rerio) are extensively studied, highly social fish that form stable shoals in the wild, however there is only mixed evidence for familiarity preferences in this species. Here, we test how a small variation in experimental design can influence preferences for familiar conspecifics in D. rerio by varying the distance between two stimulus shoals of fish in a shoaling choice paradigm. Individual subjects tested for their preference to shoal with familiar or unfamiliar groups of conspecifics showed a preference for familiar fish when the two shoals were 30 cm apart, but not when they were 45 or 60 cm apart. Thus, choice tests can be used to detect familiarity preferences in D. rerio, but only when alternate shoals are close together, as increased intershoal distances seemingly prevent subjects from displaying their preference. Longer distances may inhibit preference behavior due to the higher risk of crossing between shoals, alternatively subjects may be unable to reliably discern distinguishing cues of familiarity when the shoals are further apart. Our results demonstrate that while familiarity preferences exist in D. rerio, experimental test design is critical for detecting and measuring these successfully.

Engagement in the digital age: Understanding "what works" for participatory technologies in environmental decision-making.

Effective engagement is crucial for enhancing environmental decision-making processes, fostering more sustainable and equitable outcomes. However, the success of engagement is highly variable and context-dependent. While theoretical frameworks have been developed to explain outcome variance in engagement in environmental decision-making, they have not yet been tested in digital contexts, leaving their applicability to digital engagement processes unclear. More broadly, there are unanswered questions about the effectiveness of digital tools in achieving the goals of engagement, which have become increasingly pertinent amidst growing concerns about the potential of digital technologies for exacerbating exclusions, ethical issues, and systematically undermining democratic progress. This paper addresses this evidence gap by presenting findings from interviews with practitioners in UK public, private, and third sector organisations. Our results provide empirical insights into the technical, ethical, and inclusivity debates surrounding digital tools and their effectiveness in promoting accessible engagement, high-quality social interaction, place-based decision-making, and more trustworthy and credible outcomes. Our findings indicate that while current engagement theories are applicable to digital environments, the key explanatory factors acquire new dimensions in digital compared to in-person contexts. Drawing on the findings, this study contributes novel insights to expand current theory for explaining "what works" in engagement in environmental decisions, enhancing its relevance and applicability in the digital age. The paper concludes with evidence-led recommendations for environmental practitioners to improve engagement processes in digital and remote settings.

Adapting and translating the 'Hep B Story' App the right way: A transferable toolkit to develop health resources with, and for, Aboriginal people.

ISSUE ADDRESSED: In 2014 the 'Hep B Story App', the first hepatitis B educational app in an Aboriginal language was released. Subsequently, in 2018, it was assessed and adapted before translation into an additional 10 Aboriginal languages. The translation process developed iteratively into a model that may be applied when creating any health resource in Aboriginal languages. METHODS: The adaptation and translation of the 'Hep B Story' followed a tailored participatory action research (PAR) process involving crucial steps such as extensive community consultation, adaptation of the original material, forward and back translation of the script, content accuracy verification, voiceover recording, and thorough review before the publication of the new version. RESULTS: Iterative PAR cycles shaped the translation process, leading to a refined model applicable to creating health resources in any Aboriginal language. The community-wide consultation yielded widespread chronic hepatitis B education, prompting participants to share the story within their families, advocating for hepatitis B check-ups. The project offered numerous insights and lessons, such as the significance of allocating sufficient time and resources to undertake the process. Additionally, it highlighted the importance of implementing flexible work arrangements and eliminating barriers to work for the translators. CONCLUSIONS: Through our extensive work across the Northern Territory, we produced an educational tool for Aboriginal people in their preferred languages and developed a translation model to create resources for different cultural and linguistic groups. SO WHAT?: This translation model provides a rigorous, transferable method for creating accurate health resources for culturally and linguistically diverse populations.

Early oral antibiotic switch in Staphylococcus aureus bacteraemia: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Early Oral Switch Protocol.

BACKGROUND: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. PROTOCOL: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care). DISCUSSION: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.