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Background: Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5–7 days during an upper respiratory tract infection reduces the risk of relapse. Objectives: To determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none. Design: A randomised double-blind placebo-controlled trial, including a cost-effectiveness analysis. Setting: A total of 122 UK paediatric departments, of which 91 recruited patients. Participants: A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively). Interventions: At the start of an upper respiratory tract infection, children received 6 days of prednisolone (15 mg/m2) or an equivalent dose of placebo. Main outcome measures: The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at 1 year, which were then extrapolated over 16 years. Results: There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference –0.024, 95% confidence interval –0.14 to 0.09; p = 0.70). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs. £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis. Limitations: A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial. Conclusions: The clinical analysis indicated that giving 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from costs associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse. Future work: Further work is needed to investigate the clinical and health economic impact of relapses, interethnic differences in treatment response, the effect of different corticosteroid regimens in treating relapses, and the pathogenesis of individual viral infections and their effect on steroid-sensitive nephrotic syndrome. Trial registration: Current Controlled Trials ISRCTN10900733 and EudraCT 2012-003476-39. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 3. See the NIHR Journals Library website for further project information.

Background: The optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS). Objectives: The primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs. Design: Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis. Setting: One hundred and twenty-five UK paediatric departments. Participants: Two hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years). Interventions: The control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4, 40 mg/m2 of prednisolone on alternate days in weeks 5–8 and matching placebo on alternate days in weeks 9–18 (total 2240 mg/m2). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4; started at 60 mg/m2 of prednisolone on alternate days in weeks 5–16, tapering by 10 mg/m2 every 2 weeks (total 3150 mg/m2). Main outcome measures: The primary outcome measure was time to first relapse [Albustix® (Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months. Results: There was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rank p = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%; p = 0.7), SDNS (44% vs. 42%; p = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%; p = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (p = 0.07). SAE rates were not significantly different (25% vs. 17%; p = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696). Limitations: Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating. Conclusions: This trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit. Future work: Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted. Trial registration: Current Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.

Jacqueline Ann Nicholas,1 Aaron Lee Boster,1 Jaime Imitola,1,2 Colleen O’Connell,1 Michael Karl Racke1,21Department of Neurology and Multiple Sclerosis Center, 2Department of Neuroscience, The Ohio State University, Columbus, OH, USAAbstract: Dimethyl fumarate (DMF) is the most recent oral disease-modifying therapy approved by the US Food and Drug Administration and is indicated for the treatment of relapsing forms of multiple sclerosis (MS). Prior to approval for use in MS, DMF and its active metabolite, monomethyl fumarate, had been used for decades as two of the fumaric acid esters in Fumaderm®, a medication used in Europe for the treatment of psoriasis. The unique mechanism of action of DMF remains under evaluation; however, it has been shown to act through multiple pathways leading to shifts away from the Th1 proinflammatory response to the less inflammatory Th2 response. Preliminary data suggest that DMF may induce neuroprotective effects in central nervous system white matter, although further studies are needed to demonstrate these effects on inflammatory demyelination. The DMF Phase III clinical trials demonstrated its efficacy with regard to a reduction in the annualized relapse rate and reductions in new or enlarging T2 lesions and numbers of gadolinium-enhancing lesions on magnetic resonance imaging. DMF has a well-defined safety profile, given the experience with its use in the treatment of psoriasis, and more recently from the DMF clinical trials program and post-marketing era for treatment of MS. The safety profile and oral mode of administration of DMF place it as an attractive first-line therapy option for the treatment of relapsing forms of MS. Long-term observational studies will be needed to determine the effects of DMF on progression of disability in MS.Keywords: multiple sclerosis, dimethyl fumarate, disease-modifying therapy, Nrf2 pathway, quality of life

Abstract Cyber‐physical systems have behaviour that crosses domain boundaries during events such as planned operational changes and malicious disturbances. Traditionally, the cyber and physical systems are monitored separately and use very different toolsets and analysis paradigms. The security and privacy of these cyber‐physical systems requires improved understanding of the combined cyber‐physical system behaviour and methods for holistic analysis. Therefore, the authors propose leveraging clustering techniques on cyber‐physical data from smart grid systems to analyse differences and similarities in behaviour during cyber‐, physical‐, and cyber‐physical disturbances. Since clustering methods are commonly used in data science to examine statistical similarities in order to sort large datasets, these algorithms can assist in identifying useful relationships in cyber‐physical systems. Through this analysis, deeper insights can be shared with decision‐makers on what cyber and physical components are strongly or weakly linked, what cyber‐physical pathways are most traversed, and the criticality of certain cyber‐physical nodes or edges. This paper presents several types of clustering methods for cyber‐physical graphs of smart grid systems and their application in assessing different types of disturbances for informing cyber‐physical situational awareness. The collection of these clustering techniques provide a foundational basis for cyber‐physical graph interdependency analysis.

Abstract Power systems are facing an increasing number of cyber incidents, potentially leading to damaging consequences to both physical and cyber aspects. However, the development of analytical methods for the study of large‐scale power infrastructures as cyber‐physical systems is still in its early stages. Drawing inspiration from machine‐learning techniques, the authors introduce a method inspired by the principles of graph embedding that is tailored for quantitative risk assessment and the exploration of possible mitigation strategies of large‐scale cyber‐physical power systems. The primary advantage of the graph embedding approach lies in its ability to generate numerous random walks on a graph, simulating potential access paths. Meanwhile, it enables capturing high‐dimensional structures in low‐dimensional spaces, facilitating advanced machine‐learning applications, and ensuring scalability and adaptability for comprehensive network analysis. By employing this graph embedding‐based approach, the authors present a structured and methodical framework for risk assessment in cyber‐physical systems. The proposed graph embedding‐based risk analysis framework aims to provide a more insightful perspective on cyber‐physical risk assessment and situation awareness for power systems. To validate and demonstrate its applicability, the method has been tested on two cyber‐physical power system models: the Western System Coordinating Council (WSCC) 9‐Bus System and the Illinois 200‐Bus System, thereby showing its advantages in enhancing the accuracy of risk analysis and comprehensiveness of situational awareness.

Abstract Background Pangolins are the only mammals that have overlapping scales covering most of their bodies, and they play a crucial role in the ecosystem, biological research, and human health and disease. Previous studies indicated pangolin scale might provide an important mechanical defense to themselves. The origin and exact functions of this unique trait remain a mystery. Using a multi-omics analysis approach, we report a novel functional explanation for how mammalian scales can provide host–pathogen defense. Results Our data suggest that pangolin scales have a sophisticated structure that could potentially trap pathogens. We identified numerous proteins and metabolites exhibiting antimicrobial activity, which could suggest a role for scales in pathogen defense. Notably, we found evidence suggesting the presence of exosomes derived from diverse cellular origins, including mesenchymal stem cells, immune cells, and keratinocytes. This observation suggests a complex interplay where various cell types may contribute to the release of exosomes and antimicrobial compounds at the interface between scales and viable tissue. These findings indicate that pangolin scales may serve as a multifaceted defense system, potentially contributing to innate immunity. Comparisons with human nail and hair revealed pangolin-specific proteins that were enriched in functions relating to sensing, immune responses, neutrophil degranulation, and stress responses. We demonstrated the antimicrobial activity of key pangolin scale components on pathogenic bacteria by antimicrobial assays. Conclusions This study identifies a potential role of pangolin scales and implicates scales, as possible determinants of pathogen defense due to their structure and contents. We indicate for the first time the presence of exosomes in pangolin scales and propose the new functions of scales and their mechanisms. This new mechanism could have implications for multiple fields, including providing interesting new research directions and important insights that can be useful for synthesizing and implementing new biomimetic antimicrobial approaches.

Abstract Background Despite Spirochetales being a ubiquitous and medically important order of bacteria infecting both humans and animals, there is extremely limited information regarding their bacteriophages. Of the genus Treponema, there is just a single reported characterised prophage. Results We applied a bioinformatic approach on 24 previously published Treponema genomes to identify and characterise putative treponemal prophages. Thirteen of the genomes did not contain any detectable prophage regions. The remaining eleven contained 38 prophage sequences, with between one and eight putative prophages in each bacterial genome. The prophage regions ranged from 12.4 to 75.1 kb, with between 27 and 171 protein coding sequences. Phylogenetic analysis revealed that 24 of the prophages formed three distinct sequence clusters, identifying putative myoviral and siphoviral morphology. ViPTree analysis demonstrated that the identified sequences were novel when compared to known double stranded DNA bacteriophage genomes. Conclusions In this study, we have started to address the knowledge gap on treponeme bacteriophages by characterising 38 prophage sequences in 24 treponeme genomes. Using bioinformatic approaches, we have been able to identify and compare the prophage-like elements with respect to other bacteriophages, their gene content, and their potential to be a functional and inducible bacteriophage, which in turn can help focus our attention on specific prophages to investigate further.

Abstract Background Technological burden and medical complexity are significant drivers of clinician burnout. Electronic health record(EHR)-based population health management tools can be used to identify high-risk patient populations and implement prophylactic health practices. Their impact on clinician burnout, however, is not well understood. Our objective was to assess the relationship between ratings of EHR-based population health management tools and clinician burnout. Methods We conducted cross-sectional analyses of 2018 national Veterans Health Administration(VA) primary care personnel survey, administered as an online survey to all VA primary care personnel (n = 4257, response rate = 17.7%), using bivariate and multivariate logistic regressions. Our analytical sample included providers (medical doctors, nurse practitioners, physicians’ assistants) and nurses (registered nurses, licensed practical nurses). The outcomes included two items measuring high burnout. Primary predictors included importance ratings of 10 population health management tools (eg. VA risk prediction algorithm, recent hospitalizations and emergency department visits, etc.). Results High ratings of 9 tools were associated with lower odds of high burnout, independent of covariates including VA tenure, team role, gender, ethnicity, staffing, and training. For example, clinicians who rated the risk prediction algorithm as important were less likely to report high burnout levels than those who did not use or did not know about the tool (OR 0.73; CI 0.61-0.87), and they were less likely to report frequent burnout (once per week or more) (OR 0.71; CI 0.60-0.84). Conclusions Burned-out clinicians may not consider the EHR-based tools important and may not be using them to perform care management. Tools that create additional technological burden may need adaptation to become more accessible, more intuitive, and less burdensome to use. Finding ways to improve the use of tools that streamline the work of population health management and/or result in less workload due to patients with poorly managed chronic conditions may alleviate burnout. More research is needed to understand the causal directional of the association between burnout and ratings of population health management tools.

Abstract Background Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills. Methods The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept. Results We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist (n = 21, p = 0.05). We also observed positive trends in social skills that did not reach significance. Conclusions Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program. Trial Registration ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 – Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290 .

IntroductionPrimary–secondary school transitions are critical transitions for children that can be emotionally demanding longitudinal experiences, which can positively and negatively impact future emotional wellbeing and mental health. However, interventions that have been developed to reduce the negative outcomes children commonly experience are limited in number, sustainability, and reach and rely on a cross-sectional approach, as opposed to longitudinal evaluations. The current study evaluates Transitions 5–7, a universal, class-based 9-week intervention to develop children’s awareness and ability to cope with the multiple changes experienced over primary–secondary school transitions.MethodsThe evaluation utilized a mixed-methods approach, combining both quantitative outcome and qualitative process intervention evaluation. For the outcome evaluation, a quasi-experimental research design was used, and children of the intervention and comparison groups completed a questionnaire in Year 5 (n = 185), Year 6 (n = 217), and Year 7 (n = 162), which assessed their self-reported perception of Transitions Worries, Transitions Excitement, Emotional Wellbeing, Parental Support, and Coping Efficacy. To understand the implementation of Transitions 5–7, three focus groups were conducted with Year 6 children, 3 interviews with teachers, and 1 interview with the Transitions Manager of the local government education authority during the project, who developed Transitions 5–7.ResultsThe outcome evaluation found that children participating in the intervention showed a decrease in Transitions Worries and an increase in Transitions Excitement and Coping Efficacy compared with the comparison group, resulting in a lowered impact on Emotional Wellbeing over time. The need for a more systemic approach to primary–secondary school support provision, which is gradual, has a distinct delivery and follows a skills-based curriculum, was discussed in the process evaluation. Meta-inferences drawn demonstrate the importance of gradual emotional centered transitions provision embedded within Years 5, 6, and 7.DiscussionThe present study makes a unique empirical contribution in demonstrating the need and viability to take a preventative as opposed to a curative approach to primary–secondary school transitions support provision and begin early in Year 5. Conceptual and methodological implications for future research and implications for educational policy and practice are discussed.

ABSTRACT BACKGROUND: Chile presents one of the lowest organ donation rates, resulting in pediatric liver waitlist mortality rates up to 38.1%. Live donor liver transplantation is one of the main alternatives to decrease waitlist mortality, mostly utilized in our country for small children up to 20 kg. AIMS: The aim of this study was to report a three-case series of adult-to-pediatric living donor liver transplantation using a full left lobe graft. METHODS: We report three cases of children with more than 20 kg who received complete left hemi-grafts in different clinical scenarios. The indications and techniques adopted are discussed. RESULTS: Three children, two girls and one boy, aged 11, 7, and 3 years, were transplanted. The indications for transplant were fulminant hepatitis of autoimmune etiology, hepatoblastoma, and chronic liver failure due to autoimmune hepatitis, respectively. The evolution was satisfactory in all three children, and to date, all are well, approximately 12–24 months after the transplant. CONCLUSIONS: The use of a living donor left lateral segment (segments 2 and 3) has been successfully employed in pediatric liver transplantation. However, it is only suitable for infants and low-weight children. This approach using the whole left hemi-liver graft contributes to the reduction of small-for-size syndrome, mortality rate, and waiting times associated with deceased donors.

Background Transurethral resection of bladder tumour has been the mainstay of bladder cancer staging for > 60 years. Staging inaccuracies are commonplace, leading to delayed treatment of muscle-invasive bladder cancer. Multiparametric magnetic resonance imaging offers rapid, accurate and non-invasive staging of muscle-invasive bladder cancer, potentially reducing delays to radical treatment. Objectives To assess the feasibility and efficacy of the introducing multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour in the staging of suspected muscle-invasive bladder cancer. Design Open-label, multistage randomised controlled study in three parts: feasibility, intermediate and final clinical stages. The COVID pandemic prevented completion of the final stage. Setting Fifteen UK hospitals. Participants Newly diagnosed bladder cancer patients of age ≥ 18 years. Interventions Participants were randomised to Pathway 1 or 2 following visual assessment of the suspicion of non-muscle-invasive bladder cancer or muscle-invasive bladder cancer at the time of outpatient cystoscopy, based upon a 5-point Likert scale: Likert 1–2 tumours considered probable non-muscle-invasive bladder cancer; Likert 3–5 possible muscle-invasive bladder cancer. In Pathway 1, all participants underwent transurethral resection of bladder tumour. In Pathway 2, probable non-muscle-invasive bladder cancer participants underwent transurethral resection of bladder tumour, and possible muscle-invasive bladder cancer participants underwent initial multiparametric magnetic resonance imaging. Subsequent therapy was determined by the treating team and could include transurethral resection of bladder tumour. Main outcome measures Feasibility stage: proportion with possible muscle-invasive bladder cancer randomised to Pathway 2 which correctly followed the protocol. Intermediate stage: time to correct treatment for muscle-invasive bladder cancer. Results Between 31 May 2018 and 31 December 2021, of 638 patients approached, 143 participants were randomised; 52.1% were deemed as possible muscle-invasive bladder cancer and 47.9% probable non-muscle-invasive bladder cancer. Feasibility stage: 36/39 [92% (95% confidence interval 79 to 98%)] muscle-invasive bladder cancer participants followed the correct treatment by pathway. Intermediate stage: median time to correct treatment was 98 (95% confidence interval 72 to 125) days for Pathway 1 versus 53 (95% confidence interval 20 to 89) days for Pathway 2 [hazard ratio 2.9 (95% confidence interval 1.0 to 8.1)], p = 0.040. Median time to correct treatment for all participants was 37 days for Pathway 1 and 25 days for Pathway 2 [hazard ratio 1.4 (95% confidence interval 0.9 to 2.0)]. Limitations For participants who underwent chemotherapy, radiotherapy or palliation for multiparametric magnetic resonance imaging-diagnosed stage T2 or higher disease, it was impossible to conclusively know whether these were correct treatments due to the absence of histopathologically confirmed muscle invasion, this being confirmed radiologically in these cases. All patients had histological confirmation of their cancers. Due to the COVID-19 pandemic, we were unable to realise the final stage. Conclusion The multiparametric magnetic resonance imaging-directed pathway led to a substantial 45-day reduction in time to correct treatment for muscle-invasive bladder cancer, without detriment to non-muscle-invasive bladder cancer participants. Consideration should be given to the incorporation of multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour into the standard pathway for all patients with suspected muscle-invasive bladder cancer. The improved decision-making accelerated time to treatment, even though many patients subsequently needed transurethral resection of bladder tumour. A proportion of patients can avoid transurethral resection of bladder tumour completely, reducing costs and morbidity, given the much lower cost of magnetic resonance imaging and biopsy compared to transurethral resection of bladder tumour. Future work Further work to cross-correlate with the recently developed Vesical Imaging-Reporting and Data System will improve accuracy and aid dissemination. Longer follow-up to examine the effect of the pathway on outcomes is also required. Incorporation of liquid deoxyribonucleic acid-based biomarkers may further improve the quality of decision-making and should also be investigated further. Study registration This study is registered as ISRCTN 35296862. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/08/60) and is published in full in Health Technology Assessment; Vol. 28, No. 42. See the NIHR Funding and Awards website for further award information. Plain language summary The BladderPath trial explored how to accelerate diagnosis and avoid unnecessary surgery for patients with bladder cancer which had grown into the muscle wall of the bladder, referred to as muscle-invasive bladder cancer. Following initial outpatient diagnosis, bladder cancer patients currently undergo inpatient or day-case surgical tumour removal using a telescope (transurethral resection of bladder tumour). This surgery is fundamental to the treatment of early bladder cancer (non-muscle-invasive). However, for muscle-invasive disease, the main role of transurethral resection of bladder tumour is to confirm that the tumour has grown into the bladder muscle, and this is often inaccurate; the actual correct treatment for muscle-invasive bladder cancer patients should include chemotherapy, radiotherapy and/or bladder removal. For these patients, having transurethral resection of bladder tumour may delay this correct treatment and impact survival. Additionally, for patients determined to need palliative care due to advanced disease, the transurethral resection of bladder tumour may represent over-treatment. A magnetic resonance imaging scan with contrast agent (called multiparametric magnetic resonance imaging) gives a clearer picture of the bladder than normal scans, allowing distinction between invasive and non-invasive tumours. The BladderPath trial investigated adding multiparametric magnetic resonance imaging for patients with suspected muscle-invasive bladder cancer and the effect on treatment times. Subsequent therapy could include transurethral resection of bladder tumour if clinically determined as necessary by the treating team. Trial participants were randomly allocated either to the standard pathway (Pathway 1: all underwent transurethral resection of bladder tumour) or to a new pathway (Pathway 2). In Pathway 2, urologists conducting the initial outpatient diagnostic bladder inspections used a scale to assess whether tumours appeared to be either probably non-muscle-invasive or possibly muscle-invasive. Participants whose tumours appeared possibly muscle-invasive had initial multiparametric magnetic resonance imaging as their next investigation instead of transurethral resection of bladder tumour. We then compared the duration of time from initial diagnosis to receiving the correct treatment for participants in each pathway. Of the 143 participants, 75 (52.1%) were diagnosed as possibly muscle invasive. In Pathway 1, the duration for half of the participants in the group to have received their correct treatment for muscle-invasive bladder cancer was 98 days, which reduced to 53 days in Pathway 2. Furthermore, the duration for half of all the participants in the two groups to have received their correct treatment was 37 days for Pathway 1 and 31 days for Pathway 2. In summary, use of initial multiparametric magnetic resonance imaging in suspected muscle-invasive bladder cancer participants substantially reduced the time to correct treatment (surgery, radiotherapy, chemotherapy or instigation of palliative care) and avoided unnecessary surgery. There was no negative impact on participants with non-invasive disease. Adopting multiparametric magnetic resonance imaging into the pathway ahead of transurethral resection of bladder tumour for patients with suspected muscle-invasive bladder cancer is recommended. Scientific summary Background Bladder cancer (BC) is the fifth most common cancer in Western society. Standard management follows a pathway established > 60 years ago with the first description of transurethral resection of bladder tumour (TURBT), and prognosis has not improved for 30 years. Following visual diagnosis by outpatient flexible cystoscopy, TURBT is the subsequent diagnostic and staging tool for all patients. While TURBT is mostly well-tolerated and therapeutic for non-muscle-invasive BC (NMIBC), its role in muscle-invasive BC (MIBC) is predominantly diagnostic. Furthermore, for MIBC patients, initial TURBT often under-stages invasion (up to 30% of MIBCs are initially staged as high-grade NMIBC at first TURBT) and may contribute to extravesical tumour dissemination as a result of the piecemeal resection process. Subsequently, accurate staging by cross-sectional pelvic imaging post TURBT is impaired by post-surgical artefacts. Moreover, internationally, TURBT followed by histopathological review and multidisciplinary team (MDT) decision-making typically adds a number of weeks to the pathway, creating a delay in commencing correct radical treatment for MIBC patients and potentially worse outcomes. Thus, an ideal pathway would separate NMIBC patients from MIBC patients at the time of diagnosis by the faster and more accurate application of established technologies to expedite therapy, potentially improving outcomes. Imaging advances suggesting multiparametric (mp) magnetic resonance imaging (MRI) may allow the accurate discrimination of NMIBC from MIBC, theoretically offering a safer and faster route to radical treatment than TURBT. To test the hypothesis whether MIBC patients can be safely expedited to radical treatment by using initial mpMRI for local staging rather than TURBT, we undertook the BladderPath randomised controlled trial [NHS Research Ethics Committee (REC) approval 17/LO/1819, ISRCTN 35296862]. Objectives To assess the feasibility and efficacy of the substitution of TURBT with mpMRI in the staging of patients with suspected MIBC, hypothesising that image-directed (mpMRI) staging would shorten the time period to correct treatment for MIBC patients compared to the standard TURBT-based pathway. Methods BladderPath is a randomised trial comparing risk-stratified image-directed (mpMRI) care with TURBT for patients with newly diagnosed BC. Patients with symptoms suspicious of a new diagnosis of BC were identified via haematuria clinics, and they provided written informed consent for study participation. Ineligible patients were those unable or unwilling to undergo MRI, those with a previous BC diagnosis and those who had previously entered the study. Participants with possible MIBC (Likert 3–5 as visually assessed on a 5-point Likert scale at flexible cystoscopy) were randomised to standard TURBT assessment (Pathway 1) or mpMRI-based assessment (Pathway 2) with flexible cystoscopy tumour biopsy Pathway 2 probable NMIBC (Likert 1–2) participants underwent TURBT. Primary outcomes: Feasibility phase – proportion of Pathway 2 possible MIBC participants who correctly followed protocol (target: 80%); intermediate stage – time to first correct treatment (chemotherapy, radiotherapy, surgery, decision for palliative care) for participants with confirmed MIBC (target: 30-day improvement) and as time to TURBT or palliative care for NMIBC. Randomisation was achieved by using a computerised allocation program; stratification variables included participants’ sex, age and clinician’s initial visual assessment of muscle invasiveness of the tumour. Blinding of participants, caregivers and outcome assessors was not possible. Results Between 31 May 2018 and 31 December 2021, recruitment took place in 15 UK urology centres; 638 patients were screened as potentially eligible, of which 309 were registered and 143 were randomised (72 to Pathway 1, 71 to Pathway 2). The 166 registered patients not randomised were not found to have BC during initial cystoscopy. Three participants were subsequently found to be ineligible post randomisation (one in Pathway 1, two in Pathway 2). Seven participants withdrew from the study (three in Pathway 1, four in Pathway 2), including three participants who were confirmed as not having cancer. Nine protocol deviations were reported by nine participants (five in Pathway 1, four in Pathway 2). The primary outcome for the feasibility stage was the proportion of possible MIBC participants randomised to Pathway 2 who correctly followed the pathway protocol. In total, 36 of the 39 [92%; 95% confidence interval (CI) 79% to 98%] possible MIBC participants in Pathway 2 underwent mpMRI as per protocol. Three Pathway 2 possible MIBC participants did not undergo mpMRI post randomisation: one participant had metal in their eye, one patient withdrew (29 days post randomisation) and one underwent MRI prior to trial entry (scan was requested independently of the study). Of the 36 participants who underwent mpMRI, 17 were diagnosed as MIBC, 16 as NMIBC and 3 were inconclusive. The secondary outcome for the feasibility stage was the overall proportion of randomised participants who correctly followed the protocol in each pathway. For Pathway 1, this was defined as the number of probable NMIBC and possible MIBC participants randomly accrued who underwent TURBT at an appropriate stage, as a proportion of all participants randomised to that pathway. For Pathway 2, it was defined as the number of probable NMIBC participants who underwent TURBT plus the number of possible MIBC participants who underwent mpMRI, divided by all randomised to Pathway 2. The overall proportion of participants who correctly followed their respective protocol pathway was 96% (95% CI 88% to 99%) in each pathway. There was no statistical difference between the pathways. For the Intermediate stage, the primary outcome was time to correct treatment (TTCT) for participants who were initially classified as possible MIBC and were then confirmed to have MIBC (by TURBT or mpMRI). For the 25 participants who were initially classified as possible MIBC and were then confirmed as MIBC (14 in Pathway 1; 11 in Pathway 2), 24 participants received a correct treatment (the remaining patients died 81 days post randomisation, before a correct treatment; date last seen is used in the time-to-event analysis). Median TTCT for all participants who were initially classified as possible MIBC and were then confirmed to have MIBC (N = 25) was 77 days (95% CI 54 to 98). Median TTCT for Pathway 1 (N = 14) was 98 days (95% CI 72 to 125). Median TTCT for Pathway 2 (N = 11) was 53 days (95% CI 20 to 81). The p-value of 0.0201 suggests a statistical difference in TTCT between the pathways. A Cox model adjusting for the stratification factors of sex and age, with study centre included as a random effect, showed that the hazard ratio (HR) of an event for Pathway 2 versus Pathway 1 was 2.9 (95% CI 1.0 to 8.1, p = 0.04). An event in this model indicates a patient receiving a correct treatment; therefore, the HR of 2.9 indicates that participants in Pathway 2 received correct treatment 2.9 times quicker than those in Pathway 1. To assess the secondary outcome of TTCT for probable NMIBC participants confirmed as NMIBC, there were 58 participants initially classified as probable NMIBC and then confirmed as NMIBC (28 in Pathway 1 and 30 in Pathway 2), all of whom received correct treatment of TURBT. Median TTCT for probable NMIBC participants confirmed as NMIBC (N = 58) was 16 days (95% CI 11 to 23); median TTCT for Pathway 1 (N = 28) was 14 days (95% CI 10 to 29) and 17 days (95% CI 8 to 25) for Pathway 2 (N = 25), log-rank p = 0.6677. A Cox model adjusting for the stratification factors of sex and age showed that the HR for Pathway 2 versus Pathway 1 was 0.8 (95% CI 0.5 to 1.5). For the secondary outcome of TTCT for all randomised participants, 131 of 143 randomised participants had received a correct treatment (72 in Pathway 1 and 71 in Pathway 2); participants who had not received a correct treatment were censored at their date last seen and included in the time-to-treatment analysis. Median TTCT for all randomised participants (N = 143) was 31 days (95% CI 22 to 37); median TTCT for Pathway 1 (N = 72) was 37 days (95% CI 23 to 47) and 25 days (95% CI 18 to 35) for Pathway 2 (N = 71), log-rank p = 0.0295. A Cox model adjusting for the stratification factors of sex and age showed that the HR for Pathway 2 versus Pathway 1 was 1.4 (95% CI 0.9 to 2.0). To assess the secondary outcome of time to definitive treatment (TTDT) for all randomised participants, 137 randomised participants had received definitive treatment (6 participants did not receive definitive treatment and their date last seen was used in the time-to-event analysis). Median TTDT for all randomised participants (N = 143) was 23 days (95% CI 20 to 29); median TTDT for Pathway 1 (N = 72) was 23 days (95% CI 17 to 29) and for Pathway 2 (N = 71) was 22 days (95% CI 17 to 32), log-rank p-value of 0.9619. A Cox model adjusting for the stratification factors of sex and age showed that the HR for Pathway 2 versus Pathway 1 was 0.9 (95% CI 0.6 to 1.2). Clinical analysis Delays in administering the correct treatment for MIBC patients after initial urological consultation and disease diagnosis are internationally widespread [Russell B, Liedberg F, Khan MS, Nair R, Thurairaja R, Malde S, et al. A systematic review and meta-analysis of delay in radical cystectomy and the effect on survival in bladder cancer patients. Eur Urol Oncol 2020;3(2):239–49]. Prolonged delays contribute to poor prognosis, and so attempts to improve and refine the diagnostic and treatment pathways for BC patients are of international importance and a priority for patients and healthcare professionals alike [Russell et al. 2020; Bessa A, Maclennan S, Enting D, Bryan R, Josephs D, Hughes S, et al. Consensus in bladder cancer research priorities between patients and healthcare professionals using a four-stage modified Delphi method. Eur Urol 2019;76(2):258–9]. Although first described over 60 years ago, the piecemeal resection of bladder tumour(s), TURBT, remains the initial diagnostic and staging tool for all patients. The shortcomings of TURBT are well-reported [Bessa et al. 2019; Del Giudice F, Flammia RS, Pecoraro M, Moschini M, D’Andrea D, Messina E, et al. The accuracy of Vesical Imaging-Reporting and Data System (VI-RADS): an updated comprehensive multi-institutional, multi-readers systematic review and meta-analysis from diagnostic evidence into future clinical recommendations. World J Urol 2022;40(7):1617–28; Wallace DM, Bryan RT, Dunn JA, Begum G, Bathers S; West Midlands Urological Research Group. Delay and survival in bladder cancer. BJU Int 2002;89(9):868–78; Bryan RT, Collins SI, Daykin MC, Zeegers MP, Cheng KK, Wallace DMA, et al. Mechanisms of recurrence of Ta/T1 bladder cancer. Ann R Coll Surg Engl 2010;92(6):519–24], all of which may delay the correct radical treatment for MIBC patients or lead to incorrect therapy choices. Over the course of the last decade, data suggest that mpMRI may allow the accurate discrimination of NMIBC and MIBC, and so potentially offering a safer and faster route to radical treatment than TURBT (Panebianco et al. 2018; Del Giudice et al. 2022). We have shown that it is feasible to introduce mpMRI for initial staging into the pathway for those patients visually diagnosed with possible MIBC at outpatient diagnostic flexible cystoscopy. Moreover, we have demonstrated that by doing so, possible MIBC patients receive their correct therapy significantly quicker – 45 days quicker, even if some of these MIBC patients still require TURBT either to resolve diagnostic uncertainty or as part of their planned care (e.g. to debulk tumour prior to radiotherapy). Although the relationship between delay and survival in BC is complex (Wallace et al. 2002), it is reasonable to contemplate that administering correct treatment to MIBC patients more than 6 weeks earlier than the current standard of care can only be beneficial. Several studies report adverse outcomes associated with delays of over 3 months between bladder cancer diagnosis and radical cystectomy (Russell et al. 2020); the mpMRI-guided BladderPath pathway (Pathway 2) undercut this TTCT by a considerable margin (median TTCT 53 days), whereas the standard pathway did not (median TTCT 98 days). Unfortunately, with substantial interruptions to recruitment due to the COVID-19 pandemic, we have been unable to recruit sufficient patients to evaluate our a priori survival outcomes. Further limitations to the study are that, for patients who underwent systemic chemotherapy, radiotherapy or palliation for mpMRI-diagnosed MIBC, it is impossible to conclusively know whether these were ‘correct’ treatments in the sense that staging was radiological not pathological, that is by histological confirmation of muscle invasion. This is however the norm for staging of most cancers. All patients had histological confirmation of their cancers and all treatments were approved via the relevant MDT. An important component of this new pathway is the ability of urologists to accurately triage patients as probable NMIBC or possible MIBC at the time of outpatient diagnostic flexible cystoscopy based upon the macroscopic appearances of suspicious bladder lesions. Building upon previous evidence (Bryan et al. 2010), we have shown that 89% of visually diagnosed probable NMIBCs were pathologically confirmed as NMIBCs, demonstrating that urologists can reliably identify such tumours. Hence, the simple patient pathway change suggested by the BladderPath data described here is universally applicable and is easy to implement. Conclusions The mpMRI-directed pathway led to a substantial reduction in TTCT for MIBC participants without detriment to the TTCT for NMIBC participants. Consideration should be given to the incorporation of mpMRI ahead of TURBT in the standard pathway for all patients with suspected MIBC. A proportion of patients were able to avoid TURBT completely and the improved decision-making accelerated time to treatment, even though many patients subsequently needed TURBT as part of their treatment plan. Trial registration This trial is registered as ISRCTN 35296862. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/08/60) and is published in full in Health Technology Assessment; Vol. 28, No. 42. See the NIHR Funding and Awards website for further award information.

Background The Army Medical Department (AMEDD) Military-Civilian Trauma Team Training (AMCT3) Program was developed to enhance the trauma competency and capability of the medical force by embedding providers at busy civilian trauma centers. Few reports have been published on the outcomes of this program since its implementation.Methods The medical and billing records for the two AMCT3 embedded trauma surgeons at the single medical center were retrospectively reviewed for care provided during August 2021 through July 2022. Abstracted data included tasks met under the Army’s Individual Critical Task List (ICTL) for general surgeons. The Knowledge, Skills, and Abilities (KSA) score was estimated based on previously reported point values for procedures. To assess for successful integration of the embedded surgeons, data were also abstracted for two newly hired civilian trauma surgeons.Results The annual clinical activity for the first AMCT3 surgeon included 444 trauma evaluations and 185 operative cases. The operative cases included 80 laparotomies, 15 thoracotomies, and 15 vascular exposures. The operative volume resulted in a KSA score of 21 998 points. The annual clinical activity for the second AMCT3 surgeon included 424 trauma evaluations and 194 operative cases. The operative cases included 92 laparotomies, 8 thoracotomies, and 25 vascular exposures. The operative volume resulted in a KSA score of 22 799 points. The first civilian surgeon’s annual clinical activity included 453 trauma evaluations and 151 operative cases, resulting in a KSA score of 16 738 points. The second civilian surgeon’s annual clinical activity included 206 trauma evaluations and 96 operative cases, resulting in a KSA score of 11 156 points.Conclusion The AMCT3 partnership at this single center greatly exceeds the minimum deployment readiness metrics established in the ICTLs and KSAs for deploying general surgeons. The AMEDD experience provided a deployment-relevant case mix with an emphasis on complex vascular injury repairs.

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) of the SARS-CoV-2 S protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of the S protein compared to the closed form. In particular, the CAP sites control the dynamics of binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly additive mutations. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.

Modern power grids and other complex systems are a fusion of physical and cyber components, giving rise to intricate interdependencies. These interdependencies, however, also expose vulnerabilities that can be exploited by adversaries. This paper delves into the critical examination of these interconnections, inspired by Ecological Network Analysis (ENA). By drawing from ecological modeling, we aim to understand the role of cyber-physical interdependencies in the resilience of complex systems. We introduce various modeling methods, including bipartite and tripartite networks, to analyze and map these interdependencies in the context of the IEEE WSCC 9-bus and the ACTIV 200-bus case study. The paper explores how these models can identify key actors and assess network resilience. Through a detailed methodology, we apply ecological metrics and community identification techniques to comprehensively evaluate the system’s interactions. The findings offer insights into the interplay of cyber and physical elements in power grids and other complex systems. These analysis methods show that tripartite networks produce more information on indirect interactions within a complex network. Additionally, they provide detailed information on how disturbances could propagate in a cyber-physical power system. Denial of service scenarios for the WSCC 9-bus and the ACTIV 200-bus case studies are employed to support this conclusion.

Despite improvements in short-term and long-term outcomes of liver transplant patients, the discrepancy between the number of available livers and transplant candidates continues to increase. The use of expanded criteria donors is one strategy that can be used to address donor shortages. In recent years, preservation strategies such as normothermic machine perfusion (NMP) have been explored to improve the preservation of organs and test their viability before transplantation. We reviewed the recent literature and trials assessing the use of NMP in the setting of liver transplantation. Multiple feasibility trials have demonstrated the clinical prospect of NMP and proved its numerous advantages compared to conventional static cold storage. These advantages include preservation and viability assessment of high-risk donor allografts and grafts that would have otherwise been discarded. This review aims to address the topic of liver NMP in the setting of current and future applications in the setting of extended criteria donor grafts.

Summary: Background: Blood-based biomarkers of Alzheimer’s disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes. Methods: We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology. Findings: Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC = 0.95; Janssen AUC = 0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change. Interpretation: Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217. Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation.

BackgroundThe COVID-19 pandemic impacted the practices of most mental health providers and resulted in a rapid transition to providing telemental health services, changes that were likely related to stay-at-home policies as well as increased need for services. ObjectiveThe aim of this study was to examine whether these changes to practice have been sustained over time throughout the course of the COVID-19 pandemic and whether there are differences among mental health provider type and setting. We hypothesized that there would be an increase in the number of patients seen in person after the initial surge of the pandemic in spring 2020 and subsequent discontinuation of stay-at-home policies, though with continued implementation of telemental health services across settings. MethodsThis study surveyed 235 of the 903 mental health providers who responded to a survey in spring 2020 (Time point 1) and at a 1-year follow-up in spring 2021 (Time point 2). Differences in practice adjustments, factors related to telemental health, and number of patients seen were examined across provider type (social worker, psychologist, neuropsychologist) and setting (academic medical center [AMC], community mental health, private practice, and Veterans Affairs hospital). ResultsFrom Time point 1 to Time point 2, there was a small but significant increase in the overall number of providers who were implementing telehealth (191/235, 81% to 204/235, 87%, P=.01) and there was a significant decline in canceled or rescheduled appointments (25%-50% in 2020 to 3%-7% in 2021, P

Objective: Chronic pain is known to affect approximately a quarter of the United States population. Despite the prevalence of chronic pain, current chronic pain measures are often reliant on self reports and other similar subjective data. The purpose of this study was to examine chronic pain in a longitudinal and naturalistic setting for the potential to enhance chronic pain patient care by capturing more realistic and consistent data in everyday settings. Methods: The study sample consisted of a National Health and Nutrition Examination Survey (NHANES) sample from 2003–2004 with 4,240 participants that had an average age of 49.57(SD = 18.38) years. The NHANES sample had movement intensity data collected each minute over 7 days by wearing a hip mounted Actigraph accelerometer. This data was used to determine if chronic pain could be predicted by movement intensity. Results: A deep learning model for time series (i.e., convolutional long short-term memory network model) determined that participants’ chronic pain could be predicted with daily actigraphy movement intensity (AUC validation = 0.60, AUC test = 0.57). Additionally, participants with chronic pain had, on average, lower physical activity intensity (124.09 counts per minute, 95% CI: 112.58–135.59) than participants without chronic pain (152.29 counts per minute, 95% CI: 147.87–156.72). Conclusions: The results of this study demonstrated that passive wearable measures of physical activity could serve as a potential biomarker for chronic pain. Chronic pain could be predicted using daily activity movement intensity, which supports the value of passive data collection for assessment of chronic pain.

The SMART Pass filter (Boston Scientific) aims to reduce inappropriate shocks (IASs) from subcutaneous implantable cardioverter-defibrillators by filtering out low-frequency signals such as T waves. However, this filter is deactivated in the presence of diminished R-wave sensing. We describe a case of IAS in the setting of extensive intra-abdominal hemorrhage.

The evolution of soil structure in agricultural soils is driven by natural and anthropogenic factors including inherent soil properties, climate and soil management interventions, all acting at different spatial and temporal scales. Although the causal relationships between soil structure and these individual factors are increasingly understood, their relative importance and complex interactive effects on soil structure have so far not been investigated across a geo-climatic region.Here we present the first attempt to identify the relative importance of factors that drive the evolution of soil structure in agricultural soils as well as their direction of effect with a focus on the temperate-boreal zone. This was done using a random forest (RF) approach including soil, climate, time, and site factors as covariates. Relative entropy, as quantified by the Kullback-Leibler (KL) divergence, was used as a quantitative index of soil structure, which is derived from the particle-size distribution and soil water retention data, and integrates the effects of soil structure on pores from the micrometre-scale to large macropores. Our dataset includes 431 intact topsoil and subsoil samples from 89 agricultural sites across Sweden and Norway, which were sampled between 1953 and 2017. The relative importance of covariates for the evolution of soil structure was identified and their non-linear and non-monotonic effects on the KL divergence were investigated through partial dependence analysis. To reveal any differences between topsoils (0–30 cm; n = 174) and subsoils (30–100 cm; n = 257), the same analysis was repeated separately on these two subsets.The covariates were able to explain on average more than 50% of the variation in KL divergence for all soil samples and when only subsoil samples were included. However, the predictions were poorer for topsoil samples (≈ 35%), underlining the complex dynamics of soil structure in agricultural topsoils. Parent material was the most important predictor for the KL divergence, followed by clay content for all soil samples and sampling year for only subsoil samples. Mean annual air temperature ranked third and annual precipitation ranked fourth for subsoil samples. However, it remains unclear whether the effects of climate factors are direct (e.g., freezing and thawing, wetting and drying, rainfall impact) or indirectly expressed through interactions with soil management. The partial dependence analysis revealed a soil organic carbon threshold of around 3% below which soil structure starts to deteriorate. Besides this, our results suggest that subsoil structure in the agricultural land of Sweden deteriorated steadily during the 1950′s to 1970′s, which we attribute to traffic compaction as a consequence of agricultural intensification. We discuss our findings in the light of data bias, laboratory methods and multicollinearity and conclude that the approach followed here gave valuable insights into the drivers of soil structure evolution in agricultural soils of the temperate-boreal zone. Theses insights will be of use to inform soil management interventions that address soil structure or soil properties and functions related to it.

Clinical audit has been recognised as one of the most significant initiatives in clinical practice in recent years and can result in improvements in the quality of patient care. Clinical [...]

Mycobacterium abscessus (Mab) is an emerging human pathogen that has a high rate of incidence in immunocompromised individuals. We have found a putative secondary metabolite pathway within Mab, which may be a key factor in its pathogenesis. This novel pathway is encoded in a gene cluster spanning MAB_0284c to 0305 and is related to Streptomyces pathways, producing the secondary metabolites streptonigrin and nybomycin. We constructed an in-frame deletion of the MAB_0295 (phzC) gene and tested it in our Xenopus laevis animal model. We have previously shown that X. laevis tadpoles, which have functional lungs and T cells, can serve as a reliable comparative model for persistent Mab infection and pathogenesis. Here, we report that tadpoles intraperitoneally infected with the ∆phzC mutant exhibit early decreased bacterial loads and significantly increased survival compared with those infected with WT Mab. ∆phzC mutant Mab also induced lower transcript levels of several pro-inflammatory cytokines (IL-1β, TNF-α, iNOS, IFN-γ) than those of WT Mab in the liver and lungs. In addition, there was impaired macrophage recruitment and decreased macrophage infection in tadpoles infected with the ∆phzC mutant, by tail wound inoculation, compared to those infected with the WT bacteria, as assayed by intravital confocal microscopy. These data underline the relevance and usefulness of X. laevis tadpoles as a novel comparative animal model to identify genetic determinants of Mab immunopathogenesis, suggesting a role for this novel and uncharacterized pathway in Mab pathogenesis and macrophage recruitment.

Background: We discuss a case of an immunocompetent patient who presented with fever and tachypnoea, found to have Candida parapsilosis bone marrow infection, cultured on bone marrow aspirate sample. Candida parapsilosis is an opportunistic yeast pathogen that typically affects immunocompromised individuals, or occurs in patients with apparent introduced source; neither of these factors were present for this case. Bone marrow aspirates and trephines are not regular investigations for fever; however they can be useful diagnostic aids as evidenced in this case. Case report: An 83-year-old woman presenting with fevers and tachypnoea was being treated for a systemic bacterial infection, however was unresponsive to empirical antibiotic therapy. To exclude an occult malignancy, an 18-fluorodeoxyglucose positron emission tomography scan was conducted. Significant bone marrow uptake was noted, prompting a bone marrow aspirate and trephine to investigate for a hematological malignancy. While the trephine biopsy was benign, a culture of the aspirate grew Candida parapsilosis. Intravenous antifungal therapy was initiated; however, the patient did not improve despite targeted therapy likely due to delays in diagnosis, and was palliated. Conclusion: Our case seeks to demonstrate a novel case whereby a bone marrow aspirate culture provided a conclusive diagnosis of invasive Candida parapsilosis bone marrow infection, and guided treatment in an immunocompetent patient. It is important for clinicians to consider invasive fungal infections in febrile patients regardless of immune status. Additionally, when performing a bone marrow aspirate and trephine on a febrile patient, we recommend including aspirate fungal cultures to investigate for an invasive fungal infection.

Macropores are known to be important pathways for the rapid transport of water, solutes and colloids in soil. Nevertheless, we still know very little about how the topology and geometry of macropore networks govern water flow configurations and velocities in natural soil. In this study, we aimed at gaining more insight into macropore flow by using X-ray tomography to quantify air–water distributions in the macropore networks of undisturbed topsoil and subsoil columns of a clay soil at varying steady-state flow rates. We observed that while large fractions of the macropore network remained air-filled, the air phase only became entrapped when the irrigation rate was very close to the saturated hydraulic conductivity of the soil. The data enabled us to parameterize a kinematic wave model for water flow following the approach proposed in Jarvis et al. (2017a). Follow-up experiments would be required to evaluate whether these kinematic wave parameters derived by X-ray imaging match with those obtained from outflow measurements. We found that quantitative X-ray imaging of macropore flow through soils still remains a challenging task. We recommend that future experiments are conducted on smaller soil samples to improve image resolution and minimize experimental time spans as well as X-ray image noise and illumination bias. Such experiments could also include 3-D tracer imaging to identify the imaged macropore networks transporting most of the water (i.e. the backbone) at varying steady irrigation rates.

Introduction Infectious intracranial aneurysms (IIA) represent one of several cerebrovascular pathologies associated with infective endocarditis (IE). Neuroimaging in patients with IE, especially in those undergoing cardiac procedures, have scarcely been examined in the literature. Digital subtraction angiography (DSA), or cerebral angiogram, remains the gold standard for the detection of IIA, yet the utility of this invasive imaging modality is uncertain. Herein, we aim to better understand current national trends in the use of neuroimaging in this group of patients, and its impact on patient outcomes. Methods Hospitalizations for IE with concurrent procedures for left‐sided cardiac valve surgery (VS) were identified in the National Inpatient Sample (NIS) registry during the period of 2015‐2020 using weighted approximations and validated International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) diagnosis and procedural coding. The primary exposure was DSA and the trend of its use was evaluated during the study period. Multivariable logistic regression analysis was performed to evaluate the adjusted association of angiography with in‐hospital mortality, the primary study endpoint, while accounting for age and illness severity [quantified by All Patient Refined Diagnostic Related Groups (APR‐DRG) illness severity subclass]. Effect size was reported as adjusted odds ratio (aOR) with 95% confidence interval (CI) and a stringent statistical significance threshold of p < 0.001. Results This analysis identified 31,550 hospitalizations for IE treated with VS, of which 1,160 (3.7%) underwent DSA. Utilization of angiography significantly increased during the study period (trend p < 0.001; Kendall’s tau‐b = 0.002), with the rate of the final year of the study nearly doubling that of the first (2020 4.9% vs. 2015 2.5%, p < 0.001). IE VS patients undergoing angiography experienced significantly decreased mortality rates in comparison to those not receiving an angiogram (4.3% vs. 7.5%; p < 0.001). Following multivariable logistic regression analysis, angiography was significantly associated with decreased mortality, independent of age and illness severity (aOR 0.49, 95% CI 0.37, 0.66; p < 0.001). Conclusion The current literature on neurological complications of IE includes limited data on the defined role of neuroimaging in dictating management. The theoretical risk in IE patients undergoing cardiac procedures involving heparinization includes the risk of intracerebral hemorrhage, especially in those with IIA. While less invasive neuroimaging is thought to suffice in detecting bleeds, DSAs remain more sensitive for IIA detection. In our study, not only did the number of IE patients undergoing DSA increase over time, but they had better mortality rates. Future directions should focus on understanding the appropriate timing of imaging in relation to the patient’s disease course to optimize inpatient care.

Introduction The rapid growth of the elderly population, an increase in cardiac disease, and notable use of intracardiac prosthetic devices has led to an increased prevalence of infective endocarditis (IE). Among the sequelae observed with an IE diagnosis, acute ischemic stroke (AIS), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), vasculitis, septic emboli, cerebral abscess, and infectious intracranial aneurysms (IIA) continue to complicate overall management of this disease. Current literature on neurological complications of IE includes limited data on the defined role of neuroimaging in dictating inpatient management. Transcranial doppler (TCD) emboli monitoring with high intensity signals (HITS) offers a real time, radiation‐free, relatively low cost, non‐invasive imaging option to potentially risk stratify and identify candidates for earlier intervention to prevent further cerebrovascular (CV) complications. Methods We conducted an observational study of infective endocarditis cases admitted to our institution from April 2022 to May 2023 who had TCD with HITS completed. Baseline clinical characteristics (age, sex, date and timing of TCD with HITS study, date of last positive blood culture, organism of infection, other neuroimaging utilized) were recorded. Observations recorded included the results of the TCD with HITS studies, the overall incidence and timing of neurological complications (AIS, SAH, ICH, IIA, septic emboli, cerebral abscess), timing of valve surgery, and inpatient mortality rates. A positive HITS was defined as detection of cerebral microembolism during ultrasound monitoring of bilateral middle cerebral arteries (MCA) for 30 minutes using a TCD machine (VIASONIX Dolphin IQ). Results Between April 2022 to July 2023, we identified 22 patients with confirmed left‐sided infective endocarditis who underwent TCD with HITS. Mean age was 66 years (SD, 10), and 82% were men. Leading pathogen types were Enterococcus Faecalis (27%) and Staphylococcus Epidermidis (18%). CV complications were noted in 19/22 patients (86%), the most common being AIS (82%) and IPH (18%). Two patients (9%) were found to have a positive HITS study, both of which developed septic emboli that caused ischemic stroke in one case, and hemorrhagic stroke in the other case. Average days from admission to timing of TCD with HITS study was 8.5 days. 14/22 patients underwent valve surgery (64%) during the admission on average 9.2 days after TCD with HITS study in the negative HITS group versus 5 days in the positive HITS group. Of the positive HITS cases, one of them died inpatient. Conclusion The association between neurological complications in patients with IE and cerebral microemboli detected with TCD monitoring has yet to be elucidated. While our observational study was limited by our sample size, both of our IE patients who had positive TCD with HITS studies developed more severe CV complications, and aggressive care was sought out more urgently to further minimize complications. Future directions include pursuing a prospective study incorporating TCD with HITS monitoring for patients with IE in order to risk‐stratify neurological complications and safety of valve surgery.

Introduction Carotid artery dissection (CAD) is an uncommon and potentially life‐threatening condition that can have a delayed presentation. More commonly associated with blunt cervical trauma, CAD due to repetitive stress to the neck goes under‐recognized, making it challenging to diagnose. Herein, we aim to shed light on a unique instance of CAD after continuous microtrauma, as well as highlight diagnostic challenges associated with CAD. Methods We present a case of a 57‐year‐old man who presented with a one‐week course of unequal pupils, left‐sided headaches, left sided ptosis, and intermittent blurry vision. Exam revealed a callous where he held a violin against his left neck, having endorsed playing for several years with repeated contortion of his head to the left (Figure 1A). Magnetic resonance angiogram (MRA) of the head and neck revealed an acute dissection of the left internal carotid artery (ICA) (Figure 1B). A diagnosis of Horner’s syndrome secondary to acute dissection of the left cervical ICA was made. Consent to share this information was obtained from the patient and witnessed by another physician. Results MRA head and neck showed a 2.5 cm irregularity of the distal left ICA with high signal on fat saturated T1‐weighted images consistent with an acute dissection (Figure 1B). The patient underwent an apraclonidine test and was positive for left sided Horner’s syndrome with reversal of anisocoria after application of drops (Figure 1C). Given no evidence of stroke or thrombus on imaging, he was placed on dual antiplatelet therapy (DAPT) for three months. He was advised not to play violin for a month and to restart cautiously with a pad between his neck and the instrument. Follow‐up imaging showed eventual resolution of the CAD, while physical exam revealed improvement in ptosis and miosis. Conclusion While playing the violin involves repetitive stress on the neck, there is limited research on this specific activity as a cause of carotid artery dissection, making it a rare occurrence. Common clinical manifestations of CAD include neck pain, headache, Horner’s syndrome, tinnitus, stroke, and lower cranial nerve palsies, occurring suddenly or over time. Diagnosing CAD typically involves a combination of thorough history, physical examination, and diagnostic imaging. Ongoing research in the optimal management of CAD focuses on minimizing the risk of stroke, after factoring in variables such as location of dissection and whether it is symptomatic or not.

Background: General anaesthesia (GA) for atrial fibrillation (AF) ablation is often preferred over conscious sedation (CS) to minimize patient discomfort and reduce the risk of map disruption from patient movement but may pose an additional risk to some patients with significant comorbidity or poor cardiac function. Methods: We extracted data for 300 patients who underwent AF ablation between the years 2017 and 2019 and compared the outcomes of AF ablation with CS and GA. Results: Compared to the GA group, patients were younger in the CS group (63 versus 66 years, p = 0.02), had less persistent AF (34% versus 46%, p = 0.048) and the left atrial dimension was smaller (41 versus 45 mm, p = 0.01). More patients had cryoballoon ablation (CBA) than radiofrequency (RFA) ablation in the CS than the GA group (88% CB with CS and 56% RF with GA, p

Abstract Borrelia burgdorferi, the tick-transmitted spirochete agent of Lyme disease, has a highly segmented genome with a linear chromosome and various linear or circular plasmids. Here, by imaging several chromosomal loci and 16 distinct plasmids, we show that B. burgdorferi is polyploid during growth in culture and that the number of genome copies decreases during stationary phase. B. burgdorferi is also polyploid inside fed ticks and chromosome copies are regularly spaced along the spirochete’s length in both growing cultures and ticks. This patterning involves the conserved DNA partitioning protein ParA whose localization is controlled by a potentially phage-derived protein, ParZ, instead of its usual partner ParB. ParZ binds its own coding region and acts as a centromere-binding protein. While ParA works with ParZ, ParB controls the localization of the condensin, SMC. Together, the ParA/ParZ and ParB/SMC pairs ensure faithful chromosome inheritance. Our findings underscore the plasticity of cellular functions, even those as fundamental as chromosome segregation.

This paper investigates the effect of GaAsBi strain reduction layers (SRLs) on InAs QDs with different Bi fluxes to achieve nanostructures with improved temperature stability. The SRLs are grown at a lower temperature (370 °C) than the usual capping temperature for InAs QDs (510 °C). The study finds that GaAs capping at low temperatures reduces QD decomposition and leads to larger pyramidal dots but also increases the threading dislocation (TD) density. When adding Bi to the capping layer, a significant reduction in TD density is observed, but unexpected structural changes also occur. Increasing the Bi flux does not increase the Bi content but rather the layer thickness. The maximum Bi content for all layers is 2.4%. A higher Bi flux causes earlier Bi incorporation, along with the formation of an additional InGaAs layer above the GaAsBi layer due to In segregation from QD erosion. Additionally, the implementation of GaAsBi SRLs results in smaller dots due to enhanced QD decomposition, which is contrary to the expected function of an SRL. No droplets were detected on the surface of any sample, but we did observe regions of horizontal nanowires within the epilayers for the Bi-rich samples, indicating nanoparticle formation.

Context: Urine culture has low sensitivity in the diagnosis of urinary tract infection (UTI). Next-generation sequencing (NGS) and polymerase chain reaction (PCR) are culture-independent molecular methods available for commercial use to diagnose UTI. Objective: To systematically evaluate the evidence comparing the diagnostic and therapeutic values of molecular diagnostic methods to urine culture in the management of UTI in adults. Evidence acquisition: We performed a critical review of Embase, Ovid, and PubMed in February 2022 according to the Preferred Reporting Items for Systematic Review and Meta-analyses statement. Studies involving pregnant women, ureteral stones, ureteral stents, and percutaneous nephrostomy tubes were excluded. Risk of bias and methodological quality were assessed using the Cochrane risk of bias tool and Newcastle Ottawa Scale. Fifteen publications were selected for inclusion. Evidence synthesis: Included reports compared NGS (nine studies) and PCR (six studies) to urine culture. A meta-analysis of seven similar studies utilizing NGS demonstrates that NGS is more sensitive in the identification of urinary bacteria and detects greater species diversity per urine sample than culture. PCR protocols designed to detect a diverse range of microbes had increased sensitivity and species diversity compared with culture. Phenotypic and genotypic resistomes are concordant in approximately 85% of cases. There is insufficient evidence to compare patient symptomatic responses to antibiotic therapy guided by molecular testing versus standard susceptibility testing. Conclusions: Moderately strong evidence exists that molecular diagnostics demonstrate increased sensitivity in detecting urinary bacteria at the expense of poor specificity in controls. Additional data comparing patient symptoms and cure rates following antibiotic selection directed by molecular methods compared with culture are needed to elucidate their place in UTI care. Patient summary: We compare culture-independent molecular methods with urine culture in the management of urinary tract infection. We found good evidence that molecular methods detect more bacteria than culture; however, the clinical implications to support their routine use are unclear.

Abstract Background Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. Methods Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. Results We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. Discussion Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

Fibrin sealants have recently been thoroughly studied in several surgical specialties; however, results are conflicting. We aimed to examine the safety and efficacy of fibrin sealant patients having thyroidectomies. A thorough, systematic literature search was carried out using the terms thyroidectomy and fibrin sealant using PubMed, Cochrane Library, and Clinicaltrials.gov on December 25, 2022. The primary outcome of interest in this review was the amount of drainage, whereas hospitalization, the length of drain retention, and temporary dysphonia were secondary outcomes. Our meta-analysis (n = 249) showed that application of fibrin sealant is associated with lesser total drainage [SMD −2.76 (−4.83, −0.69); P = 0.009; I2 97%], but not with retention time of drainage [SMD −2.35 (−4.71, 0.01); P = 0.05; I2 98%], hospitalization time [SMD −1.65 (−3.70, 0.41); P = 0.12; I2 97%], and transient dysphonia [RR 1.01 (0.27, 3.82); P = 0.99; I2 0%]. The systematic review found that the use of fibrin sealant in thyroid surgery is positive in total volume drainage but not with the retention time of drainage, hospitalization time, and transient dysphonia. It is notable to remember that this interpretation is complicated by uneven, occasionally subpar technique and trial reporting, according to this systematic review's findings.

IntroductionMeasuring long-term housing outcomes is important for evaluating the impacts of services for individuals with homeless experience. However, assessing long-term housing status using traditional methods is challenging. The Veterans Affairs (VA) Electronic Health Record (EHR) provides detailed data for a large population of patients with homeless experiences and contains several indicators of housing instability, including structured data elements (e.g., diagnosis codes) and free-text clinical narratives. However, the validity of each of these data elements for measuring housing stability over time is not well-studied.MethodsWe compared VA EHR indicators of housing instability, including information extracted from clinical notes using natural language processing (NLP), with patient-reported housing outcomes in a cohort of homeless-experienced Veterans.ResultsNLP achieved higher sensitivity and specificity than standard diagnosis codes for detecting episodes of unstable housing. Other structured data elements in the VA EHR showed promising performance, particularly when combined with NLP.DiscussionEvaluation efforts and research studies assessing longitudinal housing outcomes should incorporate multiple data sources of documentation to achieve optimal performance.

Leptospirosis is a zoonotic bacterial disease affecting mammalian species worldwide. Cattle are a major susceptible host; infection with pathogenic Leptospira spp. represents a public health risk and results in reproductive failure and reduced milk yield, causing economic losses. The characterisation of outer membrane proteins (OMPs) from disease-causing bacteria dissects pathogenesis and underpins vaccine development. As most leptospire pathogenesis research has focused on Leptospira interrogans, this study aimed to characterise novel OMPs from another important genomospecies, Leptospira borgpetersenii, which has global distribution and is relevant to bovine and human diseases. Several putative L. borgpetersenii OMPs were recombinantly expressed, refolded and purified, and evaluated for function and immunogenicity. Two of these unique, putative OMPs (rLBL0972 and rLBL2618) bound to immobilised fibronectin, laminin and fibrinogen, which, together with structural and functional data, supports their classification as leptospiral adhesins. A third putative OMP (rLBL0375), did not exhibit saturable adhesion ability but, together with rLBL0972 and the included control, OmpL1, demonstrated significant cattle milk IgG antibody reactivity from infected cows. To dissect leptospire host–pathogen interactions further, we expressed alleles of OmpL1 and a novel multi-specific adhesin, rLBL2618, from a variety of genomospecies and surveyed their adhesion ability, with both proteins exhibiting divergences in extracellular matrix component binding specificity across synthesised orthologs. We also observed functional redundancy across different L. borgspetersenii OMPs which, together with diversity in function across genomospecies orthologs, delineates multiple levels of plasticity in adhesion that is potentially driven by immune selection and host adaptation. These data identify novel leptospiral proteins which should be further evaluated as vaccine and/or diagnostic candidates. Moreover, functional redundancy across leptospire surface proteins together with identified adhesion divergence across genomospecies further dissect the complex host–pathogen interactions of a genus responsible for substantial global disease burden.

Wild pollinators are critical to maintaining ecosystem services and facilitating crop production, but habitat degradation and resource loss are leading to worldwide pollinator declines. Nutrient enrichment and changes in rainfall due to global warming are drivers of global environmental change, and likely to impact pollinator foraging behavior and reproductive success through changes to the growth and phenology of flowering plants. Here, we provide a short review of pollinator conservation in the context of nutritional ecology and plant-pollinator interactions. Then, we present novel research into the effects of nutrient and rainfall variation on plant phenology. In this study, we experimentally manipulated the amount of water and supplemental nutrients available to wild sunflower (Helianthus annuus) and goldenrod (Solidago spp.) throughout their growing season. We evaluated how changes in growth and bloom time could impact resource availability for bumble bee (Bombus impatiens) queens preparing to overwinter. We found that fertilizer and rainfall alter plant bloom time by 2–18 days, though flowering response was species-specific. Fertilizer did not significantly affect plant growth or number of flowers produced when plants were grown under drought conditions. When water was not limiting, fertilized sunflowers bloomed in floral pulses. These findings carry important implications for growers and land managers, providing insight into potential drivers of wild pollinator decline and possible conservation strategies.

In value-based decision making, options are selected according to subjective values assigned by the individual to available goods and actions. Despite the importance of this faculty of the mind, the neural mechanisms of value assignments, and how choices are directed by them, remain obscure. To investigate this problem, we used a classic measure of utility maximization, the Generalized Axiom of Revealed Preference, to quantify internal consistency of food preferences in Caenorhabditis elegans, a nematode worm with a nervous system of only 302 neurons. Using a novel combination of microfluidics and electrophysiology, we found that C. elegans food choices fulfill the necessary and sufficient conditions for utility maximization, indicating that nematodes behave as if they maintain, and attempt to maximize, an underlying representation of subjective value. Food choices are well-fit by a utility function widely used to model human consumers. Moreover, as in many other animals, subjective values in C. elegans are learned, a process we find requires intact dopamine signaling. Differential responses of identified chemosensory neurons to foods with distinct growth potentials are amplified by prior consumption of these foods, suggesting that these neurons may be part of a value-assignment system. The demonstration of utility maximization in an organism with a very small nervous system sets a new lower bound on the computational requirements for utility maximization and offers the prospect of an essentially complete explanation of value-based decision making at single neuron resolution in this organism.

In this intervention article, we cultivate an anti-colonial critique of the ideational genealogy and conceptual materialisation of the social licence to operate (SLO) in the extractive industries in order to open a conversation about the racialised and colonial logics underlying its enactment and discursive practices. SLO functions to restrict the emergence of imaginary political potentials within communities impacted by extractive projects. We focus on the role of academics and social science researchers within and beyond the space of the university in engineering, shaping, and promoting dominant SLO frameworks, and endorsing the power and mythology of SLO. We do so in conversation with decolonial orientations that simultaneously analyse the colonial logics within corporate practice and galvanise epistemic justice beyond colonial and epistemic extractivism. The university, as a site for the refinement and promotion of hegemonic concepts like SLO, is an important space for post-extractive struggles.