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Purpose: The OSCE is regarded as the gold standard of competence assessment in many healthcare programs, however, there are numerous internal and external sources of variation contributing to checklist marks. There is concern amongst organisers that candidates may be unfairly disadvantaged if they follow an "excellent" preceding candidate. This study assessed if average checklist scores differed depending on who a candidate follows accounted for different sources of variation. Design/methodology/approach: This study examined assessment data from final year MBChB OSCEs at the University of Aberdeen and categorised candidates into three levels dependent on examiner awarded global scores of preceding candidates for each station. Data were modelled using a linear mixed model incorporating fixed and random effects. Findings: A total of 349 candidates sat the OSCEs. The predicted mean (95% CI) score for students following an "excellent" candidate was 21.6 (20.6, 22.6), followed "others" was 21.5 (20.5, 22.4) and followed an "unsatisfactory" student was 22.2 (21.1, 23.3). When accounted for individual, examiner and station levels variabilities, students following an "excellent" candidate did not have different mean scores compared to those who followed "other" (p = 0.829) or "unsatisfactory" candidates (p = 0.162), however, students who followed an "unsatisfactory" student scored slightly higher on average compared to those who followed "other" (p = 0.038). Originality/value: There was weak evidence that candidate's checklist variations could be attributed to who they followed, particularly those following unsatisfactory students; the difference in predicted mean scores may be of little practical relevance. Further studies with multiple centres may be warranted assuring perceived fairness of the OSCE to candidates and educators.

Abstract Prior research demonstrates that news-related social media posts using negative language are re-posted more, rewarding users who produce negative content. We investigate whether negative material from external news sites is also introduced to social media through more user posts, offering comparable incentives for journalists to adopt a negative tone. Data from four US and UK news sites (95,282 articles) and two social media platforms (579,182,075 posts on Facebook and Twitter, now X) show social media users are 1.91 times more likely to share links to negative news articles. The impact of negativity varies by news site and social media platform and, for political articles, is moderated by topic focus, with users showing a greater inclination to share negative articles referring to opposing political groups. Additionally, negativity amplifies news dissemination on social media to a greater extent when accounting for the re-sharing of user posts containing article links. These findings suggest a higher prevalence of negatively toned articles on Facebook and Twitter compared to online news sites. Further, should journalists respond to the incentives created by the heightened sharing of negative articles to social media platforms, this could even increase negative news exposure for those who do not use social media.

Abstract Background Zaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV-ZEBOV vaccination and other public health measures. People in high-risk areas may have pre-existing antibodies from asymptomatic Ebolavirus exposure that might affect response to rVSV-ZEBOV. Therefore, we assessed the impact pre-existing immunity had on post-vaccination IgG titre, virus neutralisation, and reactogenicity following vaccination. Methods In this prospective cohort study, 2115 consenting close contacts (“proches”) of EVD survivors were recruited. Proches were vaccinated with rVSV-ZEBOV and followed up for 28 days for safety and immunogenicity. Anti-GP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using live virus neutralisation. Results Ten percent were seropositive at baseline. At day 28, IgG in baseline seronegative (GMT 0.106 IU/ml, 95% CI: 0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline (both p

Abstract The Illumina Methylation array platform has facilitated countless epigenetic studies on DNA methylation (DNAme) in health and disease, yet relatively few studies have so studied its reliability, i.e., the consistency of repeated measures. Here we investigate the reliability of both type I and type II Infinium probes. We propose a method for excluding unreliable probes based on dynamic thresholds for mean intensity (MI) and ‘unreliability’, estimated by probe-level simulation of the influence of technical noise on methylation β values using the background intensities of negative control probes. We validate our method in several datasets, including newly generated Illumina MethylationEPIC BeadChip v1.0 data from paired whole blood samples taken six weeks apart and technical replicates spanning multiple sample types. Our analysis revealed that specifically probes with low MI exhibit higher β value variability between repeated samples. MI was associated with the number of C-bases in the respective probe sequence and correlated negatively with unreliability scores. The unreliability scores were substantiated through validation in a new EPIC v1.0 (blood and cervix) and a publicly available 450k (blood) dataset, as they effectively captured the variability observed in β values between technical replicates. Finally, despite promising higher robustness, the newer version v2.0 of the MethylationEPIC BeadChip retained a substantial number of probes with poor unreliability scores. To enhance current pre-processing pipelines, we developed an R package to calculate MI and unreliability scores and provide guidance on establishing optimal dynamic score thresholds for a given dataset.

Abstract Deep learning-assisted digital pathology has demonstrated the potential to profoundly impact clinical practice, even surpassing human pathologists in performance. However, as deep neural network (DNN) architectures grow in size and complexity, their explainability decreases, posing challenges in interpreting pathology features for broader clinical insights into physiological diseases. To better assess the interpretability of digital microscopic images and guide future microscopic system design, we developed a novel method to study the predictive feature length-scale that underpins a DNN’s predictive power. We applied this method to analyze a DNN’s capability in predicting brain metastasis from early-stage non-small-cell lung cancer biopsy slides. This study quantifies DNN’s attention for brain metastasis prediction, targeting features at both the cellular scale and tissue scale in H&E-stained histological whole slide images. At the cellular scale, the predictive power of DNNs progressively increases with higher resolution and significantly decreases when the resolvable feature length exceeds 5 microns. Additionally, DNN uses more macro-scale features associated with tissue architecture and is optimized when assessing visual fields greater than 41 microns. Our study computes the length-scale requirements for optimal DNN learning on digital whole-slide microscopic images, holding the promise to guide future optical microscope designs in pathology applications and facilitating downstream deep learning analysis.

Abstract The rumen microbiome is the focus of a growing body of research, mostly based on investigation of rumen fluid samples collected once from each animal. Exploring the temporal stability of rumen microbiome profiles is imperative, as it enables evaluating the reliability of findings obtained through single-timepoint sampling. We explored the temporal stability of rumen microbiomes considering taxonomic and functional aspects across the 7-month growing-finishing phase spanning 6 timepoints. We identified a temporally stable core microbiome, encompassing 515 microbial genera (e.g., Methanobacterium) and 417 microbial KEGG genes (e.g., K00856—adenosine kinase). The temporally stable core microbiome profiles collected from all timepoints were strongly associated with production traits with substantial economic and environmental impact (e.g., average daily gain, daily feed intake, and methane emissions); 515 microbial genera explained 45–83%, and 417 microbial genes explained 44–83% of their phenotypic variation. Microbiome profiles influenced by the bovine genome explained 54–87% of the genetic variation of bovine traits. Overall, our results provide evidence that the temporally stable core microbiome identified can accurately predict host performance traits at phenotypic and genetic level based on a single timepoint sample taken as early as 7 months prior to slaughter.

Abstract Public engagement with research (PEwR) has become increasingly integral to research practices. This paper explores the process and outcomes of a collaborative effort to address the ethical implications of PEwR activities and develop tools to navigate them within the context of a University Medical School. The activities this paper reflects on aimed to establish boundaries between research data collection and PEwR activities, support colleagues in identifying the ethical considerations relevant to their planned activities, and build confidence and capacity among staff to conduct PEwR projects. The development process involved the creation of a taxonomy outlining key terms used in PEwR work, a self-assessment tool to evaluate the need for formal ethical review, and a code of conduct for ethical PEwR. These tools were refined through iterative discussions and feedback from stakeholders, resulting in practical guidance for researchers navigating the ethical complexities of PEwR. Additionally, reflective prompts were developed to guide researchers in planning and conducting engagement activities, addressing a crucial aspect often overlooked in formal ethical review processes. The paper reflects on the broader regulatory landscape and the limitations of existing approval and governance processes, and prompts critical reflection on the compatibility of formal approval processes with the ethos of PEwR. Overall, the paper offers insights and practical guidance for researchers and institutions grappling with ethical considerations in PEwR, contributing to the ongoing conversation surrounding responsible research practices.

Abstract Furthering our knowledge of the skin microbiome is essential to understand health and disease in canines. To date, studies into the canine skin microbiome have focused on 16S rRNA high throughput sequencing however, these lack the granularity of species and strain level taxonomic characterisation and their associated functions. The aim of this study was to provide a comprehensive assessment of the skin microbiome by analysing the skin microbiome of 72 healthy adult colony dogs, across four distinct skin sites and four breeds, using metagenomic sequencing. Our analysis revealed that breed and skin site are drivers of variation, and a core group of taxa and genes are present within the skin microbiome of healthy dogs, comprising 230 taxa and 1219 gene families. We identified 15 species within the core microbiome that are represented by more than one strain. The biosynthesis of secondary metabolites pathway was enriched in the core microbiome suggesting the skin microbiome may play a role in colonisation resistance and protection from invading pathogens. Additionally, we uncovered the novelty of the canine skin microbiome and show that further investigation is required to increase the suitability of current databases for metagenomic sequencing of canine skin samples.

Abstract There is growing evidence that a relationship exists between mental and emotional wellbeing and the gut microbiota. Little is known regarding how the microbiota reacts to repeated acute stress events in dogs, and whether it is a predictor of stress response. In this study, we explored the impact on the gut microbiota and digestive health with two common events many pet dogs find stressful. Twenty healthy adult dogs, living within a colony, were exposed to either car travel or separation three times across eight-week intervals. Faecal samples were collected 24 h before, within 24 h, and 24–48 h after. Faecal quality and pH, and microbiota diversity and composition were analysed in context with wider published work on physiological stress measures. No significant changes were observed in faecal quality or pH with either stress event at any timepoint, indicating all pets remained in good digestive health. Microbiota analysis demonstrated no significant impact on alpha or beta diversity with either stressor. Microbial signatures previously linked to stress were not identified in these dogs and no changes were observed in the functional gut composition. Irrespective of whether the pet was considered “stressed” (i.e., exhibited an increase in serum cortisol), there was no effect on the microbiota and no taxa were predictive of stress response. Collectively, this work demonstrates, for this population, certain acute stress events have no meaningful impact on the canine gut microbiota, and it has no impact on the associated stress response.

Abstract Carbonate sediments are often regarded as problematic in geotechnical engineering due to the high variability of their properties. Understanding and quantifying this variability will become increasingly critical in the years ahead, notably with respect to upcoming developments in offshore renewable energy, for which limited in-situ data are typically available to characterise large areas. Here, six intervals from the North West Shelf of Australia, each composed of similar carbonate grains but accumulated in different environments, are investigated to better understand how the post-depositional cementation, alteration and dissolution of sediments, known as diagenesis, impact their geotechnical properties. Intervals are primarily affected by mineralogy-driven meteoric diagenesis, comprising in-situ dissolution of metastable grains and subsequent precipitation of cement that occurred when the shelf was exposed during lower sea-levels, and by marine diagenesis. In both cases, increased diagenesis results in a higher cement-to-solid ratio and compressive strength. However, while marine diagenesis is associated with a reduction in void ratio, this is not initially observed with mineralogy-driven meteoric diagenesis. Additionally, for a similar cement-to-solid ratio, microcrystalline cement results in higher compressive strength than sparite cement. The data further reveal that the level of meteoric cementation and the compressive strength increase as a function of the duration of exposure and of the regional climate, along with a reduction of the specific gravity related to the replacement of aragonite by calcite. However, increased meteoric diagenesis also leads to the formation of macro-scale heterogeneities such as calcrete layers and karsts that can affect the holistic geotechnical behaviour of such deposits.

Abstract Background Timely and informed public health responses to infectious diseases such as COVID-19 necessitate reliable information about infection dynamics. The case ascertainment rate (CAR), the proportion of infections that are reported as cases, is typically much less than one and varies with testing practices and behaviours, making reported cases unreliable as the sole source of data. The concentration of viral RNA in wastewater samples provides an alternate measure of infection prevalence that is not affected by clinical testing, healthcare-seeking behaviour or access to care. Methods We construct a state-space model with observed data of levels of SARS-CoV-2 in wastewater and reported case incidence and estimate the hidden states of the effective reproduction number, R, and CAR using sequential Monte Carlo methods. Results We analyse data from 1 January 2022 to 31 March 2023 from Aotearoa New Zealand. Our model estimates that R peaks at 2.76 (95% CrI 2.20, 3.83) around 18 February 2022 and the CAR peaks around 12 March 2022. We calculate that New Zealand’s second Omicron wave in July 2022 is similar in size to the first, despite fewer reported cases. We estimate that the CAR in the BA.5 Omicron wave in July 2022 is approximately 50% lower than in the BA.1/BA.2 Omicron wave in March 2022. Conclusions Estimating R, CAR, and cumulative number of infections provides useful information for planning public health responses and understanding the state of immunity in the population. This model is a useful disease surveillance tool, improving situational awareness of infectious disease dynamics in real-time.

Background: Minimally invasive injectable aesthetic treatments have seen a surge in popularity, particularly in the post-COVID era. However, our understanding of the psychological and social factors that influence patients’ choices when seeking these treatments is still lacking. Objective: This study explored whether the COVID-19 pandemic influenced patients’ motivations and perceptions regarding the above-mentioned treatments. Methods: A comprehensive survey was conducted among 147 patients who had received injectable aesthetic interventions at Acquisition Aesthetics, a leading UK training academy in aesthetic medicine. The survey included questions regarding motivation for treatment initiation, ongoing drivers for continuing treatment, desired outcomes, main concerns about treatment, post-treatment feelings, and the psychological impact of skin aging. Descriptive analysis was performed to explore the patterns of patient responses. Results: This findings revealed that the primary motivation for seeking aesthetic treatment was to improve confidence and address concerns about aging. Patients expressed a strong desire for natural-looking results and reported the significant psychological effects of skin aging, including feelings of self-consciousness and anxiety. After treatment, patients reported increased confidence and satisfaction with their appearance, and reduced self-consciousness. Conclusion: This study revealed that although the core motivations for improving confidence and addressing aging remain central to patients seeking aesthetic treatments, the post-COVID era saw a subtle shift toward heightened concerns about social acceptance and maintaining appearances. Understanding these subtle shifts can allow aesthetic practitioners to tailor their approaches to meet patients’ holistic needs. Level of Evidence: Level V, descriptive study

Abstract We aimed to characterize the cognitive profile of post-acute COVID-19 syndrome (PACS) patients with cognitive complaints, exploring the influence of biological and psychological factors. Participants with confirmed SARS-CoV-2 infection and cognitive complaints ≥ 8 weeks post-acute phase were included. A comprehensive neuropsychological battery (NPS) and health questionnaires were administered at inclusion and at 1, 3 and 6 months. Blood samples were collected at each visit, MRI scan at baseline and at 6 months, and, optionally, cerebrospinal fluid. Cognitive features were analyzed in relation to clinical, neuroimaging, and biochemical markers at inclusion and follow-up. Forty-nine participants, with a mean time from symptom onset of 10.4 months, showed attention-executive function (69%) and verbal memory (39%) impairment. Apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%) were prevalent. Visual memory (8%) correlated with total gray matter (GM) and subcortical GM volume. Neuronal damage and inflammation markers were within normal limits. Over time, cognitive test scores, depression, apathy, anxiety scores, MRI indexes, and fluid biomarkers remained stable, although fewer participants (50% vs. 75.5%; p = 0.012) exhibited abnormal cognitive evaluations at follow-up. Altered attention/executive and verbal memory, common in PACS, persisted in most subjects without association with structural abnormalities, elevated cytokines, or neuronal damage markers.

Purpose To explore how principles of social justice and equity are integrated into research concerning accessibility to public buildings for individuals with mobility disabilities. Methods Utilising a scoping review methodology to assess literature based on the criteria set by the Joanna Briggs Institute, seven databases were screened. Studies were selected using the framework: “persons with mobility disabilities” AND “accessibility” AND “public buildings”. A theoretical framework helped to extract codes and develop themes through an inductive-deductive analysis method. The results are presented descriptively. Results The examination of 84 studies uncovered a complex interplay between agencies, systemic challenges, discriminatory practices, and societal attitudes perpetuating marginalisation of individuals with mobility disabilities in their access to public buildings. The recommendations emphasize importance of practical measures, research imperatives, and policy developments to promote inclusivity. We present a ‘Ten-step approach’ to integrate social justice and equity into research on accessibility in public buildings for people with mobility disabilities. Conclusion Integrating diversity, active participation, and inclusive methodologies are essential to address systemic issues, discriminatory practices, and societal attitudes that hinder accessibility and inclusion. Collaborations with diverse stakeholders are crucial for policy changes, resource allocation, and advancing social justice and equity in accessibility research and practice.

Introduction Successful organ transplantation in patients with end-stage organ failure improves long-term survival, improves quality of life and reduces costs to the NHS. Despite an increase in the number of deceased organ donors over the last decade, there remains a considerable shortfall of suitable organs available for transplantation. Over half of UK donors are certified dead by neurological criteria following brain stem compression, which leads to severe physiological stress in the donor, combined with a hyperinflammatory state. Brain stem death-related dysfunction is an important reason for poor organ function and hence utilisation. For example, more than 30% of donation after brain stem death cardiac transplant recipients need short-term mechanical cardiac support, reflecting donor heart dysfunction.A small, randomised study previously showed improved outcomes for cardiac transplant recipients if the donor was given simvastatin. SIGNET takes inspiration from that study and hypothesises a potential reduction in damage to the heart and other organs during the period after diagnosis of death and prior to organ retrieval in donors that receive simvastatin.Methods and analysis SIGNET is a multicentre, single-blind, prospective, group sequential, randomised controlled trial to evaluate the benefits of a single high dose of simvastatin given to potential organ donors diagnosed dead by neurological criteria on outcomes in all organ recipients. The trial will run across a minimum of 89 UK sites with a recruitment target of 2600 donors over 4 years.Ethics and dissemination SIGNET received a favourable opinion from the London, Queen Square Research Ethics Committee (Ref: 21/LO/0412) and following approval of substantial amendment 1 in January 2023, the current protocol is version 2 (7 December 2022). Substantial amendment 1 clarified consent procedures and added additional sites and prescribers. Findings from the study will be publicly available and disseminated locally and internationally through manuscript publications in peer-reviewed journals and conference presentations at national and international platforms.Trial registration number ISRCTN11440354

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Abstract Settlement is a critical period in the life cycle of marine invertebrates with a planktonic larval stage. For reef-building invertebrates such as oysters and corals, settlement rates are predictive for long-term reef survival. Increasing evidence suggests that marine invertebrates use information from ocean soundscapes to inform settlement decisions. Sessile marine invertebrates with a planktonic stage are particularly reliant on environmental cues to direct them to ideal habitats. As gregarious settlers, oysters prefer to settle amongst members of the same species. It has been hypothesized that oyster larvae from species Crassostrea virginica and Ostrea angasi use distinct conspecific oyster reef sounds to navigate to ideal habitats. In controlled laboratory experiments we exposed Pacific Oyster Magallana gigas larvae to anthropogenic sounds from conspecific oyster reefs, vessels, combined reef-vessel sounds as well as off-reef and no speaker controls. Our findings show that sounds recorded at conspecific reefs induced higher percentages of settlement by about 1.44 and 1.64 times compared to off-reef and no speaker controls, respectively. In contrast, the settlement increase compared to the no speaker control was non-significant for vessel sounds (1.21 fold), combined reef-vessel sounds (1.30 fold), and off-reef sounds (1.18 fold). This study serves as a foundational stepping stone for exploring larval sound feature preferences within this species.

Abstract We report the first detection and prevalence of Beak and feather disease virus (BFDV) in Australia’s Red Goshawk (Erythrotriorchis radiatus). This is a new host for this pervasive pathogen amongst a growing list of non-psittacine species including birds of prey from the orders Accipitriformes (hawks, eagles, kites), Falconiformes (falcons and caracas), and Strigiformes (owls). The Red Goshawk is the first non-psittacine species listed as Endangered to be diagnosed with BFDV. We report an initial case of infection discovered post-mortem in a dead nestling and subsequent surveillance of birds from across northern Australia. We reveal BFDV prevalence rates in a wild raptor population for the first time, with detections in 25% (n = 7/28) of Red Goshawks sampled. Prevalence appears higher in juveniles compared to adults, although not statistically significant, but is consistent with studies of wild psittacines. BFDV genotypes were associated with the Loriinae (lorikeets, budgerigar, and fig parrots), Cacatuini (Cockatoos), and Polytelini (long-tailed parrots) tribes; species which are preyed upon by Red Goshawks. A positive BFDV status may be associated with lower body mass but small sample sizes precluded robust statistical analysis. We postulate the possible impacts of the virus on Red Goshawks and discuss future research priorities given these preliminary observations.

Abstract Objective Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and among the most common malignancies in young adults and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood and young adult ALL in regard to utilization and cost of care among commercially insured individuals in the United States. Results Utilizing a commercial insurance claims database, 529 pediatric and young adult patients were identified who were diagnosed with ALL between January 2016 and March 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost during the initial 8 months of therapy. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric and young adult ALL was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic’s impact on health equity and access to care, especially in vulnerable pediatric and young adult populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric and young adult cancer.

Abstract In natural environments, head movements are required to search for objects outside the field of view (FoV). Here we investigate the power of a salient target in an extended visual search array to facilitate faster detection once this item comes into the FoV by a head movement. We conducted two virtual reality experiments using spatially clustered sets of stimuli to observe target detection and head and eye movements during visual search. Participants completed search tasks with three conditions: (1) target in the initial FoV, (2) head movement needed to bring the target into the FoV, (3) same as condition 2 but the periphery was initially hidden and appeared after the head movement had brought the location of the target set into the FoV. We measured search time until participants found a more salient (O) or less salient (T) target among distractors (L). On average O’s were found faster than T’s. Gaze analysis showed that saliency facilitation occurred due to the target guiding the search only if it was within the initial FoV. When targets required a head movement to enter the FoV, participants followed the same search strategy as in trials without a visible target in the periphery. Moreover, faster search times for salient targets were only caused by the time required to find the target once the target set was reached. This suggests that the effect of stimulus saliency differs between visual search on fixed displays and when we are actively searching through an extended visual field.

Abstract ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.

Purpose: Patient-reported outcome measures (PROMs) are used in individuals experiencing long-term effects from COVID-19 infection, or Long COVID, to evaluate the quality of life and functional status of these individuals. However, little is known about which PROMs are being utilised and the psychometric properties of these PROMs. Our purpose was thus to explore which PROMs are used in Long COVID patients and to discuss the psychometric properties of the PROMs. Methods: For this rapid review, a systematic literature search was performed in the PubMed, Embase, and CINAHL databases. The found studies were screened using the PRISMA flowchart. We then performed study quality appraisal and assessed the psychometric properties of the found PROMs. Results: Per the systematic literature search and after removal of duplicates, 157 publications were identified for individual screening. After screening and eligibility assessment, 74 articles were selected for our review. In total, 74 PROMs were used and primarily comprised quality of life, fatigue, breathlessness, mental health, and smell/taste issues in COVID “long haulers.” Five studies used newly developed, COVID-19-specific PROMs. We assessed the psychometric properties of the 10 most-used PROMs. The majority were found to be reliable and valid instruments. EQ-5D-5L was the most popular and highly rated PROM. Conclusions: We assessed PROMs used in Long COVID patients and evaluated their psychometric properties. EQ-5D-5L was the most favourably rated PROM. PROMs addressing mental health issues are crucial in managing anxiety and depression in Long COVID patients. New COVID-specific PROMs assess functional status and smell/taste perception and show great utilisation potential in olfactory training at COVID smell clinics. However, many reviewed PROMs currently lack sufficient analysis of their psychometric properties. Therefore, future research needs to examine these measures. (J Patient Cent Res Rev. 2024;11:36-50.)

Abstract Background Syndromic surveillance often relies on patients presenting to healthcare. Community cohorts, although more challenging to recruit, could provide additional population-wide insights, particularly with SARS-CoV-2 co-circulating with other respiratory viruses. Methods We estimated the positivity and incidence of SARS-CoV-2, influenza A/B, and RSV, and trends in self-reported symptoms including influenza-like illness (ILI), over the 2022/23 winter season in a broadly representative UK community cohort (COVID-19 Infection Survey), using negative-binomial generalised additive models. We estimated associations between test positivity and each of the symptoms and influenza vaccination, using adjusted logistic and multinomial models. Results Swabs taken at 32,937/1,352,979 (2.4%) assessments tested positive for SARS-CoV-2, 181/14,939 (1.2%) for RSV and 130/14,939 (0.9%) for influenza A/B, varying by age over time. Positivity and incidence peaks were earliest for RSV, then influenza A/B, then SARS-CoV-2, and were highest for RSV in the youngest and for SARS-CoV-2 in the oldest age groups. Many test positives did not report key symptoms: middle-aged participants were generally more symptomatic than older or younger participants, but still, only ~ 25% reported ILI-WHO and ~ 60% ILI-ECDC. Most symptomatic participants did not test positive for any of the three viruses. Influenza A/B-positivity was lower in participants reporting influenza vaccination in the current and previous seasons (odds ratio = 0.55 (95% CI 0.32, 0.95)) versus neither season. Conclusions Symptom profiles varied little by aetiology, making distinguishing SARS-CoV-2, influenza and RSV using symptoms challenging. Most symptoms were not explained by these viruses, indicating the importance of other pathogens in syndromic surveillance. Influenza vaccination was associated with lower rates of community influenza test positivity.

Abstract Mycobacterial pathogens present a significant challenge to disease control efforts globally due to their inherent resistance to multiple antibiotics. The rise of drug-resistant strains of Mycobacterium tuberculosis has prompted an urgent need for innovative therapeutic solutions. One promising way to discover new tuberculosis drugs is by utilizing natural products from the vast biochemical space. Multidisciplinary methods can used to harness the bioactivity of these natural products. This study aimed to evaluate the antimycobacterial efficacy of functional crude extracts from bacteria isolated from gold mine tailings in South Africa. Bacterial strains were identified using 16S rRNA sequencing. The crude extracts obtained from the bacteria were tested against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc2155, and Mycobacterium aurum A+. Untargeted HPLC-qTOF and molecular networking were used to identify the functional constituents present in extracts that exhibited inhibitory activity. A virtual screening workflow (VSW) was used to filter compounds that were strong binders to Mycobacterium tuberculosis Pks13 and PknG. The ligands returned from the VSW were subjected to optimization using density functional theory (DFT) at M06-2X/6-311++ (d,p) level of theory and basis set implemented in Gaussian16 Rev.C01. The optimized ligands were re-docked against Mycobacterium tuberculosis Pks13 and PknG. Molecular dynamics simulation and molecular mechanics generalized born surface area were used to evaluate the stability of the protein–ligand complexes formed by the identified hits. The hit that showed promising binding characteristics was virtually modified through multiple synthetic routes using reaction-driven enumeration. Three bacterial isolates showed significant activity against the two strains of Mycobacterium, while only two, Bacillus subtilis and Bacillus licheniformis, exhibited activity against both Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc2155, and Mycobacterium aurum A+. The tentatively identified compounds from the bacterial crude extracts belonged to various classes of natural compounds associated with antimicrobial activity. Two compounds, cyclo-(L-Pro-4-OH-L-Leu) and vazabitide A, showed strong binding against PknG and Pks13, with pre-MD MM-GBSA values of − 42.8 kcal/mol and − 47.6 kcal/mol, respectively. The DFT-optimized compounds exhibited the same docking scores as the ligands optimized using the OPSL-4 force field. After modifying vazabitide A, its affinity to the Pks13 binding site increased to − 85.8 kcal/mol, as revealed by the post-MD MM-GBSA analysis. This study highlights the potential of bacteria isolates from gold mine tailings as a source of new scaffolds for designing and optimizing anti-Mycobacterium agents. These agents synthesized in-silico can be further tested in-vitro to evaluate their efficacy.

Abstract Antibiotic resistance is recognised as one of the biggest global threats to human and animal health. Understanding the influence of antibiotics on the canine microbiome is important to know the potential mid-to-long term effects on dysbiosis and mitigate side-effects such as antibiotic-associated diarrhoea. In this study, metronidazole was prescribed to 22 dogs for suspected giardiasis after exhibiting gastrointestinal symptoms such as diarrhoea and/or vomiting. Faecal samples were collected before, during seven days of treatment, and six months post-cessation. Faecal microbiota was assessed with 16S rRNA sequencing. Shannon diversity was reduced for up to three days after the treatment ended, and an altered community persisted for four to six weeks. All dogs recovered to a similar microbiome composition as pre-treatment. Immediately after receiving metronidazole, an increase in the relative abundance of the genera Lactobacillus, Bifidobacterium, and Enterococcus was observed. This may be due to antibiotic resistance commonly exhibited by these organisms. One-to-two weeks post-cessation, several other genera that were sensitive to the antibiotic recovered in abundances, with taxa belonging to the Erysipelotrichaceae family particularly driving composition change. Many of the bacteria initially reduced were associated with carbohydrate fermentation. This suggests scope exists to explore interventions to augment gastrointestinal health and support the re-establishment of the microbiome.

Abstract Background Black men have higher prostate-specific antigen (PSA) levels and higher prostate cancer incidence and mortality than White men, while Asian men tend to have lower prostate cancer incidence and mortality than White men. Much of the evidence comes from the USA, and information from UK populations is limited. Methods This retrospective cohort study used data on patients registered at general practices in England contributing to the Clinical Practice Research Datalink (CPRD) Aurum dataset. Those eligible were men aged 40 and over with a record of ethnicity and a PSA test result recorded between 2010 and 2017 with no prior cancer diagnosis. The aim was to assess the incidence of prostate cancer following a raised PSA test result in men from different ethnic groups. Additionally, incidence of advanced prostate cancer was investigated. Cancer incidence was estimated from multi-level logistic regression models adjusting for potential confounding factors. Results 730,515 men with a PSA test were included (88.9% White). Black men and men with mixed ethnicity had higher PSA values, particularly for those aged above 60 years. In the year following a raised PSA result (using age-specific thresholds), Black men had the highest prostate cancer incidence at 24.7% (95% CI 23.3%, 26.2%); Asian men had the lowest at 13.4% (12.2%, 14.7%); incidence for White men was 19.8% (19.4%, 20.2%). The peak incidence of prostate cancer for all groups was in men aged 70–79. Incidence of prostate cancer diagnosed at an advanced stage was similar between Black and White men. Conclusions More prostate cancer was diagnosed in Black men with a raised PSA result, but rates of advanced prostate cancer were not higher in this group. In this large primary care-based cohort, the incidence of prostate cancer in men with elevated PSA levels increases with increasing age, even when using age-adjusted thresholds, with Black men significantly more likely to be diagnosed compared to White or Asian men. The incidence of advanced stage prostate cancer at diagnosis was similar for Black and White men with a raised PSA result, but lower for Asian men.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.

Objective To gather a deep qualitative understanding of the perceived benefits and impacts of External-Beam RadioTherapy (EBRT) and TARGeted Intraoperative radioTherapy (TARGIT-IORT) using Intrabeam to assess how the treatments affected patient/care partner experiences during their cancer treatment and beyond.Design and participants A patient-led working group was established to guide study design and to help validate findings. Patients with experience of receiving EBRT or TARGIT-IORT were purposively sampled by Hampshire Hospitals NHS Foundation Trust. These patients had been offered both regimens as per their clinical features and eligibility. Semistructured interviews were conducted with 29 patients and care partners with lived experience of either EBRT (n=12, 5-day FAST-Forward regimen and n=3, 3-week regimen) or TARGIT-IORT (n=14). Thematic analysis was then carried out by two coders generating 11 themes related to EBRT or TARGIT-IORT.Setting Semistructured interviews were conducted virtually via Zoom during February and March 2023.Results A number of procedural grievances were noted among EBRT patients. EBRT was perceived as being disruptive to normal routines (work, home and travel) and caused discomfort from side effects. TARGIT-IORT was perceived by patients and care partners as the safer option and efficient with minimal if any disruptions to quality of life. The need for timely accessible information to reduce anxieties was noted in both cohorts.Conclusions This qualitative study found that patients perceived EBRT as being greatly disruptive to their lives. In contrast, the one-off feature of TARGIT-IORT given while they are asleep during surgery gives them the feeling of stamping out the cancer without conscious awareness. These insights can help healthcare staff and policy-makers further justify the incorporation of the treatment favoured by these patient perceptions (TARGIT-IORT) more widely in routine practice. Further research is planned to explore TARGIT-IORT in more diverse populations and in the 35 countries where it is an established treatment option.

Introduction Evaluating the safety and acceptability of reusing catheters for intermittent catheterisation (IC) is one of the top 10 continence research priorities identified by the UK James Lind Alliance Priority Setting Partnership in 2008. There are an estimated 50 000 IC users in England and this number is rising. Globally, both single-use catheters (thrown away after use) and multi-use/reusable ones (cleaned between uses) are used. Using multi-use catheters as well as single-use ones (mixed-use) could bring benefits (eg, reducing plastic waste and patients never running out of catheters) and offer more choice to users. Evidence is needed that mixed-use is at least as safe and acceptable as using only single-use catheters.Methods The MultICath Trial is a non-inferiority randomised controlled trial involving 578 participants. The aim is to compare mixed-use catheter management with single-use catheter management over 12 months. Participants are randomised on a 1:1 basis to either mixed-use catheter management, which includes an evidence-based cleaning method for the multi-use catheters (intervention) or single-use catheter management (control). Following randomisation, participants are followed up for 12 months. The primary outcome is at least one episode of microbiologically confirmed symptomatic urinary tract infection with help-seeking or self-help behaviour over the 12-month follow-up period. Laboratory analysis of patient-initiated urine samples is blind. Secondary outcomes include antibiotic use, microhaematuria, visible blood on catheter/in urine, quality of life and health economics. A qualitative sub-study to examine participant experiences using mixed-use is included.Ethics and dissemination Ethical review was undertaken by South Central-Hampshire A Research Ethics Committee and favourable opinion was granted on 12 July 2019 (reference: 19/SC/0334). Written, informed consent to participate was obtained from all participants. Results will be disseminated in peer-reviewed publications, in the National Institute for Health and Care Research journal library and to participants and the public via a lay summary published on the trial website.Trial registration number ISRCTN42028483.

Introduction Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin

Objective: No standardised approach exists to provide advice after urgent suspected cancer (USC) referral when cancer is not found. This study aimed to assess preferences and acceptability of receiving advice after USC referral related to: 1) managing ongoing symptoms, 2) responding to early symptoms of other cancers, 3) cancer screening, 4) reducing risks of future cancer. Methods: 2,541 patients from two English NHS Trusts were mailed a survey 1–3 months after having no cancer found following urgent suspected gastrointestinal or head and neck cancer referral. Participants were asked about: willingness to receive advice; prospective acceptability; preferences related to mode, timing and who should provide advice; and previous advice receipt. Results: 406 patients responded (16.0%) with 397 in the final analyses. Few participants had previously received advice, yet most were willing to. Willingness varied by type of advice: fewer were willing to receive advice about early symptoms of other cancers (88.9%) than advice related to ongoing symptoms (94.3%). Acceptability was relatively high for all advice types. Reducing the risk of future cancer advice was more acceptable. Acceptability was lower in those from ethnic minority groups, and with lower levels of education. Most participants preferred to receive advice from a doctor; with results or soon after; either face to face or via the telephone. Conclusions: There is a potential unmet need for advice after USC referral when no cancer is found. Equitable intervention design should focus on increasing acceptability for people from ethnic minority groups and those with lower levels of education.

BackgroundCervical cerclage, cervical pessary, and vaginal progesterone have each been shown to reduce preterm birth (PTB) in high-risk women, but to our knowledge, there has been no randomised comparison of the 3 interventions. The SuPPoRT "Stitch, Pessary, or Progesterone Randomised Trial" was designed to compare the rate of PTB Methods and findingsSuPPoRT was a multicentre, open label 3-arm randomised controlled trial designed to demonstrate equivalence (equivalence margin 20%) conducted from 1 July 2015 to 1 July 2021 in 19 obstetric units in the United Kingdom. Asymptomatic women with singleton pregnancies with transvaginal ultrasound cervical lengths measuring 14 weeks gestation); and 45.8% had prior cervical surgery. Data from 381 women were available for outcome analysis. Using binary regression, randomised therapies (cerclage versus pessary versus vaginal progesterone) were found to have similar effects on the primary outcome PTB ConclusionsIn this study, we found that for women who develop a short cervix, cerclage, pessary, and vaginal progesterone were equally efficacious at preventing PTB, as judged with a 20% equivalence margin. Commencing with any of the therapies would be reasonable clinical management. These results can be used as a counselling tool for clinicians when managing women with a short cervix.Trial registrationEU Clinical Trials register. EudraCT Number: 2015-000456-15, clinicaltrialsregister.eu., ISRCTN Registry: ISRCTN13364447, isrctn.com.

Introduction Huntington’s disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated deficits. We have developed HD-DRUM, a tablet-based app to enhance movement synchronisation skills and improve cognitive and motor abilities in people with HD. This paper outlines a randomised controlled unblinded trial protocol to determine the feasibility of a larger effectiveness trial for HD-DRUM. Additionally, the trial investigates cognitive and motor function measures, along with brain microstructure, aiming to advance our understanding of the neural mechanisms underlying training effects.Methods, design and analysis 50 individuals with HD, confirmed by genetic testing, and a Total Functional Capacity (TFC) score of 9–13, will be recruited into a two-arm randomised controlled feasibility trial. Consenting individuals with HD will be randomised to the intervention group, which entails 8 weeks of at-home usage of HD-DRUM or a usual-activity control group. All participants will undergo cognitive and motor assessments, alongside ultra-strong gradient (300 mT/m) brain microstructural MRI before and after the 8-week period. The feasibility assessment will encompass recruitment, retention, adherence and acceptability of HD-DRUM following prespecified criteria. The study will also evaluate variations in cognitive and motor performance and brain microstructure changes resulting from the intervention to determine effect size estimates for future sample size calculations.Ethics and dissemination The study has received favourable ethical opinion from the Wales Research Ethics Committee 2 (REC reference: 22/WA/0147) and is sponsored by Cardiff University (SPON1895-22) (Research Integrity, Governance and Ethics Team, Research & Innovation Services, Cardiff University, second Floor, Lakeside Building, University Hospital of Wales, Cardiff, CF14 4XW). Findings will be disseminated to researchers and clinicians in peer-reviewed publications and conference presentations, and to participants, carers and the general public via newsletters and public engagement activities. Data will be shared with the research community via the Enroll-HD platform.Trial registration number ISRCTN11906973.

BackgroundAntimicrobial resistance (AMR) represents a growing concern for public health. ObjectiveWe sought to explore the challenges associated with development and implementation of a complex intervention designed to improve AMS in hospitals. MethodsWe conducted a qualitative evaluation of a complex AMS intervention with educational, behavioral, and technological components in 5 wards of an English hospital. At 2 weeks and 7 weeks after initiating the intervention, we interviewed 25 users of the intervention, including senior and junior prescribers, a senior nurse, a pharmacist, and a microbiologist. Topics discussed included perceived impacts of different elements of the intervention and facilitators and barriers to effective use. Interviews were supplemented by 2 observations of ward rounds to gain insights into AMS practices. Data were audio-recorded, transcribed, and inductively and deductively analyzed thematically using NVivo12. ResultsTracing the adoption and impact of the various components of the intervention was difficult, as it had been introduced into a setting with competing pressures. These particularly affected behavioral and educational components (eg, training, awareness-building activities), which were often delivered ad hoc. We found that the participatory intervention design had addressed typical use cases but had not catered for edge cases that only became visible when the intervention was delivered in real-world settings (eg, variations in prescribing workflows across different specialties and conditions). ConclusionsEffective user-focused design of complex interventions to promote AMS can support acceptance and use. However, not all requirements and potential barriers to use can be fully anticipated or tested in advance of full implementation in real-world settings.

Background Enhancing detection of cryptic snakes is critical for the development of conservation and management strategies; yet, finding methods that provide adequate detection remains challenging. Issues with detecting snakes can be particularly problematic for some species, like the invasive Burmese python (Python bivittatus) in the Florida Everglades. Methods Using multiple survey methods, we predicted that our ability to detect pythons, larger snakes and all other snakes would be enhanced with the use of live mammalian lures (domesticated rabbits; Oryctolagus cuniculus). Specifically, we used visual surveys, python detection dogs, and time-lapse game cameras to determine if domesticated rabbits were an effective lure. Results Time-lapse game cameras detected almost 40 times more snakes (n = 375, treatment = 245, control = 130) than visual surveys (n = 10). We recorded 21 independent detections of pythons at treatment pens (with lures) and one detection at a control pen (without lures). In addition, we found larger snakes, and all other snakes were 165% and 74% more likely to be detected at treatment pens compared to control pens, respectively. Time-lapse cameras detected almost 40 times more snakes than visual surveys; we did not detect any pythons with python detection dogs. Conclusions Our study presents compelling evidence that the detection of snakes is improved by coupling live mammalian lures with time-lapse game cameras. Although the identification of smaller snake species was limited, this was due to pixel resolution, which could be improved by changing the camera focal length. For larger snakes with individually distinctive patterns, this method could potentially be used to identify unique individuals and thus allow researchers to estimate population dynamics.

Introduction Climate change poses a major threat to our health, livelihoods and the planet. In 2020, the UK National Health Service (NHS) committed to reducing its Scope 1, 2 and 3 emissions to reach net zero by 2045. Although a net zero NHS would help to limit the consequences of climate change, little is known about the UK general public’s values and preferences for the proposed service changes needed to reach net zero.Methods This study will elicit the public’s preferences for actions to help achieve net zero NHS in England and Scotland using a discrete choice experiment (DCE). The DCE attributes and levels describe actions that can be taken by the NHS across key areas: buildings and estates, outdoor space, travel and transport, provision of care, goods and services and food and catering. The survey was designed using online think-aloud interviews with 17 members of the public. Two versions of the survey will be administered to a sample of up to 2200 respondents. One will include a payment vehicle as income tax increases. We will estimate the relative importance of each attribute and, for the former survey, the monetary trade-offs which individuals are willing to make between attributes. Where possible, we will match both samples to gauge preference robustness with the inclusion of the monetary payment. We will test whether respondents’ preferences differ based on their socioeconomic circumstances and attitudes toward the NHS and climate change.Ethics and dissemination The University of Aberdeen’s School of Medicine, Medical Sciences and Nutrition Ethics Research Board has approved the study (reference: SERB/690090). All participants will provide informed consent. Results will be submitted to peer-reviewed publications and presented at relevant conferences and seminars. A lay summary of the research will be published on the Health Economics Research Unit website.

Introduction Approximately 40% of children with diabetic ketoacidosis (DKA) develop acute kidney injury (AKI), which increases the risk of chronic kidney damage. At present, there is limited knowledge of racial or ethnic differences in diabetes-related kidney injury in children with diabetes. Understanding whether such differences exist will provide a foundation for addressing disparities in diabetes care that may continue into adulthood. Further, it is currently unclear which children are at risk to develop worsening or sustained DKA-related AKI. The primary aim is to determine whether race and ethnicity are associated with DKA-related AKI. The secondary aim is to determine factors associated with sustained AKI in children with DKA.Methods and analysis This retrospective, multicentre, cross-sectional study of children with type 1 or type 2 diabetes with DKA will be conducted through the Paediatric Emergency Medicine Collaborative Research Committee. Children aged 2–18 years who were treated in a participating emergency department between 1 January 2020 and 31 December 2023 will be included. Children with non-ketotic hyperglycaemic-hyperosmolar state or who were transferred from an outside facility will be excluded. The relevant predictor is race and ethnicity. The primary outcome is the presence of AKI, defined by Kidney Disease: Improving Global Outcomes criteria. The secondary outcome is ‘sustained’ AKI, defined as having AKI ≥48 hours, unresolved AKI at last creatinine measurement or need for renal replacement therapy. Statistical inference of the associations between predictors (ie, race and ethnicity) and outcomes (ie, AKI and sustained AKI) will use random effects regression models, accounting for hospital variation and clustering.Ethics and dissemination The Institutional Review Board of Children’s Minnesota approved this study. 12 additional sites have obtained institutional review board approval, and all sites will obtain local approval prior to participation. Results will be presented at local or national conferences and for publication in peer-reviewed journals.

Objectives Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.Design Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.Eligibility criteria Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.Data synthesis The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.Results A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI −4.00 to 9.88, I2=79.3%; %DLco −2.03, 95% CI −4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.Conclusions There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.PROSPERO registration number CRD42023423223.

Abstract Radiation-attenuated sporozoite (RAS) vaccines can completely prevent blood stage Plasmodium infection by inducing liver-resident memory CD8+ T cells to target parasites in the liver. Such T cells can be induced by ‘Prime-and-trap’ vaccination, which here combines DNA priming against the P. yoelii circumsporozoite protein (CSP) with a subsequent intravenous (IV) dose of liver-homing RAS to “trap” the activated and expanding T cells in the liver. Prime-and-trap confers durable protection in mice, and efforts are underway to translate this vaccine strategy to the clinic. However, it is unclear whether the RAS trapping dose must be strictly administered by the IV route. Here we show that intradermal (ID) RAS administration can be as effective as IV administration if RAS are co-administrated with the glycolipid adjuvant 7DW8-5 in an ultra-low inoculation volume. In mice, the co-administration of RAS and 7DW8-5 in ultra-low ID volumes (2.5 µL) was completely protective and dose sparing compared to standard volumes (10–50 µL) and induced protective levels of CSP-specific CD8+ T cells in the liver. Our finding that adjuvants and ultra-low volumes are required for ID RAS efficacy may explain why prior reports about higher volumes of unadjuvanted ID RAS proved less effective than IV RAS. The ID route may offer significant translational advantages over the IV route and could improve sporozoite vaccine development.

Abstract The stochastic synthesis of extreme, rare climate scenarios is vital for risk and resilience models aware of climate change, directly impacting society in different sectors. However, creating high-quality variations of under-represented samples remains a challenge for several generative models. This paper investigates quantizing reconstruction losses for helping variational autoencoders (VAE) better synthesize extreme weather fields from conventional historical training sets. Building on the classical VAE formulation using reconstruction and latent space regularization losses, we propose various histogram-based penalties to the reconstruction loss that explicitly reinforces the model to synthesize under-represented values better. We evaluate our work using precipitation weather fields, where models usually strive to synthesize well extreme precipitation samples. We demonstrate that bringing histogram awareness to the reconstruction loss improves standard VAE performance substantially, especially for extreme weather events.

Abstract Background There are marked inequalities in palliative care provision. Research is needed to understand how such inequalities can be addressed, so that everyone living with advanced illness can receive the care they need, when they need it. Research into inequalities in palliative care should be guided by Patient and Public Involvement (PPI) that includes people from diverse backgrounds, who are less likely to receive specialist services. Multi-disciplinary research partnerships, bringing together primary care (the main providers of palliative care to diverse communities) and specialist palliative care, have the potential to work together in new ways to do research to address inequalities and improve palliative care in practice. This report describes a research partnership between primary care and palliative care that aimed to: (1) create opportunities for more inclusive PPI in palliative care research, (2) co-design new resources to support more equitable, diverse and inclusive PPI for palliative care, (3) propose a new framework for inclusive PPI in palliative care research. Methods PPI members were recruited via primary care and palliative care research networks from three diverse areas of the UK. A pragmatic, collaborative approach was taken to achieve the partnership aims. Online workshops were carried out to understand barriers to inclusive PPI in palliative care and to co-design resources. Evaluation included a “you said, we did” impact log and a short survey. The approach was informed by good practice principles from previous PPI, and existing theory relating to equity, equality, diversity, and inclusion. Results In total, 16 PPI members were recruited. Most were White British (n = 10), other ethnicities were Asian (n = 4), Black African (n = 1) and British mixed race (n = 1). The research team co-ordinated communication and activities, leading to honest conversations about barriers to inclusive PPI. Resources were co-designed, including a role description for an Equity, Equality, Diversity and Inclusion Champion, a “jargon buster”, an animation and an online recipe book ( http://www.re-equipp.co.uk/ ) to inform future PPI. Learning from the partnership has been collated into a new framework to inform more inclusive PPI for future palliative care research. Conclusion Collaboration and reciprocal learning across a multi-disciplinary primary care and palliative care research partnership led to the development of new approaches and resources. Research team commitment, shared vision, adequate resource, careful planning, relationship building and evaluation should underpin approaches to increase equality, diversity and inclusivity in future PPI for palliative care research.

Because of constrained personnel time, the Philadelphia Department of Public Health (Philadelphia, PA, USA) adjusted its COVID-19 contact tracing protocol in summer 2021 by prioritizing recent cases and limiting staff time per case. This action reduced required staff hours to prevent each case from 21–30 to 8–11 hours, while maintaining program effectiveness.

Abstract The neurobiological mechanisms that regulate the appetite-stimulatory properties of cannabis sativa are unresolved. This work examined the hypothesis that cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus (MBH) regulate increased appetite following cannabis vapor inhalation. Here we utilized a paradigm where vaporized cannabis plant matter was administered passively to rodents. Initial studies in rats characterized meal patterns and operant responding for palatable food following exposure to air or vapor cannabis. Studies conducted in mice used a combination of in vivo optical imaging, electrophysiology and chemogenetic manipulations to determine the importance of MBH neurons for cannabis-induced feeding behavior. Our data indicate that cannabis vapor increased meal frequency and food seeking behavior without altering locomotor activity. Importantly, we observed augmented MBH activity within distinct neuronal populations when mice anticipated or consumed food. Mechanistic experiments demonstrated that pharmacological activation of CB1R attenuated inhibitory synaptic tone onto hunger promoting Agouti Related Peptide (AgRP) neurons within the MBH. Lastly, chemogenetic inhibition of AgRP neurons attenuated the appetite promoting effects of cannabis vapor. Based on these results, we conclude that MBH neurons contribute to the appetite stimulatory properties of inhaled cannabis.

Kathryn King,1 Serena McGuinness,1 Natalie Watson,1 Christine Norton,1 Trudie Chalder,2 Wladyslawa Czuber-Dochan1 1Florence Nightingale Faculty Nursing, Midwifery and Palliative Care, King’s College London, London, UK; 2Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UKCorrespondence: Kathryn King, Email Kathryn.king@kcl.ac.ukPurpose: Between 53% and 75% of people with inflammatory bowel disease, 30%– 80% with rheumatoid arthritis, and up to 50% with multiple sclerosis do not take medications as prescribed to maintain remission. This scoping review aimed to identify effective adherence interventions for inflammatory bowel disease, but with few studies found, multiple sclerosis and rheumatoid arthritis were included to learn lessons from other conditions.Methods: Full and pilot randomised controlled trials testing medication adherence interventions for inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis conducted between 2012 and 2021 were identified in six electronic databases.Results: A total of 3024 participants were included from 24 randomised controlled trials: 10 pilot and 14 full studies. Eight investigated inflammatory bowel disease, 12 rheumatoid arthritis, and four multiple sclerosis. Nine studies (37.5%) reported significantly improved medication adherence, all involving tailored, personalised education, advice or counselling by trained health professionals, with five delivered face-to-face and 1:1. Quality of effective interventions was mixed: five rated high quality, two medium and two low quality. Interventions predominantly using technology were likely to be most effective. Secondary tools, such as diaries, calendars and advice sheets, were also efficient in increasing adherence. Only 10 interventions were based on an adherence theory, of which four significantly improved adherence.Conclusion: Tailored, face-to-face, 1:1 interactions with healthcare professionals were successful at providing personalised adherence support. Accessible, user-friendly technology-based tools supported by calendars and reminders effectively enhanced adherence. Key components of effective interventions should be evaluated and integrated further into clinical practice if viable, whilst being tailored to inflammatory conditions.Plain Language Summary: Introduction: Inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA) are inflammatory diseases where the immune system causes inflammation by mistakenly attacking itself. These lifelong conditions cannot be cured, but can usually be controlled by medication. Medication is most effective when taken as prescribed, called “adherence”. For multiple reasons, between five and eight in 10 people with IBD, RA, and MS do not take medications as advised. This review aimed to identify research that tested ways to help people living with IBD, MS, and RA take medications as prescribed. Identifying and understanding what helps can increase patient well-being and improve quality of life through better controlled inflammatory conditions.Methods: Studies testing medication adherence interventions for IBD, MS, and RA conducted between 2012 and 2021 were identified from six electronic databases.Results: A total of 3024 people with inflammatory conditions took part in 24 studies (eight on IBD, four on MS, and 12 on RA). Nine studies reported significantly improved medication adherence, all involving personalised education, advice or counselling by trained health professionals, with five delivered face-to-face and individually. Interventions predominantly using technology were the most effective. Diaries, calendars, and advice sheets also increased adherence. Ten of the interventions were based on an adherence theory, of which four improved adherence.Conclusions: Personalised adherence support was successful when:tailored to patient,one-to-one and face-to-face,with healthcare professionals,involving technology-based tools, andsupported by calendars/reminders.Components of effective interventions should be used in clinical practice where possible, made specific to each inflammatory condition.Keywords: IBD, MS, RA, treatment, medicine, drug, concordance

Avian paramyxovirus type 1 (APMV-1) is a virus of birds that results in a range of outcomes, from asymptomatic infections to outbreaks of systemic respiratory and neurologic disease, depending on the virus strain and the avian species affected. Humans are rarely affected; those who are predominantly experience mild conjunctivitis. We report a fatal case of neurologic disease in a 2-year-old immunocompromised child in Australia. Metagenomic sequencing and histopathology identified the causative agent as the pigeon variant of APMV-1. This diagnosis should be considered in neurologic conditions of undefined etiologies. Agnostic metagenomic sequencing methods are useful in such settings to direct diagnostic and therapeutic efforts.

Genomic data on the foodborne pathogen Listeria monocytogenes from Central America are scarce. We analyzed 92 isolates collected during 2009–2019 from different regions in Costa Rica, compared those to publicly available genomes, and identified unrecognized outbreaks. Our findings suggest mandatory reporting of listeriosis in Costa Rica would improve pathogen surveillance.