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Vaccines serve as a major tool against the coronavirus disease 2019 (COVID-19) pandemic, but vaccine hesitancy remains a major concern in the United States. Healthcare workers (HCWs) strongly influence a patient’s decision to get vaccinated. We evaluated HCW knowledge and attitudes regarding the COVID-19 vaccine.

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for NR to enhance liver regeneration. NR improves mitochondrial respiration in regenerating WT or mutant livers and rapidly increases oxygen consumption and glucose output in cultured hepatocytes. Our data support a direct enhancement of mitochondrial redox metabolism as the mechanism mediating improved liver regeneration after NAD supplementation and exclude signaling via SIRT1 and SIRT3. Therefore, we provide the first evidence to our knowledge for an essential role for a mitochondrial sirtuin during liver regeneration and insight into the beneficial effects of NR.

Abstract Background Mucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50–60% five-year survival rate in the US. Immune checkpoint inhibitors (ICIs) have shown promising results in prolonging survival in a subset of patients with recurrent or metastatic disease. However, challenges remain, particularly the limited efficacy of PD-1/PD-L1 blockade therapies. PD-L1 protein expression has been shown to be limited in its predictive power for ICI therapies. Emerging evidence shows that intricate characterisation of the tumour microenvironment (TME) is fundamental to understand interacting cells. This study aims to bridge the gap in understanding the tumor microenvironment by identifying distinct spatial patterns of PD-1/PD-L1 interactions and their association with immunotherapy responses in head and neck squamous cell carcinoma (HNSCC). Methods In this study, we sought to apply a more nuanced approach to understanding cellular interactions by mapping PD-1/PD-L1 interactions across whole-slide HNSCC tissue samples collected prior to ICI therapy. We used a combination of spatial proteomics (Akoya Biosciences) and an in situ proximity ligation assay (isPLA, Navinci Diagnostics) to visualise PD-1/PD-L1 interactions across cell types and cellular neighbourhoods within the tumour TME. Results Our findings indicate the existence of isPLA+ PD-1/PD-L1 interactions between macrophages/CD3 T cell-enriched neighbourhoods and tumour cells at the tumour-stroma boundaries in ICI-resistant tumours. The presence of these dense macrophage-tumour layers, which are either absent or dispersed in responders, indicates a barrier that may restrict immune cell infiltration and promote immune escape mechanisms. In contrast, responders had abundant B and T cell aggregates, predominantly around the tumour edges linked to enhanced immune responses to ICI therapy and better clinical outcomes. Conclusion This study highlights the utility of isPLA in detecting distinct tumour-immune interactions within the TME, offering new cellular interaction metrics for stratifying and optimising immunotherapy strategies.

Abstract Aims Intra‐aortic balloon pump (IABP) devices are commonly used in patients with heart failure related cardiogenic shock (HF‐CS), including those with out‐of‐proportion right ventricular (RV) dysfunction. Pulmonary artery pulsatility index (PAPi) is a haemodynamic surrogate for RV performance. We aimed to assess short‐term haemodynamic changes in patients with HF‐CS following IABP support stratified by baseline PAPi. Methods and results This is a single‐centre study of 67 consecutive patients with HF‐CS who underwent IABP placement between 2020 and 2022. The primary aim was haemodynamic changes of specific variables on pulmonary artery catheter monitoring over 72 h following IABP placement. Secondary aims were clinically significant changes in diuretic regimens, changes in inotropes or vasopressors at 72 h following IABP, along with clinical outcomes. Prior to IABP placement, 57% of the total cohort (median age 59 years [48, 69], 31% female) had Society of Cardiovascular Angiography and Interventions Stage C HF‐CS. Thirty‐eight (56%) patients had a PAPi

This article reflects on the practice of mindful eating, intrinsically tied to the concept of living well in the Misak Indigenous world. This approach emphasizes understanding eating as a sensory and spiritual connection with the land and the cyclical rhythms of the territory. The study explores the significance of chish mamik (clean food) as a pathway to spiritual alignment with pishintø waramik (living in harmony and balance). It also examines the impact of modern pressures, particularly the coloniality of consumption, which continuously disrupts various aspects of Indigenous life. In light of these challenges, the article advocates for a sentipensar (defined as an inseparability of feeling and thinking) approach to eating well and living well, grounded in parøsøtø (food autonomy) and the Misak worldview. This vision is developed through four spirals of inter-learning: mørøp (feeling), isup (thinking), aship (seeing), and marøp (practicing), aimed at integrating bodily well-being with the harmonious stewardship of the land and its cycles.

The repair of damaged DNA is an essential function for living organisms. While great strides have been made in understanding this process in animal and yeast models, our knowledge in plant DNA repair is not as developed. Plants face many sources of DNA damage which they cannot so easily avoid: UV radiation from sunlight, reactive oxygen species produced endogenously by their mitochondria and chloroplasts, reactive oxygen species accumulated while under conditions of cold, heat, or salt stress. Understanding plant DNA repair is particularly relevant as the accumulation of DNA damage can negatively impact the growth and yield of agronomically important species. In this study, a broad classification of genes related to DNA repair in the model dicot Arabidopsis thaliana was conducted using gene ontology and gene enrichment analysis. The results of this broad classification serve to elucidate pathways for further study in plant DNA damage response and repair.

A 41-year-old male with a history of tobacco and alcohol use presented to our clinic for a follow up of an incidentally diagnosed splenic mass. The patient was sent for further diagnostic evaluation, and computed tomography showed a large splenic mass with heterogenous enhancement raising concern for neoplasm. Due to the uncertain nature of the splenic lesion and high complication rate of percutaneous splenic biopsy, a splenectomy was performed. The specimen was sent to pathology, and the report favored neoplasm but was inconclusive. The samples were sent to another institution for a consult, where the patient's spleen was determined to be the result of a previously suffered hemorrhagic infarct. This case demonstrates the difficulty of diagnosing splenic lesions using diagnostic imaging and the discrepancy that may occur between radiology and pathology assessments. In the setting of uncertain pathology, the removal of what might be a functional spleen is often preferred over a percutaneous biopsy due to concerns of intraabdominal bleeding and tumor dissemination.

Arteriovenous malformations (AVMs) are rare vascular anomalies that present complex diagnostic and therapeutic challenges, particularly in uncommon locations such as the lower extremities. A 72-year-old female with chronic atrial fibrillation, hypertension, and peripheral vascular disease presented with severe lower extremity edema due to multiple AVMs below the knee. This case underscores the importance of a multidisciplinary, individualized approach in managing complex AVMs and highlights the need for advanced imaging and diverse interventional techniques to ensure effective treatment and long-term outcomes.

Background/Objectives: Days Alive and at Home within 30 days (DAH30) is a patient-centred measurement tool designed to assist with the decision-making and management of patients undergoing surgery. Thus, identifying factors associated with better DAH30 scores would support healthcare providers to optimise patient care and outcomes. This systematic review aimed to determine factors associated with DAH30 scores following surgery. Methods: A sensitive electronic search was conducted in MEDLINE, Embase, Scopus, Web of Science and CINAHL databases in September 2022. Eligible studies included patients undergoing surgery and reporting the association of preoperative and/or postoperative factors and DAH30. Risk of bias was assessed using the QUIPs tool. Results: Of the 14 studies identified, the majority (n = 13, 93%) were cohort studies, presenting moderate or high (n = 8, 60%) risk of bias. This review identified a number of factors influencing DAH30 scores in patients undergoing surgery. ASA Physical Status and surgery duration were the most common factors influencing DAH30 scores. Conclusions: Optimising patients’ health prior to surgery and reducing surgical time have the potential to improve patients’ recovery.

Abstract Movement ecology data are often collected by catching animals and fitting GPS tags. This technique is expensive, biased and comes at an extra cost for the caught individuals. New conservation technologies allow noninvasive data collection, providing ecological knowledge to aid the conservation of endangered species. Using bioacoustics, we investigated intraseason and between‐year movements of the red‐listed corncrake (Crex crex) and their relationships with landscape structure. Our goals were to track corncrake movements with minimal disturbance to the species and determine how landscape features affect these movements. We recorded males over two consecutive breeding seasons in 2022 and 2023 in an extensively farmed agricultural landscape in the West of Ireland. Individual identity was obtained through vocal characteristics of the calling males which were grouped into clusters. The areas of seminatural grassland and margin features, presence of bird refuge strips, and habitat connectivity were extracted from buffers between locations of two matching recordings (same calling male). These landscape features were used as model predictors to determine the distance that the same male covered. We found that, in a season, males moved 415 m on average (min = 10 m; max = 1805 m) between calling locations, which was more than previously thought in the Western Europe. Males also reoccurred on average 375 m (min = 23 m; max = 1231 m) away from the previous year's location. Landscape connectivity (p = 0.01, N = 42) and seminatural grassland area (p = 0.02, N = 42) were positive predictors of intraseason movements, whereas the margin area (p = 0.01, N = 35) predicted further between‐year movements. Considering our noninvasively sampled results in the Irish context, we suggest increasing the protection area around a calling male to 500 m. In this buffer, we also suggest improving the availability of seminatural grassland to 30% and presence of margin features to 3%. Further land management recommendations are provided.

The right posterior segmental duct (RPSD) draining into the cystic duct is exceedingly rare. Ligation of the cystic duct in proximity to the junction of an aberrant right hepatic duct after a cholecystectomy can lead to life threatening complications. The present case study reveals a severed anomalous RPSD and subsequent Roux-en-Y hepaticojejunostomy procedure employed to fix biliary anomaly.

Abstract Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

Several studies have correlate improved patient outcomes with increased physician–patient contacts, particularly in chronic diseases. Extending this approach to inflammatory bowel disease (IBD) care presents a promising means of improving outcomes. At LSU Health Shreveport (LSUHS), a new approach called “STABILITY” (Symptomatic Review during Biologic Therapy) was implemented during infusion therapy visits for IBD patients. These brief 15 min physician–patient interviews aimed to discuss the patients’ current IBD-related symptoms and evaluate the need for any changes in their treatment plan. Our goal was to remove a care gap and prevent intensifying symptoms created by missed appointments and loss of contact. To analyze the effectiveness of the STABILITY approach, a retrospective chart review was conducted on 111 IBD patients (18 with ulcerative colitis, 93 with Crohn’s disease) seen at LSUHS between 2011 and 2022. Since March 2019, STABILITY has been mandatory for all infusion therapy visits. The data collected included patients’ demographics, lab levels for biomarkers (fecal calprotectin, C-reactive protein, and erythrocyte sedimentation rates), hospitalizations, medication changes, and diagnosis dates before and after the implementation of STABILITY. Additionally, voluntary, anonymous infusion patient satisfaction surveys post-STABILITY were used to gather patient responses. In males with IBD, disease severity and hospitalizations were reduced significantly (p = 0.004 and 0.0234, respectively). In females with IBD, disease severity and hospitalizations were also reduced significantly (p = 0.0001 and 0.0072, respectively). In patients with UC and CD, there were significant improvements in disease severity (p = 0.043 and p = 0.0001, respectively), and CD hospitalizations were also improved (p = 0.0013). In males and females with UC, disease severity was marginally and significantly reduced (p = 0.0781 and p = 0.0379, respectively). In males and females with CD, disease severity was significantly reduced (p = 0.0161 and 0.0003, respectively), and CD male and female hospitalizations were also reduced significantly (p = 0.0436 and 0.013). Analyzing of survey responses, we found that the most patients reported improved IBD symptoms (56%), gained understanding of their condition (84%) and were in favor of continuing STABILITY consultations during infusion therapy (93%). To further investigate the impact of STABILITY, we conducted a comparative analysis between IBD patients undergoing STABILITY infusion therapy and LSUHS patients solely on self-injectable biologics. Our paired data analysis showed significant improvements in disease severity in female IBD patients (1.69 ± 0.13 vs. 1.41 ± 0.12, p = 0.0001) and male IBD patients (1.58 ± 0.16 vs. 1.2 ± 0.135, p = 0.004), in UC patients (1.833 ± 0.4.2 vs. 1.444, p = 0.043), in all CD patients (1.59 ± 0.11 vs. 1.29 ± 0.01, p = 0.0001), in male CD patients (1.52 ± 0.167 vs. 1.15 ± 0.15, p = 0.016), in female CD patients (1.66 ± 0.15 vs. 1.4 ± 0.13, p = 0.0003), in female UC patients (1.82 ± 0.32 vs. 1.45 ± 0.31, p = 0.0379), and marginally in male UC patients (p = 0.0781). Similarly, hospitalizations were significantly reduced in CD patients considered in aggregate (0.21 ± 0.04 vs. 0.11 ± 0.03, p = 0.0013), in male IBD patients (0.175 ± 0.06 vs. 0.05 ± 0.035, p = 0.024), in female IBD patients (0.21 ± 0.05 vs. 0.11 ± 0.04, p = 0.0072), in male CD patients (0.18 ± 0.07 vs. 0.06 ± 0.042, p = 0.0436), and in females with CD (0.23 ± 0.06 vs. 0.13 ± 0.04, p = 0.013). Although average values for fecal calprotectin, CRP, and sedimentation rate were frequently reduced after STABILITY interviews, these data did not reach statistical significance. These preliminary findings suggest that STABILITY may be effective in maintaining low disease activity or remission in IBD patients.

Community tutelary shrines in Taiwan have been identified as excellent resources for grassroots-level heritage. As community ritual assemblages, they are able to encode data about a settlement’s social, political and economic history in their material composition, aesthetic choices, artefacts, displays and orientations. This data paper previews a first edition dataset related to 752 such shrines found throughout the greater Taipei area in northern Taiwan. It explores the basis for such a dataset, how it can be used and what has been produced. This dataset is available on the depositar research data repository, operated out of the Institute of Information Sciences at Academia Sinica in Taipei and is publicly available for download.

Abstract Background Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally has a poor prognosis for patients with limited treatment options. While incorporating immune checkpoint inhibitors (ICIs) has now become the standard of care, the efficacy is variable, with only a subset of patients responding. The complexity of the tumor microenvironment (TME) and the role of tertiary lymphoid structures (TLS) have emerged as critical determinants for immunotherapeutic response. Methods In this study, we analyzed two independently collected R/M HNSCC patient tissue cohorts to better understand the role of TLS in response to ICIs. Utilizing a multi-omics approach, we first performed targeted proteomic profiling using the Nanostring GeoMx Digital Spatial Profiler to quantify immune-related protein expression with spatial resolution. This was further characterized by spatially resolved whole transcriptome profiling of TLSs and germinal centers (GCs). Deeper single-cell resolved proteomic profiling of the TLSs was performed using the Akoya Biosciences Phenocycler Fusion platform. Results Our proteomic analysis revealed the presence of T lymphocyte markers, including CD3, CD45, and CD8, expressing cells and upregulation of immune checkpoint marker PD-L1 within tumor compartments of patients responsive to ICIs, indicative of ‘hot tumor’ phenotypes. We also observed the presence of antigen-presenting cells marked by expression of CD40, CD68, CD11c, and CD163 with upregulation of antigen-presentation marker HLA-DR, in patients responding to ICIs. Transcriptome analysis of TLS and GCs uncovered a marked elevation in the expression of genes related to immune modulation, diverse immune cell recruitment, and a potent interferon response within the TLS structure. Notably, the distribution of TLS-tumor distance was found to be significantly different across response groups (H = 9.28, p = 0.026). The proximity of TLSs to tumor cells was found to be a critical indicator of ICI response, implying that patients with TLSs located further from tumor cells have worse outcomes. Conclusion The study underscores the multifaceted role of TLSs in modulating the immunogenic landscape of the TME in R/M HNSCC, likely influencing the efficacy of ICIs. Spatially resolved multi-omics approaches offer valuable insights into potential biomarkers for ICI response and highlight the importance of profiling the TME complexity when developing therapeutic strategies and patient stratification.

Equity requires a rethinking of the processes and methods that applied scientists and engineers work through as they develop solutions that are simultaneously technical and social. By bridging insights from science and technology studies with critical analysis of participatory development practice, we propose a framework for understanding equitable technology development. We explore this through an illustrative case of water monitoring technology development, undertaken with scientists, engineers and communities in Vanuatu. Analysis suggests a typology of five methodological considerations that are significant for the practice of equitable technology development, locating equitable technology development as both a technical and an ethical challenge.

The ever-increasing ageing of the world population is demanding superior orthopedic devices. Issues such as implant infection, poor osseointegration, or chronic inflammation remain problematic to the lifespan and long-term efficacy of implants. Fabrication of materials with bioinspired nanostructures is one emerging antibacterial strategy to prevent implant infection, however their interactions with blood components, and whether they retain their bactericidal properties in an environment displaying a complex protein corona, remains largely unexplored. In the present study, titanium alloy, commercially pure and plasma-sprayed titania were hydrothermally etched, passivated with human native plasma to develop a protein corona, and then incubated with either Staphylococcus aureus, Pseudomonas aeruginosa or human platelets. Surface analysis was first used to characterize the topography, chemical composition or crystallinity of each material. Fluorescence staining and SEM were performed to evaluate the nanostructure bactericidal properties, as well as to study platelet attachment and morphology. Composition of platelet supernatant was studied using ELISA and flow cytometry. Overall, our study showed that the bioinspired nanostructured surfaces displayed both impressive antibacterial properties in a complex environment, and a superior blood biocompatibility profile in terms of platelet activation (particularly for titanium alloy). Additionally, the amount of pro-inflammatory cytokines released by platelets was found to be no different to that found in native plasma (background levels) and, in some cases, presented a more pro-healing profile with an increased secretion of factors such as TGF-β, PDGF-BB or BMP-2. The nanostructured surfaces performed equally, or better, than hydroxyapatite-coated titanium which is one of the current gold standards in orthopedics. Although further in vivo studies are required to validate these results, such bioinspired nanostructured surfaces certainly show promise to be safely applied to medical device surfaces used in orthopedics and other areas.

Killer whales (Orcinus orca) are the apex predator in global oceans, and as such they are afforded access to prey species at all trophic levels and sizes. Due to their enhanced cognitive abilities, they are frequent predators of other ocean giants, including large sharks. Observations of these predator-prey interactions are rare globally; however, records appear to be increasing in recent years, possibly due to increased access to surveillance. Here we present reports of killer whales hunting and preying on the world’s largest fish species, the whale shark (Rhincodon typus), by collating and analyzing photo and video footage collected from four unique predation events spanning six years (2018 – 2024) in the southern Gulf of California. Across all events, orcas displayed a seemingly approach to collaboratively hunting and killing whale sharks, characterized by focusing on attacking the pelvic area (claspers and pelvic fins) which exsanguinates the prey and allows access to the lipid-rich liver. Photo identification of the killer whales revealed that an individual adult male “Moctezuma” was engaged in three of the four events, and the females involved in event four had previously been sighted with him. We suggest the potential existence of a specialized pod of elasmobranch-hunting killer whales occurring in the Gulf of California.

Background: Visualization of the guidewire during internal jugular (IJ) vein catheterization by point of care ultrasound (POCUS) has been recommended for avoiding inadvertent carotid artery dilation. The purpose of this study was to determine the accuracy of POCUS for identifying guidewires inappropriately placed in the carotid artery. Methods: This prospective, observational study involved emergency medicine (EM) residents with varying experience in guidewire visualization. Using an inanimate model, investigators placed guidewires randomly into the carotid artery or IJ vein. Residents, blinded to guidewire location, scanned the model and recorded their findings. The test performance of POCUS for arterially placed guidewires was evaluated through calculation of sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and overall accuracy, using investigator placement as the non-reference standard. Results: Twenty-five residents performed 51 observations. The test performance of POCUS for identifying arterially placed guidewires was sensitivity 95.0% (95%CI = 73.1-99.7%), specificity 96.8% (95%CI = 81.5-99.8%), NPV 96.8% (95%CI = 81.5-99.8%), and PPV 95.0% (95%CI = 73.1-99.7%). The overall accuracy was 96.1% (95%CI = 86.8-98.9%). Residents reported being very confident in their findings in 88.2% of all observations (95%CI = 76.6-94.5%), somewhat confident in 9.8% (95%CI = 4.3-21.0%), and not very confident in 2.0% (95%CI = 0.4-10.3%). No errors occurred among upper-level residents (post-graduate years 2-3) or those reporting >5 prior wire visualizations in live patients. Conclusions: This study is the first to demonstrate that physicians can easily identify misplaced guidewires located in the carotid artery with a high degree of accuracy using POCUS. We recommend routine scanning of the IJ vein and carotid artery prior to vessel dilation to reduce the likelihood of carotid artery injury.

Ecosystem functions such as biological pest control are mediated by the richness and abundance of service providers i.e., biological control agents (BCAs), relative contributions of individual taxa and community structure. This is especially relevant in the native range of agricultural herbivores, where a speciose community of co-evolved BCAs can prevent them from attaining pest status. Here, we use a powerful graphical approach to assess the functional structure of BCA communities of the fall armyworm (FAW) Spodoptera frugiperda (Lepidoptera: Noctuidae) on maize in the Neotropics. Drawing upon a curated database of all-time field and laboratory studies, we graphed patterns in the functional contribution, abundance and niche breadth for a respective 69, 53 and 3 taxa of resident parasitoids, predators and pathogens. Regardless of varying taxon coverage and rigor of the underlying studies, functional structure follows a saturating relationship in which the first three taxa account for 90–98% of aggregate biological control function. Abundance-functionality matrices prove critically incomplete, as more than 80% of invertebrate taxa miss empirically derived efficiency metrics while associated FAW infestation data are scarce. Despite its methodological shortfalls and data gaps, our work pinpoints Chelonus insularis, several taxa of egg parasitoids, Doru spp. and Orius spp. as taxa with outsized (average) functionality and conservation potential. This is also exemplified by the highly variable aggregate function across studies, with dispersion indices of 1.52 and 2.14 for invertebrate BCAs. Our work underlines the critical importance of functional ecology research, networked trials and standardized methodologies in advancing conservation biological control globally.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Smoking declines are uneven around the world, and we have few studies on the correlates of youth smoking in contexts like Saudi Arabia, where declines have been slowest. Using a broadly socio-ecological framework and network data, we report on one of the few studies to simultaneously examine peer, family, and school features associated with smoking in the Saudi context. We find strong and consistent peer and family associations with both occasional and regular smoking via direct modeling (level of peers/family that also smoke) and substantive interactions (lying to parents in the family domain, engaging in unsupervised youth-centric activities, or seeking popularity in the peer domain). Although our design precludes causal claims, our results are consistent with smoking initiation being driven by occasional use surrounding attempts to gain youth social status, whereas regular use depends on implicit family and peer acceptance.

Background: Poor patient flow or patient movement through a healthcare organisation can lead to adverse outcomes for patients and organisational inefficiency. Many hospitals have addressed suboptimal patient flow by increasing resources, such as bed stock and staffing; however, this is an unsustainable approach. In determining the nature of poor patient flow issues, it is important to collect data from healthcare professionals who manage patient flow daily. Doing so provides insights into the current state of patient flow management in its entirety, whilst also helping with the development of sustainable solutions. Methods: Thirteen semi-structured interviews were conducted with healthcare professionals who were directly involved with patient flow at a referring hospital in Tasmania, Australia. Results: Using a thematic analysis method, four major themes were developed. The first major theme was: ‘managing patient flow’ which centered around known and unknown demands on bed availability. The second theme, ‘communication for decisions’, highlighted the essential role of communication in maintaining patient flow. The third theme, ‘tools as enablers and barriers, relates to the number of software programs which can both help and hinder patient flow. The final theme of ‘increasing complexity’ is related to an apparent trend towards greater numbers of patients requiring care of an increasingly specialised nature. Conclusions: The findings of this study provide great insights into patient flow issues, with potential solutions identified to address them.

Objective: The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis. Methods: We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants. Results: Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 μg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 μg/L/h, n = 58) (mean difference, 13.2 μg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups. Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery.

Abstract Background Homelessness is associated with significant health disparities. Conventional health services often fail to address the unique needs and lived experience of homeless individuals and fail to include participatory design when planning health services. This scoping review aimed to examine areas of patient experience that are most frequently reported by people experiencing homelessness when seeking and receiving healthcare, and to identify existing surveys used to measure patient experience for this cohort. Methods A scoping review was undertaken reported according to the PRISMA-ScR 2020 Statement. Databases were searched on 1 December 2022: MEDLINE, EMBASE, APA PsychINFO and CINAHL. Included studies focused on people experiencing homelessness, healthcare services and patient experience, primary research, published in English from 2010. Qualitative papers and findings were extracted and synthesized against a modified framework based on the National Institute for Health and Care Excellence guidelines for care for people experiencing homelessness, the Institute of Medicine Framework and Lachman’s multidimensional quality model. People with lived experience of homelessness were employed as part of the research team. Results Thirty-two studies were included. Of these, 22 were qualitative, seven quantitative and three mixed methods, from the United States of America (n = 17), United Kingdom (n = 5), Australia (n = 5) and Canada (n = 4). Health services ranged from primary healthcare to outpatient management, acute care, emergency care and hospital based healthcare. In qualitative papers, the domains of ‘accessible and timely’, ‘person-centred’, and values of ‘dignity and respect’ and ‘kindness with compassion’ were most prevalent. Among the three patient experience surveys identified, ‘accessible and timely’ and ‘person-centred’ were the most frequent domains. The least frequently highlighted domains and values were ‘equitable’ and ‘holistic’. No questions addressed the ‘safety’ domain. Conclusions The Primary Care Quality-Homeless questionnaire best reflected the priorities for healthcare provision that were highlighted in the qualitative studies of people experiencing homelessness. The most frequently cited domains and values that people experiencing homelessness expressed as important when seeking healthcare were reflected in each of the three survey tools to varying degrees. Findings suggest that the principles of ‘Kindness and compassion’ require further emphasis when seeking feedback on healthcare experiences and the domains of ‘safety’, ‘equitable’, and ‘efficiency’ are not adequately represented in existing patient experience surveys.

Background: Retinal ganglion cell (RGC) loss is crucial in eye diseases like glaucoma. Axon damage and dendritic degeneration precede cell death, detectable within optical coherence tomography (OCT) resolution, indicating their correlation with neuronal degeneration. The purpose of this study is to evaluate the optical changes of early retinal degeneration. Methods: The detection of optical changes in the axotomised retinal explants was completed in six C57BL/6J mice. OCT images were acquired up to 120 min from enucleation. A grey-level co-occurrence-based texture analysis was performed on the inner plexiform layer (IPL) to monitor changes in the optical speckles using a principal component analysis (PCA) and a support vector machine (SVM). In parallel tests, retinal transparency was confirmed by a comparison of the modulation transfer functions (MTFs) at 0 and 120 min. Results: Quantitative confirmation by analysis of the MTFs confirmed the non-degradation of optical transparency during the imaging period: MTF (fx) = 0.267 ± 0.02. Textural features in the IPL could discriminate between the optical signals of RGC degeneration. The mean accuracy of the SVM classification was 86.3%; discrimination was not enhanced by the combination of the SVM and PCA (81.9%). Conclusions: Optical changes in the IPL can be detected using OCT following RGC axotomy. High-resolution OCT can provide an index of retinal neuronal integrity and its degeneration.

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in the lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in the pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRP mice with constitutively active (ca) ChREBP. These mice underwent retinal functional testing, which was followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both proteins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photoreceptor degeneration, as we observed diminished scotopic ERG amplitudes in caChREBPRP mice at P35. The retinal proteomic landscape revealed a decline in the KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific caChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBP cells exhibit a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprogramming triggering retinal functional loss in mice.

Summary: Single-cell spatial analysis of proteins is rapidly becoming increasingly important in revealing biological insights. Here, we present a protocol for automated high-plex multi-slide immunofluorescence staining and imaging of human head and neck cancer formalin-fixed paraffin-embedded (FFPE) sections using PhenoCycler-Fusion 2.0 technology. We describe steps for preparing human head and neck cancer FFPE tissues, staining with a panel of immunophenotyping markers, and Flow Cell assembly. We then detail procedures for setting up for a PhenoCycler-Fusion run, post-run Flow Cell removal, and downstream analyses.For complete details on the use and execution of this protocol, please refer to Jhaveri et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer’s disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype.

There is no safe level of air pollution for human health. Traffic-related particulate matter (PM2.5) is a major in-utero toxin, mechanisms of action of which are not fully understood. BALB/c dams were exposed to an Australian level of traffic PM2.5 (5 µg/mouse/day, intranasal, 6 weeks before mating, during gestation and lactation). Male offspring had reduced memory in adulthood, whereas memory was normal in female littermates, similar to human responses. Maternal PM2.5 exposure resulted in oxidative stress and abnormal mitochondria in male, but not female, brains. RNA-sequencing analysis showed unique sex-related changes in newborn brains. Two X-chromosome-linked histone lysine demethylases, Kdm6a and Kdm5c, demonstrated higher expression in female compared to male littermates, in addition to upregulated genes with known functions to support mitochondrial function, synapse growth and maturation, cognitive function, and neuroprotection. No significant changes in Kdm6a and Kdm5c were found in male littermates, nor other genes, albeit significantly impaired memory function after birth. In primary foetal cortical neurons, PM2.5 exposure suppressed neuron and synaptic numbers and induced oxidative stress, which was prevented by upregulation of Kdm6a or Kdm5c. Therefore, timely epigenetic adaptation by histone demethylation to open DNA for translation before birth may be the key to protecting females against prenatal PM2.5 exposure-induced neurological disorders, which fail to occur in males associated with their poor cognitive outcomes.

Background/Aims To assess the cost-effectiveness of making treatment decisions for patients with ocular hypertension (OHT) based on a risk prediction (RP) tool in the United Kingdom.Methods A discrete event simulation model was constructed to compare the cost-effectiveness of an alternative care pathway in which the treatment decision was guided by a validated RP tool in secondary care against decision-making based on the standard care (SC). Individual patient sampling was used. Patients diagnosed with OHT and with an intraocular pressure of 24 mm Hg or over entered the model with a set of predefined individual characteristics related to their risk of conversion to glaucoma. These characteristics were retrieved from electronic medical records (n=5740). Different stages of glaucoma were modelled following conversion to glaucoma.Results Almost all (99%) patients were treated using the RP strategy, and less than half (47%) of the patients were treated using the SC strategy. The RP strategy produced higher cost but also higher quality-adjusted life years (QALYs) than the SC strategy. The RP strategy was cost-effective compared with the SC strategy in the base-case analysis, with an incremental cost-effectiveness ratio value of £11 522. The RP strategy had a 96% probability of being cost-effective under a £20 000 per QALY threshold.Conclusions The use of an RP tool for the management of patients with OHT is likely to be cost-effective. However, the generalisability of the result might be limited due to the high-risk nature of this cohort and the specific RP threshold used in the study.

The nascent Aistijan movement centred around the idea of establishing a Latvian–Lithuanian state following the Second World War. This article surveys the background of the idea, with particular attention to the public diplomacy of Lithuanian American émigrés, demonstrating its prevalence during the First World War. The activities of interwar Latvian and Lithuanian rapprochement societies are outlined, noting the prominence of the Aestii – the earliest recorded inhabitants of the eastern littoral of the Baltic Sea – in both academic and popular history, in addition to the emergence of the Aistijan movement following the Second World War. Examining the initial successes and rapid decline of the movement, the article also charts developments and material circumstances of language learning practices in connection with the idea of a Latvian–Lithuanian state.

Abstract The spatial localisation of immune cells within tumours are key to understand the intercellular communications that can dictate clinical outcomes. Here, we demonstrate an analysis pipeline for highly multiplexed CODEX data to phenotype and profile spatial features and interactions in NSCLC patients that subsequently received PD1 axis immunotherapy. We found that regulatory T cells (Tregs) are enriched in non-responding patients and this was consistent with their localization within stromal and peripheral tumour-margins. Proximity-based interactions between Tregs and both monocytes (p = 0.009) and CD8+ T cells (p = 0.009) were more frequently found in non-responding patients, while macrophages were more frequently located in proximity to HLADR+ tumour cells (p = 0.01) within responding patients. Cellular neighbourhoods analysis indicated that both macrophages (p = 0.003) and effector CD4+ T cells (p = 0.01) in mixed tumour neighbourhoods, as well as CD8+ T cells (p = 0.03) in HLADR+ tumour neighbourhoods were associated with favorable clinical response. Evaluation of the inferred regulatory functions between immune cells relative to the tumour suggested that macrophages exhibit an immunosuppressive phenotype against both CD4+ and CD8+ T cells, and that this association scores more highly in ICI refractory patients. These spatial patterns are associated with overall survival in addition to ICI response and may thus indicate features for the functional understanding of the tumour microenvironment.

Abstract Early detection of sepsis is key to ensure timely clinical intervention. Since very few end-to-end pipelines are publicly available, fair comparisons between methodologies are difficult if not impossible. Progress is further limited by discrepancies in the reconstruction of sepsis onset time. This retrospective cohort study highlights the variation in performance of predictive models under three subtly different interpretations of sepsis onset from the sepsis-III definition and compares this against inter-model differences. The models are chosen to cover tree-based, deep learning, and survival analysis methods. Using the MIMIC-III database, between 867 and 2178 intensive care unit admissions with sepsis were identified, depending on the onset definition. We show that model performance can be more sensitive to differences in the definition of sepsis onset than to the model itself. Given a fixed sepsis definition, the best performing method had a gain of 1–5% in the area under the receiver operating characteristic (AUROC). However, the choice of onset time can cause a greater effect, with variation of 0–6% in AUROC. We illustrate that misleading conclusions can be drawn if models are compared without consideration of the sepsis definition used which emphasizes the need for a standardized definition for sepsis onset.

The Kingdom of Saudi Arabia (KSA) is the leading oil-exploring and -exploiting country in the world. As a result, contamination of the environment by petroleum products (mainly hydrocarbons) is common, necessitating strategies for their removal from the environment. Much work has been conducted on bacterial degradation of hydrocarbons in the KSA. This review comprehensively analyzed 43 research investigation articles on bacterial hydrocarbon degradation, mainly polyaromatic hydrocarbons (PAHs) within the KSA. More than 30 different bacterial genera were identified that were capable of degrading simple and complex PAHs, including benzo[a]pyrene and coronene. Different strategies for selecting and isolating these bacterial strains and their advantages and disadvantages were highlighted. The review also discussed the origins of sample inocula and the contributions of various research groups to this field. PAH metabolites produced by these bacteria were presented, and biochemical pathways of PAH degradation were proposed. More importantly, research gaps that could enrich our understanding of petroleum product biodegradation mechanisms were highlighted. Overall, the information presented in this paper will serve as a baseline for further research on optimizing bioremediation strategies in all petroleum-contaminated environments.

Abstract Background Knowledge of the genetic basis of health conditions can influence how the public perceives their own and others’ health. When there are known genetic associations for such conditions, genetic essentialist biases facilitate deterministic thinking and an over-emphasis of genetic causality. This study investigates the role that genetic essentialist biases play in medical decision-making. Methods Senior postgraduate medical students (N = 102) read a scenario in which a patient presents with gastroenterological symptoms. Half of the students were told that the patient tested positive for HLADQ2 – a gene implicated in, but not deterministic of, coeliac disease. The other half received no genetic information. Students were assessed on their recommendations for investigation and management using a multiple-choice questionnaire. Twenty-two of these students participated in a qualitative follow-up which used focus groups and semi-structured interviews to explore the reasoning behind students’ responses. Results Management recommendations differed between the two groups, with those receiving genetic information more likely to recommend a gluten free diet. Recommendations for further investigation did not differ significantly between groups. Interviews suggested that these findings arose despite the students’ good understanding of the common non-deterministic nature of genes, such as HLADQ2. Conclusion Differences in management recommendations suggest that the inclusion of genetic information unduly biased students towards a premature diagnosis of a serious health condition, coeliac disease. Follow-up interviews introduced the possibility that observed manipulation-based differences may have been based on anticipated expectations of examiners, rather than perceived future clinical practice. Based on the present results it is unclear whether intentional exam-taking strategies fully account for medical students’ decisions, or if they contribute in addition to the activation of genetic essentialist biases. Further research in clinical settings may ascertain whether genetic essentialist biases would truly influence medical student and doctors within their clinical practice environment.

Abstract Over the past decade, automation of digital image analysis has become commonplace in both research and clinical settings. Spurred by recent advances in artificial intelligence and machine learning (AI/ML), tissue sub-compartments and cellular phenotypes within those compartments can be identified with higher throughput and accuracy than ever before. Recently, immune checkpoints have emerged as potential targets for auto-immune diseases. As such, spatial identification of these proteins along with immune cell markers (e.g., CD3+/LAG3+ T-cells) is a crucial step in understanding the potential and/or efficacy of such treatments. Here, we describe a semi-automated imaging and analysis pipeline that identifies CD3+/LAG3+ cells in colorectal tissue sub-compartments. While chromogenic staining has been a clinical mainstay and the resulting brightfield images have been utilized in AI/ML approaches in the past, there are associated drawbacks in phenotyping algorithms that can be overcome by fluorescence imaging. To address these tradeoffs, we developed an analysis pipeline combining the strengths of brightfield and fluorescence images. In this assay, immunofluorescence imaging was conducted to identify phenotypes followed by coverslip removal and hematoxylin and eosin staining of the same section to inform an AI/ML tissue segmentation algorithm. This assay proved to be robust in both tissue segmentation and phenotyping, was compatible with automated workflows, and revealed presence of LAG3+ T-cells in ulcerative colitis biopsies with spatial context preserved.

Abstract Although placebo-controlled trials are considered the gold standard for evaluating the efficacy of healthcare interventions, they can be perceived to be controversial and challenging to conduct for surgical treatments. The SUcceSS trial is the first placebo-controlled trial of lumbar decompression surgery for symptomatic lumbar canal stenosis. The SUcceSS trial has experienced common issues affecting the implementation of randomised placebo-controlled surgery trials, accentuated by the COVID-19 pandemic. Using the SUcceSS trial as an example, we discuss key challenges and mitigation strategies specific to the conduct of a randomised placebo-controlled surgical trial. Overall, the key lessons learned were (i) involving key stakeholders early and throughout the trial design phase may increase clinician and patient willingness to participate in a placebo-controlled trial of surgical interventions, (ii) additional resources (e.g. budget, staff time) are likely required to successfully operationalise trials of this nature, (iii) the level of placebo fidelity, timing of randomisation relative to intervention delivery, and nuances of the surgical procedure under investigation should be considered carefully. Findings are based on one example of a placebo-controlled surgical trial; however, researchers may benefit from employing or building from the strategies described and lessons learned when designing or implementing future trials of this nature.

The aims of this study were to assess patient-reported outcomes and the survival of patients following curative resection for pancreas cancer. Adult patients undergoing curative pancreatic resection between April 2014 and April 2019 across six major hospitals in Sydney were invited to complete the Short-Form 36 (SF-36v2) and the Functional Assessment Cancer Therapy—Hepatobiliary (FACT-Hep) questionnaires. Time from surgery was categorised into four different time points: 3–11, 12–23, 24–35, and 36–62 months. Survival analyses were performed using Kaplan–Meier and log-rank tests. A total of 278 patients underwent curative resection. Mean (SD) age was 65.0 (13.2), and 50.7% (n = 141) were males. Out of the 205 (74%) alive patients, 128 (62%) completed the study surveys. The physical component score and total FACT-Hep scores showed no significant changes over time. The mental component score improved from 3–11 months to 12–23 months (p = 0.009) and from 3–11 months to 36–62 months (p = 0.007). Survivorship showed a significant difference between malignancy, pre-malignancy, and benign disease groups, with 45.8 months (95%CI: 42.4–49.1), 40.3 months (95%CI: 36.4–44.2), and 41.3 months (95%CI: 37.9–44.9), respectively. For patients undergoing curative resection for pancreatic cancer, mental component scores improved over time, whereas overall survival outcomes seem to be influenced according to cancer pathology.

Abstract The interpretation of LHC data, and the assessment of possible hints of new physics, require the precise knowledge of the proton structure in terms of parton distribution functions (PDFs). We present a systematic methodology designed to determine whether and how global PDF fits might inadvertently ‘fit away’ signs of new physics in the high-energy tails of the distributions. We showcase a scenario for the High-Luminosity LHC, in which the PDFs may completely absorb such signs of new physics, thus biasing theoretical predictions and interpretations. We discuss strategies to single out the effects in this scenario, and disentangle the inconsistencies that stem from them. Our study brings to light the synergy between the high luminosity programme at the LHC and future low-energy non-LHC measurements of large-x sea quark distributions. The analysis code used in this work is made public so that any users can test the robustness of the signal associated to a given BSM model against absorption by the PDFs.

Abstract High grade serous ovarian carcinoma (HGSOC) is a highly heterogeneous disease that typically presents at an advanced, metastatic state. The multi-scale complexity of HGSOC is a major obstacle to predicting response to neoadjuvant chemotherapy (NACT) and understanding critical determinants of response. Here we present a framework to predict the response of HGSOC patients to NACT integrating baseline clinical, blood-based, and radiomic biomarkers extracted from all primary and metastatic lesions. We use an ensemble machine learning model trained to predict the change in total disease volume using data obtained at diagnosis (n = 72). The model is validated in an internal hold-out cohort (n = 20) and an independent external patient cohort (n = 42). In the external cohort the integrated radiomics model reduces the prediction error by 8% with respect to the clinical model, achieving an AUC of 0.78 for RECIST 1.1 classification compared to 0.47 for the clinical model. Our results emphasize the value of including radiomics data in integrative models of treatment response and provide methods for developing new biomarker-based clinical trials of NACT in HGSOC.

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

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Since 2016, the fall armyworm (FAW) Spodoptera frugiperda has spread over extensive areas of the tropics and subtropics, imperiling food security, economic progress and the livelihoods of millions of cereal farmers. Although FAW has received long-standing scientific attention in its home range in the Americas, chemical inputs feature prominently in its mitigation and biological control uptake is globally lagging. Here, building upon a quantitative review of the global literature, we methodically dissect FAW biological control science. Of the known entomopathogens (46), parasitoids (304) and predators (215) of FAW, approx. 40% have been subject to laboratory- or field-level scrutiny. Laboratory-level performance has partially been assessed for 14–18% of the above invertebrate taxa. Yet, organismal, geographic, methodological and thematic biases hamper efforts to relate in-field biodiversity to actual ecosystem service delivery. Often, single-guild ‘snapshot’ surveys are preferred over comprehensive bio-inventories or population dynamics appraisals, trophic interactions are wrongly inferred from co-occurrence, standard pest infestation metrics are lacking and natural enemy censuses are performed arbitrarily. Diurnal biota receive inordinate attention, while egg and pupal predation - the main biotic sources of mortality - are routinely overlooked. Multiple microbial and invertebrate biota are investigated with a view towards mass-rearing and augmentative release, but the basis for agent selection is often unclear. Lastly, conservation biological control receives marginal attention and cross-disciplinary engagement with the agroecology domain is lagging. We lay out several steps, including standardized methodologies, smart use of biodemographic toolkits, networked field trials and a fortification of its ecological underpinnings, to sharpen the science of (FAW) biological control and urge further momentum in its global implementation.

Mechanisms underlying long COVID remain poorly understood. Patterns of immunological responses in individuals with long COVID may provide insight into clinical phenotypes. Here we aimed to identify these immunological patterns and study the inflammatory processes ongoing in individuals with long COVID. We applied an unsupervised hierarchical clustering approach to analyze plasma levels of 42 biomarkers measured in individuals with long COVID. Logistic regression models were used to explore associations between biomarker clusters, clinical variables, and symptom phenotypes. In 101 individuals, we identified three inflammatory clusters: a limited immune activation cluster, an innate immune activation cluster, and a systemic immune activation cluster. Membership in these inflammatory clusters did not correlate with individual symptoms or symptom phenotypes, but was associated with clinical variables including age, BMI, and vaccination status. Differences in serologic responses between clusters were also observed. Our results indicate that clinical variables of individuals with long COVID are associated with their inflammatory profiles and can provide insight into the ongoing immune responses.

Abstract Background Racial inequities exist in treatment and outcomes in patients with acute stroke. Objectives Our objective was to determine if racial inequities exist in the time-lapse between patient presentation and provider assessment in patients with stroke-like symptoms in Emergency Departments (ED) across the U.S. Methods This study is a retrospective, observational study of the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2014–2018. We identified visits with stroke-like symptoms and stratified the proportion of door-to-provider (DTP) times by racial groups. We used broad and narrow definitions of stroke-like symptoms. We performed bivariate and multivariate analyses using race and clinical and demographic characteristics as covariates. Results Between 2014–2018, there were an average of 138.58 million annual ED visits. Of the total ED visits, 0.36% to 7.39% of the ED visits presented with stroke-like symptoms, and the average DTP time ranged from 39 to 49 min. The proportion of the visits with a triage level of 1 (immediate) or 2 (emergent) ranged from 16.03% to 23.27% for stroke-like symptoms. We did not find statistically significant racial inequities in DTP or ED triage level. We found significantly longer DTP times in non-Hispanic blacks (15.88 min, 95% CI: 4.29–27.48) and Hispanics (by 14.77 min, 95% CI: 3.37–26.16) than non-Hispanic whites that presented with atypical stroke-like symptoms. We observed that non-Hispanic whites were significantly more diagnosed with a stroke/TIA than other racial minority groups (p = 0.045) for atypical stroke-like symptoms. Conclusion In our population-based analysis, we did not identify systemic racial inequities in the DTP times or ED triage level at ED triage for stroke-like symptoms.