Quantitative 23Na magnetic resonance imaging in the abdomen at 3 T.

OBJECTIVES: To assess the feasibility of sodium-23 MRI for performing quantitative and non-invasive measurements of total sodium concentration (TSC) and relaxation in a variety of abdominal organs. MATERIALS AND METHODS: Proton and sodium imaging of the abdomen was performed in 19 healthy volunteers using a 3D cones sequence and a sodium-tuned 4-rung transmit/receive body coil on a clinical 3 T system. The effects of B1 non-uniformity on TSC measurements were corrected using the double-angle method. The long-component of 23Na T2* relaxation time was measured using a series of variable echo-times. RESULTS: The mean and standard deviation of TSC and long-component 23Na T2* values were calculated across the healthy volunteer group in the kidneys, cerebrospinal fluid (CSF), liver, gallbladder, spleen, aorta, and inferior vena cava. DISCUSSION: Mean TSC values in the kidneys, liver, and spleen were similar to those reported using 23Na-MRI previously in the literature. Measurements in the CSF and gallbladder were lower, potentially due to the reduced spatial resolution achievable in a clinically acceptable scan time. Mean long-component 23Na T2* values were consistent with previous reports from the kidneys and CSF. Intra-population standard error was larger in smaller, fluid-filled structures due to fluid motion and partial volume effects.

AMBRA1 levels predict resistance to MAPK inhibitors in melanoma.

Intrinsic and acquired resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma remains a major therapeutic challenge. Here, we show that the clinical development of resistance to MAPKi is associated with reduced tumor expression of the melanoma suppressor Autophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression levels of AMBRA1 predict a poor response to MAPKi treatment. Functional analyses show that loss of AMBRA1 induces phenotype switching and orchestrates an extracellular signal-regulated kinase (ERK)-independent resistance mechanism by activating focal adhesion kinase 1 (FAK1). In both in vitro and in vivo settings, melanomas with low AMBRA1 expression exhibit intrinsic resistance to MAPKi therapy but higher sensitivity to FAK1 inhibition. Finally, we show that the rapid development of resistance in initially MAPKi-sensitive melanomas can be attributed to preexisting subclones characterized by low AMBRA1 expression and that cotreatment with MAPKi and FAK1 inhibitors (FAKi) effectively prevents the development of resistance in these tumors. In summary, our findings underscore the value of AMBRA1 expression for predicting melanoma response to MAPKi and supporting the therapeutic efficacy of FAKi to overcome MAPKi-induced resistance.

Inequalities in birth before arrival at hospital in South West England: a multimethods study of neonatal hypothermia and emergency medical services call-handler advice.

OBJECTIVES: To examine inequalities in birth before arrival (BBA) at hospitals in South West England, understand which groups are most likely to experience BBA and how this relates to hypothermia and outcomes (phase A). To investigate opportunities to improve temperature management advice given by emergency medical services (EMS) call-handlers during emergency calls regarding BBA in the UK (phase B). DESIGN: A two-phase multimethod study. Phase A analysed anonymised data from hospital neonatal records between January 2018 and January 2021. Phase B analysed anonymised EMS call transcripts, followed by focus groups with National Health Service (NHS) staff and patients. SETTING: Six Hospital Trusts in South West England and two EMS providers (ambulance services) in South West and North East England. PARTICIPANTS: 18 multidisciplinary NHS staff and 22 members of the public who had experienced BBA in the UK. RESULTS: 35% (64/184) of babies conveyed to hospital were hypothermic on arrival. When compared with national data on all births in the South West, we found higher percentages of women with documented safeguarding concerns at booking, previous live births and 'late bookers' (booking their pregnancy >13 weeks gestation). These women may, therefore, be more likely to experience BBA. Preterm babies, babies to first-time mothers and babies born to mothers with disability or safeguarding concerns at booking were more likely to be hypothermic following BBA. Five main themes emerged from qualitative data on call-handler advice: (1) importance placed on neonatal temperature; (2) advice on where the baby should be placed following birth; (3) advice on how to keep the baby warm; (4) timing of temperature management advice and (5) clarity and priority of instructions. CONCLUSIONS: Findings identified factors associated with BBA and neonatal hypothermia following BBA. Improvements to EMS call-handler advice could reduce the number of babies arriving at hospital hypothermic.

Which elements of hospital-based clinical decision support tools for the assessment and management of children with head injury can be adapted for use by paramedics in prehospital care? A systematic mapping review and narrative synthesis.

OBJECTIVE: Hospital-based clinical decision tools support clinician decision-making when a child presents to the emergency department with a head injury, particularly regarding CT scanning. However, there is no decision tool to support prehospital clinicians in deciding which head-injured children can safely remain at scene. This study aims to identify clinical decision tools, or constituent elements, which may be adapted for use in prehospital care. DESIGN: Systematic mapping review and narrative synthesis. DATA SOURCES: Searches were conducted using MEDLINE, EMBASE, PsycINFO, CINAHL and AMED. ELIGIBILITY CRITERIA: Quantitative, qualitative, mixed-methods or systematic review research that included a clinical decision support tool for assessing and managing children with head injury. DATA EXTRACTION AND SYNTHESIS: We systematically identified all in-hospital clinical decision support tools and extracted from these the clinical criteria used in decision-making. We complemented this with a narrative synthesis. RESULTS: Following de-duplication, 887 articles were identified. After screening titles and abstracts, 710 articles were excluded, leaving 177 full-text articles. Of these, 95 were excluded, yielding 82 studies. A further 14 studies were identified in the literature after cross-checking, totalling 96 analysed studies. 25 relevant in-hospital clinical decision tools were identified, encompassing 67 different clinical criteria, which were grouped into 18 categories. CONCLUSION: Factors that should be considered for use in a clinical decision tool designed to support paramedics in the assessment and management of children with head injury are: signs of skull fracture; a large, boggy or non-frontal scalp haematoma neurological deficit; Glasgow Coma Score less than 15; prolonged or worsening headache; prolonged loss of consciousness; post-traumatic seizure; amnesia in older children; non-accidental injury; drug or alcohol use; and less than 1 year old. Clinical criteria that require further investigation include mechanism of injury, clotting impairment/anticoagulation, vertigo, length of time of unconsciousness and number of vomits.

Extremophilic microbial metabolism and radioactive waste disposal.

Decades of nuclear activities have left a legacy of hazardous radioactive waste, which must be isolated from the biosphere for over 100,000 years. The preferred option for safe waste disposal is a deep subsurface geological disposal facility (GDF). Due to the very long geological timescales required, and the complexity of materials to be disposed of (including a wide range of nutrients and electron donors/acceptors) microbial activity will likely play a pivotal role in the safe operation of these mega-facilities. A GDF environment provides many metabolic challenges to microbes that may inhabit the facility, including high temperature, pressure, radiation, alkalinity, and salinity, depending on the specific disposal concept employed. However, as our understanding of the boundaries of life is continuously challenged and expanded by the discovery of novel extremophiles in Earth's most inhospitable environments, it is becoming clear that microorganisms must be considered in GDF safety cases to ensure accurate predictions of long-term performance. This review explores extremophilic adaptations and how this knowledge can be applied to challenge our current assumptions on microbial activity in GDF environments. We conclude that regardless of concept, a GDF will consist of multiple extremes and it is of high importance to understand the limits of polyextremophiles under realistic environmental conditions.

Evidências de validade da Escala RASH - Relação, Autonomia, Separação e Heteronomia em uma amostra de brasileiros e norte americanos / Evidenced of validity of the RASH Scale - Relation, Autonomy, Separation and Heteronomy in a sample of brazilians and north americans / Evidencias de validez de la Escala RASH - Relación, Autonomía, Separación y Heteronomía en una muestra de brasileños y norteamericanos

A Escala RASH (relação, autonomia, separação e heteronomia) foi desenvolvida para investigar padrões de self em estudos transculturais. No presente estudo, foi realizada uma análise fatorial da escala RASH em amostras brasileiras e norte-americanas, com o objetivo de fornecer uma medida de quatro fatores com bons índices de ajuste. Buscou-se confirmar o padrão de self autônomo-relacionado nas duas amostras e também a relação entre o nível de escolaridade dos pais e tipos de valores que desejam para seus filhos. Coletou-se dados de 756 participantes (EUA, n = 519, Brasil, n = 237), pais ou responsáveis por alunos de 7 a 14 anos. Foram realizadas análise fatorial exploratória e confirmatória, medidas de invariância e estatísticas básicas como média, desvio padrão e correlação. Os resultados corroboram uma estrutura de quatro fatores do instrumento e os padrões autorrelatados nas duas culturas. O instrumento pode auxiliar em pesquisas transculturais sobre o desenvolvimento de valores e captar diferenças entre culturas.(AU)

The RASH scale (which stands for relation, autonomy, separation, and heteronomy) was developed to investigate patterns of self in cross-cultural studies. In the present study, a factor analysis of the RASH scale was conducted in Brazilian and North American samples, with the aim of providing a four-factor measure with good fit indices. The aim was to confirm the pattern of autonomous-relational self in the two samples and also the relationship among the parents' level of education and the types of values they want for their children. We collected data from 756 participants (n = 519, USA; n = 237, Brazil), parents or guardians of students aged 7 to 14 years. Exploratory and confirmatory factor analyses, invariance measures and basic statistics such as mean, standard deviation, and correlation were performed. The results confirmed the four-factor structure of the instrument and self-reported patterns in the two cultures. The instrument can help in cross-cultural research on the development of values and capture differences between cultures.(AU)

La escala RASH (relación, autonomía, separación y heteronomía) se desarrolló para investigar patrones del self en estudios transculturales. En el presente estudio, se realizó una validación de la escala RASH en muestras brasileñas y norteamericanas, con el objetivo de proporcionar una medida de cuatro factores con buenos índices de ajuste. Se buscó confirmar el patrón de self autónomo-relacionado en ambas muestras, así como la relación entre el nivel educativo de los padres y los tipos de valores que desean para sus hijos. Se recopilaron datos de 756 participantes (n = 519 en EE. UU.; N = 237 en Brasil), padres o tutores de estudiantes de 7 a 14 años. Se llevaron a cabo análisis factoriales exploratorios y confirmatorios, seguidos de medidas de invarianza y cálculos de estadísticas básicas como media, desviación estándar y correlación. Los resultados respaldaron la estructura de cuatro factores del instrumento y los patrones autoinformados en ambas culturas. El instrumento puede ser útil para investigaciones interculturales sobre el desarrollo de valores y para capturar las diferencias entre culturas.(AU)

How do emergency department staff respond to behaviour that challenges displayed by people living with dementia? A mixed-methods study.

OBJECTIVES: To investigate staff experiences of, and approaches to behaviour that challenges displayed by patients with dementia in the emergency department (ED). Behaviour that challenges is defined as 'actions that detract from the well-being of individuals due to the physical or psychological distress they cause within the settings they are performed', and can take many forms including aggressive physical actions, shouting and verbal aggression and non-aggressive behaviour including repetitive questioning, inappropriate exposure and resistance to care. DESIGN: Mixed-methods study consisting of an online survey and semistructured telephone interviews. Quantitative data were analysed and presented using descriptive statistics. Qualitative data were analysed thematically. SETTING: The EDs of three National Health Service (NHS) Hospital Trusts in Southwest England. PARTICIPANTS: Multidisciplinary NHS staff working in the ED. RESULTS: Fifty-two online survey responses and 13 telephone interviews were analysed. Most (24/36, 67%) survey respondents reported that they had received general training in relation to dementia in the last 2-5 years, however, less than a fifth (4/23, 17%) had received any ED-specific dementia training. All (48/48) felt that behaviour that challenges could potentially be prevented, though resource constraints and practice variation were identified. Four main themes emerged from the qualitative data: (1) the 'perfect storm' of the ED; (2) behaviour that challenges is preventable with the right resources; (3) improvisation and (4) requirement for approaches that are specific to the ED. CONCLUSIONS: The findings of this study suggest that ED staff do not feel that they are prepared to respond effectively to behaviour that challenges displayed by people living with dementia. Future work could adapt or develop an intervention to support ED staff in responding to behaviour that challenges.

Machine learning analysis of wing venation patterns accurately identifies Sarcophagidae, Calliphoridae and Muscidae fly species.

In medical, veterinary and forensic entomology, the ease and affordability of image data acquisition have resulted in whole-image analysis becoming an invaluable approach for species identification. Krawtchouk moment invariants are a classical mathematical transformation that can extract local features from an image, thus allowing subtle species-specific biological variations to be accentuated for subsequent analyses. We extracted Krawtchouk moment invariant features from binarised wing images of 759 male fly specimens from the Calliphoridae, Sarcophagidae and Muscidae families (13 species and a species variant). Subsequently, we trained the Generalized, Unbiased, Interaction Detection and Estimation random forests classifier using linear discriminants derived from these features and inferred the species identity of specimens from the test samples. Fivefold cross-validation results show a 98.56 ± 0.38% (standard error) mean identification accuracy at the family level and a 91.04 ± 1.33% mean identification accuracy at the species level. The mean F1-score of 0.89 ± 0.02 reflects good balance of precision and recall properties of the model. The present study consolidates findings from previous small pilot studies of the usefulness of wing venation patterns for inferring species identities. Thus, the stage is set for the development of a mature data analytic ecosystem for routine computer image-based identification of fly species that are of medical, veterinary and forensic importance.

Factors that influence the administration of tranexamic acid (TXA) to trauma patients in prehospital settings: a systematic review.

OBJECTIVE: In the UK there are around 5400 deaths annually from injury. Tranexamic acid (TXA) prevents bleeding and has been shown to reduce trauma mortality. However, only 5% of UK major trauma patients who are at risk of haemorrhage receive prehospital TXA. This review aims to examine the evidence regarding factors influencing the prehospital administration of TXA to trauma patients. DESIGN: Systematic literature review. DATA SOURCES: AMED, CENTRAL, CINAHL, Cochrane Database of Systematic Reviews, Conference Proceedings Citation Index-Science, Embase and MEDLINE were searched from January 2010 to 2020; searches were updated in June 2022. CLINICALTRIALS: gov and OpenGrey were also searched and forward and backwards citation chasing performed. ELIGIBILITY CRITERIA: All primary research reporting factors influencing TXA administration to trauma patients in the prehospital setting was included. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers performed the selection process, quality assessment and data extraction. Data were tabulated, grouped by setting and influencing factor and synthesised narratively. RESULTS: Twenty papers (278 249 participants in total) were included in the final synthesis; 13 papers from civilian and 7 from military settings. Thirteen studies were rated as 'moderate' using the Effective Public Health Practice Project Quality Assessment Tool. Several common factors were identified: knowledge and skills; consequences and social influences; injury type (severity, injury site and mechanism); protocols; resources; priorities; patient age; patient sex. CONCLUSIONS: This review highlights an absence of high-quality research. Preliminary evidence suggests a host of system and individual-level factors that may be important in determining whether TXA is administered to trauma patients in the prehospital setting. FUNDING AND REGISTRATION: This review was supported by Research Capability Funding from the South Western Ambulance Service NHS Foundation Trust and the National Institute for Health Research Applied Research Collaboration South West Peninsula. PROSPERO REGISTRATION NUMBER: CRD42020162943.

The OpenMolcas Web: A Community-Driven Approach to Advancing Computational Chemistry.

The developments of the open-source OpenMolcas chemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcas can address, while showing that OpenMolcas is an attractive platform for state-of-the-art atomistic computer simulations.

Can artificial intelligence pass the Fellowship of the Royal College of Radiologists examination? Multi-reader diagnostic accuracy study.

OBJECTIVE: To determine whether an artificial intelligence candidate could pass the rapid (radiographic) reporting component of the Fellowship of the Royal College of Radiologists (FRCR) examination. DESIGN: Prospective multi-reader diagnostic accuracy study. SETTING: United Kingdom. PARTICIPANTS: One artificial intelligence candidate (Smarturgences, Milvue) and 26 radiologists who had passed the FRCR examination in the preceding 12 months. MAIN OUTCOME MEASURES: Accuracy and pass rate of the artificial intelligence compared with radiologists across 10 mock FRCR rapid reporting examinations (each examination containing 30 radiographs, requiring 90% accuracy rate to pass). RESULTS: When non-interpretable images were excluded from the analysis, the artificial intelligence candidate achieved an average overall accuracy of 79.5% (95% confidence interval 74.1% to 84.3%) and passed two of 10 mock FRCR examinations. The average radiologist achieved an average accuracy of 84.8% (76.1-91.9%) and passed four of 10 mock examinations. The sensitivity for the artificial intelligence was 83.6% (95% confidence interval 76.2% to 89.4%) and the specificity was 75.2% (66.7% to 82.5%), compared with summary estimates across all radiologists of 84.1% (81.0% to 87.0%) and 87.3% (85.0% to 89.3%). Across 148/300 radiographs that were correctly interpreted by >90% of radiologists, the artificial intelligence candidate was incorrect in 14/148 (9%). In 20/300 radiographs that most (>50%) radiologists interpreted incorrectly, the artificial intelligence candidate was correct in 10/20 (50%). Most imaging pitfalls related to interpretation of musculoskeletal rather than chest radiographs. CONCLUSIONS: When special dispensation for the artificial intelligence candidate was provided (that is, exclusion of non-interpretable images), the artificial intelligence candidate was able to pass two of 10 mock examinations. Potential exists for the artificial intelligence candidate to improve its radiographic interpretation skills by focusing on musculoskeletal cases and learning to interpret radiographs of the axial skeleton and abdomen that are currently considered "non-interpretable."

Impact of Phenol-Enriched Olive Oils on Serum Metabonome and Its Relationship with Cardiometabolic Parameters: A Randomized, Double-Blind, Cross-Over, Controlled Trial.

Phenol-rich foods consumption such as virgin olive oil (VOO) has been shown to have beneficial effects on cardiovascular diseases. The broader biochemical impact of VOO and phenol-enriched OOs remains, however, unclear. A randomized, double-blind, cross-over, controlled trial was performed with thirty-three hypercholesterolemic individuals who ingested for 3-weeks (25 mL/day): (1) an OO enriched with its own olive oil phenolic compounds (PCs) (500 ppm; FOO); (2) an OO enriched with its own olive oil PCs (250 ppm) plus thyme PCs (250 ppm; FOOT); and (3) a VOO with low phenolic content (80 ppm). Serum lipid and glycemic profiles, serum 1H-NMR spectroscopy-based metabolomics, endothelial function, blood pressure, and cardiovascular risk were measured. We combined OPLS-DA with machine learning modelling to identify metabolites discrimination of the treatment groups. Both phenol-enriched OO interventions decreased the levels of glutamine, creatinine, creatine, dimethylamine, and histidine in comparison to VOO one. In addition, FOOT decreased the plasma levels of glycine and DMSO2 compared to VOO, while FOO decreased the circulating alanine concentrations but increased the plasma levels of acetone and 3-HB compared to VOO. Based on these findings, phenol-enriched OOs were shown to result in a favorable shift in the circulating metabolic phenotype, inducing a reduction in metabolites associated with cardiometabolic diseases.

Do general practitioners working in or alongside the emergency department improve clinical outcomes or experience? A mixed-methods study.

OBJECTIVES: To examine the effect of general practitioners (GPs) working in or alongside the emergency department (GPED) on patient outcomes and experience, and the associated impacts of implementation on the workforce. DESIGN: Mixed-methods study: interviews with service leaders and NHS managers; in-depth case studies (n=10) and retrospective observational analysis of routinely collected national data. We used normalisation process theory to map our findings to the theory's four main constructs of coherence, cognitive participation, collective action and reflexive monitoring. SETTING AND PARTICIPANTS: Data were collected from 64 EDs in England. Case site data included: non-participant observation of 142 clinical encounters; 467 semistructured interviews with policy-makers, service leaders, clinical staff, patients and carers. Retrospective observational analysis used routinely collected Hospital Episode Statistics alongside information on GPED service hours from 40 hospitals for which complete data were available. RESULTS: There was disagreement at individual, stakeholder and organisational levels regarding the purpose and potential impact of GPED (coherence). Participants criticised policy development and implementation, and staff engagement was hindered by tensions between ED and GP staff (cognitive participation). Patient 'streaming' processes, staffing and resource constraints influenced whether GPED became embedded in routine practice. Concerns that GPED may increase ED attendance influenced staff views. Our quantitative analysis showed no detectable impact on attendance (collective action). Stakeholders disagreed whether GPED was successful, due to variations in GPED model, site-specific patient mix and governance arrangements. Following statistical adjustment for multiple testing, we found no impact on: ED reattendances within 7 days, patients discharged within 4 hours of arrival, patients leaving the ED without being seen; inpatient admissions; non-urgent ED attendances and 30-day mortality (reflexive monitoring). CONCLUSIONS: We found a high degree of variability between hospital sites, but no overall evidence that GPED increases the efficient operation of EDs or improves clinical outcomes, patient or staff experience. TRIAL REGISTRATION NUMBER: ISCRTN5178022.

Molecular basis for antiviral activity of pediatric neutralizing antibodies targeting SARS-CoV-2 Spike receptor binding domain

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV- 2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC-evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

Clinical effectiveness of short course oral prednisone for stricture prevention after semi-circumferential esophageal endoscopic submucosal dissection.

Background and study aims Esophageal strictures (ES) occur frequently after semi-circumferential endoscopic submucosal dissection (ESD) for the eradication of superficial esophageal neoplasms and negatively impact a patient's quality of life. Oral corticosteroids have been shown to be clinically effective, but the most appropriate drug, dose and duration is yet to be determined. The aim of the study was to investigate the clinical effectiveness and safety of 30 mg prednisone with a shortened tapering schedule on ES after semi-circumferential ESD. Patients and methods This was a retrospective observational study that analyzed consecutive patients with esophageal neoplasms who underwent semi-circumferential ESD with a resection defect greater than 75 % of the circumference that received a protocol of oral steroids for stricture prevention. On postoperative day 3, 30 mg prednisone was prescribed, tapering weekly to 20 mg/10 mg/5 mg over 4 weeks. Follow-up included clinic consultation and endoscopic review at weeks 2 and 4. Effectiveness outcomes included ES rates, safety, tolerability, resection, dilatation and recurrence rates. Results Ninety ESD procedures were carried out during the specified time period and 18 patients met the inclusion criteria for the final analysis. The mean age was 61.5 years, lesion size was 52.5 mm, and final histology was squamous cell carcinoma in all patients. Incidence of intra-procedure complications was: bleeding 5.5 % (1/18) and ES 5.5 % (1/18), requiring a median two endoscopic dilatations. En bloc, R0 and curative resection rates were 88.8 %, 72.2 %, and 55.5 %, respectively. Conclusions The short tapering schedule of 30 mg oral prednisone is clinically efficacious and safe for prevention of ES after semi-circumferential ESD in Latin American patients.

An S1 subunit vaccine and combination adjuvant (COVAC-1) elicits robust protection against SARS-CoV-2 challenge in African green monkeys

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent responsible for the ongoing global pandemic. With over 500 million cases and more than 6 million deaths reported globally, the need for access to effective vaccines is clear. An ideal SARS-CoV-2 vaccine will prevent pathology in the lungs and prevent virus replication in the upper respiratory tract, thus reducing transmission. Here, we assessed the efficacy of an adjuvanted SARS-CoV-2 S1 subunit vaccine, called COVAC-1, in an African green monkey (AGM) model. AGMs immunized and boosted with COVAC-1 were protected from SARS-CoV-2 challenge compared to unvaccinated controls based on reduced pathology and reduced viral RNA levels and infectious virus in the respiratory tract. Both neutralizing antibodies and antibodies capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) were observed in vaccinated animals prior to the challenge. COVAC-1 induced effective protection, including in the upper respiratory tract, thus supporting further development and utility for determining the mechanism that confers this protection. AUTHOR SUMMARYVaccines that can prevent the onward transmission of SARS-CoV-2 and prevent disease are highly desirable. Whether this can be accomplished without mucosal immunization by a parenterally administered subunit vaccine is not well established. Here we demonstrate that following two vaccinations, a protein subunit vaccine containing the S1 portion of the SARS-CoV-2 spike glycoprotein and the novel adjuvant TriAdj significantly reduces the amount of virus in the lungs and also mediates rapid clearance of the virus from the upper respiratory tract. Further support of the effectiveness of COVAC-1 was the observation of reduced pathology in the lungs and viral RNA being largely absent from tissues, blood, and rectal swabs. Thus COVAC-1 appears promising at mediating protection in both the upper and lower respiratory tract and may be capable of reducing subsequent transmission of SARS-CoV-2. Further investigation into the mechanism of protection in the upper respiratory tract and the initial immune response that supports this would be warranted.

Study to investigate the prevalence of human papillomavirus in Barrett's oesophagus using a novel screening methodology.

INTRODUCTION: Human papillomavirus (HPV) is strongly associated with Barrett's dysplasia and oesophageal cancer suggesting a role in carcinogenesis. HPV persistence predicts treatment failure after endotherapy for Barrett's dysplasia. This pilot study applies a novel HPV screening tool (previously only used in the oropharynx) to detect HPV DNA directly and determine the prevalence rates in Barrett's oesophagus (BO). METHOD: DNA was extracted from 20 formalin-fixed BO samples. HPV DNA was detected using real-time PCR and gel electrophoresis. RESULTS: 5 out of 20 patients were identified as positive for HPV. Prevalence was 25% in patients with BO. CONCLUSION: This method can be used in BO's tissue to determine HPV infection. Adoption of this as a screening test could potentially revolutionise future research in this area. If a clear link between HPV and Barrett's dysplasia can be confirmed, this qPCR method has the potential to aid in monitoring and/or dysplasia detection by stratifying those most at risk and aid in the development of new therapies.

SARS-CoV-2 accessory protein ORF8 decreases antibody-dependent cellular cytotoxicity

SARS-CoV-2 Spike glycoprotein is the major target of host neutralizing antibodies and the most changing viral protein in the continuously emerging SARS-CoV-2 variants as a result of frequent viral evasion from host antibody responses. In addition, SARS-CoV-2 encodes multiple accessory proteins that modulate host antiviral immunity by different mechanisms. Among all SARS-CoV-2 accessory proteins, ORF8 is rapidly evolving and a deletion in this protein has been linked to milder disease. Here, we studied the effect of ORF8 on peripheral blood mononuclear cells (PBMC). Specifically, we found that ORF8 can bind monocytes as well as NK cells. Strikingly, ORF8 binds CD16a (Fc{gamma}RIIIA) with nanomolar affinity and decreases the overall level of CD16 at the surface of monocytes and, to a lesser extent, NK cells. Strikingly, this decrease significantly reduces the capacity of PBMCs and particularly monocytes to mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, our data identifies a new immune-evasion activity used by SARS-CoV-2 to escape humoral responses.