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The Nuffield Department of Medicine (NDM) at the University of Oxford has a global reach and significant breadth in terms of capabilities and capacity.
Influence of context on engagement with COVID-19 testing: a scoping review of barriers and facilitators to testing for healthcare workers, care homes and schools in the UK
ObjectiveThe UK government’s response to the COVID-19 pandemic included a ‘test, trace and isolate’ strategy. Testing services for healthcare workers, care homes and schools accounted for the greatest spend and volume of tests. We reviewed relevant literature to identify common and unique barriers and facilitators to engaging with each of these testing services.DesignScoping review.Search strategyPubMed, Scopus and the WHO COVID-19 Research Database were searched for evidence published between 1 January 2020 and 7 November 2022. This was supplemented by evidence identified via free-text searches on Google Scholar and provided by the UK Health Security Agency (UKHSA).Data extraction and synthesisData were extracted by a team of reviewers and synthesised thematically under the broad headings of perceptions, experiences, barriers and facilitators to engaging with the COVID-19 testing programme.ResultsThis study included 40 sources, including 17 from projects that informed UKHSA’s decisions during the pandemic. Eight themes emerged and were used to categorise barriers and facilitators to engaging with the testing services for healthcare workers, care homes and schools: (1) perceived value, (2) trust in the tests and public bodies, (3) importance of infrastructure, (4) impact of media and social networks, (5) physical burden of the test, (6) perceived capability to undertake testing, (7) importance of relevant information and 8) consequences of testing.ConclusionsUniversal barriers and facilitators to engagement with the testing programme related to the core elements of each testing service, such as uncomfortable specimen collection and the influence of media and peers; these could be mitigated or leveraged to increase engagement across settings. However, the individuals involved, perceptions of value and available resources differed across services, leading to unique experiences between settings. Thus, consideration of context is crucial when designing and implementing a testing programme in response to a pandemic.
Risk analysis for outpatient experimental infection as a pathway for affordable RSV vaccine development.
Controlled human infection models (CHIMs) are an important tool for accelerating clinical development of vaccines. CHIM costs are driven by quarantine facilities but may be reduced by performing CHIM in the outpatient setting. Furthermore, outpatient CHIMs offer benefits beyond costs, such as a participant-friendly approach and increased real-world aspect. We analyze safety, logistic and ethical risks of respiratory syncytial virus (RSV) CHIM in the outpatient setting. A review of the literature identified outpatient CHIMs involving respiratory pathogens. RSV transmission risk was assessed using data from our inpatient and outpatient RSV CHIMs (EudraCT 020-004137-21). Fifty-nine outpatient CHIMs using RSV, Streptococcus pneumoniae, rhinovirus, and an ongoing Bordetella Pertussis outpatient CHIM were included. One transmission event was recorded. In an inpatient RSV CHIM, standard droplet and isolation measures were sufficient to limit RSV transmission and no symptomatic third-party transmission was measured in the first outpatient RSV CHIM. Logistic and ethical advantages support outpatient CHIM adoption. We propose a framework for outpatient RSV CHIM with risk mitigation strategies to enhance affordable vaccine development.
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.
Hide and seek with falsified medicines: Current challenges and physico-chemical and biological approaches for tracing the origin of trafficked products.
The criminal trafficking of falsified medical products is a worldwide, yet still largely overlooked, public health problem. A falsified medicine fraudulently misrepresents its identity, composition and/or source, often being ineffective or toxic for patients. Although techniques have been developed to detect falsified medicines, it remains a challenge to trace where- and by whom- the products are manufactured. We aim to discuss plausible biological and physico-chemical analytical techniques that could reveal information about the origin of medical falsifications. We first provide a brief overview on the prevalence, criminal activities, health impacts and (bio)chemical features of falsified medical products. We then explore diverse laboratory approaches, that are used in food fraud, illicit drug and wildlife trafficking investigations, and discuss how they could be combined and redirected towards tracing falsified medicine origin and hence empowering enforcement to counter this pernicious but neglected global health problem.
Survey of healthcare-associated sink infrastructure, and sink trap antibiotic residues and biochemistry, in twenty-nine UK hospitals.
BackgroundHospital sinks are linked to healthcare-associated infections. Antibiotics and chemicals in sink traps can select for pathogens and antimicrobial resistance (AMR). Optimizing sink design and usage can mitigate sink-to-patient dissemination of pathogens.AimTo perform a large-scale survey of hospital sink infrastructure.MethodsTwenty-nine UK hospitals submitted photos and metadata for sinks across three wards (intensive care unit (ICU)/medical/surgical; January-March 2023). Photos were used to classify sink design as 'optimal' according to guidelines and published studies. Sink trap aspirates were dipstick-tested for antibiotics and chemistry. Logistic regression was used to characterize associations of ward type and sink location with optimal sink design or detectable trap antibiotics.FindingsOf 287 sinks surveyed, 111 were in ICUs, 92 in medical wards, and 84 in surgical wards; 77 were in medicines/drug preparation rooms, 97 on patient bays, 25 in patient side-rooms, and 88 in sluice rooms. Sink-to-bed ratios ranged from 0.23 to 2.83 sinks per patient bed and were higher on ICUs (1.21 versus 0.82 and 0.84 on medical and surgical wards, respectively; P = 0.04). The median sink-to-patient distance was 1.5 m (interquartile range: 1.00-2.21 m). Sink design varied widely; it was deemed 'optimal' for 65/122 (53%) sinks in patient bays/side-rooms and 'optimal' design was associated with side-room location (P = 0.03). Antibiotics were detected in 95/287 (33%) sink traps and were associated with medicines/drug preparation rooms (P <0.001). Sink trap chemicals detected included metals, chlorine, and fluoride.ConclusionSinks are common in hospitals, frequently close to patients, and often sub-optimally designed. Commonly used antibiotics were detected in a third of sink traps and may contribute to the selection of pathogens and AMR in these reservoirs, and subsequent transmission to patients.
Barriers to publishing early phase clinical trials: the oncologists’ perspective
Abstract Introduction Findings from early phase studies are not always placed in the public domain. This study aims to explore why many early phase clinical oncology studies are not published, as well as identify the potential barriers investigators encountered in the publication process. Methods Semi-structured interviews were conducted among investigators with experience in early phase clinical oncology studies. Interviews were analyzed using reflexive thematic analysis. Results Twenty-one investigators were interviewed. The majority worked in Europe (n = 13), while other investigators were based in North America (n = 4), Asia (n = 2) or Oceania (n = 2). We identified three reasons why investigators believed publishing early phase clinical trial results was important: (1) there is an ethical and moral responsibility; (2) there should be no loss of knowledge to society; and (3) there should be no waste of resources. Four main barriers in the publication process of early phase clinical trials were identified: (1) practical barriers (eg, an increased complexity of number of trials/trial sites), (2) insufficient resources (eg, money, time and human), (3) limited motivation (eg, limited intrinsic motivation of the investigator or limited prospect of return for the sponsor), and (4) inadequate collaboration (eg, different interests between industry partners and investigators). Finally, five major stakeholders were identified that can potentially contribute to improving the publication process: (1) journal editors, (2) sponsors, (3) investigators, (4) regulatory bodies, and (5) society. Investigator suggestions for improving this process, for each stakeholder, are presented. Conclusions This study highlights the barriers experienced in publishing early phase clinical trials. Recognizing and acknowledging these barriers is crucial to devise effective strategies to improve the publishing and public sharing of early phase clinical trials.
Peptide-specific natural killer cell receptors
Abstract Class I and II human leukocyte antigens (HLA-I and HLA-II) present peptide antigens for immunosurveillance by T cells. HLA molecules also form ligands for a plethora of innate, germline-encoded receptors. Many of these receptors engage HLA molecules in a peptide sequence independent manner, with binding sites outside the peptide binding groove. However, some receptors, typically expressed on natural killer (NK) cells, engage the HLA presented peptide directly. Remarkably, some of these receptors display exquisite specificity for peptide sequences, with the capacity to detect sequences conserved in pathogens. Here, we review evidence for peptide-specific NK cell receptors (PSNKRs) and discuss their potential roles in immunity.
Biallelic FGF4 Variants Linked to Thoracic Dystrophy and Respiratory Insufficiency.
The thoracic dystrophies are inherited skeletal conditions where abnormal embryonic development of the thoracic skeleton results in a narrow chest, pulmonary hypoplasia, and respiratory insufficiency, which can be severe or lethal. The majority of thoracic dystrophies are due to biallelic alterations in genes needed for normal ciliary function. However, despite the identification of over 20 genes as causal for the thoracic dystrophy phenotype, around 20% of patients remain without a molecular diagnosis. We present two unrelated families with a clinical diagnosis of thoracic dystrophy with associated respiratory insufficiency without a molecular diagnosis on previous genetic testing. Both harbor rare biallelic and predicted deleterious missense substitutions in FGF4, a gene known to be essential for formation of the thoracic skeleton in mice. We demonstrate that the phenotype is restricted to short ribs, abnormally narrow chest, and respiratory insufficiency, without other diagnostic clinical or radiological signs. We suggest that biallelic alterations in FGF4 are a newly identified disease association of thoracic dystrophy.
A comparison of national seasonal influenza treatment guidelines across the Asia Pacific region.
Seasonal influenza leads to 2-3 million infections and up to 650,000 global deaths annually, with particularly high mortality in Asia and relatively low annual vaccination rates for prevention. Relatively lower attention is paid to antiviral treatment as a facet of influenza response strategy both in research and national policy. This study compares national influenza treatment guidelines across countries in the Asia Pacific region, and assesses the antiviral recommendations, comprehensiveness, availability, and quality, compared with World Health Organisation (WHO) guidelines. Ministry of Health websites were searched, and key stakeholders were contacted to obtain national influenza treatment guidelines. Official guidelines detailing pharmacologic treatment for seasonal influenza were included. Key data for comparison were extracted and quality appraisal was conducted using the AGREE II instrument. Out of 49 countries and areas in the World Health Organisation Western Pacific and South-East Asia regions, under half (14/49; 28.6%) had established national influenza treatment guidelines. Nine (9/49; 18.4%) reported no seasonal flu guidelines at all, and information could not be obtained for 25 (51.0%). All guidelines recommend oseltamivir in line with WHO recommendations, although rationale and evidence reviews were often missing. There was variation in recommendations for other antivirals, indications for treatment, definitions of severity and recency of publication. The AGREE II tool quality assessments revealed the highest average scores were observed in the 'presentation' domain and lowest scores in 'editorial independence' and 'rigour of development' domains, demonstrating limited evidence-based guideline development. The variability in recommendations and definitions highlight the need for a stronger evidence base with direct comparisons of antiviral treatment for hard and soft endpoints, and improvements in systematic guideline development. Established treatment guidelines are a key component of national influenza response strategy and in the post-covid pandemic era, renewed attention to seasonal influenza management is surely warranted.
Drug Combinations Targeting FAK and MEK Overcomes Tumor Heterogeneity in Glioblastoma
Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis, largely owing to its heterogeneity and the involvement of multiple intracellular signaling pathways that contribute to drug resistance. While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying effective drug combinations across the broader GBM population remains a challenge. Integrin-mediated signaling, particularly through Focal Adhesion Kinase (FAK), plays a pivotal role in GBM pathogenesis and invasion, making it a potential therapeutic target and component of future drug combination strategies. Methods: In this study, we utilized a chemogenomic screening approach to identify synergistic drug combinations that target FAK in glioblastoma. We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and subsequently discovered that combining FAK inhibitors such as VS4718 with MEK inhibitors, particularly trametinib, demonstrated synergistic effects. This potent combination was validated using various 2D and 3D assays, including cell viability/apoptosis assessment, synergistic analysis, cellular imaging, and target engagement assays. This combination also effectively inhibited spheroid growth and invasion across a diverse panel of patient-derived GBM stem cells. Molecular mechanisms underlying these effects include suppression of multiple kinase signaling pathways and enhanced apoptosis, elucidated using Reverse-Phase Protein Array (RPPA) profiling and Western blot validation. Result: In vivo, combination therapy significantly reduced the tumor volume in orthotopic transplantation models. Conclusions: These findings suggest that the combination of FAK and MEK inhibitors represents a promising therapeutic strategy to overcome the challenges of GBM treatment.
Structural characterization of antibody-responses following Zolgensma treatment for AAV capsid engineering to expand patient cohorts.
Monoclonal antibodies are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids that are used as gene therapy delivery vectors. The presence of pre-existing neutralizing antibodies in large portions of the human population poses a significant challenge for AAV-mediated gene therapy, primarily targeting the capsid leading to vector inactivation and loss of treatment efficacy. This study structurally characterizes the interactions of 21 human-derived neutralizing antibodies from three patients treated with the AAV9 vector, Zolgensma®, utilizing high-resolution cryo-electron microscopy. The antibodies bound to the 2-fold depression or the 3-fold protrusions do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with many antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with antibody escape phenotypes. These AAV9 capsid variants have the potential to expand the patient cohort to include those that were previously excluded due to their pre-existing neutralizing antibodies against the wtAAV9 capsid, and the possibly of further treatment to those requiring redosing.
The latency time of SARS-CoV- 2 Delta variant in infection- and vaccine-naive individuals from Vietnam
Abstract Background The latency time (from infection to infectiousness) guides the choice of measures required to control an infectious disease. Estimates of the SARS-CoV- 2 latency time are sparse due to lack of appropriate and representative data. Infection time is rarely known exactly and exposure information may be subject to several biases. Information on the endpoint requires repeated testing. Moreover, estimation is challenging because both the starting point and endpoint are typically interval censored and data may be subject to length-biased sampling (truncation). Methods We collected detailed information on exposure from public health reports produced during an outbreak with the SARS-CoV- 2 Delta variant in Ho Chi Minh City, Vietnam, in May-July 2021. Using a custom digital form and application facilitated reliable choices on exposure window. This comprehensive data set on exposure and test results from 1951 individuals, collected in the absence of large-scale vaccination or earlier infection, is the first of its kind outside of China. We accounted for the doubly interval censored nature of the observations and went beyond the standard assumption of a constant infection risk over calendar time (exponential growth) and allowed for flexibility regarding the latency time (generalized gamma distribution). We addressed right truncation due to a cutoff in data collection and a finite quarantine length. Employing a Bayesian approach, using the program , made the analyses relatively straightforward. Results Assuming exponential growth, our estimate of SARS-CoV- 2 Delta variant’s mean latency time was 3.22 (95% Credible Interval 2.89 - 3.55) days; the median was 1.81 (95% CrI 1.44- 2.16) days; the 95 th percentile was 10.98 (95% CrI 9.91 - 12.41) days. These values were much larger if a uniform infection risk was assumed. Conclusions Using a Bayesian approach with the program, we were able to estimate the SARS-CoV- 2 latency time distribution of the Delta variant in infection-naive and vaccine-naive individuals. Estimates were sensitive to the assumptions made regarding the risk of infection within the exposure window. Compared to earlier studies, the median latency time was shorter, while the 95 th percentile was larger. Our results stress the importance of thoughtful data collection and analysis for evidence-based control of an infectious disease.
Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation.
Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma, where desmosomes are mutated in more than 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes is associated with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these decreases in expression occur in keratinocytes in the microenvironment rather than in primary melanoma cells. In further support of a microenvironmental origin, we find that desmosome gene knockdown in keratinocytes yields markedly increased proliferation of adjacent melanoma cells in keratinocyte and melanoma cocultures. Similar increases in melanoma proliferation are observed in media preconditioned with desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.