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A new report is being released today that unveils 50 female leaders in healthcare business in the UK, which includes Oxford's Professor Sumi Biswas.
Creating different global health futures: mapping the health research ecosystem and taking decolonial action.
This paper promotes reflexive consideration of health research practices using a decolonisation lens. We propose both incremental and more radical action in five domains: knowledge production, funding and programmes, dissemination, uptake, and education and training. We suggest four steps towards transformation and share a reflexive tool to operationalise these steps.
Structural maturation of the matrix lattice is not required for HIV-1 particle infectivity.
During HIV-1 maturation, the matrix (MA) lattice underlying the viral membrane undergoes a structural rearrangement, and the newly released capsid (CA) protein forms a mature CA. While it is well established that CA formation is essential for particle infectivity, the functional role of MA structural maturation remains unclear. Here, we examine maturation of an MA triple mutant, L20K/E73K/A82T, which, despite replicating similarly to wild-type (WT) in some cell lines, exhibits distinct biochemical behaviors that suggest altered MA-MA interactions. Cryo-electron tomography with subtomogram averaging reveals that, although the MA lattice in immature L20K/E73K/A82T virions closely resembles that of the WT, mature L20K/E73K/A82T virions lack a detectable MA lattice. All-atom molecular dynamics simulations suggest that this absence results from destabilized inter-trimer MA interactions in mature L20K/E73K/A82T mutant virions. These findings suggest that an ordered, membrane-associated mature MA lattice is not essential for HIV-1 infectivity, providing insights into the structural requirements for HIV-1 particle maturation and generation of infectious particles.
Short tandem repeat polymorphism in the promoter region of cyclophilin 19B drives its transcriptional upregulation and contributes to drug resistance in the malaria parasite Plasmodium falciparum.
Resistance of the human malaria parasites, Plasmodium falciparum, to artemisinins is now fully established in Southeast Asia and is gradually emerging in Sub-Saharan Africa. Although nonsynonymous SNPs in the pfk13 Kelch-repeat propeller (KREP) domain are clearly associated with artemisinin resistance, their functional relevance requires cooperation with other genetic factors/alterations of the P. falciparum genome, collectively referred to as genetic background. Here we provide experimental evidence that P. falciparum cyclophilin 19B (PfCYP19B) may represent one putative factor in this genetic background, contributing to artemisinin resistance via its increased expression. We show that overexpression of PfCYP19B in vitro drives limited but significant resistance to not only artemisinin but also piperaquine, an important partner drug in artemisinin-based combination therapies. We showed that PfCYP19B acts as a negative regulator of the integrated stress response (ISR) pathway by modulating levels of phosphorylated eIF2α (eIF2α-P). Curiously, artemisinin and piperaquine affect eIF2α-P in an inverse direction that in both cases can be modulated by PfCYP19B towards resistance. Here we also provide evidence that the upregulation of PfCYP19B in the drug-resistant parasites appears to be maintained by a short tandem repeat (SRT) sequence polymorphism in the gene's promoter region. These results support a model that artemisinin (and other drugs) resistance mechanisms are complex genetic traits being contributed to by altered expression of multiple genes driven by genetic polymorphism at their promoter regions.
A phase 1/2a clinical trial to assess safety and immunogenicity of an adenoviral-vectored capsular group B meningococcal vaccine
Capsular group B meningococcus (MenB) remains an important cause of disease globally, and additional vaccines against MenB would aid in reducing the incidence of infection. Previous work has demonstrated that a MenB adenoviral-vectored vaccine, ChAdOx1 MenB.1, elicited high serum bactericidal responses in preclinical models after a single dose, supporting further clinical development of this vaccine. Here, we report the results of a trial designed to assess the safety and immunogenicity of ChAdOx1 MenB.1 in healthy adults aged 18 to 50. In this phase 1/2a, single-center trial, participants received one or two doses of ChAdOx1 MenB.1 at days 0 and 180. One dose of ChAdOx1 MenB.1 was also given at day 180 to some individuals primed with one dose of 4CMenB at day 0. Participants recorded their symptoms in an electronic diary after vaccination, and safety blood readouts were monitored. Serum bactericidal antibody (SBA) assays were performed against a panel of MenB target strains. ChAdOx1 MenB.1 was well tolerated with no safety concerns and elicited protective SBA titers against a MenB strain expressing a homologous factor H–binding protein (fHbp) variant in 100% of participants after two doses. However, cross-reactivity analysis indicated a low SBA response to strains expressing heterologous fHbp, suggesting that a multivalent vaccine may be needed. In sum, ChAdOx1 MenB.1 is immunogenic in humans, and addition of another fHbp variant or of another antigen in this platform could provide an approach to extend protection against endemic MenB disease.
Results from a UK consensus about the optimal prescribing of medium strength triple therapy in uncontrolled adult asthma patients in the NHS
ABSTRACT Context: An inhaled corticosteroid (ICS) in combination with a long-acting β2-agonist (LABA) is a common treatment approach for asthma patients not controlled on ICS alone, but a significant proportion of patients remain uncontrolled on this combination and treatment adherence can also be a challenge. One of the options for adults whose asthma is uncontrolled in an ICS/LABA is the addition of a long-acting muscarinic receptor antagonist (LAMA), an approach commonly referred to as ‘triple therapy’. The use of medium-strength ICS/LABA/LAMA is established in treating chronic obstructive pulmonary disease but is less well-established in asthma. Lack of clarity exists regarding who should prescribe ICS/LABA/LAMA and in which patients, and this is compounded by a lack of consistency among guidelines. Aims: To define the optimal prescribing of medium-strength ICS/LABA/LAMA triple therapy in adult asthma patients uncontrolled on ICS/LABA. Methods and Material: Using a modified Delphi method, a panel of experts developed 39 Likert scale statements across six key domains. These statements were used to develop an online survey that was distributed to healthcare providers (HCPs) working with adult asthma throughout the UK. The threshold for consensus was set at 75%. Results: In total, 314 responses were received from primary and secondary care stakeholders involved in the management of asthma. On analysis, 22/39 statements reached a very strong agreement (≥90%) and 16/39 attained strong agreement (≥75% and < 90). From these results, the panellists developed a set of twelve recommendations to help define how an optimal approach for prescribing triple therapy in patients who are uncontrolled on an ICS/LABA can be achieved. Conclusions: The strength of agreement shows that HCPs support the use of medium-strength ICS/LABA/LAMA triple therapy in appropriate asthma patients, and that clarity is needed regarding how best this can be achieved. The proposed set of recommendations provides such guidance to support the prescribing of triple therapy in primary care.
Exploring patients’ and carers’ experiences, understandings and expectations of COPD exacerbations:an interview study
BackgroundChronic obstructive pulmonary disease (COPD) exacerbations are clinically significant events that affect millions of people globally.AimTo explore patients’ and carers’ experiences, understanding, and expectations of, as well as their responses to, exacerbations.Design & settingSemi-structured interviews conducted with patients who have COPD and their carers from four sites across England.MethodInterviews were conducted with a purposive sample of patients with COPD and their carers recruited from four sites in England: two in Yorkshire, one in Hampshire and one in London. Interviews were theoretically informed by the Breathing Space concept and analysed using reflexive thematic analysis. This research is reported in line with the Standards for Reporting Qualitative Research.ResultsForty patient participants were recruited: 21 were female, 28 were White, with a mean age 69 years (standard deviation [SD] = 8.1 years), mean COPD duration = 11.3 years (SD = 8.3 years), median exacerbations in past year = 1.5 (range 0–9). Seven carer participants were recruited; of these, six were female and six were White. Three themes were identified: the language that clinicians use in COPD is important; episodes of symptom worsening have profound impacts on patients and carers; and patients’ early experiences, including the responses of clinicians to their help-seeking, have a lasting effect on their behaviour. How patients respond to symptom worsening can be considered holistically in the context of the Breathing Space framework. Breathlessness affected all patient participants and was a key symptom that precipitated action.ConclusionsOur findings show how early help-seeking experiences shape later behaviour. Early emphasis on symptom management, preparation for exacerbations, and post-exacerbation reviews are practical ways that clinicians can support patients and carers to manage these events better. The Breathing Space concept provides a useful framework to identify needs and tailor COPD management appropriately.
Accelerated immune ageing is associated with COVID-19 disease severity
Abstract Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ($$\beta$$ β = 0.174, p = 0.043), with a major influence being disease severity ($$\beta$$ β = 0.188, p = 0.01). Conclusions Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.
Effectiveness and safety of shortened intensive treatment for children with tuberculous meningitis (SURE): a protocol for a phase 3 randomised controlled trial evaluating 6 months of antituberculosis therapy and 8 weeks of aspirin in Asian and African children with tuberculous meningitis
IntroductionChildhood tuberculous meningitis (TBM) is a devastating disease. The long-standing WHO recommendation for treatment is 2 months of intensive phase with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by 10 months of isoniazid and rifampicin. In 2022, WHO released a conditional recommendation that 6 months of intensified antituberculosis therapy (ATT) could be used as an alternative for drug-susceptible TBM. However, this has never been evaluated in a randomised clinical trial. Trials evaluating ATT shortening regimens using high-dose rifampicin and drugs with better central nervous system penetration alongside adjuvant anti-inflammatory therapy are needed to improve outcomes.Methods and analysisTheShortened Intensive Therapy for Children with Tuberculous Meningitis (SURE) trial is a phase 3, randomised, partially blinded, factorial trial being conducted in Asia (India and Vietnam) and Africa (Uganda, Zambia and Zimbabwe). It is coordinated by the Medical Research Council Clinical Trial Unit at University College London (MRCCTU at UCL). 400 children (aged 29 days to <18 years) with clinically diagnosed TBM will be randomised, using a factorial design, to either a 24-week intensified regimen (isoniazid (20 mg/kg), rifampicin (30 mg/kg), pyrazinamide (40 mg/kg) and levofloxacin (20 mg/kg)) or the standard 48-week ATT regimen and 8 weeks of high-dose aspirin or placebo. The primary outcome for the first randomisation is all-cause mortality, and for the second randomisation is the paediatric modified Rankin Scale (mRS), both at 48 weeks. Nested substudies include pharmacokinetics, pharmacogenetics, pathophysiology, diagnostics and prognostic biomarkers, in-depth neurodevelopmental outcomes, MRI and health economics.Ethics and disseminationLocal ethics committees at all participating study sites and respective regulators approved the SURE protocol. Ethics approval was also obtained from UCL, UK (14935/001). Informed consent from parents/carers and assent from age-appropriate children are required for all participants. Results will be published in international peer-reviewed journals, and appropriate media will be used to summarise results for patients and their families and policymakers.Trial registrationISRCTN40829906(registered 13 November 2018).
T cell memory response to MPXV infection exhibits greater effector function and migratory potential compared to MVA-BN vaccination.
In 2022, a global mpox outbreak occurred, and remains a concern today. The T cell memory response to MPXV (monkeypox virus) infection has not been fully investigated. In this study, we evaluate this response in convalescent and MVA-BN (Modified Vaccinia Ankara - Bavarian Nordic) vaccinated individuals using VACV-infected cells. Strong CD8+ and CD4+ T cell responses are observed, and T cell responses are biased towards viral early expressed proteins. We identify seven immunodominant HLA-A*02:01 restricted MPXV-specific epitopes and focus our detailed phenotypic and scRNAseq analysis on the immunodominant HLA-A*02:01-G5R18-26-specific CD8+ T cell response. While tetramer+CD8+ T cells share similar differentiation and activation phenotypes, T cells from convalescent individuals show greater cytotoxicity, migratory potential to site of infection and TCR clonal expansion. Our data suggest that effective functional profiles of MPXV-specific memory T cells induced by Mpox infection may have an implication on the long-term protective responses to future infection.
Consultation report - considerations for a regulatory pathway for bivalent Salmonella Typhi/Paratyphi A vaccines for use in endemic countries.
Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A and, to a lesser extent, S. Paratyphi B and C, remains a significant cause of mortality and morbidity in resource-constrained settings. Typhoid conjugate vaccines (TCVs) protect against S. Typhi but no vaccine to date protects against paratyphoid fever. There are several bivalent S. Typhi/Paratyphi A products in development; however, the low incidence of paratyphoid fever in many settings limits the feasibility of phase 3 efficacy studies. Two bivalent vaccines adding the S. Paratyphi A-specific O:2 lipopolysaccharide conjugated to a protein carrier to TCV constructs have successfully completed phase 1 studies and will progress rapidly in their development. The WHO's Product Development for Vaccines Advisory Committee (PDVAC) endorsed a regulatory pathway for a bivalent S. Typhi/Paratyphi A vaccine that contemplates demonstrating protective efficacy against S. Paratyphi A infection in a controlled human infection model (CHIM). Since the use of CHIM data in lieu of phase 3 efficacy studies and to identify markers of immune protection is not yet widely accepted by regulatory bodies, the WHO organized a consultation with vaccine developers, manufacturers, and regulators. The purpose of the meeting was to discuss the feasibility and considerations for the licensure of a bivalent S. Typhi/Paratyphi A vaccine. The aim of the consultation was to gain alignment among key stakeholders and facilitate the pathway to licensure in endemic countries.
Mass testing for discovery and control of COVID-19 outbreaks in adult social care: an observational study and cost-effectiveness analysis of 14 805 care homes in England
IntroductionWe retrospectively evaluated the impact of COVID-19 testing among residents and staff in social care homes in England.MethodsWe obtained 80 million reported PCR and lateral flow device (LFD) test results, from 14 805 care homes (residents and staff) in England, conducted between October 2020 and March 2022. These testing data were then linked to care home characteristics, test costs and 24 500 COVID-19-related deaths of residents. We decomposed the mechanism of outbreak mitigation into outbreak discovery and outbreak control and used Poisson regressions to investigate how reported testing intensity was associated with the size of outbreak discovered and to uncover its association with outbreak control. We used negative binomial regressions to determine the factors influencing COVID-19-related deaths subsequent to outbreaks. We performed a cost-effectiveness analysis of the impact of testing on preventing COVID-19-related deaths of residents.ResultsReported testing intensity generally reflected changes in testing policy over time, although there was considerable heterogeneity among care homes. Client type was the strongest determinant of whether COVID-19-related deaths in residents occurred subsequent to testing positive. Higher staff-to-resident ratios were associated with larger outbreak sizes but rapid outbreak control and a decreased risk of COVID-19-related deaths. Assuming our regression estimates represent causal effects, care home testing in England was cost-effective at preventing COVID-19-related deaths among residents during the pandemic and approximately 3.5 times more cost-effective prior to the vaccine rollout.ConclusionsPCR and LFD testing was likely an impactful intervention for detecting and controlling COVID-19 outbreaks in care homes in England and cost-effective for preventing COVID-19-related deaths among residents. In future pandemics, testing must be prioritised for care homes, especially if severe illness and death particularly affect older people or individuals with characteristics similar to care home residents, and an efficacious vaccine is unavailable.
Delineating Mpl-dependent and -independent phenotypes of Jak2 V617F- positive MPNs in vivo.
The Jak2 V617F mutation stands as the main driver of myeloproliferative neoplasms (MPNs) by constitutively activating signaling of several type I cytokine receptors, namely those for erythropoietin (EpoR), thrombopoietin (TpoR), and Granulocyte Colony Stimulating Factor (G-CSFR). Among these, TpoR assumes a pivotal role in hematopoietic stem cell renewal and differentiation, being positioned as a key driver of MPNs alongside mutated Jak2. However, the impact of TpoR/MPL absence in the context of Jak2 V617F in vivo has been explored only through a transgenic Jak2 V617F mouse model, where regulation of Jak2 expression does not depend on its natural promoter. In this study, we use a novel mouse model expressing Jak2 V617F under its endogenous promoter at the heterozygous state within a Mpl knock-out background. Our findings indicate that erythrocytosis, leukocytosis and moderate splenomegaly with mild spleen peri-vascular fibrosis persist even in the absence of Mpl expression. Notably, the inherent growth-stimulating effect induced by Jak2 V617F remains consistent across diverse early hematopoietic progenitor populations in the absence of Mpl but is reduced at the stem cell level and does not allow clonal expansion in competitive transplantation. Our results delineate Mpl-dependent and -independent phenotypes induced by Jak2 V617F and confirm that inhibiting Mpl expression at the stem cell level negates the long-term advantage of the mutant clone. Consequently, while MPL emerges as a major player in Jak2 V617F positive MPNs, our study underscores that it is not the exclusive contributor, broadening the spectrum for therapeutic intervention.
Assessments and developments in constructing a National Health Index for policy-making, in the UK
Composite indicators are useful for summarizing and comparing changes among different communities. The UK Office for National Statistics has created an annual England Health Index (2015-2018) comprised of three main health domains - lives, places, and people - to monitor health over time and across different geographical areas and evaluate the nation's health. We reviewed the conceptual coherence and statistical requirements, focusing on three main steps: correlation analysis at different levels, comparison of the implemented weights, and a sensitivity and uncertainty analysis. Based on the results, we have highlighted features that have improved the statistical requirements of the forthcoming UK Health Index.
International collaboration to advance research preparedness and response
Pandemic preparedness and research response bring together multiple disciplines and organizations to coordinate action across geographical and specialty boundaries. At their best, these international collaborations provide rapid, robust answers to key scientific questions. But several recent pandemics, notably coronavirus disease 2019 (COVID-19), have revealed less than ideal levels of international collaboration. This chapter discusses factors that limit collaboration and some of the risks of a global research response ecosystem prone to delay and error. Using several case studies as examples, this chapter proposes measures to better prepare and implement international collaborations in future outbreaks, including the strategic allocation of funding to support well-designed, expedited clinical research to answer key clinical and public health questions.