ABSTRACT
BACKGROUND: Early detection of intermediate hyperglycaemia, otherwise known as non-diabetic hyperglycaemia (NDH) is crucial to identify people at high risk of developing type 2 diabetes mellitus (T2DM) who could benefit from preventative interventions. Failure to identify NDH may also increase the risks of T2DM-related complications at the time of T2DM diagnosis. We investigate sociodemographic inequalities in identification of NDH in England. METHODS: We used nationwide data from the English National Health Service (NHS) National Diabetes Audit, which includes all people who were newly identified with NDH (N = 469,910) or diagnosed with T2DM (N = 222,795) between 1st April 2019 and 31st March 2020. We used regression models to explore inequalities in the under identification of NDH by area-level deprivation and age group. RESULTS: Of those with a new T2DM diagnosis, 67.3% had no previous record of NDH. The odds of no previous NDH being recorded were higher amongst people living in more deprived areas (Odds ratio (OR) 1.15 (95% confidence intervals (CI) [1.12, 1.19]) most deprived (Q1) compared to least deprived (Q5) quintile) and younger individuals (OR 4.02 (95% CI [3.79, 4.27] under 35s compared to age 75-84)). Deprivation-related inequalities persisted after stratification by age group, with the largest inequalities amongst middle and older age groups. People living in more deprived areas and younger people also had shorter recorded NDH duration before progression to T2DM, and higher T2DM severity at the time of diagnosis. CONCLUSIONS: There is under identification of NDH relative to diagnosis of T2DM amongst people living in more deprived areas and particularly amongst younger people, resulting in missed opportunities for targeted T2DM prevention efforts and potentially contributing to inequalities in T2DM prevalence and severity. More active NDH case-finding amongst these groups may be an important first step in helping to reduce inequalities in T2DM.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/epidemiology , England/epidemiology , Female , Middle Aged , Male , Aged , Adult , Age Factors , State Medicine , Socioeconomic Factors , Risk Factors , Health Status Disparities , Social Deprivation , Hyperglycemia/epidemiology , Aged, 80 and over , Young Adult , Early DiagnosisABSTRACT
OBJECTIVES: Increasingly, healthcare and public health strategists invite us to look at healthcare organisations as not just care providers but as anchor institutions (ie, large community-rooted organisations with significant impact in the local economy, social fabric and overall community well-being). In response, this study explores the mechanisms through which healthcare organisations can impact social determinants of health and communities in their local areas. DESIGN: We conducted case studies with interviews and synthesised the findings using a realist approach to produce a set of explanations (programme theory) of how healthcare organisations can have a positive impact on the overall well-being of local communities by operating as anchor institutions. SETTING: Secondary healthcare organisations in England, including mental health and community services. PARTICIPANTS: Staff from case study sites which were directly employed or actively engaged in the organisation's anchor institution strategy. Data collection took place from early June to the end of August 2023. RESULTS: We found four building blocks for effective anchor activity including employment, spending, estates and sustainability. Healthcare organisations-as anchor institutions-can improve the social determinants of health for their local communities through enabling accessible paths for local community recruitment and career progression; empowering local businesses to join supply chains boosting income and wealth; transforming organisational spaces into community assets; and supporting local innovation and technology to achieve their sustainability goals. These blocks need to be integrated across organisations on the basis of a population health approach promoted by supportive leadership, and in collaboration with a diverse range of local partners. CONCLUSIONS: Healthcare organisations have the potential for a positive impact on the overall well-being of local communities. Policymakers should support healthcare organisations to leverage employment, spending, estates and sustainability to help address the unequal distribution of the social determinants of health.
Subject(s)
Social Determinants of Health , Humans , England , Secondary Care/organization & administration , Organizational Case Studies , Community Health Services/organization & administrationABSTRACT
BACKGROUND: The response to the COVID-19 pandemic saw a significant increase in demand for the voluntary, community, faith and social enterprise (VCFSE) sector to provide support to local communities. In Greater Manchester (GM), the VCFSE sector and informal networks provided health and wellbeing support in multiple ways, culminating in its crucial supportive role in the provision of the COVID-19 vaccination rollout across the GM city region. However, the support provided by the VCFSE sector during the pandemic remains under-recognised. The aims of the study were to: understand the views and experiences of marginalised communities in GM during the COVID-19 pandemic; explore how community engagement initiatives played a role during the pandemic and vaccine rollout; assess what can be learnt from the work of key stakeholders (community members, VCFSEs, health-system stakeholders) for future health research and service delivery. METHODS: The co-designed study utilised a participatory approach throughout and was co-produced with a Community Research Advisory Group (CRAG). Focus groups and semi-structured interviews were conducted remotely between September-November 2021, with 35 participants from local marginalised communities, health and care system stakeholders and VCFSE representatives. Thematic framework analysis was used to analyse the data. RESULTS: Local communities in GM were not supported sufficiently by mainstream services during the course of the COVID-19 pandemic, resulting in increased pressure onto the VCFSE sector to respond to local communities' need. Community-based approaches were deemed crucial to the success of the vaccination drive and in providing support to local communities more generally during the pandemic, whereby such approaches were in a unique position to reach members of diverse communities to boost uptake of the vaccine. Despite this, the support delivered by the VCFSE sector remains under-recognised and under-valued by the health system and decision-makers. CONCLUSIONS: A number of challenges associated with collaborative working were experienced by the VSCE sector and health system in delivering the vaccination programme in partnership with the VCFSE sector. There is a need to create a broader, more inclusive health system which allows and promotes inter-sectoral working. Flexibility and adaptability in ongoing and future service delivery should be championed for greater cross-sector working.
Subject(s)
COVID-19 , Qualitative Research , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Female , Male , Adult , SARS-CoV-2 , Pandemics/prevention & control , Middle Aged , COVID-19 Vaccines/administration & dosage , Focus Groups , England/epidemiology , Community Health Services/organization & administration , Health Services Needs and DemandABSTRACT
The transformative potential of gene editing technologies hinges on the development of safe and effective delivery methods. In this study, we developed a temperature-sensitive and interferon-silent Sendai virus (ts SeV) as a novel delivery vector for CRISPR-Cas9 and for efficient gene editing in sensitive human cell types without inducing IFN responses. ts SeV demonstrates unprecedented transduction efficiency in human CD34+ hematopoietic stem and progenitor cells (HSPCs) including transduction of the CD34+/CD38-/CD45RA-/CD90+(Thy1+)/CD49fhigh stem cell enriched subpopulation. The frequency of CCR5 editing exceeded 90% and bi-allelic CCR5 editing exceeded 70% resulting in significant inhibition of HIV-1 infection in primary human CD14+ monocytes. These results demonstrate the potential of the ts SeV platform as a safe, efficient, and flexible addition to the current gene-editing tool delivery methods, which may help to further expand the possibilities in personalized medicine and the treatment of genetic disorders.
ABSTRACT
BACKGROUND: There are clear inequalities in COVID - 19 vaccination rates amongst marginalised groups, with lower rates for some minoritised ethnic and religious groups, younger people, those living in more deprived areas, and with lower socio-economic status. Existing research focuses on psychological and socio-economic factors that influence vaccine uptake and does not explore broader social and historical contexts. Understanding inequalities in COVID-19 vaccine uptake requires a critical examination of the drivers of, and barriers to, vaccination. METHODS: We present findings from a co-designed qualitative research study undertaken during the COVID-19 pandemic. Focus groups and interviews were used to examine the context underpinning responses to the COVID-19 vaccination in Greater Manchester, particularly focussing on experiences of marginalisation. Thematic framework analysis was used to analyse the data. RESULTS: We found that the public's responses to the COVID-19 vaccination programme are intertwined with a longstanding history of institutional distrust and disenfranchisement, resulting from experiences of marginalisation and social inequalities. This was exacerbated further by the disproportionate impacts of the COVID-19 pandemic on minoritised ethnic groups, younger people, and those with existing health conditions. CONCLUSIONS: Histories of structural inequalities experienced by minoritised groups invoked feelings of suspicion and scepticism at the motivations of the agencies behind the vaccination rollout. This highlights the need for a contextualised analysis of attitudes to vaccines, considering pre-existing inequalities, which may be especially relevant for conceptualising public responses to the vaccination programme. Finally, our study shows the important ways in which public (dis)trust can impact public health policies. We recommend this should be incorporated into responses to future public health crises.
Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Pandemics , Vaccination , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Transgender, non-binary, and gender diverse people face discrimination and barriers to accessing health care. Existing evidence suggests higher rates of mental health conditions among these groups compared with binary and cisgender groups. However, information is limited by poor gender recording in health records and surveys. We aimed to provide the first national estimates of gender-related inequalities in self-reported mental health conditions and mental health support across 15 gender groups in England. METHODS: We used changes to the 2021 and 2022 nationally representative cross-sectional English General Pracitioner (GP) Patient Surveys and used age-adjusted logistic regression to predict probabilities of two outcomes: first, self-reporting a mental health condition and second, self-reporting unmet mental health needs. We report results for 15 exposure groups: five gender groups (female, male, non-binary, prefer to self-describe, and prefer not to say), within three cisgender or transgender identity groups (cisgender, transgender, or prefer not to say). We explored potential mediation by adding covariates. FINDINGS: Of the 1â520â457 respondents in the estimation sample, 861â017 (51·4%) were female, 645â300 (47·4%) were male, 2600 (0·3%) were non-binary, 2277 (0·2%) self-described their gender, and 9263 (0·7%) preferred not to state their gender. 1â499â852 (98·3%) respondents were cisgender, 7994 (0·7%) were transgender, and 12â611 (1·0%) preferred not to say their cisgender or transgender identity. We found wide gender-related inequalities in the probability of self-reporting a mental health condition, with the highest probabilities among non-binary patients who were transgender (47·21% [95% CI 42·86-51·60]) or preferred not to say their cisgender or transgender identity (32·90% [26·50-40·00]), and among transgender patients who self-described their gender (35·03% [27·39-43·53]). With the exception of non-binary patients in each case, probabilities were lowest among cisgender patient groups (ranging from male at 8·80% [8·69-8·92] to female at 11·97% [11·86-12·07]) and patients who preferred not to say their cisgender or transgender identity (ranging from female 7·15% [6·06-8·42] to prefer to self-describe 10·37% [7·13-14·86]). Inequalities in other health conditions and socioeconomic factors might mediate some of these inequalities. Probabilities of self-reported unmet mental health needs were lowest among cisgender male (15·55% [15·33-15·76]) and female (15·93% [15·76-16·10]) patients with increased probabilities among all other groups, ranging from 19·95% (17·57-22·57) in transgender male patients to 28·64% (26·23-31·17) among patients who preferred not to say their gender or their cisgender or transgender identity. Inequalities in interactions with health-care professionals may mediate much of these inequalities. INTERPRETATION: Together with existing evidence, our findings showed large gender-related inequalities in self-reported mental health outcomes in England. Given the existence of self-reported unmet mental health needs, we suggest that better health care system inclusivity and health-care professional training are needed, alongside broader improvements in the social and legal environment for transgender, non-binary, and gender diverse people. FUNDING: National Institute for Health and Care Research.
Subject(s)
Health Services Accessibility , Mental Health , Humans , Male , Female , Cross-Sectional Studies , Self Report , Surveys and Questionnaires , Health Inequities , Primary Health CareABSTRACT
BACKGROUND: There are known socioeconomic inequalities in annual seasonal influenza (flu) vaccine uptake. The Coronavirus Disease 2019 (COVID-19) pandemic was associated with multiple factors that may have affected flu vaccine uptake, including widespread disruption to healthcare services, changes to flu vaccination eligibility and delivery, and increased public awareness and debate about vaccination due to high-profile COVID-19 vaccination campaigns. However, to the best of our knowledge, no existing studies have investigated the consequences for inequalities in flu vaccine uptake, so we aimed to investigate whether socioeconomic inequalities in flu vaccine uptake have widened since the onset of the COVID-19 pandemic. METHODS AND FINDINGS: We used deidentified data from electronic health records for a large city region (Greater Manchester, population 2.8 million), focusing on 3 age groups eligible for National Health Service (NHS) flu vaccination: preschool children (age 2 to 3 years), primary school children (age 4 to 9 years), and older adults (age 65 years plus). The sample population varied between 418,790 (2015/16) and 758,483 (2021/22) across each vaccination season. We estimated age-adjusted neighbourhood-level income deprivation-related inequalities in flu vaccine uptake using Cox proportional hazards models and the slope index of inequality (SII), comparing 7 flu vaccination seasons (2015/16 to 2021/22). Among older adults, the SII (i.e., the gap in uptake between the least and most income-deprived areas) doubled over the 7 seasons from 8.48 (95% CI [7.91,9.04]) percentage points to 16.91 (95% CI [16.46,17.36]) percentage points, with approximately 80% of this increase occurring during the pandemic. Before the pandemic, income-related uptake gaps were wider among children, ranging from 15.59 (95% CI [14.52,16.67]) percentage points to 20.07 (95% CI [18.94,21.20]) percentage points across age groups and vaccination seasons. Among preschool children, the uptake gap increased in 2020/21 to 25.25 (95% CI [24.04,26.45]) percentage points, before decreasing to 20.86 (95% CI [19.65,22.05]) percentage points in 2021/22. Among primary school children, inequalities increased in both pandemic years to reach 30.27 (95% CI [29.58,30.95]) percentage points in 2021/22. Although vaccine uptake increased during the pandemic, disproportionately larger increases in uptake in less deprived areas created wider inequalities in all age groups. The main limitation of our approach is the use of a local dataset, which may limit generalisability to other geographical settings. CONCLUSIONS: The COVID-19 pandemic led to increased inequalities in flu vaccine uptake, likely due to changes in demand for vaccination, new delivery models, and disruptions to healthcare and schooling. It will be important to investigate the causes of these increased inequalities and to examine whether these increased inequalities also occurred in the uptake of other routine vaccinations. These new wider inequalities in flu vaccine uptake may exacerbate inequalities in flu-related morbidity and mortality.
Subject(s)
COVID-19 , Influenza Vaccines , Influenza, Human , Child, Preschool , Humans , Child , Aged , Influenza Vaccines/therapeutic use , Pandemics/prevention & control , Cohort Studies , COVID-19 Vaccines , State Medicine , COVID-19/epidemiology , COVID-19/prevention & control , Influenza, Human/epidemiology , Influenza, Human/prevention & control , England/epidemiology , Educational StatusABSTRACT
In publicly-funded healthcare systems, waiting times for care should be based on need rather than ability to pay. Studies have shown that individuals with lower socioeconomic status face longer waits for planned inpatient care, but there is little evidence on inequalities in waiting times for emergency care. We study waiting times in emergency departments (EDs) following arrival by ambulance, where health consequences of extended waits may be severe. Using data from all major EDs in England during the 2016/17 financial year, we find patients from more deprived areas face longer waits during some parts of the ED care pathway. Inequalities in waits are small, but more deprived individuals also receive less complex ED care, are less likely to be admitted for inpatient care, and are more likely to re-attend ED or die shortly after attendance. Patient-physician interactions and unconscious bias towards more deprived patients may be important sources of inequalities.
Subject(s)
Emergency Service, Hospital , Social Class , England , Hospitalization , HumansABSTRACT
[This corrects the article DOI: 10.1371/journal.pmed.1003932.].
ABSTRACT
Humans have four IgG antibody subclasses that selectively or differentially engage immune effector molecules to protect against infections. Although IgG1 has been studied in detail and is the subclass of most approved antibody therapeutics, increasing evidence indicates that IgG3 is associated with enhanced protection against pathogens. Here, we report that IgG3 has superior capacity to mediate intracellular antiviral immunity compared with the other subclasses due to its uniquely extended and flexible hinge region, which facilitates improved recruitment of the cytosolic Fc receptor TRIM21, independently of Fc binding affinity. TRIM21 may also synergize with complement C1/C4-mediated lysosomal degradation via capsid inactivation. We demonstrate that this process is potentiated by IgG3 in a hinge-dependent manner. Our findings reveal differences in how the four IgG subclasses mediate intracellular immunity, knowledge that may guide IgG subclass selection and engineering of antiviral antibodies for prophylaxis and therapy.
Subject(s)
Antiviral Agents , Immunoglobulin G , Antibodies, Viral , Complement System Proteins , Humans , Receptors, FcABSTRACT
BACKGROUND: COVID-19 vaccine uptake is lower amongst most minority ethnic groups compared to the White British group in England, despite higher COVID-19 mortality rates. Here, we add to existing evidence by estimating inequalities for 16 minority ethnic groups, examining ethnic inequalities within population subgroups, and comparing the magnitudes of ethnic inequalities in COVID-19 vaccine uptake to those for routine seasonal influenza vaccine uptake. METHODS AND FINDINGS: We conducted a retrospective cohort study using the Greater Manchester Care Record, which contains de-identified electronic health record data for the population of Greater Manchester, England. We used Cox proportional hazards models to estimate ethnic inequalities in time to COVID-19 vaccination amongst people eligible for vaccination on health or age (50+ years) criteria between 1 December 2020 and 18 April 2021 (138 days of follow-up). We included vaccination with any approved COVID-19 vaccine, and analysed first-dose vaccination only. We compared inequalities between COVID-19 and influenza vaccine uptake adjusting by age group and clinical risk, and used subgroup analysis to identify populations where inequalities were widest. The majority of individuals (871,231; 79.24%) were White British. The largest minority ethnic groups were Pakistani (50,268; 4.75%), 'other White background' (43,195; 3.93%), 'other ethnic group' (34,568; 3.14%), and Black African (18,802; 1.71%). In total, 83.64% (919,636/1,099,503) of eligible individuals received a COVID-19 vaccine. Uptake was lower compared to the White British group for 15 of 16 minority ethnic groups, with particularly wide inequalities amongst the groups 'other Black background' (hazard ratio [HR] 0.42, 95% CI 0.40 to 0.44), Black African (HR 0.43, 95% CI 0.42 to 0.44), Arab (HR 0.43, 95% CI 0.40 to 0.48), and Black Caribbean (HR 0.43, 95% CI 0.42 to 0.45). In total, 55.71% (419,314/752,715) of eligible individuals took up influenza vaccination. Compared to the White British group, inequalities in influenza vaccine uptake were widest amongst the groups 'White and Black Caribbean' (HR 0.63, 95% CI 0.58 to 0.68) and 'White and Black African' (HR 0.67, 95% CI 0.63 to 0.72). In contrast, uptake was slightly higher than the White British group amongst the groups 'other ethnic group' (HR 1.11, 95% CI 1.09 to 1.12) and Bangladeshi (HR 1.08, 95% CI 1.05 to 1.11). Overall, ethnic inequalities in vaccine uptake were wider for COVID-19 than influenza vaccination for 15 of 16 minority ethnic groups. COVID-19 vaccine uptake inequalities also existed amongst individuals who previously took up influenza vaccination. Ethnic inequalities in COVID-19 vaccine uptake were concentrated amongst older and extremely clinically vulnerable adults, and the most income-deprived. A limitation of this study is the focus on uptake of the first dose of COVID-19 vaccination, rather than full COVID-19 vaccination. CONCLUSIONS: Ethnic inequalities in COVID-19 vaccine uptake exceeded those for influenza vaccine uptake, existed amongst those recently vaccinated against influenza, and were widest amongst those with greatest COVID-19 risk. This suggests the COVID-19 vaccination programme has created additional and different inequalities beyond pre-existing health inequalities. We suggest that further research and policy action is needed to understand and remove barriers to vaccine uptake, and to build trust and confidence amongst minority ethnic communities.
Subject(s)
COVID-19 Vaccines/therapeutic use , Ethnicity/statistics & numerical data , Influenza Vaccines/therapeutic use , Patient Participation/statistics & numerical data , Vaccination/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/prevention & control , Cohort Studies , Female , Humans , Influenza, Human/prevention & control , Male , Middle Aged , Minority Groups/statistics & numerical data , Retrospective Studies , SARS-CoV-2/immunology , Socioeconomic Factors , United Kingdom/epidemiology , Young AdultABSTRACT
BACKGROUND: The BNT162b2 mRNA vaccine has been shown to be effective at preventing serious COVID-19 events in clinical trials. There is less evidence on effectiveness in real-world settings, especially for older people. Here, we aimed to estimate vaccine effectiveness in the context of the rapid NHS mass-vaccination programme in England, exploiting age-based vaccination eligibility thresholds to minimise and correct for selection bias. METHODS: We studied 170,226 individuals between the ages of 80 and 83 years from community settings outside care homes who received one dose of BNT162b2 mRNA between the 15 and 20 December 2020 and were scheduled a second dose 21 days later. We matched these vaccine recipients to slightly younger (aged 76-79 years) persons not yet eligible to receive the vaccine on gender, area of residence, area deprivation, health status, living arrangements, acute illness, and history of seasonal flu vaccination. We compared their rates of COVID-19 positivity and hospitalisation in the subsequent 45 days. We adjusted for the increasing concentration of COVID-19 positivity in the control population caused by the requirement to have no COVID-19 symptoms prior to vaccination. RESULTS: Emergency hospital admissions were 51.0% (95% confidence interval 19.9 to 69.5%) lower and positive COVID-19 tests were 55.2% (40.8 to 66.8%) lower for vaccinated individuals compared to matched controls 21 to 27 days after first vaccination. Emergency admissions were 75.6% (52.8 to 87.6%) lower, and positive COVID-19 tests were 70.1% (55.1 to 80.1%) lower 35 to 41 days after first vaccination when 79% of participants had received a second dose within 26 days of their first dose. CONCLUSIONS: Receipt of the BNT162b2 mRNA vaccine is effective at reducing COVID-19 hospitalisations and infections. The nationwide vaccination of older adults in England with the BNT162b2 mRNA vaccine reduced the burden of COVID-19.
Subject(s)
COVID-19 , Influenza Vaccines , Aged , Aged, 80 and over , BNT162 Vaccine , COVID-19 Vaccines , Case-Control Studies , England/epidemiology , Hospitalization , Humans , Mass Vaccination , RNA, Messenger , SARS-CoV-2ABSTRACT
Severe congenital neutropenia (SCN) is a life-threatening disorder most often caused by dominant mutations of ELANE that interfere with neutrophil maturation. We conducted a pooled CRISPR screen in human hematopoietic stem and progenitor cells (HSPCs) that correlated ELANE mutations with neutrophil maturation potential. Highly efficient gene editing of early exons elicited nonsense-mediated decay (NMD), overcame neutrophil maturation arrest in HSPCs from ELANE-mutant SCN patients, and produced normal hematopoietic engraftment function. Conversely, terminal exon frameshift alleles that mimic SCN-associated mutations escaped NMD, recapitulated neutrophil maturation arrest, and established an animal model of ELANE-mutant SCN. Surprisingly, only -1 frame insertions or deletions (indels) impeded neutrophil maturation, whereas -2 frame late exon indels repressed translation and supported neutrophil maturation. Gene editing of primary HSPCs allowed faithful identification of variant pathogenicity to clarify molecular mechanisms of disease and encourage a universal therapeutic approach to ELANE-mutant neutropenia, returning normal neutrophil production and preserving HSPC function.
Subject(s)
Leukocyte Elastase , Neutropenia , Animals , Congenital Bone Marrow Failure Syndromes , Gene Editing , Humans , Leukocyte Elastase/genetics , Mutation/genetics , Neutropenia/genetics , VirulenceABSTRACT
BACKGROUND: The population of older adults (ie, those aged ≥55 years) in England is becoming increasingly ethnically diverse. Previous reports indicate that ethnic inequalities in health exist among older adults, but information is limited by the paucity of data from small minority ethnic groups. This study aimed to analyse inequalities in health-related quality of life (HRQoL) and five determinants of health in older adults across all ethnic groups in England. METHODS: In this cross-sectional study, we analysed data from five waves (July 1, 2014, to April 7, 2017) of the nationally representative English General Practice Patient Survey (GPPS). Study participants were adults aged 55 years or older who were registered with general practices in England. We used regression models (age-adjusted and stratified by gender) to estimate the association between ethnicity and HRQoL, measured by use of the EQ-5D-5L index and its domains (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression). We also estimated associations between ethnicity and five determinants of health (presence of long-term conditions or multimorbidity, experience of primary care, degree of support from local services, patient self-confidence in managing own health, and degree of area-level social deprivation). We examined robustness to differential handling of missing data, alternative EQ-5D-5L value sets, and differences in area-level social deprivation. FINDINGS: There were 1â416â793 GPPS respondents aged 55 years and older. 1â394â361 (98·4%) respondents had complete data on ethnicity and gender and were included in our analysis. Of these, 152â710 (11·0%) self-identified as belonging to minority ethnic groups. HRQoL was worse for men or women, or both, in 15 (88·2%) of 17 minority ethnic groups than the White British ethnic group. In both men and women, inequalities were widest for Gypsy or Irish Traveller (linear regression coefficient -0·192 [95% CI -0·318 to -0·066] in men; -0·264 [-0·354 to -0·173] in women), Bangladeshi (-0·111 [-0·136 to -0·087] in men; -0·209 [-0·235 to -0·184] in women), Pakistani (-0·084 [-0·096 to -0·073] in men; -0·206 [-0·219 to -0·193] in women), and Arab (-0·061 [-0·086 to -0·035] in men; -0·145 [-0·180 to -0·110] in women) ethnic groups, with magnitudes generally greater for women than men. Differentials tended to be widest for the self-care EQ-5D-5L domain. Ethnic inequalities in HRQoL were accompanied by increased prevalence of long-term conditions or multimorbidity, poor experiences of primary care, insufficient support from local services, low patient self-confidence in managing their own health, and high area-level social deprivation, compared with the White British group. INTERPRETATION: We found evidence of wide ethnic inequalities in HRQoL and five determinants of health for older adults in England. Outcomes varied between minority ethnic groups, highlighting heterogeneity in the direction and magnitude of associations. We recommend further research to understand the drivers of inequalities, together with policy changes to improve equity of socioeconomic opportunity and access to services for older adults from minority ethnic groups. FUNDING: University of Manchester and National Institute for Health Research.
Subject(s)
Ethnicity/statistics & numerical data , Health Status Disparities , Minority Groups/statistics & numerical data , Quality of Life , Social Determinants of Health , Aged , Aged, 80 and over , Cross-Sectional Studies , England , Female , Humans , Male , Middle AgedABSTRACT
Paramyxoviruses such as human parainfluenza virus type-3 (HPIV3) and measles virus (MeV) are a substantial health threat. In a high-throughput screen for inhibitors of HPIV3 (a major cause of acute respiratory infection), we identified GHP-88309-a non-nucleoside inhibitor of viral polymerase activity that possesses unusual broad-spectrum activity against diverse paramyxoviruses including respiroviruses (that is, HPIV1 and HPIV3) and morbilliviruses (that is, MeV). Resistance profiles of distinct target viruses overlapped spatially, revealing a conserved binding site in the central cavity of the viral polymerase (L) protein that was validated by photoaffinity labelling-based target mapping. Mechanistic characterization through viral RNA profiling and in vitro MeV polymerase assays identified a block in the initiation phase of the viral polymerase. GHP-88309 showed nanomolar potency against HPIV3 isolates in well-differentiated human airway organoid cultures, was well tolerated (selectivity index > 7,111) and orally bioavailable, and provided complete protection against lethal infection in a Sendai virus mouse surrogate model of human HPIV3 disease when administered therapeutically 48 h after infection. Recoverees had acquired robust immunoprotection against reinfection, and viral resistance coincided with severe attenuation. This study provides proof of the feasibility of a well-behaved broad-spectrum allosteric antiviral and describes a chemotype with high therapeutic potential that addresses major obstacles of anti-paramyxovirus drug development.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , DNA-Directed RNA Polymerases/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Respirovirus/drug effects , Respirovirus/enzymology , Adaptive Immunity , Administration, Oral , Allosteric Regulation , Animals , Antiviral Agents/administration & dosage , Cell Line , Enzyme Inhibitors/administration & dosage , Humans , Immunohistochemistry , Mice , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Respiratory Mucosa/virology , Respirovirus/immunology , Structure-Activity RelationshipABSTRACT
The risk of spillover of enzootic paramyxoviruses and the susceptibility of recipient human and domestic animal populations are defined by a broad collection of ecological and molecular factors that interact in ways that are not yet fully understood. Nipah and Hendra viruses were the first highly lethal zoonotic paramyxoviruses discovered in modern times, but other paramyxoviruses from multiple genera are present in bats and other reservoirs that have unknown potential to spillover into humans. We outline our current understanding of paramyxovirus reservoir hosts and the ecological factors that may drive spillover, and we explore the molecular barriers to spillover that emergent paramyxoviruses may encounter. By outlining what is known about enzootic paramyxovirus receptor usage, mechanisms of innate immune evasion, and other host-specific interactions, we highlight the breadth of unexplored avenues that may be important in understanding paramyxovirus emergence.
Subject(s)
Disease Resistance/genetics , Paramyxoviridae Infections/epidemiology , Paramyxovirinae/pathogenicity , Phylogeny , Zoonoses/epidemiology , Animals , Cats , Chiroptera/virology , Disease Susceptibility/immunology , Disease Vectors , Dogs , Host-Pathogen Interactions , Humans , Paramyxoviridae Infections/immunology , Paramyxoviridae Infections/transmission , Paramyxoviridae Infections/veterinary , Paramyxovirinae/classification , Paramyxovirinae/genetics , Rodentia/virology , Zoonoses/immunology , Zoonoses/transmission , Zoonoses/virologyABSTRACT
During infection with non-enveloped viruses, antibodies stimulate immunity from inside cells by activating the cytosolic Fc receptor TRIM21. This intracellular humoral response relies on opsonized viral particles reaching the cytosol intact but the antigenic and kinetic constraints involved are unknown. We have solved the structure of a potent TRIM21-dependent neutralizing antibody in complex with human adenovirus 5 hexon and show how these properties influence immune activity. Structure-guided mutagenesis was used to generate antibodies with 20,000-fold variation in affinity, on-rates that differ by ~50-fold and off-rates by >175-fold. Characterization of these variants during infection revealed that TRIM21-dependent neutralization and NFκB activation was largely unaffected by on-rate kinetics. In contrast, TRIM21 antiviral activity was exquisitely dependent upon off-rate, with sub-µM affinity antibodies nevertheless unable to stimulate signaling because of fast dissociation kinetics. These results define the antibody properties required to elicit an efficient intracellular immune response during viral infection.
Subject(s)
Adenoviruses, Human/chemistry , Antibodies, Neutralizing/chemistry , Antigens, Viral/chemistry , Immunity, Humoral/drug effects , Immunoglobulin Fab Fragments/chemistry , Ribonucleoproteins/chemistry , Adenoviruses, Human/growth & development , Adenoviruses, Human/immunology , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibody Affinity , Antigens, Viral/genetics , Antigens, Viral/immunology , Binding Sites , Cloning, Molecular , Crystallography, X-Ray , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , HEK293 Cells , Humans , Immunoglobulin Fab Fragments/genetics , Immunoglobulin Fab Fragments/immunology , Kinetics , Models, Molecular , NF-kappa B/pharmacology , Neutralization Tests , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Engineering , Protein Interaction Domains and Motifs , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Ribonucleoproteins/genetics , Ribonucleoproteins/immunology , Structure-Activity RelationshipABSTRACT
Nipah virus (NiV, Henipavirus) is a highly lethal emergent zoonotic paramyxovirus responsible for repeated human outbreaks of encephalitis in South East Asia. There are no approved vaccines or treatments, thus improved understanding of NiV biology is imperative. NiV matrix protein recruits a plethora of cellular machinery to scaffold and coordinate virion budding. Intriguingly, matrix also hijacks cellular trafficking and ubiquitination pathways to facilitate transient nuclear localization. While the biological significance of matrix nuclear localization for an otherwise cytoplasmic virus remains enigmatic, the molecular details have begun to be characterized, and are conserved among matrix proteins from divergent paramyxoviruses. Matrix protein appropriation of cellular machinery will be discussed in terms of its early nuclear targeting and later role in virion assembly.
Subject(s)
Encephalitis/genetics , Nipah Virus/genetics , Viral Matrix Proteins/genetics , Virion/genetics , Animals , Cytoplasm/genetics , Cytoplasm/virology , Disease Outbreaks , Encephalitis/virology , Humans , Nipah Virus/growth & development , Nipah Virus/pathogenicity , Virus Assembly/geneticsABSTRACT
Ab-coated viruses can be detected in the cytosol by the FcR tripartite motif-containing 21 (TRIM21), which rapidly recruits the proteasomal machinery and triggers induction of immune signaling. As such, TRIM21 plays a key role in intracellular protection by targeting invading viruses for destruction and alerting the immune system. A hallmark of immunity is elicitation of a balanced response that is proportionate to the threat, to avoid unnecessary inflammation. In this article, we show how Ab affinity modulates TRIM21 immune function. We constructed a humanized monoclonal IgG1 against human adenovirus type 5 (AdV5) and a panel of Fc-engineered variants with a wide range of affinities for TRIM21. We found that IgG1-coated viral particles were neutralized via TRIM21, even when affinity was reduced by as much as 100-fold. In contrast, induction of NF-κB signaling was more sensitive to reduced affinity between TRIM21 and the Ab variants. Thus, TRIM21 mediates neutralization under suboptimal conditions, whereas induction of immune signaling is balanced according to the functional affinity for the incoming immune stimuli. Our findings have implications for engineering of antiviral IgG therapeutics with tailored effector functions.