Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21.

During pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we found that recognition of intracellular antibodies by TRIM21 activated immune signaling. TRIM21 catalyzed the formation of Lys63 (K63)-linked ubiquitin chains and stimulated the transcription factor pathways of NF-κB, AP-1, IRF3, IRF5 and IRF7. Activation resulted in the production of proinflammatory cytokines, modulation of natural killer stress ligands and induction of an antiviral state. Intracellular antibody signaling was abrogated by genetic deletion of TRIM21 and was restored by ectopic expression of TRIM21. The sensing of antibodies by TRIM21 was stimulated after infection by DNA or RNA nonenveloped viruses or intracellular bacteria. Thus, the antibody-TRIM21 detection system provides potent, comprehensive activation of the innate immune system independently of known pattern-recognition receptors.

Age- and deprivation-related inequalities in identification of people at high risk of type 2 diabetes in England.

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.

Marginalisation and distrust in the context of the COVID-19 vaccination programme: experiences of communities in a northern UK city region.

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.

"We might not have been in hospital, but we were frontline workers in the community": a qualitative study exploring unmet need and local community-based responses for marginalised groups in Greater Manchester during the COVID-19 pandemic.

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.

Evaluating socioeconomic inequalities in influenza vaccine uptake during the COVID-19 pandemic: A cohort study in Greater Manchester, England.

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.

Ethnic inequalities in COVID-19 vaccine uptake and comparison to seasonal influenza vaccine uptake in Greater Manchester, UK: A cohort study.

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.

Correction: Ethnic inequalities in COVID-19 vaccine uptake and comparison to seasonal influenza vaccine uptake in Greater Manchester, UK: A cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003932.].

Effects of BNT162b2 mRNA vaccine on COVID-19 infection and hospitalisation amongst older people: matched case control study for England.

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.

TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity.

Antibodies are key molecules in the fight against infections. Although previously thought to mediate protection solely in the extracellular environment, recent research has revealed that antibody-mediated protection extends to the cytosolic compartment of cells. This postentry viral defense mechanism requires binding of the antibody to a cytosolic Fc receptor named tripartite motif containing 21 (TRIM21). In contrast to other Fc receptors, TRIM21 shows remarkably broad isotype specificity as it does not only bind IgG but also IgM and IgA. When viral pathogens coated with these antibody isotypes enter the cytosol, TRIM21 is rapidly recruited and efficient neutralization occurs before the virus has had the time to replicate. In addition, inflammatory signaling is induced. As such, TRIM21 acts as a cytosolic sensor that engages antibodies that have failed to protect against infection in the extracellular environment. Here, we summarize our current understanding of how TRIM21 orchestrates humoral immunity in the cytosolic environment.

TRIM21 Immune Signaling Is More Sensitive to Antibody Affinity Than Its Neutralization Activity.

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.

Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21.

Tripartite motif (TRIM) 21 is a cytosolic antibody receptor that neutralizes antibody-coated viruses that penetrate the cell and simultaneously activates innate immunity. Here we show that the conjugation of TRIM21 with K63-linked ubiquitin (Ub-(63)Ub) catalyzed by the sequential activity of nonredundant E2 Ub enzymes is required for its dual antiviral functions. TRIM21 is first labeled with monoubiquitin (monoUb) by the E2 Ube2W. The monoUb is a substrate for the heterodimeric E2 Ube2N/Ube2V2, resulting in TRIM21-anchored Ub-(63)Ub. Depletion of either E2 abolishes Ub-(63)Ub and Ub-(48)Ub conjugation of TRIM21, NF-κB signaling, and virus neutralization. The formation of TRIM21-Ub-(63)Ub precedes proteasome recruitment, and we identify an essential role for the 19S-resident and degradation-coupled deubiquitinase Poh1 in TRIM21 neutralization, signaling, and cytokine induction. This study elucidates a complex mechanism of step-wise ubiquitination and deubiquitination activities that allows contemporaneous innate immune signaling and neutralization by TRIM21.

TRIM21 Promotes cGAS and RIG-I Sensing of Viral Genomes during Infection by Antibody-Opsonized Virus.

Encapsidation is a strategy almost universally employed by viruses to protect their genomes from degradation and from innate immune sensors. We show that TRIM21, which targets antibody-opsonized virions for proteasomal destruction, circumvents this protection, enabling the rapid detection and degradation of viral genomes before their replication. TRIM21 triggers an initial wave of cytokine transcription that is antibody, rather than pathogen, driven. This early response is augmented by a second transcriptional program, determined by the nature of the infecting virus. In this second response, TRIM21-induced exposure of the viral genome promotes sensing of DNA and RNA viruses by cGAS and RIG-I. This mechanism allows early detection of an infection event and drives an inflammatory response in mice within hours of viral challenge.

Intracellular antibody receptor TRIM21 prevents fatal viral infection.

Host species have evolved mechanisms that can inhibit pathogen replication even after a cell has been successfully invaded. Here we show that tripartite-motif protein 21 (TRIM21), a ubiquitously expressed E3 ubiquitin ligase that targets viruses inside the cytosol, protects mice against fatal viral infection. Upon infection with mouse adenovirus-1, naive mice lacking TRIM21 succumb to encephalomyelitis within 7 d. In contrast, wild-type mice rapidly up-regulate TRIM21 and control viremia. Trim21 heterozygous mice have a haploinsufficiency phenotype in which reduced TRIM21 expression leads to a viral load that is higher than wild types but lower than knockouts. TRIM21 is a high-affinity antibody receptor that allows antibodies to operate inside an infected cell. In passive transfer experiments at high viral dose, antisera that fully protects wild-type mice fails to protect most Trim21 knockout animals. These results demonstrate that TRIM21 provides potent antiviral protection and forms an important part of the humoral immune response.

Intracellular antibody immunity.

Antibodies allow the immune system to target pathogens despite their tremendous diversity and rapid evolution. Once bound to a pathogen, antibodies induce a broad range of effector mechanisms, including phagocytosis and complement. However, these mechanisms are all initiated in the extracellular space, meaning that pathogens like viruses evade them upon infection of their target cells. Recently, it has been shown that, in addition to mediating extracellular immune responses, antibodies also activate immunity inside infected cells. Antibodies that are bound to the surface of non-enveloped viruses or bacteria are carried into the cell during pathogen entry. Once inside the cell, these pathogen-attached antibodies are recognised by a highly conserved, high affinity cytosolic antibody receptor called TRIM21. TRIM21 initiates both sensor and effector responses that reduce viral replication and induce an antiviral state. These responses are an important part of antiviral immunity and the removal of TRIM21 results in uncontrolled viraemia and death in a mouse model of infection.

How can healthcare organisations improve the social determinants of health for their local communities? Findings from realist-informed case studies among secondary healthcare organisations in England.

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.

Gender-related self-reported mental health inequalities in primary care in England: a cross-sectional analysis using the GP Patient Survey.

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 1 520 457 respondents in the estimation sample, 861 017 (51·4%) were female, 645 300 (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. 1 499 852 (98·3%) respondents were cisgender, 7994 (0·7%) were transgender, and 12 611 (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.

Paramyxovirus matrix proteins modulate host cell translation via exon-junction complex interactions in the cytoplasm.

Viruses have evolved myriad strategies to exploit the translation machinery of host cells to potentiate their replication. However, how paramyxovirus (PMVs) modulate cellular translation for their own benefit has not been systematically examined. Utilizing puromycylation labeling, overexpression of individual viral genes, and infection with wild-type virus versus its gene-deleted counterpart, we found that PMVs significantly inhibit host cells' nascent peptide synthesis during infection, with the viral matrix being the primary contributor to this effect. Using the rNiV-NPL replicon system, we discovered that the viral matrix enhances viral protein translation without affecting viral mRNA transcription and suppresses host protein expression at the translational level. Polysome profile analysis revealed that the HPIV3 matrix promotes the association of viral mRNAs with ribosomes, thereby enhancing their translation efficiency during infection. Intriguingly, our NiV-Matrix interactome identified the core exon-junction complex (cEJC), critical for mRNA biogenesis, as a significant component that interacts with the paramyxoviral matrix predominantly in the cytoplasm. siRNA knockdown of eIF4AIII simulated the restriction of cellular functions by the viral matrix, leading to enhanced viral gene translation and a reduction in host protein synthesis. Moreover, siRNA depletion of cEJC resulted in a 2-3 log enhancement in infectious virus titer for various PMVs but not SARS-CoV-2, enterovirus D68, or influenza virus. Our findings characterize a host translational interference mechanism mediated by viral matrix and host cEJC interactions. We propose that the PMV matrix redirects ribosomes to translate viral mRNAs at the expense of host cell transcripts, enhancing viral replication, and thereby enhancing viral replication. These insights provide a deeper understanding of the molecular interactions between paramyxoviruses and host cells, highlighting potential targets for antiviral strategies.

A temperature-sensitive and interferon-silent Sendai virus vector for CRISPR-Cas9 delivery and gene editing in primary human cells.

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.

LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease.

Socioeconomic inequality in access to timely and appropriate care in emergency departments.

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.