Disproportionate infection, hospitalisation and death from COVID-19 in ethnic minority groups and Indigenous Peoples: an application of the Priority Public Health Conditions analytical framework.

The COVID-19 pandemic has resulted in disproportionate consequences for ethnic minority groups and Indigenous Peoples. We present an application of the Priority Public Health Conditions (PPHC) framework from the World Health Organisation (WHO), to explicitly address COVID-19 and other respiratory viruses of pandemic potential. This application is supported by evidence that ethnic minority groups were more likely to be infected, implying differential exposure (PPHC level two), be more vulnerable to severe disease once infected (PPHC level three) and have poorer health outcomes following infection (PPHC level four). These inequities are driven by various interconnected dimensions of racism, that compounds with socioeconomic context and position (PPHC level one). We show that, for respiratory viruses, it is important to stratify levels of the PPHC framework by infection status and by societal, community, and individual factors to develop optimal interventions to reduce inequity from COVID-19 and future infectious diseases outbreaks.

Association between ethnicity and migration status with the prevalence of single and multiple long-term conditions in UK healthcare workers.

BACKGROUND: Healthcare workers' (HCW) well-being has a direct effect on patient care. However, little is known about the prevalence and patterns of long-term medical conditions in HCWs, especially those from ethnic minorities. This study evaluated the burden of multiple long-term conditions (MLTCs), i.e. the presence of two or more single long-term conditions (LTCs), among HCWs in the United Kingdom (UK) and variation by ethnicity and migration status. METHODS: We used baseline data from the UK-REACH cohort study collected December 2020-March 2021. We used multivariable logistic regression, adjusting for demographic, occupational and lifestyle factors to examine the relationship between self-reported LTCs/MLTCs and ethnicity, migration status and time since migration to the UK. RESULTS: Of 12,100 included HCWs, with a median age of 45 years (IQR: 34-54), 27% were overseas-born, and 30% were from non-White ethnic groups (19% Asian, 4% Black, 4% Mixed, 2% Other). The most common self-reported LTCs were anxiety (14.9%), asthma (12.2%), depression (10.7%), hypertension (8.7%) and diabetes (4.0%). Mental health conditions were more prevalent among UK-born than overseas-born HCWs for all ethnic groups (adjusted odds ratio (aOR) using White UK-born as the reference group each time: White overseas-born 0.77, 95%CI 0.66-0.95 for anxiety). Diabetes and hypertension were more common among Asian (e.g. Asian overseas, diabetes aOR 2.97, 95%CI 2.30-3.83) and Black (e.g. Black UK-born, hypertension aOR 1.77, 95%CI 1.05-2.99) groups than White UK-born. After adjustment for age, sex and deprivation, the odds of reporting MLTCs were lower in most ethnic minority groups and lowest for those born overseas, compared to White UK-born (e.g. White overseas-born, aOR 0.68, 95%CI 0.55-0.83; Asian overseas-born aOR 0.75, 95%CI 0.62-0.90; Black overseas-born aOR 0.52, 95%CI 0.36-0.74). The odds of MLTCs in overseas-born HCWs were equivalent to the UK-born population in those who had settled in the UK for ≥ 20 years (aOR 1.14, 95%CI 0.94-1.37). CONCLUSIONS: Among UK HCWs, the prevalence of common LTCs and odds of reporting MLTCs varied by ethnicity and migrant status. The lower odds of MLTCs in migrant HCWs reverted to the odds of MLTCs in UK-born HCWs over time. Further research on this population should include longitudinal studies with linkage to healthcare records. Interventions should be co-developed with HCWs from different ethnic and migrant groups focussed upon patterns of conditions prevalent in specific HCW subgroups to reduce the overall burden of LTCs/MLTCs.

Four key problems that will need to be addressed during the next pandemic.

In June 2023, the UK began official hearings for its independent investigation into pandemic preparedness. Thus far, the inquiry has been told that planning has been wholly inadequate and that a future outbreak is inevitable. We present here four key problems that contributed to significant morbidity and mortality during the Coronavirus 2019 (COVID-19) pandemic over the past 3 years in the UK - and which will contribute to excess morbidity and mortality in the next outbreak. First, there was misunderstanding about what procedures were deemed as aerosol generating. Aerosol transmission has always been a component of respiratory viruses; however, no specific aerosol-generating procedures are required to transmit any respiratory pathogens over long distances. Second, policy-makers were too binary in their answers to the public in terms of questions about severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). This meant that, as evidence evolved and different conclusions were drawn, the public lost faith in both the UK Government and science. Third, public health guidance did not take into account that certain groups would be impacted differentially by public health guidelines and instead used a one-size-fits-all approach to non-pharmaceutical interventions. Finally, there was worsening of existing inequalities, especially in ethnic minority groups, that resulted in excessive numbers within certain cohorts becoming infected.

Tuning Phosphine Oxide-Substituted ortho-Carboranes for Improved Biphasic Electrochemical UO22+ Capture and Release.

We report the synthesis and characterization of a series of new, tunable 1,2-bis(diarylphosphine oxide)-ortho-carboranes, derivatives of our previously reported uranyl (UO22+) capture agent 1,2-(Ph2PO)2-1,2-C2B10H10 (POCb). The series features new cage-substituted variants of POCb, namely, 9-I-POCb (POCbI), 9,12-I2-POCb (POCbI2), 9,12-Me2-POCb (POCbMe2), 9,12-Et2-POCb (POCbEt2), and 4,5,7,8,9,10,11,12-Me8-POCb (POCbMe8). Aryl-substituted variants include 1,2-((4-MeO-Ph)2PO)2-Cb ((OMe)POCb) and 1,2-((4-F-Ph)2PO)2-Cb ((F)POCb). The effects of electron-withdrawing (EWG) and electron-donating (EDG) groups on resulting carborane redox potentials were assessed using electrochemical means, and the resulting Lewis basicities were quantified using empirical and competition-based NMR experiments. In organic solution, carboranes substituted with EWGs exhibited weaker coordination to UO22+, whereas those with EDGs exhibited stronger coordination. Similar to the previously reported unsubstituted POCb, the tunable new series of carboranes were electrochemically reduced and used for the biphasic capture of UO22+ from an aqueous to an organic phase and back again (release) through electrochemical oxidation. Extraction and back-extraction efficiencies were determined by analyses of the aqueous phases by ICP-OES. While all reduced nido-carboranes efficiently extracted UO22+ in high yields (78-88%)─with seemingly no correlation to the aforementioned measured Lewis basicities─we found the back-extraction of UO22+ to be significantly improved from POCb and, surprisingly, more closely related to their hydrophobic rather than their Lewis basic properties.

Investigating the impact of financial concerns on symptoms of depression in UK healthcare workers: data from the UK-REACH nationwide cohort study.

BACKGROUND: Exploration of the association between financial concerns and depression in UK healthcare workers (HCWs) is paramount given the current 'cost of living crisis', ongoing strike action and recruitment/retention problems in the National Health Service. AIMS: To assess the impact of financial concerns on the risk of depression in HCWs, how these concerns have changed over time and what factors might predict financial concerns. METHOD: We used longitudinal survey data from a UK-wide cohort of HCWs to determine whether financial concerns at baseline (December 2020 to March 2021) were associated with depression (measured with the Public Health Questionnaire-2) at follow-up (June to October 2022). We used logistic regression to examine the association between financial concerns and depression, and ordinal logistic regression to establish predictors of developing financial concerns. RESULTS: A total of 3521 HCWs were included. Those concerned about their financial situation at baseline had higher odds of developing depressive symptoms at follow-up. Financial concerns increased in 43.8% of HCWs and decreased in 9%. Those in nursing, midwifery and other nursing roles had over twice the odds of developing financial concerns compared with those in medical roles. CONCLUSIONS: Financial concerns are increasing in prevalence and predict the later development of depressive symptoms in UK HCWs. Those in nursing, midwifery and other allied nursing roles may have been disproportionately affected. Our results are concerning given the potential effects on sickness absence and staff retention. Policy makers should act to alleviate financial concerns to reduce the impact this may have on a discontent workforce plagued by understaffing.

Pathways to ethnic inequalities in COVID-19 health outcomes in the United Kingdom: A systematic map.

BACKGROUND: Marked ethnic inequalities in COVID-19 infection and its consequences have been documented. The aim of this paper is to identify the range and nature of evidence on potential pathways which lead to ethnic inequalities in COVID-19 related health outcomes in the United Kingdom (UK). METHODS: We searched six bibliographic and five grey literature databases from 1st December 2019 to 23rd February 2022 for research on pathways to ethnic inequalities in COVID-19 health outcomes in the UK. Meta-data were extracted and coded, using a framework informed by a logic model. Open Science Framework Registration: DOI 10.17605/OSF.IO/HZRB7. RESULTS: The search returned 10,728 records after excluding duplicates, with 123 included (83% peer-reviewed). Mortality was the most common outcome investigated (N = 79), followed by infection (N = 52). The majority of studies were quantitative (N = 93, 75%), with four qualitative studies (3%), seven academic narrative reviews (6%), nine third sector reports (7%) and five government reports (4%), and four systematic reviews or meta-analyses (3%). There were 78 studies which examined comorbidities as a pathway to mortality, infection, and severe disease. Socioeconomic inequalities (N = 67) were also commonly investigated, with considerable research into neighbourhood infrastructure (N = 38) and occupational risk (N = 28). Few studies examined barriers to healthcare (N = 6) and consequences of infection control measures (N = 10). Only 11% of eligible studies theorised racism to be a driver of inequalities and 10% (typically government/third sector reports and qualitative studies) explored this as a pathway. CONCLUSION: This systematic map identified knowledge clusters that may be amenable to subsequent systematic reviews, and critical gaps in the evidence-base requiring additional primary research. Most studies do not incorporate or conceptualise racism as the fundamental cause of ethnic inequalities and therefore the contribution to literature and policy is limited.

Ethnic differences in cellular and humoral immune responses to SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis.

Background: Few studies have compared SARS-CoV-2 vaccine immunogenicity by ethnic group. We sought to establish whether cellular and humoral immune responses to SARS-CoV-2 vaccination differ according to ethnicity in UK Healthcare workers (HCWs). Methods: In this cross-sectional analysis, we used baseline data from two immunological cohort studies conducted in HCWs in Leicester, UK. Blood samples were collected between March 3, and September 16, 2021. We excluded HCW who had not received two doses of SARS-CoV-2 vaccine at the time of sampling and those who had serological evidence of previous SARS-CoV-2 infection. Outcome measures were SARS-CoV-2 spike-specific total antibody titre, neutralising antibody titre and ELISpot count. We compared our outcome measures by ethnic group using univariable (t tests and rank-sum tests depending on distribution) and multivariable (linear regression for antibody titres and negative binomial regression for ELISpot counts) tests. Multivariable analyses were adjusted for age, sex, vaccine type, length of interval between vaccine doses and time between vaccine administration and sample collection and expressed as adjusted geometric mean ratios (aGMRs) or adjusted incidence rate ratios (aIRRs). To assess differences in the early immune response to vaccination we also conducted analyses in a subcohort who provided samples between 14 and 50 days after their second dose of vaccine. Findings: The total number of HCWs in each analysis were 401 for anti-spike antibody titres, 345 for neutralising antibody titres and 191 for ELISpot. Overall, 25.4% (19.7% South Asian and 5.7% Black/Mixed/Other) were from ethnic minority groups. In analyses including the whole cohort, neutralising antibody titres were higher in South Asian HCWs than White HCWs (aGMR 1.47, 95% CI [1.06-2.06], P = 0.02) as were T cell responses to SARS-CoV-2 S1 peptides (aIRR 1.75, 95% CI [1.05-2.89], P = 0.03). In a subcohort sampled between 14 and 50 days after second vaccine dose, SARS-CoV-2 spike-specific antibody and neutralising antibody geometric mean titre (GMT) was higher in South Asian HCWs compared to White HCWs (9616 binding antibody units (BAU)/ml, 95% CI [7178-12,852] vs 5888 BAU/ml [5023-6902], P = 0.008 and 2851 95% CI [1811-4487] vs 1199 [984-1462], P < 0.001 respectively), increments which persisted after adjustment (aGMR 1.26, 95% CI [1.01-1.58], P = 0.04 and aGMR 2.01, 95% CI [1.34-3.01], P = 0.001). SARS-CoV-2 ELISpot responses to S1 and whole spike peptides (S1 + S2 response) were higher in HCWs from South Asian ethnic groups than those from White groups (S1: aIRR 2.33, 95% CI [1.09-4.94], P = 0.03; spike: aIRR, 2.04, 95% CI [1.02-4.08]). Interpretation: This study provides evidence that, in an infection naïve cohort, humoral and cellular immune responses to SARS-CoV-2 vaccination are stronger in South Asian HCWs than White HCWs. These differences are most clearly seen in the early period following vaccination. Further research is required to understand the underlying mechanisms, whether differences persist with further exposure to vaccine or virus, and the potential impact on vaccine effectiveness. Funding: DIRECT and BELIEVE have received funding from UK Research and Innovation (UKRI) through the COVID-19 National Core Studies Immunity (NCSi) programme (MC_PC_20060).

Persistence of immune responses after heterologous and homologous third COVID-19 vaccine dose schedules in the UK: eight-month analyses of the COV-BOOST trial.

BACKGROUND: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms. METHODS: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation. RESULTS: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became significantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms. CONCLUSIONS: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns.

Ethnic inequalities in COVID-19 infection, hospitalisation, intensive care admission, and death: a global systematic review and meta-analysis of over 200 million study participants.

Background: COVID-19 has exacerbated existing ethnic inequalities in health. Little is known about whether inequalities in severe disease and deaths, observed globally among minoritised ethnic groups, relates to greater infection risk, poorer prognosis, or both. We analysed global data on COVID-19 clinical outcomes examining inequalities between people from minoritised ethnic groups compared to the ethnic majority group. Methods: Databases (MEDLINE, EMBASE, EMCARE, CINAHL, Cochrane Library) were searched from 1st December 2019 to 3rd October 2022, for studies reporting original clinical data for COVID-19 outcomes disaggregated by ethnicity: infection, hospitalisation, intensive care unit (ICU) admission, and mortality. We assessed inequalities in incidence and prognosis using random-effects meta-analyses, with Grading of Recommendations Assessment, Development, and Evaluation (GRADE) use to assess certainty of findings. Meta-regressions explored the impact of region and time-frame (vaccine roll-out) on heterogeneity. PROSPERO: CRD42021284981. Findings: 77 studies comprising over 200,000,000 participants were included. Compared with White majority populations, we observed an increased risk of testing positive for infection for people from Black (adjusted Risk Ratio [aRR]:1.78, 95% CI:1.59-1.99, I2 = 99.1), South Asian (aRR:3.00, 95% CI:1.59-5.66, I2 = 99.1), Mixed (aRR:1.64, 95% CI:1.02-1.67, I2 = 93.2) and Other ethnic groups (aRR:1.36, 95% CI:1.01-1.82, I2 = 85.6). Black, Hispanic, and South Asian people were more likely to be seropositive. Among population-based studies, Black and Hispanic ethnic groups and Indigenous peoples had an increased risk of hospitalisation; Black, Hispanic, South Asian, East Asian and Mixed ethnic groups and Indigenous peoples had an increased risk of ICU admission. Mortality risk was increased for Hispanic, Mixed, and Indigenous groups. Smaller differences were seen for prognosis following infection. Following hospitalisation, South Asian, East Asian, Black and Mixed ethnic groups had an increased risk of ICU admission, and mortality risk was greater in Mixed ethnic groups. Certainty of evidence ranged from very low to moderate. Interpretation: Our study suggests that systematic ethnic inequalities in COVID-19 health outcomes exist, with large differences in exposure risk and some differences in prognosis following hospitalisation. Response and recovery interventions must focus on tackling drivers of ethnic inequalities which increase exposure risk and vulnerabilities to severe disease, including structural racism and racial discrimination. Funding: ESRC:ES/W000849/1.

Ultrasound-mediated delivery of flexibility-tunable polymer drug conjugates for treating glioblastoma.

Effective chemotherapy delivery for glioblastoma multiforme (GBM) is limited by drug transport across the blood-brain barrier and poor efficacy of single agents. Polymer-drug conjugates can be used to deliver drug combinations with a ratiometric dosing. However, the behaviors and effectiveness of this system have never been well investigated in GBM models. Here, we report flexible conjugates of hyaluronic acid (HA) with camptothecin (CPT) and doxorubicin (DOX) delivered into the brain using focused ultrasound (FUS). In vitro toxicity assays reveal that DOX-CPT exhibited synergistic action against GBM in a ratio-dependent manner when delivered as HA conjugates. FUS is employed to improve penetration of DOX-HA-CPT conjugates into the brain in vivo in a murine GBM model. Small-angle x-ray scattering characterizations of the conjugates show that the DOX:CPT ratio affects the polymer chain flexibility. Conjugates with the highest flexibility yield the highest efficacy in treating mouse GBM in vivo. Our results demonstrate the association of FUS-enhanced delivery of combination chemotherapy and the drug-ratio-dependent flexibility of the HA conjugates. Drug ratio in the polymer nanocomplex may thus be employed as a key factor to modulate FUS drug delivery efficiency via controlling the polymer flexibility. Our characterizations also highlight the significance of understanding the flexibility of drug carriers in ultrasound-mediated drug delivery systems.

Transmission of monkeypox/mpox virus: A narrative review of environmental, viral, host, and population factors in relation to the 2022 international outbreak.

Monkeypox virus (MPXV) has spread globally. Emerging studies have now provided evidence regarding MPXV transmission, that can inform rational evidence-based policies and reduce misinformation on this topic. We aimed to review the evidence on transmission of the virus. Real-world studies have isolated viable viruses from high-touch surfaces for as long as 15 days. Strong evidence suggests that the current circulating monkeypox (mpox) has evolved from previous outbreaks outside of Africa, but it is yet unknown whether these mutations may lead to an inherently increased infectivity of the virus. Strong evidence also suggests that the main route of current MPXV transmission is sexual; through either close contact or directly, with detection of culturable virus in saliva, nasopharynx, and sperm for prolonged periods and the presence of rashes mainly in genital areas. The milder clinical presentations and the potential presence of presymptomatic transmission in the current circulating variant compared to previous clades, as well as the dominance of spread amongst men who have sex with men (MSMs) suggests that mpox has a developed distinct clinical phenotype that has increased its transmissibility. Increased public awareness of MPXV transmission modalities may lead to earlier detection of the spillover of new cases into other groups.

A modular vaccine platform enabled by decoration of bacterial outer membrane vesicles with biotinylated antigens.

Engineered outer membrane vesicles (OMVs) derived from Gram-negative bacteria are a promising technology for the creation of non-infectious, nanoparticle vaccines against diverse pathogens. However, antigen display on OMVs can be difficult to control and highly variable due to bottlenecks in protein expression and localization to the outer membrane of the host cell, especially for bulky and/or complex antigens. Here, we describe a universal approach for avidin-based vaccine antigen crosslinking (AvidVax) whereby biotinylated antigens are linked to the exterior of OMVs whose surfaces are remodeled with multiple copies of a synthetic antigen-binding protein (SNAP) comprised of an outer membrane scaffold protein fused to a biotin-binding protein. We show that SNAP-OMVs can be readily decorated with a molecularly diverse array of biotinylated subunit antigens, including globular and membrane proteins, glycans and glycoconjugates, haptens, lipids, and short peptides. When the resulting OMV formulations are injected in mice, strong antigen-specific antibody responses are observed that depend on the physical coupling between the antigen and SNAP-OMV delivery vehicle. Overall, these results demonstrate AvidVax as a modular platform that enables rapid and simplified assembly of antigen-studded OMVs for application as vaccines against pathogenic threats.