Driving delivery and uptake of catch-up vaccination among adolescent and adult migrants in UK general practice: a mixed methods pilot study.

BACKGROUND: Migrants in the UK and Europe face vulnerability to vaccine-preventable diseases (VPDs) due to missed childhood vaccines and doses and marginalisation from health systems. Ensuring migrants receive catch-up vaccinations, including MMR, Td/IPV, MenACWY, and HPV, is essential to align them with UK and European vaccination schedules and ultimately reduce morbidity and mortality. However, recent evidence highlights poor awareness and implementation of catch-up vaccination guidelines by UK primary care staff, requiring novel approaches to strengthen the primary care pathway. METHODS: The 'Vacc on Track' study (May 2021-September 2022) aimed to measure under-vaccination rates among migrants in UK primary care and establish new referral pathways for catch-up vaccination. Participants included migrants aged 16 or older, born outside of Western Europe, North America, Australia, or New Zealand, in two London boroughs. Quantitative data on vaccination history, referral, uptake, and sociodemographic factors were collected, with practice nurses prompted to deliver catch-up vaccinations following UK guidelines. Focus group discussions and in-depth interviews with staff and migrants explored views on delivering catch-up vaccination, including barriers, facilitators, and opportunities. Data were analysed using STATA12 and NVivo 12. RESULTS: Results from 57 migrants presenting to study sites from 18 countries (mean age 41 [SD 7.2] years; 62% female; mean 11.3 [SD 9.1] years in UK) over a minimum of 6 months of follow-up revealed significant catch-up vaccination needs, particularly for MMR (49 [86%] required catch-up vaccination) and Td/IPV (50 [88%]). Fifty-three (93%) participants were referred for any catch-up vaccination, but completion of courses was low (6 [12%] for Td/IPV and 33 [64%] for MMR), suggesting individual and systemic barriers. Qualitative in-depth interviews (n = 39) with adult migrants highlighted the lack of systems currently in place in the UK to offer catch-up vaccination to migrants on arrival and the need for health-care provider skills and knowledge of catch-up vaccination to be improved. Focus group discussions and interviews with practice staff (n = 32) identified limited appointment/follow-up time, staff knowledge gaps, inadequate engagement routes, and low incentivisation as challenges that will need to be addressed. However, they underscored the potential of staff champions, trust-building mechanisms, and community-based approaches to strengthen catch-up vaccination uptake among migrants. CONCLUSIONS: Given the significant catch-up vaccination needs of migrants in our sample, and the current barriers to driving uptake identified, our findings suggest it will be important to explore this public health issue further, potentially through a larger study or trial. Strengthening existing pathways, staff capacity and knowledge in primary care, alongside implementing new strategies centred on cultural competence and building trust with migrant communities will be important focus areas.

Peer support for people living with hepatitis B virus-A foundation for treatment expansion.

Chronic hepatitis B infection (CHB) affects 300 million people worldwide and is being targeted by the United Nations 2030 Sustainable Development Goals (SDGs) and the World Health Organisation (WHO), working towards elimination of hepatitis B virus (HBV) as a public health threat. In this piece, we explore the evidence and potential impact of peer support to enhance and promote interventions for people living with CHB. Peer support workers (PSWs) are those with lived experience of an infection, condition or situation who work to provide support for others, aiming to improve education, prevention, treatment and other clinical interventions and to reduce the physical, psychological and social impacts of disease. Peer support has been shown to be a valuable tool for improving health outcomes for people living with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), but to date has not been widely available for communities affected by HBV. HBV disproportionately affects vulnerable and marginalised populations, who could benefit from PSWs to help them navigate complicated systems and provide advocacy, tackle stigma, improve education and representation, and optimise access to treatment and continuity of care. The scale up of peer support must provide structured and supportive career pathways for PSWs, account for social and cultural needs of different communities, adapt to differing healthcare systems and provide flexibility in approaches to care. Investment in peer support for people living with CHB could increase diagnosis, improve retention in care, and support design and roll out of interventions that can contribute to global elimination goals.

Co-designing a theory-informed, multicomponent intervention to increase vaccine uptake with Congolese migrants: A qualitative, community-based participatory research study (LISOLO MALAMU).

INTRODUCTION: Disparities in the uptake of routine and COVID-19 vaccinations have been observed in migrant populations, and attributed to issues of mistrust, access and low vaccine confidence. Participatory research approaches and behaviour change theory hold the potential for developing tailored vaccination interventions that address these complex barriers in partnership with communities and should be explored further. METHODS: This study used a theory-informed, community-based participatory research approach to co-design a culturally tailored behaviour change intervention aimed at increasing COVID-19 vaccine uptake among Congolese migrants in London, United Kingdom (2021-2022). It was designed and led by a community-academic partnership in response to unmet needs in the Congolese community as the COVID-19 pandemic started. Barriers and facilitators to COVID-19 vaccination, information and communication preferences, and intervention suggestions were explored through qualitative in-depth interviews with Congolese migrants, thematically analysed, and mapped to the theoretical domains framework (TDF) and the capability, opportunity, motivation, behaviour model to identify target behaviours and strategies to include in interventions. Interventions were co-designed and tailored in workshops involving Congolese migrants. RESULTS: Thirty-two Congolese adult migrants (24 (75%) women, mean 14.3 (SD: 7.5) years in the United Kingdom, mean age 52.6 (SD: 11.0) years) took part in in-depth interviews and 16 (same sample) took part in co-design workshops. Fourteen barriers and 10 facilitators to COVID-19 vaccination were identified; most barrier data related to four TDF domains (beliefs about consequences; emotion; social influences and environmental context and resources), and the behavioural diagnosis concluded interventions should target improving psychological capability, reflective and automatic motivations and social opportunities. Strategies included culturally tailored behaviour change techniques based on education, persuasion, modelling, enablement and environmental restructuring, which resulted in a co-designed intervention comprising community-led workshops, plays and posters. Findings and interventions were disseminated through a community celebration event. CONCLUSIONS: Our study demonstrates how behavioural theory can be applied to co-designing tailored interventions with underserved migrant communities through a participatory research paradigm to address a range of health issues and inequalities. Future research should build on this empowering approach, with the goal of developing more sensitive vaccination services and interventions which respond to migrant communities' unique cultural needs and realities. PATIENT OR PUBLIC CONTRIBUTION: Patient and public involvement (PPI) were embedded in the participatory study design and approach, with community members co-producing all stages of the study and co-authoring this paper. An independent PPI board (St George's Migrant Health Research Group Patient and Public Involvement Advisory Board) comprising five adult migrants with lived experience of accessing healthcare in the United Kingdom were also consulted at significant points over the course of the study.

Transcriptional analysis of immune response genes during pathogenesis of cytomegalovirus retinitis in mice with murine acquired immunodeficiency syndrome.

Human cytomegalovirus (HCMV) is an opportunistic human herpesvirus that causes a sight-threatening retinitis in immunosuppressed patients, especially those with AIDS. Using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunodeficiency (MAIDS), we have been attempting to define with greater clarity the immunologic mechanisms that contribute to the progression of AIDS-related HCMV retinitis in the unique immunosuppressive setting of HIV infection. Toward this end, we provide herein a comprehensive assessment of immune response gene expression during the onset and development of MAIDS-related MCMV retinitis employing NanoString nCounter. In so doing, we analyzed and compared the intraocular expressions of 561 immune response genes within MCMV-infected eyes of groups of healthy mice, MCMV-infected mice with MAIDS of 4 weeks' (MAIDS-4) duration, and MCMV-infected eyes of mice with MAIDS of 10 weeks' (MAIDS-10) duration. These animal groups show a progression of retinal disease from absolute resistance to retinitis development in healthy mice to the development of classic full-thickness retinal necrosis in MAIDS-10 mice but through an intermediate stage of retinal disease development in MAIDS-4 mice. Our findings showed that increased susceptibility to MCMV retinitis during the progression of MAIDS is associated with robust upregulation or downregulation of a surprisingly large number of immune response genes that operate within several immune response pathways often unique to each animal group. Analysis of 14 additional immune response genes associated with programmed cell death pathways suggested involvement of necroptosis and pyroptosis during MAIDS-related MCMV retinitis pathogenesis. Use of the NanoString nCounter technology provided new and unexpected information on the immunopathogenesis of retinitis within MCMV-infected eyes of mice with retrovirus-induced immunosuppression. Our findings may provide new insights into the immunologic events that operate during the pathogenesis of AIDS-related HCMV retinitis.

Isolation and Characterization of a ssDNA Aptamer against Major Soluble Antigen of Renibacterium salmoninarum.

Bacterial kidney disease (BKD) is a major health problem of salmonids, affecting both wild and cultured salmon. The disease is caused by Renibacterium salmoninarum (Rs), a fastidious, slow-growing and strongly Gram-positive diplobacillus that produces chronic, systemic infection characterized by granulomatous lesions in the kidney and other organs, often resulting in death. Fast detection of the pathogen is important to limit the spread of the disease, particularly in hatcheries or aquaculture facilities. Aptamers are increasingly replacing conventional antibodies as platforms for the development of rapid diagnostic tools. In this work, we describe the first instance of isolating and characterizing a ssDNA aptamer that binds with high affinity to p57 or major soluble antigen (MSA), the principal antigen found on the cell wall surface of Rs. Specifically, in this study a construct of the full-length protein containing a DNA binding domain (MSA-R2c) was utilized as target. Aptamers were isolated from a pool of random sequences using GO-SELEX (graphene oxide-systematic evolution of ligands by exponential enrichment) protocol. The selection generated multiple aptamers with conserved motifs in the random region. One aptamer with high frequency of occurrence in different clones was characterized and found to display a strong binding affinity to MSA-R2c with a Kd of 3.0 ± 0.6 nM. The aptamer could be potentially utilized for the future development of a sensor for rapid and onsite detection of Rs in water or in infected salmonids, replacing time-consuming and costly lab analyses.

Evidence for the involvement of interleukin-1α during development of experimental cytomegalovirus retinitis in immunosuppressed mice.

Interleukin-1α (IL-1α) is an alarmin involved in the recruitment of macrophages and neutrophils during tissue inflammation. IL-1α can undergo cleavage by proteases, such as calpain-1, that enhances IL-1α binding to its receptor, although proteolytic cleavage is not necessary for biological activity. Macrophages and neutrophils are involved in the retinal inflammation associated with development of AIDS-related human cytomegalovirus (HCMV) retinitis. We therefore performed studies to test the hypothesis that IL-1α gene expression is stimulated intraocularly during retinitis development using two mouse models of murine cytomegalovirus (MCMV) retinitis that differ in method of immunosuppression, one by retrovirus-induced immunosuppression (MAIDS) and the other by corticosteroid-induced immunosuppression. MCMV-infected eyes of groups of retinitis-susceptible mice with MAIDS of 10 weeks duration (MAIDS-10 mice) and retinitis-susceptible corticosteroid-treated mice showed significant stimulation of IL-1α mRNA. Western blot analysis confirmed IL-1α protein production within the MCMV-infected eyes of MAIDS-10 mice. Whereas significant intraocular calpain-1 mRNA and protein production were also observed within MCMV-infected eyes of MAIDS-10 mice, the MCMV-infected eyes of retinitis-susceptible corticosteroid-treated mice showed a pattern of mRNA synthesis equivalent to that found within the MCMV-infected eyes of healthy mice that fail to develop retinitis. Our findings suggest a role for the alarmin IL-1α in the pathogenesis of MCMV retinitis in immunosuppressed mice. These findings may extend to the pathogenesis of HCMV retinitis in patients with AIDS or other forms of immunosuppression.

Atypical cytomegalovirus retinal disease in pyroptosis-deficient mice with murine acquired immunodeficiency syndrome.

Pyroptosis is a caspase-dependent programmed cell death pathway that initiates and sustains inflammation through release of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18 following formation of gasdermin D (GSDMD)-mediated membrane pores. To determine the possible pathogenic contributions of pyroptosis toward development of full-thickness retinal necrosis during AIDS-related human cytomegalovirus retinitis, we performed a series of studies using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS). Initial investigations demonstrated significant transcription and translation of key pyroptosis-associated genes within the ocular compartments of MCMV-infected eyes of mice with MAIDS. Subsequent investigations compared MCMV-infected eyes of groups of wildtype MAIDS mice with MCMV-infected eyes of groups of caspase-1-/- MAIDS mice, GSDMD-/- MAIDS mice, or IL-18-/- MAIDS mice to explore a possible contribution of pyroptosis towards the pathogenesis of MAIDS-related MCMV retinitis. Histopathologic analysis revealed typical full-thickness retinal necrosis in 100% of MCMV-infected eyes of wildtype MAIDS mice. In sharp contrast, none (0%) of MCMV-infected eyes of MAIDS mice that were deficient in either caspase-1, GSDMD, or IL-18 developed full-thickness retinal necrosis but instead exhibited an atypical pattern of retinal disease characterized by thickening and proliferation of the retinal pigmented epithelium layer with relative sparing of the neurosensory retina. Surprisingly, MCMV-infected eyes of all groups of deficient MAIDS mice harbored equivalent intraocular amounts of infectious virus as seen in MCMV-infected eyes of groups of wildtype MAIDS mice despite failure to develop full-thickness retinal necrosis. We conclude that pyroptosis plays a significant role in the development of full-thickness retinal necrosis during the pathogenesis of MAIDS-related MCMV retinitis. This observation may extend to the pathogenesis of AIDS-related HCMV retinitis and other AIDS-related opportunistic virus infections.

A National Survey of Patient Completion of Cognitive Behavioral Therapy for Chronic Pain: The Role of Therapist Characteristics, Attempt Rates, and Modification.

The implementation of evidence-based psychotherapies, including patient-level measures such as penetration and rates of successfully completing a course of therapy, has received increasing attention. While much attention has been paid to the effect of patient-level factors on implementation, relatively little attention has been paid to therapist factors (e.g., professional training, experience). OBJECTIVE: The current study explores therapists' decisions to offer a particular evidence-based psychotherapy (cognitive behavioral therapy for chronic pain; CBT-CP), whether and how they modify CBT-CP, and the relationship between these decisions and patient completion rates. METHODS: The study utilized survey responses from 141 Veterans Affairs therapists certified in CBT-CP. RESULTS: Therapists reported attempting CBT-CP with a little less than one half of their patients with chronic pain (mean = 48.8%, s.d.=35.7). Therapist were generally split between reporting modifying CBT-CP for either very few or most of their patients. After controlling for therapist characteristics and modification, therapist-reported percentage of patients with attempted CBT-CP was positively associated with completion rates, t (111) = 4.57, p<.001. CONCLUSIONS: Therapists who attempt CBT-CP more frequently may experience better completion rates, perhaps due to practice effects or contextual factors that support both attempts and completion. Future research should examine this relationship using objective measures of attempt rates and completion.

Parthanatos-associated proteins are stimulated intraocularly during development of experimental murine cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression.

The mechanisms that contribute to retinal tissue destruction during the onset and progression of AIDS-related human cytomegalovirus (HCMV) retinitis remain unclear. Evidence for the stimulation of multiple cell death pathways including apoptosis, necroptosis, and pyroptosis during the pathogenesis of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS) has been reported. Parthanatos is a caspase-independent cell death pathway mediated by rapid overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) and distinct from other cell death pathways. Using the MAIDS model of MCMV retinitis, studies were performed to test the hypothesis that intraocular MCMV infection of mice with MAIDS stimulates parthanatos-associated messenger RNAs (mRNAs) and proteins within the eye during the development of retinal necrosis that takes place by 10 days after MCMV infection. MCMV-infected eyes of MAIDS mice exhibited significant stimulation of PARP-1 mRNA and proteins at 3 days after infection but declined thereafter at 6 and 10 days after infection. Additional studies showed the intraocular stimulation of mRNAs or proteins before MCMV retinitis development for two additional participants in parthanatos, polymer of ADP-ribose and poly (ADP-ribose) glycohydrolase. These results provide new evidence for a role for parthanatos during MAIDS-related MCMV retinitis that may also extend to AIDS-related HCMV retinitis.

Implementation of Perioperative Music Using the Consolidated Framework for Implementation Research.

BACKGROUND: Complementary integrative health therapies have a perioperative role in the reduction of pain, analgesic use, and anxiety, and increasing patient satisfaction. However, long implementation lags have been quantified. The Consolidated Framework for Implementation Research (CFIR) can help mitigate this translational problem. METHODS: We reviewed evidence for several nonpharmacological treatments (CFIR domain: characteristics of interventions) and studied external context and organizational readiness for change by surveying providers at 11 Veterans Affairs (VA) hospitals (domains: outer and inner settings). We asked patients about their willingness to receive music and studied the association between this and known risk factors for opioid use (domain: characteristics of individuals). We implemented a protocol for the perioperative use of digital music players loaded with veteran-preferred playlists and evaluated its penetration in a subgroup of patients undergoing joint replacements over a 6-month period (domain: process of implementation). We then extracted data on postoperative recovery time and other outcomes, comparing them with historic and contemporary cohorts. RESULTS: Evidence varied from strong and direct for perioperative music and acupuncture, to modest or weak and indirect for mindfulness, yoga, and tai chi, respectively. Readiness for change surveys completed by 97 perioperative providers showed overall positive scores (mean >0 on a scale from -2 to +2, equivalent to >2.5 on the 5-point Likert scale). Readiness was higher at Durham (+0.47) versus most other VA hospitals (range +0.05 to +0.63). Of 3307 veterans asked about willingness to receive music, approximately 68% (n = 2252) answered "yes." In multivariable analyses, a positive response (acceptability) was independently predicted by younger age and higher mean preoperative pain scores (>4 out of 10 over 90 days before admission), factors associated with opioid overuse. Penetration was modest in the targeted subset (39 received music out of a possible 81 recipients), potentially reduced by device nonavailability due to diffusion into nontargeted populations. Postoperative recovery time was not changed, suggesting smooth integration into workflow. CONCLUSIONS: CFIR-guided implementation of perioperative music was feasible at a tertiary VA hospital, with moderate penetration in a high-risk subset of patients. Use of digital music players with preferred playlists was supported by strong evidence, tension for change, modest readiness among providers, good acceptability among patients (especially those at risk for opioid overuse), and a protocolized approach. Further study is needed to identify similar frameworks for effective knowledge-translation activities.

An alternative role for Foxp3 as an effector T cell regulator controlled through CD40.

The BDC2.5 T cell clone is highly diabetogenic, but the transgenic mouse generated from that clone is surprisingly slow in diabetes development. Although defining pathogenic effector T cells in autoimmunity has been inconsistent, CD4(+) cells expressing the CD40 receptor (Th40 cells) are highly diabetogenic in NOD mice, and NOD.BDC2.5.TCR.Tg mice possess large numbers of these cells. Given the importance of CD40 for pathogenic T cell development, BDC2.5.CD40(-/-) mice were created. Regulatory T cells, CD4(+)CD25(hi)Foxp3(+), develop normally, but pathogenic effector cells are severely reduced in number. Th40 cells from diabetic BDC2.5 mice rapidly induce diabetes in NOD.scid recipients, but Th40 cells from prediabetic mice transfer diabetes very slowly. Demonstrating an important paradigm shift, effector Th40 cells from prediabetic mice are Foxp3(+). As mice age, moving to type 1 diabetes development, Th40 cells lose Foxp3. When Th40 cells that are Foxp3(+) are transferred to NOD.scid recipients, disease is delayed. Th40 cells that are Foxp3(-) rapidly transfer disease. Th40 cells from BDC2.5.CD40(-/-) mice do not transfer disease nor do they lose Foxp3 expression. Mechanistically, Foxp3(+) cells produce IL-17 but do not produce IFN-γ, whereas Foxp3(-) Th40 cells produce IFN-γ and IL-2. This poses a new consideration for the function of Foxp3, as directly impacting effector T cell function.

A CD40-targeted peptide controls and reverses type 1 diabetes in NOD mice.

AIMS/HYPOTHESIS: The CD40-CD154 interaction directs autoimmune inflammation. Therefore, a long-standing goal in the treatment of autoimmune disease has been to control the formation of that interaction and thereby prevent destructive inflammation. Antibodies blocking CD154 are successful in mouse models of autoimmune disease but, while promising when used in humans, unfortunate thrombotic events have occurred, forcing the termination of those studies. METHODS: To address the clinical problem of thrombotic events caused by anti-CD154 antibody treatment, we created a series of small peptides based on the CD154 domain that interacts with CD40 and tested the ability of these peptides to target CD40 and prevent type 1 diabetes in NOD mice. RESULTS: We identified a lead candidate, the 15-mer KGYY15 peptide, which specifically targets CD40-positive cells in a size- and sequence-dependent manner. It is highly efficient in preventing hyperglycaemia in NOD mice that spontaneously develop type 1 diabetes. Importantly, KGYY15 can also reverse new-onset hyperglycaemia. KGYY15 is well tolerated and functions to control the cytokine profile of culprit Th40 effector T cells. The KGYY15 peptide is 87% homologous to the human sequence, suggesting that it is an important candidate for translational studies. CONCLUSIONS/INTERPRETATION: Peptide KGYY15 constitutes a viable therapeutic option to antibody therapy in targeting the CD40-CD154 interaction in type 1 diabetes. Given the involvement of CD40 in autoimmunity in general, it will also be important to evaluate KGYY15 in the treatment of other autoimmune diseases. This alternative therapeutic approach opens new avenues of exploration in targeting receptor-ligand interactions.

Oncogene-dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma.

Undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue malignancies. Patients with large, high-grade sarcomas often develop fatal lung metastases. Understanding the mechanisms underlying sarcoma metastasis is needed to improve treatment of these patients. Micro-RNAs (miRNAs) are a class of small RNAs that post-transcriptionally regulate gene expression. Global alterations in miRNAs are frequently observed in a number of disease states including cancer. The signalling pathways that regulate miRNA biogenesis are beginning to emerge. To test the relevance of specific oncogenic mutations in miRNA biogenesis in sarcoma, we used primary soft tissue sarcomas expressing either Braf(V600E) or Kras(G12D). We found that Braf(V600E) mutant tumours, which have increased MAPK signalling, have higher levels of mature miRNAs and enhanced miRNA processing. To investigate the relevance of oncogene-dependent alterations in miRNA biogenesis, we introduced conditional mutations in Dicer and showed that Dicer haploinsufficiency promotes the development of distant metastases in an oncogene-dependent manner. These results demonstrate that a specific oncogenic mutation can cooperate with mutation in Dicer to promote tumour progression in vivo.

Hepatitis B infection and immunity in Migrant Children and Pregnant Persons in Europe: A Systematic Review and Meta-Analysis.

BACKGROUND: The WHO's global hepatitis strategy aims to achieve viral hepatitis elimination by 2030. Migrant children and pregnant persons represent an important target group for prevention strategies. However, evidence on the burden of chronic hepatitis B (CHB) infection, and the factors affecting incidence, is lacking. METHODS: EMBASE, Global Health, Global Index Medicus, Web of Science and Medline were searched for articles in any language from 1/1/2012 to 8/6/2022. Studies reporting CHB prevalence, disease severity, complications and/or prevention strategies including vaccination, prevention of vertical transmission, and access to care/treatment in migrant children and pregnant migrants were included. Pooled estimates of CHB prevalence and Hepatitis B vaccination (HBV) coverage among migrant children were calculated using random effects meta-analysis. FINDINGS: 42 studies were included, 27 relating to migrant children and 15 to pregnant migrants across 12 European countries, involving data from 64 773 migrants. Migrants had a higher incidence of CHB than host populations. Among children, the pooled prevalence of CHB was higher for unaccompanied minors (UAM) (5%, [95% CI: 3-7%]) compared to other child migrants including internationally adopted children (IAC) and refugees (1%, [95% CI: 1-2%]). Region of origin was identified as a risk factors for CHB, with children from Africa and pregnant migrants from Africa, Eastern Europe and China at highest risk. Pooled estimates of HBV vaccine coverage were lower among UAM (12%, [95% CI: 3-21%]) compared to other child migrants (50%, [95% CI: 37-63%]). CONCLUSION: A range of modifiable determinants of HBV prevalence in migrant children and pregnant persons were identified including sub-optimal screening, prevention, and continuum of care. There is a need to develop evidence-based approaches in hepatitis care for these groups, thereby contributing towards global viral hepatitis elimination goals.

Understanding the views of adult migrants around catch-up vaccination for missed routine immunisations to define strategies to improve coverage: A UK in-depth interview study.

BACKGROUND: The World Health Organization's (WHO) Immunization Agenda 2030 emphasises ensuring equitable access to vaccination across the life course. This includes placing an emphasis on migrant populations who may have missed key childhood vaccines, doses, and boosters due to disrupted healthcare systems and the migration process, or differing vaccination schedules in home countries. Guidelines exist in the UK for offering catch-up vaccinations to adolscent and adult migrants with incomplete or uncertain vaccination status (including MMR, Td-IPV, MenACWY, HPV), but emerging evidence suggests awareness and implementation in primary care is poor. It is unclear whether patient-level barriers to uptake of catch-up vaccinations also exist. We explored experiences and views around catch-up vaccination among adult migrants from a range of backgrounds, to define strategies for improving catch-up vaccination policy and practice. METHODS: In-depth semi-structured interviews were carried out in two phases with adult migrant populations (refugees, asylum seekers, undocumented migrants, those with no recourse to public funds) on views and experiences around vaccination, involving a team of peer researchers from specific migrant communities trained through the study. In Phase 1, we conducted remote interviews with migrants resident in the UK for < 10 years, from diverse backgrounds. In Phase 2, we engaged specifically Congolese and Angolan migrants as part of a community-based participatory study. Topic guides were developed iteratively and piloted. Participants were recruited using purposive, opportunistic and snowball sampling methods. Interviews were conducted in English (interpreters offered), Lingala or French and were audio-recorded, transcribed and analysed using a thematic framework approach in NVivo 12. RESULTS: 71 participants (39 in Phase 1, 32 in Phase 2) were interviewed (Mean age 43.6 [SD:12.4] years, 69% female, mean 9.5 [SD:7] years in the UK). Aside from COVID-19 vaccines, most participants reported never having been offered vaccinations or asked about their vaccination history since arriving in the UK as adults. Few participants mentioned being offered specific catch-up vaccines (e.g. MMR/Td-IPV) when attending a healthcare facility on arrival in the UK. Vaccines such as flu vaccines, pregnancy-related or pre-travel vaccination were more commonly mentioned. In general, participants were not aware of adult catch-up vaccination but regarded it positively when it was explained. A few participants expressed concerns about side-effects, risks/inconveniences associated with access (e.g. links to immigration authorities, travel costs), preference for natural remedies, and hesitancy to engage in further vaccination campaigns due to the intensity of COVID-19 vaccination campaigns. Trust was a major factor in vaccination decisions, with distinctions noted within and between groups; some held a healthcare professional's recommendation in high regard, while others were less trusting towards the healthcare system because of negative experiences of the NHS and past experiences of discrimination, injustice and marginalisation by wider authorities. CONCLUSIONS: The major barrier to adult catch-up vaccination for missed routine immunisations and doses in migrant communities in the UK is the limited opportunities, recommendations or tailored vaccination information presented to migrants by health services. This could be improved with financial incentives for provision of catch-up vaccination in UK primary care, alongside training of healthcare professionals to support catch-up immunisation and raise awareness of existing guidelines. It will also be essential to address root causes of mistrust around vaccination, where it exists among migrants, by working closely with communities to understand their needs and meaningfully involving migrant populations in co-producing tailored information campaigns and culturally relevant interventions to improve coverage.

The immune status of migrant populations in Europe and implications for vaccine-preventable disease control: a systematic review and meta-analysis.

BACKGROUND: Ensuring vaccination coverage reaches established herd immunity thresholds (HIT) is the cornerstone of any vaccination programme. Diverse migrant populations in European countries have been associated with cases of vaccine-preventable diseases (VPD) and outbreaks, yet it is not clear to what extent they are an under-immunised group. METHODS: We did a systematic review and meta-analysis to synthesise peer-reviewed published primary research reporting data on the immune status of migrants in EU/EEA countries, the UK and Switzerland, calculating their pooled immunity coverage for measles, mumps, rubella, and diphtheria using random-effects models. We searched on Web of Science, Embase, Global Health and MEDLINE (January 1st 2000 to June 10th 2022), with no language restrictions. The protocol is registered with PROSPERO (CRD42018103666). FINDINGS: Of 1103 abstracts screened, 62 met eligibility criteria, of which 39 were included in the meta-analysis. The meta-analysis included 75 089 migrants, predominantly from outside Europe. Pooled immunity coverage among migrant populations was well below the recommended HIT for diphtheria (n = 7, 57.4% [95% CI: 43.1-71.7%] I2 = 99% vs HIT 83-86%), measles (n = 21, 83.7% [95% CI: 79.2-88.2] I2 = 99% vs HIT 93-95%), and mumps (n = 8, 67.1% [95% CI: 50.6-83.6] I2 = 99% vs HIT 88-93%), and midway for rubella (n = 29, 85.6% [95% CI: 83.1-88.1%] I2 = 99% vs HIT 83-94%), with high heterogeneity across studies. INTERPRETATION: Migrants in Europe are an under-immunised group for a range of important VPDs, with this study reinforcing the importance of engaging children, adolescents, and adults in 'catch-up' vaccination initiatives on arrival for vaccines, doses, and boosters they may have missed in their home countries. Co-designing strategies to strengthen catch-up vaccination across the life-course in under-immunised groups is an important next step if we are to meet European and global targets for VPD elimination and control and ensure vaccine equity.

Multi-infection screening for migrant patients in UK primary care: Challenges and opportunities.

Background: Migrants in Europe face a disproportionate burden of undiagnosed infection, including tuberculosis, blood-borne viruses, and parasitic infections and many belong to an under-immunised group. The European Centre for Disease Control (ECDC) has called for innovative strategies to deliver integrated multi-disease screening to migrants within primary care, yet this is poorly implemented in the UK. We did an in-depth qualitative study to understand current practice, barriers and solutions to infectious disease screening in primary care, and to seek feedback on a collaboratively developed digitalised integrated clinical decision-making tool called Health Catch UP!, which supports multi-infection screening for migrant patients. Methods: Two-phase qualitative study of UK primary healthcare professionals, in-depth semi-structured telephone-interviews were conducted. In Phase A, we conducted interviews with clinical staff (general practitioners (GPs), nurses, health-care-assistants (HCAs)); these informed data collection and analysis for phase B (administrative staff). Data were analysed iteratively, using thematic analysis. Results: In phase A, 48 clinicians were recruited (25 GPs, 15 nurses, seven HCAs, one pharmacist) and 16 administrative staff (11 Practice-Managers, five receptionists) in phase B. Respondents were positive about primary care's ability to effectively deliver infectious disease screening. However, we found current infectious disease screening lacks a standardised approach and many practices have no system for screening meaning migrant patients are not always receiving evidence-based care (i.e., NICE/ECDC/UKHSA screening guidelines). Barriers to screening were reported at patient, staff, and system-levels. Respondents reported poor implementation of existing screening initiatives (e.g., regional latent TB screening) citing overly complex pathways that required extensive administrative/clinical time and lacked financial/expert support. Solutions included patient/staff infectious disease champions, targeted training and specialist support, simplified care pathways for screening and management of positive results, and financial incentivisation. Participants responded positively to Health Catch-UP!, stating it would systematically integrate data and support clinical decision-making, increase knowledge, reduce missed screening opportunities, and normalisation of primary care-based infectious disease screening for migrants. Conclusions: Our results suggest that implementation of infectious disease screening in migrant populations is not comprehensively done in UK primary care. Primary health care professionals support the concept of innovative digital tools like Health Catch-UP! and that they could significantly improve disease detection and effective implementation of screening guidance but that they require robust testing and resourcing.

CD40 engagement of CD4+ CD40+ T cells in a neo-self antigen disease model ablates CTLA-4 expression and indirectly impacts tolerance.

Biomarkers defining pathogenic effector T (Teff) cells slowly have been forthcoming and towards this we identified CD4(+) T cells that express CD40 (CD4(+) CD40(+) ) as pathogenic in the NOD type 1 diabetes (T1D) model. CD4(+) CD40(+) T cells rapidly and efficiently transfer T1D to NOD.scid recipients. To study the origin of CD4(+) CD40(+) T cells and disease pathogenesis, we employed a dual transgenic model expressing OVA(323-339) peptide as a neo-self antigen on islet ß cells and medullary thymic epithelial cells (mTECs) and a transgenic TCR recognizing the OVA(323-339) peptide. CD4(+) CD40(+) T cells and Treg cells each recognizing the cognate neo-antigen, rather than being deleted through central tolerance, drastically expanded in the thymus. In pancreatic lymph nodes of DO11.RIPmOVA mice, CD4(+) CD40(+) T cells and Treg cells are expanded in number compared with DO11 mice and importantly, Treg cells remain functional throughout the disease process. When exposed to neo-self antigen, CD4(+) CD40(+) T cells do not express the auto-regulatory CTLA-4 molecule while naïve CD4(+) CD40(+) T cells do. DO11.RIPmOVA mice develop autoimmune-type diabetes. CD40 engagement has been shown to prevent CTLA-4 expression and injecting anti-CD40 in DO11.RIPmOVA mice significantly exacerbates disease. These data suggest a unique means by which CD4(+) CD40(+) T cells thwart tolerance.

Functional characterisation of human cells harbouring a novel t(2p;7p) translocation involving TNS3 and EXOC6B genes.

BACKGROUND: Tensin3 is an intracellular cytoskeleton-regulating protein, the loss of which is associated with increased cell motility, as has been observed in some human cancers. A novel chromosomal translocation, t(2;7)(p13;p12), present in a patient with a complex syndromic phenotype, directly involves Tensin3 (TNS3) and EXOC6B genes. This translocation could impair the expression of Tensin3 and ExoC6B proteins, and potentially produce two novel fusion transcripts. In the present study, we have investigated the expression and phenotypic features of these potential products in cultured cells from the proband. METHODS: Skin fibroblasts isolated from the proband as well as an age-matched control were grown in cell culture. Cells were used for quantitative RT-PCR, western blot and immunofluorescent confocal microscopy, which determined Tensin3 gene and protein expression. Phase-contrast and confocal microscopy additionally revealed cellular phenotype differences. A scratch wound assay monitored by live cell imaging measured cellular migration rates. RESULTS: The levels of Tensin3 at both mRNA and protein levels were lower in proband cells versus control fibroblasts. Proband cells displayed broader and shorter morphologies versus control fibroblasts, and immunofluorescent staining revealed additional Tensin3 expression along cytoskeletal filaments and the cell periphery only in control fibroblasts. In addition, proband fibroblasts showed a significantly higher migration rate than control cells over 24 h. CONCLUSIONS: The phenotypic changes observed in proband cells may arise from TNS3 haploinsufficiency, causing partial loss of full-length Tensin3 protein. These results further expose a role for Tensin3 in cytoskeletal organisation and cell motility and may also help to explain the syndromic features observed in the patient.