Genetic determinants of Helicobacter pylori vacuolating cytotoxin activity

Helicobacter pylori infection is the main cause of peptic ulcer disease, and a significant risk factor for gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. A major virulence determinant is the vacuolating cytotoxin VacA, which causes cytoplasmic vacuolation, and other effects on epithelial cells. Sequence polymorphisms occur throughout vacA, the two most diverse regions being the signal region (s1 or s2) and the mid region (m1 or m2). Type s1/m1 strains are associated with toxigenicity in vitro, and greater disease risk. The published papers presented here aimed to investigate the role of vacA polymorphism on cytotoxin activity. By constructing isogenic hybrid variants of toxigenic and nontoxigenic strains, it was shown that differences within the signal region determined the vacuolating activity of the toxin, while differences in the mid-region conferred the cell-specificity of the vacuolating phenotype. These studies also led to the discovery of a new polymorphic determinant of vacuolating activity, the intermediate region, and it was shown that this region affected toxin activity in vitro, and was a better marker of gastric adenocarcinoma in an Iranian population than signal or mid-region type. Geographical variation in vacA allelic type exists, and it was shown that s1b-type strains, associated with reduced disease risk in the west, predominated in South Africa, which may have implications for the level of gastric disease in this region. The first occurrence of the rare s2/m1 vacA allele was also reported, supporting the view that vacA allelic diversity is due to recombination. Finally, VacA is an autotransporter, and possesses a single pair of cysteine residues near the C-terminus of the mature protein, spaced 11 residues apart. This feature is conserved among several autotransporters, and it is shown that these cysteines are required for high level VacA production, which may have implications for the autotransport process

Helicobacter pylori Membrane Vesicles Stimulate Innate Pro- and Anti-Inflammatory Responses and Induce Apoptosis in Jurkat T Cells

Persistent Helicobacter pylori infection induces chronic inflammation in the human gastric mucosa, which is associated with development of peptic ulceration, gastric atrophy, and gastric adenocarcinoma. It has been postulated that secretion of immunomodulatory molecules by H. pylori facilitates bacterial persistence, and membrane vesicles (MV), which have the potential to cross the gastric epithelial barrier, may mediate delivery of these molecules to host immune cells. However, bacterial MV effects on human immune cells remain largely uncharacterized to date. In the present study, we investigated the immunomodulatory effects of H. pylori MV with and without the vacuolating cytotoxin, VacA, which inhibits human T cell activity. We show a high degree of variability in the toxin content of vesicles between two H. pylori strains (SS1 and 60190). Vesicles from the more toxigenic 60190 strain contain more VacA (s1i1 type) than vesicles from the SS1 strain (s2i2 VacA), but engineering the SS1 strain to produce s1i1 VacA did not increase the toxin content of its vesicles. Vesicles from all strains tested, including a 60190 isogenic mutant null for VacA, strongly induced interleukin-10 (IL-10) and IL-6 production by human peripheral blood mononuclear cells independently of the infection status of the donor. Finally, we show that H. pylori MV induce T cell apoptosis and that this is enhanced by, but not completely dependent on, the carriage of VacA. Together, these findings suggest a role for H. pylori MV in the stimulation of innate pro- and anti-inflammatory responses and in the suppression of T cell immunity

A Role for the Vacuolating Cytotoxin, VacA, in Colonization and Helicobacter pylori-Induced Metaplasia in the Stomach

Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gas-tric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and in flammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cag PAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA+ background

Promoting influenza vaccine for children

This autumn influenza vaccine will again be offered to all 2- and 3-year-olds in general practice. In addition, all children in clinical risk groups aged 6 months and above should be offered the vaccine. Children in primary school years from reception class to year 4 will also be offered the vaccine as part of the on-going extension of influenza vaccination to healthy children. Since the start of the paediatric programme, transmission of influenza has reduced across all age groups in those parts of the country vaccinating all children of primary school age. Children under 5 years of age have the highest rate of hospital admissions for influenza. However, many parents do not think that influenza is a serious illness and it is the vaccine they are most likely to decline. Health professionals are the most trusted source of advice and information about vaccination, so staff in general practice have a crucial role to play in recommending this vaccine to parents. Health professionals are the most trusted source of advice and information about vaccination, so practice nurses have a crucial role to play in recommending the influenza vaccine to parents and increasing uptake </jats:p

Viability of investing in ecological infrastructure in South Africa’s water supply areas

Ecological infrastructure (natural ecosystems that provide important services and save on built infrastructure costs) can have an important role in securing water supply, particularly in water-scarce areas, but this importance is not reflected in investment decisions, partly due to a lack of evidence. In South Africa, one of the main threats to water supply is the proliferation of woody invasive alien plants which significantly reduce stream flow and water yields. We used existing spatial data and estimates of the impact of woody invasive plants on flows and water yields and on restoration costs to analyse the viability of investing in ecological infrastructure at the scale of major water supply areas. The analysis involved comparison of the costs and effects on water yields of catchment restoration with those of planned built infrastructure interventions designed to meet increasing water demands in the medium to long term. The cost-effectiveness analysis used the unit reference value as a measure of comparison, which is based on the discounted flows of costs and water supplied over a defined time. Restoration could supply 24% of the combined yield of planned built infrastructure interventions by 2050, and is not only cost-effective but has the added advantage of a range of co-benefits delivered by improving ecosystem health. This finding suggests that investing in ecological infrastructure should be considered ahead of new built-infrastructure projects. Significance: • Clearing invasive alien plants from South Africa’s main water catchment areas could increase water yields by 997 million m3 by 2050 relative to a business-as-usual approach, equivalent to a quarter of the yield gains through implementation of built infrastructure interventions planned over the same period. • Invasive alien plant clearing would be more cost-effective than built infrastructure interventions in all water supply systems, except one, the Orange River System. • These findings add to the growing body of literature that advocates for ecological infrastructure investments to secure hydrological ecosystem services

Localising vaccination services:Qualitative insights on public health and minority group collaborations to co-deliver coronavirus vaccines

Ethnic and religious minorities have been disproportionately affected by the SARSCoV-2 pandemic and are less likely to accept coronavirus vaccinations. Orthodox (Haredi) Jewish neighbourhoods in England experienced high incidences of SARSCoV-2 in 2020-21 and measles outbreaks (2018-19) due to suboptimal childhood vaccination coverage. The objective of our study was to explore how the COVID-19 vaccination programme (CVP) was co-delivered between public health services and an Orthodox Jewish health organisation. Methods included 28 semi-structured interviews conducted virtually with public health professionals, community welfare and religious representatives, and household members. We examined CVP delivery from the perspectives of those involved in organising services and vaccine beneficiaries. Interview data was contextualised within debates of the CVP in Orthodox (Haredi) Jewish print and social media. Thematic analysis generated five considerations: i) Prior immunisation-related collaboration with public health services carved a role for Jewish health organisations to host and promote coronavirus vaccination sessions, distribute appointments, and administer vaccines ii) Public health services maintained responsibility for training, logistics, and maintaining vaccination records; iii) The localised approach to service delivery promoted vaccination in a minority with historically suboptimal levels of coverage; iv) Co-delivery promoted trust in the CVP, though a minority of participants maintained concerns around safety; v) Provision of CVP information and stakeholders' response to situated (context-specific) challenges and concerns. Drawing on this example of CVP co-delivery, we propose that a localised approach to delivering immunisation programmes could address service provision gaps in ways that involve trusted community organisations. Localisation of vaccination services can include communication or implementation strategies, but both approaches involve consideration of investment, engagement and coordination, which are not cost-neutral. Localising vaccination services in collaboration with welfare groups raises opportunities for the on-going CVP and other immunisation programmes, and constitutes an opportunity for ethnic and religious minorities to collaborate in safeguarding community health.<br/

Developing a career and education framework for advanced clinical practice in midwifery

Introduction: This study outlines the nature of Advanced Clinical Practice in Midwifery (ACPiM), reporting on a stakeholder analysis as part of a national project to develop a career framework for advanced practice in midwifery on behalf of the National Health Service (NHS) in England. Methods: Between June and July 2022, 31 advanced practice midwives were recruited across England within the NHS settings. Convenience sampling was used to identify midwives working as advanced practitioners, and those pursuing this career route. Focus group and one-to-one interviews were conducted, recorded, and transcribed. These stakeholder data were then analyzed using a reflexive thematic approach. Results: ACP midwives were active across many professional settings. The findings resulted in three themes: Midwifery autonomy, Desire for progression, and Avenues of support. Midwifery autonomy highlighted a midwifery desire to utilize specialist skills and expert decision-making to provide holistic care directly to women and families. Desire for progression highlighted that, regardless of career stage, midwives aspired to advance their practice requiring a range of pathways to fulfil career satisfaction and meet local population health needs. Avenues of support discussed the barriers and facilitators to progression, highlighting the need for service vision, a multi-disciplinary approach to facilitate support for individuals, and strong midwifery leadership. Conclusions: Although the ACPiM role is desired by maternity institutions and organizations, midwives remain unclear about how to achieve this position, and employers remain unsure of how an ACPiM could transform services. If midwives are to successfully achieve ACPiM status, organizational support is needed to facilitate individuals drive for career progression, resulting in a strengthened workforce and improved patient experience

Co-production of an educational package for the universal human papillomavirus (HPV) vaccination programme tailored for schools with low uptake:A participatory study protocol

AIM: To co-produce with young people an educational package about the human papillomavirus (HPV) vaccine that is tailored to increase vaccine uptake in schools and populations with lower uptake. INTRODUCTION: Persistent infection with HPV can result in cancers affecting men and especially women. From September 2019, the English-schools-based HPV vaccination programme was expanded to include young men (in addition to young women) aged 12-13 years. Some young people attending schools with lower uptake of the vaccine have unmet information needs. We hypothesise that mechanisms to address information needs and increase young people's autonomy in consent procedures will result in higher uptake. METHODS AND ANALYSIS: The Medical Research Council's framework for development and evaluation of complex interventions will inform intervention development. Recruitment of young people aged 12-15 years and key stakeholders (National Health Service commissioners, school staff, immunisation nurses and youth workers/practitioners) will be facilitated through existing links with healthcare organisations, schools and youth organisations in areas with lower uptake of the HPV vaccination programme. The proposed research will comprise three phases: (1) a rapid review of adolescent immunisation materials and preliminary qualitative interviews with young people and key stakeholders, (2) theory development and co-production of HPV vaccine communication materials through an iterative process with young people and (iii) testing delivery mechanisms and acceptability of the educational package in four schools with lower uptake. ETHICS AND DISSEMINATION: The University of Bristol's Faculty of Health Sciences and London School of Hygiene and Tropical Medicine's Research Ethics Committees provided approvals for the study. A dissemination event for young people and key stakeholders and webinar with the National Immunisation Network will be organised. The study findings will be published in peer-reviewed journals and presented at conferences. Recommendations for a future larger scale study will be made

Optimising informed consent in school-based adolescent vaccination programmes in England: A multiple methods analysis.

The process of obtaining informed consent for school-based adolescent immunisation provides an opportunity to engage families. However, the fact that parental consent needs to be obtained remotely adds complexity to the process and can have a detrimental effect on vaccine uptake. We conducted a multiple methods analysis to examine the practice of obtaining informed consent in adolescent immunisation programmes. This involved a thematic analysis of consent related data from 39 interviews with immunisation managers and providers collected as part of a 2017 service evaluation of the English adolescent girls' HPV vaccine programme and a descriptive statistical analysis of data from questions related to consent included in a 2017 survey of parents' and adolescents' attitudes to adolescent vaccination. The findings indicated that the non-return of consent forms was a significant logistical challenge for immunisation teams, and some were piloting opt-out consent mechanisms, increasing the proportion of adolescents consenting for their own immunisations, and introducing electronic consent. Communicating vaccine related information to parents and schools and managing uncertainties about obtaining adolescent self-consent for vaccination were the main practical challenges encountered. Survey data showed that parents and adolescents generally agreed on vaccine decisions although only 32% of parents discussed vaccination with their teenager. Parental awareness about the option for adolescents to self-consent for vaccination was limited and adolescents favoured leaving the decision-making to parents. From the interviews and variability of consent forms it was evident that health professionals were not always clear about the best way to manage the consent process. Some were also unfamiliar with self-consent processes and lacked confidence in assessing for 'Gillick competency'. Developing pathways and related interventions to improve the logistics and practice of consent in school-based adolescent immunisation programmes could help improve uptake

Impact of a nurse‐led enhanced monitoring, management and contact tracing intervention for chronic hepatitis B in England, 2015‐2017

Around 200,000 people live with chronic hepatitis B in England. Despite national guidance on identification and management of cases and their close contacts, testing rates of close contacts is as low as 43% in high prevalence areas of London. Our study aimed to determine whether a nurse‐led enhanced management and contact tracing of chronically infected individuals improved testing uptake, vaccination and onward referral of close contacts. The study was conducted across Greater Manchester and East of England regions between October 2015 and July 2017. All HBV chronically infected individuals registered with a GP and their close contacts were eligible for recruitment. The proportion of contacts who were tested, vaccinated and referred where appropriate were compared before and after the nurse‐led intervention. Baseline and outcome information was collected using questionnaires. The intervention improved case referral rates by an additional 14% (from 86% (88/102 cases) to 99.7%; 648/650 cases). The proportion of contacts tested increased from 34% to 72%‐94% with 18 new cases of HBV diagnosed. Amongst close contacts tested, vaccination rates of at least three doses increased from 77% (43/56) to 93% (452/491) during the study. Our study has shown that nurse‐led enhanced management greatly improves identification, testing and vaccination of close contacts. The identification of new acute and chronic cases is likely to make the intervention cost effective and local health commissioners should consider providing a nurse‐led service as part of hepatitis B care pathways