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Pertussis vaccines have been effective at reducing pertussis-associated morbidity and mortality. However, they have a complex array of limitations, particularly associated with the duration of protection against clinical disease and imperfect immunity (carriage and transmission). Little is known about risk factors for pertussis vaccination failure. Understanding pertussis vaccination failure risk is most important in the paediatric population. This study aims to investigate risk factors for pertussis vaccination failure in (1) infants between birth and six weeks of age born to mothers who received pertussis booster vaccinations during pregnancy and (2) infants after the completion of the primary series (approximately five months old) to four years old. This will be achieved in a two-step process for each study group. Pertussis vaccination failure cases will first be described using a case series study design, relevant case characteristics will be sourced from six national administrative datasets. The case series study results will help select candidate risk factors (hypothesis generating step) to be tested in the retrospective cohort study (hypothesis testing step). Pattern analysis will be used to investigate risk factor patterns in the cohort study. The identification of higher risk groups enables targeting strategies, such as additional doses, to better prevent pertussis disease.

Abstract Background Rapid timescales for the design and delivery of research were common during the COVID-19 pandemic. The recruitment and retention of healthcare workers (HCWs) as participants in research studies are notoriously challenging, but this was exacerbated during the pandemic by the unprecedented demand placed on the workforce. The SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN study) is a prospective multicentre cohort study following HCWs in the UK. This paper discusses the strategies and challenges associated with recruitment and retention of HCW participants in Scotland. Methods There were 44,546 HCWs recruited to the SIREN study, of whom 6,285 were recruited by research teams at ten different research sites in Scotland between October 2020 and March 2021. Information on target and actual sample size, availability of resource, recruitment rate, and recruitment and engagement strategies by site was collated from SIREN study documentation and discussions with local key SIREN site staff. Individual-level data from 6,153 HCW participants with ongoing consent for all data usage were also collated, including socio-demographic data and information on withdrawal (in first year) and opt-in to a study extension after one year. Factors associated with these outcomes were explored in logistic regression analyses. Results Different recruitment strategies were used in each site according to local agreements, protocol and staff capacity, with the recruitment period ranging from 13 to 160 days. The locally-agreed recruitment target was met in four sites. The proportion of participants who withdrew in the first year ranged from 3.1 to 24.8% by site, while subsequent opt-in to a 12-month study extension ranged from 28.6 to 74.8%. The sites with the highest proportions of withdrawals were the same four sites with lowest proportions of opt-in. On an individual level, there was a lower level of retention among younger participants, and those from lower socio-economic backgrounds and minority ethnic groups. Conclusions Site-specific factors including research-readiness likely had a significant influence on recruitment and retention, more so than the specific recruitment or retention strategies employed. Independent of site factors, individual-level variables influenced recruitment and retention, suggesting targeted strategies may be needed to promote research engagement among particular socio-demographic groups.

Abstract Background Participant involvement in research studies is not a new concept, yet barriers to implementation remain and application varies. This is particularly true for pandemic response research studies, where timeframes are condensed, pressure is high and the value and inclusion of participant involvement can be overlooked. The SIREN Participant Involvement Panel (PIP) provides a case study for participant involvement in pandemic research, working in partnership with people who the research is for and about. Methods SIREN and the British Society for Immunology (BSI) recruited and ran two phases of the PIP, involving 15 members in total over a 16-month period. Phase 1 ran between January and August 2022 and Phase 2 between October 2022 and March 2023. Activity figures including recruitment interest and PIP meeting attendance were recorded. To evaluate how the PIP has influenced SIREN, feedback was collected from (a) researchers presenting at the PIP and (b) PIP members themselves. Evaluation at the end of Phase 1 informed our approach to Phase 2. Thematic grouping was planned to identify key lessons learned. Results Applications increased from n = 30 to n = 485 between Phase 1 and Phase 2 of the PIP, a more than 15-fold increase. The SIREN PIP positively impacted the design, implementation and evaluation phases of the study and sub-studies. Feedback from PIP members themselves was positive, with members highlighting that they found the role rewarding and felt valued. Learnings from the PIP have been condensed into five key themes for applying to future pandemic response research studies: the importance of dedicated resources; recruiting the right panel; understanding motivations for participant involvement; providing flexible options for involvement and enabling the early involvement of participants. Conclusions The SIREN PIP has demonstrated the value of actively involving people who research is for and about. The PIP has provided an active feedback mechanism for research and demonstrated a positive influence on both SIREN study researchers and PIP members themselves. This paper makes the case for participant involvement in future pandemic research studies. Future work should include improved training for researchers and we would support the development of a national PIP forum as part of future pandemic research preparedness.

Alzheimer’s disease (AD), characterized by memory loss and cognitive decline, affects nearly 50 million people worldwide. Amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) of phosphorylated Tau protein (pTau) are key histopathological features of the disease in the brain, and recent advances have also identified AD histopathology in the retina. Thus, the retina represents a central nervous system (CNS) tissue highly amenable to non-invasive diagnostic imaging that shows promise as a biomarker for early AD. Given the devastating effects of AD on patients, their families, and society, new treatment modalities that can significantly alter the disease course are urgently needed. In this study, we have developed and characterized a novel human retinal organoid (RO) model derived from induced pluripotent stem cells (iPSCs) from patients with familial AD due to mutations in the amyloid precursor protein gene (APP). Using immunofluorescence and histological staining, we evaluated the cellular composition and AD histopathological features of AD-ROs compared to control ROs from healthy individuals. We found that AD-ROs largely resemble their healthy control counterparts in cellular composition but display increased levels of Aβ and pTau. We also present proof of principle of an assay to quantify amyloid levels in whole ROs. This in vitro model of the human AD retina constitutes a new tool for drug screening, biomarker discovery, and pathophysiological studies.

Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Since June 2020, the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study has conducted routine PCR testing in UK healthcare workers and sequenced PCR-positive samples. SIREN detected increases in infections and reinfections and detected Omicron subvariant emergence contemporaneous with national surveillance. SIREN methodology can be used for variant surveillance.

Depression is a prevalent and debilitating mental health condition that poses significant challenges for healthcare providers, researchers, and policymakers. The diagnostic coding specificity of depression is crucial for improving patient care, resource allocation, and health outcomes. We propose a novel approach to assess risk-adjusted coding specificity for individuals diagnosed with depression using a vast cohort of over one million inpatient hospitalizations in the United States. Considering various clinical, demographic, and socioeconomic characteristics, we develop a risk-adjusted model that assesses diagnostic coding specificity. Results demonstrate that risk-adjustment is necessary and useful to explain variability in the coding specificity of principal (AUC = 0.76) and secondary (AUC = 0.69) diagnoses. Our approach combines a multivariate logistic regression at the patient hospitalization level to extract risk-adjusted probabilities of specificity with a Poisson Binomial approach at the facility level. This method can be used to identify healthcare facilities that over- and under-specify diagnostic coding when compared to peer-defined standards of practice.

BackgroundChildren under 18 years of age account for approximately 1 in 3 internet users worldwide. Largely unregulated, the internet-based world is evolving rapidly and becoming increasingly intrusive. There is a dearth of objective research globally on children’s real-time experiences of the internet-based world. ObjectiveThis paper reports an objective methodology to study the nature and extent of children’s internet-based world, their engagement with it, and how this impacts their health and well-being. MethodsA total of 180 year 8 students from 12 schools will be recruited into the study within the Wellington region of Aotearoa, New Zealand. Children use Zoom video teleconferencing software to record real-time, screen-shared internet-based content, for 4 consecutive days. Data on demographics, health and well-being, and attitudes and perceived behaviors in relation to the internet-based world are collected. Phone screen-time balances are retrieved. Data collection commenced in June 2021 and is anticipated to be completed in 2023. ResultsRecordings show children exploring diverse web-based settings and content, including personalized content curated by algorithms on platforms such as TikTok, YouTube, and Instagram. Preliminary analysis shows that the data can be used to study a wide range of topics. Behavioral Observation Research Interaction Software is being used to manually code recordings. Artificial Intelligence techniques are also being applied, including hashtag extraction, optical character recognition, as well as object, pattern, speech, and lyric recognition. ConclusionsThis novel methodology reveals the unique internet-based experiences of children. It is underpinned by a commitment to ensuring that their rights are protected. It seeks to provide concrete evidence on internet usage in this group and to facilitate appropriate political and societal action to effectively regulate the internet-based world to prevent harm to children. International Registered Report Identifier (IRRID)DERR1-10.2196/39017

The degree to which Open Educational Resources (OER) reflect the values of its institutional provider depends on questions of economics and the level of support amongst its academics. For project managers establishing OER repositories, the latter question - how to cultivate, nurture and maintain academic engagement - is critical. Whilst participating in the HEFCE funded institutional OER programme (2009-10), the team at the University of Exeter encountered a range of academic opinions on OER, and followed many as they rode the peaks and troughs of opportunities and challenges that this kind of work entails. This paper discusses the potential motivators for academics in providing OER material, as an understanding of these is helpful when introducing the subject to new contributors, and when informing planning decisions - both procedural and financial - so that key incentives are protected. We will also look at the reasons for some academic scepticism surrounding OER and how these views can be - if not tempered - then at least understood with a view to informing future policy.The enthusiastic advocacy that some academics possess in relation to OER is borne of their vision of its use. It is important to ensure that the high priority objective of obtaining academic support does not overlook instances where there is tension between this vision, and what can be achieved with available resources. We will discuss the key information that OER managers need in order to mitigate this scenario. OER projects do not work in isolation from internal competition and it has been essential to be sensitive to the conflicting pressures that academics have to contend with in their work profile. We will discuss the value of establishing where an OER project sits within an institution’s educational and research strategies, and its financial framework, the questions to ask and the signs to spot to obtain this information, and how managers can use this knowledge to make decisions, avoid pitfalls and garner support. This will involve addressing academic initiatives and reward schemes, including a discussion of how IPR and copyright can not only present challenges but also play an important role in motivating and demonstrating academic engagement. This paper draws upon formal and informal engagement with a range of stakeholders who have been involved in the project, including the many colleagues who attended several staff development sessions.