Pass the tissue: restoring researcher access to legal human donations.

The sensitivity of human tissue and previous instances of misuse have, rightfully, led to the introduction of far-reaching oversight and regulatory mechanisms for accessing, storing and sharing samples. However, these restrictions, in tandem with more broad-based privacy regulations, have had the unintended consequence of obstructing legitimate requests for medical materials. This is of real detriment to ambitions for biomedical research, most notably the precision medicine agenda. As such, this paper makes the case for facilitating authorised researcher access to human tissue and associated data along practical medical ethics lines, detailing how liberating samples from unfit regulations, re-evaluating biobanks, diversifying considerations for donor benefit-risk, future proofing donor consent and flattening hierarchies of donation acceptability equate to a more cohesive and respectful means of managing biological samples and information than is achieved at present.

Defining and Risk-Stratifying Immunosuppression (the DESTINIES Study): Protocol for an Electronic Delphi Study.

BACKGROUND: Globally, there are marked inconsistencies in how immunosuppression is characterized and subdivided into clinical risk groups. This is detrimental to the precision and comparability of disease surveillance efforts-which has negative implications for the care of those who are immunosuppressed and their health outcomes. This was particularly apparent during the COVID-19 pandemic; despite collective motivation to protect these patients, conflicting clinical definitions created international rifts in how those who were immunosuppressed were monitored and managed during this period. We propose that international clinical consensus be built around the conditions that lead to immunosuppression and their gradations of severity concerning COVID-19. Such information can then be formalized into a digital phenotype to enhance disease surveillance and provide much-needed intelligence on risk-prioritizing these patients. OBJECTIVE: We aim to demonstrate how electronic Delphi objectives, methodology, and statistical approaches will help address this lack of consensus internationally and deliver a COVID-19 risk-stratified phenotype for "adult immunosuppression." METHODS: Leveraging existing evidence for heterogeneous COVID-19 outcomes in adults who are immunosuppressed, this work will recruit over 50 world-leading clinical, research, or policy experts in the area of immunology or clinical risk prioritization. After 2 rounds of clinical consensus building and 1 round of concluding debate, these panelists will confirm the medical conditions that should be classed as immunosuppressed and their differential vulnerability to COVID-19. Consensus statements on the time and dose dependencies of these risks will also be presented. This work will be conducted iteratively, with opportunities for panelists to ask clarifying questions between rounds and provide ongoing feedback to improve questionnaire items. Statistical analysis will focus on levels of agreement between responses. RESULTS: This protocol outlines a robust method for improving consensus on the definition and meaningful subdivision of adult immunosuppression concerning COVID-19. Panelist recruitment took place between April and May of 2024; the target set for over 50 panelists was achieved. The study launched at the end of May and data collection is projected to end in July 2024. CONCLUSIONS: This protocol, if fully implemented, will deliver a universally acceptable, clinically relevant, and electronic health record-compatible phenotype for adult immunosuppression. As well as having immediate value for COVID-19 resource prioritization, this exercise and its output hold prospective value for clinical decision-making across all diseases that disproportionately affect those who are immunosuppressed. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/56271.

A Profile of Influenza Vaccine Coverage for 2019-2020: Database Study of the English Primary Care Sentinel Cohort.

BACKGROUND: Innovation in seasonal influenza vaccine development has resulted in a wider range of formulations becoming available. Understanding vaccine coverage across populations including the timing of administration is important when evaluating vaccine benefits and risks. OBJECTIVE: This study aims to report the representativeness, uptake of influenza vaccines, different formulations of influenza vaccines, and timing of administration within the English Primary Care Sentinel Cohort (PCSC). METHODS: We used the PCSC of the Oxford-Royal College of General Practitioners Research and Surveillance Centre. We included patients of all ages registered with PCSC member general practices, reporting influenza vaccine coverage between September 1, 2019, and January 29, 2020. We identified influenza vaccination recipients and characterized them by age, clinical risk groups, and vaccine type. We reported the date of influenza vaccination within the PCSC by International Standard Organization (ISO) week. The representativeness of the PCSC population was compared with population data provided by the Office for National Statistics. PCSC influenza vaccine coverage was compared with published UK Health Security Agency's national data. We used paired t tests to compare populations, reported with 95% CI. RESULTS: The PCSC comprised 7,010,627 people from 693 general practices. The study population included a greater proportion of people aged 18-49 years (2,982,390/7,010,627, 42.5%; 95% CI 42.5%-42.6%) compared with the Office for National Statistics 2019 midyear population estimates (23,219,730/56,286,961, 41.3%; 95% CI 4.12%-41.3%; P<.001). People who are more deprived were underrepresented and those in the least deprived quintile were overrepresented. Within the study population, 24.7% (1,731,062/7,010,627; 95% CI 24.7%-24.7%) of people of all ages received an influenza vaccine compared with 24.2% (14,468,665/59,764,928; 95% CI 24.2%-24.2%; P<.001) in national data. The highest coverage was in people aged ≥65 years (913,695/1,264,700, 72.3%; 95% CI 72.2%-72.3%). The proportion of people in risk groups who received an influenza vaccine was also higher; for example, 69.8% (284,280/407,228; 95% CI 69.7%-70%) of people with diabetes in the PCSC received an influenza vaccine compared with 61.2% (983,727/1,607,996; 95% CI 61.1%-61.3%; P<.001) in national data. In the PCSC, vaccine type and brand information were available for 71.8% (358,365/498,923; 95% CI 71.7%-72%) of people aged 16-64 years and 81.9% (748,312/913,695; 95% CI 81.8%-82%) of people aged ≥65 years, compared with 23.6% (696,880/2,900,000) and 17.8% (1,385,888/7,700,000), respectively, of the same age groups in national data. Vaccination commenced during ISO week 35, continued until ISO week 3, and peaked during ISO week 41. The in-week peak in vaccination administration was on Saturdays. CONCLUSIONS: The PCSC's sociodemographic profile was similar to the national population and captured more data about risk groups, vaccine brands, and batches. This may reflect higher data quality. Its capabilities included reporting precise dates of administration. The PCSC is suitable for undertaking studies of influenza vaccine coverage.

Postpandemic Sentinel Surveillance of Respiratory Diseases in the Context of the World Health Organization Mosaic Framework: Protocol for a Development and Evaluation Study Involving the English Primary Care Network 2023-2024.

BACKGROUND: Prepandemic sentinel surveillance focused on improved management of winter pressures, with influenza-like illness (ILI) being the key clinical indicator. The World Health Organization (WHO) global standards for influenza surveillance include monitoring acute respiratory infection (ARI) and ILI. The WHO's mosaic framework recommends that the surveillance strategies of countries include the virological monitoring of respiratory viruses with pandemic potential such as influenza. The Oxford-Royal College of General Practitioner Research and Surveillance Centre (RSC) in collaboration with the UK Health Security Agency (UKHSA) has provided sentinel surveillance since 1967, including virology since 1993. OBJECTIVE: We aim to describe the RSC's plans for sentinel surveillance in the 2023-2024 season and evaluate these plans against the WHO mosaic framework. METHODS: Our approach, which includes patient and public involvement, contributes to surveillance objectives across all 3 domains of the mosaic framework. We will generate an ARI phenotype to enable reporting of this indicator in addition to ILI. These data will support UKHSA's sentinel surveillance, including vaccine effectiveness and burden of disease studies. The panel of virology tests analyzed in UKHSA's reference laboratory will remain unchanged, with additional plans for point-of-care testing, pneumococcus testing, and asymptomatic screening. Our sampling framework for serological surveillance will provide greater representativeness and more samples from younger people. We will create a biomedical resource that enables linkage between clinical data held in the RSC and virology data, including sequencing data, held by the UKHSA. We describe the governance framework for the RSC. RESULTS: We are co-designing our communication about data sharing and sampling, contextualized by the mosaic framework, with national and general practice patient and public involvement groups. We present our ARI digital phenotype and the key data RSC network members are requested to include in computerized medical records. We will share data with the UKHSA to report vaccine effectiveness for COVID-19 and influenza, assess the disease burden of respiratory syncytial virus, and perform syndromic surveillance. Virological surveillance will include COVID-19, influenza, respiratory syncytial virus, and other common respiratory viruses. We plan to pilot point-of-care testing for group A streptococcus, urine tests for pneumococcus, and asymptomatic testing. We will integrate test requests and results with the laboratory-computerized medical record system. A biomedical resource will enable research linking clinical data to virology data. The legal basis for the RSC's pseudonymized data extract is The Health Service (Control of Patient Information) Regulations 2002, and all nonsurveillance uses require research ethics approval. CONCLUSIONS: The RSC extended its surveillance activities to meet more but not all of the mosaic framework's objectives. We have introduced an ARI indicator. We seek to expand our surveillance scope and could do more around transmissibility and the benefits and risks of nonvaccine therapies.

Disparities in COVID-19 mortality amongst the immunosuppressed: A systematic review and meta-analysis for enhanced disease surveillance.

BACKGROUND: Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group. METHODS: We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent comparators. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755. FINDINGS: We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups. INTERPRETATION: Excess COVID-associated mortality among the immunosuppressed compared to the immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission.

A targeted approach to vaccine hesitancy.

This short communication makes the case for targeted vaccine research when attempting to counter hesitancy, especially amongst vulnerable or rarefied patient groups. Far from disincentivizing vaccination, the freedom to research and publicize the limitations of these technologies for certain groups and personalizing dosing, pacing, adjuvants, and time-sensitive alternatives in response is essential for optimizing health outcomes while neutralizing the vaccine research landscape itself. Vaccine evangelism only arouses suspicion when it is not tempered by rigorous research into differential vaccine benefit-risk in this way. That said, the long-standing politicization of vaccination-a topic vulnerable to misinterpretation and media sensationalism-along with the commercial incentives associated with universal adoption makes more comparative and critical research difficult to fund and promote in practice. Likewise, a prescriptive approach to vaccination does little to address the issues of vaccine inequality that contribute to both hesitancy and conspiracy globally and will likely prove financially prohibitive in certain markets. These obstacles are not insurmountable, however, provided that comparative research is centrally subsidized, regulations ensure that vaccine development trials explore differentiated outcomes, especially amongst high-risk or rare groups, and findings are used to prioritize global vaccine allocation to those that stand to benefit most from them.

COVID-19 vaccine effectiveness against hospitalisation and death of people in clinical risk groups during the Delta variant period: English primary care network cohort study.

BACKGROUND: COVID-19 vaccines have been shown to be highly effective against hospitalisation and death following COVID-19 infection. COVID-19 vaccine effectiveness estimates against severe endpoints among individuals with clinical conditions that place them at increased risk of critical disease are limited. METHODS: We used English primary care medical record data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre sentinel network (N > 18 million). Data were linked to the National Immunisation Management Service database, Second Generation Surveillance System for virology test data, Hospital Episode Statistics, and death registry data. We estimated adjusted vaccine effectiveness (aVE) against COVID-19 infection followed by hospitalisation and death among individuals in specific clinical risk groups using a cohort design during the delta-dominant period. We also report mortality statistics and results from our antibody surveillance in this population. FINDINGS: aVE against severe endpoints was high, 14-69d following a third dose aVE was 96.4% (95.1%-97.4%) and 97.9% (97.2%-98.4%) for clinically vulnerable people given a Vaxzevria and Comirnaty primary course respectively. Lower aVE was observed in the immunosuppressed group: 88.6% (79.1%-93.8%) and 91.9% (85.9%-95.4%) for Vaxzevria and Comirnaty respectively. Antibody levels were significantly lower among the immunosuppressed group than those not in this risk group across all vaccination types and doses. The standardised case fatality rate within 28 days of a positive test was 3.9/1000 in people not in risk groups, compared to 12.8/1000 in clinical risk groups. Waning aVE with time since 2nd dose was also demonstrated, for example, Comirnaty aVE against hospitalisation reduced from 96.0% (95.1-96.7%) 14-69days post-dose 2-82.9% (81.4-84.2%) 182days+ post-dose 2. INTERPRETATION: In all clinical risk groups high levels of vaccine effectiveness against severe endpoints were seen. Reduced vaccine effectiveness was noted among the immunosuppressed group.

The Impact of Point-of-Care Testing for Influenza on Antimicrobial Stewardship (PIAMS) in UK Primary Care: Protocol for a Mixed Methods Study.

BACKGROUND: Molecular point-of-care testing (POCT) used in primary care can inform whether a patient presenting with an acute respiratory infection has influenza. A confirmed clinical diagnosis, particularly early in the disease, could inform better antimicrobial stewardship. Social distancing and lockdowns during the COVID-19 pandemic have disturbed previous patterns of influenza infections in 2021. However, data from samples taken in the last quarter of 2022 suggest that influenza represents 36% of sentinel network positive virology, compared with 24% for respiratory syncytial virus. Problems with integration into the clinical workflow is a known barrier to incorporating technology into routine care. OBJECTIVE: This study aims to report the impact of POCT for influenza on antimicrobial prescribing in primary care. We will additionally describe severe outcomes of infection (hospitalization and mortality) and how POCT is integrated into primary care workflows. METHODS: The impact of POCT for influenza on antimicrobial stewardship (PIAMS) in UK primary care is an observational study being conducted between December 2022 and May 2023 and involving 10 practices that contribute data to the English sentinel network. Up to 1000 people who present to participating practices with respiratory symptoms will be swabbed and tested with a rapid molecular POCT analyzer in the practice. Antimicrobial prescribing and other study outcomes will be collected by linking information from the POCT analyzer with data from the patient's computerized medical record. We will collect data on how POCT is incorporated into practice using data flow diagrams, unified modeling language use case diagrams, and Business Process Modeling Notation. RESULTS: We will present the crude and adjusted odds of antimicrobial prescribing (all antibiotics and antivirals) given a POCT diagnosis of influenza, stratifying by whether individuals have a respiratory or other relevant diagnosis (eg, bronchiectasis). We will also present the rates of hospital referrals and deaths related to influenza infection in PIAMS study practices compared with a set of matched practices in the sentinel network and the rest of the network. We will describe any difference in implementation models in terms of staff involved and workflow. CONCLUSIONS: This study will generate data on the impact of POCT testing for influenza in primary care as well as help to inform about the feasibility of incorporating POCT into primary care workflows. It will inform the design of future larger studies about the effectiveness and cost-effectiveness of POCT to improve antimicrobial stewardship and any impact on severe outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46938.

Representativeness, Vaccination Uptake, and COVID-19 Clinical Outcomes 2020-2021 in the UK Oxford-Royal College of General Practitioners Research and Surveillance Network: Cohort Profile Summary.

BACKGROUND: The Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) is one of Europe's oldest sentinel systems, working with the UK Health Security Agency (UKHSA) and its predecessor bodies for 55 years. Its surveillance report now runs twice weekly, supplemented by online observatories. In addition to conducting sentinel surveillance from a nationally representative group of practices, the RSC is now also providing data for syndromic surveillance. OBJECTIVE: The aim of this study was to describe the cohort profile at the start of the 2021-2022 surveillance season and recent changes to our surveillance practice. METHODS: The RSC's pseudonymized primary care data, linked to hospital and other data, are held in the Oxford-RCGP Clinical Informatics Digital Hub, a Trusted Research Environment. We describe the RSC's cohort profile as of September 2021, divided into a Primary Care Sentinel Cohort (PCSC)-collecting virological and serological specimens-and a larger group of syndromic surveillance general practices (SSGPs). We report changes to our sampling strategy that brings the RSC into alignment with European Centre for Disease Control guidance and then compare our cohort's sociodemographic characteristics with Office for National Statistics data. We further describe influenza and COVID-19 vaccine coverage for the 2020-2021 season (week 40 of 2020 to week 39 of 2021), with the latter differentiated by vaccine brand. Finally, we report COVID-19-related outcomes in terms of hospitalization, intensive care unit (ICU) admission, and death. RESULTS: As a response to COVID-19, the RSC grew from just over 500 PCSC practices in 2019 to 1879 practices in 2021 (PCSC, n=938; SSGP, n=1203). This represents 28.6% of English general practices and 30.59% (17,299,780/56,550,136) of the population. In the reporting period, the PCSC collected >8000 virology and >23,000 serology samples. The RSC population was broadly representative of the national population in terms of age, gender, ethnicity, National Health Service Region, socioeconomic status, obesity, and smoking habit. The RSC captured vaccine coverage data for influenza (n=5.4 million) and COVID-19, reporting dose one (n=11.9 million), two (n=11 million), and three (n=0.4 million) for the latter as well as brand-specific uptake data (AstraZeneca vaccine, n=11.6 million; Pfizer, n=10.8 million; and Moderna, n=0.7 million). The median (IQR) number of COVID-19 hospitalizations and ICU admissions was 1181 (559-1559) and 115 (50-174) per week, respectively. CONCLUSIONS: The RSC is broadly representative of the national population; its PCSC is geographically representative and its SSGPs are newly supporting UKHSA syndromic surveillance efforts. The network captures vaccine coverage and has expanded from reporting primary care attendances to providing data on onward hospital outcomes and deaths. The challenge remains to increase virological and serological sampling to monitor the effectiveness and waning of all vaccines available in a timely manner.

Towards Equitable and Resilient Digital Primary Care Systems: An International Comparison and Insight for Moving Forward.

OBJECTIVE: While the COVID-19 pandemic provided a global stimulus for digital health capacity, its development has often been inequitable, short-term in planning, and lacking in health system coherence. Inclusive digital health and the development of resilient health systems are broad outcomes that require a systematic approach to achieving them. This paper from the IMIA Primary Care Informatics Working Group (WG) provides necessary first steps for the design of a digital primary care system that can support system equity and resilience. METHODS: We report on digital capability and growth in maturity in four key areas: (1) Vaccination/Prevention, (2) Disease management, (3) Surveillance, and (4) Pandemic preparedness for Australia, Canada, and the United Kingdom (data from England). Our comparison looks at seasonal influenza management prior to COVID-19 (2019-20) compared to COVID-19 (winter 2020 onwards). RESULTS: All three countries showed growth in digital maturity from the 2019-20 management of influenza to the 2020-21 year and the management of the COVID-19 pandemic. However, the degree of progress was sporadic and uneven and has led to issues of system inequity across populations. CONCLUSION: The opportunity to use the lessons learned from COVID-19 should not be wasted. A digital health infrastructure is not enough on its own to drive health system transformation and to achieve desired outcomes such as system equity and resilience. We must define specific measures to track the growth of digital maturity, including standardized and fit-for-context data that is shared accurately across the health and socioeconomic sectors.