Abstract
Background There is limited evidence to support the current standard recurrent urinary tract infection (rUTI) definition of ≥2 UTIs within 6 months or ≥3 within 12 months. Information about reinfection risk after meeting criteria for rUTI may aid decisions on the value of prophylactic approaches.
Aim To estimate the risk of subsequent UTI associated with different rUTI definitions.
Design & setting Electronic health record study using Infections in Oxfordshire Research Database (IORD, 2008–2019) and the Clinical Practice Research Datalink Aurum (CPRD Aurum, 2010–2019).
Method We identified community-acquired UTIs, separated by 28 days, in non-pregnant women aged ≥16 years. We created candidate rUTI definitions, varying the time window from 3–9 months, and the number of UTIs required to meet the definition from 2–3 episodes. For each definition, we calculated Kaplan–Meier risk estimates of subsequent UTIs within 6 and 12 months after meeting rUTI criteria.
Results Of eligible women with at least one UTI, 18% (15 617/84 809) in IORD and 20% (334 487/1 703 088) in CPRD Aurum experienced ≥1 rUTI (current definition). The risk of at least two subsequent UTIs within 12 months after meeting the current rUTI definition rose from 17% (IORD) and 16% (CPRD Aurum) to 33% (IORD) and 32% (CPRD Aurum) under a rUTI definition of ≥3 UTIs within 6 months. Risk of subsequent UTI also increased with age.
Conclusion Risk estimates of subsequent UTIs after a rUTI vary according to the definition of rUTI adopted. Estimates provided here could support shared decision making around UTI prophylaxis and stratification of populations included in future rUTI research.
How this fits in
Recurrent urinary tract infection (rUTI) occurs frequently among women who experience urinary tract infection (UTI). Current guidelines define rUTI as ≥2 UTIs within 6 months or ≥3 within 12 months, but there is no evidence underpinning this definition, and no contemporaneous estimates of how the risk of a new UTI varies over time from an index infection. Using two different datasets, we demonstrate that the risk of a subsequent UTI was higher in women who had more UTIs in the preceding months and in older women, enabling more personalised assessment of rUTI risk. Clinicians could use these results to inform patient-focused, shared decision making around starting prophylaxis and other preventive measures.
Introduction
UTI is the most common bacterial infection managed in primary care.1 Most infections occur in women, with an incidence rate four times greater than in men,2 and there were >400 million cases globally in 2019.3 rUTI are also common4 and are associated with increased morbidity, sexual dysfunction, and negative physical and emotional impacts.5,6 UTI carries increased risk of complications such as pyelonephritis and bloodstream infection.7
Diagnostic criteria for UTI have been extensively reviewed,8 but criteria for rUTI are less evidence-based. European Association of Urology guidelines define rUTI as ‘recurrences of uncomplicated and/or complicated UTIs, with a frequency of at least three UTIs/year or two UTIs in the last six months’.9 National Institute for Health and Care Excellence (NICE) guidelines for antimicrobial prescribing for rUTI use the same definition.10 Others have also used an equivalent composite definition4,11 but some use only the first or the second part.12 No scientific justification is offered for these definitions and their clinical utility has not been assessed.
Current guidelines advise that women who have been identified as having recurrent UTI should be offered preventive management options, including long-term antibiotics, methenamine hippurate, or topical vaginal oestrogen.10 There is mostly low-quality evidence on the effectiveness of these treatment options, with effectiveness varying according to the type of treatment, duration, and study population. For instance, compared with placebo, antibiotic prophylaxis for 6–12 months significantly reduced the risk of subsequent UTIs in non-pregnant women who had experienced at least one rUTI.13 A systematic review of the use of oestrogen for subsequent UTI prevention in postmenopausal women who had experienced at least one rUTI found similar results, but these differ depending on the type and duration of oestrogen therapy.14 In general, the currently recommended strategies are associated with side effects, and, in the case of long-term antibiotics, with higher risk of antibiotic resistance.13 Although women meeting current criteria for rUTI have been demonstrated to have increased risk of experiencing multiple subsequent infections,15 we do not know which women are at greatest risk of subsequent, or frequent, recurrence. Greater understanding of how likely an individual woman with rUTI is to experience further UTIs could inform shared decision making around antibiotic prophylaxis and other preventive measures.
This study aimed to explore the relationship between a range of potential diagnostic definitions of rUTI and the risk of subsequent UTI, using primary care data from two large UK cohorts. This may enable more personalised assessment of recurrence risk to inform shared decision making about initiating prophylaxis.
Method
We performed an electronic health record study using two sources: the Infections in Oxfordshire Research Database (IORD)16 and the Clinical Practice Research Datalink (CPRD) Aurum database.17 As the two databases differ in geographical coverage and criteria for UTI coding, they were analysed separately. Table 1 compares the two databases, and the inclusion and exclusion criteria used in this study. UTI is much less common in men, is subject to different investigation and management, and may be underpinned by different aetiologies. Including men in the analysis would introduce additional heterogeneity and reduce the precision of estimates. The focus of this study was therefore on rUTI in women.
Infections in Oxfordshire Research Database
IORD is a de-identified electronic database containing microbiology and urine culture results from specimens collected in primary and secondary care, which were tested at the Oxford University Hospitals NHS Foundation Trust, serving a patient population of around 750 000. These results are linked to patient demographic data and clinical records.
We extracted all urine culture results from women aged ≥16 years between 2008 and 2019. For the primary analysis, we defined UTI as positive culture of a known uropathogen (pure or predominant growth ≥104 cfu/ml) from a sample taken in the community, or within 48 hours after hospitalisation (that is, microbiological definition because primary care clinical codes not available). A sensitivity analysis used any culture result (positive, mixed, equivocal, or negative) as indicative of possible UTI, as a request for urine culture from primary care typically indicates clinical suspicion.
We excluded urine samples taken within 28 days after hospital admission or another index urine sample (as the latter were judged likely to be related to the index infection), and samples recorded as being taken for antenatal screening.15
Clinical Practice Research Datalink Aurum
CPRD Aurum contains anonymised longitudinal routinely collected electronic patient health records from UK general practices using EMIS Web general practice patient management software. It contains the coded part of records including diagnoses, laboratory results, GP observations, and demographic information. Data quality measures include the patient ‘acceptable flag’ (a marker that identifies invalid records).18 The dataset was linked to Hospital Episode Statistics (HES) Admitted Patient Care data and the CPRD Pregnancy Register.
We used CPRD data from 2010–2019 and extracted an initial cohort of women aged ≥16 years from English general practices who were eligible for HES linkage and had at least one record containing a medical code for UTI or suspected UTI in their current practice. From consultations with these codes (Appendix A), we defined UTI as those that additionally met at least one of the criteria shown in Table 1. We used HES-linked hospitalisation dates to distinguish likely community-acquired versus hospital-acquired infections, as also described in Table 1.
UTI episodes
In observational datasets, it is not usually possible to distinguish between instances of relapse (or ‘persistence’), in which the same organism as the index infection remains detectable, and reinfection with either the same or a different species. Other studies used a 2-week threshold to distinguish between these scenarios, or required a sterile culture in the interim.19,20 Here, we consider that infections more than 28 days apart, whether caused by the same or a different species, are likely to represent different infection episodes. A 2010 study on the duration and severity of UTI episodes found that the average duration of a UTI episode was 3.3 days.21 While there is a small risk of misclassification, we expect the large majority of episodes separated by 28 days to correspond to different episodes. Previous work has shown that reducing this interval to 14 days has a minimal effect on the number of distinct episodes identified.15
Candidate new rUTI definitions
The most widely used composite rUTI definition is two UTIs within 6 months or three within 12 months. However, as it is impossible to have three UTIs in 12 months without at least two of these falling within a 6-month window, the 12-month element is redundant for defining the onset of a period of recurrent UTI (Supplementary Figure S1). We therefore term ‘two UTIs within 6 months’ the ‘base definition’ against which to benchmark other candidate definitions.
Based on input from a panel of public contributors with rUTI, we considered candidate rUTI definitions of the form ‘X episodes of UTI within Y months’. We varied the number of UTIs required to meet the definition from X = 2 episodes (base definition) to either 2 or 3 episodes, and the time window from Y = 6 months (base definition) to 3, 4, 5, 6, 7, 8, or 9 months. This creates 14 possible candidate definitions. For each dataset, the number and proportion of women meeting each rUTI definition at any time during the study period were calculated.
Performance of rUTI definitions
Input from our public contributors suggested that patients at high risk of experiencing further UTIs after being classified with rUTI are those with ≥2 subsequent UTI episodes within the next 12 months. For comparison, we also estimated the risk of ≥1 and ≥3 subsequent UTIs within 6 months and within 12 months. We planned to quantify the risk of ≥4, ≥6, and ≥8 more subsequent UTIs within 6 and 12 months, but only a small proportion of individuals experienced these numbers of UTIs in our datasets.
Statistical analysis
In both datasets, an index rUTI event for each patient, under each proposed rUTI definition, was defined as the first time within the study period at which the rUTI definition was met.
Kaplan–Meier estimates (with 95% confidence intervals) were calculated for ≥1, ≥2, and ≥3 subsequent UTIs within 6 and 12 months after first meeting the rUTI criteria, under each candidate definition, censoring patients at the end of the study period.
We quantified the extent to which rUTI definitions classified the same percentage of women as the base rUTI definition, using percentage agreement measures (overall, positive, and negative). Positive percentage agreement was defined as the percentage of women who were classified as having rUTI using a candidate new definition out of those classified as having rUTI by the base definition. Negative percentage agreement was the percentage of women who were classified as not having a rUTI using a candidate definition out of those classified as not having rUTI by the base definition. Overall percentage agreement was the percentage of women who were classified equally by the candidate and base definitions.
For each definition, analyses were also stratified by decades of age at the time of meeting the definition. Analysis was performed using Stata (version 18.0).
Results
IORD cohort
For the IORD cohort, the primary analysis included 84 809 women with one or more positive urine culture results (167 008 UTI episodes, Figure 1), of whom 15 617 (18%) met the base rUTI definition. Median age at this time was 68 years (interquartile range; IQR: 45–80 years); and women contributed median 3.7 years (IQR: 1.4–6.7 years) follow-up from their first rUTI to the end of the study. For the sensitivity analysis, 201 927 women had one or more urine cultures (positive or not), of whom 64 260 (32%) met the base rUTI definition, with median 5.1 years (IQR: 2.2–8.3 years) follow-up.
The figure is a two-column inclusion and exclusion flow chart for the IORD and CPRD Aurum cohorts. Each column shows the sequence of cohort selection steps, with boxes connected by downward arrows.In the left column, the IORD cohort starts with “About 1% of the population of England”. The next step includes 232 203 women aged 16 years or older with at least one urine culture requested between 2008 and 2019, representing 1 134 785 urine cultures. After restricting to cultures considered acceptable, community collected, and not for antenatal screening, the cohort includes 201 927 women and 697 626 urine cultures. After including only positive cultures, the cohort includes 84 809 women and 188 209 cultures. After excluding UTIs falling within 28 days, the final IORD cohort includes 84 809 women and 167,008 UTI episodes.In the right column, the CPRD Aurum cohort starts with 37 238 363 individuals eligible for linkage. The next step includes 9 850 773 eligible women with acceptable data linkage, aged 16 years or older, from 2010 to 2019. The next step includes 1 803 493 women with at least one eligible UTI consultation, based on criteria in Appendix A, representing 5 851 541 UTI consultations. After excluding non-community UTIs, the cohort includes 1 762 165 women and 5 561 038 UTI consultations. After excluding UTIs falling within pregnancy periods or outside the study period, the cohort includes 1 703 088 women and 3 937 015 UTI consultations. After excluding UTIs falling within 28 days, the final CPRD Aurum cohort includes 1 703 088 women and 3 451 034 UTI episodes.
*Urine cultures requested from primary settings or within 48 hours after an inpatient admission >28 days apart from any previous hospitalisation. Excluded: mislinked patients, patients without microbiology, catheter specimens, cultures with test results >24 hours before collection date. CPRD = Clinical Practice Research Datalink Aurum. IORD = Infections in Oxfordshire Research Database. UTI = urinary tract infection
CPRD Aurum cohort
In the CPRD Aurum cohort, 9 850 773 women had acceptable data and were eligible for HES linkage. Of these, 1 803 493 (18%) met the UTI criteria at least once. After applying additional exclusion criteria, 1 703 088 of these women remained (17% of the original cohort), contributing 3 451 034 UTI episodes (Figure 1). Of these women, 695 552 had at least two UTI episodes, and 334 487 of these met the base rUTI definition (20% of those with at least one UTI). The median age at this time was 57 years (IQR: 36–75 years), younger than the IORD cohort (Supplementary Figure S2). Women contributed median 3.4 years (IQR: 1.4–6.1 years) follow-up from their first rUTI to the end of the study.
Comparison of candidate rUTI definitions
Table 2 shows the effect of changing the rUTI definition on the percentage of women ever meeting the definition during the study period. For definitions requiring two subsequent UTI episodes, changing the timeframe from the base definition of 6 months to 3 months reduced the percentage of women meeting the definition by around one-third in both IORD (from 18% to 12%) and CPRD Aurum (from 20% to 12%) datasets. Changing the number of required UTI episodes from two to three caused a much greater reduction in the percentage meeting the definition; for example, for 6 months, from 18% to 4% in IORD and from 20% to 4% in CPRD Aurum. Changing the definition had relatively little impact on the age distribution of women classified with rUTI (Supplementary Table S1).
Figure 2 and Supplementary Table S2 show the risk of subsequent UTIs over time, following the index rUTI. More stringent rUTI definitions (three episodes rather than two; shorter time intervals) were associated with higher probability of subsequent UTIs within the following 6 or 12 months. Under the base definition, the risk of at least two subsequent UTIs within the following 12 months was 17% (IORD) and 16% (CPRD). This rose to 33% (IORD) and 32% (CPRD) under the ‘3 within 6 months’ definition. Changing the timeframe of the rUTI definition had a smaller impact on the estimated risk of subsequent UTI.
The figure is a four-panel plot comparing estimated risks of subsequent urinary tract infections after first meeting a recurrent or persistent urinary tract infection definition. The left column is labelled IORD and the right column is labelled CPRD. The top row shows estimated 6-month risk of subsequent UTIs, and the bottom row shows estimated 12-month risk of subsequent UTIs.In all panels, the x-axis is the “Time window to define rUTI”, ranging from 3 to 9. The y-axis shows risk of subsequent UTIs as a percentage, from 0% to 80%. Each point has a bar representing the corresponding 95% confidence interval. The legend compares definitions requiring either 2 or 3 UTI episodes, and outcomes of at least 1, 2, or 3 subsequent UTIs.Across both databases and both follow-up periods, estimated risk generally decreases as the time window used to define rUTI becomes longer. Risks are consistently higher for outcomes requiring at least 1 subsequent UTI than for outcomes requiring at least 2 or at least 3 subsequent UTIs. Risks are also consistently higher over 12 months than over 6 months.For the 6-month follow-up panels, the highest estimated risks are for definitions based on 3 episodes followed by at least 1 subsequent UTI. These are roughly 50% at a 3-month definition window and decrease to about 40% by a 9-month window. Estimates based on 2 episodes followed by at least 1 subsequent UTI are lower, starting at about 32% and decreasing to the high 20% range. Estimates for at least 2 subsequent UTIs are lower still, generally around 5% to 15%, and estimates for at least 3 subsequent UTIs are the lowest, generally below 5%.For the 12-month follow-up panels, the same pattern is present but risks are higher. Definitions based on 3 episodes followed by at least 1 subsequent UTI have the highest estimates, starting around 68% to 70% at a 3-month definition window and decreasing to just under 60% by a 9-month window. Definitions based on 2 episodes followed by at least 1 subsequent UTI are lower, generally declining from around 48% to the low 40% range. Estimates for at least 2 subsequent UTIs range from roughly the mid-teens to about 20%, and estimates for at least 3 subsequent UTIs are lowest, generally around 5% to 8%.The IORD and CPRD panels show broadly similar trends. CPRD estimates appear slightly smoother and generally similar to, or marginally lower than, IORD estimates for comparable definitions and outcomes.
Under the base definition, the risk of two subsequent UTIs within the following 12 months progressively increased with age among women aged >40 years in both datasets. In IORD, the risk changed from 13% in those aged 40–49 years to 21% in those aged 70–79 years, and 22% in those aged >90 years; in CPRD, from 13% to 21% to 26% in the same age groups (Figure 3). This trend was similar for the different rUTI definitions, with corresponding risks being much higher under stricter rUTI definitions across all age groups (Supplementary Tables S3–4, Supplementary Figures S3–6).
The left panel is labelled “6 months” and the right panel is labelled “12 months”. In both panels, the x-axis shows age groups: 16–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, 80–89, and ≥90 years. The y-axis shows risk of subsequent UTIs as a percentage, ranging from 0% to 80%. Each estimate is shown with a bar representing the corresponding 95% confidence interval. Three series are plotted in each panel, representing the risk of at least one, at least two, and at least three subsequent UTIs.In the 6-month panel, the risk of at least one subsequent UTI is the highest of the three outcomes and generally increases with age. The estimate is about 20% in people aged 16–19 and remains around 20% to 23% through age 40–49, then rises from about 26% at age 50–59 to about 32% at age 60–69, 33% at age 70–79, 36% at age 80–89, and about 37% in those aged ≥90.The 6-month risk of at least two subsequent UTIs is lower, increasing from roughly 3% to 5% in the younger age groups to around 6% to 8% in older age groups. The 6-month risk of at least three subsequent UTIs is lowest, remaining close to 0% to 2% across all age groups.In the 12-month panel, risks are higher than in the 6-month panel for all age groups and outcomes. The risk of at least one subsequent UTI is about 32% in people aged 16–19, about 29% in ages 20–29 and 30–39, then increases with age: about 39% at age 40–49, 41% at age 50–59, 46% at age 60–69, 50% at age 70–79, 53% at age 80–89, and approximately 55% in those aged ≥90.The 12-month risk of at least two subsequent UTIs is lower than the risk of at least one subsequent UTI but also increases with age overall. It is approximately 8% to 11% in the youngest three age groups, about 14% to 15% in ages 40–59, then rises to about 19% at age 60–69, 21% at age 70–79, and about 23% in ages 80–89 and ≥90.The 12-month risk of at least three subsequent UTIs is the lowest of the three outcomes, ranging from about 3% to 5% in younger and middle age groups and increasing to about 8% to 10% in the oldest age groups.Overall, the figure shows that the risk of subsequent UTIs after meeting the base rUTI definition increases with age, is higher over 12 months than over 6 months, and is highest for at least one subsequent UTI and lowest for at least three subsequent UTIs.
Supplementary Tables S5-7 additionally compare the proposed rUTI definitions using percentage measures, and confirm that switching from a 2-episode to a 3-episode definition had a greater impact than varying the time window between UTI episodes.
Discussion
Summary
We have demonstrated that among women meeting criteria for rUTI, more previous UTIs, UTIs that occurred closer in time, and greater age all increased the risk of additional subsequent UTI episodes. Defining rUTI as three, rather than the current two, UTIs in 6 months doubled the risk of having two UTIs in the subsequent 12 months (from 16% to 32%). The risk increased still further in the oldest age groups (under the base definition, from 13% in women aged 40–49 years to 21% in those aged 70–79 years). Our study therefore provides novel risk information that could be used to personalise treatment decisions with patients who have experienced multiple UTIs.
Strengths and limitations
This study used two large databases, and demonstrated consistent results in terms of risk estimates between them even though their demographic profile and procedures for identifying UTI cases differed. The data predated COVID-19 and so was unaffected by abrupt changes in diagnosis and prescribing caused by the pandemic.22
The lack of additional available data means that we could not contextualise the findings based on the treatment that was provided to patients once the definition of rUTI was reached. We could not capture the patients’ full UTI history before study entry, or consider adverse outcomes after rUTI that might be important to patients such as hospitalisation. The study is also subject to usual limitations of using routinely collected data, including accuracy of coding.23 The IORD dataset, using urine culture results alone, may over-represent women with more complex trajectories of infection and may also include some cases of asymptomatic bacteriuria. The CPRD Aurum dataset used only coded, rather than free-text, information fields, and so some UTI episodes may have been missed. Our analyses assumed that individuals remained ‘at-risk’ throughout the study period: some may have moved away from the area, meaning that subsequent UTIs were not ascertained. This would also bias our estimates downwards; that is, true risk would be greater.
Comparison with existing literature
The current rUTI definition, widely adopted in guidelines and research studies, is not underpinned by any epidemiological evidence. There have been no previous attempts to characterise the impact of different possible definitions of rUTI and age on the risk of subsequent UTIs. An epidemiological study using Welsh primary care electronic records found that relatively few women who met the definition for rUTI received antibiotic prophylaxis, arguing for the value of more relevant definitions based on risk of subsequent UTI.24 The increased UTI risk with increasing age found in this study aligns with their finding that prophylactic antibiotic prescribing increased with increasing age.
Implications for research and practice
Current guidelines recommend a number of prophylaxis options, including vaginal oestrogen, methenamine hippurate, and antibiotic prophylaxis.10 All are associated with potential side effects or risks, with antibiotic prophylaxis in particular being associated with potential future antibiotic resistance.25 The new information provided by this study could allow clinicians and patients to have more nuanced conversations regarding the likely benefit of prophylaxis, balancing the need to take a daily medication against the likelihood of recurrence. It could also allow clinicians to use electronic records searches to identify and approach women who may benefit most from methenamine hippurate, now that this is part of national guidance. For women considering prophylactic antibiotics, a different threshold for defining rUTI could be considered, to inform discussions balancing risk of subsequent UTI with treatment-related side effects. As more evidence emerges regarding the clinical effectiveness of antibiotic and non-antibiotic options, we envisage a decision tool that could help women understand how these treatments could modify their risk of recurrence. In research, future trials of rUTI interventions could consider using inclusion criteria appropriate for the risk profile of the intervention. The extent to which different prophylaxis approaches can modify the risk of subsequent UTI for different patient groups requires future evaluation, possibly via target trial emulation.
Notes
Funding
This research was funded by a National Institute for Health and Care Research (NIHR) Advanced fellowship awarded to G.H. MVM, TRF, and GH receive funding from the NIHR HealthTech Research Centre for Community Healthcare at Oxford Health NHS Foundation Trust. TRF receives funding from the NIHR Applied Research Collaboration Oxford and Thames Valley at Oxford Health NHS Foundation Trust. MS reports a grant from The Baily Thomas Charitable Fund. ASW is an NIHR Senior Investigator. ASW and NS are supported by the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance (NIHR200915), a partnership between the UK Health Security Agency (UKHSA) and the University of Oxford, the NIHR Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Ethical approval
IORD has approval from the South Central Research Ethics Committee (19SC/0403) and Confidentiality Advisory Group of the Health Research Authority (HRA) (19CAG0144) for research without individual patient consent. CPRD obtains annual ethics approval from the UK HRA Research Ethics Committee and Section 251 of the NHS Act 2006 regulatory support, through the HRA Confidentiality Advisory Group (CAG). These approvals allow CPRD to collect and share anonymised patient data for research purposes without needing individual patient consent.
The study obtained ethics approval through the CPRD Research Data Governance process (Protocol Number 20_174).
Provenance
Freely submitted; externally peer reviewed.
Data
The data analysed during this study may be obtained from a third party and are not publicly available. The data were obtained from the Clinical Practice Research Datalink (CPRD) and the Infections in Oxfordshire Research Database (IORD) under licence and cannot be shared by the authors. Researchers wishing to access these data should apply directly to CPRD via the Research Data Governance (RDG) process (https://www.cprd.com/) and to IORD via its research application and governance process (https://oxfordbrc.nihr.ac.uk/research-themes/modernising-medical-microbiology-and-big-infection-diagnostics/iord-about/). CPRD data are provided by patients and collected by the NHS as part of their care and support.
Acknowledgements
We are grateful to the Public and Patient Involvement members, Sandra North, Val Tate, Susannah Fraser, and Feri Ghandi, for contributing to this project.
This study is based in part on data from the Clinical Practice Research Datalink obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the NHS as part of their care and support. HES Data/ONS Data copyright © (2020), re-used with the permission of The Health & Social Care Information Centre. All rights reserved.
This work uses data provided by patients and collected by the UK’s National Health Service as part of their care and support. We thank all the people of Oxfordshire who contribute to the Infections in Oxfordshire Research Database. Research Database Team: L Butcher, H Boseley, C Crichton, DW Crook, D Eyre, O Freeman, J Gearing (community), R Harrington, K Jeffery, M Landray, A Pal, TEA Peto, TP Quan, J Robinson (community), J Sellors, B Shine, AS Walker, D Waller. Patient and Public Panel: G Blower, C Mancy, P McLoughlin, B Nichols.
Competing interests
The authors declare that no competing interests exist.
- Received October 30, 2025.
- Accepted November 11, 2025.
- Copyright © 2026, The Authors
This article is Open Access: CC BY license (https://creativecommons.org/licenses/by/4.0/)
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