Abstract
Background
Acquired carbapenemase-producing organisms (CPO), particularly acquired carbapenemase-producing Enterobacterales (CPE), pose a major public health challenge due to limited treatment options.
Objectives
To evaluate associations between CPO positivity and ethnic group, Index of Multiple Deprivation (IMD) and healthcare exposure, and to apply a statistical model to quantify these relationships.
Patients and methods
A retrospective observational analysis of CPO cases identified at a London teaching hospital (2016–2023) was conducted. Microbiological, clinical and demographic data were reviewed. Cases were classified as hospital onset healthcare associated (HOHA), community onset healthcare associated (COHA) or community onset community associated (COCA). Socioeconomic status was assessed using IMD. Positive and negative cases were compared by medical specialty, age, sex and ethnicity. Odds ratios for risk factors were estimated, and a mixed-effects logistic regression model was applied.
Results
A total of 679 CPO isolates were detected in 651 patients. OXA-48-like (56.1%) and NDM (38.9%) were the predominant carbapenemases. HOHA accounted for 42.1% of cases, COCA for 39% and COHA for 18.9%. Renal, vascular and liver specialties had the highest proportions of CPO-positive patients. Females had 0.8 times the odds of CPO positivity compared with males, and risk increased with age until mid-life. White British patients had 0.62 times the odds of CPO positivity compared with other ethnic groups. IMD analysis showed a bell-shaped distribution, with highest prevalence in mid-deprivation quintiles.
Conclusion
CPOs arise from both healthcare-associated and community pathways. Differentiating HOHA, COHA and COCA enhances understanding of local epidemiology and supports targeted infection-prevention strategies including medical specialties.
Background
Acquired carbapenemase-producing organisms (CPO) have emerged as a significant public health threat, particularly within hospital settings.1–3 These organisms produce enzymes, such as KPC, NDM, VIM, OXA-48-like and IMP, that degrade carbapenems, a class of antibiotics often considered the last line of defence against multi-drug-resistant Gram-negative bacteria, rendering them ineffective. The emergence of CPO in hospitals reflects the increasing complexity of antibiotic resistance and national guidance emphasizes local risk assessment based on prevalence, patient mix and healthcare linkages.4,5
The global rise in acquired carbapenemase-producing Enterobacterales (CPE), Acinetobacter baumannii and Pseudomonas aeruginosa is linked to increased morbidity, mortality6–9 and healthcare costs.10 In the UK, the incidence of CPO, particularly CPE, has seen a worrying rise11 with the highest reported rates of CPO in London.12 A recent national audit13 demonstrated a high incidence of CPO in our hospital. It also demonstrated variability in hospital screening strategies. London hospitals such as the Royal Free Hospital (RFH), which serve a diverse and densely populated region containing areas with high levels of deprivation and a significant number of international travellers, face unique challenges in detecting and controlling the spread of these organisms.
Socioeconomic variables such as ethnic group and the Index of Multiple Deprivation (IMD) have emerged as critical determinants in the spread of antimicrobial resistance (AMR) including CPO.14–17 Higher deprivation scores are associated with higher AMR prevalence through potential causal factors including increased household crowding and community antimicrobial use.14 A recent systematic review of the prevalence of CPE in the UK included 32 studies, of which four were conducted across healthcare and community settings; however, none reported whether the CPE were healthcare or community acquired.11
To address this knowledge gap, the data categorized cases by community or hospital healthcare association, as well as medical specialty.
Understanding risk factors including health inequalities and the community and hospital healthcare associations of cases is crucial for developing targeted infection prevention and control (IPC) and antimicrobial stewardship interventions to reduce the incidence and impact of CPO.
Patients and methods
Setting and population
Microbiological and clinical data of all confirmed CPO cases isolated at the RFH between 1 January 2016 and 31 December 2023 were included in this study. Microbiology, Epidemiology, data categorization of HOHA (hospital onset, healthcare associated), COHA (community-onset, healthcare associated), COCA (community-onset, community-associated) and statistical analysis are described in detail in Supplementary Appendix S1 (Methods) (available as Supplementary data at JAC-AMR Online).
Results
Demographic data
Between 1 January 2016 and 31 December 2023, there were 679 CPO cases arising in 651 patients. Of these cases, 407 arose in males (59.9%) and 272 in females (40.1%). The most common age group among cases was 60–69 years (Figure 1). Whereas UK Health Security Agency (UKHSA) national surveillance reports the highest population rates of CPO in individuals aged >85 years, direct comparison with age-specific rates was not possible because the current study was not population-based and did not have access to suitable denominator data.18
Figure 1.
Population pyramid of age and sex distribution of 651 cases of carbapenemase resistant organisms, from 2017 to 2023.
The predominant ethnicity stated was white (n = 272, 41.8%) followed by other ethnic groups Table 1.
Table 1.
Ethnicity of patients harbouring carbapenemase resistant organisms
| Ethnicity | Number | Percentage |
|---|---|---|
| white | 272 | 41.8 |
| unknown | 147 | 22.5 |
| Asian or Asian British | 111 | 17.1 |
| other ethnic group | 63 | 9.7 |
| black, black British, Caribbean or African | 54 | 8.3 |
Of the 463 patients who had CPO within the catchment area of the hospital, there were 42 districts with a population of 1 890 687 with CPO-positive cases accounting for 0.02% of the population.
Microbiological and clinical data
Of 679 CPO cases, the index samples by specimen type were screening samples in 567 cases (83.5%), sterile site samples in 23 cases (3.4%) and other samples including urine in 89 cases (13.1%).
Of the 679 CPO cases, 670 isolates contained single carbapenemase genes; OXA-48-like (n = 381, 56.1%), NDM (n = 264, 38.9%), KPC (n = 16, 2.4%), VIM (n = 6, 0.9%) and IMP (n = 5, 0.7%). Seven isolates contained a combination of two carbapenemase genes: NDM + OXA 48-like (n = 4, 0.6%), KPC + NDM (n = 2, 0.3%) and OXA-48-like + IMP (n = 1, 0.1%). Yearly trends show the greatest increases were of OXA-48-like cases (n = 8 to 114, increase of 1235%) followed by NDM cases (n = 20 to 74, increase of 270%) (Figure 2).
Figure 2.
Bar graph showing the yearly trends of the different carbapenemase genes. Data shown here are of individual genes, but of these isolates there were isolates containing more than one gene including NDM + OXA-48-Like 48 (n = 4), KPC + NDM (n = 2) and OXA-48-like + IMP (n = 1). Absence of a bar indicates zero detections for that carbapenemase family in that year.
The most common CPO was E. coli accounting for 40.2% of CPO detections (n = 263, most common OXA-48-like 157, NDM 102) followed by Klebsiella pneumoniae, 32.4% (n = 211, most common OXA-48-like 112, NDM 88), Enterobacter cloacae complex, 8.9% (n = 58, most common OXA-48-like 28, NDM 25), Citrobacter freundii, 7.1% (n = 46, most common OXA-48-like 34, NDM 8) and Klebsiella oxytoca, 2.6% % (n = 17, most common OXA-like 48 13, NDM 2) (Supplementary Table S1).
Analysis of healthcare associations showed that most CPO cases were HOHA cases (n = 274, 42.1%) followed by COCA cases (n = 254, 39%) and COHA cases (n = 123, 18.9%) although the predominance of HOHA and COCA cases differed by year (Figure 3).
Figure 3.
Annual numbers of deduplicated CPO isolates classified as COCA, COHA and HOHA between 2016 and 2023. Numbers displayed on bars indicate isolate counts.
The most diverse ranges of CPO genes and host organisms were identified in HOHA cases (Figure 4 and Table S2). Sixty-one percent (n = 397) of cases were classified as having a healthcare exposure (COHA or HOHA) as defined in the Patients and methods section (Table S2). Results show that HOHA cases included the widest range of organisms and carbapenemase types (including rare species such as Leclercia, Morganella, Raoultella). COCA is heavily skewed towards NDM-positive E. coli and K. pneumoniae whereas COHA sits in between, with moderate diversity. The presence of multiple carbapenemase combinations (e.g. KPC + NDM, OXA-48-like + IMP) was more frequent in HOHA cases, indicating complex resistance patterns (Table S2).
Figure 4.
Distribution of deduplicated CPO isolate counts by carbapenemase mechanism among COCA, COHA and HOHA infections between 2016 and 2023. Stacked bars represent the number of deduplicated isolates belonging to each carbapenemase family or carbapenemase combination.
The specialities to which the 651 CPO-positive patients were assigned were analysed. nephrology (n = 89, 13.7%) has the highest number of CPO-positive patients followed by vascular surgery (n = 76, 11.7%) and hepatology (n = 52, 7.8%) (Table S3). This concentration in renal, hepato-pancreato-biliary and vascular specialties may reflect the increased vulnerability of patients undergoing invasive procedures or those with complex comorbidities, highlighting the need for targeted infection prevention strategies in these high-risk groups.
Trends by deprivation
Of the 651 cases, 615 patients had information available for the MDI analysis. MDI information was not available for patients who were CPO negative. Trend analysis shows an increase of CPO incidence across all MDI categories between 2016 and 2023 (Figure 5).
Figure 5.
IMD distribution in percentiles of CPO of cases between 2016 and 2023. IMD is a measure of the relative level of disadvantage across small areas in England. The data are presented as IMD percentages, Bars represent numbers of CPO cases assigned to each IMD quintile, ranging from the 20% most deprived to the 20% least deprived neighbourhoods in England.
Figure 6 shows the detected CPO cases by IMD decile and sex between 2016 and 2023. Unlike the UKHSA national surveillance report,18 which shows a decline in CPO incidence rates from the most deprived to the least deprived decile,19 our findings demonstrate a bell-curve distribution: CPO cases increase from the most deprived to decile 5 before decreasing towards the least deprived (Figure 6).
Figure 6.
Distribution of CPO cases by sex across IMD deciles. Bars represent numbers of male and female CPO cases assigned to each IMD decile between 2016 and 2023.
Risk factors for CPO
For the statistical model analysis, a total of 57, 777 positive and negative cases (2017–2023) were available during the study period and met the criteria for sufficient numbers for the model. A total of 621 positive cases (1.26%) were therefore included in the model. The data collection period included COVID-19, which had a significant impact on the CPO and CPO proportion trends. The final model provided strong evidence supporting a concave relationship between age and the odds of CPO, which increased with age until middle age, after which the odds begin to decline. After controlling for other variables in the model, the estimated odds of CPO for females were 0.8 times the estimated odds for male and white ethnic group individuals had 0.62 times the odds of CPO compared with other ethnic groups collectively. There was insufficient evidence to support statistically significant changes in CPO odds between the COVID-19 period (2020) and the years up to 2021. Relative to 2020, the odds of CPO increased beginning in 2022, with estimated odds ratios of 1.63 in 2022 and 2.11 in 2023 (Table S4, Figure 7).
Figure 7.
Observed and model-predicted annual counts of CPO cases at the RFH from 2017 to 2023, showing the impact of COVID-19 and subsequent increase in cases post-2021. Dashed lines indicate the COVID-19 pandemic period from 2020 to 2021.
The impact of the COVID-19 pandemic in 2020 and 2021 substantially affected the relationship between CPO cases and testing volumes, introducing more low points and weakening the correlation because the percentage of positive patients was lower in 2021 compared with other years (excluding 2020). Although the Royal College of Pathologists issued guidance during the COVID-19 pandemic that permitted reduction of carbapenem-resistant Enterobacterales (CRE) screening in lower-risk settings, the local CPO screening policy at the RFH was not formally changed.20 However, adherence to screening protocols may have been affected during periods of peak operational pressure, although this was not formally monitored as resources were prioritized towards the pandemic response. When 2020 and 2021 were excluded to account for this distortion, a strong linear association was observed between CPO cases and the number of tests, with an estimated R-squared value of 96%. Each yearly increase of 1000 tests was associated with an estimated 29 additional CPO cases, equivalent to ∼2.9% positivity for every extra 1000 patients screened (Figure 8, Figure S1).
Figure 8.
Yearly number of CPO cases and number of tests (negative and positive CPO) at the Royal Free from 2016 to 2024 excluding the years 2020 and 2021.
Figure 9 shows annual trends in both the absolute number of CPO cases and the percentage of positive cases from 2017 to 2023. The impact of the COVID-19 pandemic is evident, with a sharper decline in positive CPO case percentage compared with the absolute case numbers during 2020–2021, when positivity fell to ∼1% in 2020 and <1% in 2021. After 2021, both metrics rise markedly, but the percentage of positives increases more steeply than case counts, indicating that post-pandemic recovery was accompanied by a higher proportion of CPO among tested samples.
Figure 9.
Numbers of CPO cases and CPO percentage of cases tested positive at the RFH from samples from years 2017 to 2023.
The age average and white ethnic group percentage show different patterns over time between the positive and negative CPO cases. In the negative cases, the white ethnic group shows a declining trend and average age shows a significant reduction during the COVID-19 pandemic period, after which it increases towards the pre-pandemic average. For the positive CPO cases, there is no specific trend either for the age average or the British percentage (Figure 10).
Figure 10.
British ethnicity proportion (percentage) and the patient average age at the Royal Free for the sample years 2017 to 2023 (0, CPO-negative cases; 1, CPO-positive cases).
Discussion
This study provides a comprehensive analysis of acquired CPOs within a London hospital over an 8-year period, offering valuable insights into the epidemiology of these highly resistant pathogens. The results reveal a marked increase in CPO cases, particularly those involving OXA-48-like and NDM carbapenemases, which are consistent with national trends.
A predominance of HOHA and COHA cases (61% of positive cases, combined) was found that underscores the significant role the hospital environment plays in the propagation of these resistant organisms. This finding reinforces the importance of prioritizing screening of patients with healthcare contact, as these individuals are at risk of acquiring CPO during hospital stays, making targeted swabbing in high-risk wards and after previous or during prolonged admissions a key strategy for early detection and containment.
The significant proportion of COHA cases (18.9%) highlights the risk of healthcare-associated transmission that becomes apparent only after discharge, underscoring the need for continued vigilance and potentially extended follow-up care to prevent further spread. This aligns with a previous study, which reported a notable percentage of CRE cases as COHA, reinforcing that cases and infections can occur beyond the hospital stay.21 At the same time, the occurrence of COCA cases (39%) suggests that community transmission of CPOs is an emerging threat, requiring broader public health interventions outside hospital settings. A scoping review similarly emphasized the importance of distinguishing between hospital-acquired and community-onset infections for effective surveillance and control strategies.22 These findings underscore the need for tailored infection control strategies that consider the specific onset categories to effectively mitigate the spread of CPOs. A limitation of this study is that healthcare exposure was assessed using RFH admissions only; therefore, some cases classified as COCA may have had recent healthcare contact at other institutions and may have been misclassified as COHA.
There was a notable difference in organism diversity across acquisition categories: HOHA cases exhibited the greatest diversity of species and resistance mechanisms, followed by COHA, while COCA cases were dominated by fewer species, primarily Escherichia coli and Klebsiella pneumoniae. This suggests that hospital-onset infections may involve more complex microbiological profiles, potentially reflecting prolonged exposure to healthcare environments and selective pressures.
The observed decline in average age among CPO-negative cases during the pandemic may partly explain the reduction in CPO detection, as younger patients—who are less likely to carry CPO—were more frequently screened, while older, higher-risk patients were less likely to be admitted or tested. Similarly, peaks in British ethnicity among negatives during 2020 Q3–Q4 and 2021 Q2 could reflect fewer non-British patients presenting for care, possibly due to reduced elective admission activity or travel restrictions. For positive cases, the lack of a clear trend suggests that pandemic-related changes in hospital services, reduced social mixing and travel limitations may have influenced patient demographics without substantially altering the underlying risk profile for CPO acquisition. The finding that British ethnic group individuals had 0.62 times the odds of CPO compared with other ethnic groups collectively suggests that the observed increase in CPO prevalence may be partly related to a decreasing proportion of tests conducted among British ethnic group individuals over time, reinforcing the importance of demographic context in interpreting prevalence trends. In addition, changes to the hospital screening programme over the study period are likely to have influenced case ascertainment. Screening eligibility expanded beyond critical care and established high-risk specialties to include additional patient groups over time. Consequently, some of the observed increase in CPO detections may reflect enhanced screening coverage in addition to underlying changes in CPO epidemiology.
The predominance of OXA-48-like and NDM carbapenemases in our cohort is also consistent with contemporary global epidemiology. Internationally, the dissemination of CPOs has been driven by the expansion of successful epidemic clones and the horizontal transfer of resistance plasmids, with OXA-48-like, NDM, KPC, VIM and IMP enzymes now established across multiple regions worldwide. As a major international city, London serves a highly diverse population and functions as a global travel hub; therefore, the epidemiology observed at our institution is likely to reflect a combination of endemic UK transmission and imported CPOs associated with international travel, healthcare exposure abroad and medical tourism. This is particularly relevant for patients with links to regions where CPOs are highly endemic, including the Indian subcontinent and parts of Europe, Africa and the Middle East. The predominance of OXA-48-like and NDM carbapenemases and the substantial proportion of community-associated cases observed in this study are consistent with the increasing global dissemination of CPO between healthcare and community settings.23
Specialties at increased risk
Analysis of patient specialties revealed that CPO-positive cases were concentrated in certain clinical areas, with nephrology accounting for the highest proportion (13.7%), followed by vascular surgery (11.7%) and hepatology (7.8%). This distribution probably reflects the increased vulnerability of patients in these specialties, who often undergo invasive procedures, require indwelling devices or experience prolonged hospital stays: factors known to elevate the risk of acquiring multidrug-resistant organisms. Nephrology units, for instance, showed the highest number of CPO-positive patients, which is consistent with findings from Zhang et al., who reported that kidney transplant recipients are particularly susceptible to carbapenem-resistant Klebsiella pneumoniae infections, especially after the first month post-transplantation.24
Similarly, vascular surgery may be associated with increased risk of acquired CPE acquisition due to extensive use of indwelling medical devices and procedural complexity. The routine use of vascular grafts, intravascular catheters and surgical drains is a well-established risk factor for colonization and infection with carbapenem-resistant organisms. A systematic review and meta-analysis demonstrated that the presence of medical devices is associated with a significantly increased risk of carbapenem-resistant Pseudomonas aeruginosa infection, highlighting the role of device-related exposure in facilitating acquisition of carbapenem-resistant pathogens.25
Liver units, particularly those managing liver transplant patients, also exhibit higher CPO infection rates. Patients undergoing liver transplantation are at elevated risk due to factors such as immunosuppression, invasive procedures and prolonged hospitalization. A review by Righi discussed the increased susceptibility of liver transplant recipients to multidrug-resistant infections, including carbapenem-resistant organisms.26
Importantly, the sampling strategy was deliberately focused on high-risk specialties, which indicates that targeted screening in these areas is both warranted and effective in proactively identifying CPO carriers. Such findings reinforce the need for sustained surveillance and tailored infection prevention measures in high-risk units such as renal and vascular units, as well as liver services, to mitigate transmission and protect vulnerable patient populations.
Impact of deprivation on CPO distribution
The analysis of CPO cases in relation to the IMD revealed a complex pattern, with infections peaking in patients from middle IMD quintiles rather than following the expected trend of higher rates in the most deprived areas. This bell-curve distribution suggests that the relationship between socioeconomic status and CPO infection risk may be more intricate than previously understood. Factors such as healthcare access, comorbidities and differences in healthcare-seeking behaviour could influence this pattern. A study by Alividza et al. highlighted that poverty increases the risk of contracting infectious diseases and therefore exposure to antibiotics, yet there is lacking evidence on the relationship between income and non-income dimensions of poverty and antimicrobial resistance (AMR).17
Further research is needed to fully understand these dynamics and to develop targeted interventions that address the social determinants of health in the context of AMR. The English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) report 2023 to 2024 indicates that deprivation is a significant factor influencing the burden of antibiotic-resistant infections, including CPOs.27 The report notes that the rates of reported CPOs from all clinical sites per 100 000 population doubled since 2021, with absolute numbers of episodes reported across all sample groups having increased. Thirty-day all-cause mortality in the context of a CPO infection from a sterile site was 22.9% in 2023.27
Understanding the complex interplay between socioeconomic factors and CPO distribution is crucial for implementing effective public health strategies. Targeted interventions that consider the social determinants of health can help mitigate the spread of antimicrobial-resistant infections and reduce health inequalities.
Current national guidance recommends risk-based screening for acquired CPE, including consideration of local epidemiology, patient acuity, and level of interventions (e.g. long-term ventilation, rehabilitation facilities).4 Although age >65 years is highlighted as a key risk factor in national reports,18 our findings from a London teaching hospital indicate that applying age-based screening alone would miss a substantial proportion of CPO cases. In this setting, epidemiology and risk factors differed markedly from national trends, with atypical patterns in age, ethnicity, IMD and medical specialty distribution. These results underscore that screening strategies should not only vary by region but also incorporate local risk profiles as part of local risk assessments. This approach aligns with the UKHSA framework, emphasizing targeted screening where risk is greatest, and highlights the need for dynamic, context-sensitive strategies to effectively contain CPO transmission.
Conclusion and future directions
Overall, this study highlights the increasing burden of CPOs in hospital and community settings, the importance of understanding infection onset categories and the need for the consideration of targeted interventions in high-risk hospital specialties. The application of categorization of infections into HOHA, COHA and COCA, as well as the identification of demographic factors and specific specialties at increased risk, offers new insights that can inform infection prevention strategies. Future research should continue to explore these areas, particularly the impact of socioeconomic factors on CPO distribution and the effectiveness of targeted interventions in hospitals and the community.
Supplementary Material
Acknowledgements
The NIHR Health Protection Research Unit (HPRU) in Healthcare Associated Infections and Antimicrobial Resistance (AMR) is a partnership between UK Health Security Agency (UKHSA) and the University of Oxford in collaboration with the University of Leeds, Animal and Plant Health Agency and European Bioinformatics Institute.
We gratefully acknowledge the microbiology laboratory staff for their diligent work in processing and confirming CPO isolates, and the Infection Prevention and Control (IPC) team for their essential role in implementing follow-up measures to contain transmission.
Contributor Information
Marie Anne Chattaway, Department of Microbiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London, UK; Gastrointestinal Bacteria Reference Unit, United Kingdom Health Security Agency, Colindale, London, UK; NIHR Health Protection Research Unit (HPRU) in Healthcare Associated Infections and Antimicrobial Resistance (AMR), University of Oxford, Oxford, UK.
Ayoub Saei, Statistical Unit, United Kingdom Health Security Agency, Colindale, London, UK.
David Ho, Infection Prevention and Control Services, Royal Free London NHS Foundation Trust, Pond Street, London, UK.
Jelena Heaphy, Infection Prevention and Control Services, Royal Free London NHS Foundation Trust, Pond Street, London, UK.
Vicky Pang, Infection Prevention and Control Services, Royal Free London NHS Foundation Trust, Pond Street, London, UK.
Rebecca Lester, Department of Microbiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London, UK; Antimicrobial Resistance & Healthcare Associated Infections, United Kingdom Health Security Agency, Colindale, London, UK; Division of Infection and Immunity, University College London, London, UK.
Damien J F Mack, Department of Microbiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London, UK.
Funding
No specific funding was received for this work. Data were generated as part of the routine work of the Royal Free London NHS Foundation Trust. MAC received funding from National School of HealthCare Science as part of the Higher Specialist Scientist Training Programme.
Marie Chattaway is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Gastrointestinal Infections at University of Norwich and Public Health Genomics at University of Birmingham in partnership with United Kingdom Health Security Agency, in collaboration with University of Newcastle, and are based at UKHSA. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health and Social Care or UKHSA.
Transparency declarations
All authors: none to declare.
Ethical considerations
This study was conducted as a retrospective analysis of routinely collected clinical and microbiological data within the NHS. All data were fully anonymized prior to analysis and handled in accordance with local information governance and data protection requirements. Under the UK Health Research Authority decision tools, Research Ethics Committee review was not required for this activity because it involved secondary analysis of routinely collected anonymized clinical data. The Trust is permitted to process such data for infection prevention, public health surveillance and service evaluation purposes under applicable NHS governance arrangements.
Data availability
All data used in this study were collected as part of routine NHS clinical care and are not publicly available due to patient confidentiality. Anonymized aggregated data may be available from the corresponding author on reasonable request.
Supplementary data
Appendix S1, Figure S1 and Tables S1–S4 are available as Supplementary data at JAC-AMR Online.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data used in this study were collected as part of routine NHS clinical care and are not publicly available due to patient confidentiality. Anonymized aggregated data may be available from the corresponding author on reasonable request.