Ovarian cancer symptoms in pre-clinical invasive epithelial ovarian cancer - An exploratory analysis nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

OBJECTIVE: UKCTOCS provides an opportunity to explore symptoms in preclinical invasive epithelial ovarian cancer (iEOC). We report on symptoms in women with pre-clinical (screen-detected) cancers (PC) compared to clinically diagnosed (CD) cancers. METHODS: In UKCTOCS, 202638 postmenopausal women, aged 50-74 were randomly allocated (April 17, 2001-September 29, 2005) 2:1:1 to no screening or annual screening till Dec 31,2011, using a multimodal or ultrasound strategy. Follow-up was through national registries. An outcomes committee adjudicated on OC diagnosis, histotype, stage. Eligible women were those diagnosed with iEOC at primary censorship (Dec 31, 2014). Symptom details were extracted from trial clinical-assessment forms and medical records. Descriptive statistics were used to compare symptoms in PC versus CD women with early (I/II) and advanced (III/IV/unable to stage) stage high-grade-serous (HGSC) cancer. ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. RESULTS: 1133 (286PC; 847CD) women developed iEOC. Median age (years) at diagnosis was earlier in PC compared to CD (66.8PC, 68.7CD, p = 0.0001) group. In the PC group, 48% (112/234; 90%, 660/730CD) reported symptoms when questioned. Half PC (50%, 13/26PC; 36%, 29/80CD; p = 0.213) women with symptomatic HGSC had >1symptom, with abdominal symptoms most common, both in early (62%, 16/26, PC; 53% 42/80, CD; p = 0.421) and advanced (57%, 49/86, PC; 74%, 431/580, CD; p = 0.001) stages. In symptomatic early-stage HGSC, compared to CD, PC women reported more gastrointestinal (change in bowel habits and dyspepsia) (35%, 9/26PC; 9%, 7/80CD; p = 0.001) and systemic (mostly lethargy/tiredness) (27%, 7/26PC; 9%, 7/80CD; p = 0.017) symptoms. CONCLUSIONS: Our findings, add to the growing evidence, that we should reconsider what constitutes alert symptoms for early tubo-ovarian cancer. We need a more nuanced complex of key symptoms which is then evaluated and refined in a prospective trial.

Insights from UKCTOCS for design, conduct and analyses of large randomised controlled trials.

Abstract: Randomised controlled trials are challenging to deliver. There is a constant need to review and refine recruitment and implementation strategies if they are to be completed on time and within budget. We present the strategies adopted in the United Kingdom Collaborative Trial of Ovarian Cancer Screening, one of the largest individually randomised controlled trials in the world. The trial recruited over 202,000 women (2001-5) and delivered over 670,000 annual screens (2001-11) and over 3 million women-years of follow-up (2001-20). Key to the successful completion were the involvement of senior investigators in the day-to-day running of the trial, proactive trial management and willingness to innovate and use technology. Our underlying ethos was that trial participants should always be at the centre of all our processes. We ensured that they were able to contact either the site or the coordinating centre teams for clarifications about their results, for follow-up and for rescheduling of appointments. To facilitate this, we shared personal identifiers (with consent) with both teams and had dedicated reception staff at both site and coordinating centre. Key aspects were a comprehensive online trial management system which included an electronic data capture system (resulting in an almost paperless trial), biobanking, monitoring and project management modules. The automation of algorithms (to ascertain eligibility and classify results and ensuing actions) and processes (scheduling of appointments, printing of letters, etc.) ensured the protocol was closely followed and timelines were met. Significant engagement with participants ensured retention and low rates of complaints. Our solutions to the design, conduct and analyses issues we faced are highly relevant, given the renewed focus on trials for early detection of cancer. Future work: There is a pressing need to increase the evidence base to support decision making about all aspects of trial methodology. Trial registration: ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/46/01. The long-term follow-up UKCTOCS (2015 20) was supported by National Institute for Health and Care Research (NIHR HTA grant 16/46/01), Cancer Research UK, and The Eve Appeal. UKCTOCS (2001-14) was funded by the MRC (G9901012 and G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. Researchers at UCL were supported by the NIHR UCL Hospitals Biomedical Research Centre and by the MRC Clinical Trials Unit at UCL core funding (MC_UU_00004/09, MC_UU_00004/08, MC_UU_00004/07). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health and Social Care.

Randomised controlled trials help us decide whether new health-care approaches are better than those in current use. To successfully complete these on time and within budget, there is a constant need to review and revise the procedures used for delivering various aspects such as invitation, enrolment, follow-up of participants, delivery of the new test, data collection, and analysis. We report on the processes used in the United Kingdom Collaborative Trial of Ovarian Cancer Screening, one of the largest such trials. The United Kingdom Collaborative Trial of Ovarian Cancer Screening enrolled over 202,000 women (2001­5), delivered over 670,000 yearly screens (2001­11) and followed all participants until 2020. Key to our successful completion were the involvement of senior investigators in day-to-day running of the trial, a pre-emptive approach to issues, a willingness to innovate, and the use of technology. Our underlying ethos was that trial participants should always be at the centre of all our processes. We ensured that they were able to always contact either their local or the central team for clarifications and rescheduling of appointments. To facilitate this, we shared participant contact details (with consent) with both teams. We built a comprehensive electronic system to manage all aspects of the trial. This included online forms that the teams completed in real time (resulting in an almost paperless trial) and systems to check and manage trial processes and track blood samples. We automated key steps such as checking whether participants were eligible, assigning correct action based on results of screening tests, scheduling appointments and printing letters. As a result, all participants were treated as set out in the trial plan. Our engagement with participants ensured that they continued participating and we had a low rate of complaints. We faced issues with regard to our initial trial design and the way we planned to analyse the data. We feel that our solutions are highly relevant, especially as there is a renewed focus on trials for early detection of cancer.

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial.

BACKGROUND: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. METHODS: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]). INTERPRETATION: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. FUNDING: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.

Mortality impact, risks, and benefits of general population screening for ovarian cancer: the UKCTOCS randomised controlled trial.

Background: Ovarian and tubal cancers are lethal gynaecological cancers, with over 50% of the patients diagnosed at advanced stage. Trial design: Randomised controlled trial involving 27 primary care trusts adjacent to 13 trial centres based at NHS Trusts in England, Wales and Northern Ireland. Methods: Postmenopausal average-risk women, aged 50-74, with intact ovaries and no previous ovarian or current non-ovarian cancer. Interventions: One of two annual screening strategies: (1) multimodal screening (MMS) using a longitudinal CA125 algorithm with repeat CA125 testing and transvaginal scan (TVS) as second line test (2) ultrasound screening (USS) using TVS alone with repeat scan to confirm any abnormality. The control (C) group had no screening. Follow-up was through linkage to national registries, postal follow-up questionnaires and direct communication with trial centres and participants. Objective: To assess comprehensively risks and benefits of ovarian cancer screening in the general population. Outcome: Primary outcome was death due to ovarian or tubal cancer as assigned by an independent outcomes review committee. Secondary outcomes included incidence and stage at diagnosis of ovarian and tubal cancer, compliance, performance characteristics, harms and cost-effectiveness of the two screening strategies and a bioresource for future research. Randomisation: The trial management system confirmed eligibility and randomly allocated participants using computer-generated random numbers to MMS, USS and C groups in a 1:1:2 ratio. Blinding: Investigators and participants were unblinded and outcomes review committee was masked to randomisation group. Analyses: Primary analyses were by intention to screen, comparing separately MMS and USS with C using the Versatile test. Results: 1,243,282 women were invited and 205,090 attended for recruitment between April 2001 and September 2005. Randomised: 202,638 women: 50,640 MMS, 50,639 USS and 101,359 C group. Numbers analysed for primary outcome: 202,562 (>99.9%): 50,625 (>99.9%) MMS, 50,623 (>99.9%) USS, and 101,314 (>99.9%) C group. Outcome: Women in MMS and USS groups underwent 345,570 and 327,775 annual screens between randomisation and 31 December 2011. At median follow-up of 16.3 (IQR 15.1-17.3) years, 2055 women developed ovarian or tubal cancer: 522 (1.0% of 50,625) MMS, 517 (1.0% of 50,623) USS, and 1016 (1.0% of 101314) in C group. Compared to the C group, in the MMS group, the incidence of Stage I/II disease was 39.2% (95% CI 16.1 to 66.9) higher and stage III/IV 10.2% (95% CI -21.3 to 2.4) lower. There was no difference in stage in the USS group. 1206 women died of the disease: 296 (0.6%) MMS, 291 (0.6%) USS, and 619 (0.6%) C group. There was no significant reduction in ovarian and tubal cancer deaths in either MMS (p = 0.580) or USS (p = 0.360) groups compared to the C group. Overall compliance with annual screening episode was 80.8% (345,570/420,047) in the MMS and 78.0% (327,775/420,047) in the USS group. For ovarian and tubal cancers diagnosed within one year of the last test in a screening episode, in the MMS group, the sensitivity, specificity and positive predictive values were 83.8% (95% CI 78.7 to 88.1), 99.8% (95% CI 99.8 to 99.9), and 28.8% (95% CI 25.5 to 32.2) and in the USS group, 72.2% (95% CI 65.9 to 78.0), 99.5% (95% CI 99.5 to 99.5), and 9.1% (95% CI 7.8 to 10.5) respectively. The final within-trial cost-effectiveness analysis was not undertaken as there was no mortality reduction. A bioresource (UKCTOCS Longitudinal Women's Cohort) of longitudinal outcome data and over 0.5 million serum samples including serial annual samples in women in the MMS group was established and to date has been used in many new studies, mainly focused on early detection of cancer. Harms: Both screening tests (venepuncture and TVS) were associated with minor complications with low (8.6/100,000 screens MMS; 18.6/100,000 screens USS) complication rates. Screening itself did not cause anxiety unless more intense repeat testing was required following abnormal screens. In the MMS group, for each screen-detected ovarian or tubal cancer, an additional 2.3 (489 false positives; 212 cancers) women in the MMS group had unnecessary false-positive (benign adnexal pathology or normal adnexa) surgery. Overall, 14 (489/345,572 annual screens) underwent unnecessary surgery per 10,000 screens. In the USS group, for each screen-detected ovarian or tubal cancer, an additional 10 (1630 false positives; 164 cancers) underwent unnecessary false-positive surgery. Overall, 50 (1630/327,775 annual screens) women underwent unnecessary surgery per 10,000 screens. Conclusions: Population screening for ovarian and tubal cancer for average-risk women using these strategies should not be undertaken. Decreased incidence of Stage III/IV cancers during multimodal screening did not translate to mortality reduction. Researchers should be cautious about using early stage as a surrogate outcome in screening trials. Meanwhile the bioresource provides a unique opportunity to evaluate early cancer detection tests. Funding: Long-term follow-up UKCTOCS (2015-2020) - National Institute for Health and Care Research (NIHR HTA grant 16/46/01), Cancer Research UK, and The Eve Appeal. UKCTOCS (2001-2014) - Medical Research Council (MRC) (G9901012/G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. Researchers at UCL were supported by the NIHR UCL Hospitals Biomedical Research Centre and by MRC Clinical Trials Unit at UCL core funding (MR_UU_12023).

Text: Most women with ovarian cancer are diagnosed after the disease has spread widely (advanced stage ­ III and IV) and more than half die within 5 years. We wanted to find out if testing women without symptoms could pick up ovarian cancer at an earlier stage before it has spread beyond the ovaries and tubes and reduce deaths. We also wanted to assess the risks and benefits of such screening. Text: We invited over 1.2 million women living near 13 centres in England, Wales and Northern Ireland. Of them, 202,638 joined the trial. All women were between 50 and 74 and were no longer having periods. They had never been diagnosed with ovarian cancer or were not having treatment for any other cancer. They did not have many relatives with ovarian or breast cancer. The volunteers were placed into one of three groups at random. List: 1. The blood test group contained 50,640 women who had yearly CA125 blood tests. If these showed a moderate or high chance of ovarian cancer, they had repeat CA125 tests and a scan. List: 2. The scan group contained 50,639 women who had yearly internal scans of their ovaries and tubes which were repeated if they showed an abnormality. List: 3. The no-screening group contained 101,359 women. Text: Those in the blood and scan groups had screening every year until December 2011. We sent all women health questionnaires and also, with their permission, received information about them from the national cancer and death registries till mid-2020. Text: Women in the screened groups had an average of eight years of screening. We followed them for approximately 16 years after they had joined the trial. During this period, 2055 women were diagnosed with ovarian and tubal cancer. It was about 1 in 100 women (1%) in all three groups. List: • 522 of 50,625 in the blood group. List: • 517 of 50,623 in the scan group. List: • 1016 of 101,314 in the no-screening group. Text: More women were diagnosed with early-stage cancer and fewer were diagnosed with advanced cancer in the blood group compared to the no-screening group. There was no difference in the number diagnosed with early or advanced disease between the scan and no-screening group. Despite this difference, the number of women in each group who died from ovarian and tubal cancer was similar in all three groups: 296 of 50,625 (0.6%) in the blood group, 291 of 50,623 (0.6%) in the scan group and 619 of 101,314 (0.6%) in the no-screening group. Other results showed. List: • Overall, 81% women in the blood group and 78% in the scan group attended all of their annual screening appointments. List: • In the blood group, screening detected 84% of ovarian and tubal cancers diagnosed within one year of the test and correctly classified as normal 99.8% of women who did not have ovarian and tubal cancer. List: • In the scan group, screening detected 72% of ovarian and tubal cancers diagnosed within one year of the last test and correctly classified 99.5% of those who did not have ovarian and tubal cancer. List: • Both screening tests were associated with minor complications. List: • While screening did not increase anxiety, there was slightly increased worry in women who were asked to return for more intense repeat testing. List: • Both screening methods picked up changes that were in fact not ovarian cancer. This meant that women had unnecessary surgery together with the worry and risk of complications that go with it. List: ◦ In the blood group 14 women had unnecessary surgery for every 10,000 women screened annually. This means that for each woman found to have ovarian cancer, an additional 2 women had unnecessary surgery. List: ◦ In the scan group 50 women had unnecessary surgery for every 10,000 women screened annually. This means that for each woman found to have ovarian cancer, an additional 10 women had unnecessary surgery. List: • A biobank with all the donated data and over 0.5 million serum samples, including yearly samples from women in the blood group, was built and continues to be used in many new studies, mainly focused on early detection of cancer. Text: Screening using the CA125 blood test or transvaginal ultrasound scan to test for ovarian cancer did not save lives. Additionally, it was associated with some harm. Therefore, an ovarian cancer screening programme for most women cannot be currently recommended. The trial also showed for the first time that ovarian cancer can be detected earlier through screening. However, for screening to save lives, the test needs to pick up many more women earlier in the course of the disease so that available treatments are effective. The biobank provides an opportunity for scientists to see if newer tests for cancer can detect the disease earlier.

Human mobility increased with vaccine coverage and attenuated the protection of COVID-19 vaccination: A longitudinal study of 107 countries.

Background: The World Health Organization has raised concerns that vaccinated people may reduce physical and social distancing more than necessary. With imperfect vaccine protection and the lifting of mobility restrictions, understanding how human mobility responded to vaccination and its potential consequence is critical. We estimated vaccination-induced mobility (VM) and examined whether it attenuates the effect of COVID-19 vaccination on controlling case growth. Methods: We collected a longitudinal data set of 107 countries between 15 February 2020 and 6 February 2022 from Google COVID-19 Community Mobility Reports, the Oxford COVID-19 Government Response Tracker, Our World in Data, and World Development Indicators. We measured mobility in four categories of location: retail and recreational places, transit stations, grocery stores and pharmacies, and workplaces. We applied panel data models to address unobserved country characteristics and used Gelbach decomposition to evaluate the extent to which VM has offset vaccination effectiveness. Results: Across locations, a 10-percentage-point (pp) increase in vaccine coverage was associated with a 1.4-4.3 pp increase in mobility (P < 0.001). VM was greater in lower-income countries (up to 7.9 pps; 95% confidence interval (CI) = 5.3 to 10.5, P < 0.001) and in earlier stages of vaccine rollouts (up to 19.2 pps; 95% CI = 15.1 to 23.2%, P < 0.001). VM decreased the effectiveness of vaccines in controlling case growth by 33.4% in retail and recreation places (P < 0.001), 26.4% in transit stations (P < 0.001), and 15.4% in grocery stores and pharmacies (P = 0.002). Conclusions: VM provides support for the Peltzman effect; it attenuates but does not completely counter vaccine effectiveness. Our study findings suggest strategies for mitigating the unintended consequences of VM, including reducing short-term mobility responses after vaccination, prioritizing mobility in grocery-type places and workplaces, and accelerating rollouts at earlier stages of vaccination, especially in lower-income countries.

Evaluation of the NHS England evidence-based interventions programme: a difference-in-difference analysis.

BACKGROUND: The NHS England evidence-based interventions programme (EBI), launched in April 2019, is a novel nationally led initiative to encourage disinvestment in low value care. METHOD: We sought to evaluate the effectiveness of this policy by using a difference-in-difference approach to compare changes in volume between January 2016 and February 2020 in a treatment group of low value procedures against a control group unaffected by the EBI programme during our period of analysis but subsequently identified as candidates for disinvestment. RESULTS: We found only small differences between the treatment and control group after implementation, with reductions in volumes in the treatment group 0.10% (95% CI 0.09% to 0.11%) smaller than in the control group (equivalent to 16 low value procedures per month). During the month of implementation, reductions in volumes in the treatment group were 0.05% (95% CI 0.03% to 0.06%) smaller than in the control group (equivalent to 7 low value procedures). Using triple difference estimators, we found that reductions in volumes were 0.35% (95% CI 0.26% to 0.44%) larger in NHS hospitals than independent sector providers (equivalent to 47 low value procedures per month). We found no significant differences between clinical commissioning groups that did or did not volunteer to be part of a demonstrator community to trial EBI guidance, but found reductions in volume were 0.06% (95% CI 0.04% to 0.08%) larger in clinical commissioning groups that posted a deficit in the financial year 2018/19 before implementation (equivalent to 4 low value procedures per month). CONCLUSIONS: Our analysis shows that the EBI programme did not accelerate disinvestment for procedures under its remit during our period of analysis. However, we find that financial and organisational factors may have had some influence on the degree of responsiveness to the EBI programme.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

United Kingdom: Health System Review.

This analysis provides a review of developments in financing, governance, organisation and delivery, health reforms and performance of the health systems in the United Kingdom. The United Kingdom has enjoyed a national health service with access based on clinical need, and not ability to pay for over 70 years. This has provided several important benefits including protection against the financial consequences of ill-health, redistribution of wealth from rich to poor, and relatively low administrative costs. Despite this, the United Kingdom continues to lag behind many other comparable high-income countries in key measures including life expectancy, infant mortality and cancer survival. Total health spending in the United Kingdom is slightly above the average for Europe, but it is below many other comparable high-income countries such as Germany, France and Canada. The United Kingdom also has relatively lower levels of doctors, nurses, hospital beds and equipment than many other comparable high-income countries. Wider social determinants of health also contribute to poor outcomes, and the United Kingdom has one of the highest levels of income inequality in Europe. Devolution of responsibility for health care services since the late 1990s to Scotland, Wales and Northern Ireland has resulted in divergence in policies between countries, including in prescription charges, and eligibility for publicly funded social care services. However, more commonalities than differences remain between these health care systems. The United Kingdom initially experienced one of the highest death rates associated with COVID-19; however, the success and speed of the United Kingdom's vaccination programme has since improved the United Kingdom's performance in this respect. Principal health reforms in each country are focusing on facilitating cross-sectoral partnerships and promoting integration of services in a manner that improves the health and well-being of local populations. These include the establishment of integrated care systems in England, integrated joint boards in Scotland, regional partnership boards in Wales and integrated partnership boards in Northern Ireland. Policies are also being developed to align the social care funding model closer to the National Health Service funding model. These include a cap on costs over an individual's lifetime in England, and a national care service free at the point of need in Scotland and Wales. Currently, and for the future, significant investment is needed to address major challenges including a growing backlog of elective care, and staffing shortfalls exacerbated by Brexit.

The diffusion of robotic surgery: Examining technology use in the English NHS.

This paper examines the adoption and diffusion of medical technology as associated with the dramatic recent increase in the surgical use of robots. We consider specifically the sequential adoption and diffusion patterns of three interrelated surgical technologies within a single healthcare system (the English NHS): robotic, laparoscopic and open radical prostatectomy. Robotic and laparoscopic techniques are minimally invasive procedures with similar patient benefits, but the newer robotic technique requires a high initial investment cost to purchase the robot and carries high maintenance costs over time. Using data from a large UK administrative database, Hospital Episodes Statistics, for the period 2000-2018, we analyse 173 hospitals performing radical prostatectomy, the most prevalent and earliest surgical area of adoption of robotic surgery. Our empirical analysis first identifies substitution effects, with robotic surgery replacing the incumbent technology, including the recently diffused laparoscopic technology. We then quantify the spillover of robotic surgery as it diffuses to other surgical specialties. Finally, we perform time-to-event analysis at the hospital level to quantitatively examine the adoption. Results show that a higher number of urologists and a wealthier referral area favor robot adoption.

Promoting innovation while controlling cost: The UK's approach to health technology assessment.

New technologies, including pharmaceuticals and medical devices, can improve treatment options in healthcare but also bring concerns about rising healthcare costs. We undertake a narrative review of the United Kingdom's (UK) approach to appraising new health technologies. We find that the National Institute for Health and Care Excellence (NICE), Scottish Medicines Consortium (SMC) and All Wales Medicines Strategy Group (AWMSG) have contributed to the UK's robust and transparent approach towards the evaluation of new health technologies using the cost per QALY approach. However, there are limitations to this approach including several external benefits not captured, bias against less treatable diseases, and deciding the appropriate level of the threshold. NICE, SMC, and AWMSG have attempted to overcome some of these limitations by considering additional factors such as end-of-life criteria, highly specialised treatments, and populations that experience unmet need. Looking to the future, the advent of 'personalised' and 'genomic' medicine, will likely mean the UK has to accommodate an increasing number of 'step-change' and 'highly specialised' technologies as well as respond to changes in pharmaceutical licensing and increasing use of real-world evidence.

United Kingdom: health system summary

This Health System Summary is based on the United Kingdom: Health System Review (HiT) published in 2022. Health System Summaries use a concise format to communicate central features of country health systems and analyze available evidence on the organization, financing and delivery of health care. They also provide insights into key reforms and the varied challenges testing the performance of the health system.

United Kingdom: health system review

This analysis provides a review of developments in financing, governance, organisation and delivery, health reforms and performance of the health systems in the United Kingdom.

Predicting Hospital Resource Use During COVID-19 Surges: A Simple but Flexible Discretely Integrated Condition Event Simulation of Individual Patient-Hospital Trajectories.

OBJECTIVES: To assist with planning hospital resources, including critical care (CC) beds, for managing patients with COVID-19. METHODS: An individual simulation was implemented in Microsoft Excel using a discretely integrated condition event simulation. Expected daily cases presented to the emergency department were modeled in terms of transitions to and from ward and CC and to discharge or death. The duration of stay in each location was selected from trajectory-specific distributions. Daily ward and CC bed occupancy and the number of discharges according to care needs were forecast for the period of interest. Face validity was ascertained by local experts and, for the case study, by comparing forecasts with actual data. RESULTS: To illustrate the use of the model, a case study was developed for Guy's and St Thomas' Trust. They provided inputs for January 2020 to early April 2020, and local observed case numbers were fit to provide estimates of emergency department arrivals. A peak demand of 467 ward and 135 CC beds was forecast, with diminishing numbers through July. The model tended to predict higher occupancy in Level 1 than what was eventually observed, but the timing of peaks was quite close, especially for CC, where the model predicted at least 120 beds would be occupied from April 9, 2020, to April 17, 2020, compared with April 7, 2020, to April 19, 2020, in reality. The care needs on discharge varied greatly from day to day. CONCLUSIONS: The DICE simulation of hospital trajectories of patients with COVID-19 provides forecasts of resources needed with only a few local inputs. This should help planners understand their expected resource needs.

Evaluation of progress toward universal health coverage in Myanmar: A national and subnational analysis.

BACKGROUND: Universal health coverage (UHC) encompasses 2 main components: access to essential healthcare services and protection from financial hardship when using healthcare. This study examines Myanmar's efforts to achieve UHC on a national and subnational level. It is a primer of studying the concept of UHC on a subnational level, and it also establishes a baseline for assessing future progress toward reaching UHC in Myanmar. METHODS AND FINDINGS: The study uses the Demographic and Health Survey (2015) and the Myanmar Living Conditions Survey (MLCS; 2017) and adapts a previously developed UHC index to provide insights into the main barriers preventing the country's progress toward UHC. We find a negative correlation between the UHC index and the state/region poverty levels. The equity of access analysis reveals significant pro-rich inequity in access to all essential healthcare services. Socioeconomic status and limited availability of healthcare infrastructure are the main driving forces behind the unequal access to interventions that are crucial to achieving UHC by 2030. Finally, financial risk protection analysis shows that the poor are less likely to use healthcare services, and, once they do, they are at a greater risk of suffering financial catastrophe. Limitations of this study revolve around its correlational, rather than causal, nature. CONCLUSIONS: We suggest a 2-pronged approach to help Myanmar achieve UHC: Government and state authorities should reduce the financial burden of seeking healthcare, and, coupled with this, significant investment in and expansion of health infrastructure and the health workforce should be made, particularly in the poorer and more remote states.

Association of Annual Intensive Care Unit Sepsis Caseload With Hospital Mortality From Sepsis in the United Kingdom, 2010-2016.

Importance: Sepsis is associated with a high burden of inpatient mortality. Treatment in intensive care units (ICUs) that have more experience treating patients with sepsis may be associated with lower mortality. Objective: To assess the association between the volume of patients with sepsis receiving care in an ICU and hospital mortality from sepsis in the UK. Design, Setting, and Participants: This retrospective cohort study used data from adult patients with sepsis from 231 UK ICUs between 2010 and 2016. Demographic and clinical data were extracted from the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme database. Data were analyzed from January 1, 2010, to December 31, 2016. Exposures: Annual sepsis case volume in an ICU in the year of a patient's admission. Main Outcomes and Measures: Hospital mortality after ICU admission for sepsis assessed using a mixed-effects logistic model in a 3-level hierarchical structure based on the number of individual patients nested in years nested within ICUs. Results: Among 273 001 patients included in the analysis, the median age was 66 years (interquartile range, 53-76 years), 148 149 (54.3%) were male, and 248 275 (91.0%) were White. The mean ICNARC-2018 illness severity score was 21.0 (95% CI, 20.9-21.0). Septic shock accounted for 19.3% of patient admissions, and 54.3% of patients required mechanical ventilation. The median annual sepsis volume per ICU was 242 cases (interquartile range, 177-334 cases). The study identified a significant association between the volume of sepsis cases in the ICU and mortality from sepsis; in the logistic regression model, hospital mortality was significantly lower among patients admitted to ICUs in the highest quartile of sepsis volume compared with the lowest quartile (odds ratio [OR], 0.89; 95% CI, 0.82-0.96; P = .002). With volume modeled as a restricted cubic spline, treatment in a larger ICU was associated with lower hospital mortality. A lower annual volume threshold of 215 patients above which hospital mortality decreased significantly was found; 38.8% of patients were treated in ICUs below this threshold volume. There was no significant interaction between ICU volume and severity of illness as described by the ICNARC-2018 score (ß [SE], -0.00014 [0.00024]; P = .57). Conclusions and Relevance: The findings suggest that patients with sepsis in the UK have higher odds of survival if they are treated in an ICU with a larger sepsis case volume. The benefit of a high sepsis case volume was not associated with the severity of the sepsis episode.

Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

BACKGROUND: Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS. METHODS: In this randomised controlled trial, postmenopausal women aged 50-74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1-17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (-41·8 to -2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (-21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group. INTERPRETATION: The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended. FUNDING: National Institute for Health Research, Cancer Research UK, and The Eve Appeal.

The changing health needs of the UK population.

The demographics of the UK population are changing and so is the need for health care. In this Health Policy, we explore the current health of the population, the changing health needs, and future threats to health. Relative to other high-income countries, the UK is lagging on many health outcomes, such as life expectancy and infant mortality, and there is a growing burden of mental illness. Successes exist, such as the striking improvements in oral health, but inequalities in health persist as well. The growth of the ageing population relative to the working-age population, the rise of multimorbidity, and persistent health inequalities, particularly for preventable illness, are all issues that the National Health Service (NHS) will face in the years to come. Meeting the challenges of the future will require an increased focus on health promotion and disease prevention, involving a more concerted effort to understand and tackle the multiple social, environmental, and economic factors that lie at the heart of health inequalities. The immediate priority of the NHS will be to mitigate the wider and long-term health consequences of the COVID-19 pandemic, but it must also strengthen its resilience to reduce the impact of other threats to health, such as the UK leaving the EU, climate change, and antimicrobial resistance.

Securing a sustainable and fit-for-purpose UK health and care workforce.

Approximately 13% of the total UK workforce is employed in the health and care sector. Despite substantial workforce planning efforts, the effectiveness of this planning has been criticised. Education, training, and workforce plans have typically considered each health-care profession in isolation and have not adequately responded to changing health and care needs. The results are persistent vacancies, poor morale, and low retention. Areas of particular concern highlighted in this Health Policy paper include primary care, mental health, nursing, clinical and non-clinical support, and social care. Responses to workforce shortfalls have included a high reliance on foreign and temporary staff, small-scale changes in skill mix, and enhanced recruitment drives. Impending challenges for the UK health and care workforce include growing multimorbidity, an increasing shortfall in the supply of unpaid carers, and the relative decline of the attractiveness of the National Health Service (NHS) as an employer internationally. We argue that to secure a sustainable and fit-for-purpose health and care workforce, integrated workforce approaches need to be developed alongside reforms to education and training that reflect changes in roles and skill mix, as well as the trend towards multidisciplinary working. Enhancing career development opportunities, promoting staff wellbeing, and tackling discrimination in the NHS are all needed to improve recruitment, retention, and morale of staff. An urgent priority is to offer sufficient aftercare and support to staff who have been exposed to high-risk situations and traumatic experiences during the COVID-19 pandemic. In response to growing calls to recognise and reward health and care staff, growth in pay must at least keep pace with projected rises in average earnings, which in turn will require linking future NHS funding allocations to rises in pay. Through illustrative projections, we show that, to sustain annual growth in the workforce at approximately 2·4%, increases in NHS expenditure of 4% annually in real terms will be required. Above all, a radical long-term strategic vision is needed to ensure that the future NHS workforce is fit for purpose.