Background: Bariatric surgery can improve health outcomes but high-quality comparative evidence about different procedures is limited. Objective: To compare the effectiveness and cost-effectiveness of Roux-en-Y gastric bypass (Bypass), adjustable gastric banding (Band) and sleeve gastrectomy (Sleeve) for people living with severe obesity. Design, setting and participants: Multicentre, parallel-group, randomised controlled trial conducted in 12 National Health Service hospitals. Adults with a body mass index >= 35 kg/m2 with comorbidity or body mass index >= 40 kg/m2 without comorbidity were eligible. Participants were initially randomised 1 : 1 to Bypass or Band. After 32 months of recruitment, the trial was adapted to include Sleeve, and participants were randomised to Bypass, Band or Sleeve thereafter. Participants were followed up for 3 years. Interventions: Bypass, Band and Sleeve surgery. Main outcome measures: Primary outcomes were self-reported quality of life (EQ-5D-5L utility score) and weight (at least 50% excess weight lost) at 3 years. Sleeve and Bypass were each considered superior to Band if there was non-inferior excess weight loss (< 12% difference between groups) and superior quality of life. Sleeve was considered superior to Bypass by the same criteria. Secondary outcomes included comorbidities, adverse health events, generic and disease-specific quality of life at 6, 12, 24 and 36 months post randomisation, dietary intake, binge eating behaviour and cost-effectiveness. Results: One thousand three hundred and fifty-one participants were randomised between December 2012 and September 2019. Five participants withdrew consent to use their data, leaving 1346 (462 Bypass, 464 Band, 420 Sleeve). The mean age was 47.3 years, 1020 (75.9%) were women and the mean weight and body mass index was 129.7 kg and 46.4 kg/m(2), respectively. Overall, 1183 (87.5%) of participants underwent surgery within 3 years, with a median waiting time of 5 months (interquartile range 2.5-10.1 months). At least 50% excess weight loss at 3 years was achieved for 276/405 (68.1%) participants randomised to Bypass, 97/383 (25.3%) randomised to Band and 142/342 (41.5%) randomised to Sleeve [adjusted risk difference (Bypass-Band) + 40.7%, 98% confidence interval (+ 33.9% to + 47.5%); (Sleeve-Band) + 14.7% (+ 5.2% to + 24.2%), (Sleeve-Bypass)-26.0% (-35.8% to-16.3%)]. Mean EQ-5D scores at 3 years were 0.72 (standard deviation 0.29), 0.62 (0.33) and 0.68 (0.30) for participants randomised to Bypass, Band and Sleeve, respectively [adjusted mean difference (Bypass-Band) + 0.079 (+ 0.040 to + 0.117), (Sleeve-Band) + 0.045 (+ 0.006 to + 0.085), (Sleeve-Bypass)-0.033 (-0.072 to + 0.006)]. Secondary outcomes showed similar trends. The adverse event rate was highest in the Band group and lowest with Sleeve. Bypass was the most cost-effective procedure, with probabilities < 0.3 that Sleeve or Band was the most cost-effective. Limitations: The study was impacted by the COVID-19 pandemic which prevented some participants having surgery and/or attending hospital for study follow-up appointments, which impacted on the completeness of data for these visits. Conclusions: Bypass and Sleeve are more effective than Band. Sleeve has inferior excess weight loss and lower mean quality-of-life score than Bypass.

To describe healthcare resource utilization (HCRU), direct costs, and survival of DLBCL patients in Sweden. This retrospective cohort study followed adult patients with DLBCL from 2015 to 2023 using Swedish national registers. Time in specialty care was calculated as days per-person-year (PPY). Nordic diagnosis-related-group weights were used to estimate costs. 7,503 patients were diagnosed with DLBCL. Median age was 73.0 years; 56.9

Health technology assessment (HTA) of haemato-oncology therapies typically requires extrapolation of long-term survival beyond a trial’s follow-up. Health technology assessment agencies must balance caution around uncertainty in early follow-up trial data whilst aiming to provide timely access. This study qualitatively and quantitatively assessed how eight HTA agencies considered maturing data and external evidence. The eight HTA appraisals were based on ZUMA-7, a phase III trial for axicabtagene ciloleucel (axi-cel) for second-line diffuse large B-cell lymphoma. ZUMA-7 survival data were submitted with either a 25-month (‘Interim’) or 47-month (‘Primary’) follow-up. To inform axi-cel Interim survival extrapolations, external evidence was available from a prior mature single-arm trial for third-line or later diffuse large B-cell lymphoma (ZUMA-1). A qualitative assessment of eight different submissions to HTA agencies was undertaken to determine key discussion points. The value and cost of waiting for evidence to mature between Interim and Primary analyses were quantified using value of information methods to evaluate the impact of waiting for further evidence collection on population health. Agencies used varied approaches to account for uncertainty in survival extrapolations in both Interim and Primary analyses. No agency considered external evidence fully during Interim submissions; one used it partially to inform clinical plausibility; four did not consider it. Health technology assessment agencies that did not consider the relevance of ZUMA-1 were more inclined to wait for more mature evidence to mitigate uncertainty. When ZUMA-1 aided in determining a plausible range for Interim extrapolations, the less valuable more mature evidence became, with the cost of waiting for Primary analysis results exceeding the value conferred. There was limited consideration of external evidence during the included HTA submissions. In the future, it is recommended that external evidence should be considered to a greater degree by both manufacturers and HTA agencies when extrapolating survival to ensure appropriate and timely HTA decisions that minimise the undue burden on healthcare systems.

Introduction Response assessment with interim PET/CT (iPET) in 1L treatment (tx) is in NCCN guidelines for DLBCL and becoming US standard of care. iPET was recently added to UK guidelines and is established practice in France. iPET is used as an indicator of response to tx and prognosis and may support earlier decision-making for tx intensification or switch to second-line (2L) tx. iPET may be pertinent to CAR-T tx given that early planning facilitates prompt tx, especially in high-risk cases. However, iPET use and subsequent tx are not well-characterized in the US. The purpose of this study is to describe real-world 1L iPET use for US patients (pts) presumed refractory after 1L and characteristics of subsequent tx. Methods This is a retrospective real-world study of data from 01/2017-12/2023 in a US database of administrative health claims for members of large commercial and Medicare Advantage health plans. All adult (18+ years) pts with available demographic characteristics, evidence of DLBCL diagnosis with 12+ months of prior continuous enrollment, and 2+ cycles of 1L R-CHOP or R-EPOCH were included; 1L must have initiated 150+ days before data cutoff to allow the potential for 6+ cycles. Descriptive statistics summarized available pt/clinical characteristics, tx, and iPET use with continuous variables as medians (interquartile range [IQR]). iPET was defined as a scan between start of Cycle 2 and 5 in 1L (or for pts with 4 or fewer cycles, within 60 days from last 1L cycle start). Duration of 1L was time from 1L start to last cycle start without adding time for clinical benefit. Subgroup analyses were performed in pts who received 2L tx within 120 days after the last 1L R-CHOP cycle start as a proxy for presumed-refractory disease since PET/CT scan results were unavailable. The results were stratified by iPET/no iPET and by total 1L cycles received suggesting early switch (2-4 cycles)/standard switch (5 or more cycles) to 2L. Tx-free interval (TFI) was time from last 1L cycle start to 2L start and time-to-next tx (TTNT) was time from 1L start to 2L start. Results In total, 5,916 pts were included with a median age of 73 years (66, 79). Pts were mostly White (76%), Male (55%), and Medicare insured (77%). Approximately half (53%) of pts had no NCI-defined comorbidities, and 919 (16%) pts had two or more. Follow-up time from 1L start was 20 months (9, 39). Of this 1L cohort, nearly all (96%) received R-CHOP (median: 5 cycles [4, 6]) with a median time from 1L start to last 1L cycle start of 105 days (70, 107). Almost two-thirds of pts (63%) received iPET (62% in 2017-21 & 67% in 2022-23). Baseline characteristics in pts who received iPET were largely similar to no iPET pts. Time from 1L start to iPET was 60 days (52, 76). Approximately half (48%) of iPET occurred between start of Cycle 3 and 4, with the rest split between start of Cycle 2 and 3 (26%) and start of Cycle 4 and 5 (26%). A subset of 265 pts who received 1L R-CHOP (R-EPOCH not assessed due to sample size) had presumed-refractory disease; 184 (69%) had iPET. The most common regimen class received in 2L was chemo-immunotherapy in pts with iPET (64%) and without iPET (67%); CAR-T was used in 15 pts (8.2%) with iPET, and in 2 (2.5%) without iPET. Among presumed-refractory pts with iPET, early switch pts (n=79) had a TFI of 47 days (41, 59) and TTNT of 118 days (101, 128); standard switch pts (n=105) had a TFI of 67 days (58, 77) and TTNT of 174 days (162, 183). In pts without iPET, early switch pts (n=24) had a TFI of 29 days (22, 51) and TTNT of 68 days (62, 84); standard switch pts (n=57) had a TFI of 63 days (47, 75) and TTNT of 168 days (157, 187). Conclusions These data suggest iPET use is common in US pts with DLBCL. In presumed-refractory pts who received 2L, early switch after iPET had shorter TFI/TTNT than pts with standard switch. The smallest group were early switchers without iPET who yielded the shortest TFI/TTNT, consistent with a subpopulation that experiences clear early tx failure (e.g., symptomatic progression) or is identified via other methods (e.g., interim CT scan). In pts with or without iPET who ultimately had standard switch, the question remains if these pts would benefit from earlier referral to 2L CAR-T given their 1L therapy subsequently failed. Most data were prior to the approval of 2L CAR-T in 2022, potentially understating the role of iPET in earlier referral to a novel, beneficial tx option. Interpretation is however limited without iPET results and additional clinical data, warranting further study.

IntroductionNovel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective.MethodsA three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients.ResultsThe analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively.DiscussionThis study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

Introduction: The treatment paradigm of R/R DLBCL was revolutionized based on the results of two recently published phase III trials where chimeric antigen receptor T-cell (CAR T) therapy showed significant benefit over high-dose chemotherapy and autologous stem-cell transplant (HDT+ASCT) for patients (pts) with early R/R DLBCL. Following the results of these trials and the confirmatory real-world evidence (RWE), the German Society of Haematology and Medical Oncology (DGHO) revised its guidelines in 2024. In this updated guideline, second line (2L) R/R DLBCL pts are stratified based on their CAR T eligibility and axicabtagene ciloleucel (axi-cel) or lisocabtagene maraleucel (liso-cel) are recommended for pts with refractory disease and early relapse. Pts with late relapse are still evaluated for HDT+ASCT and considered for CAR T in the third line plus setting (3L+). In addition, bispecific antibodies (BsAb) glofitamab and epcoritamab have been approved and are also recommended for use in the 3L+ setting. Despite these recommendations, due to a misinterpretation of eligibility and non-clinical barriers, some pts may still not receive CAR T therapy and are misallocated to different pathways which may affect their outcomes. In this study we examine the cumulative effect of this misallocation by modelling survival outcomes for pts who do not follow their intended pathway based on the DGHO guideline. Methods: A patient-level simulation model based on the DGHO guideline was built using data from over 18 sources (including trials and RWE) to simulate lifetime health outcomes of various R/R DLBCL treatment pathways. As per the guideline, we simulated three treatment pathways for CAR T eligible patients: 1) 2L CAR T for early R/R pts followed by 3L BsAb; 2) 2L HDT+ASCT for late relapses, then 3L CAR T; 3) 2L chemoimmunotherapy for ASCT ineligible late relapses and 3L CAR T. In the alternative scenario, CAR T eligible pts are misallocated to treatments according to the CAR T ineligible pathway of the DGHO guideline. Long-term outcomes were extrapolated using validated statistical models. Finally, we estimated the impact on survival if an increasing proportion of CAR T eligible pts follow the alternative CAR T ineligible pathway due to misallocation or suboptimal referral by assigning a varying probability of misallocation. Results: In the base case, we estimate the misallocation rate of 21% based on a chart review of 126 German pts from 50 physicians. An additional sensitivity analysis using 10% and 30% misallocation rates was explored given the uncertainty of this parameter. Based on 2,191 pts with DLBCL in Germany who are R/R after 1L therapy and CAR T eligible, a misallocation rate of 21% equated to 460 pts being misallocated to the CAR T ineligible pathway. In terms of outcomes, the estimated 5-year overall survival were projected to be 52%, 57% and 48% for pathways 1-3 respectively, and 34% for those who follow the CAR T ineligible pathway. Therefore, misallocation is estimated to decrease life expectancy by over 8 months per pt on average. If this applies to the whole German DLBCL incident population, we can expect 83 lives lost at 5 years. In the sensitivity analysis, the estimated number of lives lost at 5 years was between 40 and 120. Conclusions: Our comprehensive treatment sequencing model in DLBCL is based on 18 compelling data sources including clinical trials and RWE. Using simulation modelling, we show that misallocation of CAR T eligibility due to clinical and non-clinical reasons leads to pts receiving alternative sequence of treatments which is likely to reduce the overall survival, resulting in suboptimal outcomes at population level. Our results hold true over a range of misallocation rates. We acknowledge that clinical practice is variable, and guidelines may not be appropriate for all pts. Nonetheless, greater efforts are needed to ensure that CAR T eligible pts are identified systematically, and referral pathways are optimized to ensure all eligible pts receive CAR T therapy.

Background:Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives:The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design:The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting:The study was set in primary and secondary care in England from 2010 to 2017. Participants:Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources:Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions:Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures:Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results:The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions:This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations:The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work:Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration:This trial is registered as ISRCTN76607611. Funding:This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

Introduction Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel), and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies, such as mosunetuzumab (mosun), are novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) that have recently been approved by the US Food and Drug Administration. This analysis assessed the cost-effectiveness of axi-cel compared to mosun in r/r 3L+ FL from a US third-party payer perspective. Methods A three-state (progression-free [PF], progressed disease [PD], and death) partitioned-survival model was used to compare the two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 (NCT03105336) and GO29781 (NCT02500407) trial data were used to inform progression-free survival (PFS) and overall survival (OS) for axi-cel and mosun, respectively. Survival curves for axi-cel were estimated using an exponential distribution for both PFS and OS. In the base case analysis, 40% of axi-cel patients alive at 5 years were assumed to experience long-term remission (i.e., functional cure), and therefore followed general population mortality adjusted by a standardized mortality ratio. This assumption was informed by the literature. Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel exponential survival curves. For PFS, the HR value was estimated via a matching indirect comparison to adjust for differences between the trial populations. As a conservative assumption, a HR of 1.0 was used to model mosun OS due to lack of published results. The mosun arm did not include the cure assumption at 5 years because long-term remission is not expected with monoclonal antibodies in r/r FL. Health state utilities (HSU), healthcare resource use (HCRU), and treatment pattern inputs were obtained from literature. Costs for treatment and administration, adverse event management, monitoring resource use, HCRU, and end-of-life were included in the model. Key model outcomes included discounted (at 3% per year) total and incremental costs, life years (LYs), and quality adjusted life years (QALYs), as well as incremental cost-effectiveness ratios (ICERs). Scenario analyses were conducted on the cure assumption and all input parameters were individually varied by ±20% of their base case values in one-way sensitivity analysis (OWSA) to assess parameter uncertainty. Results Axi-cel use led to increases of 1.51 LY and 1.80 QALY (Table 1) compared to mosun. Progression-free survival for axi-cel patients was 7.11 LY compared to 1.80 LY for mosun, which resulted in a PF state cost increase of $215,045 primarily driven by the one-time cost of axi-cel treatment. Conversely, axi-cel costs were $63,000 less than mosun in the PD state, as patients spent less time with PD and had lower costs for subsequent treatment lines. Total incremental costs for axi-cel were $151,425, resulting in an ICER of $84,016/QALY gained. Analysis of lower cure fractions indicated cost-effectiveness across a wide range of values. Additionally, the OWSA indicated the most impactful inputs for the ICER were mean patient age, the relative dose intensity (RDI) of mosun, PF and PD HSUs, and PD HCRU. Inputs with the largest impact on total incremental costs were RDI, HCRU, and CAR-T infusion hospitalization duration. Conclusions Axi-cel is cost-effective versus mosun in r/r 3L+ FL at an ICER of $84,016/QALY gained, which is far lower than the commonly-cited US willingness-to-pay threshold of $150,000/QALY. This analysis demonstrates the value of using axi-cel, reflecting the aggregate benefits of a one-time therapy, reduction in need for subsequent treatment lines, and population segment experiencing effective cure.

The story of dying in the 21st century is a story of paradox. While many people are overtreated in hospitals with families and communities relegated to the margins, still more remain undertreated, dying of preventable conditions and without access to basic pain relief. The unbalanced and contradictory picture of death and dying is the basis for this Commission. How people die has changed radically over recent generations. Death comes later in life for many and dying is often prolonged. Death and dying have moved from a family and community setting to primarily the domain of health systems. Futile or potentially inappropriate treatment can continue into the last hours of life. The roles of families and communities have receded as death and dying have become unfamiliar and skills, traditions, and knowledge are lost. Death and dying have become unbalanced in high-income countries, and increasingly in low-and-middle-income countries; there is an excessive focus on clinical interventions at the end of life, to the detriment of broader inputs and contributions. The COVID-19 pandemic has meant that death is prominent in daily media reports and health systems have been overwhelmed. People have died the ultimate medicalised deaths, often alone but for masked staff in hospitals and intensive care units, unable to communicate with family except electronically. This situation has further fuelled the fear of death, reinforcing the idea of health-care services as the custodian of death. Climate change, the COVID-19 pandemic, environmental destruction, and attitudes to death in high-income countries have similar roots—our delusion that we are in control of, and not part of, nature. Large sums are being invested to dramatically extend life, even achieve immortality, for a small minority in a world that struggles to support its current population. Health care and individuals appear to struggle to accept the inevitability of death. Philosophers and theologians from around the globe have recognised the value that death holds for human life. Death and life are bound together: without death there would be no life. Death allows new ideas and new ways. Death also reminds us of our fragility and sameness: we all die. Caring for the dying is a gift, as some philosophers and many carers, both lay and professional, have recognised. Much of the value of death is no longer recognised in the modern world, but rediscovering this value can help care at the end of life and enhance living. Treatment in the last months of life is costly and a cause of families falling into poverty in countries without universal health coverage. In high-income countries between 8% and 11·2% of annual health expenditure for the entire population is spent on the less than 1% who die in that year. Some of this high expenditure is justified, but there is evidence that patients and health professionals hope for better outcomes than are likely, meaning treatment that is intended to be curative often continues for too long. Conversations about death and dying can be difficult. Doctors, patients, or family members may find it easier to avoid them altogether and continue treatment, leading to inappropriate treatment at the end of life. Palliative care can provide better outcomes for patients and carers at the end of life, leading to improved quality of life, often at a lower cost, but attempts to influence mainstream health-care services have had limited success and palliative care broadly remains a service-based response to this social concern. Rebalancing death and dying will depend on changes across death systems—the many inter-related social, cultural, economic, religious, and political factors that determine how death, dying, and bereavement are understood, experienced, and managed. A reductionist, linear approach that fails to recognise the complexity of the death system will not achieve the rebalancing needed. Just as they have during the COVID-19 pandemic, the disadvantaged and powerless suffer most from the imbalance in care when dying and grieving. Income, education, gender, race, ethnicity, sexual orientation, and other factors influence how much people suffer in death systems and the capacity they possess to change them. Radically reimagining a better system for death and dying, the Lancet Commission on the Value of Death has set out the five principles of a realistic utopia: a new vision of how death and dying could be. The five principles are: the social determinants of death, dying, and grieving are tackled; dying is understood to be a relational and spiritual process rather than simply a physiological event; networks of care lead support for people dying, caring, and grieving; conversations and stories about everyday death, dying, and grief become common; and death is recognised as having value. Systems are constantly changing, and many programmes are underway that encourage the rebalancing of our relationship with death, dying, and grieving. Communities from varied geographies are challenging norms and rules about caring for dying people, and models of citizen and community action, such as compassionate communities, are emerging. Policy and legislation changes are recognising the impact of bereavement and supporting the availability of medication to manage pain when dying. Hospitals are changing their culture to openly acknowledge death and dying; health-care systems are beginning to work in partnership with patients, families, and the public on these issues and to integrate holistic care of the dying throughout health services. Key messages•Dying in the 21st century is a story of paradox. Although many people are overtreated in hospitals, still more remain undertreated, dying of preventable conditions and without access to basic pain relief.•Death, dying, and grieving today have become unbalanced. Health care is now the context in which many encounter death and as families and communities have been pushed to the margins, their familiarity and confidence in supporting death, dying, and grieving has diminished. Relationships and networks are being replaced by professionals and protocols.•Climate change, the COVID-19 pandemic, and our wish to defeat death all have their origins in the delusion that we in control of, not part of, nature.•Rebalancing death and dying will depend on changes across death systems—the many inter-related social, cultural, economic, religious, and political factors that determine how death, dying, and bereavement are understood, experienced, and managed.•The disadvantaged and powerless suffer most from the imbalance in care for those dying and grieving.•The Lancet Commission on the Value of Death sets out five principles of a realistic utopia, a new vision of how death and dying could be. The five principles are: the social determinants of death, dying, and grieving are tackled; dying is understood to be a relational and spiritual process rather than simply a physiological event; networks of care lead support for people dying, caring, and grieving; conversations and stories about everyday death, dying, and grief become common; and death is recognised as having value.•The challenge of transforming how people die and grieve today has been recognised and responded to by many around the world. Communities are reclaiming death, dying and grief as social concerns, restrictive policies on opioid availability are being transformed and health-care professionals are working in partnership with people and families, but more is needed.•To achieve our ambition to rebalance death, dying and grieving, radical changes across all death systems are needed. It is a responsibility for us all, including global bodies and governments, to take up this challenge. The Commission will continue its work in this area. •Dying in the 21st century is a story of paradox. Although many people are overtreated in hospitals, still more remain undertreated, dying of preventable conditions and without access to basic pain relief.•Death, dying, and grieving today have become unbalanced. Health care is now the context in which many encounter death and as families and communities have been pushed to the margins, their familiarity and confidence in supporting death, dying, and grieving has diminished. Relationships and networks are being replaced by professionals and protocols.•Climate change, the COVID-19 pandemic, and our wish to defeat death all have their origins in the delusion that we in control of, not part of, nature.•Rebalancing death and dying will depend on changes across death systems—the many inter-related social, cultural, economic, religious, and political factors that determine how death, dying, and bereavement are understood, experienced, and managed.•The disadvantaged and powerless suffer most from the imbalance in care for those dying and grieving.•The Lancet Commission on the Value of Death sets out five principles of a realistic utopia, a new vision of how death and dying could be. The five principles are: the social determinants of death, dying, and grieving are tackled; dying is understood to be a relational and spiritual process rather than simply a physiological event; networks of care lead support for people dying, caring, and grieving; conversations and stories about everyday death, dying, and grief become common; and death is recognised as having value.•The challenge of transforming how people die and grieve today has been recognised and responded to by many around the world. Communities are reclaiming death, dying and grief as social concerns, restrictive policies on opioid availability are being transformed and health-care professionals are working in partnership with people and families, but more is needed.•To achieve our ambition to rebalance death, dying and grieving, radical changes across all death systems are needed. It is a responsibility for us all, including global bodies and governments, to take up this challenge. The Commission will continue its work in this area. These innovations do not yet amount to a whole system change, but something very close to the Commission's realistic utopia has been achieved in Kerala, India, over the past three decades. Death and dying have been reclaimed as a social concern and responsibility through a broad social movement comprised of tens of thousands of volunteers complemented by changes to political, legal, and health systems. To achieve the ambition of radical change across death systems we present a series of recommendations, outlining the next steps that we urge policy makers, health and social care systems, civil society, and communities to take. Death and dying must be recognised as not only normal, but valuable. Care of the dying and grieving must be rebalanced, and we call on people throughout society to respond to this challenge.

Background: Few studies have assessed how patient preferences influence end-of-life costs. Aim: To estimate mean monthly healthcare costs in 2019 Singapore Dollars (SGD) at five time points within the last year of life and identify how patients’ preferences for the trade-off between treatment cost containment and life-extension and other factors affect these costs. Design: Mean monthly costs were quantified in the last 1, 3, 6, 9, and 12-months before death. Univariate and multivariate analyses were conducted. Setting/participants: Billing records for 286 deceased participants in the Cost and Medical Care of Patients with Advanced Serious Illness (COMPASS) cancer cohort study in Singapore. Results: Mean monthly costs were $5140 (95% CI: $4750; $5520) in the 12-months before death and rose to $8350 (95% CI: $7110; $9590) 1-month before death. Participants preferring higher cost containment/less life-extension defied the trend of increasing costs closer to death (mean monthly costs of $4630 (95% CI: $3690; $ 5580) and $4850 (95% CI: $2850; $6850) (12-months and 1-month before death respectively). Participants preferring lower cost containment/more life-extension had costs that were $1050 (95% CI: $49; $2051) and $5220 (95% CI: $2320; $8130) higher than those preferring lower costs/less life-extension 12-months and 1-month before death respectively. Conclusions: On average, cancer patients in Singapore can expect to spend $61,680 in the last year of life. Of broader relevance is that patient preferences and other observable factors clearly influence these costs, suggesting that policymakers and patients can better predict and budget for end-of-life costs by considering these factors.

Background and objective Up-to-date economic burden of asthma in Singapore is currently unknown.Methods We quantify the per capita and total annual costs of asthma for adults and children by level of symptom control (uncontrolled, partly controlled, and well controlled) via a cross-sectional online survey administered to a national web panel. Participants were asked about healthcare utilisation, days missed from work, and reduced productivity due to their symptoms. These values were then monetised and multiplied by prevalence estimates of adult and child asthmatics to generate total costs.Results A total of 300 adults and 221 parents of children with asthma were included in analysis. The total annual cost of adult asthma was estimated to be SGD 1.74 billion (US$1.25 billion) with 42% coming from the uncontrolled group, 45% from the partly controlled group, and 13% from the well-controlled group. For children, the total cost is SGD 0.35 billion (US$0.25 billion), with 64%, 26% and 10% coming from each group respectively. Combined, the annual economic burden of asthma in Singapore is SGD 2.09 billion (US$1.50 billion) with 79% due to productivity losses.Conclusion Poorly controlled asthma imposes a significant economic burden. Therefore, better control of disease has the potential to generate not only health improvements, but also medical expenditure savings and productivity gains.

Background Singapore’s front-of-pack (FOP) Healthier Choice Symbol (HCS) label is an easy to understand signal to consumers of how they can make a healthier choice within a given food category. We assess its effectiveness at influencing food purchases and diet quality.Methods Randomized controlled trial using a 3×3 within-subject crossover design with adult Singapore residents recruited online. Each participant shopped once in three conditions on an experimental online grocery store in random order: 1) no FOP control; 2) Similar to Arm 1 except select products displayed HCSs, as would occur in stores in Singapore; 3) Similar to Arm 2 with additional information displaying Physical Activity Equivalents (PAEs) per serving of each product. Participants with minimum of one control and one intervention condition shop were analyzed. First-differenced regressions on calories per serving (primary) and other measures of diet quality were used to compare purchasing behavior across conditions. Results From January 2019 to April 2019, 117 participants were randomized: 10 (8·5%) completed one shop; 2 completed two shops (1.7%); and 105 (89·7%) completed all three, resulting in 317 unique shops. The HCS, without PAEs, led to a statistically significant five-percentage point increase in the proportion of HCS products purchased. However, we could not reject the null hypothesis of no difference in calories per serving in either HCS (95% CI, -10·63: 20·01) or when combined with PAEs (95% CI, -5·25: 21·54) or differences in any of the diet quality measures assessed.Conclusions The HCS influences purchasing patterns, but does not, either alone or in combination with a PAE label, appear to reduce caloric intake or improve overall diet quality. These findings suggest that the HCS label, as currently applied, may be the wrong label for addressing rising rates of obesity and non-communicable diseases in Singapore.

Background Several front-of-pack (FOP) labels identify healthier options by comparing foods within product categories. Alternative approaches label healthier options by comparing across categories. Which approach is superior remains unknown. The objective of this study was to test the effect of a within-category versus across-category FOP lower calorie label on 1) the percentage of labeled products purchased, 2) several measures of calories purchased (total, per dollar and per serving), and 3) total spending. We also tested the moderating effects of hunger and mood on purchasing patterns. Methods Using an online grocery store, we conducted a 3 × 3 crossover trial involving actual purchases with 146 participants randomly exposed to: 1) no labeling control; 2) within-category lower calorie labels, and; 3) across-category lower calorie labels. We labeled the 20% of products with the lowest calories per serving within or across categories. Purchases were compared using a fixed effects regression on first-differenced outcomes. Results Relative to the control condition, there was a 3 percentage point increase ( p = 0.01) in labelled products purchased in the within-category arm and a non-significant decrease of 1 percentage point ( p = 0.711) in the across-category arm. There was no significant difference in the proportion of labeled products purchased between the two labelling conditions. Neither strategy resulted in reductions in any measure of calories purchased or in total spending. When limited to beverages, there was a 398 cal reduction ( p = 0.01) in the within-category arm and a 438 cal reduction ( p < 0.01) in the across-category arm versus the control. Mood and hunger did not modify the effects for either strategy. Conclusions Results provide evidence that both labelling strategies have the potential to influence food purchasing patterns. However, we cannot definitely state that one labelling approach is superior or even that an increase in the proportion of labelled products purchased will lead to a reduction in calories purchased. Trial registration The American Economic Association’s registry for randomized controlled trials, RCT ID: AEARCTR-0002325; Prospectively Registered October 06, 2017. In compliance with ICMJE policy, the trial was also registered on Clinicaltrials.gov, RCT ID: [ NCT04165447 ]. Retrospectively Registered 11 November 2019.

Objective: To understand the prevalence of behavioral and characterological self-blame and their associations with stated preferences for life-extension and the use of pain-relief medication in a multi-country cohort of advanced cancer patients. Methods: The prevalence of self-blame and reasons participants attributed to their diagnosis was assessed in a sample of 968 advanced cancer patients enrolled in one of five sites from four Asian countries of the multi-country cross-sectional survey titled APRROACH. Ordered probit and Firth logistic regressions were used to determine associations between each type of self-blame and two treatment-related outcomes: participants' stated preference for life-extension and the use of pain-relief medication in the last 24 h. Results: Behavioral and characterological self-blame were reported by 41% and 49% of the participants respectively, with only 19% and 2% of participants providing a logically consistent reason for the two types of self-blame. We observed no statistically significant differences in stated preferences for life-extension for either type of self-blame and in the use of pain-relief medication for participants reporting behavioral self-blame. However, participants reporting characterological self-blame were 9.7% (95% CI, 2.0% to 17.3%; p = 0.014) more likely to report using pain-relief medication compared to participants not reporting characterological self-blame. Conclusions: A substantial proportion of patients report self-blame and those reporting characterological self-blame appear more likely to use pain medication. Therefore, developing interventions aimed at reducing characterological self-blame might help patients receive only appropriate treatments as opposed to treatments pursued in response to feelings of self-blame.

Public health taxes on less healthy food and beverage products have been shown to be effective in various settings. However, it is unclear if observed reductions in the quantity of taxed products purchased is a result of price increases due to the tax or the accompanying messaging and if the effects are influenced by the level of support for such taxes within the population. 941 adults residing in Singapore were randomized and asked to shop in one of four versions of a fully functional on-line experimental grocery store: 1) no tax control: 2) implicit tax showing only post-tax prices (i.e., 20% higher than control prices) on high-in-calorie products; 3) fake tax showing pre-tax prices and a label falsely indicating that the price includes a 20 % tax on high-in-calorie products; and 4) explicit tax showing the same label as in 3) and an actual 20 % price increase applied to the high-in-calorie products. The proportion of high-incalorie products purchased was 14 % in the control arm. We were unable to reject the null hypothesis of no effect in the implicit Lax arm compared to control (0.08. 95 % CI 3.31 to 1.77) or in the fake Lax arm compared to the control (2.59, 95 % CI -5.04 to 0.00) but observed a statistically significant 3.35 percentage point decrease (95 % CI -6.01 to -0.5) in the explicit tax arm compared to control. We were unable to reject the null hypothesis of no effect in any of the outcomes related to diet quality. Individuals who support the tax showed greater responsiveness to the explicit and fake taxes compared to those who do not (price elasticities of demand of -1.38 and -0.51 respectively). Results suggest that reductions in the proportions of high-in-calorie products purchased may be largely attributable to explicit messaging rather than to price increases. However, even when effective. policymakers should recognize that changes in purchasing patterns may not improve diet quality and that results may not generalize to other areas where levels of support differ. (C) 2020 The Authors. Published by Elsevier B.V.

Introduction People with type 2 diabetes (T2D) can improve glycaemic control or even achieve remission through weight loss and reduce their use of medication and risk of cardiovascular disease. The Glucose Lowering through Weight management (GLoW) trial will evaluate whether a tailored diabetes education and behavioural weight management programme (DEW) is more effective and cost-effective than a diabetes education (DE) programme in helping people with overweight or obesity and a recent diagnosis of T2D to lower their blood glucose, lose weight and improve other markers of cardiovascular risk.Methods and analysis This study is a pragmatic, randomised, single-blind, parallel group, two-arm, superiority trial. We will recruit 576 adults with body mass index>25 kg/m2 and diagnosis of T2D in the past 3 years and randomise them to a tailored DEW or a DE programme. Participants will attend …

OBJECTIVES:There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients.MATERIALS AND METHODS:We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted.RESULTS:A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time.CONCLUSIONS:This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.

Introduction People with type 2 diabetes (T2D) can improve glycaemic control or even achieve remission through weight loss and reduce their use of medication and risk of cardiovascular disease. The Glucose Lowering through Weight management (GLoW) trial will evaluate whether a tailored diabetes education and behavioural weight management programme (DEW) is more effective and cost-effective than a diabetes education (DE) programme in helping people with overweight or obesity and a recent diagnosis of T2D to lower their blood glucose, lose weight and improve other markers of cardiovascular risk.Methods and analysis This study is a pragmatic, randomised, single-blind, parallel group, two-arm, superiority trial. We will recruit 576 adults with body mass index> 25 kg/m2 and diagnosis of T2D in the past 3 years and randomise them to a tailored DEW or a DE programme. Participants will attend …

Background This study provides an integrated assessment of the economic and social impacts of genomic sequencing for the detection of monogenic disorders resulting in intellectual disability (ID). Methods Multiple knowledge bases were cross-referenced and analysed to compile a reference list of monogenic disorders associated with ID. Multiple literature searches were used to quantify the health and social costs for the care of people with ID. Health and social expenditures and the current cost of whole-exome sequencing and whole-genome sequencing were quantified in relation to the more common causes of ID and their impact on lifespan. Results On average, individuals with ID incur annual costs in terms of health costs, disability support, lost income and other social costs of US$172 000, accumulating to many millions of dollars over a lifetime. Conclusion The diagnosis of monogenic disorders through genomic testing provides the opportunity to improve the diagnosis and management, and to reduce the costs of ID through informed reproductive decisions, reductions in unproductive diagnostic tests and increasingly targeted therapies.