The cost-effectiveness of procalcitonin for guiding antibiotic prescribing in individuals hospitalized with COVID-19: part of the PEACH study.

BACKGROUND: Many hospitals introduced procalcitonin (PCT) testing to help diagnose bacterial coinfection in individuals with COVID-19, and guide antibiotic decision-making during the COVID-19 pandemic in the UK. OBJECTIVES: Evaluating cost-effectiveness of using PCT to guide antibiotic decisions in individuals hospitalized with COVID-19, as part of a wider research programme. METHODS: Retrospective individual-level data on patients hospitalized with COVID-19 were collected from 11 NHS acute hospital Trusts and Health Boards from England and Wales, which varied in their use of baseline PCT testing during the first COVID-19 pandemic wave. A matched analysis (part of a wider analysis reported elsewhere) created groups of patients whose PCT was/was not tested at baseline. A model was created with combined decision tree/Markov phases, parameterized with quality-of-life/unit cost estimates from the literature, and used to estimate costs and quality-adjusted life years (QALYs). Cost-effectiveness was judged at a £20 000/QALY threshold. Uncertainty was characterized using bootstrapping. RESULTS: People who had baseline PCT testing had shorter general ward/ICU stays and spent less time on antibiotics, though with overlap between the groups' 95% CIs. Those with baseline PCT testing accrued more QALYs (8.76 versus 8.62) and lower costs (£9830 versus £10 700). The point estimate was baseline PCT testing being dominant over no baseline testing, though with uncertainty: the probability of cost-effectiveness was 0.579 with a 1 year horizon and 0.872 with a lifetime horizon. CONCLUSIONS: Using PCT to guide antibiotic therapy in individuals hospitalized with COVID-19 is more likely to be cost-effective than not, albeit with uncertainty.

Evidence of quality of life for hospitalised patients with COVID-19: a scoping review.

Background: Information on the quality of life of people hospitalised with COVID-19 is important, both in assessing the burden of disease and the cost-effectiveness of treatments. However, there were potential barriers to collecting such evidence. Objective: To review the existing evidence on quality of life for people hospitalised with COVID-19, with a focus on the amount of evidence available and methods used. Design: A scoping review with systematic searches. Results: A total of 35 papers were selected for data extraction. The most common study type was economic evaluation (N = 13), followed by cross-sectional (N = 10). All economic evaluations used published utility values for other conditions to represent COVID-19 inpatients' quality of life. The most popular quality-of-life survey measure was the Pittsburgh Sleep Quality Index (N = 8). There were 12 studies that used a mental health-related survey and 12 that used a sleep-related survey. Five studies used EQ-5D, but only one collected responses from people in the acute phase of COVID-19. Studies reported a negative impact on quality of life for people hospitalised with COVID-19, although many studies did not include a formal comparison group. Limitations: Although it used systematic searches, this was not a full systematic review. Conclusion: Quality-of-life data were collected from people hospitalised with COVID-19 from relatively early in the pandemic. However, there was a lack of consensus as to what survey measures to use, and few studies used generic health measures. Economic evaluations for COVID-19 treatments did not use utilities collected from people with COVID-19. In future health crises, researchers should be vigilant for opportunities to collect quality-of-life data from hospitalised patients but should try to co-ordinate as well as ensuring generic health measures are used more. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132254.

Quality of life can be measured using short, simple surveys. It is important to assess quality of life in this way, as it can show how health conditions affect people. Quality-of-life surveys can also be used to measure how treatments benefit people and to judge whether it is cost-effective to fund them. COVID-19 is a new disease, with new treatments developed to treat it. COVID-19 also created possible barriers to collecting quality-of-life survey data, especially from people in hospital at the start of the pandemic. This paper reviews studies which report data on quality of life for people hospitalised with COVID-19, especially how much evidence is available and how the studies were carried out. There were 35 studies included in the review. Of these, 13 assessed how cost-effective treatments for COVID-19 were. None of them collected survey responses directly from patients. Instead, they used data previously collected from people with other conditions such as influenza to represent people with COVID-19's quality of life. The studies which did collect data from patients used a wide variety of different surveys, which made comparing their results difficult. Mental health-related surveys were used by 12 studies, and a further 12 used sleep-related surveys. Relatively few studies used general surveys which could assess the overall effect of COVID-19 on people's quality of life. In future health crises, we recommend using more general quality-of-life measures. We also recommend that researchers co-ordinate to reduce the number of different surveys they use, as this will make comparing results easier.

Fixing the Leaky Pipe: How to Improve the Uptake of Patient-Reported Outcomes-Based Prognostic and Predictive Models in Cancer Clinical Practice.

PURPOSE: This discussion paper outlines challenges and proposes solutions for successfully implementing prediction models that incorporate patient-reported outcomes (PROs) in cancer practice. METHODS: We organized a full-day multidisciplinary meeting of people with expertise in cancer care delivery, PRO collection, PRO use in prediction modeling, computing, implementation, and decision science. The discussions presented here focused on identifying challenges to the development, implementation and use of prediction models incorporating PROs, and suggesting possible solutions. RESULTS: Specific challenges and solutions were identified across three broad areas. (1) Understanding decision making and implementation: necessitating multidisciplinary collaboration in the early stages and throughout; early stakeholder engagement to define the decision problem and ensure acceptability of PROs in prediction; understanding patient/clinician interpretation of PRO predictions and uncertainty to optimize prediction impact; striving for model integration into existing electronic health records; and early regulatory alignment. (2) Recognizing the limitations to PRO collection and their impact on prediction: incorporating validated, clinically important PROs to maximize model generalizability and clinical engagement; and minimizing missing PRO data (resulting from both structural digital exclusion and time-varying factors) to avoid exacerbating existing inequalities. (3) Statistical and modeling challenges: incorporating statistical methods to address missing data; ensuring predictive modeling recognizes complex causal relationships; and considering temporal and geographic recalibration so that model predictions reflect the relevant population. CONCLUSION: Developing and implementing PRO-based prediction models in cancer care requires extensive multidisciplinary working from the earliest stages, recognition of implementation challenges because of PRO collection and model presentation, and robust statistical methods to manage missing data, causality, and calibration. Prediction models incorporating PROs should be viewed as complex interventions, with their development and impact assessment carried out to reflect this.

Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting. METHODS: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants. FINDINGS: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication. INTERPRETATION: To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).

Acceptability, fidelity and trial experience of four intervention components to support medication adherence in women with breast cancer: A process evaluation protocol for a pilot fractional factorial trial.

Background: The Refining and Optimising a behavioural intervention to Support Endocrine Therapy Adherence (ROSETA) programme has developed four intervention components aiming to improve medication adherence in women with early-stage breast cancer. These are (a) text messages, (b) information leaflet, (c) Acceptance and Commitment Therapy-based guided self-help (ACT), (d) side-effect management website. Guided by the Multiphase Optimisation Strategy, our pilot trial will use a fractional factorial design to evaluate the feasibility of undertaking a larger optimisation trial. The pilot will include a process evaluation to maximise learning regarding the fidelity and acceptability of the intervention components before proceeding with a larger trial. The trial process evaluation has three aims: to assess the (1) fidelity and (2) acceptability of the intervention components; and (3) to understand participant's trial experience, and barriers and facilitators to recruitment and retention. Methods: The process evaluation will use multiple methods. Fidelity of the intervention components will be assessed using self-reported questionnaire data, trial data on intervention component adherence, and observations of the ACT sessions. Acceptability of the intervention components and trial experience will be explored using an acceptability questionnaire and interviews with patients and trial therapists. Trial experience will be assessed using a questionnaire and interviews with participants, while barriers and facilitators to recruitment and retention will be assessed using a questionnaire completed by research nurses and participant interviews. The pilot trial opened for recruitment on 20th May 2022 and was open at the time of submission. Conclusions: This process evaluation will provide information regarding whether the intervention components can be delivered with fidelity within a national healthcare setting and are acceptable to participants. We will also better understand participant experience in a pilot trial with a fractional factorial design, and any barriers and facilitators to recruitment and retention. Registration: ISRCTN registry ( ISRCTN10487576, 16/12/2021).

BACKGROUND: The majority of women with early-stage breast cancer are recommended adjuvant endocrine therapy (AET) to reduce the chances of their cancer coming back. Many women given this medication don't take it every day or stop taking it earlier than they should. We have developed four different interventions to help women take AET. These are; text messages reminding women to take AET; an information leaflet explaining how AET works and its benefits and side-effects; a therapy programme to reduce distress, consisting of five support sessions and four module booklets; and a website with strategies to manage AET side-effects. We are now testing whether these interventions can be delivered within the NHS in different combinations, in a small trial. STUDY METHODS: We have three aims: 1. To find out if the interventions can be given and are received in the way they were supposed to (fidelity).2. To find out if the support received as part of the trial was acceptable to women with breast cancer (acceptability).3. To find out what women's experience was of taking part in the trial overall (trial experience). To do this we will: 1. Interview participants to ask them how acceptable they found the interventions, what they understood, whether they used the interventions, and how they found participating in the trial.2. Interview therapists who delivered the therapy programme to see if they delivered it as they were supposed to, and how they found delivering the intervention.3. Ask participants to complete questionnaires about how acceptable the interventions were, and whether they read and used them.4. Ask the staff involved in finding participants for the trial about challenges and improvements. We will use what we find to make improvements in a future trial where we will test whether the interventions help women to take AET.

We need to talk about values: a proposed framework for the articulation of normative reasoning in health technology assessment.

It is acknowledged that health technology assessment (HTA) is an inherently value-based activity that makes use of normative reasoning alongside empirical evidence. But the language used to conceptualise and articulate HTA's normative aspects is demonstrably unnuanced, imprecise, and inconsistently employed, undermining transparency and preventing proper scrutiny of the rationales on which decisions are based. This paper - developed through a cross-disciplinary collaboration of 24 researchers with expertise in healthcare priority-setting - seeks to address this problem by offering a clear definition of key terms and distinguishing between the types of normative commitment invoked during HTA, thus providing a novel conceptual framework for the articulation of reasoning. Through application to a hypothetical case, it is illustrated how this framework can operate as a practical tool through which HTA practitioners and policymakers can enhance the transparency and coherence of their decision-making, while enabling others to hold them more easily to account. The framework is offered as a starting point for further discussion amongst those with a desire to enhance the legitimacy and fairness of HTA by facilitating practical public reasoning, in which decisions are made on behalf of the public, in public view, through a chain of reasoning that withstands ethical scrutiny.

Refining and optimising a behavioural intervention to support endocrine therapy adherence (ROSETA) in UK women with breast cancer: protocol for a pilot fractional factorial trial.

INTRODUCTION: Women with breast cancer who do not adhere to adjuvant endocrine therapy (AET) have increased risks of mortality and recurrence. There are multiple barriers to AET adherence, including medication side-effects, beliefs about medication, memory and psychological distress. We developed four intervention components, each targeting a different barrier. This pilot trial is part of the preparation phase of the Multiphase Optimisation Strategy, and aims to establish key trial parameters, establish intervention component adherence, establish availability and feasibility of outcome and process data, estimate variability in planned outcome measures and estimate cost of developing and delivering each intervention component. METHODS AND ANALYSIS: The four intervention components are as follows: short message service text reminders (target: memory); a written information leaflet (target: medication beliefs); a guided self-help Acceptance and Commitment Therapy programme (target: psychological flexibility to reduce distress) and a self-management website (target: side-effect management). To evaluate the feasibility of recruitment, acceptability of the intervention components and the availability of outcome data, we will conduct a multisite, exploratory pilot trial using a 24-1 fractional factorial design, with a nested process evaluation. We will randomise 80 women with early-stage breast cancer who have been prescribed AET to one of eight experimental conditions. This will determine the combination of intervention components they receive, ranging from zero to four, with all conditions receiving usual care. Key outcomes of interest include medication adherence and quality of life. Progression to the optimisation phase will be based on predefined criteria for consent rates, patient adherence to intervention components and availability of medication adherence data. ETHICS AND DISSEMINATION: The study was reviewed by the Wales Research Authority Research Ethics Committee 3 (21/WA/0322). Written informed consent will be obtained from all patients before randomisation. The results of this trial will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRTCN10487576.

Progression of frailty as measured by a cumulative deficit index: A systematic review.

BACKGROUND: Frailty is a risk factor for adverse health outcomes. There is a paucity of literature on frailty progression defined by a cumulative deficit model among community dwelling older people. The objective of this review was to synthesise evidence on these changes in health and mortality among community-dwelling older people. METHODS: Six databases (Medline, Embase, CINAHL, Cochrane, PsycInfo, Web of Science) and a clinical trials registry were searched in July 2021. The inclusion criteria were studies using a frailty index and providing information on transition between frailty states or to death in community-dwelling older people aged ≥ 50. Exclusion criteria were studies examining specific health conditions, conference abstracts and non-English studies. To standardise the follow-up period and facilitate comparison, we converted the transition probabilities to annual transition rates. RESULTS: Two reviewers independently screened 5078 studies and 61 studies were included for analysis. Of these, only three used the same frailty state cut-points to facilitate cross-cohort comparison. This review found that frailty tends to increase with time, people who are frail at baseline have greater likelihood to progress in frailty and die, and the main factor that accelerates frailty progression is age. Other risk factors for progression are having chronic disease, smoking, obesity, low-income or/and low-education levels. A frailty index is an accurate predictor of adverse outcomes and death. DISCUSSION: This systematic review demonstrated that worsening in frailty was a common frailty transition, and older people who are frail at baseline are more likely to die. A frailty index has significant power to predict adverse health outcomes. It is a useful tool for within-cohort comparison but there are challenges comparing different cohorts due to dependence of frailty progression on age and differences in how frailty index is defined and measured.

Replacing performance status with a simple patient-reported outcome in palliative radiotherapy prognostic modelling.

Background and purpose: Prognostication is key to determining care in advanced incurable cancer. Although performance status (PS) has been shown to be a strong prognostic predictor, inter-rater reliability is limited, restricting models to specialist settings. This study assessed the extent to which a simple patient-reported outcome measure (PROM), the EQ-5D, may replace PS for prognosis of patients with bone metastases. Materials and methods: Data from 1,011 patients in the Dutch Bone Metastasis Study were used. Cox proportional hazards models were developed to investigate the prognostic value of models incorporating PS alone, the EQ-5D SC dimension alone, all EQ-5D dimensions and EQ-VAS, and finally all dimensions and PS. Three prognostic groups were identified and performance assessed using the Harrell's C-index and Altman-Royston index of separation. Results: Replacing performance status (PS) with the self-care (SC) dimension of the EQ-5D provides similar model performance. In our SC-based model, three groups are identified with median survival of 86 days (95 % CI 76-101), 174 days (95 % CI 145-213), and 483 days (95 % CI 431-539). Whilst not statistically significantly different, the C-index was 0.706 for the PS-only model, 0.718 for SC-only and 0.717 in our full model, suggesting patient-report outcome models perform as well as that based on PS. Conclusion: Prognostic performance was similar across all models. The SC model provides prognostic value similar to that of PS, particularly where a prognosis of<6 months is considered. Larger, more contemporaneous studies are needed to assess the extent to which PROMs may be of prognostic value, particularly where specialist assessment is less feasible.

Economic Evaluation Evidence for Resource-Allocation Decision Making: Bridging the Gap for Local Decision Makers Using English Case Studies.

Best-practice economic evaluation methods for health-related decision making at a national level in England are well established, and as a first principle generally involve attempting to maximise the amount of health generated from the health system's budget. Such methods are applied in ways that are broadly transparent and accountable, often at arm's length from explicit political pressures. At local levels of decision making, however, decision making is arguably less likely to be applied according to established overarching principles, is less transparent and is more subject to political pressures. This may be owing to a multiplicity of reasons, for example, undesirability/inappropriateness of such methods, or a failure to make the methods clear to local decision makers. We outline principles for economic evaluations and break down these methods into their component parts, considering their relevance in the English local context. These include taxonomies of decision-making frameworks, budgets, costs, outcome, and characterisations of cost effectiveness. We also explore the role of broader factors, including the relevance of assuming a single fixed budget, pressures resulting from political and budgetary cycles and affordability. We consider the data requirements to inform such deliberations. By setting out principles for economic evaluation methods in a clear language aimed at local decision making, a potential role for such methods can be established, which to date has failed to emerge. While the extent to which these methods can and should be applied are a matter for continued debate, the establishment of such a mutual understanding may assist in the improvement of methods for such decision making and the outcomes resulting from their application.

Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear. METHODS: ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care. DISCUSSION: Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. TRIAL REGISTRATION: ISRCTN ISRCTN48075063 . Registered on 7th June 2019.

Early economic evaluation of an intervention to improve uptake of the NHS England Diabetes Prevention Programme.

BACKGROUND: Despite reported increases in referral numbers, a large proportion of those with prediabetes still decline participation in the NHS England Diabetes Prevention Programme (NDPP). The aim of this study was to explore whether investment in interventions to improve uptake of the programme has the potential to be cost-effective. METHODS: An early cost-utility analysis was conducted using a Markov model parameterized based on secondary data sources. We explored different uptake scenarios and the impact that this had on the maximum allowable intervention price based on cost-effectiveness at the UK NICE willingness to pay threshold of £20,000 (US$ 25,913). Value of information analyses were conducted to explore the potential value of further research to resolve uncertainty at each uptake level. RESULTS: As uptake levels increase, the maximum allowable intervention price and overall expected value of removing decision uncertainty increases. For 5 percentage and 50 percentage points increase in uptake levels, the maximum allowable intervention price is £41.86 (US$ 54.23) and £418.59 (US$ 542.34) per person, and the overall expected value of removing decision uncertainty are £361,818,839 (US$ 468,786,625) and £1,468,712,316 (US$ 1,902,921,063) respectively. CONCLUSION: There is headroom for investment in interventions that improve uptake to the NDPP, thereby allowing the programme itself to be delivered in a manner that remains cost-effective.

Implementation of biopsychosocial supported self-management for chronic primary oro-facial pain including temporomandibular disorders: A theory, person and evidence-based approach.

BACKGROUND: Aims of the study were to: Implement supported self-management for chronic primary oro-facial pain in a clinical setting. Evaluate its impact on consultation rates, pain severity, interference with life and patient experience. METHODS: Sixty-six patients with chronic primary oro-facial pain received the intervention at a facial pain clinic at Leeds Dental Institute, UK. Brief Pain Inventory (BPI) scores measured pain severity and interference with life before and after the intervention. Process mining outlined patient care pathways. Monthly consultation rates measured 12 months before and after the intervention were used to evaluate burden on healthcare services and economic impact. Patient feedback was assessed via Patient and Public involvement discussion groups. RESULTS: Mean BPI scores significantly improved after intervention-from 5.70 (SD 1.89) to 3.78 (SD 2.34) (p < .001); mean pain interference score reduced from 19.95 (SD 9.41) to 12.05 (SD 9.64) (p < .001). Average monthly consultations significantly (p = .001) reduced from 0.42/month before the intervention to 0.16/month after the intervention. Economic assessment showed cost savings of £293 per patient per year. Process mining showed high rates of service usage with 31 patients also attending 51 other specialist services between them. Patient and Public Involvement discussion groups with 5 patients identified that the intervention was a 'constant companion' and should be implemented at the outset in the care pathway. CONCLUSION: Supported self-management for chronic primary oro-facial pain has a positive impact on health outcomes (physical functioning, pain intensity and patient experience), as well as service usage and healthcare costs when implemented in a secondary care clinical setting. Reconfiguring current care pathways to upscale early implementation of such interventions should be a priority for future testing.

Survival outcome and prognostic factors of patients with nasopharyngeal cancer in Yogyakarta, Indonesia: A hospital-based retrospective study.

PURPOSE: This study aimed to determine the survival outcome and prognostic factors of patients with nasopharyngeal cancer accessing treatment in Yogyakarta, Indonesia. METHODS: Data on 759 patients with NPC diagnosed from 2007 to 2016 at Dr Sardjito General Hospital were included. Potential prognostic variables included sociodemographic, clinicopathology and treatment parameters. Multivariable analyses were implemented using semi-parametric Cox proportional hazards modelling and fully parametric survival analysis. RESULTS: The median time of observation was 14.39 months. In the whole cohort the median observed survival was 31.08 months. In the univariable analysis, age, education status, insurance type, BMI, ECOG index, stage and treatment strategy had an impact on overall survival (OS) (p values <0.01). Semi-parametric multivariable analyses with stage stratification showed that education status, ECOG index, and treatment modality were independent prognostic factors for OS (p values <0.05). In the fully parametric models age, education status, ECOG index, stage, and treatment modality were independent prognostic factors for OS (p values <0.05). For both multivariable analyses, all treatment strategies were associated with a reduced hazard (semi-parametric models, p values <0.05) and a better OS (parametric models, p values <0.05) compared with no treatment. Furthermore, compared with radiation alone or chemotherapy alone, a combination of chemotherapy and radiation either in a form of concurrent chemoradiotherapy (CCRT), sequential chemotherapy and radiation, or induction chemotherapy followed by CCRT demonstrated a reduced hazard (hazard ratio/HR 0.226, 95% confidence interval/CI 0.089-0.363, and HR 0.390, 95%CI 0.260-0.519) and a better OS (time ratio/TR 3.108, 95%CI 1.274-4.942 and TR 2.531, 95%CI 1.829-3.233) (p values < 0.01). CONCLUSIONS: Median OS for the cohort was low compared to those reported in both endemic and non-endemic regions. By combining the findings of multivariable analyses, we showed that age, education status, ECOG index, stage and first treatment modality were independent predictors for the OS.

Healthcare trajectories and costs in the last year of life: a retrospective primary care and hospital analysis.

OBJECTIVES: To analyse healthcare utilisation and costs in the last year of life in England, and to study variation by cause of death, region of patient residence and socioeconomic status. METHODS: This is a retrospective cohort study. Individuals aged 60 years and over (N=108 510) who died in England between 2010 and 2017 were included in the study. RESULTS: Healthcare utilisation and costs in the last year of life increased with proximity to death, particularly in the last month of life. The mean total costs were higher among males (£8089) compared with females (£6898) and declined with age at death (£9164 at age 60-69 to £5228 at age 90+) with inpatient care accounting for over 60% of total costs. Costs decline with age at death (0.92, 95% CI 0.88 to 0.95, p<0.0001 for age group 90+ compared with to the reference category age group 60-69) and were lower among females (0.91, 95% CI 0.90 to 0.92, p<0.0001 compared with males). Costs were higher (1.09, 95% CI 1.01 to 1.14, p<0.0001) in London compared with other regions. CONCLUSIONS: Healthcare utilisation and costs in the last year of life increase with proximity to death, particularly in the last month of life. Finer geographical data and information on healthcare supply would allow further investigating whether people receiving more planned care by primary care and or specialist palliative care towards the end of life require less acute care.

The relationship between early life urbanicity and depression in late adulthood: evidence from the Survey of Health, Ageing and Retirement in Europe.

OBJECTIVES: We aimed to study the association of childhood urbanicity with depressive symptoms in late adulthood. DESIGN, SETTING AND PARTICIPANTS: We used linear and logistic regressions to analyse data drawn from 20 400 respondents from the Survey of Health, Ageing and Retirement in Europe, a panel dataset incorporating a representative sample of the 50+ population in 13 European countries. OUTCOMES AND ANALYSIS: Childhood urbanicity was determined using self-reports of the respondents' circumstances at age 10, and late-adulthood depression using the EURO-D scale. We conditioned on circumstances early in life as well as later in life, most importantly late-adulthood urbanicity. We estimated the associations using linear regression models and limited dependent variable models. RESULTS: A pooled regression of both men and women suggested that childhood urbanicity is associated non-monotonically with depression in late adulthood and is particularly apparent for those spending their childhoods in suburban settings. We found that individuals who spend the longest time in their childhood in a suburban home exhibit an average increase in probability of 3.4 (CI 1.1 to 5.7) percentage points in reporting four or more depressive symptoms. The association was robust to the inclusion of a host of household characteristics associated with childhood urbanicity and was independent of current urbanicity and current income. When broken down by gender, we found some evidence of associations between depressive outcomes and urban living for men, and stronger evidence of such associations with urban and suburban living for women who exhibit an increase of 5.6 (CI 2.2 to 9.0) percentage points in reporting four or more depressive symptoms. CONCLUSIONS: Our analysis reveals a relationship between childhood urbanicity and depression in late adulthood. The evidence presented on the nature of this relationship is not straightforward but is broadly suggestive of a link, differing by gender, between greater urbanicity and higher levels of depressive symptoms. The life-long nature of this association may potentially inform policy agendas aimed at improving urban and suburban living conditions.

Implications of Nonmarginal Budgetary Impacts in Health Technology Assessment: A Conceptual Model.

OBJECTIVES: This paper introduces a framework with which to conceptualize the decision-making process in health technology assessment for new interventions with high budgetary impacts. In such circumstances, the use of a single threshold based on the marginal productivity of the healthcare system is inappropriate. The implications of this for potential partial implementation, horizontal equity, and pharmaceutical pricing are illustrated using this framework. RESULTS: Under the condition of perfect divisibility and given an objective of maximizing health, a large budgetary impact of a new treatment may imply that optimal implementation is partial rather than full, even at a given incremental cost-effectiveness ratio that would nevertheless mean the decision to accept the treatment in full would not lead to a net reduction in health. In a one-shot price-setting game, this seems to give rise to potential horizontal equity concerns. When the assumption of fixity of the incremental cost-effectiveness ratio (arising from the assumed exogeneity of the manufacturer's price) is relaxed, it can be shown that the threat of partial implementation may be sufficient to give rise to an incremental cost-effectiveness ratio at which cost the entire potential population is treated, maximizing health at an increased level, and with no contravention of the horizontal equity principle.

Childhood Socioeconomic Status and Late-Adulthood Mental Health: Results From the Survey on Health, Ageing and Retirement in Europe.

Objectives: A growing literature acknowledges the association between childhood socioeconomic status (SES) and health in late adulthood (i.e., 50+). Less, however, is known about the association with mental health outcomes, such as depression. We use the Survey on Health, Ageing, and Retirement in Europe (SHARE) to analyze overall and gender-specific associations between childhood SES and late-adulthood depression. Methods: Using life history and contemporaneous data from 21,989 SHARE respondents in combination with principal component analysis we construct indices of childhood SES. We measure late-adulthood depression using the EURO-D scale. Contemporaneous SES is operationalized as the logarithm of household equivalized income. We estimate associations using linear regression models. Results: We document a positive association between childhood SES and the late-adulthood EURO-D score. The association persists even when allowing for contemporaneous SES. Zooming in on gender-specific associations reveals that the association for mental health is particularly pronounced for women. Discussion: Our findings reveal the long-term association between childhood socioeconomic conditions and depression later in life, which persists even after taking into account current socioeconomic conditions and are stronger for women than for men. These results imply that boosting childhood socioeconomic conditions can potentially have effects lasting well beyond the childhood phase.

Health care expenditures, age, proximity to death and morbidity: Implications for an ageing population.

This paper uses Hospital Episode Statistics, English administrative data, to investigate the growth in admitted patient health care expenditures and the implications of an ageing population. We use two samples of around 40,000 individuals who (a) used inpatient health care in the financial year 2005/06 and died by the end of 2011/12 and (b) died in 2011/12 and had some hospital utilisation since 2005/06. We use a panel structure to follow individuals over seven years of this administrative data, containing estimates of inpatient health care expenditures (HCE), information regarding individuals' age, time-to-death (TTD), morbidities at the time of an admission, as well as the hospital provider, year and season of admission. We show that HCE is principally determined by proximity to death rather than age, and that proximity to death is itself a proxy for morbidity.

A discrete latent factor model for smoking, cancer and mortality.

This paper investigates the relationship between smoking and ill-health, with a focus on the onset of cancer. A discrete latent factor model for smoking and health outcomes, allowing for these to be commonly affected by unobserved factors, is jointly estimated, using the British Health and Lifestyle Survey (HALS) dataset. Post-estimation predictions suggest the reduction in time-to-cancer to be 5.7 years for those with an exposure of 30 pack-years, compared to never-smokers. Estimation of posterior probabilities for class membership shows that individuals in certain classes exhibit similar observables but highly divergent health outcomes, suggesting that unobserved factors influence outcomes. The use of a joint model changes the results substantially. The results show that failure to account for unobserved heterogeneity leads to differences in survival times between those with different smoking exposures to be overestimated by more than 50% (males, with 30 pack-years of exposure).