Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91).

BACKGROUND: The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control. 10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects. We aimed to determine whether these effects would wane by extending follow-up for another 14 years. METHODS: 5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years. Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan-Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837. FINDINGS: Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3-26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2-17; p=0·015) for death from any cause, 17% (6-26; p=0·002) for myocardial infarction, and 26% (14-36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively. Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5-32; p=0·010) for death from any cause and 31% (12-46; p=0·003) for myocardial infarction. Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy. INTERPRETATION: Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible. FUNDING: University of Oxford Nuffield Department of Population Health Pump Priming.

Examining the impact of structural uncertainty across ten type 2 diabetes models: Results from the 2022 Mount Hood Challenge.

OBJECTIVE: The Mount Hood Diabetes Challenge Network aimed to examine the impact of model structural uncertainty on the estimated cost-effectiveness of interventions for type 2 diabetes. METHODS: Ten independent modelling groups completed a blinded simulation exercise to estimate the cost-effectiveness of three interventions in two type 2 diabetes populations. Modelling groups were provided with a common baseline population, cost and utility values associated with different model health states, and instructions regarding time horizon and discounting. We collated the results to identify variation in predictions of net monetary benefit (NMB), and the drivers of those differences. RESULTS: Overall, modelling groups agreed which interventions had a positive NMB (i.e. were cost-effective), though estimates of NMB varied substantially- by up to £23,696 for one intervention. Variation was mainly driven through differences in risk equations for complications of diabetes and their implementation between models. The number of modelled health states was also a significant predictor of NMB. CONCLUSIONS: This exercise demonstrates that structural uncertainty between different health economic models impacts cost-effectiveness estimates. Whilst it is reassuring that a decision maker would likely reach similar conclusions on which interventions were cost-effective using most models, the range in numerical estimates generated across different models would nevertheless be important for price-setting negotiations with intervention developers. Minimising the impact of structural uncertainty on healthcare decision making therefore remains an important priority. Model registries, which record and compare the impact of structural assumptions, offer one potential avenue to improve confidence in the robustness of health economic modelling.

Values, challenges, and responses associated with high-priced potential cures: perspectives of diverse stakeholders in South Korea.

BACKGROUND: The emergence of high-priced potential cures has sparked significant health policy discussions in South Korea, where the healthcare system is funded through a single-payer National Health Insurance model. We conducted focus group interviews (FGIs) and accompanying surveys with diverse stakeholders to comprehensively understand related issues and find better solutions to the challenges brought by these technologies. METHODS: From October to November 2022, 11 FGIs were conducted with stakeholders from various sectors, including government payers, policy and clinical experts, civic and patient organisations, and the pharmaceutical industry, involving a total of 25 participants. These qualitative discussions were supplemented by online surveys to effectively capture and synthesise stakeholder perspectives. RESULTS: Affordability was identified as a critical concern by 84% of stakeholders, followed by clinical uncertainty (76%) and limited value for money (72%). Stakeholders expressed a preference for both financial-based controls and outcome-based pricing strategies to mitigate these challenges. Despite the support for outcome-based refunds, payers raised concerns about the feasibility of instalment payment models, whether linked to outcomes or not, due to the specific challenges of the Korean reimbursement system and the potential risk of 'cumulative liabilities' from ongoing payments for previously administered treatments. In addition, the FGIs highlighted the need for clear budgetary limits for drugs with high uncertainties, with mixed opinions on the creation of special silo funds (64.0% agreement). Less than half (48%) endorsed the use of external reference pricing, currently applied to such essential drugs in South Korea. A significant majority (84%), predominantly non-pharma stakeholders, advocated for addressing cost-effectiveness uncertainty through re-assessment once long-term clinical data become available. CONCLUSIONS: This study uncovers a broad agreement among stakeholders on the need for more effective value assessment methodologies for high-priced potential cures, stressing the importance of more robust and comprehensive re-assessment supported by long-term data collection, rather than primarily relying on external reference pricing. Each type of stakeholders exhibited a cautious approach to their specific uncertainties, suggesting that new funding strategies should accommodate these uncertainties with predefined guidelines and agreements prior to the initiation of managed entry agreements.

Citizens from 13 countries share similar preferences for COVID-19 vaccine allocation priorities.

How does the public want a COVID-19 vaccine to be allocated? We conducted a conjoint experiment asking 15,536 adults in 13 countries to evaluate 248,576 profiles of potential vaccine recipients who varied randomly on five attributes. Our sample includes diverse countries from all continents. The results suggest that in addition to giving priority to health workers and to those at high risk, the public favors giving priority to a broad range of key workers and to those with lower income. These preferences are similar across respondents of different education levels, incomes, and political ideologies, as well as across most surveyed countries. The public favored COVID-19 vaccines being allocated solely via government programs but were highly polarized in some developed countries on whether taking a vaccine should be mandatory. There is a consensus among the public on many aspects of COVID-19 vaccination, which needs to be taken into account when developing and communicating rollout strategies.

The COVID-19 pandemic and health-related quality of life across 13 high- and low-middle-income countries: A cross-sectional analysis.

BACKGROUND: Most research on the Coronavirus Disease 2019 (COVID-19) health burden has focused on confirmed cases and deaths, rather than consequences for the general population's health-related quality of life (HRQoL). It is also important to consider HRQoL to better understand the potential multifaceted implications of the COVID-19 pandemic in various international contexts. This study aimed to assess the association between the COVID-19 pandemic and changes in HRQoL in 13 diverse countries. METHODS AND FINDINGS: Adults (18+ years) were surveyed online (24 November to 17 December 2020) in 13 countries spanning 6 continents. Our cross-sectional study used descriptive and regression-based analyses (age adjusted and stratified by gender) to assess the association between the pandemic and changes in the general population's HRQoL, measured by the EQ-5D-5L instrument and its domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and how overall health deterioration was associated with individual-level (socioeconomic, clinical, and experiences of COVID-19) and national-level (pandemic severity, government responsiveness, and effectiveness) factors. We also produced country-level quality-adjusted life years (QALYs) associated to COVID-19 pandemic-related morbidity. We found that overall health deteriorated, on average across countries, for more than one-third of the 15,480 participants, mostly in the anxiety/depression health domain, especially for younger people (<35 years old) and females/other gender. This translated overall into a 0.066 mean "loss" (95% CI: -0.075, -0.057; p-value < 0.001) in the EQ-5D-5L index, representing a reduction of 8% in overall HRQoL. QALYs lost associated with morbidity were 5 to 11 times greater than QALYs lost based on COVID-19 premature mortality. A limitation of the study is that participants were asked to complete the prepandemic health questionnaire retrospectively, meaning responses may be subject to recall bias. CONCLUSIONS: In this study, we observed that the COVID-19 pandemic was associated with a reduction in perceived HRQoL globally, especially with respect to the anxiety/depression health domain and among younger people. The COVID-19 health burden would therefore be substantially underestimated if based only on mortality. HRQoL measures are important to fully capture morbidity from the pandemic in the general population.

Effects of Allopurinol on the Progression of Chronic Kidney Disease.

BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).

Clinically Translatable Transcrocetin Delivery Platform for Correction of Tumor Hypoxia and Enhancement of Radiation Therapy Effects.

Improving the tumor reoxygenation to sensitize the tumor to radiation therapy is a cornerstone in radiation oncology. Here, the pre-clinical development of a clinically transferable liposomal formulation encapsulating trans sodium crocetinate (NP TSC) is reported to improve oxygen diffusion through the tumor environment. Early pharmacokinetic analysis of the clinical trial of this molecule performed on 37 patients orient to define the optimal fixed dosage to use in a triple-negative breast cancer model to validate the therapeutic combination of radiation therapy and NP TSC. Notably, it is reported that this formulation is non-toxic in both humans and mice at the defined fixed concentration, provides a normalization of the tumor vasculature within 72 h window after systemic injection, leads to a transient increase (50% improvement) in the tumor oxygenation, and significantly improves the efficacy of both mono-fractionated and fractionated radiation therapy treatment. Together, these findings support the introduction of a first-in-class therapeutic construct capable of tumor-specific reoxygenation without associated toxicities.

Economic effects for citizens and the government of a country-level tobacco endgame strategy: a modelling study.

BACKGROUND: Aotearoa-New Zealand (A/NZ) was the first country to pass a comprehensive commercial tobacco endgame strategy into law. Key components include the denicotinisation of smoked tobacco products and a major reduction in tobacco retail outlets. Understanding the potential long-term economic impacts of such measures is important for government planning. DESIGN: A tobacco policy simulation model that evaluated the health impacts of the A/NZ Smokefree Action Plan was extended to evaluate the economic effects from both government and citizen perspectives. Estimates were presented in 2021 US$, discounted at 3% per annum. RESULTS: The modelled endgame policy package generates considerable growth in income for the A/NZ population with a total cumulative gain of US$31 billion by 2050. From a government perspective, increased superannuation payments and reduced tobacco excise tax revenue result in a negative net financial position and a cumulative shortfall of US$11.5 billion by 2050. In a sensitivity analysis considering future labour force changes, the government's cumulative net position remained negative by 2050, but only by US$1.9 billion. CONCLUSIONS: A policy such as the A/NZ Smokefree Action Plan is likely to produce substantial economic benefits for citizens, and modest impacts on government finances related to reduced tobacco tax and increases in aged pensions due to increased life expectancy. Such costs can be anticipated and planned for and might be largely offset by future increases in the size of the labour force and the proportion of people 65+ years old working in the formal economy.

Cost-effectiveness of professional-mode flash glucose monitoring in general practice among adults with type 2 diabetes: Evidence from the GP-OSMOTIC trial.

AIM: To assess the cost-effectiveness of professional-mode flash glucose monitoring in adults with type 2 diabetes in general practice compared with usual clinical care. METHODS: An economic evaluation was conducted as a component of the GP-OSMOTIC trial, a pragmatic multicentre 12-month randomised controlled trial enrolling 299 adults with type 2 diabetes in Victoria, Australia. The economic evaluation was conducted from an Australian healthcare sector perspective with a lifetime horizon. Health-related quality of life (EQ-5D) and total healthcare costs were compared between the intervention and the usual care group within the trial period. The 'UKPDS Outcomes Model 2' was used to simulate post-trial lifetime costs, life expectancy and quality-adjusted life years (QALYs). RESULTS: No significant difference in health-related quality of life and costs was found between the two groups within the trial period. Professional-mode flash glucose monitoring yielded greater QALYs (0.03 [95% CI: 0.02, 0.04]) and a higher cost (A$3807 [95% CI: 3604, 4007]) compared with usual clinical care using a lifetime horizon under the trial-based monitoring frequency, considered not cost-effective (incremental cost-effectiveness ratio = A$120,228). The intervention becomes cost-effective if sensor price is reduced to lower than 50%, or monitoring frequency is decreased to once per year while maintaining the same treatment effect on HbA1c . CONCLUSIONS: Including professional-mode flash glucose monitoring every 3 months as part of a management plan for people with type 2 diabetes in general practice is not cost-effective, but could be if the sensor price or monitoring frequency can be reduced.

The comparative mortality of an elite group in the long run of history: an observational analysis of politicians from 11 countries.

This study aims to compare the mortality rate and life expectancy of politicians with those of the age and gender-matched general populations. This was an observational analysis of mortality rates of politicians (i.e. members of national parliaments with available data on dates of birth, death and election, gender, and life tables) in 11 developed countries. Politicians were followed from date of first election until either death or the last available year with life table data. Relative mortality differences were estimated using standardised mortality ratios (SMRs). Absolute inequalities were quantified as the difference in survival by deducting a population's remaining life expectancy from politicians' remaining life expectancy at age 45, estimated using Gompertz parametric proportional hazards models. We included 57,561 politicians (with follow-up ranging from 1816-2016 for France to 1949-2017 for Germany). In almost all countries politicians had similar rates of mortality to the general population in the early part of the twentieth century. Relative mortality and survival differences (favouring politicians) increased considerably over the course of the twentieth century, with recent SMRs ranging from 0.45 (95%CI 0.41-0.50) in Italy to 0.82 (95%CI 0.69-0.95) in New Zealand. The peak life expectancy gaps ranged from 4.4 (95% CI, 3.5-5.4) years in the Netherlands to 7.8 (95% CI, 7.2-8.4) years in the US. Our results show large relative and absolute inequalities favouring politicians in every country. In some countries, such as the US, relative inequalities are at the greatest level in over 150 years.

Eliciting risk preferences that predict risky health behavior: A comparison of two approaches.

Information on attitudes to risk could increase understanding of and explain risky health behaviors. We investigate two approaches to eliciting risk preferences in the health domain, a novel "indirect" lottery elicitation approach with health states as outcomes and a "direct" approach where respondents are asked directly about their willingness to take risks. We compare the ability of the two approaches to predict health-related risky behaviors in a general adult population. We also investigate a potential framing effect in the indirect lottery elicitation approach. We find that risk preferences elicited using the direct approach can better predict health-related risky behavior than those elicited using the indirect approach. Moreover, a seemingly innocuous change to the framing of the lottery question results in significantly different risk preference estimates, and conflicting conclusions about the ability of the indicators to predict risky health behaviors.

Effect of rapid weight loss incorporating hot salt water immersion on changes in body mass, blood markers, and indices of performance in male mixed martial arts athletes.

PURPOSE: To investigate the effects of rapid weight loss (RWL), incorporating comparison of hot water immersion (HWI) in fresh or salt water, on changes in body mass, blood markers, and indices of performance in mixed martial arts athletes. METHODS: In a crossover design comparing fresh water (FWB) to salt water (SWB; 5.0%wt/vol Epsom salt) bathing, 13 males performed 20 min of HWI (~ 40.3 °C) followed by 40 min wrapped in a heated blanket, twice in sequence (2 h total). Before bathing, ~ 26 to ~ 28 h of fluid and dietary restriction was undertaken, and ~ 24 to ~ 26 h of a high carbohydrate diet and rehydration was undertaken as recovery. RESULTS: During the entire RWL process, participants lost ~ 5.3% body mass. Body mass lost during the 2 h hot bath protocol was 2.17 ± 0.81 kg (~ 2.7% body mass) and 2.24 ± 0.64 kg (~ 2.8% body mass) for FWB and SWB, respectively (P = 0.647 between trials). Blood urea nitrogen, creatinine, sodium, chloride, hemoglobin, and hematocrit were increased (all P < 0.05), and plasma volume was decreased (~ 14%; P < 0.01), but did not differ between FWB and SWB, and were similar to baseline values after recovery. No indices of performance (e.g., countermovement jump, isometric strength, and functional threshold power) were impacted when RWL was followed by the recovery process. CONCLUSION: Under the conditions of this hot bath protocol, fluid loss was not augmented by the addition of ~ 5.0%wt/vol of Epsom salt during HWI, and RWL of ~ 5.3% body mass followed by > 24 h of recovery did not impact indices of performance.

Development of a life expectancy table for individuals with type 1 diabetes.

AIMS/HYPOTHESIS: Tables reporting life expectancies by common risk factors are available for individuals with type 2 diabetes; however, there is currently no published equivalent for individuals with type 1 diabetes. We aimed to develop a life expectancy table using a recently published simulation model for individuals with type 1 diabetes. METHODS: The simulation model was developed using data from a real-world population of patients with type 1 diabetes selected from the Swedish National Diabetes Register. The following six important risk factors were included in the life table: sex; age; current smoking status; BMI; eGFR; and HbA1c. For each of 1024 cells in the life expectancy table, a synthetic cohort containing 1000 individuals was created, with other risk factors assigned values representative of the real-world population. The simulations were executed for all synthetic cohorts and life expectancy for each cell was calculated as mean survival time of the individuals in the respective cohort. RESULTS: There was a substantial variation in life expectancy across patients with different risk factor levels. Life expectancy of 20-year-old men varied from 29.3 years to 50.6 years, constituting a gap of 21.3 years between those with worst and best risk factor levels. In 20-year-old women, this gap was 18.9 years (life expectancy range 35.0-53.9 years). The variation in life expectancy was a function of the combination of risk factor values, with HbA1c and eGFR consistently showing a negative and positive correlation, respectively, with life expectancy at any level combination of other risk factors. Individuals with the lowest level (20 kg/m2) and highest level of BMI (35 kg/m2) had a lower life expectancy compared with those with a BMI of 25 kg/m2. Non-smokers and women had a higher life expectancy than smokers and men, respectively, with the difference in life expectancy ranging from 0.4 years to 2.7 years between non-smokers and smokers, and from 1.9 years to 5.9 years between women and men, depending on levels of other risk factors. CONCLUSIONS/INTERPRETATION: The life expectancy table generated in this study shows a substantial variation in life expectancy across individuals with different modifiable risk factors. The table allows for rapid communications of risk in an easily understood format between healthcare professionals, health economists, researchers, policy makers and patients. Particularly, it supports clinicians in their discussion with patients about the benefits of improving risk factors.

Disease-related income and economic productivity loss in New Zealand: A longitudinal analysis of linked individual-level data.

BACKGROUND: Reducing disease can maintain personal individual income and improve societal economic productivity. However, estimates of income loss for multiple diseases simultaneously with thorough adjustment for confounding are lacking, to our knowledge. We estimate individual-level income loss for 40 conditions simultaneously by phase of diagnosis, and the total income loss at the population level (a function of how common the disease is and the individual-level income loss if one has the disease). METHODS AND FINDINGS: We used linked health tax data for New Zealand as a high-income country case study, from 2006 to 2007 to 2015 to 2016 for 25- to 64-year-olds (22.5 million person-years). Fixed effects regression was used to estimate within-individual income loss by disease, and cause-deletion methods to estimate economic productivity loss at the population level. Income loss in the year of diagnosis was highest for dementia for both men (US$8,882; 95% CI $6,709 to $11,056) and women ($7,103; $5,499 to $8,707). Mental illness also had high income losses in the year of diagnosis (average of about $5,300 per year for males and $4,100 per year for females, for 4 subcategories of: depression and anxiety; alcohol related; schizophrenia; and other). Similar patterns were evident for prevalent years of diagnosis. For the last year of life, cancers tended to have the highest income losses, (e.g., colorectal cancer males: $17,786, 95% CI $15,555 to $20,018; females: $14,192, $12,357 to $16,026). The combined annual income loss from all diseases among 25- to 64-year-olds was US$2.72 billion or 4.3% of total income. Diseases contributing more than 4% of total disease-related income loss were mental illness (30.0%), cardiovascular disease (15.6%), musculoskeletal (13.7%), endocrine (8.9%), gastrointestinal (7.4%), neurological (6.5%), and cancer (4.5%). The limitations of this study include residual biases that may overestimate the effect of disease on income loss, such as unmeasured time-varying confounding (e.g., divorce leading to both depression and income loss) and reverse causation (e.g., income loss leading to depression). Conversely, there may also be offsetting underestimation biases, such as income loss in the prodromal phase before diagnosis that is misclassified to "healthy" person time. CONCLUSIONS: In this longitudinal study, we found that income loss varies considerably by disease. Nevertheless, mental illness, cardiovascular, and musculoskeletal diseases stand out as likely major causes of economic productivity loss, suggesting that they should be prioritised in prevention programmes.

Placebo Surgery Controlled Trials: Do They Achieve What They Set Out To Do? A Systematic Review.

OBJECTIVE: To explore whether placebo surgery controlled trials achieve what they set out to do by investigating discrepancy between projected and actual design aspects of trials identified through systematic review methods. SUMMARY BACKGROUND: Interest in placebo surgery controlled trials is growing in response to concerns regarding unnecessary surgery and the societal cost of low-value healthcare. As questions about the justifiability of using placebo controls in surgery have been addressed, attention is now being paid to more practical concerns. METHODS: Six databases were searched from inception - May 2020 (MEDLINE, Embase, Emcare, APA PsycInfo, CINAHL, Cochrane Library). Placebo surgery controlled trials with a published protocol were included. Three authors extracted "projected" design aspects from protocols and "actual" design aspects from main findings papers. Absolute and relative difference between projected and actual design aspects were presented for each trial. Trials were grouped according to whether they met their target sample size ("completed") and were concluded in a timely fashion. Pairs of authors assessed risk of bias. RESULTS: Of 24 trials with data available to analyse; 3 were completed and concluded within target timeframe; 10 were completed and concluded outside the target timeline; 4 were completed without clear target timeframes; 2 were incomplete and concluded within the target framework; 5 were incomplete and concluded outside the target timeline. Trials which reached the recruitment target underestimated trial duration by 88% and number of recruitment sites by 87%. CONCLUSIONS: Trialists need to factor additional time and sites into future placebo surgery controlled trials. A robust reporting framework of projected and actual trial design is imperative for trialists to learn from their predecessors. REVIEW REGISTRATION: PROSPERO (CRD42019133296).

Estimating risk factor progression equations for the UKPDS Outcomes Model 2 (UKPDS 90).

OBJECTIVES: To estimate 13 equations that predict clinically plausible risk factor time paths to inform the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model version 2 (UKPDS-OM2). METHODS: Data from 5102 UKPDS participants from the 20-year trial, and the 4031 survivors with 10 years further post-trial follow-up, were used to derive equations for the time paths of 13 clinical risk factors: HbA1c , systolic blood pressure, LDL-cholesterol, HDL-cholesterol, BMI, micro- or macro-albuminuria, creatinine, heart rate, white blood cell count, haemoglobin, estimated glomerular filter rate, atrial fibrillation and peripheral vascular disease (PVD). The incidence of events and death predicted by the UKPDS-OM2 when informed by the new risk factor equations was compared with the observed cumulative rates up to 25 years. RESULTS: The new equations were based on 24 years of follow-up and up to 65,252 person-years of data. Women were associated with higher values of all continuous risk factors except for haemoglobin. Older age and higher BMI at diagnosis were associated with higher rates of PVD (HR 1.06 and 1.02), atrial fibrillation (HR 1.10 and 1.08) and micro- or macro-albuminuria (HR 1.01 and 1.18). Smoking was associated with higher rates of developing PVD (HR 2.38) and micro- and macro-albuminuria (HR 1.39). The UKPDS-OM2, informed by the new risk factor equations, predicted event rates for complications and death consistent with those observed. CONCLUSIONS: The new equations allow risk factor time paths beyond observed data, which should improve modelling of long-term health outcomes for people with type 2 diabetes when using the UKPDS-OM2 or other models.

Smoking Cessation and Quality of Life: Insights From Analysis of Longitudinal Australian Data, an Application for Economic Evaluations.

OBJECTIVES: A number of studies have shown an association between smoking habit and quality of life, but these have mainly involved cross-sectional data. This study takes advantage of longitudinal panel data to estimate the effect of the transition from "smoker" to "ex-smoker" status (smoking cessation) on health-related quality of life (HRQoL), measured by SF-36, in an Australian general population sample. METHODS: Panel data from 13 waves (2001-2013) of a nationally representative longitudinal survey of Household Income and Labour Dynamics of Australia (HILDA) were used; 1858 respondents (5% of total HILDA sample) who experienced only 1 cessation event in their HILDA life were selected. HRQoL trajectories elicited by SF-36 (0-100 scale, worst to best health) were modeled before and after cessation events using a piecewise (segmented) 2-way fixed-effect linear regression, adopted to capture within-person differences. This enabled measurement of changes of regression slopes and intercept while controlling time-invariant characteristics (eg, country of birth, gender) and time-varying changes in health status. RESULTS: Annual pre-post intervention improvements were estimated for the following dimensions: role physical 0.65 (95% CI 0.62-1.24), bodily pain 0.48 (95% CI 0.10-0.86), general health 0.55 (95% CI 0.2-0.9), and the physical component summary score 0.22 (95% CI 0.01-0.04). Immediate effects (discontinuity at the time of cessation) of smoking cessation existed for bodily pain -1.5 (95% CI -2.52 to -0.40) and general health 1.82 (95% CI 1.01-2.62). The effects for mental health domains were not significant. CONCLUSIONS: Adjusting for all unmeasured time-invariant confounders and controlling the effect of time, this study revealed the varied effects of smoking cessation on HRQoL; it has positive effect on physical and general health but nonsignificant effect on mental aspects. Preference-based utility measures based on SF-6D capture changes that can be measured in several of the domains of the SF-36.

Synthesis of Passerini-3CR Polymers and Assembly into Cytocompatible Polymersomes.

The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles into polymersomes. Carboxy-functionalized poly(ethylene glycol) methyl ether is reacted with AB-type bifunctional monomers and tert-butyl isocyanide in a single process via Passerini-3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini-3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post-functionalization with a dye, Cyanine-5 (Cy5). The obtained P1-Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA-MB-231 triple-negative breast cancer cells. P1-Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini-3CR.

Population norms for quality adjusted life years for the United States of America, China, the United Kingdom and Australia.

Health economics uses quality adjusted life years (QALYs) to help healthcare decision makers. However, unlike life expectancy for which age- and sex-dependent national life tables are available, no general population norms exist to use as a benchmark against which to compare observed or modeled projections of QALYs in sub-populations or patients. We developed a 2-state Markov model to generate QALY population norms for the USA, UK, China and Australia. Annual age- and sex-specific probabilities of all-cause mortality were taken from life tables combined with general population country-specific age- and sex-specific health state utilities for the EQ-5D-3L (all countries); and SF-6D (Australia) multi-attribute utility instruments (MAUI). To validate our QALY benchmark model we found that the model closely predicted population life expectancies. Using EQ-5D-3L, undiscounted QALYs for males/females aged 18 years ranged 54.62/58.90 (USA), 55.55/60.21 (China), 57.11/60.16 (Australia), and 58.01/61.43 (UK) years. SF-6D benchmark QALYs for Australia were consistently lower than those generated from the EQ-5D-3L. The gap in undiscounted QALYs between the UK (highest) and the USA (lowest) was 2.53 QALYs in women and 3.39 QALYs in men aged 18 years. Our model's QALY population norms can be used for internal validation of future health economic models for the country-specific value sets for the instruments that we adopted, and when quantifying burden of disease in terms of QALYs lost due to illness compared to the general population. We have created a publicly available repository to continuously include QALY benchmarks that use country-specific value sets for other MAUIs and life expectancies.

Lessons from the pandemic on the value of research infrastructure.

The COVID-19 pandemic has shed a spotlight on the resilience of healthcare systems, and their ability to cope efficiently and effectively with unexpected crises. If we are to learn one economic lesson from the pandemic, arguably it is the perils of an overfocus on short-term allocative efficiency at the price of lack of capacity to deal with uncertain future challenges. In normal times, building spare capacity with 'option value' into health systems may seem inefficient, the costs potentially exceeding the benefits. Yet the fatal weakness of not doing so is that this can leave health systems highly constrained when dealing with unexpected, but ultimately inevitable, shocks-such as the COVID-19 pandemic. In this article, we argue that the pandemic has highlighted the potentially enormous option value of biomedical research infrastructure. We illustrate this with reference to COVID-19 response work supported by the United Kingdom National Institute for Health Research Oxford Biomedical Research Centre. As the world deals with the fallout from the most serious economic crisis since the Great Depression, pressure will soon come to review government expenditure, including research funding. Developing a framework to fully account for option value, and understanding the public appetite to pay for it, should allow us to be better prepared for the next emerging problem.