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Background: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. Purpose: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. Results: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, −1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation ( P = .03; 6.4 points in favor of ACI; 95% CI, −0.4 to 13.1). More participants experienced a serious adverse event with ACI ( P = .02). Conclusion: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. Registration: International Standard Randomised Controlled Trial Number: 48911177

Objectives To quantify the associations between shielding status and loneliness at the start of the COVID-19 pandemic, and physical activity (PA) levels throughout the pandemic. Methods Demographic, health and lifestyle characteristics of 7748 cognitively healthy adults aged >50, and living in London, were surveyed from April 2020 to March 2021. The International Physical Activity Questionnaire (IPAQ) short-form assessed PA before COVID-19 restrictions, and up to 6 times over 11 months. Linear mixed models investigated associations between baseline shielding status, loneliness, and time-varying PA. Results Participants who felt ‘often lonely’ at the outset of the pandemic completed an average of 522 and 547 fewer Metabolic Equivalent of Task (MET) minutes/week (95% CI: -809, -236, pConclusions Those shielding or lonely at pandemic onset were likely to have completed low levels of PA during the pandemic. These associations are influenced by co-morbidities and health status.

This thesis provides a set of novel Monte Carlo methods to perform Bayesian inference, with an emphasis on a state-space modelling framework. The thesis comprises three self-contained research papers. The first paper works at the interface of modelling and inference, extending existing work to develop a new model for medium and high-dimensional data possessing step-changes changes in the correlation structure. A bespoke inference routine is developed, with experimental results demonstrating the speed-up of convergence to equilibrium under a novel alteration of a particle Gibbs sampler for change-point detection. The second paper is concerned with the problem of obtaining unbiased estimators for the smoothing problem in state-space models. New methodology is developed leveraging recent developments in unbiased Markov chain Monte Carlo (MCMC) in conjunction with a particle independent Metropolis–Hastings Markov kernel. We show that the resulting coupling time can be precisely characterised. As a result, it is possible to study the large sample limit of the coupling time to help guide the choice in an algorithmic tuning parameter (the number of particles in this case). The third and final paper develops this methodology further, to obtain unbiased estimators for MCMC algorithms in settings where the likelihood may be unavailable to evaluate pointwise. The motivation for this work is to find a simple means by which to parallelise exact Bayesian inference in state-space models. The focus is primarily on pseudo-marginal algorithms and particle MCMC, in which the mixing behaviour of the algorithm is typically polynomially ergodic. In this setting we propose new methodology to allow the obtention of unbiased estimators of expectations of stationary distributions of these Markov chains. In addition, we extend existing results to both prove the validity and characterise the computational efficiency of these estimators, in terms of algorithmic tuning parameters. We evaluate the resulting methodology on otherwise intractable state-space and latent variable models, including a multivariate probit model popular in econometrics and a nonlinear state-space model arising in neuroscience. Additional algorithmic extensions are provided and subsequently applied to a parameter inference problem in a high-dimensional Ising model.

Additional file 1:. CONSORT 2010 checklist of information to include when reporting a pilot or feasibility trial.

Additional file 2: Appendix 1. COMPASS-ND procedures by visit. Appendix 2. Diet Screening Questionnaire. Appendix 3. Brain Health Food Guide pamphlet. Appendix 4. Example DIET and ED group class schedule. Appendix 5. Eating Plan Self-Assessment. Appendix 6. Exercise session feedback form. Appendix 7. DIET session feedback form. Appendix 8. ED session feedback form. Appendix 9. Full list of LEAD outcome assessments.

BACKGROUND: Reliable, widely accessible and affordable biomarkers for predicting Alzheimer's disease (AD) brain pathology status are a necessity to aid development of prevention strategies in cognitively healthy at-risk older adults, at the right timepoint. Measurements of the key neuropathological hallmark beta-amyloid (Aβ) by PET neuroimaging or cerebrospinal fluid measures reflect its accumulation in the brain, yet recent methodological advancements now enable blood-based measures reflecting cerebral amyloid burden. OBJECTIVES: The current study validated the capacity of plasma Aβ42/Aβ40 measured using six different assays to predict amyloid positivity in a subgroup of cognitively unimpaired (CU) participants in the ADNI study and assessed its ability to discriminate CU from AD cases. We also explored economic viability of using two different plasma amyloid assays for pre-screening in AD prevention trials and as routine clinical diagnostic tool, versus amyloid PET alone. DESIGN: A cross-sectional analysis of plasma and brain amyloid data, including comparative cost analysis of the plasma biomarkers in relation to brain amyloid PET. SETTING: Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS: ADNI participants consisting of 115 CU, mild cognitive impairment and AD cases who had plasma Aβ42/Aβ40 measured with six platforms. MEASUREMENTS: Plasma Aβ42/Aβ40 was measured via six different platforms: three immunoassays (Roche, Quanterix and ADx Neurosciences) and three mass spectrometry (MS) based assays (WashU, Shimadzu and Gothenburg). Aβ-PET imaging was conducted within three months of plasma sampling using [18F]florbetapir. RESULTS: There was a weak to moderate correlation of plasma Aβ42/Aβ40 ratio between platforms. The MS-based WashU test had the highest capacity to discriminate between CU and AD (area under the curve, AUC = 0.734, 95% CI: 0.613-0.854; P = 0.008). Within the CU group, the WashU plasma amyloid test had the best discriminative capacity to distinguish Aβ+ from Aβ- (AUC = 0.753, 95% CI: 0.601-0.905; P = 0.003) closely followed by the immunoassay from Roche (AUC = 0.737, 95% CI: 0.597-0.877; P = 0.006). The exploratory economic analyses showed that the use of Roche or WashU plasma amyloid assay as a pre-screening tool prior to Aβ-PET scans for clinical trial recruitment significantly reduced total screening cost (saving up to $5882 per recruited patient) expected in an AD prevention trial. CONCLUSIONS: With few available treatment strategies, dementia prevention is a global priority. CU individuals at risk for AD are the target population for dementia prevention but have been poorly studied. Our findings confirming diagnostic value of ultrasensitive immunoassays and high-performance immunoprecipitation coupled with MS for measurement of plasma Aβ42/Aβ40 to detect PET amyloid positivity in CU participants allude to potential clinical utility of this biomarker. Plasma Aβ42/Aβ40 could be optimal for pre-selecting at-risk candidates for more invasive and expensive investigations across AD prevention clinical trials and clinical care for a rapidly ageing population.

OBJECTIVES: To assess the cost-effectiveness of uterine artery embolisation (UAE) and myomectomy for women with symptomatic uterine fibroids wishing to avoid hysterectomy. DESIGN: Economic evaluation alongside the FEMME randomised controlled trial. SETTING: 29 UK hospitals. POPULATION: Premenopausal women who had symptomatic uterine fibroids amenable to UAE or myomectomy wishing to avoid hysterectomy. 254 women were randomised to UAE (127) and myomectomy (127). METHODS: A within-trial cost-utility analysis was conducted from the perspective of the UK NHS. MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs) measured using the EuroQoL EQ-5D-3L, combined with costs to estimate cost-effectiveness over 2 and 4 years of follow-up. RESULTS: Over a 2-year time horizon, UAE was associated with higher mean costs (difference £645; 95% CI -1381 to 2580) and lower QALYs (difference -0.09; 95% CI -0.11 to -0.04) when compared with myomectomy. Similar results were observed over the 4-year time horizon. Thus, UAE was dominated by myomectomy. Results of the sensitivity analyses were consistent with the base case results for both years. Over 2 years, UAE was associated with higher costs (difference £456; 95% CI -1823 to 3164) and lower QALYs (difference -0.06; 95% CI -0.11 to -0.02). CONCLUSIONS: Myomectomy is a cost-effective option for the treatment of uterine fibroids. The differences in costs and QALYs are small. Women should be fully informed and have the option to choose between the two procedures.

The transport of heat and salt through turbulent ice shelf–ocean boundary layers is a large source of uncertainty within ocean models of ice shelf cavities. This study uses small-scale, high-resolution, 3D numerical simulations to model an idealized boundary layer beneath a melting ice shelf to investigate the influence of ambient turbulence on double-diffusive convection (i.e., convection driven by the difference in diffusivities between salinity and temperature). Isotropic turbulence is forced throughout the simulations and the temperature and salinity are initialized with homogeneous values similar to observations. The initial temperature and the strength of forced turbulence are varied as controlling parameters within an oceanographically relevant parameter space. Two contrasting regimes are identified. In one regime double-diffusive convection dominates, and in the other convection is inhibited by the forced turbulence. The convective regime occurs for high temperatures and low turbulence levels, where it is long lived and affects the flow, melt rate, and melt pattern. A criterion for identifying convection in terms of the temperature and salinity profiles, and the turbulent dissipation rate, is proposed. This criterion may be applied to observations and theoretical models to quantify the effect of double-diffusive convection on ice shelf melt rates.

Evaluation of land at 295-301 Histon Road, Cambridge, Cambridgeshire

Supplemental material, sj-docx-1-ctj-10.1177_17407745211024751 for Interim data monitoring in cluster randomised trials: Practical issues and a case study by K Hemming, J Martin, I Gallos, A Coomarasamy and L Middleton in Clinical Trials

Supplemental material, sj-docx-2-ctj-10.1177_17407745211024751 for Interim data monitoring in cluster randomised trials: Practical issues and a case study by K Hemming, J Martin, I Gallos, A Coomarasamy and L Middleton in Clinical Trials