Brain alterations in regions associated with end-organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study.

BACKGROUND: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). METHODS: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. RESULTS: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). INTERPRETATION: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM.

The use of parent-completed questionnaires to investigate developmental outcomes in large populations of children exposed to antiseizure medications in pregnancy.

OBJECTIVE: This study was undertaken to assess the utility of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and the Vineland Adaptive Behavior Scales-2nd Edition (VABS-II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large-population signal generation initiatives. METHODS: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development-3rd Edition (BSID-III), the VABS-II, and the ASQ-3 (n = 223). The sensitivity and specificity of the ASQ-3 and VABS-II to identify developmental delay at 24 months were examined, using the BSID-III to define cases. RESULTS: The ASQ-3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ-3 and BSID-III at 24 months, the ASQ-3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut-points resulted in improved properties and may be preferred in certain contexts. The VABS-II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID-III referral data (sensitivity = 100.0%, specificity = 96.6%). SIGNIFICANCE: Both the ASQ-3 and VABS-II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at-risk groups. These findings identify the ASQ-3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS-II has excellent psychometric properties, it is more labor-intensive for both the research team and participants and is available in fewer languages than the ASQ-3.

Fast approximate inference for multivariate longitudinal data.

Collecting information on multiple longitudinal outcomes is increasingly common in many clinical settings. In many cases, it is desirable to model these outcomes jointly. However, in large data sets, with many outcomes, computational burden often prevents the simultaneous modeling of multiple outcomes within a single model. We develop a mean field variational Bayes algorithm, to jointly model multiple Gaussian, Poisson, or binary longitudinal markers within a multivariate generalized linear mixed model. Through simulation studies and clinical applications (in the fields of sight threatening diabetic retinopathy and primary biliary cirrhosis), we demonstrate substantial computational savings of our approximate approach when compared to a standard Markov Chain Monte Carlo, while maintaining good levels of accuracy of model parameters.

Neurodevelopment of babies born to mothers with epilepsy: A prospective observational cohort study.

OBJECTIVE: Despite widespread monotherapy use of lamotrigine or levetiracetam during pregnancy, prospectively collected, blinded child development data are still limited. The NaME (Neurodevelopment of Babies Born to Mothers With Epilepsy) Study prospectively recruited a new cohort of women with epilepsy and their offspring for longitudinal follow-up. METHODS: Pregnant women of <21 weeks gestation (n = 401) were recruited from 21 hospitals in the UK. Data collection occurred during pregnancy (recruitment, trimester 3) and at 12 and 24 months of age. The primary outcome was blinded assessment of infant cognitive, language, and motor development on the Bayley Scales of Infant and Toddler Development (3rd edition) at 24 months of age with supplementary parent reporting on the Vinelands Adaptive Behavior Scales (2nd edition). RESULTS: There were 394 live births, with 277 children (70%) completing the Bayley assessment at 24 months. There was no evidence of an association of prenatal exposure to monotherapy lamotrigine (-.74, SE = 2.9, 95% confidence interval [CI] = -6.5 to 5.0, p = .80) or levetiracetam (-1.57, SE = 3.1, 95% CI = -4.6 to 7.7, p = .62) with poorer infant cognition, following adjustment for other maternal and child factors in comparison to nonexposed children. Similar results were observed for language and motor scores. There was no evidence of an association between increasing doses of either lamotrigine or levetiracetam. Nor was there evidence that higher dose folic acid supplementation (≥5 mg/day) or convulsive seizure exposure was associated with child development scores. Continued infant exposure to antiseizure medications through breast milk was not associated with poorer outcomes, but the number of women breastfeeding beyond 3 months was low. SIGNIFICANCE: These data are reassuring for infant development following in utero exposure to monotherapy lamotrigine or levetiracetam, but child development is dynamic, and future follow-up is required to rule out later emerging effects.

Rapid antigen testing in COVID-19 management for school-aged children: an observational study in Cheshire and Merseyside, UK.

BACKGROUND: Twice weekly lateral flow tests (LFTs) for secondary school children was UK Government policy from 8 March 2021. We evaluate use of LFTs (both supervised at test centres, and home test kits) in school-aged children in Cheshire and Merseyside. METHODS: We report (i) number of LFT positives (ii) proportion of LFT positive with confirmatory reverse transcription polymerase chain reaction (PCR) test within 2 days, and (iii) agreement between LFT-positive and confirmatory PCR, and dependence of (i-iii) on COVID-19 prevalence. FINDINGS: 1 248 468 LFTs were taken by 211 255 12-18 years old, and 163 914 by 52 116 5-11 years old between 6 November 2020 and 31 July 2021. Five thousand three hundred and fourteen (2.5%) 12-18 years old and 1996 (3.8%) 5-11 years old returned LFT positives, with 3829 (72.1%) and 1535 (76.9%) confirmatory PCRs, and 3357 (87.7%) and 1383 (90.1%) confirmatory PCR-positives, respectively.Monthly proportions of LFT positive with PCR negative varied between 4.7% and 35.3% in 12-18 years old (corresponding proportion of all tests positive: 9.7% and 0.3%).Deprivation and non-White ethnicity were associated with reduced uptake of confirmatory PCR. INTERPRETATION: Substantial inequalities in confirmatory testing need more attention to avoid further disadvantage through education loss. When prevalence is low additional measures, including confirmatory testing, are needed. Local Directors of Public Health taking more control over schools testing may be needed. FUNDING: DHSC, MRC, NIHR, EPSRC.

Association of SARS-CoV-2 viral load distributions with individual demographics and suspected variant type: results from the Liverpool community testing pilot, England, 6 November 2020 to 8 September 2021.

BackgroundThe PCR quantification cycle (Cq) is a proxy measure of the viral load of a SARS-CoV-2-infected individual.AimTo investigate if Cq values vary according to different population characteristics, in particular demographic ones, and within the COVID-19 pandemic context, notably the SARS-CoV-2 type/variant individuals get infected with.MethodsWe considered all positive PCR results from Cheshire and Merseyside, England, between 6 November 2020 and 8 September 2021. Cq distributions were inspected with Kernel density estimates. Multivariable quantile regression models assessed associations between people's features and Cq.ResultsWe report Cq values for 188,821 SARS-CoV-2 positive individuals. Median Cqs increased with decreasing age for suspected wild-type virus and Alpha variant infections, but less so, if not, for Delta. For example, compared to 30-39-year-olds (median age group), 5-11-year-olds exhibited 1.8 (95% CI: 1.5 to 2.1), 2.2 (95% CI: 1.8 to 2.6) and 0.8 (95% CI: 0.6 to 0.9) higher median Cqs for suspected wild-type, Alpha and Delta positives, respectively, in multivariable analysis. 12-18-year-olds also had higher Cqs for wild-type and Alpha positives, however, not for Delta. Overall, in univariable analysis, suspected Delta positives reported 2.8 lower median Cqs than wild-type positives (95% CI: 2.7 to 2.8; p < 0.001). Suspected Alpha positives had 1.5 (95% CI: 1.4 to 1.5; p < 0.001) lower median Cqs than wild type.ConclusionsWild-type- or Alpha-infected school-aged children (5-11-year-olds) might transmit less than adults (> 18 years old), but have greater mixing exposures. Smaller differences in viral loads with age occurred in suspected Delta infections. Suspected-Alpha- or Delta-infections involved higher viral loads than wild type, suggesting increased transmission risk. COVID-19 control strategies should consider age and dominant variant.

Investigation of urinary volatile organic compounds as novel diagnostic and surveillance biomarkers of bladder cancer.

BACKGROUND: The diagnosis and surveillance of urothelial bladder cancer (UBC) require cystoscopy. There is a need for biomarkers to reduce the frequency of cystoscopy in surveillance; urinary volatile organic compound (VOC) analysis could fulfil this role. This cross-sectional study compared the VOC profiles of patients with and without UBC, to investigate metabolomic signatures as biomarkers. METHODS: Urine samples were collected from haematuria clinic patients undergoing diagnostic cystoscopy and UBC patients undergoing surveillance. Urinary headspace sampling utilised solid-phase microextraction and VOC analysis applied gas chromatography-mass spectrometry; the output underwent metabolomic analysis. RESULTS: The median participant age was 70 years, 66.2% were male. Of the haematuria patients, 21 had a new UBC diagnosis, 125 had no cancer. In the surveillance group, 75 had recurrent UBC, 84 were recurrence-free. A distinctive VOC profile was observed in UBC patients compared with controls. Ten VOCs had statistically significant abundances useful to classify patients (false discovery rate range 1.9 × 10-7-2.8 × 10-2). Two prediction models were evaluated using internal validation. An eight-VOC diagnostic biomarker panel achieved AUROC 0.77 (sensitivity 0.71, specificity 0.72). A six-VOC surveillance biomarker panel obtained AUROC 0.80 (sensitivity 0.71 and specificity 0.80). CONCLUSIONS: Urinary VOC analysis could aid the diagnosis and surveillance of UBC.

Effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines for reducing susceptibility to infection with the Delta variant (B.1.617.2) of SARS-CoV-2.

BACKGROUND: From January to May 2021 the alpha variant (B.1.1.7) of SARS-CoV-2 was the most commonly detected variant in the UK. Following this, the Delta variant (B.1.617.2) then became the predominant variant. The UK COVID-19 vaccination programme started on 8th December 2020. Prior to the Delta variant, most vaccine effectiveness studies focused on the alpha variant. We therefore aimed to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in preventing symptomatic and asymptomatic infection with respect to the Delta variant in a UK setting. METHODS: We used anonymised public health record data linked to infection data (PCR) using the Combined Intelligence for Population Health Action resource. We then constructed an SIR epidemic model to explain SARS-CoV-2 infection data across the Cheshire and Merseyside region of the UK. Vaccines were assumed to be effective after 21 days for 1 dose and 14 days for 2 doses. RESULTS: We determined that the effectiveness of the Oxford-AstraZeneca vaccine in reducing susceptibility to infection is 39% (95% credible interval [34, 43]) and 64% (95% credible interval [61, 67]) for a single dose and a double dose respectively. For the Pfizer-BioNTech vaccine, the effectiveness is 20% (95% credible interval [10, 28]) and 84% (95% credible interval [82, 86]) for a single-dose and a double dose respectively. CONCLUSION: Vaccine effectiveness for reducing susceptibility to SARS-CoV-2 infection shows noticeable improvement after receiving two doses of either vaccine. Findings also suggest that a full course of the Pfizer-BioNTech provides the optimal protection against infection with the Delta variant. This reinforces the need to complete the full course programme to maximise individual protection and reduce transmission.

Changing patterns of SARS-CoV-2 infection through Delta and Omicron waves by vaccination status, previous infection and neighbourhood deprivation: a cohort analysis of 2.7 M people.

BACKGROUND: Our study examines if SARS-CoV-2 infections varied by vaccination status, if an individual had previously tested positive and by neighbourhood socioeconomic deprivation across the Delta and Omicron epidemic waves of SARS-CoV-2. METHODS: Population cohort study using electronic health records for 2.7 M residents in Cheshire and Merseyside, England (3rd June 2021 to 1st March 2022). Our outcome variable was registered positive test for SARS-CoV-2. Explanatory variables were vaccination status, previous registered positive test and neighbourhood socioeconomic deprivation. Cox regression models were used to analyse associations. RESULTS: Originally higher SARS-CoV-2 rates in the most socioeconomically deprived neighbourhoods changed to being higher in the least deprived neighbourhoods from the 1st September 2021, and were inconsistent during the Omicron wave. Individuals who were fully vaccinated (two doses) were associated with fewer registered positive tests (e.g., individuals engaged in testing between 1st September and 27th November 2021-Hazards Ratio (HR) = 0.48, 95% Confidence Intervals (CIs) = 0.47-0.50. Individuals with a previous registered positive test were also less likely to have a registered positive test (e.g., individuals engaged in testing between 1st September and 27th November 2021-HR = 0.16, 95% CIs = 0.15-0.18. However, the Omicron period saw smaller effect sizes for both vaccination status and previous registered positive test. CONCLUSIONS: Changing patterns of SARS-CoV-2 infections during the Delta and Omicron waves reveals a dynamic pandemic that continues to affect diverse communities in sometimes unexpected ways.

Safety and cost-effectiveness of individualised screening for diabetic retinopathy: the ISDR open-label, equivalence RCT.

AIMS/HYPOTHESIS: Using variable diabetic retinopathy screening intervals, informed by personal risk levels, offers improved engagement of people with diabetes and reallocation of resources to high-risk groups, while addressing the increasing prevalence of diabetes. However, safety data on extending screening intervals are minimal. The aim of this study was to evaluate the safety and cost-effectiveness of individualised, variable-interval, risk-based population screening compared with usual care, with wide-ranging input from individuals with diabetes. METHODS: This was a two-arm, parallel-assignment, equivalence RCT (minimum 2 year follow-up) in individuals with diabetes aged 12 years or older registered with a single English screening programme. Participants were randomly allocated 1:1 at baseline to individualised screening at 6, 12 or 24 months for those at high, medium and low risk, respectively, as determined at each screening episode by a risk-calculation engine using local demographic, screening and clinical data, or to annual screening (control group). Screening staff and investigators were observer-masked to allocation and interval. Data were collected within the screening programme. The primary outcome was attendance (safety). A secondary safety outcome was the development of sight-threatening diabetic retinopathy. Cost-effectiveness was evaluated within a 2 year time horizon from National Health Service and societal perspectives. RESULTS: A total of 4534 participants were randomised. After withdrawals, there were 2097 participants in the individualised screening arm and 2224 in the control arm. Attendance rates at first follow-up were equivalent between the two arms (individualised screening 83.6%; control arm 84.7%; difference -1.0 [95% CI -3.2, 1.2]), while sight-threatening diabetic retinopathy detection rates were non-inferior in the individualised screening arm (individualised screening 1.4%, control arm 1.7%; difference -0.3 [95% CI -1.1, 0.5]). Sensitivity analyses confirmed these findings. No important adverse events were observed. Mean differences in complete case quality-adjusted life-years (EuroQol Five-Dimension Questionnaire, Health Utilities Index Mark 3) did not significantly differ from zero; multiple imputation supported the dominance of individualised screening. Incremental cost savings per person with individualised screening were £17.34 (95% CI 17.02, 17.67) from the National Health Service perspective and £23.11 (95% CI 22.73, 23.53) from the societal perspective, representing a 21% reduction in overall programme costs. Overall, 43.2% fewer screening appointments were required in the individualised arm. CONCLUSIONS/INTERPRETATION: Stakeholders involved in diabetes care can be reassured by this study, which is the largest ophthalmic RCT in diabetic retinopathy screening to date, that extended and individualised, variable-interval, risk-based screening is feasible and can be safely and cost-effectively introduced in established systematic programmes. Because of the 2 year time horizon of the trial and the long time frame of the disease, robust monitoring of attendance and retinopathy rates should be included in any future implementation. TRIAL REGISTRATION: ISRCTN 87561257 FUNDING: The study was funded by the UK National Institute for Health Research. Graphical abstract.

Prediction of Survival Among Patients Receiving Transarterial Chemoembolization for Hepatocellular Carcinoma: A Response-Based Approach.

BACKGROUND AND AIMS: The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. APPROACH AND RESULTS: Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. CONCLUSIONS: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.

Incidence of sight-threatening diabetic retinopathy in an established urban screening programme: An 11-year cohort study.

AIMS: Systematic annual screening to detect sight-threatening diabetic retinopathy (STDR) is established in the United Kingdom. We designed an observational cohort study to provide up-to-date data for policy makers and clinical researchers on incidence of key screening endpoints in people with diabetes attending one screening programme running for over 30 years. METHODS: All people with diabetes aged ≥12 years registered with general practices in the Liverpool health district were offered inclusion. Data sources comprised: primary care (demographics, systemic risk factors), Liverpool Diabetes Eye Screening Programme (retinopathy grading), Hospital Eye Services (slit lamp biomicroscopy assessment of screen positives). RESULTS: 133,366 screening episodes occurred in 28,384 people over 11 years. Overall incidences were: screen positive 6.7% (95% CI 6.5-6.8), screen positive for retinopathy 3.1% (3.0-3.1), unassessable images 2.6% (2.5-2.7), other significant eye diseases 1.0% (1.0-1.1). 1.6% (1.6-1.7) had sight-threatening retinopathy confirmed by slit lamp biomicroscopy. The annual incidence of screen positive and screen positive for retinopathy showed consistent declines from 8.8%-10.6% and 4.4%-4.6% in 2007/09 to 4.4%-6.8% and 2.3%-2.9% in 2013/17, respectively. Rates of STDR (true positive) were consistently below 2% after 2008/09. Screen positive rates were higher in first time attenders (9.9% [9.4-10.2] vs. 6.1% [6.0-6.2]) in part due to ungradeable images (4.1% vs. 2.3%) and other eye disease (2.4% vs. 0.8%). 4.5% (3.9-5.2) of previous non-attenders had sight-threatening retinopathy. Compared with people with type 2 diabetes, those with type 1 disease demonstrated higher rates of screen positive (11.9% vs. 6.0%) and STDR (6.4% vs. 1.2%). Overall prevalence of any retinopathy was 27.2% (27.0-27.4). CONCLUSIONS: In an established screening programme with a stable population screen, positive rates show a consistent fall over time to a low level. Of those who are screen positive, fewer than 50% are screen positive for diabetic retinopathy. Most are due to sight threatening maculopathy. The annual incidence of STDR is under 2% suggesting future work on redefining screen positive and supporting extended intervals for people at low risk. Higher rates of screen positive and STDR are seen in first time attenders. Those who have never attended for screening should be specifically targeted.

Enhanced lateral flow testing strategies in care homes are associated with poor adherence and were insufficient to prevent COVID-19 outbreaks: results from a mixed methods implementation study.

INTRODUCTION: Care homes have been severely affected by the SARS-CoV-2 pandemic. Rapid antigen testing could identify most SARS-CoV-2 infected staff and visitors before they enter homes. We explored implementation of staff and visitor testing protocols using lateral flow devices (LFDs). METHODS: An evaluation of a SARS-CoV-2 LFD-based testing protocol in 11 care homes in Liverpool, UK, including staff and visitor testing, plus a qualitative exploratory study in nine of these homes. The proportion of pilot homes with outbreaks, and outbreak size, were compared to non-pilot homes in Liverpool. Adherence to testing protocols was evaluated. Fifteen staff were interviewed, and transcript data were thematically coded using an iterative analysis to identify and categorize factors influencing testing implementation. RESULTS: In total, 1,638 LFD rapid tests were performed on 407 staff. Protocol adherence was poor with 8.6% of staff achieving >75% protocol adherence, and 25.3% achieving $\ge$50%. Six care homes had outbreaks during the study. Compared to non-pilot care homes, there was no evidence of significant difference in the proportion of homes with outbreaks, or the size of outbreaks. Qualitative data showed difficulty implementing testing strategies due to excessive work burden. Factors influencing adherence related to test integration and procedural factors, socio-economic factors, cognitive overload and the emotional value of testing. CONCLUSION: Implementation of staff and visitor care home LFD testing protocols was poorly adhered to and consequently did not reduce the number or scale of COVID-19 outbreaks. More focus is needed on the contextual and behavioural factors that influence protocol adherence.

TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy.

BACKGROUND: Combination antiretroviral therapy results in metabolic abnormalities which increase cardiovascular disease risk. We evaluated whether telmisartan reduces insulin resistance in human immunodeficiency virus (HIV)-positive individuals on antiretrovirals. METHODS: We conducted a multicenter, randomized, open-label, dose-ranging controlled trial of telmisartan. Participants with HIV infection receiving combination antiretroviral therapy were randomized equally to either no intervention (control) or 20, 40, or 80 mg telmisartan once daily. The adaptive design allowed testing of all dose(s) of telmisartan in stage I, with the promising dose(s) being taken into stage II. The primary outcome measure was reduction in homeostasis model assessment of insulin resistance (HOMA-IR) at 24 weeks. RESULTS: A total of 377 patients were recruited. In stage I, 48, 49, 47, and 45 patients were randomized to control and 20, 40, and 80 mg telmisartan, respectively (total n = 189). At the interim analysis, 80 mg telmisartan was taken forward into stage II. At the end of stage II (n = 105, control; 106, 80-mg arm), there were no differences in HOMA-IR (estimated effect, 0.007; SE, 0.106) at 24 weeks between the telmisartan (80 mg) and nonintervention arms. Longitudinal analysis over 48 weeks showed no change in HOMA-IR, lipid or adipokine levels. There were significant (P ≤ .05), but marginal, improvements in revised Quantitative Insulin Sensitivity Check Index (QUICKI) (0.004) and plasma hs-CRP (-0.222 mg/L) and reduction in liver fat content (1.714 mean reduction; P = .005). CONCLUSIONS: No significant effect of telmisartan was demonstrated on the primary outcome (HOMA-IR), but there were marginal improvements with some secondary outcome measures. Further studies in this population are warranted to identify novel strategies for preventing cardiovascular morbidity and mortality. CLINICAL TRIAL REGISTRATION: ISRCTN registry (51069819).

Bayesian joint modelling of longitudinal and time to event data: a methodological review.

BACKGROUND: In clinical research, there is an increasing interest in joint modelling of longitudinal and time-to-event data, since it reduces bias in parameter estimation and increases the efficiency of statistical inference. Inference and prediction from frequentist approaches of joint models have been extensively reviewed, and due to the recent popularity of data-driven Bayesian approaches, a review on current Bayesian estimation of joint model is useful to draw recommendations for future researches. METHODS: We have undertaken a comprehensive review on Bayesian univariate and multivariate joint models. We focused on type of outcomes, model assumptions, association structure, estimation algorithm, dynamic prediction and software implementation. RESULTS: A total of 89 articles have been identified, consisting of 75 methodological and 14 applied articles. The most common approach to model the longitudinal and time-to-event outcomes jointly included linear mixed effect models with proportional hazards. A random effect association structure was generally used for linking the two sub-models. Markov Chain Monte Carlo (MCMC) algorithms were commonly used (93% articles) to estimate the model parameters. Only six articles were primarily focused on dynamic predictions for longitudinal or event-time outcomes. CONCLUSION: Methodologies for a wide variety of data types have been proposed; however the research is limited if the association between the two outcomes changes over time, and there is also lack of methods to determine the association structure in the absence of clinical background knowledge. Joint modelling has been proved to be beneficial in producing more accurate dynamic prediction; however, there is a lack of sufficient tools to validate the prediction.

Using prognostic and predictive clinical features to make personalised survival prediction in advanced hepatocellular carcinoma patients undergoing sorafenib treatment.

BACKGROUND: Sorafenib is the current standard of care for patients with advanced hepatocellular carcinoma (aHCC) and has been shown to improve survival by about 3 months compared to placebo. However, survival varies widely from under three months to over two years. The aim of this study was to build a statistical model that allows personalised survival prediction following sorafenib treatment. METHODS: We had access to 1130 patients undergoing sorafenib treatment for aHCC as part of the control arm for two phase III randomised clinical trials (RCTs). A multivariable model was built that predicts survival based on baseline clinical features. The statistical approach permits both group-level risk stratification and individual-level survival prediction at any given time point. The model was calibrated, and its discrimination assessed through Harrell's c-index and Royston-Sauerbrei's R2D. RESULTS: The variables influencing overall survival were vascular invasion, age, ECOG score, AFP, albumin, creatinine, AST, extra-hepatic spread and aetiology. The model-predicted survival very similar to that observed. The Harrell's c-indices for training and validation sets were 0.72 and 0.70, respectively indicating good prediction. CONCLUSIONS: Our model ('PROSASH') predicts patient survival using baseline clinical features. However, it will require further validation in a routine clinical practice setting.

Identifying patients who will not reachieve remission after breakthrough seizures.

OBJECTIVE: We aim to identify people with epilepsy who are unlikely to reachieve a 12-month remission within 2 years after experiencing a breakthrough seizure following an initial 12-month remission. METHODS: We apply a novel longitudinal discriminant approach to data from the Standard and New Antiepileptic Drugs study to dynamically predict the risk of a patient not achieving a second remission after a breakthrough seizure by combining both baseline covariates (collected at the time of breakthrough seizure) and follow-up data. RESULTS: The model classifies 83% of patients. Of these, 73% of patients (95% confidence interval [CI] = 58%-88%) who did not achieve a second remission were correctly identified (sensitivity), and 84% of patients (95% CI = 69%-96%) who achieved a second remission were correctly identified (specificity). The area under the curve from our model was 87% (95% CI = 80%-94%). Patients who did not achieve a second remission were correctly identified on average after 10 months of observation postbreakthrough. Occurrence of seizures after breakthrough and the number of seizures experienced were the most informative longitudinal variables. These longitudinal profiles were influenced by the following baseline covariates: age at breakthrough seizure, presence of neurological insult, and number of antiepileptic drugs required to achieve first remission. SIGNIFICANCE: Using longitudinal data gathered during patient follow-up allows more accurate predictions than using baseline covariates in a standard Cox model. The model developed in this paper is a useful first step in developing a tool for identifying patients who develop drug resistance after an initial remission.

Personalized risk-based screening for diabetic retinopathy: A multivariate approach versus the use of stratification rules.

AIMS: To evaluate our proposed multivariate approach to identify patients who will develop sight-threatening diabetic retinopathy (STDR) within a 1-year screen interval, and explore the impact of simple stratification rules on prediction. MATERIALS AND METHODS: A 7-year dataset (2009-2016) from people with diabetes (PWD) was analysed using a novel multivariate longitudinal discriminant approach. Level of diabetic retinopathy, assessed from routine digital screening photographs of both eyes, was jointly modelled using clinical data collected over time. Simple stratification rules based on retinopathy level were also applied and compared with the multivariate discriminant approach. RESULTS: Data from 13 103 PWD (49 520 screening episodes) were analysed. The multivariate approach accurately predicted whether patients developed STDR or not within 1 year from the time of prediction in 84.0% of patients (95% confidence interval [CI] 80.4-89.7), compared with 56.7% (95% CI 55.5-58.0) and 79.7% (95% CI 78.8-80.6) achieved by the two stratification rules. While the stratification rules detected up to 95.2% (95% CI 92.2-97.6) of the STDR cases (sensitivity) only 55.6% (95% CI 54.5-56.7) of patients who did not develop STDR were correctly identified (specificity), compared with 85.4% (95% CI 80.4-89.7%) and 84.0% (95% CI 80.7-87.6%), respectively, achieved by the multivariate risk model. CONCLUSIONS: Accurate prediction of progression to STDR in PWD can be achieved using a multivariate risk model whilst also maintaining desirable specificity. While simple stratification rules can achieve good levels of sensitivity, the present study indicates that their lower specificity (high false-positive rate) would therefore necessitate a greater frequency of eye examinations.

Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection.

BACKGROUND & AIMS: Resection is the most widely used potentially curative treatment for patients with early hepatocellular carcinoma (HCC). However, recurrence within 2 years occurs in 30-50% of patients, being the major cause of mortality. Herein, we describe 2 models, both based on widely available clinical data, which permit risk of early recurrence to be assessed before and after resection. METHODS: A total of 3,903 patients undergoing surgical resection with curative intent were recruited from 6 different centres. We built 2 models for early recurrence, 1 using preoperative and 1 using pre and post-operative data, which were internally validated in the Hong Kong cohort. The models were then externally validated in European, Chinese and US cohorts. We developed 2 online calculators to permit easy clinical application. RESULTS: Multivariable analysis identified male gender, large tumour size, multinodular tumour, high albumin-bilirubin (ALBI) grade and high serum alpha-fetoprotein as the key parameters related to early recurrence. Using these variables, a preoperative model (ERASL-pre) gave 3 risk strata for recurrence-free survival (RFS) in the entire cohort - low risk: 2-year RFS 64.8%, intermediate risk: 2-year RFS 42.5% and high risk: 2-year RFS 20.7%. Median survival in each stratum was similar between centres and the discrimination between the 3 strata was enhanced in the post-operative model (ERASL-post) which included 'microvascular invasion'. CONCLUSIONS: Statistical models that can predict the risk of early HCC recurrence after resection have been developed, extensively validated and shown to be applicable in the international setting. Such models will be valuable in guiding surveillance follow-up and in the design of post-resection adjuvant therapy trials. LAY SUMMARY: The most effective treatment of hepatocellular carcinoma is surgical removal of the tumour but there is often recurrence. In this large international study, we develop a statistical method that allows clinicians to estimate the risk of recurrence in an individual patient. This facility enhances communication with the patient about the likely success of the treatment and will help in designing clinical trials that aim to find drugs that decrease the risk of recurrence.

Interventions for eye movement disorders due to acquired brain injury.

BACKGROUND: Acquired brain injury can cause eye movement disorders which may include: strabismus, gaze deficits and nystagmus, causing visual symptoms of double, blurred or 'juddery' vision and reading difficulties. A wide range of interventions exist that have potential to alleviate or ameliorate these symptoms. There is a need to evaluate the effectiveness of these interventions and the timing of their implementation. OBJECTIVES: We aimed to assess the effectiveness of any intervention and determine the effect of timing of intervention in the treatment of strabismus, gaze deficits and nystagmus due to acquired brain injury. We considered restitutive, substitutive, compensatory or pharmacological interventions separately and compared them to control, placebo, alternative treatment or no treatment for improving ocular alignment or motility (or both). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (containing the Cochrane Eyes and Vision Trials Register) (2017, Issue 5), MEDLINE Ovid, Embase Ovid, CINAHL EBSCO, AMED Ovid, PsycINFO Ovid, Dissertations & Theses (PQDT) database, PsycBITE (Psychological Database for Brain Impairment Treatment Efficacy), ISRCTN registry, ClinicalTrials.gov, Health Services Research Projects in Progress (HSRProj), National Eye Institute Clinical Studies Database and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The databases were last searched on 26 June 2017. No date or language restrictions were used in the electronic searches for trials. We manually searched the Australian Orthoptic Journal, British and Irish Orthoptic Journal, and ESA, ISA and IOA conference proceedings. We contacted researchers active in this field for information about further published or unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any intervention for ocular alignment or motility deficits (or both) due to acquired brain injury. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We used standard methods expected by Cochrane. We employed the GRADE approach to interpret findings and assess the quality of the evidence. MAIN RESULTS: We found five RCTs (116 participants) that were eligible for inclusion. These trials included conditions of acquired nystagmus, sixth cranial nerve palsy and traumatic brain injury-induced ocular motility defects. We did not identify any relevant studies of restitutive interventions.We identified one UK-based trial of a substitutive intervention, in which botulinum toxin was compared with observation in 47 people with acute sixth nerve palsy. At four months after entry into the trial, people given botulinum toxin were more likely to make a full recovery (reduction in angle of deviation within 10 prism dioptres), compared with observation (risk ratio 1.19, 95% CI 0.96 to 1.48; low-certainty evidence). These same participants also achieved binocular single vision. In the injection group only, there were 2 cases of transient ptosis out of 22 participants (9%), and 4 participants out of 22 (18%) with transient vertical deviation; a total complication rate of 24% per injection and 27% per participant. All adverse events recovered. We judged the certainty of evidence as low, downgrading for risk of bias and imprecision. It was not possible to mask investigators or participants to allocation, and the follow-up between groups varied.We identified one USA-based cross-over trial of a compensatory intervention. Oculomotor rehabilitation was compared with sham training in 12 people with mild traumatic brain injury, at least one year after the injury. We judged the evidence from this study to be very low-certainty. The study was small, data for the sham training group were not fully reported, and it was unclear if a cross-over study design was appropriate as this is an intervention with potential to have a permanent effect.We identified three cross-over studies of pharmacological interventions for acquired nystagmus, which took place in Germany and the USA. These studies investigated two classes of pharmacological interventions: GABAergic drugs (gabapentin, baclofen) and aminopyridines (4-aminopyridines (AP), 3,4-diaminopyridine (DAP)). We judged the evidence from all three studies as very low-certainty because of small numbers of participants (which led to imprecision) and risk of bias (they were cross-over studies which did not report data in a way that permitted estimation of effect size).One study compared gabapentin (up to 900 mg/day) with baclofen (up to 30 mg/day) in 21 people with pendular and jerk nystagmus. The follow-up period was two weeks. This study provides very low-certainty evidence that gabapentin may work better than baclofen in improving ocular motility and reducing participant-reported symptoms (oscillopsia). These effects may be different in pendular and jerk nystagmus, but without formal subgroup analysis it is unclear if the difference between the two types of nystagmus was chance finding. Quality of life was not reported. Ten participants with pendular nystagmus chose to continue treatment with gabapentin, and one with baclofen. Two participants with jerk nystagmus chose to continue treatment with gabapentin, and one with baclofen. Drug intolerance was reported in one person receiving gabapentin and in four participants receiving baclofen. Increased ataxia was reported in three participants receiving gabapentin and two participants receiving baclofen.One study compared a single dose of 3,4-DAP (20 mg) with placebo in 17 people with downbeat nystagmus. Assessments were made 30 minutes after taking the drug. This study provides very low-certainty evidence that 3,4-DAP may reduce the mean peak slow-phase velocity, with less oscillopsia, in people with downbeat nystagmus. Three participants reported transient side effects of minor perioral/distal paraesthesia.One study compared a single dose of 4-AP with a single dose of 3,4-DAP (both 10 mg doses) in eight people with downbeat nystagmus. Assessments were made 45 and 90 minutes after drug administration. This study provides very low-certainty evidence that both 3,4-DAP and 4-AP may reduce the mean slow-phase velocity in people with downbeat nystagmus. This effect may be stronger with 4-AP. AUTHORS' CONCLUSIONS: The included studies provide insufficient evidence to inform decisions about treatments specifically for eye movement disorders that occur following acquired brain injury. No information was obtained on the cost of treatment or measures of participant satisfaction relating to treatment options and effectiveness. It was possible to describe the outcome of treatment in each trial and ascertain the occurrence of adverse events.