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Background The PCR quantification cycle (Cq) is a proxy measure of the viral load of a SARS-CoV-2-infected individual. Aim To 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. Methods We 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. Results We 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 qs than wild type. Conclusions Wild-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.

Background Currently, no generally approved medical treatment can delay the onset of age-related macular degeneration (AMD) or slow the progression of degenerative changes. Repurposing drugs with beneficial effects on AMD pathophysiology offers a route to new treatments which is faster, cost-effective, and safer for patients. Recent studies indicate a potential role for metformin in delaying AMD development and progression. In this context, we conducted a systematic review and meta-analysis to look for beneficial associations between metformin and AMD. Methods We systematically searched Medline and Embase (via Ovid), Web of Science, and ClinicalTrials.gov databases for clinical studies in humans that examined the associations between metformin treatment and AMD published from inception to February 2021. We calculated pooled odds ratio (OR) with 95% confidence interval (CI) considering a random effect model in the meta-analysis. Results Five retrospective studies met the inclusion criteria. There are no prospective studies that have reported the effect of metformin in AMD. The meta-analysis showed that people taking metformin were less likely to have AMD although statistical significance was not met (pooled adjusted OR = 0.80, 95% CI 0.54–1.05, I2 = 98.8%). Subgroup analysis of the association between metformin and early and late AMD could not be performed since the data was not available from the included studies. Conclusions Analysis of retrospective data suggests a signal that metformin may be associated with decreased risk of any AMD. It should be interpreted with caution because of the failure to meet statistical significance, the small number of studies, and the limitation of routine record data. However prospective studies are warranted in generalizable populations without diabetes, of varied ethnicities, and AMD stages. Clinical trials are needed to determine if metformin has efficacy in treating early and late-stage AMD. Supplementary Information The online version contains supplementary material available at 10.1007/s40123-021-00344-3.

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.

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.

Objective To assess the performance of the SARS-CoV-2 antigen rapid lateral flow test (LFT) versus polymerase chain reaction testing in the asymptomatic general population attending testing centres. Design Observational cohort study. Setting Community LFT pilot at covid-19 testing sites in Liverpool, UK. Participants 5869 asymptomatic adults (≥18 years) voluntarily attending one of 48 testing sites during 6-29 November 2020. Interventions Participants were tested using both an Innova LFT and a quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) test based on supervised self-administered swabbing at testing sites. Main outcome measures Sensitivity, specificity, and predictive values of LFT compared with RT-qPCR in an epidemic steady state of covid-19 among adults with no classic symptoms of the disease. Results Of 5869 test results, 22 (0.4%) LFT results and 343 (5.8%) RT-qPCR results were void (that is, when the control line fails to appear within 30 minutes). Excluding the void results, the LFT versus RT-qPCR showed a sensitivity of 40.0% (95% confidence interval 28.5% to 52.4%; 28/70), specificity of 99.9% (99.8% to 99.99%; 5431/5434), positive predictive value of 90.3% (74.2% to 98.0%; 28/31), and negative predictive value of 99.2% (99.0% to 99.4%; 5431/5473). When the void samples were assumed to be negative, a sensitivity was observed for LFT of 37.8% (26.8% to 49.9%; 28/74), specificity of 99.6% (99.4% to 99.8%; 5431/5452), positive predictive value of 84.8% (68.1% to 94.9%; 28/33), and negative predictive value of 93.4% (92.7% to 94.0%; 5431/5814). The sensitivity in participants with an RT-qPCR cycle threshold (Ct) of 10 6 RNA copies/mL) was 90.9% (58.7% to 99.8%; 10/11), a Ct of 10 4 RNA copies/mL) was 69.4% (51.9% to 83.7%; 25/36), and a Ct of >24.4 (4 RNA copies/mL) was 9.7% (1.9% to 23.7%; 3/34). LFT is likely to detect at least three fifths and at most 998 in every 1000 people with a positive RT-qPCR test result with high viral load. Conclusions The Innova LFT can be useful for identifying infections among adults who report no symptoms of covid-19, particularly those with high viral load who are more likely to infect others. The number of asymptomatic adults with lower Ct (indicating higher viral load) missed by LFT, although small, should be considered when using single LFT in high consequence settings. Clear and accurate communication with the public about how to interpret test results is important, given the chance of missing some cases, even at high viral loads. Further research is needed to understand how infectiousness is reflected in the viral antigen shedding detected by LFT versus the viral loads approximated by RT-qPCR.

Background\ud \ud Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.\ud \ud \ud Methods\ud \ud In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.\ud \ud \ud Findings\ud \ud Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8–32·7) in March 9 to April 26, 2020, to 16·4% (15·0–17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65–0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94–0·95) of the reduction in in-hospital mortality.\ud \ud \ud Interpretation\ud \ud The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.\ud \ud \ud Funding\ud \ud National Institute for Health Research and the Medical Research Council.

Background Large-scale asymptomatic testing of communities in Liverpool (UK) for SARS-CoV-2 was used as a public health tool for containing COVID-19. The aim of the study is to explore social and spatial inequalities in uptake and case-detection of rapid lateral flow SARS-CoV-2 antigen tests (LFTs) offered to people without symptoms of COVID-19. Methods Linked pseudonymised records for asymptomatic residents in Liverpool who received a LFT for COVID-19 between 6th November 2020 to 31st January 2021 were accessed using the Combined Intelligence for Population Health Action resource. Bayesian Hierarchical Poisson Besag, York, and Mollie models were used to estimate ecological associations for uptake and positivity of testing. Findings 214 525 residents (43%) received a LFT identifying 5192 individuals as positive cases of COVID-19 (1.3% of tests were positive). Uptake was highest in November when there was military assistance. High uptake was observed again in the week preceding Christmas and was sustained into a national lockdown. Overall uptake were lower among males (e.g. 40% uptake over the whole period), Black Asian and other Minority Ethnic groups (e.g. 27% uptake for ‘Mixed' ethnicity) and in the most deprived areas (e.g. 32% uptake in most deprived areas). These population groups were also more likely to have received positive tests for COVID-19. Models demonstrated that uptake and repeat testing were lower in areas of higher deprivation, areas located further from test sites and areas containing populations less confident in the using Internet technologies. Positive tests were spatially clustered in deprived areas. Interpretation Large-scale voluntary asymptomatic community testing saw social, ethnic, digital and spatial inequalities in uptake. COVID-19 testing and support to isolate need to be more accessible to the vulnerable communities most impacted by the pandemic, including non-digital means of access. Funding Department of Health and Social Care (UK) and Economic and Social Research Council.

Background: The Innova SARS-CoV-2 antigen rapid lateral flow test (LFT) offers fast detection of COVID-19 cases. This study assesses the performance of LFT in the general population attending asymptomatic testing centres. Methods: Observational cohort study to compare LFT with reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) results based on two self-administrated swab samples per participant taken within minutes among individuals declaring no classic symptoms, attending asymptomatic testing sites in Liverpool, UK, between 6th and 29th of November 2020. Findings: 5869 individuals attended 48 testing sites in Liverpool. The relative sensitivity of LFT versus RT-qPCR, excluding void tests, was 40∙0% (95% CI: 28∙5 to 52∙4; 28/70). The specificity was 99∙9% (99∙8 to 99∙99; 5431/5434), positive predictive value was 90∙3% (74∙2 to 98∙0; 28/31) and negative predictive value was 99∙2% (99∙0 to 99∙4; 5431/5473). For cases with RT-qPCR cycle threshold CT 10 6 RNA copies/ml), sensitivity was 90∙9% (58∙7 to 99∙8; 10/11), for CT 10 4 RNA copies/ml), sensitivity was 69∙4% (51∙9 to 83∙7; 25/36), and for CT >24∙4 (viral load Interpretation: Innova LFT is a helpful tool for identifying infections among people who declare no symptoms of COVID-19, particularly those with high viral load and so more likely to infect others. The number of cases with lower CT (indicating higher viral load) missed by LFT, although small, should be considered, with due caution over using single LFT in high-consequence settings. Clear and accurate communication with the public about how to interpret test results is important. Further research is needed to understand how infectiousness is reflected in the viral antigen shedding detected by LFT versus the viral loads approximated by RT-qPCR. Funding: This evaluation was commissioned by the UK Department of Health and Social Care. Declaration of Interests: This evaluation was commissioned by the UK Department of Health and Social Care. IEB, MGF, MGS, DMH, GB and CPC received grant funding from the UK Department of Health and Social Care to evaluate LFT in the Liverpool pilot discussed in this article. IEB reports fees from AstraZeneca as chief data scientist adviser via Liverpool University and a senior investigator grant from the National Institute for Health Research (NIHR) outside the submitted work. MGS is Chair of the Infectious Disease Scientific Advisory Board and a minority shareholder in Integrum Scientific LLC, Greensboro, NC, USA, a company that has interests in COVID-19 testing but not with lateral flow technology, and reports grants from the NIHR, the Medical Research Council, and the Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool. Ethics Approval Statement: The University of Liverpool provided secondary data analysis as part of a UK national service evaluation with data collection by the UK Department of Health and Social Care (DHSC; Sponsor) As per the National Health Service (NHS) Research Authority guidelines, this work did not require ethical approval.

Background: The aim of the study is to explore social and spatial inequalities in uptake and case-detection of rapid lateral flow SARS-CoV-2 antigen tests (LFTs) offered to people without symptoms of COVID-19.Methods: Linked pseudonymised records for asymptomatic residents in Liverpool (UK) who received a LFT for COVID-19 between 6th November 2020 to 31st January 2021 were accessed using the Combined Intelligence for Population Health Action (CIPHA) data resource. Bayesian Hierarchical Poisson Besag, York, and Mollié models were used to estimate ecological associations for uptake and positivity of testing.Findings: 214 525 residents (43%) received a LFT identifying 5557 individuals as positive cases of COVID-19 (1.3%). Uptake was highest in November when there was military assistance. High uptake was observed again in the week preceding Christmas and was sustained into a national lockdown. Overall uptake and repeat testing were lower among males (e.g. 40% uptake over the whole period), Black Asian and other Minority Ethnic groups (e.g. 27% uptake for ‘Mixed’ ethnicity) and in the most deprived areas (e.g. 32% uptake in most deprived areas). These population groups were also more likely to have received positive tests for COVID-19. Models demonstrated that uptake and repeat testing were lower in areas of higher deprivation, areas located further from test sites and areas containing populations less confident in the using Internet technologies. Positive tests were spatially clustered in deprived areas.Interpretation: Large-scale voluntary asymptomatic community testing saw social, ethnic, and spatial inequalities in an ‘inverse care’ pattern, but with an added digital exclusion factor. COVID-19 testing and support to isolate need to be more accessible to the vulnerable communities most impacted by the pandemic, including non-digital means of access.Funding: Department of Health and Social Care (UK), National Institute for Health Research and Economic and Social Research Council).Conflict of Interest: None declared.Ethical Approval: The University of Liverpool has provided secondary data analysis as part of a national service evaluation with data collected by Department of Health and Social Care (Sponsor) for quality assurance of Innova lateral flow tests in a public health service intervention. There was no research commissioned by Department of Health and Social Care on this aspect of the Liverpool pilot of asymptomatic, community testing. As such, research ethics approval was not sought by the Department of Health and Social Care. Some aspects of the evaluation requiring fieldwork and primary data collection by the University of Liverpool were subject to ethical approval, which was confirmed prior to the commencement of activities by the University of Liverpool’s Research Ethics Committee. The provision of secondary data analysis and interpretation did not require further ethical approval. Cheshire & Merseyside Health & Care Partnership Combined Intelligence for Population HealthAction (CIPHA) Data Access Committee approved access to the data and analysis contained in the study. MAST/SMART was defined as ‘an emergency public health intervention during an extraordinary event’ which were subject to the legal and ethical provisions of a health protection activity and COVID-19 specifically. The secondary analysis of data provided in a health protection activity is not classified as research, and so does not require research ethics committee review (see http://www.hradecisiontools.org.uk/research/docs/DefiningResearchTable_Oct2017-1.pdf).

BackgroundMortality rates of UK patients hospitalised with COVID-19 appeared to fall during the first wave. We quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.MethodsThe International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK recruited a prospective cohort admitted to 247 acute UK hospitals with COVID-19 in the first wave (March to August 2020). Outcome was hospital mortality within 28 days of admission. We performed a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and hospital mortality adjusting for confounders (demographics, comorbidity, illness severity) and quantifying potential mediators (respiratory support and steroids).FindingsUnadjusted hospital mortality fell from 32.3% (95%CI 31.8, 32.7) in March/April to 16.4% (95%CI 15.0, 17.8) in June/July 2020. Reductions were seen in all ages, ethnicities, both sexes, and in comorbid and non-comorbid patients. After adjustment, there was a 19% reduction in the odds of mortality per 4 week period (OR 0.81, 95%CI 0.79, 0.83). 15.2% of this reduction was explained by greater disease severity and comorbidity earlier in the epidemic. The use of respiratory support changed with greater use of non-invasive ventilation (NIV). 22.2% (OR 0.94, 95%CI 0.94, 0.96) of the reduction in mortality was mediated by changes in respiratory support.InterpretationThe fall in hospital mortality in COVID-19 patients during the first wave in the UK was partly accounted for by changes in case mix and illness severity. A significant reduction was associated with differences in respiratory support and critical care use, which may partly reflect improved clinical decision making. The remaining improvement in mortality is not explained by these factors, and may relate to community behaviour on inoculum dose and hospital capacity strain.FundingNIHR & MRCKey points / Research in ContextEvidence before this studyRisk factors for mortality in patients hospitalised with COVID-19 have been established. However there is little literature regarding how mortality is changing over time, and potential explanations for why this might be. Understanding changes in mortality rates over time will help policy makers identify evolving risk, strategies to manage this and broader decisions about public health interventions.Added value of this studyMortality in hospitalised patients at the beginning of the first wave was extremely high. Patients who were admitted to hospital in March and early April were significantly more unwell at presentation than patients who were admitted in later months. Mortality fell in all ages, ethnic groups, both sexes and in patients with and without comorbidity, over and above contributions from falling illness severity. After adjustment for these variables, a fifth of the fall in mortality was explained by changes in the use of respiratory support and steroid treatment, along with associated changes in clinical decision-making relating to supportive interventions. However, mortality was persistently high in patients who required invasive mechanical ventilation, and in those patients who received non-invasive ventilation outside of critical care.Implications of all the available evidenceThe observed reduction in hospital mortality was greater than expected based on the changes seen in both case mix and illness severity. Some of this fall can be explained by changes in respiratory care, including clinical learning. In addition, introduction of community policies including wearing of masks, social distancing, shielding of vulnerable patients and the UK lockdown potentially resulted in people being exposed to less virus.The decrease in mortality varied depending on the level of respiratory support received. Patients receiving invasive mechanical ventilation have persistently high mortality rates, albeit with a changing case-mix, and further research should target this group.Severe COVID-19 disease has primarily affected older people in the UK. Many of these people, but not all have significant frailty. It is essential to ensure that patients and their families remain at the centre of decision-making, and we continue with an individualised approach to their treatment and care.

Background: Varying the intervals in retinopathy screening informed by personal risk offers reallocation of resources to better target high risk groups and address the increasing prevalence of diabetes. However, safety data especially on extended intervals is minimal. Aim: To evaluate the safety, efficacy and cost effectiveness (CE) of individualized variable-interval risk-based screening in a population setting compared to usual care. Methods: Masked 2 arm, parallel assignment, equivalence RCT (largest to date in screening) with independent trials unit monitoring in people with diabetes aged ≥12 years attending screening in a single English program. Randomization was 1:1 to individualized screening (active group; 6, 12 or 24 months for high, medium and low risk) determined by a risk calculation engine using real-time local demographic, retinal and clinical data, compared with annual screening (control). CE analysis measuring NHS and societal costs took a 2-year time horizon. Findings: 4534 participants entered the study - after withdrawals/loss to follow-up: active 2097; control 2224. Attendance rates at first follow-up visit (primary outcome, safety) were equivalent (per protocol analysis, 5% margin): active 83.6% control 84.7% (difference 1.0, 90% CI -0.8, 2.9). STDR detection rates were non-inferior (1.5% margin): active 1.43% control 1.71% (difference -0.28, CI -0.93, 0.36). Quality of life (EQ5D5L, HUI3) was not significantly different between the groups. Incremental cost saving per person was £18.75 (NHS cost) rising to £49.96 with societal costs. A 39.3% reduction in number of appointments was seen. Conclusions: All parties involved in diabetes care can be reassured that extended and personalized screening intervals can safely be introduced in established screening program. Scale-up with further validation outside a research setting is recommended. Views expressed are solely those of the authors. Disclosure D.M. Broadbent: None. A. Wang: None. C.P. Cheyne: None. J.G. Lathe: None. I.M. Stratton: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Bayer AG, Boehringer Ingelheim International GmbH. J. Vora: None. M. Garcia-Finana: None. M. James: None. S.P. Harding: None. Funding UK National Institute for Health Research

Background: Varying diabetic retinopathy (DR) screening intervals, informed by personal risk-levels, empowers people with diabetes (PWD), and offers reallocation of resources to high risk groups, while addressing the increasing prevalence of diabetes. Safety data on extending intervals is minimal. We evaluated the safety, efficacy and cost effectiveness of individualised risk-based variable-interval population screening compared to usual care, with design input from PWD. Methods: Two-arm, parallel assignment, equivalence randomised controlled trial (minimum 2 year follow-up) in PWD aged ≥12 years registered with one English screening programme. Randomisation was 1:1 to individualised screening (6, 12 or 24 months for high, medium and low risk) determined by a risk calculation engine, using local demographic, screening and clinical data, or to annual screening (control). Primary outcome was attendance (safety). A secondary safety outcome was the development of sight threatening DR (STDR). Cost effectiveness was evaluated within a 2 year time horizon from NHS and societal perspectives. Findings: 4534 participants were randomised, 2265 to the individualised and 2269 to the control arm. Attendance rates at first follow-up were equivalent between individualised (1754/2097, 83·6%) and control (1883/2224, 84·7%) arms (difference -1·0, 95% CI -3·2 to 1·2). STDR detection rates were non-inferior: individualised 1·4%, control 1·7% (- 0·3, -1·1 to 0·5). Sensitivity analyses confirmed findings. Incremental QALYs/person were non-significant: EQ-5D-5L 0·035 (CI -0·04, 0·13), HUI3 0·009 (CI -0·09, 0·10). Incremental cost savings were £21·31 (CI 15·24, 26·79)/person for the NHS and £28·87 (CI 21·08, 35·78) including societal costs. 43·2% fewer screening appointments were required in the individualised arm. Interpretation: Stakeholders involved in diabetes care can be reassured by this largest ophthalmic RCT in DR screening to date that extended and individualised risk-based intervals can be safely and cost effectively introduced in established screening programmes. Trial Registration Number: ISRCTN 87561257. Funding Statement: This study was funded by the UK National Institute for Health Research (NIHR) (Programme Grants for Applied Research, RP-PG-1210-12016). Declaration of Interests: We declare no competing interests. Professor Mark Gabbay is part-funded by the NIHR Collaboration for Leadership in Applied Health Research and Care North West Coast. Ethics Approval Statement: A UK NHS Research Ethics Committee approved the trial (14/NW/0034).

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.

Aims/hypothesis Individualised variable-interval risk-based screening offers better targeting and improved cost-effectiveness in screening for diabetic retinopathy. We developed a generalisable risk calculation engine (RCE) to assign personalised intervals linked to local population characteristics, and explored differences in assignment compared with current practice. Methods Data from 5 years of photographic screening and primary care for people with diabetes, screen negative at the first of > 1 episode, were combined in a purpose-built near-real-time warehouse. Covariates were selected from a dataset created using mixed qualitative/quantitative methods. Markov modelling predicted progression to screen-positive (referable diabetic retinopathy) against the local cohort history. Retinopathy grade informed baseline risk and multiple imputation dealt with missing data. Acceptable intervals (6, 12, 24 months) and risk threshold (2.5%) were established with patients and professional end users. Results Data were from 11,806 people with diabetes (46,525 episodes, 388 screen-positive). Covariates with sufficient predictive value were: duration of known disease, HbA1c, age, systolic BP and total cholesterol. Corrected AUC (95% CIs) were: 6 months 0.88 (0.83, 0.93), 12 months 0.90 (0.87, 0.93) and 24 months 0.91 (0.87, 0.94). Sensitivities/specificities for a 2.5% risk were: 6 months 0.61, 0.93, 12 months 0.67, 0.90 and 24 months 0.82, 0.81. Implementing individualised RCE-based intervals would reduce the proportion of people becoming screen-positive before the allocated screening date by > 50% and the number of episodes by 30%. Conclusions/interpretation The Liverpool RCE shows sufficient performance for a local introduction into practice before wider implementation, subject to external validation. This approach offers potential enhancements of screening in improved local applicability, targeting and cost-effectiveness. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4386-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Objective: To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning. Methods: This was a cross-sectional observational study. Children exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses. Results: In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (−10.6, 95% confidence interval [CI] −16.3 to −5.0, p < 0.001), verbal abilities (−11.2, 95% CI −16.8 to −5.5, p < 0.001), nonverbal abilities (−11.1, 95% CI −17.3 to −4.9, p < 0.001), and expressive language ability (−2.3, 95% CI −3.4 to −1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate. Conclusions: Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

Visual field assessment is an important clinical evaluation for eye disease and neurological injury. We evaluated Octopus semi-automated kinetic peripheral perimetry (SKP) and Humphrey static automated central perimetry for detection of neurological visual field loss in patients with pituitary disease. We carried out a prospective cross-sectional diagnostic accuracy study comparing Humphrey central 30-2 SITA threshold programme with a screening protocol for SKP on Octopus perimetry. Humphrey 24-2 data were extracted from 30-2 results. Results were independently graded for presence/absence of field defect plus severity of defect. Fifty patients (100 eyes) were recruited (25 males and 25 females), with mean age of 52.4 years (SD = 15.7). Order of perimeter assessment (Humphrey/Octopus first) and order of eye tested (right/left first) were randomised. The 30-2 programme detected visual field loss in 85%, the 24-2 programme in 80%, and the Octopus combined kinetic/static strategy in 100% of eyes. Peripheral visual field loss was missed by central threshold assessment. Qualitative comparison of type of visual field defect demonstrated a match between Humphrey and Octopus results in 58%, with a match for severity of defect in 50%. Tests duration was 9.34 minutes (SD = 2.02) for Humphrey 30-2 versus 10.79 minutes (SD = 4.06) for Octopus perimetry. Octopus semi-automated kinetic perimetry was found to be superior to central static testing for detection of pituitary disease-related visual field loss. Where reliant on Humphrey central static perimetry, the 30-2 programme is recommended over the 24-2 programme. Where kinetic perimetry is available, this is preferable to central static programmes for increased detection of peripheral visual field loss.

Background People with diabetic retinopathy tend to have lower levels of health-related quality of life than individuals with no retinopathy. Strategies for screening and treatment have been shown to be cost-effective. In order to reduce the bias in cost-effectiveness estimates, systematic reviews of health state utility values (HSUVs) are crucial for health technology assessment and the development of decision analytic models. A review and synthesis of HSUVs for the different stages of disease progression in diabetic retinopathy has not previously been conducted. Methods/Design We will conduct a systematic review of the available literature that reports HSUVs for people with diabetic retinopathy, in correspondence with current stage of disease progression and/or visual acuity. We will search Medline, EMBASE, Web of Science, Cost-Effectiveness Analysis Registry, Centre for Reviews and Dissemination Database, and EconLit to identify relevant English-language articles. Data will subsequently be synthesized using linear mixed effects modeling meta-regression. Additionally, reported disease severity classifications will be mapped to a four-level grading scale for diabetic retinopathy. Discussion The systematic review and meta-analysis will provide important evidence for future model-based economic evaluations of technologies for diabetic retinopathy. The meta-regression will enable the estimation of utility values at different disease stages for patients with particular characteristics and will also highlight where the design of the study and HSUV instrument have influenced the reported utility values. We believe this protocol to be the first of its kind to be published. Systematic review registration PROSPERO CRD42014012891 Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0006-6) contains supplementary material, which is available to authorized users.

Objective. To delineate the risk to child IQ associated with commonly prescribed antiepileptic drugs. Methods. Children born to women with epilepsy (n=243) and women without epilepsy (n=287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at six years of age. Maternal and child demographics were collected and entered into statistical models. Results. The adjusted mean IQ was 9.7 points lower (95% CI -4·9 to -14·6; P800mg daily) valproate, with a similar significant effect observed for the verbal, non-verbal and spatial subscales. Children exposed to high dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8·0; 2·5 to 19·7; P Conclusions. Consistent with data from younger cohorts, school aged children exposed to valproate at maternal doses over 800mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

OBJECTIVE: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. METHODS: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. RESULTS: After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] -24.5 to -7.1, p

In recent years questions have arisen about whether there are any links between handedness and academic abilities as well as other factors. In this study we investigate the effects of gender, writing hand, relative hand skill, and UK region on mathematics and reading test scores by applying a multivariate linear mixed-effects model. A data sample based on 11,847 11-year-old pupils across the UK from the National Child Development Study was considered for the analysis. Our results show that pupils who write with one hand while having better skill with their other hand (i.e., inconsistent writing hand and superior hand) obtained lower test scores in both reading and mathematics than pupils with consistent writing hand and superior hand. Furthermore, we confirm previous findings that degree of relative hand skill has a significant effect on both reading and maths scores and that this association is not linear. We also found higher scores of reading in children from the south of England, and of mathematics in children from the south of England and Scotland, when compared to other UK regions.