Cancer incidence and mortality in 23 000 patients with type 1 diabetes in the UK: Long-term follow-up.

Type 2 diabetes is associated with raised risk of several cancers, but for type 1 diabetes risk data are fewer and inconsistent We assembled a cohort of 23 473 UK patients with insulin-treated diabetes diagnosed at ages <30, almost all of whom will have had type 1 diabetes, and for comparison 5058 diagnosed at ages 30 to 49, of whom we estimate two-thirds will have had type 2, and followed them for an average of 30 years for cancer incidence and mortality compared with general population rates. Patients aged <30 at diabetes diagnosis had significantly raised risks only for ovarian (standardised incidence ratio = 1.58; 95% confidence interval 1.16-2.11; P < .01) and vulval (3.55; 1.94-5.96; P < .001) cancers, with greatest risk when diabetes was diagnosed at ages 10-14. Risks of cancer overall (0.89; 0.84-0.95; P < .001) and sites including lung and larynx were significantly diminished. Patients diagnosed with diabetes at ages 30 to 49 had significantly raised risks of liver (1.76;1.08-2.72) and kidney (1.46;1.03-2.00) cancers, and reduced risk of cancer overall (0.89; 0.84-0.95). The raised ovarian and vulval cancer risks in patients with type 1 diabetes, especially with diabetes diagnosed around pubertal ages, suggest possible susceptibility of these organs at puberty to metabolic disruption at diabetes onset. Reduced risk of cancer overall, particularly smoking and alcohol-related sites, might reflect adoption of a healthy lifestyle.

Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

Type 1 diabetes incidence in Scotland between 2006 and 2019.

AIMS: To describe type 1 diabetes incidence in Scotland between 2006 and 2019. METHODS: Repeated annual cross-sectional studies of type 1 diabetes incidence were conducted. Incident cases were identified from the Scottish Care Information-Diabetes Collaboration (SCI-DC), a population-based register of people with diagnosed diabetes derived from primary and secondary care data. Mid-year population estimates for Scotland were used as the denominator to calculate annual incidence with stratification by age and sex. Joinpoint regression was used to investigate whether incidence changed during the study period. Age and sex-specific type 1 diabetes incidence over the whole time period was estimated by quintile of the Scottish Index of Multiple Deprivation (SIMD), an area-based measure, in which Q1 and Q5 denote the most and least deprived fifths of the population, respectively, with quasi-Poisson regression used to compare incidence for Q5 compared to Q1. RESULTS: The median (IQR) age of the study population of 14,564 individuals with incident type 1 diabetes was 24.1 (12.3-42.4) years, 56% were men, 23% were in Q1 and 16% were in Q5. Incidence of T1DM was higher in men than women overall (at around 22 and 17 per 100,000, respectively) and in under 15 year olds (approximately 40 per 100,000 in both sexes) than other age groups and was similar across the study period in all strata. There was an inverse association between socio-economic status and type 1 diabetes incidence for 15-29, 30-49 and 50+ year olds [incidence rate ratio (IRR) for Q5 compared to Q1; IRR (95% CI) 0.52 (0.47-0.58), 0.68 (0.61-0.76) and 0.53(0.46-0.61), respectively] but not for under 15 year olds [1.02 (0.92-1.12)]. CONCLUSION: Incidence of type 1 diabetes varies by age, sex and socio-economic status and has remained approximately stable from 2006 to 2019 in Scotland.

Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.

PURPOSE: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR. DESIGN: Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom. PARTICIPANTS: Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease. METHODS: A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists). MAIN OUTCOME MEASURES: Primary outcome: sensitivity of the new pathway. SECONDARY OUTCOMES: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings. RESULTS: The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits. CONCLUSIONS: The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.

Laser peripheral iridoplasty for chronic angle closure.

BACKGROUND: In at least a third of primary angle closure cases, appositional angle closure persists after laser peripheral iridotomy, and further intervention may be considered. Laser peripheral iridoplasty (LPIp) can be used in treating chronic angle closure when angle closure persists after laser peripheral iridotomy. Previous reviews have found insufficient data to determine its clinical effectiveness, compared to other interventions. This is an update of a Cochrane Review first published in 2008 and updated in 2012. It examines all studies to date to establish whether LPIp shows any effectiveness over other available treatment options. OBJECTIVES: To assess the effectiveness of laser peripheral iridoplasty in the treatment of people with chronic angle closure, when compared to laser peripheral iridotomy, medical therapy or no further treatment. SEARCH METHODS: We searched various electronic databases. The date of the search was 20 December 2020. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) assessing the use of LPIp in cases of suspected primary angle closure (PACS), confirmed primary angle closure (PAC), or primary chronic angle-closure glaucoma (PACG). We applied no restrictions with respect to gender, age or ethnicity of participants. Trials evaluating LPIp for acute attacks of angle closure were not eligible. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two authors independently assessed studies for risk of bias using Cochrane's 'risk of bias' tool. We collected adverse effects information from the trials. MAIN RESULTS: We included four RCTs involving 252 participants (276 eyes). In total, three different methods of intervention were used and 15 outcomes reported, with different time points. We used narrative synthesis to describe the majority of the findings, as meta-analysis was only possible for a limited number of outcomes due to the variation in study design and outcomes assessed. Study Characteristics Participants were adults recruited from outpatient settings in the UK, Singapore, China and Korea with either PACS, PAC or PACG. All studies compared argon LPIp (as either a primary or secondary procedure) to an alternative intervention or no further treatment. Three studies were of parallel group design, and one within-person, randomised by eye. All studies showed elements of high risk of bias. Due to the nature of the intervention assessed, a lack of masking of both participants and assessors was noted in all trials. Findings Laser peripheral iridoplasty with iridotomy versus iridotomy alone as a primary procedure Two RCTs assessed the use of argon LPIp as a primary procedure with peripheral iridotomy, compared with peripheral iridotomy alone. However, neither study reported data for the primary outcome, disease progression. Argon LPIp showed no evidence of effect on: final mean intraocular pressure (IOP) at 3 months and 12 months (mean difference (MD) 0.39 mmHg, 95% confidence interval (CI) -1.07 to 1.85; I2 = 38%; 2 studies, 174 participants; low-certainty evidence); further surgical or laser intervention at 12 months (risk ratio (RR) 1.21, 95% CI 0.66 to 2.21; 1 study, 126 participants; low-certainty evidence); or mean number of additional medications required at 12 months (MD 0.10, 95% CI -0.34 to 0.54; 1 study, 126 participants; low-certainty evidence). Complications were assessed at 3 to 12 months (2 studies, 206 participants; low-certainty evidence) and found to be mild and uncommon, with comparable levels between groups. The only severe complication encountered was one case of malignant glaucoma in one study's argon LPIp group. Quality of life measures were not assessed. In the other study, investigators found that argon LPIp showed no evidence of effect on final mean anterior segment optical coherence tomography (AS-OCT) measurements, including anterior chamber depth (MD 0.00 mm, 95% CI -0.10 to 0.10; 24 participants, 48 eyes; very low-certainty evidence). Laser peripheral iridoplasty as a secondary procedure versus no treatment One RCT assessed the use of argon LPIp as a secondary procedure compared with no further treatment in 22 participants over three months. Disease progression, additional medications required, complications, further surgical or laser intervention, and quality of life outcomes were not assessed. There was only very low-certainty evidence regarding final maximum IOP value (MD -1.81 mmHg, 95% CI -3.11 to -0.51; very low-certainty evidence), with no evidence of effect on final minimum IOP values (MD -0.31 mmHg, 95% CI -1.93 to 1.31; very low-certainty evidence). The evidence is very uncertain about the effect of argon LPIp on AS-OCT parameters. The trial did not report AS-OCT measurements for the control group. Laser peripheral iridoplasty as a secondary procedure versus medication One RCT assessed the use of argon LPIp as a secondary procedure compared with travoprost 0.004% in 80 participants over 12 months. The primary outcome of disease progression was reported for this method: argon LPIp showed no evidence of effect on mean final cup/disk ratio (MD -0.03, 95% CI -0.11 to 0.05; low-certainty evidence). Argon LPIp showed no evidence of effect for: mean change in IOP (MD -1.20 mmHg, 95% CI -2.87 to 0.47; low-certainty evidence) or mean number of additional medications (MD 0.42, 95% CI 0.23 to 0.61; low-certainty evidence). Further surgical intervention was required by one participant in the intervention group alone, with none in the control group  (low-certainty evidence). No serious adverse events were reported, with mild complications consisting of two cases of 'post-laser IOP spike' in the argon LPIp group. Quality of life measures were not assessed. The evidence is very uncertain about the effect of argon LPIp on AS-OCT parameters. The trial did not report AS-OCT measurements for the control group. Adverse events Availability of data were limited for adverse effects. Similar rates were observed in control and intervention groups, where reported. Serious adverse events were rare. AUTHORS' CONCLUSIONS: After reviewing the outcomes of four RCTs, argon LPIp as an intervention may be no more clinically effective than comparators in the management of people with chronic angle closure. Despite a potential positive impact on anterior chamber morphology, its use in clinical practice in treating people with chronic angle closure is not supported by the results of trials published to date. Given these results, further research into LPIp is unlikely to be worthwhile.

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.

A brief introduction to health economics.

To convince policy-makers or funders of health care of the value of orthopaedic interventions, we need to consider value for money (cost-effectiveness), as well as clinical effectiveness. This article provides an introduction to health economics to set the scene for papers on the use of allografts in the knee.

Allografts in reconstruction of the posterior cruciate ligament: a health economics perspective.

PURPOSE: To review the relative cost-effectiveness of allografts and autografts in reconstruction of the posterior cruciate ligament. METHODS: Systematic review and cost-effectiveness analysis. RESULTS: The available evidence does not show any significant difference in clinical effectiveness between autografts and allografts. Given that, only a cost analysis is provided, which shows that allografts are more costly. CONCLUSION: Given the lack of any benefit of allografts over autografts, autografts should be preferred on cost grounds, if available. However, there may be situations where an allograft is indicated, for example, in multiple ligament reconstructions. LEVEL OF EVIDENCE: IV.

Autograft or allograft for reconstruction of anterior cruciate ligament: a health economics perspective.

PURPOSE: To assess the clinical and cost-effectiveness of allografts versus autografts in the reconstruction of anterior cruciate ligaments. METHODS: Systematic review of comparative clinical effectiveness and cost-effectiveness analysis. RESULTS: Both autograft and allograft reconstruction are highly effective. Recent studies show little difference in failure rates between autografts and allografts (about 6% and 7%, respectively). In cost-effectiveness analysis, the price differential is the main factor, making autografts the first choice. However, there will be situations, particularly in revision ACL reconstruction, where an allograft may be preferred, or may be the only reasonable option available. CONCLUSION: In ACL reconstruction, clinical results with autografts are as good as or slightly better than with allografts. Allografts cost more, indicating that autografts are more cost-effective and should usually be first choice. LEVEL OF EVIDENCE: II.

The cost-effectiveness of osteochondral allograft transplantation in the knee.

PURPOSE: Osteochondral allografts (OCA) consist of a layer of hyaline cartilage and a layer of underlying bone. They are used to repair combined defects of articular cartilage and bone. Such defects often occur in people far too young to have knee arthroplasty, for whom the main alternative to OCA is conservative symptomatic care, which will not prevent development of osteoarthritis. The aim of this report was to assess the cost-effectiveness of osteochondral allograft transplantation in the knee. METHODS: Systematic review of evidence on clinical effectiveness and economic modelling. RESULTS: The evidence on osteochondral allograft transplantation comes from observational studies, but often based on good quality prospective registries of all patients having such surgery. Without controlled trials, it was necessary to use historical cohorts to assess the effect of osteochondral grafts. There is good evidence that OCA are clinically effective with a high graft survival rate over 20 years. If an OCA graft fails, there is some evidence that revision with a second OCA is also effective, though less so than primary OCA. Economic modelling showed that osteochondral allograft transplantation was highly cost-effective, with costs per quality adjusted life year much lower than many other treatments considered cost effective. CONCLUSIONS: Osteochondral allograft transplantation appears highly cost-effective though the cost per quality adjusted life year varies according to the widely varying costs of allografts. Based on one small study, revision OCA also appears very cost-effective, but more evidence is needed. LEVEL OF EVIDENCE: II.

Meniscal allograft transplantation after meniscectomy: clinical effectiveness and cost-effectiveness.

PURPOSE: To assess the clinical effectiveness and cost-effectiveness of meniscal allograft transplantation (MAT) after meniscal injury and subsequent meniscectomy. METHODS: Systematic review of clinical effectiveness and cost-effectiveness analysis. RESULTS: There is considerable evidence from observational studies, of improvement in symptoms after meniscal allograft transplantation, but we found only one small pilot trial with a randomised comparison with a control group that received non-surgical care. MAT has not yet been proven to be chondroprotective. Cost-effectiveness analysis is not possible due to a lack of data on the effectiveness of MAT compared to non-surgical care. CONCLUSION: The benefits of MAT include symptomatic relief and restoration of at least some previous activities, which will be reflected in utility values and hence in quality-adjusted life years, and in the longer term, prevention or delay of osteoarthritis, and avoidance or postponement of some knee replacements, with resulting savings. It is likely to be cost-effective, but this cannot be proven on the basis of present evidence. LEVEL OF EVIDENCE: IV.

Mortality risk remains higher in individuals with type 1 diabetes: A population-based cohort study (the Ayrshire diabetes follow-up cohort [ADOC]).

AIMS: Type 1 diabetes is associated with an increased risk of cardiovascular disease and all-cause mortality. Numerous studies have demonstrated that outcomes for diabetes are improved by intensive glycaemic control, blood pressure control, and treatment of dyslipidaemia in addition to cessation of smoking. The aim of this study was to compare mortalities in individuals with type 1 diabetes with that in non-diabetic individuals, and to investigate the effects of age, gender, glycaemic control, socio-economic status, hypertension, ischaemic heart disease (IHD), smoking status, body mass index (BMI) and dyslipidaemia. METHODS: A population-based analysis in Ayrshire and Arran, Scotland included 253 304 non-diabetic individuals and 1324 individuals with type 1 diabetes who were tracked from 2009 to 2014. RESULTS: Patients with type 1 diabetes had higher mortality rates than non-diabetic individuals (HR, 3.20; P < .01), with relative mortality in female individuals with type 1 diabetes being higher than that in males (OR, 2.38 vs 1.52; P < .01). Increasing age (HR, 2.37), smoking (HR, 1.85), IHD (HR, 1.62) and hypertension (HR, 1.21) (all P < .01) increased mortality risk. A hypertensive female with type 1 diabetes and IHD who smoked had an HR of 11.6 compared with a non-smoking, normotensive non-diabetic female without IHD. For a hypertensive male with type 1 diabetes and IHD who smoked, HR was 6.96. BMI > 30 kg/m2 was associated with reduced mortality risk in both non-diabetic (HR, 0.61) and diabetic subjects (HR, 0.40). CONCLUSIONS: This study confirmed that the risk of mortality in individuals with type 1 diabetes remains elevated. Further studies are required to understand how gender affects the disparity in mortality and why obesity appears to be protective.

PRIORITIES FOR HEALTH ECONOMIC METHODOLOGICAL RESEARCH: RESULTS OF AN EXPERT CONSULTATION.

BACKGROUND: The importance of economic evaluation in decision making is growing with increasing budgetary pressures on health systems. Diverse economic evidence is available for a range of interventions across national contexts within Europe, but little attention has been given to identifying evidence gaps that, if filled, could contribute to more efficient allocation of resources. One objective of the Research Agenda for Health Economic Evaluation project is to determine the most important methodological evidence gaps for the ten highest burden conditions in the European Union (EU), and to suggest ways of filling these gaps. METHODS: The highest burden conditions in the EU by Disability Adjusted Life Years were determined using the Global Burden of Disease study. Clinical interventions were identified for each condition based on published guidelines, and economic evaluations indexed in MEDLINE were mapped to each intervention. A panel of public health and health economics experts discussed the evidence during a workshop and identified evidence gaps. RESULTS: The literature analysis contributed to identifying cross-cutting methodological and technical issues, which were considered by the expert panel to derive methodological research priorities. CONCLUSIONS: The panel suggests a research agenda for health economics which incorporates the use of real-world evidence in the assessment of new and existing interventions; increased understanding of cost-effectiveness according to patient characteristics beyond the "-omics" approach to inform both investment and disinvestment decisions; methods for assessment of complex interventions; improved cross-talk between economic evaluations from health and other sectors; early health technology assessment; and standardized, transferable approaches to economic modeling.

Parents' information and support needs when their child is diagnosed with type 1 diabetes: a qualitative study.

AIM AND OBJECTIVE: The aim of this study was to describe and explore parents' information and support needs when their child is diagnosed with type 1 diabetes, including their views about the timing and chronology of current support provision. Our objective was to identify ways in which parents could be better supported in the future. DESIGN AND PARTICIPANTS: Semi-structured interviews were conducted with 54 parents of children with type 1 diabetes in four paediatric diabetes clinics in Scotland. Data were analysed using an inductive, thematic approach. FINDINGS: Parents described needing more reassurance after their child was diagnosed before being given complex information about diabetes management, so they would be better placed psychologically and emotionally to absorb this information. Parents also highlighted a need for more emotional and practical support from health professionals when they first began to implement diabetes regimens at home, tailored to their personal and domestic circumstances. However, some felt unable to ask for help or believed that health professionals were unable to offer empathetic support. Whilst some parents highlighted a need for support delivered by peer parents, others who had received peer support conveyed ambivalent views about the input and advice they had received. CONCLUSIONS: Our findings suggest that professionals should consider the timing and chronology of support provision to ensure that parents' emotional and informational needs are addressed when their child is diagnosed and that practical advice and further emotional support are provided thereafter, which takes account of their day-to-day experiences of caring for their child.

Improving communication and recall of information in paediatric diabetes consultations: a qualitative study of parents' experiences and views.

BACKGROUND: Parents of non-adolescent children with type 1 diabetes are responsible for most of their child's diabetes management tasks. Consultations are used to provide diabetes education, review clinical progress and promote diabetes management tasks. This study explored parents' experiences of, and views about, their child's diabetes consultations. The objective was to identify ways in which consultations could be improved to aid communication, understanding and knowledge retention. METHODS: In-depth interviews with 54 parents of children (aged ≤12 years) with type 1 diabetes. Data were analysed using an inductive thematic approach. RESULTS: Parents' accounts revealed structural and contextual factors which could hinder effective communication and knowledge acquisition during consultations. Most reported feeling anxious going into consultations and worrying about being reprimanded by health professionals if their child's glycaemic control had not improved. As a consequence, many parents highlighted problems concentrating and assimilating information during consultations. In extreme cases, worries about being reprimanded led parents to omit or fabricate information when discussing their child's treatment or even to their cancelling appointments. Many parents described wanting opportunities to speak to health professionals alone because young children could be distracting and/or they did not want to raise distressing issues in front of their child. Parents described the benefits of receiving clinical advice from health professionals familiar with their family circumstances and disliking attending busy clinics and seeing different health professionals on each occasion. Parents also highlighted the benefits of receiving treatment recommendations in a written form after the consultation. DISCUSSION AND CONCLUSIONS: This study has highlighted unrecognised and undocumented aspects of the consultation which may result in parents leaving uncertain about the main issues discussed and with questions unanswered and support needs unaddressed. Structural and contextual changes to consultations are recommended to improve concentration, knowledge acquisition and retention. These include: sending letters/written summaries after consultations highlighting key decisions, providing opportunities for parents to consult health professionals without their child being present, encouraging parents to ask more questions during consultations, having procedures in place to promote continuity of care and providing parents with consistent and non-contradictory advice.

Pathways to diagnosis: a qualitative study of the experiences and emotional reactions of parents of children diagnosed with type 1 diabetes.

OBJECTIVE: The aim of this study was to explore from parents' perspectives the circumstances and events which led to their child being diagnosed with type 1 diabetes (T1D). The objective was to understand reasons for delays in seeking treatment and parents' emotional reactions to diagnosis so others can be better informed and supported in future. METHODS: In-depth interviews with 54 parents of children (aged ≤12 yr) with T1D were conducted. Data analysis used an inductive, thematic approach. RESULTS: Parents described a 'prompt' and a 'delayed' pathway to their child being diagnosed. Parents who considered the diagnosis to be 'prompt' reported how they, or other people, had recognized their child had developed symptoms of T1D which resulted in a rapid presentation to health care professionals. In contrast, parents who perceived their child's diagnosis to be 'delayed' did not recognize signs of T1D and attributed their child's deteriorating health to other conditions, being out of routines and/or their stage of development. These parents often only sought medical help when symptoms became extreme. All parents were distressed by their child's diagnosis; however, parents in the 'delayed' pathway expressed unresolved feelings of guilt, particularly when their child was diagnosed with diabetic ketoacidosis. DISCUSSION: Parents' and other people's knowledge about T1D can affect the duration between onset of their child's symptoms and diagnosis. Campaigns to raise awareness should ensure that parents are made aware of symptoms and that T1D can develop during childhood. Health care professionals could discuss with parents the events preceding their child's diagnosis to better determine their emotional support needs.

Postcolposcopy management of women with histologically proven CIN 1: results from TOMBOLA.

OBJECTIVES: This study aimed to determine during 36 months of follow-up the (1) clinical outcomes and (2) influence of high-risk human papillomavirus (HPV) status on the risk of progression to cervical intraepithelial neoplasia 2+ (CIN 2+), among women with histologically proven CIN 1. MATERIALS AND METHODS: This is an ad hoc analysis of women with CIN 1 within TOMBOLA, a randomized trial of the management of women with low-grade cervical cytology. Women from the colposcopy arm with CIN 1 confirmed on punch biopsies and managed conservatively by cytology every 6 months in primary care were included. Sociodemographic data and a sample for HPV testing were collected at recruitment. Data on the sample women were extracted to calculate the cumulative incidence of CIN 2+ and the performance characteristics of the baseline HPV test. Detection of CIN 2 or worse (CIN 2+) during follow-up or at exit colposcopy was analyzed. RESULTS: A total of 171 women were included. Their median age was 29 years. Fifty-two percent were high-risk HPV positive, 17% were HPV-16 positive, and 11% were HPV-18 positive. Overall, 21 women (12%) developed CIN 2+, with a median time to detection of 25 months. Factors associated with progression to CIN 2+ were presence of HPV-18 (relative risk = 3.04; 95% CI = 1.09-8.44) and HPV-16 and/or HPV-18 at recruitment (relative risk = 3.98; 95% CI = 1.60-9.90). The sensitivity and specificity of a combined HPV-16/HPV-18 test for the detection of CIN 2+ during 3 years were 58% and 78%, respectively. CONCLUSIONS: Our results suggest that women with confirmed CIN 1 have low rates of progression to high-grade CIN within 3 years. Because the median time to progression was 25 months, conservative management could recommend the next repeat cytology at 2 years.

Early pregnancy HbA1c as the first screening test for gestational diabetes: results from three prospective cohorts.

BACKGROUND: More than 90% of gestational diabetes cases are estimated to occur in low-income and middle-income countries (LMICs). Most current guidelines recommend an oral glucose tolerance test (OGTT) at 24-28 weeks of gestation. The OGTT is burdensome, especially in LMICs, resulting in a high proportion of women not being screened. We aimed to develop a simple and effective screening strategy for gestational diabetes. METHODS: STRiDE, a prospective cohort study, was set up in seven centres in south India and seven centres in western Kenya, and included pregnant women aged 18-50 years of age and at less than 16 weeks of gestation (<20 weeks in Kenya), confirmed by dating ultrasound. We assessed the efficacy of early pregnancy HbA1c (venous and capillary point-of-care), either alone or as part of a composite risk score with age, BMI, and family history of diabetes, in predicting gestational diabetes at 24-28 weeks of gestation, in two LMICs (India and Kenya) and in a UK multi-ethnic population from the PRiDE study. A key secondary outcome was to assess whether an early pregnancy composite risk score can reduce the need for OGTTs. Gestational diabetes was diagnosed using current WHO criteria. FINDINGS: Between Feb 15, 2016, Dec 13, 2019, we enrolled 3070 participants in India and 4104 in Kenya. 4320 participants were included from the PRiDE cohort. Gestational diabetes prevalence by OGTT at 24-28 weeks was 19·2% in India, 3·0% in Kenya, and 14·5% in the UK. Early pregnancy HbA1c was independently associated with incidence of gestational diabetes at 24-28 weeks of gestation. Adjusted risk ratios were 1·60 (95% CI 1·19-2·16) in India, 3·49 (2·8-4·34) in Kenya, and 4·72 (3·82-5·82) in the UK. Composite risk score models that combined venous or point-of-care HbA1c with age, BMI, and family history of diabetes best predicted testing positive for gestational diabetes. A population-specific, two-threshold screening strategy of rule-in and rule-out gestational diabetes using early pregnancy composite risk score could reduce the requirement of OGTTs by 50-64%. For the HbA1c-alone model, the thresholds were 5·4% (rule in) and 4·9% (rule out) in India, 6·0% (rule in) and 5·2% (rule out) in Kenya, and 5·6% (rule in) and 5·2% (rule out) in the UK. INTERPRETATION: Early pregnancy HbA1c offers a simple screening test for gestational diabetes, allowing those at highest risk to receive early intervention and greatly reduce the need for OGTTs. This can also be carried out using point-of-care HbA1c in LMICs. FUNDING: UK Medical Research Council and the Indian Department of Biotechnology.

Surveillance of people with previously successfully treated diabetic macular oedema and proliferative diabetic retinopathy by trained ophthalmic graders: cost analysis from the EMERALD study.

BACKGROUND/AIMS: Surveillance of people with previously successfully treated diabetic macular oedema (DMO) and proliferative diabetic retinopathy (PDR) adds pressure on ophthalmology services. This study evaluated a new surveillance pathway entailing multimodal imaging reviewed by trained ophthalmic graders and compared it with the current standard care (face-to-face evaluation by an ophthalmologist). METHODS: Cost analysis of the new ophthalmic grader pathway, compared with the standard of care, from the perspective of the UK National Health Service, based on evidence from the Effectiveness of Multimodal imaging for the Evaluation of Retinal oedema And new vesseLs in Diabetic retinopathy study. Resource use data were prospectively obtained including times to undertake each procedure. Effectiveness was assessed in terms of sensitivity and specificity of referral decisions in the grader pathway. Costs (SDs) were analysed per 100 patients separately for DMO and PDR at 2018/2019 costs. RESULTS: For DMO, where sensitivity was very high (97%), the cost difference (savings) for the grader's pathway would be £1390 per 100 patients. For PDR, the cost would be reduced by £461 for seven-field Early Treatment for Diabetic Retinopathy Study (ETDRS) images and by £1889 for ultrawide field images, per 100 patients. Ultrawide images required less time to be obtained and read than seven-field ETDRS. The real savings would be in ophthalmologist time, which could be then redirected to the evaluation of people at high risk of visual loss. CONCLUSIONS: Surveillance of people with previously successfully treated DMO and PDR by trained ophthalmic graders can achieve satisfactory results and release ophthalmologist time. TRIAL REGISTRATION NUMBERS: NCT03490318, ISRCTN10856638.

REducing Colonoscopies in patients without significant bowEl DiseasE: the RECEDE Study - protocol for a prospective diagnostic accuracy study.

INTRODUCTION: Demand for colonoscopies and CT colonography (CTC) is exceeding capacity in National Health Service Trusts. In many patients colonoscopies and CTCs show no significant bowel disease (SBD). Faecal Immunochemical Testing (FIT) is being introduced to prioritise patients for colonoscopies but is insufficient to identify non-SBD patients meaning colonoscopy and CTC demand remains high. The REducing Colonoscopies in patients without significant bowEl DiseasE (RECEDE) study aims to test urine volatile organic compound (VOC) analysis alongside FIT to improve detection of SBD and to reduce the number of colonoscopies and CTCs. METHODS AND ANALYSIS: This is a multicentre, prospective diagnostic accuracy study evaluating whether stool FIT plus urine VOC compared with stool FIT alone improves detection of SBD in patients referred for colonoscopy or CTC due to persistent lower gastrointestinal symptoms. To ensure SBD is not missed, the dual test requires a high sensitivity, set at 97% with 95% CI width of 5%. Our assumption is that to achieve this sensitivity requires 200 participants with SBD. Further assuming 19% of all participants will have SBD and 55% of all participants will return both stool and urine samples we will recruit 1915 participants. The thresholds for FIT and VOC results diagnosing SBD have been pre-set. If either FIT or VOC exceeds the respective threshold, the participant will be classed as having suspected SBD. As an exploratory analysis we will be testing different thresholds. The reference comparator will be a complete colonoscopy or CTC. Secondary outcomes will look at optimising the FIT and VOC thresholds for SBD detection. An economic evaluation, using a denovo decision analytic model, will be carried out determine the costs, benefits and overall cost-effectiveness of FIT +VOC vs FIT followed by colonoscopy. ETHICS AND DISSEMINATION: Ethical approval was obtained by Liverpool Central Research Ethics Committee (20/NW/0346). TRIAL REGISTRATION NUMBER: RECEDE is registered on Clinicaltrials.gov NCT04516785 & ISRCTN14982373. This protocol was written and published before results of the trial were available.