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Aims/hypothesis The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status. Methods The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering). Results A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction 1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a −0.92 μm difference (95% CI −0.96 to −0.88 μm) in arteriolar diameter for those without diabetes, and a −0.58 μm difference (95% CI −0.76 to −0.41 μm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters. Conclusions/interpretation We provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications. Data Availability The data supporting the results reported here are available through the UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). Graphical abstract

The aim of this study was to assess whether adiposity or body composition relates to microvascular characteristics of the retina, indicative of cardiometabolic function. A fully automated QUARTZ software processed retinal images from 68,550 UK Biobank participants (aged 40-69 years). Differences in retinal vessel diameter and tortuosity with body composition measures from the Tanita analyzer were obtained by using multilevel regression analyses adjusted for age, sex, ethnicity, clinic, smoking, and Townsend deprivation index. Venular tortuosity and diameter increased by approximately 2% (P

AIMS: The extent that pre-diabetic fasting plasma glucose (FPG) levels influence the effectiveness of lifestyle interventions in preventing type 2 diabetes (T2DM) is uncertain. We aimed to determine if the outcome of lifestyle intervention in people with impaired glucose tolerance (IGT) differs in those with normal or impaired FPG levels. METHODS: Using data from the Da Qing Diabetes Prevention Outcome Study, a 30-year follow-up of a six-year randomized trial of lifestyle intervention in 576 people with IGT, we conducted a post-hoc analysis to compare the efficacy of intervention to reduce the incidence of T2DM and its complications in those with baseline FPG 100 mg/dL group. In those with FPG 100 mg/dL group. CONCLUSIONS: Lifestyle intervention reduced the incidence of T2DM in people with IGT regardless of baseline FPG levels, and in those with FPG

BACKGROUND: Open reduction and internal fixation (ORIF) of proximal humerus fractures in elderly individuals (age >70) carries a relatively high short-term complication and reoperation rate but is generally durable once healed. Reverse total shoulder arthroplasty (RTSA) for fractures may be associated with superior short-term quality of life but carries the lifelong liabilities of joint replacement. The tradeoff between short and long-term risks, coupled with disparities in quality of life and cost, makes this clinical decision amenable to cost-effectiveness analysis. METHODS: A Markov state-transition model was constructed with a base case of a 75 year-old patient. Reoperation rates, quality of life values, mortality rates, and costs were based upon published literature. The model was run until all patients had died to simulate the accumulated costs and benefits. RESULTS: RTSA was associated with greater quality of life (7.11 QALYs) than ORIF (6.22 QALYs). RTSA was cost-effective with an incremental cost-effectiveness ratio of $3,945/QALY and $27,299/ QALY from payor and hospital perspectives, respectively. RTSA was favored and cost-effective at any age above 65 and any Charlson Score. The model was sensitive to the utility of both procedures CONCLUSION: RTSA resulted in a higher quality of life and was cost-effective in comparison to ORIF for elderly patients. Level of Evidence: III

Background Data on the cost-effectiveness of lifestyle-based diabetes prevention programs are mostly from high-income countries, which cannot be extrapolated to low- and middle-income countries. We performed a trial-based cost-effectiveness analysis of a lifestyle intervention targeted at preventing diabetes in India. Methods The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial of 1007 individuals conducted in 60 polling areas (electoral divisions) in Kerala state. Participants (30–60 years) were those with a high diabetes risk score and without diabetes on an oral glucose tolerance test. The intervention group received a 12-month peer-support lifestyle intervention involving 15 group sessions delivered in community settings by trained lay peer leaders. There were also linked community activities to sustain behavior change. The control group received a booklet on lifestyle change. Costs were estimated from the health system and societal perspectives, with 2018 as the reference year. Effectiveness was measured in terms of the number of diabetes cases prevented and quality-adjusted life years (QALYs). Three times India’s gross domestic product per capita (US$6108) was used as the cost-effectiveness threshold. The analyses were conducted with a 2-year time horizon. Costs and effects were discounted at 3% per annum. One-way and multi-way sensitivity analyses were performed. Results Baseline characteristics were similar in the two study groups. Over 2 years, the intervention resulted in an incremental health system cost of US$2.0 (intervention group: US$303.6; control group: US$301.6), incremental societal cost of US$6.2 (intervention group: US$367.8; control group: US$361.5), absolute risk reduction of 2.1%, and incremental QALYs of 0.04 per person. From a health system perspective, the cost per diabetes case prevented was US$95.2, and the cost per QALY gained was US$50.0. From a societal perspective, the corresponding figures were US$295.1 and US$155.0. For the number of diabetes cases prevented, the probability for the intervention to be cost-effective was 84.0% and 83.1% from the health system and societal perspectives, respectively. The corresponding figures for QALY gained were 99.1% and 97.8%. The results were robust to discounting and sensitivity analyses. Conclusions A community-based peer-support lifestyle intervention was cost-effective in individuals at high risk of developing diabetes in India over 2 years. Trial registration The trial was registered with Australia and New Zealand Clinical Trials Registry (ACTRN12611000262909). Registered 10 March 2011.

Purpose Normal weight obesity (NWO) is a unique phenotype of obesity associated with high cardiovascular mortality. There is limited literature on assessing the effect of therapeutic interventions on the cardiometabolic health of these individuals. We studied the effect of a peer-led lifestyle intervention on key cardiometabolic parameters (blood glucose, blood pressure, and plasma lipids) in individuals with NWO. Methods This study is a secondary data analysis of the Kerala Diabetes Prevention Program, a cluster-randomized controlled study that involves a peer-led, real-life lifestyle intervention for individuals from the community between the ages of 30 and 60 years with a high diabetes risk. Participants underwent a rigorous cardiometabolic evaluation at baseline and at 2-year follow-up. Findings A total of 292 recruited individuals with NWO were randomized into the intervention (n = 159) and control (n = 133) arms. At 2 years of follow-up, there was minimal but statistically significant improvement in systolic blood pressure and serum HDL level in the intervention arm, but no statistical difference was seen in other lipid and glycemic parameters. Implications This study provides early evidence of the effect of a lifestyle intervention in a cohort of individuals with NWO. Only systolic blood pressure and serum HDL level had a mild favorable change in the intervention arm when compared with the control arm.

The prevention of type 2 diabetes mellitus (T2DM) is a target priority for the WHO and the United Nations and is a key priority in the 2018 Berlin Declaration, which is a global call for early actions related to T2DM. Health-care policies advocate that individuals at high risk of developing T2DM undertake lifestyle modification, irrespective of whether the prediabetes phenotype is defined by hyperglycaemia in the postprandial state (impaired glucose tolerance) and/or fasting state (impaired fasting glucose) or by intermediate HbA1c levels. However, current evidence indicates that diabetes prevention programmes based on lifestyle change have not been successful in preventing T2DM in individuals with isolated impaired fasting glucose. We propose that further research is needed to identify effective lifestyle interventions for individuals with isolated impaired fasting glucose. Furthermore, we call for the identification of innovative approaches that better identify people with impaired glucose tolerance, who benefit from the currently available lifestyle-based diabetes prevention programmes.

BackgroundCardiometabolic disorders are frequently observed among those who have obesity as measured by body mass index (BMI). However, there is limited data available on the cardiometabolic profile of those who are non-obese by BMI but with a high body fat percentage (BFP), a phenotype frequently observed in the Indian population. We examined the prevalence of individuals with normal weight obesity (NWO) and the cardiometabolic profile of NWO individuals at high risk for type 2 diabetes(T2D) in a south Asian population.Material and methodsIn the Kerala Diabetes Prevention Program, individuals aged between 30 to 60 years were screened using the Indian Diabetes Risk Score(IDRS) in 60 rural communities in the Indian state of Kerala. We used data from the baseline survey of this trial for this analysis which included 1147 eligible high diabetes risk individuals(IDRS >60). NWO was defined as BMI within the normal range and a high BFP (as per Asia-pacific ethnicity based cut-off); Non-obese (NO) as normal BMI and BFP and overtly obese (OB) as BMI ≥25 kg/m2 irrespective of the BFP. Data on demographic, clinical and biochemical characteristics were collected using standardized questionnaires and protocols. Body fat percentage was assessed using TANITA body composition analyser (model SC330), based on bioelectrical impedance.ResultsThe mean age of participants was 47.3 ± 7.5 years and 46% were women. The proportion with NWO was 32% (n = 364; 95% CI: 29.1 to 34.5%), NO was 17% (n = 200) and OB was 51% (n = 583). Among those with NWO, 19.7% had T2D, compared to 18.7% of those who were OB (p value = 0.45) and 8% with NO (p value = 0.003). Among those with NWO, mean systolic and diastolic blood pressure were 129 ± 20; 78 ± 12 mmHg, compared to 127 ± 17; 78±11 mmHg among those with OB (p value = 0.12;0.94) and 120 ± 16; 71±10 mmHg among with NO (p valueConclusionsAlmost one-third of this South Asian population, at high risk for T2D, had normal weight obesity. The significantly higher cardiometabolic risk associated with increased adiposity even in lower BMI individuals has important implications for recognition in clinical practice.

Obesity indicators are known to predict the presence of type 2 diabetes mellitus (T2DM); however, evidence for which indicator best identifies undiagnosed T2DM in the Indian population is still very limited. In the present study we examined the utility of different obesity indicators to identify the presence of undiagnosed T2DM and determined their appropriate cut point for each obesity measure. Individuals were recruited from the large-scale population-based Kerala Diabetes Prevention Program. Oral glucose tolerance tests was performed to diagnose T2DM. Receiver operating characteristic (ROC) curve analyses were used to compare the association of different obesity indicators with T2DM and to determine the optimal cut points for identifying T2DM. A total of 357 new cases of T2DM and 1352 individuals without diabetes were identified. The mean age of the study participants was 46⋅4 (sd 7⋅4) years and 62 % were men. Waist circumference (WC), waist:hip ratio (WHR), waist:height ratio (WHtR), BMI, body fat percentage and fat per square of height were found to be significantly higher (P < 0⋅001) among those with diabetes compared with individuals without diabetes. In addition, ROC for WHR (0⋅67; 95 % 0⋅59, 0⋅75), WHtR (0⋅66; 95 % 0⋅57, 0⋅75) and WC (0⋅64; 95 % 0⋅55, 0⋅73) were shown to better identify patients with T2DM. The proposed cut points with an optimal sensitivity and specificity for WHR, WHtR and WC were 0⋅96, 0⋅56 and 86 cm for men and 0⋅88, 0⋅54 and 83 cm for women, respectively. The present study has shown that WHR, WHtR and WC are better than other anthropometric measures for detecting T2DM in the Indian population. Their utility in clinical practice may better stratify at-risk patients in this population than BMI, which is widely used at present.

Retinal microvasculature changes reflect systemic small vessel damage from obesity. The impact of bariatric surgery induced weight loss on the microvasculature is relatively unknown. We hypothesized that weight loss following bariatric surgery would be associated with improved structural changes in the retinal microvasculature, reflecting an overall improvement in microvascular health. The study included 22 obese subjects scheduled for bariatric surgery (laparoscopic Roux-en-Y gastric bypass or a sleeve gastrectomy) and 15 lean, age-matched controls. Ophthalmic examination, including fundus photography, was performed at baseline and 6-months. Retinal microvasculature caliber was analysed quantitatively using a semi-automated computer program and summarized as central retinal artery equivalent (CRAE) and venular equivalent (CRVE). Mean weight loss at 6 months was 26.1 kg ± 8 kg in the bariatric surgery group. Retinal artery caliber increased (136.0 ± 1.4 to 141.4 ± 1.4 µm, p = 0.013) and venular caliber decreased (202.9 ± 1.9 to 197.3 ± 1.9 µm, p = 0.046) in the bariatric surgery group by 6 months, with no change in arteriolar (136.6 ± 1.1 to 134.5 ± 1.2, p = 0.222) or venular (195.1 ± 2.1 to 193.3 ± 2.2, p = 0.550) caliber in the control group. The arteriolar to venular ratio increased in the bariatric surgery group, with no change in the control group at 6 months. The findings suggest obesity-related microvascular changes are reversible after bariatric surgery-induced weight loss. The capacity for the retinal microvasculature to improve following bariatric surgery suggests plasticity of the human microvasculature early in the disease course.

In this study, wettability behavior of B4C substrate as well as B4C/crystalline rice husk ash and B4C/amorphous rice husk ash substrates with two aluminum alloys were studied. The electrical resistivity, thermal expansion coefficients, and thermal diffusivity of bilayer Al/B4C/rice husk ash composite fabricated by one-step pressureless infiltration were measured and the obtained data were systemically analyzed using the Taguchi method and analysis of variance. Boron carbide substrates after addition of amorphous or crystalline rice husk ash display good wettability with molten aluminum alloys. The results show that, electrical resistivity of Al/B4C/rice husk ash composites is mainly influenced by initial preform porosity, while the coefficient of thermal expansion of composites is determined by the chemical composition of infiltrated alloys. The measured values for coefficient of thermal expansion (10.5 × 10−6/℃) and electrical resistivity (0.60 × 10−5 Ω.m) of Al/B4C/rice husk ash composites, fabricated according to analysis of variance's optimal conditions are in good agreement with those of the projected values (11.02 × 10−6/℃ and 0.65 × 10−5 Ω.m, respectively). The difference between the corresponding values obtained from verification tests and projected values, for electrical resistivity and coefficient of thermal expansion are less than 5%. Finally, as a material selection approach, the strengths and weaknesses of the composites have been graphed in the form of radar diagrams.

Importance Diagnostic variation among pathologists interpreting cutaneous melanocytic lesions could lead to suboptimal care. Objective To estimate the potential association of second-opinion strategies in the histopathologic diagnosis of cutaneous melanocytic lesions with diagnostic accuracy and 1-year population-level costs in the US. Design, Setting, and Participants Decision analysis with 1-year time horizon including melanocytic lesion diagnoses available from US pathologists participating in the Melanoma Pathology Study (M-Path) and from the study panel of reference pathologists who classified cases using the MPATH-Dx classification tool. M-Path data collection occurred from July 2013 through March 2015; analyses for the present study were performed between April 2015 and January 2021. Exposures Various second-opinion strategies for interpretation of melanocytic cutaneous lesions. Main Outcomes and Measures Estimated accuracy of pathologists’ diagnoses, defined as concordance with the reference panel diagnoses, and 1-year postbiopsy medical costs under various second-opinion strategies. Expected percentage of concordant diagnoses, including percentages of overinterpretation and underinterpretation, and 1-year costs of medical care per 100 000 in the US population. Results Decision-analytic model parameters were based on diagnostic interpretations for 240 cases by 187 pathologists compared with reference panel diagnoses. Without second opinions, 83.2% of diagnoses in the US were estimated to be accurate—ie, concordant with the reference diagnosis; with overinterpretation (8.0%) or underinterpretation (8.8%), and 16 850 misclassified diagnoses per 100 000 biopsies. Accuracy increased under all second-opinion strategies. Accuracy (87.4% concordance with 3.6% overinterpretation and 9.1% underinterpretation) and cost (an increase of more than $10 million per 100 000 biopsies per year) were highest when second opinions were universal (eg, performed on all biopsies), relative to no second opinions. A selective second-opinion strategy based on pathologists’ desire or institutional requirements for a second opinion was most accurate (86.5% concordance; 4.4% overinterpretation; 9.1% underinterpretation) and would reduce costs by more than $1.9 million per 100 000 skin biopsies relative to no second opinions. Improvements in diagnostic accuracy with all second-opinion strategies were associated with reductions in overinterpretation but not underinterpretation. Conclusions and Relevance In this decision-analytic model, selective second-opinion strategies for interpretation of melanocytic skin lesions showed the potential to improve diagnostic accuracy and decrease costs relative to no second opinions or universal second opinions.

The thermal oxidation reactions of the intermetallic phases Al8Mo3 and AlMo3 were investigated and analyzed by ex-situ powder-x-ray diffraction (XRD), difference thermal analysis (DTA), thermogravimetry (TGA), and infrared spectroscopy (IR). The initial oxidation reactions in air were found to yield Al2O3 and AlMo3 in the case of Al8Mo3 (Tonset =725 °C), and MoO3 as well as Al8−xMo3 (Tonset =435 °C) for the pure intermetallic phase AlMo3, respectively. Thus, both intermetallic phases are coexisting in an equilibrium within a temperature range of 300 °C under oxidizing conditions. The formation of β-Al2(MoO4)3 followed the second oxidizing process of the respective minority component at elevated temperatures. Decomposition and evaporation of the volatile MoO3 yielded α-Al2O3 as the residue at 1000 °C.

The effect of following processing parameters on the electrical and thermomechanical properties of Al/Si3N4 deposited silica composites was investigated using the Taguchi method and analysis of variance (ANOVA): infiltration temperature and time, atmosphere, effect of Si3N4 coating, porosity content in the preforms, and magnesium content in the alloy. The contributions of each of the parameters to modulus of elasticity, electrical resistivity, coefficient of thermal expansion (CTE), and thermal diffusivity of the resulting composites were determined. The maximum modulus of elasticity and electrical resistivity of obtained composites were 265 GPa, and 1.37 × 10−3 Ω m, respectively. These values were achieved in composites fabricated from Si3N4 preforms under conditions of temperature (1200 ০C), time (120 min), porosity of 40 vol %, Al-9Mg-13Si alloy, in the atmosphere of N2. The minimum value of CTE obtained was 5.3 × 10−6/০C. This value was achieved in composites fabricated from Si3N4 coated silica under the same mentioned conditions. The thermal diffusivity of four fabricated samples (two samples with the highest and two samples with lowest electrical resistivity) was measured. The results show that the highest value of thermal diffusivity (20.4 mm2/s) among fabricated composites is belonged to the one with highest value of electrical resistivity.

The mechanical, electrical and thermal properties as well as thermal expansion of Al/SiC/RHA (rice husk ash) monolayer and bilayer composite have been studied using the Taguchi method and analysis of variance (ANOVA). The parameter that most significantly affects the modulus of elasticity of Al/SiC/RHA bilayer composites is processing time, with contribution percentages of 68 and 27% calculated from stress-strain graphs and ultrasonic method, respectively. However, the factor which mostly affects bending strength, CTE value and electrical resistivity of composites is process temperature with contribution percentages of 32, 28, and 22%, respectively. The projected values for modulus of elasticity (170 GPa), bending strength (369 MPa), CTE (8.9 × 10 −6 /°C) and electrical resistivity (0.0019 Ω m) of Al/SiC/RHA composites are in excellent agreement with those obtained in the verification tests under the optimal conditions according to ANOVA.

Hypertension remains a major contributor to the global burden of disease. The measurement of blood pressure continues to have pitfalls related to both physiological aspects and acute variation. As the left ventricle (LV) remains one of the main target organs of hypertension, and echocardiographic measures of structure and function carry prognostic information in this setting, the development of a consensus position on the use of echocardiography in this setting is important. Recent developments in the assessment of LV hypertrophy and LV systolic and diastolic function have prompted the preparation of this document. The focus of this work is on the cardiovascular responses to hypertension rather than the diagnosis of secondary hypertension. Sections address the pathophysiology of the cardiac and vascular responses to hypertension, measurement of LV mass, geometry, and function, as well as effects of treatment.

Supplemental Digital Content is available in the text., To examine the baseline associations of retinal vessel morphometry with blood pressure (BP) and arterial stiffness in United Kingdom Biobank. The United Kingdom Biobank included 68 550 participants aged 40 to 69 years who underwent nonmydriatic retinal imaging, BP, and arterial stiffness index assessment. A fully automated image analysis program (QUARTZ [Quantitative Analysis of Retinal Vessel Topology and Size]) provided measures of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiovascular disease risk factors/outcomes were examined using multilevel linear regression to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing within person clustering), adjusted for age, sex, ethnicity, clinic, body mass index, smoking, and deprivation index. Greater arteriolar tortuosity was associated with higher systolic BP (relative increase, 1.2%; 95% CI, 0.9; 1.4% per 10 mmHg), higher mean arterial pressure, 1.3%; 0.9, 1.7% per 10 mmHg, and higher pulse pressure (PP, 1.8%; 1.4; 2.2% per 10 mmHg). Narrower arterioles were associated with higher systolic BP (−0.9 µm; −0.94, −0.87 µm per 10 mmHg), mean arterial pressure (−1.5 µm; −1.5, −1.5 µm per 10 mmHg), PP (−0.7 µm; −0.8, −0.7 µm per 10 mmHg), and arterial stiffness index (−0.12 µm; −0.14, −0.09 µm per ms/m2). Associations were in the same direction but marginally weaker for venular tortuosity and diameter. This study assessing the retinal microvasculature at scale has shown clear associations between retinal vessel morphometry, BP, and arterial stiffness index. These observations further our understanding of the preclinical disease processes and interplay between microvascular and macrovascular disease.

We aimed to examine whether a lifestyle intervention was effective in reducing cardiovascular disease (CVD) risk in individuals at high-risk of developing diabetes in a low- and middle-income setting. The Kerala Diabetes Prevention Program was evaluated by a cluster-randomized controlled trial (2013-2016) of 1007 individuals (aged 30-60 years) at high-risk for diabetes (Indian Diabetes Risk Score ≥ 60 and without diabetes) in Kerala state, India. Sixty polling areas in Kerala were randomized to intervention or control groups by an independent statistician using a computer-generated randomization sequence. Participants from 30 intervention communities received a 12-month structured peer-support lifestyle intervention program involving 15 group sessions and linked community activities, aimed at supporting and maintaining lifestyle change. The primary outcome for this analysis was the predicted 10-year CVD risk at two years, assessed using the Framingham Risk Score. The mean age at baseline was 46.0 (SD: 7.5) years, and 47.2% were women. Baseline 10-year CVD risk was similar between study groups. The follow-up rate at two years was 95.7%. The absolute risk reduction in predicted 10-year CVD risk between study groups was 0.69% (95% CI: 0.09% to 1.29%, p=0.024) at one year and 0.69% (95% CI: 0.10% to 1.29%, p=0.023) at two years. The favorable change in CVD risk with the intervention condition was mainly due to the reduction in tobacco use (change index: -0.25, 95% CI: -0.42 to -0.09). Our findings suggest that a community-based peer-support lifestyle intervention could reduce CVD risk in individuals at high-risk of developing diabetes in India. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12611000262909.

Diabetes & Metabolism - Sous presse. Manuscrit accepte. Disponible en ligne depuis le mercredi 28 octobre 2020

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.

Purpose To determine the incremental cost-effectiveness of a new telemedicine technician-based assessment relative to an existing model of family physician (FP)–based assessment of diabetic retinopathy (DR) in Singapore from the health system and societal perspectives. Design Model-based, cost-effectiveness analysis of the Singapore Integrated Diabetic Retinopathy Program (SiDRP). Participants A hypothetical cohort of patients aged 55 years with type 2 diabetes previously not screened for DR. Methods The SiDRP is a new telemedicine-based DR screening program using trained technicians to assess retinal photographs. We compared the cost-effectiveness of SiDRP with the existing model in which FPs assess photographs. We developed a hybrid decision tree/Markov model to simulate the costs, effectiveness, and incremental cost-effectiveness ratio (ICER) of SiDRP relative to FP-based DR screening over a lifetime horizon. We estimated the costs from the health system and societal perspectives. Effectiveness was measured in terms of quality-adjusted life-years (QALYs). Result robustness was calculated using deterministic and probabilistic sensitivity analyses. Main Outcome Measures The ICER. Results From the societal perspective that takes into account all costs and effects, the telemedicine-based DR screening model had significantly lower costs (total cost savings of S$173 per person) while generating similar QALYs compared with the physician-based model (i.e., 13.1 QALYs). From the health system perspective that includes only direct medical costs, the cost savings are S$144 per person. By extrapolating these data to approximately 170 000 patients with diabetes currently being screened yearly for DR in Singapore's primary care polyclinics, the present value of future cost savings associated with the telemedicine-based model is estimated to be S$29.4 million over a lifetime horizon. Conclusions While generating similar health outcomes, the telemedicine-based DR screening using technicians in the primary care setting saves costs for Singapore compared with the FP model. Our data provide a strong economic rationale to expand the telemedicine-based DR screening program in Singapore and elsewhere.

Background: Data on participant recruitment into diabetes prevention trials are limited in low- and middle-income countries (LMICs). We aimed to provide a detailed analysis of participant recruitment into a community-based diabetes prevention trial in India. Methods: The Kerala Diabetes Prevention Program was conducted in 60 polling areas (electoral divisions) of the Neyyatinkara taluk (subdistrict) in Trivandrum district, Kerala state. Individuals (age 30–60 years) were screened with the Indian Diabetes Risk Score (IDRS) at their homes followed by an oral glucose tolerance test (OGTT) at community-based clinics. Individuals at high-risk of developing diabetes (IDRS score ≥60 and without diabetes on the OGTT) were recruited. Results: A total of 1007 participants (47.2% women) were recruited over nine months. Pilot testing, personal contact and telephone reminders from community volunteers, and gender matching of staff were effective recruitment strategies. The major recruitment challenges were: (1) during home visits, one-third of potential participants could not be contacted, as they were away for work; and (2) men participated less frequently in the OGTT screening than women (75.2% vs. 84.2%). For non-participation, lack of time (42.0%) was most commonly cited followed by ‘I am already feeling healthy’ (30.0%), personal reasons (24.0%) and ‘no benefit to me or my family’ (4.0%). An average of 17 h were spent to recruit one participant with a cost of US$23. The initial stage of screening and recruitment demanded higher time and costs. Conclusions: This study provides valuable information for future researchers planning to implement community-based diabetes prevention trials in India or other LMICs. Trial registration: Australia and New Zealand Clinical Trials Registry: ACTRN12611000262909. Keywords: Diabetes, Recruitment, Challenges, Costs, Staff time, India

Background This study examined the association between ideal cardiovascular health ( CVH ) and the retinal microvasculature in midadulthood. Methods and Results The Cardiovascular Risk in Young Finns Study included children from 5 Finnish University cities, who were chosen randomly from the national population register. Participants ranged from 12 to 18 years in childhood (1986) and from 37 to 43 years in midadulthood (2011). Ideal CVH was defined according to the American Heart Association criteria. Retinal microvascular measures included diameters, lengths, length:diameter ratio, and tortuosity. From childhood to adulthood, fasting plasma glucose and blood pressure were significantly higher in those with impaired fasting glucose or diabetes mellitus. Childhood ideal CVH was negatively associated with adult arteriolar tortuosity (β=−0.008; 95% confidence interval [CI], −0.01 to −0.003; P =0.001). Improved ideal CVH from childhood to adulthood was positively associated with adult arteriolar diameter (β=0.122; 95% CI, 0.01–0.24; P =0.033) and negatively associated with adult length:diameter ratio (β=−0.666; 95% CI, −1.25 to −0.08; P =0.026). When stratified by glucose metabolism, among those with diabetes mellitus and impaired fasting glucose, there was a negative association between childhood ideal CVH and adult venular diameter (diabetes mellitus: β=−2.75; 95% CI , −5.46 to −0.04; P =0.047; impaired fasting glucose: β=−2.13; 95% CI, −4.18 to −0.08; P =0.042). Conclusions This study is the first to comprehensively examine the impact of CVH from childhood to midadulthood on quantitative measures of the retinal microvasculature. Ideal CVH in childhood and improvement in CVH from childhood to adulthood appears to have a protective effect on the retinal microvasculature in those with, without, and at risk of diabetes mellitus.

Objectives The Melanocytic Pathology Study (MPath) reported variation in community pathologists’ interpretations of melanocytic skin lesions relative to reference diagnoses developed through consensus by a panel of three experts. Little is known about the impact of second (2nd) opinion strategies on false positives (FP- overdiagnosis relative to consensus diagnosis) or false negatives (FN-underdiagnosis relative to consensus diagnosis) in melanocytic lesion diagnosis, or on patient care costs incurred within one year of biopsy. Method Lesion severity was classified into five classes based on the nature of clinical follow-up care required. Relative to the reference diagnoses, community pathologists overcalled (FP) or undercalled (FN) as follows: Class I (FP: 7.8%), Class II (FN: 62.8%, FP: 12.5%), Class III (FN: 54.1%, FP: 5.5%), Class IV (FN: 48.1%, FP: 9.1%), Class V (FN: 27.9%). We assessed second opinion strategies on (1) concordance between community pathologists’ diagnoses and diagnoses rendered by the reference panel, and (2) patient care costs incurred during the first year following biopsy. Second opinion strategies assessed included: no 2nd opinion; 2nd opinion obtained for all lesions; 2nd opinion required for some lesions by institutional policyor based on pathologists’ preference. For each second opinion strategy, decision analysis was used to estimate the expected percent of concordant diagnoses, FN, and FP. Standardized care pathways were used to estimate care costs in the year following biopsy. Results Without a 2nd opinion, 83.2% of biopsies received a concordant diagnosis with 8.0% FP and 8.8% FN. Concordance increased under all 2nd opinion strategies and was highest (87.4%) with universally obtained 2nd opinions, resulting in 3.6% FP and 9.1% FN While the proportion of FN cases was fairly consistent across 2nd opinion strategies (range: 8.8% to 9.2%) the proportion FP cases ranged from 3.6% to 7.6%. Per 1 00 000 biopsies, the costs were estimated as $118.6 million with no 2nd opinions, and 127.6 million with 2nd opinions obtained for all lesions. Second opinion strategies based on institutional policy and/or pathologist preference reduced FP cases without appreciable change in FN cases, and led to lower costs in the year following diagnosis (approximately $117 million/100,000). Conclusions While 2nd opinion strategies did not appreciably alter the proportion of FN cases, they did result in fewer FP cases. If selectively implemented, 2nd opinion strategies have the potential to save resources and improve care in the year following biopsy. Such strategies could be mandated through regulatory channels.

Background Randomized controlled trials (RCTs) suggest that supplementation with omega-3 polyunsaturated fatty acids (n-3PUFAs) may favourably modify cardiometabolic biomarkers in type 2 diabetes (T2DM). Previous meta-analyses are limited by insufficient sample sizes and omission of meta-regression techniques, and a large number of RCTs have subsequently been published since the last comprehensive meta-analysis. Updated information regarding the impact of dosage, duration or an interaction between these two factors is therefore warranted. The objective was to comprehensively assess the effect of n-3PUFAs supplementation on cardiometabolic biomarkers including lipid profiles, inflammatory parameters, blood pressure, and indices of glycaemic control, in people with T2DM, and identify whether treatment dosage, duration or an interaction thereof modify these effects. Methods Databases including PubMed and MEDLINE were searched until 13th July 2017 for RCTs investigating the effect of n-3PUFAs supplementation on lipid profiles, inflammatory parameters, blood pressure, and indices of glycaemic control. Data were pooled using random-effects meta-analysis and presented as standardised mean difference (Hedges g) with 95% confidence intervals (95% CI). Meta-regression analysis was performed to investigate the effects of duration of supplementation and total dosage of n-3PUFAs as moderator variables where appropriate. Results A total of 45 RCTs were identified, involving 2674 people with T2DM. n-3PUFAs supplementation was associated with significant reductions in LDL [ES: − 0.10, (95% CI − 0.17, − 0.03); p = 0.007], VLDL (ES: − 0.26 (− 0.51, − 0.01); p = 0.044], triglycerides (ES: − 0.39 (− 0.55, − 0.24; p ≤ 0.001] and HbA1c (ES: − 0.27 (− 0.48, − 0.06); p = 0.010]. Moreover, n-3PUFAs supplementation was associated with reduction in plasma levels of TNF-α [ES: − 0.59 (− 1.17, − 0.01); p = 0.045] and IL-6 (ES: − 1.67 (− 3.14, − 0.20); p = 0.026]. All other lipid markers, indices of glycaemic control, inflammatory parameters, and blood pressure remained unchanged (p > 0.05). Conclusions n-3PUFAs supplementation produces favourable hypolipidemic effects, a reduction in pro-inflammatory cytokine levels and improvement in glycaemia. Neither duration nor dosage appear to explain the observed heterogeneity in response to n-3PUFAs. Trial registration This trial was registered at http://www.crd.york.ac.uk as CRD42016050802

Background The major efficacy trials on diabetes prevention have used resource-intensive approaches to identify high-risk individuals and deliver lifestyle interventions. Such strategies are not feasible for wider implementation in low- and middle-income countries (LMICs). We aimed to evaluate the effectiveness of a peer-support lifestyle intervention in preventing type 2 diabetes among high-risk individuals identified on the basis of a simple diabetes risk score. Methods and findings The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial conducted in 60 polling areas (clusters) of Neyyattinkara taluk (subdistrict) in Trivandrum district, Kerala state, India. Participants (age 30–60 years) were those with an Indian Diabetes Risk Score (IDRS) ≥60 and were free of diabetes on an oral glucose tolerance test (OGTT). A total of 1,007 participants (47.2% female) were enrolled (507 in the control group and 500 in the intervention group). Participants from intervention clusters participated in a 12-month community-based peer-support program comprising 15 group sessions (12 of which were led by trained lay peer leaders) and a range of community activities to support lifestyle change. Participants from control clusters received an education booklet with lifestyle change advice. The primary outcome was the incidence of diabetes at 24 months, diagnosed by an annual OGTT. Secondary outcomes were behavioral, clinical, and biochemical characteristics and health-related quality of life (HRQoL). A total of 964 (95.7%) participants were followed up at 24 months. Baseline characteristics of clusters and participants were similar between the study groups. After a median follow-up of 24 months, diabetes developed in 17.1% (79/463) of control participants and 14.9% (68/456) of intervention participants (relative risk [RR] 0.88, 95% CI 0.66–1.16, p = 0.36). At 24 months, compared with the control group, intervention participants had a greater reduction in IDRS score (mean difference: −1.50 points, p = 0.022) and alcohol use (RR 0.77, p = 0.018) and a greater increase in fruit and vegetable intake (≥5 servings/day) (RR 1.83, p = 0.008) and physical functioning score of the HRQoL scale (mean difference: 3.9 score, p = 0.016). The cost of delivering the peer-support intervention was US$22.5 per participant. There were no adverse events related to the intervention. We did not adjust for multiple comparisons, which may have increased the overall type I error rate. Conclusions A low-cost community-based peer-support lifestyle intervention resulted in a nonsignificant reduction in diabetes incidence in this high-risk population at 24 months. However, there were significant improvements in some cardiovascular risk factors and physical functioning score of the HRQoL scale. Trial registration Australia and New Zealand Clinical Trials Registry ACTRN12611000262909., Thirunavukkarasu Sathish and colleagues report findings from a community, peer-supported trial to reduce diabetes onset in high-risk individuals in India., Author summary Why was this study done? In low- and middle-income countries (LMICs), there is an urgent need to develop low-cost strategies for identifying high-risk individuals and delivering lifestyle interventions to prevent diabetes. What did the researchers do and find? We conducted a cluster-randomized controlled trial in a community-setting in India to test whether a peer-support lifestyle intervention could reduce diabetes risk at 24 months. We identified high-risk individuals on the basis of a simple diabetes risk score. There was a nonsignificant reduction in diabetes risk in this high-risk population at 24 months. However, there were significant improvements in some risk factors for cardiovascular disease and a measure of quality of life. The intervention cost was low at US$22.5 per participant over 12 months. What do these findings mean? Risk scores for better identifying people at highest risk for diabetes are needed, particularly in resource-constrained settings. It is important to identify ways to improve program adherence and engagement, possibly by using more flexible modes of program delivery, e.g., at worksites and by text messaging.

Background Cardiometabolic health among adult offspring of hypertensive disorders of pregnancy ( HDP ) is relatively unknown. We hypothesized that offspring of HDP would have abnormalities in the retinal microvasculature and cardiac structure by midadulthood. Methods and Results The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish university cities. The mean age of participants was 40 years (range 34–49 years) at the time of retinal photography and cardiac assessment. Offspring born ≥37 weeks of gestation and appropriate for gestational age (n=1006) were included. Offspring of HDP had higher systolic blood pressure (β=4.68, P P =0.009), and waist circumference (β=0.25, P =0.042), compared with offspring of normotensive pregnancies. However, no differences in fasting glucose, insulin, lipid profile, carotid intima media thickness, or brachial artery flow‐mediated dilatation were shown. Retinal arteriolar diameters were narrower (β=−0.43, P =0.009) and longer (β=32.5, P =0.023) and the arteriolar length‐to‐diameter ratio was higher (β=2.32, P =0.006) among offspring of HDP , after adjustment for age and sex. Left atrial volume indexed to body surface area (β=1.34, P =0.040) was increased. Adjustment for the confounding effects of birth weight, body mass index, smoking and socioeconomic status, and the mediating effect of hypertension had little impact on the associations. Conclusions Abnormalities of the retinal microvasculature and cardiac structure are seen in offspring of HDP in midadulthood. These findings may need to be considered in future primary prevention strategies of cardiovascular disease among offspring of HDP .

Background To assess the proportion of Australian Indigenous adults who require eye care services (separately among those with and without diabetes) and determine implications for eye care service planning. Design The National Indigenous Eye Health Survey (NIEHS) was a population-based study of 30 randomly selected geographical areas. Participants The NIEHS included 1189 Indigenous adults aged 40–80 years. Methods A standardized eye examination was performed. Main Outcome Measure The number requiring eye care services by diabetes status. Results Those with diabetes were older (median 53 years) than those without diabetes (median age 50 years), P

Objective The present study examined the impact of BP from childhood to mid-adulthood on retinal microvascular architecture. Methods The Cardiovascular Risk in Young Finns Study included children aged 3–18 years, from five Finnish University cities, with participants chosen randomly from the national population registrar from those areas. The age of participants included in the current analyses in childhood (1980) ranged from three to nine years and in mid-adulthood (2011) ranged from 34 to 40 years (complete data n = 657). Measures of retinal microvasculature architecture measured in adulthood included diameters, tortuosity, lengths, and LDR. Results Regression analysis showed a strong negative association between childhood systolic BP and adult arteriolar diameter (standardized regression coefficient [β] −0.300; p

OBJECTIVE: We hypothesized that preterm birth and being born SGA would be associated with changes in retinal microvascular architecture and that these changes would be more marked among those born preterm. We further hypothesized that these microvascular changes would correlate with early markers of CVD in mid-adulthood. METHODS: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish University cities. Retinal microvascular architecture of participants born preterm, born at term and SGA and a control group born at term and AGA were compared (aged 34-49 years). RESULTS: In participants born preterm, arteriolar tortuosity (×10(2)) was higher-means (standard error), 0.06 (0.01) versus 0.04 (0.01), p = 0.001, arteriolar length (pixels) were greater-644.9 (35.9) versus 591.7 (33.5), p = 0.007 and arteriolar diameters (pixels) were narrower-19.9 (0.4) versus 20.3 (0.3), p = 0.034 compared to participants born AGA, after adjustment. In participants born SGA, only arteriolar tortuosity was higher-0.05 (0.01) versus 0.04 (0.01), p = 0.074 compared to participants born AGA. CONCLUSION: This study demonstrated that being born SGA and in particular preterm birth are associated with changes in retinal microvascular architecture. The prenatal and immediate postnatal environment may contribute to the mechanisms.

Most studies relating blood pressure (BP) to target organ damage measure BP at the brachial artery, but pulse pressure (PP) and systolic BP (SBP) in the aorta are lower than the corresponding peripheral measures. In adults, aortic (central) PP and SBP have been shown to be more closely related to

Background To evaluate the effect of phacoemulsification on trabeculectomy function. Design Retrospective case–control study. Participants Forty-eight patients who underwent trabeculectomy surgery and had at least 2 years of follow up. Methods Patients were classified into two groups: patients who had phacoemulsification subsequent to trabeculectomy (Trab_phaco, n = 18) and patients who were pseudophakic for greater than 6 months preceding their trabeculectomy (Phaco_trab, n = 30). Groups were matched for length of follow up of 2 years from time of trabeculectomy. Main Outcome Measures The primary outcome measures were target intraocular pressure of criteria A, ≤12 mmHg; B, ≤15 mmHg; C, ≤18 mmHg with or without additional topical treatment. A separate measure for bleb function failure was also used; with failure defined as the need for additional topical antiglaucoma therapy or surgical intervention to achieve control of intraocular pressure. Results There was no significant difference in achieving each intraocular pressure criterion between groups (12 months, P = 1.0; 24 months, P = 0.330). In the first 12 months, significantly more trabeculectomies in the Trab_phaco group failed, requiring additional intervention to control the IOP (39%) compared with the Phaco_trab (10%) group (P = 0.028). Although this trend continued at 24 months, there were no significant differences in failure rates (P = 0.522). Conclusions Phacoemulsification performed after trabeculectomy significantly increased rates of bleb failure in the following 12 months but not at 24 months.

Objectives We hypothesized that trajectories of adiposity across childhood would be associated with retinal microcirculatory diameters at age 12 years, independent of BP. Methods The ALSPAC followed a cohort of children born in 1991–1992. The current study includes all children with retinal images acquired at the 12 years clinic and individual trajectories of PI from 0 to 2 years and BMI from 2 to 10 years. Retinal microvascular measures included retinal arteriolar and venular diameters. Results Children in this analysis had a birth weight of 3.5 ± 0.4 kg, a PI of 26.2 ± 2.4 kg/m3 and a gestational age of 39.7 ± 1.4 weeks (mean ± SD). Analysis of growth trajectories showed that lower PI at birth was associated with narrower retinal arterioles. Higher PI at birth was associated with wider venular diameter, and a stronger positive association was evident between BMI change at 5–5.5 and 8.5–10 years with wider venular diameters. Current fat mass was also associated with wider venular diameters. Conclusions Retinal arterioles and venules are differentially associated with growth in early life and childhood adiposity. Early adiposity may adversely affect the microcirculation, with important implications for cardiovascular risk in adulthood.

Background Diabetic retinopathy (DR) is a blinding yet treatable complication of diabetes. DR screening is highly cost-effective at reducing blindness. Amidst the rapidly growing diabetic population in Asia, the prevalence of DR in the region is relatively less well known. Aims To review existing national DR screening guidelines of 50 countries in Asia, compare them against the International Council of Ophthalmology (ICO) guideline, and summarise the prevalence rates of DR and sight-threatening DR (STDR) in these countries. Methods We systematically searched for published guidelines from the National Guideline Clearinghouse and other databases, and contacted local diabetic and ophthalmological associations of all 50 Asian countries. Results Eleven Asian countries have published relevant guidelines, nine of which pertain to general diabetes care and two are DR-specific, covering less than half of Asia9s population. The median DR prevalence among patients with diabetes is 30.5% (IQR: 23.2%–36.8%), similar to the USA and the UK. However, rates of STDR are consistently higher. All guidelines from the 11 Asian countries fulfil the ICO standard on when to start and repeat screening, except for screening interval for pregnant patients. However, only 2 of the 11 guidelines fulfil the ICO referral criteria and 6 partially fulfil. A third of the recommendations on screening process, equipment and personnel is either unavailable or incomplete. Conclusions Countries in Asia need to establish more comprehensive and evidence-based DR screening guidelines to facilitate the execution of robust screening programmes that could help reduce DR-related blindness, improve patient outcomes and reduce healthcare costs.