Low birthweight in patients with type 2 diabetes is associated with elevated risk of cardiovascular events and mortality.

AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes and CVD. This prospective cohort study investigated whether lower birthweight increases CVD risk after diagnosis of type 2 diabetes. METHODS: Original midwife records were evaluated for 8417 participants recently diagnosed with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Patients were followed for the first occurrence of a composite CVD endpoint (myocardial infarction, coronary revascularisation, peripheral arterial disease, stroke, unstable angina, heart failure or CVD death), a three-component endpoint comprising major adverse cardiovascular events (MACE), and all-cause mortality. Ten-year risks were estimated using the Aalen-Johansen estimator considering non-CVD death as a competing risk. HRs were determined by Cox regression. Models were controlled for sex, age, calendar year at birth, family history of diabetes and born-at-term status. RESULTS: A total of 1187 composite CVD endpoints, 931 MACE, and 1094 deaths occurred during a median follow-up period of 8.5 years. The 10-year standardised composite CVD risk was 19.8% in participants with a birthweight <3000 g compared with 16.9% in participants with a birthweight of 3000-3700 g, yielding a risk difference (RD) of 2.9% (95% CI 0.4, 5.4) and an adjusted HR of 1.20 (95% CI 1.03, 1.40). The 10-year MACE risk for birthweight <3000 g was similarly elevated (RD 2.4%; 95% CI 0.1, 4.7; HR 1.22; 95% CI 1.01, 1.46). The elevated CVD risk was primarily driven by stroke, peripheral arterial disease and CVD death. All-cause mortality showed no substantial difference. CONCLUSIONS/INTERPRETATION: Having a birthweight <3000 g is associated with higher CVD risk among patients with type 2 diabetes, driven primarily by risk of stroke and CVD death.

Low-grade inflammation in persons with recently diagnosed type 2 diabetes: The role of abdominal adiposity and putative mediators.

AIMS: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities. MATERIALS AND METHODS: We measured waist circumference, clinical characteristics, and inflammatory markers i.e. tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), in >9000 persons with recently diagnosed T2D. We applied multiple mediation analysis using structural equation modelling, with adjustment for age and sex. RESULTS: Waist circumference as a proxy for abdominal adiposity was positively associated with all inflammatory markers. Hence, a one-standard deviation (SD) increase in waist circumference (SD = 15 cm) was associated with a 22%, 35%, and 46% SD increase in TNF-α (SD = 1.5 pg/mL), IL-6 (SD = 4.4 pg/mL), and hsCRP (SD = 6.9 mg/L), respectively. The level of hyperinsulinaemia assessed by fasting C-peptide was quantitatively the most important mediator, accounting for 9%-25% of the association between abdominal adiposity and low-grade inflammation, followed by low physical activity (5%-7%) and high triglyceride levels (2%-6%). Although mediation of adiposity-induced inflammation by greater comorbidity and higher glycated haemoglobin levels reached statistical significance, their impact was minor (1%-2%). CONCLUSIONS: In persons with recently diagnosed T2D, there was a clear association between abdominal adiposity and low-grade inflammation. A considerable part (20%-40%) of this association was mediated by other factors, with hyperinsulinaemia as a potentially important driver of adiposity-induced inflammation in T2D.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

N-Terminal Pro-Brain Type Natriuretic Peptide Predicts Cardiovascular Events Independently of Arterial Stiffness, Assessed By Carotid-to-Femoral Pulse Wave Velocity, in Apparently Healthy Subjects.

AIM: This study aimed to evaluate whether N-terminal pro-brain natriuretic peptide (NT-proBNP) and carotid-to-femoral pulse wave velocity (PWV) carried independent prognostic value in predicting cardiovascular events in apparently healthy individuals beyond traditional risk factors. METHODS: A total of 1,872 participants aged 41, 51, 61, or 71 years from the MONItoring of trends and determinants in CArdiovascular disease (MONICA) study were included. Traditional risk factors were assessed, including: smoking status; mean systolic and diastolic blood pressure; body mass index; fasting plasma glucose; serum triglycerides; total, high-density, and low-density lipoprotein cholesterol; NT-proBNP; and PWV. The principal endpoint that was assessed during 16 years of follow-up was a composite of major adverse cardiovascular events (MACE). The secondary endpoints were cardiovascular mortality (CVM), hospitalisation for coronary artery disease (CAD), and a composite of hospitalisation for heart failure (HF) or atrial fibrillation (AF). RESULTS: At baseline, NT-proBNP was associated with PWV (ß=0.14; p<0.001), but not after adjustment for traditional risk factors (ß=-0.01; p=0.67). In models including traditional risk factors and PWV, NT-proBNP was associated with all four outcomes (HRMACE=1.33, 95% CI 1.16-1.52; HRCVM=2.02, 95% CI 1.65-2.48; HRCAD=1.29, 95% CI 1.07-1.55; and HRHF or AF=1.79, 95% CI 1.40-2.28). In the same model, PWV was only associated with CVM (HRCVM=1.20, 95% CI 1.01-1.41). No interactions between NT-proBNP and PWV were found. N-terminal pro-brain natriuretic peptide significantly improved net reclassification (NRI) for MACE (NRI=0.12; p=0.03), CVM (NRI=0.33; p<0.001), and HF or AF (NRI=0.33; p<0.001) beyond traditional risk factors, while PWV did not aid in net reclassification improvement for any endpoint. CONCLUSIONS: In apparently healthy individuals, NT-proBNP and PWV predicted cardiovascular events independently. N-terminal pro-brain natriuretic peptide improved reclassification for the prediction of MACE, CVM, and hospitalisation for HF or AF beyond traditional risk factors, while PWV did not.

Birthweight is associated with clinical characteristics in people with recently diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes but it is unknown whether low birthweight is associated with distinct clinical characteristics at disease onset. We examined whether a lower or higher birthweight in type 2 diabetes is associated with clinically relevant characteristics at disease onset. METHODS: Midwife records were traced for 6866 individuals with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Using a cross-sectional design, we assessed age at diagnosis, anthropomorphic measures, comorbidities, medications, metabolic variables and family history of type 2 diabetes in individuals with the lowest 25% of birthweight (<3000 g) and highest 25% of birthweight (>3700 g), compared with a birthweight of 3000-3700 g as reference, using log-binomial and Poisson regression. Continuous relationships across the entire birthweight spectrum were assessed with linear and restricted cubic spline regression. Weighted polygenic scores (PS) for type 2 diabetes and birthweight were calculated to assess the impact of genetic predispositions. RESULTS: Each 1000 g decrease in birthweight was associated with a 3.3 year (95% CI 2.9, 3.8) younger age of diabetes onset, 1.5 kg/m2 (95% CI 1.2, 1.7) lower BMI and 3.9 cm (95% CI 3.3, 4.5) smaller waist circumference. Compared with the reference birthweight, a birthweight of <3000 g was associated with more overall comorbidity (prevalence ratio [PR] for Charlson Comorbidity Index Score ≥3 was 1.36 [95% CI 1.07, 1.73]), having a systolic BP ≥155 mmHg (PR 1.26 [95% CI 0.99, 1.59]), lower prevalence of diabetes-associated neurological disease, less likelihood of family history of type 2 diabetes, use of three or more glucose-lowering drugs (PR 1.33 [95% CI 1.06, 1.65]) and use of three or more antihypertensive drugs (PR 1.09 [95% CI 0.99, 1.20]). Clinically defined low birthweight (<2500 g) yielded stronger associations. Most associations between birthweight and clinical characteristics appeared linear, and a higher birthweight was associated with characteristics mirroring lower birthweight in opposite directions. Results were robust to adjustments for PS representing weighted genetic predisposition for type 2 diabetes and birthweight. CONCLUSION/INTERPRETATION: Despite younger age at diagnosis, and fewer individuals with obesity and family history of type 2 diabetes, a birthweight <3000 g was associated with more comorbidities, including a higher systolic BP, as well as with greater use of glucose-lowering and antihypertensive medications, in individuals with recently diagnosed type 2 diabetes.

A six-month low-carbohydrate diet high in fat does not adversely affect endothelial function or markers of low-grade inflammation in patients with type 2 diabetes: an open-label randomized controlled trial.

BACKGROUND: While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. METHODS: In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (< 20 E% carbohydrates, 50-60 E% fat) or a control diet (50-60 E% carbohydrates, 20-30 E% fat) for six months. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were assessed by ultrasound in the brachial artery together with plasma interleukin-6 (IL-6) and serum high-sensitivity C-reactive protein (hsCRP) in the participants at baseline (n = 70) and after six months (n = 64). RESULTS: The FMD and NID were unaltered in both groups after six months, and there were no between-group differences in change of either FMD (p = 0.34) or NID (p = 0.53) in response to the interventions. The circulating hsCRP and IL-6 levels decreased only in response to LCD (both p < 0.05). However, comparing changes over time with the control diet, the LCD did not reduce either IL-6 (p = 0.25) or hsCRP (p = 0.07) levels. The lack of changes in FMD and NID in response to LCD persisted after adjustment for cardiovascular risk factors. CONCLUSION: A LCD high in fat for six months does not adversely affect endothelial function or selected markers of low-grade inflammation, which suggests that this nutritional approach does not increase the risk of cardiovascular disease. Trial registration ClinicalTrials.gov (NCT03068078).

The influence of age and sex on the prognostic importance of traditional cardiovascular risk factors, selected circulating biomarkers and other markers of subclinical cardiovascular damage.

PURPOSE OF REVIEW: There is an increasing need for improved risk stratification to better individualize cardiovascular preventive measures. Although age and sex are strong and easily obtained cardiovascular risk factors (CVRFs), their influence on the prognostic importance of other CVRF, circulating biomarkers and other markers of subclinical cardiovascular damage has not previously been systematically and critically appraised. Therefore, we have revisited the European MORGAM and the Danish MONI10 cohorts. RECENT FINDINGS: Theoretically, the relative risk of many CVRF is expected to be lower in older healthy individuals due to a combination of selection bias by disease, higher absolute risk primarily due to older age, and the fact that the CVRF and markers may primarily influence or reflect early parts of the cardiovascular disease process. This influence of age may vary between sexes, as the cardiovascular disease process is delayed and possibly different in women compared with men. SUMMARY: Adjusted for the remaining Systematic COronary Risk Evaluation (SCORE) CVRF, higher SBP, serum cholesterol, soluble urokinase-type plasminogen activator receptor, left ventricular mass index and atherosclerotic plaques were more closely associated with outcomes in individuals younger than 52 years with some sex-specific differences, whereas higher N-terminal pro-brain natriuretic peptide and urine albumin/creatine ratio were more closely associated with outcomes in subjects aged 61 or 71 years.

Effects of adding exercise to usual care in patients with either hypertension, type 2 diabetes or cardiovascular disease: a systematic review with meta-analysis and trial sequential analysis.

OBJECTIVE: To assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. DESIGN: Systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. DATA SOURCES: The CENTRAL, MEDLINE, EMBASE, Science Citation Index Expanded on Web of Science and BIOSIS searched from inception to July 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included all randomised clinical trials adding any form of trialist defined exercise to usual care versus usual care in participants with either hypertension, type 2 diabetes or cardiovascular disease irrespective of setting, publication status, year and language. OUTCOME AND MEASURES: The primary outcomes were all-cause mortality, serious adverse events and quality of life. DATA EXTRACTION AND SYNTHESIS: Five independent reviewers extracted data and assessed risk of bias in pairs. Our methodology was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Grading of Recommendations Assessment, Development and Evaluation and Cochrane Risk of Bias-version 1. RESULTS: We included 950 trials, of which 248 trials randomising 21 633 participants reported on our predefined outcomes. All included trials were at high risk of bias. The major types of exercise reported were dynamic aerobic exercise (126/248 trials), dynamic resistance exercise (25/248 trials), and combined aerobic and resistance exercise (58/248 trials). The study participants were included due to cardiovascular diseases (189/248 trials), type 2 diabetes (41/248 trials) or hypertension (16/248 trials). The median intervention period was 3 months (IQR: 2-4 months) and the median follow-up period was 6 months (IQR: 3-8 months) after randomisation. Meta-analyses and trial sequential analyses showed evidence of a beneficial effect of adding exercise to usual care when assessing all-cause mortality (risk ratio (RR) 0.82; 95% CI 0.73 to 0.93; I2=0%, moderate certainty of evidence) and serious adverse events (RR 0.79; 95% CI 0.71 to 0.88; I2=0%, moderate certainty of evidence). We did not find evidence of a difference between trials from different economic regions, type of participants, type of exercise or duration of follow-up. Quality of life was assessed using several different tools, but the results generally showed that exercise improved quality of life, but the effect sizes were below our predefined minimal important difference. CONCLUSIONS: A short duration of any type of exercise seems to reduce the risk of all-cause mortality and serious adverse events in patients with either hypertension, type 2 diabetes or cardiovascular diseases. Exercise seems to have statistically significant effects on quality of life, but the effect sizes seem minimal. PROSPERO REGISTRATION NUMBER: CRD42019142313.

Plasma Galectin-4 Levels Are Increased after Stroke in Mice and Humans.

Epidemiological studies have associated plasma galectin-4 (Gal-4) levels with prevalent and incident diabetes, and with an increased risk of coronary artery disease. To date, data regarding possible associations between plasma Gal-4 and stroke are lacking. Using linear and logistic regression analyses, we tested Gal-4 association with prevalent stroke in a population-based cohort. Additionally, in mice fed a high-fat diet (HFD), we investigated whether plasma Gal-4 increases in response to ischemic stroke. Plasma Gal-4 was higher in subjects with prevalent ischemic stroke, and was associated with prevalent ischemic stroke (odds ratio 1.52; 95% confidence interval 1.01-2.30; p = 0.048) adjusted for age, sex, and covariates of cardiometabolic health. Plasma Gal-4 increased after experimental stroke in both controls and HFD-fed mice. HFD exposure was devoid of impact on Gal-4 levels. This study demonstrates higher plasma Gal-4 levels in both experimental stroke and in humans that experienced ischemic stroke.

Galectin-4 levels in hospitalized versus non-hospitalized subjects with obesity: the Malmö Preventive Project.

BACKGROUND: Obesity is strongly associated with the development of cardiovascular disease (CVD). However, the heterogenous nature of obesity in CVD-risk is still poorly understood. We aimed to explore novel CVD biomarkers and their possible association with presumed unhealthy obesity, defined as hospitalized subjects with obesity (HO). METHODS: Ninety-two proteins associated with CVD were analyzed in 517 (mean age 67 ± 6 years; 33.7% women) individuals with obesity (BMI ≥30 kg/m2) from the Malmö Preventive Project cohort, using a proximity extension array technique from the Olink CVD III panel. Individuals with at least one recorded hospitalization for somatic disease prior to study baseline were defined as HO phenotypes. Associations between proteins and HO (n = 407) versus non-hospitalized subjects with obesity (NHO, n = 110), were analyzed using multivariable binary logistic regression, adjusted for traditional risk factors. RESULTS: Of 92 analyzed unadjusted associations between biomarkers and HO, increased levels of two proteins were significant at a false discovery rate < 0.05: Galectin-4 (Gal-4) and insulin-like growth factor-binding protein 1 (IGFBP-1). When these two proteins were included in logistic regression analyses adjusted for age and sex, Gal-4 remained significant. Gal-4 was independently associated with the HO phenotype in multivariable logistic regression analysis (OR 1.72; CI95% 1.16-2.54). Post-hoc analysis revealed that this association was only present in the subpopulation with diabetes (OR 2.26; CI95% 1.25-4.07). However, an interaction analysis was performed, showing no significant interaction between Gal-4 and prevalent diabetes (p = 0.16). CONCLUSIONS: In middle-aged and older individuals with obesity, increased Gal-4 levels were associated with a higher probability of HO. This association was only significant in subjects with diabetes only, further implying a role for Gal-4 in diabetes and its complications.

Identification and fine mapping of a major QTL (qRtsc8-1) conferring resistance to maize tar spot complex and validation of production markers in breeding lines.

KEY MESSAGE: A major QTL of qRtsc8-1 conferring TSC resistance was identified and fine mapped to a 721 kb region on chromosome 8 at 81 Mb, and production markers were validated in breeding lines. Tar spot complex (TSC) is a major foliar disease of maize in many Central and Latin American countries and leads to severe yield loss. To dissect the genetic architecture of TSC resistance, a genome-wide association study (GWAS) panel and a bi-parental doubled haploid population were used for GWAS and selective genotyping analysis, respectively. A total of 115 SNPs in bin 8.03 were detected by GWAS and three QTL in bins 6.05, 6.07, and 8.03 were detected by selective genotyping. The major QTL qRtsc8-1 located in bin 8.03 was detected by both analyses, and it explained 14.97% of the phenotypic variance. To fine map qRtsc8-1, the recombinant-derived progeny test was implemented. Recombinations in each generation were backcrossed, and the backcross progenies were genotyped with Kompetitive Allele Specific PCR (KASP) markers and phenotyped for TSC resistance individually. The significant tests for comparing the TSC resistance between the two classes of progenies with and without resistant alleles were used for fine mapping. In BC5 generation, qRtsc8-1 was fine mapped in an interval of ~ 721 kb flanked by markers of KASP81160138 and KASP81881276. In this interval, the candidate genes GRMZM2G063511 and GRMZM2G073884 were identified, which encode an integral membrane protein-like and a leucine-rich repeat receptor-like protein kinase, respectively. Both genes are involved in maize disease resistance responses. Two production markers KASP81160138 and KASP81160155 were verified in 471 breeding lines. This study provides valuable information for cloning the resistance gene, and it will also facilitate the routine implementation of marker-assisted selection in the breeding pipeline for improving TSC resistance.

Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial.

AIM: To investigate the efficacy and safety of a non-calorie-restricted low-carbohydrate diet (LCD) on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes (T2D) instructed to maintain their non-insulin antidiabetic medication and physical activity. MATERIALS AND METHODS: In an open-label randomized controlled trial, patients with T2D were randomized 2:1 to either a LCD with a maximum of 20 E% (percentage of total energy intake) from carbohydrates (n = 49) or a control diet with 50-60 E% from carbohydrates (n = 22) for 6 months. Examinations at enrolment and after 3 and 6 months included blood sample analyses, anthropometrics, blood pressure, accelerometer-based assessment of physical activity, and food diaries. Total fat mass and lean mass were determined by dual-energy x-ray absorptiometry scan. The mean difference in change between groups from baseline are reported. RESULTS: The LCD group decreased carbohydrate intake to 13.4 E% and increased fat intake to 63.2 E%, which was -30.5 ± 2.2 E% lower for carbohydrates and 30.6 ± 2.2 E% higher for fat, respectively, compared with the control group (all P < .001). The LCD reduced HbA1c after 3 months (-8.9 ± 1.7 mmol/mol; P < .0001), and this was maintained after 6 months (-7.5 ± 1.8 mmol/mol; P < .0001) compared with the control diet. The LCD also reduced weight (-3.9 ± 1.0 kg), body mass index (-1.4 ± 0.4 kg/m2 ), and waist circumference (-4.9 ± 1.3 cm) compared with the control diet (all P < .01), accompanied by reductions in total fat mass (-2.2 ± 1.0 kg; P = .027) and lean mass (-1.3 ± 0.6 kg; P = .017). No changes in blood lipids or blood pressure were seen after 6 months. The level of physical activity was maintained, and there were no episodes of severe hypoglycaemia. CONCLUSION: A non-calorie-restricted LCD high in fat has significant beneficial effects on glycaemic control and body composition, and does not adversely affect cardiovascular risk factors in patients with T2D. Reducing carbohydrate intake to 10-25 E% appears to be an effective and safe nutritional approach with respect to classical cardiovascular risk factors and hypoglycaemia.

Unstable Angina as a Component of Primary Composite Endpoints in Clinical Cardiovascular Trials: Pros and Cons.

BACKGROUND: Unstable angina (UA) is a component of acute coronary syndrome that is only occasionally included in primary composite endpoints in clinical cardiovascular trials. The aim of this paper is to elucidate the potential benefits and disadvantages of including UA in such contexts. SUMMARY: UA comprises <10% of patients with acute coronary syndromes in contemporary settings. Based on the pathophysiological similarities, it is ideal as a part of a composite endpoint along with myocardial infarction (MI). By adding UA as a component of a primary composite endpoint, the number of events and feasibility of the trial should increase, thus decreasing its size and cost. Furthermore, UA has both economic and quality of life implications on a societal and an individual level. However, there are important challenges associated with the use of UA as an endpoint. With the introduction of high-sensitivity troponins, the number of individuals diagnosed with UA has decreased to rather low levels, with a reciprocal increase in the number of MI. In addition, UA is particularly challenging to define given the subjective assessment of the index symptoms, rendering a high risk of bias. To minimize bias, strict criteria are warranted, and events should be adjudicated by a blinded endpoint adjudication committee. KEY MESSAGES: UA should only be chosen as a component of a primary composite endpoint in cardiovascular trials after thoroughly evaluating the pros and cons. If it is chosen to include UA, appropriate precautions should be taken to minimize possible bias.

Long-term Weight Loss in a Primary Care-Anchored eHealth Lifestyle Coaching Program: Randomized Controlled Trial.

BACKGROUND: Long-term weight loss in people living with obesity can reduce the risk and progression of noncommunicable diseases. Observational studies suggest that digital coaching can lead to long-term weight loss. OBJECTIVE: We investigated whether an eHealth lifestyle coaching program for people living with obesity with or without type 2 diabetes led to significant, long-term (12-month) weight loss compared to usual care. METHODS: In a randomized controlled trial that took place in 50 municipalities in Denmark, 340 people living with obesity with or without type 2 diabetes were enrolled from April 16, 2018, to April 1, 2019, and randomized via an automated computer algorithm to an intervention (n=200) or a control (n=140) group. Patients were recruited via their general practitioners, the Danish diabetes organization, and social media. The digital coaching intervention consisted of an initial 1-hour face-to-face motivational interview followed by digital coaching using behavioral change techniques enabled by individual live monitoring. The primary outcome was change in body weight from baseline to 12 months. RESULTS: Data were assessed for 200 participants, including 127 from the intervention group and 73 from the control group, who completed 12 months of follow-up. After 12 months, mean body weight and BMI were significantly reduced in both groups but significantly more so in the intervention group than the control group (-4.5 kg, 95% CI -5.6 to -3.4 vs -1.5 kg, 95% CI -2.7 to -0.2, respectively; P<.001; and -1.5 kg/m2, 95% CI -1.9 to -1.2 vs -0.5 kg/m2, 95% CI -0.9 to -0.1, respectively; P<.001). Hemoglobin A1c was significantly reduced in both the intervention (-6.0 mmol/mol, 95% CI -7.7 to -4.3) and control (-4.9 mmol/mol, 95% CI -7.4 to -2.4) groups, without a significant group difference (all P>.46). CONCLUSIONS: Compared to usual care, digital lifestyle coaching can induce significant weight loss for people living with obesity, both with and without type 2 diabetes, after 12 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT03788915; https://clinicaltrials.gov/ct2/show/NCT03788915.

Genetic dissection of Striga hermonthica (Del.) Benth. resistance via genome-wide association and genomic prediction in tropical maize germplasm.

KEY MESSAGE: Genome-wide association revealed that resistance to Striga hermonthica is influenced by multiple genomic regions with moderate effects. It is possible to increase genetic gains from selection for Striga resistance using genomic prediction. Striga hermonthica (Del.) Benth., commonly known as the purple witchweed or giant witchweed, is a serious problem for maize-dependent smallholder farmers in sub-Saharan Africa. Breeding for Striga resistance in maize is complicated due to limited genetic variation, complexity of resistance and challenges with phenotyping. This study was conducted to (i) evaluate a set of diverse tropical maize lines for their responses to Striga under artificial infestation in three environments in Kenya; (ii) detect quantitative trait loci associated with Striga resistance through genome-wide association study (GWAS); and (iii) evaluate the effectiveness of genomic prediction (GP) of Striga-related traits. An association mapping panel of 380 inbred lines was evaluated in three environments under artificial Striga infestation in replicated trials and genotyped with 278,810 single-nucleotide polymorphism (SNP) markers. Genotypic and genotype x environment variations were significant for measured traits associated with Striga resistance. Heritability estimates were moderate (0.42) to high (0.92) for measured traits. GWAS revealed 57 SNPs significantly associated with Striga resistance indicator traits and grain yield (GY) under artificial Striga infestation with low to moderate effect. A set of 32 candidate genes physically near the significant SNPs with roles in plant defense against biotic stresses were identified. GP with different cross-validations revealed that prediction of performance of lines in new environments is better than prediction of performance of new lines for all traits. Predictions across environments revealed high accuracy for all the traits, while inclusion of GWAS-detected SNPs led to slight increase in the accuracy. The item-based collaborative filtering approach that incorporates related traits evaluated in different environments to predict GY and Striga-related traits outperformed GP for Striga resistance indicator traits. The results demonstrated the polygenic nature of resistance to S. hermonthica, and that implementation of GP in Striga resistance breeding could potentially aid in increasing genetic gain for this important trait.

Maximizing efficiency of genomic selection in CIMMYT's tropical maize breeding program.

KEY MESSAGE: Historical data from breeding programs can be efficiently used to improve genomic selection accuracy, especially when the training set is optimized to subset individuals most informative of the target testing set. The current strategy for large-scale implementation of genomic selection (GS) at the International Maize and Wheat Improvement Center (CIMMYT) global maize breeding program has been to train models using information from full-sibs in a "test-half-predict-half approach." Although effective, this approach has limitations, as it requires large full-sib populations and limits the ability to shorten variety testing and breeding cycle times. The primary objective of this study was to identify optimal experimental and training set designs to maximize prediction accuracy of GS in CIMMYT's maize breeding programs. Training set (TS) design strategies were evaluated to determine the most efficient use of phenotypic data collected on relatives for genomic prediction (GP) using datasets containing 849 (DS1) and 1389 (DS2) DH-lines evaluated as testcrosses in 2017 and 2018, respectively. Our results show there is merit in the use of multiple bi-parental populations as TS when selected using algorithms to maximize relatedness between the training and prediction sets. In a breeding program where relevant past breeding information is not readily available, the phenotyping expenditure can be spread across connected bi-parental populations by phenotyping only a small number of lines from each population. This significantly improves prediction accuracy compared to within-population prediction, especially when the TS for within full-sib prediction is small. Finally, we demonstrate that prediction accuracy in either sparse testing or "test-half-predict-half" can further be improved by optimizing which lines are planted for phenotyping and which lines are to be only genotyped for advancement based on GP.

Sex- and age-related differences in the predictive capability of circulating biomarkers: from the MONICA 10 cohort.

OBJECTIVES: The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and soluble urokinase plasminogen activator receptor (suPAR) differed in their ability to predict cardiovascular outcomes beyond traditional risk factors in younger and older men and women without known cardiovascular disease. Design. Prospective population-based cohort study of 1951 individuals from the MONItoring of trends and determinants in Cardiovascular disease (MONICA) study, examined 1993-1994. Participants were stratified into four groups based on sex and age. Subjects aged 41 or 51 years were classified as younger; those aged 61 or 71 years were classified as older. The principal endpoint was death from cardiovascular causes. Predictive capabilities of biomarkers were tested using Cox proportional-hazards regression, Harrell's concordance-index, net reclassification improvement, and classification and regression tree (CART) analysis. Results. Median follow-up was 18.5 years, during which 19/597 younger men, 100/380 older men, 12/607 younger women, and 46/367 older women had died from a cardiovascular cause. NT-proBNP was independently associated with death from cardiovascular causes among all participants (p ≤ .02) except younger women (p = .70), whereas hs-CRP was associated with this endpoint in men (p ≤ .007), and suPAR in older men only (p < .001). None of the biomarkers improved discrimination ability beyond traditional risk factors (p ≥ .07). However, NT-proBNP enhanced reclassification in men and older women. CART-analysis showed that NT-proBNP was generally of greater value among men, and suPAR among women. Conclusions. Hs-CRP, NT-proBNP, and suPAR displayed different associations with cardiovascular death among apparently healthy younger and older men and women.

Genomic prediction across years in a maize doubled haploid breeding program to accelerate early-stage testcross testing.

KEY MESSAGE: Genomic selection with a multiple-year training population dataset could accelerate early-stage testcross testing by skipping the first-stage yield testing, which significantly saves the time and cost of early-stage testcross testing. With the development of doubled haploid (DH) technology, the main task for a maize breeder is to estimate the breeding values of thousands of DH lines annually. In early-stage testcross testing, genomic selection (GS) offers the opportunity of replacing expensive multiple-environment phenotyping and phenotypic selection with lower-cost genotyping and genomic estimated breeding value (GEBV)-based selection. In the present study, a total of 1528 maize DH lines, phenotyped in multiple-environment trials in three consecutive years and genotyped with a low-cost per-sample genotyping platform of rAmpSeq, were used to explore how to implement GS to accelerate early-stage testcross testing. Results showed that the average prediction accuracy estimated from the cross-validation schemes was above 0.60 across all the scenarios. The average prediction accuracies estimated from the independent validation schemes ranged from 0.23 to 0.32 across all the scenarios, when the one-year datasets were used as training population (TRN) to predict the other year data as testing population (TST). The average prediction accuracies increased to a range from 0.31 to 0.42 across all the scenarios, when the two-years datasets were used as TRN. The prediction accuracies increased to a range from 0.50 to 0.56, when the TRN consisted of two-years of breeding data and 50% of third year's data converted from TST to TRN. This information showed that GS with a multiple-year TRN set offers the opportunity to accelerate early-stage testcross testing by skipping the first-stage yield testing, which significantly saves the time and cost of early-stage testcross testing.

Factors affecting the fruit and vegetable intake in Nepal and its association with history of self-reported major cardiovascular events.

BACKGROUND: The World Health Organization recommends consumption of a minimum of 400 g of fruits and vegetables per day for prevention of cardiovascular disease. Low fruit and vegetable intake is associated with an increased risk of stroke by 11% and ischemic heart disease by 31%. The present study aims to explore factors affecting the fruit and vegetable intake in Nepal and its association with history of self-reported major cardiovascular events (myocardial infarction and stroke). METHOD: Data for this cross-sectional study were collected as part of the study "Community Based Management of Hypertension in Nepal" initiated in the Lekhnath Municipality in 2013. Demographic and nutrition information were collected using the WHO STEPwise approach to a surveillance tool. Descriptive statistics identified the frequency and percentage of fruit and vegetable intake. A Chi-square test examined the association between fruit and vegetable intake and history of self-reported cardiovascular events, socio-demographic and cardiovascular risk factors. Binary logistic regression analysis identified odds ratio with 95% confidence intervals between fruit and vegetable intake and history of self-reported cardiovascular events. RESULTS: The mean and median intake of fruits and vegetables were 3.3 ± 0.79 and 3 servings respectively. Of the 2815 respondents, 2% (59) reported having a history of major cardiovascular events. The adjusted odds of having a history of major cardiovascular events was 2.22 (95%CI, 1.06-4.66) for those who consumed < 3 servings compared to those who consumed ≥3 servings of fruits and vegetables a day. CONCLUSION: The respondents who consumed < 3 servings of fruits and vegetables a day had higher odds of a history of major cardiovascular events in comparison to those who consumed ≥3 servings. This finding may carry a policy recommendation for those settings where the current recommendation of having ≥5 servings of fruits and vegetables a day is not possible. Our findings also suggest that surviving a major cardiovascular event was not enough in itself to modify nutritional intake. As many Nepali consumes low amount of fruits and vegetables, appropriate measures should be taken to increase this consumption to prevent cardiovascular morbidity and mortality.

The Prospective Studies of Atherosclerosis (Proof-ATHERO) Consortium: Design and Rationale.

Atherosclerosis - the pathophysiological mechanism shared by most cardiovascular diseases - can be directly or indirectly assessed by a variety of clinical tests including measurement of carotid intima-media thickness, carotid plaque, -ankle-brachial index, pulse wave velocity, and coronary -artery calcium. The Prospective Studies of Atherosclerosis -(Proof-ATHERO) consortium (https://clinicalepi.i-med.ac.at/research/proof-athero/) collates de-identified individual-participant data of studies with information on atherosclerosis measures, risk factors for cardiovascular disease, and incidence of cardiovascular diseases. It currently comprises 74 studies that involve 106,846 participants from 25 countries and over 40 cities. In summary, 21 studies recruited participants from the general population (n = 67,784), 16 from high-risk populations (n = 22,677), and 37 as part of clinical trials (n = 16,385). Baseline years of contributing studies range from April 1980 to July 2014; the latest follow-up was until June 2019. Mean age at baseline was 59 years (standard deviation: 10) and 50% were female. Over a total of 830,619 person-years of follow-up, 17,270 incident cardiovascular events (including coronary heart disease and stroke) and 13,270 deaths were recorded, corresponding to cumulative incidences of 2.1% and 1.6% per annum, respectively. The consortium is coordinated by the Clinical Epidemiology Team at the Medical University of Innsbruck, Austria. Contributing studies undergo a detailed data cleaning and harmonisation procedure before being incorporated in the Proof-ATHERO central database. Statistical analyses are being conducted according to pre-defined analysis plans and use established methods for individual-participant data meta-analysis. Capitalising on its large sample size, the multi-institutional collaborative Proof-ATHERO consortium aims to better characterise, understand, and predict the development of atherosclerosis and its clinical consequences.