The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 ...receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants METHODS: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models.
Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028.
These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk.
https://www.clinicaltrials.gouv . Unique Identifier NCT01394952).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infectious disease transmission from domestic sheep threatens the persistence of bighorn sheep (Ovis canadensis) populations throughout western North America. Quantifying spatial separation between ...the 2 species is an essential component in assessing the risk of disease transmission. We present a spatial analysis to evaluate infectious disease risks for endangered Sierra Nevada bighorn sheep (O. c. sierrae; hereafter Sierra bighorn sheep). Our approach accounted for spatial separation between the species as well as the configuration of resources that influences Sierra bighorn sheep movement. We assessed the potential for contact by predicting where Sierra bighorn sheep were likely to be located and travel. We combined a resource selection probability function with a cost distance analysis to quantify the risk of grazing domestic sheep in proximity to Sierra bighorn sheep core home range from a habitat perspective. We compared our approach to a standard buffer approach and determined that our cost distance model better quantified how risk varied among grazing parcels. Sierra bighorn sheep selected and traveled within habitat that included escape terrain. Our model, which included a log normal transformation, characterized the high relative cost (i.e., reduced likelihood) to traveling beyond selected habitat and predicted that such movement is less likely. As a result, our habitat‐based risk threshold was 48% smaller in area than the standard buffer area that included landscape that bighorn did not use. Our method establishes a risk threshold that can be used by land managers to optimize public and private grazing regimes and minimize the risk of disease transmission.
Risk of disease transmission between domestic sheep and bighorn sheep is the most serious threat to bighorn conservation throughout the western United States and Canada. Managing this risk is a major challenge for land managers. We developed a spatially explicit model to quantify the potential for contact between bighorn and domestic sheep.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional ...organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8-8.4 year; late childhood: 8.5-11.3 year; early adolescence: 11.4-14.7 year; late adolescence: 14.8-18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces.
IntroductionEngland has invested considerably in diabetes care through such programs as the Quality and Outcomes Framework (QOF) and National Diabetes Audit (NDA). Associations between program ...indicators and clinical endpoints, such as amputation, remain unclear. We examined associations between primary care indicators and incident lower limb amputation.Research design and methodsThis population-based retrospective cohort study, spanning 2010–2017, was comprised of adults in England with type 2 diabetes and no history of lower limb amputation. Exposures at baseline (2010–2011) were attainment of QOF glycated hemoglobin (HbA1c), blood pressure and total cholesterol indicators, and number of NDA processes completed. Propensity score matching was performed and multivariable Cox proportional hazards models, adjusting for disease-related, comorbidity, lifestyle, and sociodemographic factors, were fitted using matched samples for each exposure.Results83 688 individuals from 330 English primary care practices were included. Mean follow-up was 3.9 (SD 2.0) years, and 521 (0.6%) minor or major amputations were observed (1.62 per 1000 person-years). HbA1c and cholesterol indicator attainment were associated with considerably lower risks of minor or major amputation (adjusted HRs; 95% CIs) 0.61 (0.49 to 0.74; p<0.0001) and 0.67 (0.53 to 0.86; p=0.0017), respectively). No evidence of association between blood pressure indicator attainment and amputation was observed (adjusted HR 0.88 (0.73 to 1.06; p=0.1891)). Substantially lower amputation rates were observed among those completing a greater number of NDA care processes (adjusted HRs 0.45 (0.24 to 0.83; p=0.0106), 0.67 (0.47 to 0.97; p=0.0319), and 0.38 (0.20 to 0.70; p=0.0022) for comparisons of 4–6 vs 0–3, 7–9 vs 0–3, and 7–9 vs 4–6 processes, respectively). Results for major-only amputations were similar for HbA1c and blood pressure, though cholesterol indicator attainment was non-significant.ConclusionsComprehensive primary care-based secondary prevention may offer considerable protection against diabetes-related amputation. This has important implications for diabetes management and medical decision-making for patients, as well as type 2 diabetes quality improvement programs.
Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine ...mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 0.82–0.88) and ER-negative (OR = 0.87 0.82–0.91) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 0.91–0.95 and OR = 1.06 1.03–1.09) and ER-negative (OR = 0.95 0.91–0.98 and OR = 1.08 1.04–1.13) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 0.90–0.96). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1–4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We have previously described rat insulinoma INS-1-derived cell lines with robust or poor glucose-stimulated insulin secretion (GSIS). In the current study, we have further resolved these lines into ...three classes: class 1, glucose-unresponsive/glucagon-expressing; class 2, glucose-unresponsive/glucagon-negative; and class 3, glucose-responsive/glucagon-negative. The transcription factor Nkx2.2 was expressed with relative abundance of 3.3, 1.0, and 1.0 in class 1, class 2, and class 3 cells, respectively, whereas Nkx6.1 expression had the opposite trend: 1.0, 2.6, and 6.4 in class 1, class 2, and class 3 cells, respectively. In class 1 cells, overexpressed Nkx6.1 suppressed glucagon expression but did not affect the levels of several other prominent beta cell transcription factors. RNA interference (RNAi)-mediated suppression of Nkx6.1 in class 3 cells resulted in a doubling of glucagon mRNA, with no effect on Pdx1 levels, whereas suppression of Pdx1 in class 3 cells caused a 12-fold increase in glucagon transcript levels, demonstrating independent effects of Nkx6.1 and Pdx1 on glucagon expression in beta cell lines. RNAi-mediated suppression of Nkx6.1 expression in class 3 cells also caused a decrease in GSIS from 13.9- to 3.7-fold, whereas suppression of Pdx1 reduced absolute amounts of insulin secretion without affecting fold response. Finally, RNAi-mediated suppression of Nkx6.1 mRNA in primary rat islets was accompanied by a significant decrease in GSIS relative to control cells. In sum, our studies have revealed roles for Nkx6.1 in suppression of glucagon expression and control of GSIS in islet beta cells.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Using a population-based sampling strategy, the National Institutes of Health (NIH) Magnetic Resonance Imaging Study of Normal Brain Development compiled a longitudinal normative reference database ...of neuroimaging and correlated clinical/behavioral data from a demographically representative sample of healthy children and adolescents aged newborn through early adulthood. The present paper reports brain volume data for 325 children, ages 4.5-18 years, from the first cross-sectional time point. Measures included volumes of whole-brain gray matter (GM) and white matter (WM), left and right lateral ventricles, frontal, temporal, parietal and occipital lobe GM and WM, subcortical GM (thalamus, caudate, putamen, and globus pallidus), cerebellum, and brainstem. Associations with cross-sectional age, sex, family income, parental education, and body mass index (BMI) were evaluated. Key observations are: 1) age-related decreases in lobar GM most prominent in parietal and occipital cortex; 2) age-related increases in lobar WM, greatest in occipital, followed by the temporal lobe; 3) age-related trajectories predominantly curvilinear in females, but linear in males; and 4) small systematic associations of brain tissue volumes with BMI but not with IQ, family income, or parental education. These findings constitute a normative reference on regional brain volumes in children and adolescents.
Vicente-Rodríguez, G, Rey-López, JP, Ruíz, JR, Jiménez-Pavón, D, Bergman, P, Ciarapica, D, Heredia, JM, Molnar, D, Gutierrez, A, Moreno, LA, and Ortega, FB. Interrater reliability and time ...measurement validity of speed-agility field tests in adolescents. J Strength Cond Res 25(7)2059-2063, 2011—The aim of this study was to examine the interrater reliability (trained vs. untrained raters) and criterion-related validity (manual vs. automatic timing) of the 4 × 10-m shuttle run and 30-m running speed tests (times measured). The study comprised 85 adolescents (38 girls) aged 13.0-16.9 years from the Healthy Lifestyle in Europe by Nutrition in Adolescence study. The time required to complete the 4 × 10-m shuttle run and 30-m running tests was simultaneously measured (a) manually with a stopwatch by both trained and untrained raters (for interrater reliability analysis), and (b) by using photoelectric cells (for validity analysis). Systematic error, random error, and heteroscedasticity were studied with repeated-measured analysis of variance and Bland-Altman plots. The systematic error for untrained vs. trained raters and the untrained raters vs. photoelectric cells were in all cases ∼0.1 seconds (p < 0.01), that is, untrained raters recorded higher times. No systematic error was found between trained raters and photoelectric cells (p > 0.05). No heteroscedasticity was shown in any case (p > 0.05). The findings indicate that manual measurements by a trained rater, using a stopwatch, seem to be a valid method to assess speed and agility fitness testing in adolescents. Researchers must be trained to minimize the measurement error.
Accurate height and weight measurement can be challenging in older adults and complicates nutritional status assessment. Other parameters like the neutrophil-to-lymphocyte ratio (NLR) and the ...lymphocyte count (LC) could be an option to these measurements. We aimed to test these variables as subrogates of body mass index (BMI) or calf-circumference (CC) for malnutrition screening in community-dwelling older adults.
This is a secondary analysis from the Salud, Bienestar y Envejecimiento (SABE) survey from Ecuador (2009). Includes data on demographics, health-related factors, physical assessments, and complete blood count, allowing to calculate NLR and LC to be used as part of the Mini Nutritional Assessment (MNA), instead of the BMI. Consequently, 4 models were included: standard MNA, MNA-CC, MNA-NLR and MNA-LC. Finally, age, sex, and comorbidities were considered as confounding variables.
In our analysis of 1,663 subjects, 50.81% were women. Positive correlations with standard MNA were found for MNA-NLR (Estimate = 0.654, p < 0.001) MNA-CC (Estimate = 0.875, p value < 0.001) and MNA-LC (Estimate = 0.679, p < 0.001). Bland-Altman plots showed the smallest bias in MNA-CC. Linear association models revealed varying associations between MNA variants and different parameters, being MNA-NLR strongly associated with all of them (e.g. Estimate = 0.014, p = 0.001 for albumin), except BMI.
The newly proposed model classified a greater number of subjects at risk of malnutrition and fewer with normal nutrition compared to the standard MNA. Additionally, it demonstrated a strong correlation and concordance with the standard MNA. This suggests that hematological parameters may offer an accurate alternative and important insights into malnutrition.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Treatment options for sarcopenia are currently limited, and primarily rely on two main therapeutic approaches: resistance-based physical activity and dietary interventions. However, details about ...specific nutrients in the diet or supplementation are unclear. We aim to investigate the relationship between nutrient intake and lean mass, function, and strength. Data were derived from the Gothenburg H70 birth cohort study in Sweden, including 719,70-year-olds born in 1944 (54.1% females). For independent variables, the diet history method (face-to-face interviews) was used to estimate habitual food intake during the preceding three months. Dependent variables were gait speed (muscle performance), hand grip strength (muscle strength), and the appendicular lean soft tissue index (ALSTI). Linear regression analyses were performed to analyze the relationship between the dependent variables and each of the covariates. Several nutrients were positively associated with ALSTI, such as polyunsaturated fatty acids (DHA, EPA), selenium, zinc, riboflavin, niacin equivalent, vitamin B12, vitamin D, iron, and protein. After correction for multiple comparisons, there were no remaining correlations with handgrip and gait speed. Findings of positive correlations for some nutrients with lean mass suggest a role for these nutrients in maintaining muscle volume. These results can be used to inform clinical trials to expand the preventive strategies and treatment options for individuals at risk of muscle loss and sarcopenia.
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