Impact of Visit-to-Visit Glycemic Variability on the Risks of Macrovascular and Microvascular Events and All-Cause Mortality in Type 2 Diabetes: The ADVANCE Trial

OBJECTIVE There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODS ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3–24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTS Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05–2.55) and 3.31 (1.57–6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65–4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONS Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes

Proteasomal degradation of BRAHMA promotes Boron tolerance in Arabidopsis

High levels of boron (B) induce DNA double-strand breaks (DSBs) in eukaryotes, including plants. Here we show a molecular pathway of high B-induced DSBs by characterizing Arabidopsis thaliana hypersensitive to excess boron mutants. Molecular analysis of the mutants revealed that degradation of a SWItch/Sucrose Non-Fermentable subunit, BRAHMA (BRM), by a 26S proteasome (26SP) with specific subunits is a key process for ameliorating high-B-induced DSBs. We also found that high-B treatment induces histone hyperacetylation, which increases susceptibility to DSBs. BRM binds to acetylated histone residues and opens chromatin. Accordingly, we propose that the 26SP limits chromatin opening by BRM in conjunction with histone hyperacetylation to maintain chromatin stability and avoid DSB formation under high-B conditions. Interestingly, a positive correlation between the extent of histone acetylation and DSB formation is evident in human cultured cells, suggesting that the mechanism of DSB induction is also valid in animals

PENERAPAN MODEL PEMBELAJARAN KOOPERATIF TIPE MAKE A MATCH DENGAN MEDIA FLASH CARD UNTUK MENINGKATKAN HASIL BELAJAR BAHASA INGGRIS PESERTA DIDIK KELAS V MI IRSYADUT THOLIBIN TUGU REJOTANGAN TULUNGAGUNG

ABSTRAK Skripsi dengan judul “Penerapan Model Pembelajaran Kooperatif Tipe Make A Match Dengan Media Flash Card Untuk Meningkatkan Hasil Belajar Bahasa Inggris Peserta Didik Kelas V MI Irsyadut Tholibin Tugu Rejotangan Tulungagung”ini ditulis oleh Sufiya, Ulfa Ayu Ainin NIM. 2817133194, Jurusan Pendidikan Guru Madrasah Ibtidaiyah, Fakultas Tarbiyah dan Ilmu Keguruan, Institut Agama Islam Negeri Tulungagung, yang dibimbing oleh Bapak Dr. Susanto, M.Pd. Kata Kunci: Make A Match, Flash Card, Hasil Belajar, Bahasa Inggris. Penelitian ini dilatar belakangi oleh permasalahan pembelajaran Bahasa Inggris di MI Irsyadut Tholibin, Rejotangan Tulungagung. Berdasarkan hasil observasi awal permasalahan tersebut disebabkan oleh penggunaan metode pembelajaran yang kurang bervariatif bagi peserta didik, sehingga peserta didik menjadi lebih cepat bosan dan kurang aktif selama proses pembelajaran. Tentu saja hal tersebut menyebabkan hasil belajar peserta didik yang rendah. Rumusan masalah dalam penulisan skripsi ini adalah: 1) Bagaimana penerapan Model Pembelajaran Kooperatif Tipe Make A Match yang dikembangkan dengan media Flash Card pada mata pelajaran Bahasa Inggris pokok bahasan Shapes Kelas V MI Irsyadut Tholibin, Rejotangan Tulungagung? 2) Bagaimana peningkatan keaktifan pada mata pelajaran Bahasa Inggris materi Shapes melalui penerapan Model Pembelajaran Kooperatif Tipe Make A Match yang dikembangkan dengan media Flash Card pada peserta didik Kelas V MI Irsyadut Tholibin, Rejotangan Tulungagung? 3) Bagaimana peningkatan hasil belajar pada mata pelajaran Bahasa Inggris materi Shapes melalui penerapan Model Pembelajaran Kooperatif Tipe Make A Match yang dikembangkan dengan media Flash Card pada peserta didik Kelas V MI Irsyadut Tholibin, Rejotangan Tulungagung? Penelitian ini menggunakan penelitian tindakan kelas (PTK) sebanyak dua siklus. Setiap siklus terdiri dari empat tahap, yaitu perencanaan, pelaksanaan, pengamatan, dan refleksi. Adapun teknik pengumpulan datanya menggunakan tes, wawancara, observasi, catatan lapangan, dan dokumentasi. Tes digunakan untuk menggali data tentang hasil belajar peserta didik. Sedangkan observasi, wawancara, dan catatan lapangan digunakan untuk menggali data tentang proses pembelajaran Bahasa Inggris, respon peserta didik, keadaan peserta didik dan guru serta keaktifan peserta didik. Analisis data yang digunakan mencakup reduksi data, penyajian data, dan penarikan kesimpulan. Akhirnya dalam refleksi I dan II data yang terkumpul dianalisis untuk mengetahui apakah indikator yang telah ditentukan sebelumnya sudah dipenuhi apa tidak. Hasil penelitian menunjukkan bahwa penerapan Model Pembelajaran Kooperatif Tipe Make A Match yang dikembangkan dengan media Flash Card dengan langkah-langkahnya dapat meningkatkan keaktifan dan hasil belajar peserta didik. Keaktifan peserta didik dalam pembelajaran Bahasa Inggris meningkat dari Siklus I ke Siklus II yaitu pada Siklus I keaktifan peserta didik mencapai taraf keberhasilan 80% dengan kriteria baik dan pada Siklus II keaktifan peserta didik mencapai taraf keberhasilan 95% dengan kriteria sangat baik. Sedangkan hasil belajar Bahasa Inggris peserta didik meningkatkan, yaitu pada Pre Test rata-rata peserta didik yaitu 44,37 dengan ketuntasan belajar 4,17%, meningkat pada Siklus I rata- rata peserta didik 74,37 dengan ketuntasan belajar pada Siklus I 70,83%. Hasil belajar peserta didik meningkat pada Siklus II yaitu dengan rata-rata 96 dengan ketuntasan belajar 100%. Dari data tersebut terlihat bahwa penerapan Model Pembelajaran Kooperatif Tipe Make A Match dengan media Flash Card dapat meningkatkan hasil belajar Bahasa Inggris peserta didik Kelas V MI Irsyadut Tholibin, Tugu Rejotangan Tulungagung

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.The EPIC Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). NJW, NGF, and FI were supported by the Medical Research Council Epidemiology Unit core funding [MC_UU_12015/1 and MC_UU_12015/5]. NJW and NGF acknowledge support from the National Institute for Health Research Cambridge Biomedical Research Centre [IS-BRC-1215-20014] and NJW is an NIHR Senior Investigator

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention

World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions

BACKGROUND: To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. METHODS: In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. FINDINGS: Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629-0·741) to 0·833 (0·783-0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt. INTERPRETATION: We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. FUNDING: World Health Organization, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, UK Medical Research Council, and National Institute for Health Research

Age-specific impact of diabetes mellitus on the risk of cardiovascular mortality: An overview from the evidence for Cardiovascular Prevention from Observational Cohorts in the Japan Research Group (EPOCH-JAPAN)

Background: Diabetes mellitus is a strong risk factor for cardiovascular disease. However, the age-specific association of diabetes with cardiovascular risk, especially in the elderly, remains unclear in non-Western populations. Methods: A pooled analysis was conducted using 8 cohort studies (mean follow-up period, 10.3 years) in Japan, combining the data from 38,854 individual participants without history of cardiovascular disease. In all, 1867 of the participants had diabetes, defined based on the 1998 World Health Organization criteria. The association between diabetes and the risk of death from cardiovascular disease, coronary heart disease (CHD), and stroke was estimated using a stratified Cox model, accounting for variability of baseline hazard functions among cohorts. Results: During the follow-up, 1376 subjects died of cardiovascular disease (including 268 of coronary heart disease and 621 of stroke). Diabetes was associated with an increased risk of cardiovascular death after multivariable adjustment (hazard ratio [HR] 1.62; 95% confidence interval [CI], 1.35–1.94). Similarly, diabetes was a risk factor for CHD (HR 2.13; 95% CI, 1.47–3.09) and stroke (HR 1.40; 95% CI, 1.05–1.85). In the age-stratified analysis of the risk of cardiovascular death, the relative effects of diabetes were consistent across age groups (p for heterogeneity . 0.18), whereas the excess absolute risks of diabetes were greater in participants in their 70s and 80s than in younger subjects. Conclusions: The management of diabetes is important to reduce the risk of death from cardiovascular disease, not only in midlife but also in late life, in the Japanese population