Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes

IMPORTANCE: Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. OBJECTIVE: To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals). INTERVENTIONS: Passive follow-up of study participants previously treated with fenofibrate or masked placebo. MAIN OUTCOMES AND MEASURES: Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. RESULTS: The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95). CONCLUSIONS AND RELEVANCE: Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000620

Estudos sobre a nutrição mineral do milho: II. efeito de doses crescentes de N, R e K no crescimento, produção e composição mineral da variedade Piranão em condições controladas

Maize plants, Piranão cultivar, were grown in nutrient solution with 5 levels each of N, R and K till harvest. Nitrate reductase activity and putrescine level were determined in leaves of plants in the N and K series, respectively, at silking stage. Upper and lower leaves were analysed for N, R and K in the corresponding treatments at the end of the life cycle. The main conclusions were the following : 5.1 There was a linear effect of level of N in the substrate on dry matter production. 5.2. High activities of nitrate reductase suggest that under natural conditions the variety should be very responsive to N fertilization. 5.3. An asymptotic response curve was found in the treatments with increasing levels of R in the medium, as well as in the case of the K treatments. 5.4. Curves of response of roots (dry matter) showed a tendency to level of as a function of increasing levels of element at lower concentrations than the components aeral part of the plant (leaves, stems, ears). 5.5. Determination of leaf putrescine did not of prove a better indicator of the K status leaf K. 5.6. The variety under study seems to be relatively more efficient in the utilization of N for yield components; the efficiency for utilization of K, is rather low and that for R is intermediate, findings that should have a bearing on the fertilization in field conditions.O milho, var. Piranão, foi cultivado em solução nutritiva com níveis crescentes de N, R e K. Houve resposta linear à adição de N e assintótica às doses de R e de K. A determinação da atividade da reductase de nitrato se correlacionou melhor com a produção da matéria seca que a do N total nas folhas. O teor de potássio total nas folhas, por sua vez refletiu melhor o estado nutricional que a determinação de putrescina nas folhas

Light-based methods for predicting circadian phase in delayed sleep–wake phase disorder

Methods for predicting circadian phase have been developed for healthy individuals. It is unknown whether these methods generalize to clinical populations, such as delayed sleep-wake phase disorder (DSWPD), where circadian timing is associated with functional outcomes. This study evaluated two methods for predicting dim light melatonin onset (DLMO) in 154 DSWPD patients using ~ 7 days of sleep-wake and light data: a dynamic model and a statistical model. The dynamic model has been validated in healthy individuals under both laboratory and field conditions. The statistical model was developed for this dataset and used a multiple linear regression of light exposure during phase delay/advance portions of the phase response curve, as well as sleep timing and demographic variables. Both models performed comparably well in predicting DLMO. The dynamic model predicted DLMO with root mean square error of 68 min, with predictions accurate to within ± 1 h in 58% of participants and ± 2 h in 95%. The statistical model predicted DLMO with root mean square error of 57 min, with predictions accurate to within ± 1 h in 75% of participants and ± 2 h in 96%. We conclude that circadian phase prediction from light data is a viable technique for improving screening, diagnosis, and treatment of DSWPD.Jade M. Murray, Michelle Magee, Tracey L. Sletten, Christopher Gordon, Nicole Lovato, Krutika Ambani ... et al

A PERIOD3 variable-number-tandem-repeat polymorphism modulates melatonin treatment response in Delayed Sleep-Wake Phase Disorder

We examined whether a polymorphism of the PERIOD3 gene (PER3; rs57875989) modulated the sleep promoting effects of melatonin in Delayed Sleep-Wake Phase Disorder (DSWPD). One hundred and four individuals (53 males; 29.4±10.0 years) with DSWPD and a delayed dim light melatonin onset (DLMO) collected buccal swabs for genotyping (PER3(4/4) n=43; PER3 5 allele [heterozygous and homozygous] n=60). Participants were randomised to placebo or 0.5mg melatonin taken 1 hour before desired bedtime (or ~ 1.45 h before DLMO), with sleep attempted at desired bedtime (4 weeks; 5-7 nights/week). We assessed sleep (diary and actigraphy), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Patient-Reported Outcomes Measurement Information System (PROMIS: Sleep Disturbance, Sleep-Related Impairment), Sheehan Disability Scale (SDS), and Patient- and Clinician-Global Improvement (PGI-C, CGI-C). Melatonin treatment response on actigraphic sleep onset time did not differ between genotypes. For PER3(4/4) carriers, self-reported sleep onset time was advanced by a larger amount and sleep onset latency (SOL) was shorter in melatonin-treated patients compared to those receiving placebo (P=0.008), while actigraphic sleep efficiency in the first third of the sleep episode (SE T1) did not differ. For PER3 5 carriers, actigraphic SOL and SE T1 showed a larger improvement with melatonin (P<0.001). Melatonin improved ISI (P=0.005), PROMIS Sleep Disturbance (P<0.001) and Sleep-Related Impairment (P=0.017), SDS (P=0.019), PGI-C (P=0.028), and CGI-C (P=0.016) in PER3(4/4) individuals only. Melatonin did not advance circadian phase. Overall, PER3(4/4) DSWPD patients have a greater response to melatonin treatment. PER3 genotyping may therefore improve DSWPD patient outcomes.Michelle Magee, Tracey L. Sletten, Jade M. Murray, Christopher J. Gordon, Nicole Lovato, Delwyn J. Bartlett, David J. Kennaway, Steven W. Lockley, Leon C. Lack, Ronald R. Grunstein, Simon N. Archer, Shantha M.W. Rajaratnam, Delayed Sleep on Melatonin, DelSoM, Study Grou