When a calorie is not just a calorie : Diet quality and timing as mediators of metabolism and healthy aging

Funding Information: We thank Dr. Yih-Woei Fridell of the National Institute on Aging for organizing the meeting, as well as the NIA Division of Aging Biology for their support. We thank Dr. Gino Cortopassi for his edits and suggestions. The figures were created with BioRender.com. The Mihaylova lab is supported in part by the NIA (R00AG054760), Office of the NIH Director (DP2CA271361), the American Federation for Aging Research, the V Foundation, Pew Biomedical Scholar award, and startup funds from the Ohio State University. The Delibegovic lab is funded by the British Heart Foundation, Diabetes UK, BBSRC, NHS Grampian, Tenovus Scotland, and the Development Trust (University of Aberdeen). J.J.R. is supported by NIA PO1AG062817, R21AG064290, and R21AG071156. Research support for J.B. was from NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK127800, R01DK113011, R01DK090625, and R01DK050203 and the National Institute on Aging (NIA) grants R01AG065988 and P01AG011412, as well as the University of Chicago Diabetes Research and Training Center grant P30DK020595. This work was supported by NIH grants AG065992 to G.M. and AG068550 to G.M. and S.P. as well as UAB Startup funds 3123226 and 3123227 to G.M. R.S. is supported by NIH grants RF1AG043517, R01AG065985, R01DK123327, R56AG074568, and P01AG031782. Z.C. is primarily funded by The Welch Foundation (AU-1731-20190330) and NIH/NIA (R01AG065984, R56AG063746, RF1AG061901, and R56AG076144). A.C. is supported by NIA grant R01AG065993. W.W.J. is supported by the NIH (R01DC020031). M.S.-H. is supported by NIH R01 R35GM127049, R01 AG045842, and R21 NS122366. The research in the Dixit lab was supported in part by NIH grants AG031797, AG045712, P01AG051459, AR070811, AG076782, AG073969, and AG068863 and Cure Alzheimer's Fund (CAF). A.E.T.-M. is supported by the NIH/NIA (AG075059 and AG058630), NIAMS (AR071133), NHLBI (HL153460), pilot and feasibility funds from the NIDDK-funded UAB Nutrition Obesity Research Center (DK056336) and the NIA-funded UAB Nathan Shock Center (AG050886), and startup funds from UAB. J.A.M. is supported by the Intramural Research Program, NIA, NIH. The Panda lab is supported by the NIH (R01CA236352, R01CA258221, RF1AG068550, and P30CA014195), the Wu Tsai Human Performance Alliance, and the Joe and Clara Tsai Foundation. The Lamming lab is supported in part by the NIA (AG056771, AG062328, AG061635, and AG081482), the NIDDK (DK125859), startup funds from UW-Madison, and the U.S. Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government. D.W.L. has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. S.P. is the author of the books The Circadian Code and The Circadian Diabetes Code. Funding Information: We thank Dr. Yih-Woei Fridell of the National Institute on Aging for organizing the meeting, as well as the NIA Division of Aging Biology for their support. We thank Dr. Gino Cortopassi for his edits and suggestions. The figures were created with BioRender.com . The Mihaylova lab is supported in part by the NIA ( R00AG054760 ), Office of the NIH Director ( DP2CA271361 ), the American Federation for Aging Research , the V Foundation , Pew Biomedical Scholar award, and startup funds from the Ohio State University . The Delibegovic lab is funded by the British Heart Foundation , Diabetes UK , BBSRC , NHS Grampian , Tenovus Scotland , and the Development Trust ( University of Aberdeen ). J.J.R. is supported by NIA PO1AG062817 , R21AG064290 , and R21AG071156 . Research support for J.B. was from NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK127800 , R01DK113011 , R01DK090625 , and R01DK050203 and the National Institute on Aging (NIA) grants R01AG065988 and P01AG011412 , as well as the University of Chicago Diabetes Research and Training Center grant P30DK020595 . This work was supported by NIH grants AG065992 to G.M. and AG068550 to G.M. and S.P., as well as UAB Startup funds 3123226 and 3123227 to G.M. R.S. is supported by NIH grants RF1AG043517 , R01AG065985 , R01DK123327 , R56AG074568 , and P01AG031782 . Z.C. is primarily funded by The Welch Foundation ( AU-1731-20190330 ) and NIH/NIA ( R01AG065984 , R56AG063746 , RF1AG061901 , and R56AG076144 ). A.C. is supported by NIA grant R01AG065993 . W.W.J. is supported by the NIH ( R01DC020031 ). M.S.-H. is supported by NIH R01 R35GM127049 , R01 AG045842 , and R21 NS122366 . The research in the Dixit lab was supported in part by NIH grants AG031797 , AG045712 , P01AG051459 , AR070811 , AG076782 , AG073969 , and AG068863 and Cure Alzheimer's Fund (CAF). A.E.T.-M. is supported by the NIH/NIA ( AG075059 and AG058630 ), NIAMS ( AR071133 ), NHLBI ( HL153460 ), pilot and feasibility funds from the NIDDK -funded UAB Nutrition Obesity Research Center ( DK056336 ) and the NIA -funded UAB Nathan Shock Center ( AG050886 ), and startup funds from UAB . J.A.M. is supported by the Intramural Research Program, NIA, NIH . The Panda lab is supported by the NIH ( R01CA236352 , R01CA258221 , RF1AG068550 , and P30CA014195 ), the Wu Tsai Human Performance Alliance , and the Joe and Clara Tsai Foundation . The Lamming lab is supported in part by the NIA ( AG056771 , AG062328 , AG061635 , and AG081482 ), the NIDDK ( DK125859 ), startup funds from UW-Madison , and the U.S. Department of Veterans Affairs ( I01-BX004031 ), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government.Peer reviewedPostprin

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

2019 ESC/EAS guidelines for the management of dyslipidaemias : Lipid modification to reduce cardiovascular risk

Correction: Volume: 292 Pages: 160-162 DOI: 10.1016/j.atherosclerosis.2019.11.020 Published: JAN 2020Peer reviewe

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Mendelian randomization of blood lipids for coronary heart disease

Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10−6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.M.V.H. was funded by a UK Medical Research Council Population Health Scientist Fellowship (G0802432). F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre. D.I.S. is supported by a Medical Research Council Doctoral Training Award and a grant from the Rosetrees Foundation. ME.K. is supported by the National Institute of Aging and the National Heart, Lung and Blood Institute (HL36310). S.E.H. and P.J.T. are supported by the British Heart Foundation (BHF RG 08/008, PG/07/133/24260), UK Medical Research Council, the US National Institutes of Health (grant NHLBI 33014) and Du Pont Pharma, Wilmington, USA. N.J.S. holds a Chair funded by the British Heart Foundation and is an NIHR Senior Investigator. MI.K. is supported by the National Institute of Aging, the Medical Research Council, the British Heart Foundation, and the National Heart, Lung and Blood Institute and the Academy of Finland. A.D.H. and J.P.C. are supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre. Funding to pay the Open Access publication charges for this article was provided by RCUK

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Opportunities of information communication technologies for providing pharmaceutical care in the COVID-19 pandemic

This article discusses the opportunities of information and communication technologies for providing pharmaceutical care in the context of the COVID-19 pandemic. The global COVID-19 pandemic has necessitated a reorientation of the concept of providing health care to large-scale implementation of information technologies to improve the quality of medical and pharmaceutical services for the population. It had a significant impact on pharmacy, which necessitated changes in the management of pharmaceutical care for patients. Rapid and urgent measures were taken by the pharmacists, who found themselves at the forefront. Telepharmacy has proven to be a successful solution in the fight against the virus in the conditions of physical distance. The introduction of modern information and communication technologies worldwide will create significant advantages for more efficient use of resources and management of pharmaceutical care

Bulgarian community pharmacists’ attitudes and barriers towards pharmaceutical care provision for pregnant women

The aim of this study was to assess the attitudes and perceived barriers towards pharmaceutical care provision for pregnant women in Bulgarian community pharmacies. A cross-sectional web-based study was carried out among community pharmacists in Plovdiv region, Bulgaria. The survey instrument was a self-administered questionnaire including 18 statements based on a five-point Likert scale. Descriptive statistics were applied to respondents’ characteristics and opinion regarding attitudes and barriers towards pharmaceutical care provision for pregnant women. A total of 122 community pharmacists completed the survey. The majority of respondents (90%) agreed or strongly agreed with the statement that providing pharmaceutical care will improve health and awareness of pregnant women. The statement that providing pharmaceutical care brings professional satisfaction, obtained the highest mean score of 4.61. Half of the respondents (50.8%) were worried about taking risks associated with assuming responsibility for the treatment outcomes of pregnant women. One of the main barriers for providing pharmaceutical care was the lack of time (mean score = 4.10). Other major barriers were the lack of additional training (83.9%) and electronic medical record of the pregnant women (68.9%). Overall Bulgarian community pharmacists have positive attitudes towards providing pharmaceutical care to pregnant women. Conducting additional training courses and workshops will help for the active involvement of the pharmacist in the care of pregnant women

Bulgarian community pharmacists’ attitudes and barriers towards pharmaceutical care provision for pregnant women

The aim of this study was to assess the attitudes and perceived barriers towards pharmaceutical care provision for pregnant women in Bulgarian community pharmacies. A cross-sectional web-based study was carried out among community pharmacists in Plovdiv region, Bulgaria. The survey instrument was a self-administered questionnaire including 18 statements based on a five-point Likert scale. Descriptive statistics were applied to respondents’ characteristics and opinion regarding attitudes and barriers towards pharmaceutical care provision for pregnant women. A total of 122 community pharmacists completed the survey. The majority of respondents (90%) agreed or strongly agreed with the statement that providing pharmaceutical care will improve health and awareness of pregnant women. The statement that providing pharmaceutical care brings professional satisfaction, obtained the highest mean score of 4.61. Half of the respondents (50.8%) were worried about taking risks associated with assuming responsibility for the treatment outcomes of pregnant women. One of the main barriers for providing pharmaceutical care was the lack of time (mean score = 4.10). Other major barriers were the lack of additional training (83.9%) and electronic medical record of the pregnant women (68.9%). Overall Bulgarian community pharmacists have positive attitudes towards providing pharmaceutical care to pregnant women. Conducting additional training courses and workshops will help for the active involvement of the pharmacist in the care of pregnant women