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Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.
Ray, KK, Nicholls, SJ, Buhr, KA, Ginsberg, HN, Johansson, JO, Kalantar-Zadeh, K, Kulikowski, E, Toth, PP, Wong, N, Sweeney, M, et al
JAMA. 2020;(16):1565-1573
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IMPORTANCE Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes. OBJECTIVE To test whether apabetalone significantly reduces major adverse cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019. INTERVENTIONS Patients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care. MAIN OUTCOMES AND MEASURES The primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke. RESULTS Among 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]). CONCLUSIONS AND RELEVANCE Among patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02586155.
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Association of HTRA1 and ARMS2 gene polymorphisms with response to intravitreal ranibizumab among neovascular age-related macular degenerative subjects.
Mohamad, NA, Ramachandran, V, Mohd Isa, H, Chan, YM, Ngah, NF, Ching, SM, Hoo, FK, Wan Sulaiman, WA, Inche Mat, LN, Mohamed, MH
Human genomics. 2019;(1):13
Abstract
BACKGROUND The association of HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms with response to intravitreal ranibizumab therapy among neovascular AMD (nAMD) subjects in Malaysia was determined in this study, followed by the expression of HTRA1 and ARMS2 genes. RESULTS Both single nucleotide polymorphisms (SNPs) recorded a significant association between nAMD and controls with HTRA1 rs11200638 at P = 0.018 (OR = 1.52, 95% CI = 1.07-215) and ARMS2 rs10490924 at P < 0.001 (OR = 2.44, 95% CI = 1.75-3.42). An association was also observed in response to ranibizumab for both SNPs in a logistic regression analysis (P < 0.001). The mRNA levels in the HTRA1 variant between responder and non-responder groups were significantly different for the homozygous non-risk GG genotype (P = 0.032). CONCLUSIONS The HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms are associated with nAMD among Malaysians. Both gene polymorphisms were also correlated with response to intravitreal ranibizumab therapy based on visual and anatomical outcomes especially the HTRA1 rs11200638 variant.
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Effect of selective BET protein inhibitor apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: Rationale, design, and baseline characteristics of the BETonMACE trial.
Ray, KK, Nicholls, SJ, Ginsberg, HD, Johansson, JO, Kalantar-Zadeh, K, Kulikowski, E, Toth, PP, Wong, N, Cummings, JL, Sweeney, M, et al
American heart journal. 2019;:72-83
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Abstract
After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. DESIGN Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. SUMMARY BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.
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A study protocol of Older Person's Exercise and Nutrition Study (OPEN) - a sit-to-stand activity combined with oral protein supplement - effects on physical function and independence: a cluster randomized clinical trial.
Grönstedt, H, Vikström, S, Cederholm, T, Franzén, E, Seiger, Å, Wimo, A, Faxén-Irving, G, Boström, AM
BMC geriatrics. 2018;(1):138
Abstract
BACKGROUND Poor nutrition and age per see add to the development of sarcopenia, i.e. loss of muscle mass and strength, which contributes to increased risk of impaired activities of daily living (ADL) and reduced independence. Protein deficiency plays an important role in the development of sarcopenia. In order to increase the muscle mass protein intake should be combined with physical exercise. A daily physical activity, the sit-to-stand exercise, has been proven to decrease older persons' dependence in ADL. Our study aims to evaluate the effects of the sit-to-stand exercise in combination with a protein-rich nutritional supplement, on physical function and independence in frail nursing home residents. The resident's perceptions and experiences of the intervention and the staff's experiences of supporting the resident to complete the intervention will also be explored. METHODS The study is a two-arm cluster-randomized controlled trial which will be performed in nursing homes at two municipalities in Sweden. We will recruit 120 residents, age 75 or older and able to stand up from a seated position. Residents (n = 60) randomized to the intervention group will perform the sit-to-stand exercise at four occasions daily and will be offered a protein-rich oral supplement, twice a day. The intervention period will last for 12 weeks and measures of physical function, nutritional status, quality of life and health economy will be performed at baseline and at 12-weeks follow-up. The primary outcome will be the number of chair rises performed in 30 s. The control group will receive standard care. Data will be analysed by intention-to-treat analysis and with mixed effect models. During the last part of the intervention period individual interviews with the residents, on the topic of feasibility with the OPEN concept will be held. Likewise, focus-group-interviews with staff will be performed. DISCUSSION The residents' physical and mental health could be expected to improve. Even the work situation for staff could be positively affected. One innovative feature of the OPEN study is the simple intervention consisting of a basic daily activity that can be performed by several nursing home residents with the support of existing staff and available resources. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02702037.
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The effects of angiotensin receptor neprilysin inhibition by sacubitril/valsartan on adipose tissue transcriptome and protein expression in obese hypertensive patients.
Stinkens, R, van der Kolk, BW, Jordan, J, Jax, T, Engeli, S, Heise, T, Jocken, JW, May, M, Schindler, C, Havekes, B, et al
Scientific reports. 2018;(1):3933
Abstract
Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (Ptime*group = 0.195), hormone-sensitive lipase (HSL) (Ptime*group = 0.458), HSL-ser660 phosphorylation (Ptime*group = 0.340), NP receptor-A (NPRA) (Ptime*group = 0.829) and OXPHOS complexes (Ptime*group = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients.
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Energy and Protein in Critically Ill Patients with AKI: A Prospective, Multicenter Observational Study Using Indirect Calorimetry and Protein Catabolic Rate.
Sabatino, A, Theilla, M, Hellerman, M, Singer, P, Maggiore, U, Barbagallo, M, Regolisti, G, Fiaccadori, E
Nutrients. 2017;(8)
Abstract
The optimal nutritional support in Acute Kidney Injury (AKI) still remains an open issue. The present study was aimed at evaluating the validity of conventional predictive formulas for the calculation of both energy expenditure and protein needs in critically ill patients with AKI. A prospective, multicenter, observational study was conducted on adult patients hospitalized with AKI in three different intensive care units (ICU). Nutrient needs were estimated by different methods: the Guidelines of the European Society of Parenteral and Enteral Nutrition (ESPEN) for both calories and proteins, the Harris-Benedict equation, the Penn-State and Faisy-Fagon equations for energy. Actual energy and protein needs were repeatedly measured by indirect calorimetry (IC) and protein catabolic rate (PCR) until oral nutrition start, hospital discharge or renal function recovery. Forty-two patients with AKI were enrolled, with 130 IC and 123 PCR measurements obtained over 654 days of artificial nutrition. No predictive formula was precise enough, and Bland-Altman plots wide limits of agreement for all equations highlight the potential to under- or overfeed individual patients. Conventional predictive formulas may frequently lead to incorrect energy and protein need estimation. In critically ill patients with AKI an increased risk for under- or overfeeding is likely when nutrient needs are estimated instead of measured.
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Validation of a Novel Biomarker Panel for the Detection of Ovarian Cancer.
Leung, F, Bernardini, MQ, Brown, MD, Zheng, Y, Molina, R, Bast, RC, Davis, G, Serra, S, Diamandis, EP, Kulasingam, V
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2016;(9):1333-40
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BACKGROUND Ovarian cancer is the most lethal gynecological malignancy. Our integrated -omics approach to ovarian cancer biomarker discovery has identified kallikrein 6 (KLK6) and folate-receptor 1 (FOLR1) as promising candidates but these markers require further validation. METHODS KLK6, FOLR1, CA125, and HE4 were investigated in three independent serum cohorts with a total of 20 healthy controls, 150 benign controls, and 216 ovarian cancer patients. The serum biomarker levels were determined by ELISA or automated immunoassay. RESULTS All biomarkers demonstrated elevations in the sera of ovarian cancer patients compared with controls (P < 0.01). Overall, CA125 and HE4 displayed the strongest ability (AUC 0.80 and 0.82, respectively) to identify ovarian cancer patients and the addition of HE4 to CA125 improved the sensitivity from 36% to 67% at a set specificity of 95%. In addition, the combination of HE4 and FOLR1 was a strong predictor of ovarian cancer diagnosis, displaying comparable sensitivity (65%) to the best-performing CA125-based models (67%) at a set specificity of 95%. CONCLUSIONS The markers identified through our integrated -omics approach performed similarly to the clinically approved markers CA125 and HE4. Furthermore, HE4 represents a powerful diagnostic marker for ovarian cancer and should be used more routinely in a clinical setting. IMPACT The implications of our study are 2-fold: (i) we have demonstrated the strengths of HE4 alone and in combination with CA125, lending credence to increasing its usage in the clinic; and (ii) we have demonstrated the clinical utility of our integrated -omics approach to identifying novel serum markers with comparable performance to clinical markers. Cancer Epidemiol Biomarkers Prev; 25(9); 1333-40. ©2016 AACR.
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FTO gene: association to weight regain after lifestyle intervention in overweight children.
Reinehr, T, Wolters, B, Roth, CL, Hinney, A
Hormone research in paediatrics. 2014;(6):391-6
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OBJECTIVE Polymorphisms in intron 1 of the 'fat mass and obesity-associated' (FTO) gene are associated with weight status. We hypothesized that the risk allele at a polymorphism in intron 1 of FTO is associated with weight regain after end of lifestyle intervention. METHODS We longitudinally analyzed the changes of weight status as BMI-SDS in 346 unrelated overweight children (mean age 10.6 ± 2.6 years, 45% male, mean BMI-SDS 2.39 ± 0.49) both at the end of a 1-year lifestyle intervention and 1 year after the end of this intervention. We genotyped the obesity risk SNP rs9939609 at FTO by ARMS-PCR. RESULTS The children reduced their BMI-SDS (-0.29 ± 0.33; p < 0.001) during intervention and increased their BMI-SDS between the end of intervention and 1 year later (+0.10 ± 0.41; p < 0.001). The obesity risk allele at FTO SNP rs9939609 was not associated with BMI-SDS reduction during the lifestyle intervention (p = 0.622), but with weight regain 1 year after end of the intervention in multiple linear regression analyses adjusted for age, sex, pubertal stage, and baseline BMI-SDS (Bonferroni corrected p = 0.002). CONCLUSIONS The obesity risk allele at a polymorphism in intron 1 of FTO was associated with weight regain 1 year after a 1-year lifestyle intervention.
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Daily protein intake and patient outcomes in severe acute kidney injury: findings of the randomized evaluation of normal versus augmented level of replacement therapy (RENAL) trial.
Bellomo, R, Cass, A, Cole, L, Finfer, S, Gallagher, M, Lee, J, Lo, S, McArthur, C, McGuinness, S, Norton, R, et al
Blood purification. 2014;(4):325-34
Abstract
BACKGROUND AND AIMS We aimed to examine the association between daily protein intake (DPI) and outcomes in patients from the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial. METHODS We analyzed the association between DPI and clinical outcomes using multivariable logistic regression, Cox proportional hazards models and time-adjusted analysis. RESULTS During ICU stay, mean DPI was 37.6 g/day among survivors and 37.7 g/day among nonsurvivors (p = 0.96; DPI of 0.5 g/kg/day). Only 159 (10.9%) of the patients received a mean DPI of >1 g/kg. Patients with a DPI above the median had a 43.1% mortality compared with 46.1% for a DPI below the median (p = 0.25). On multivariate analysis, a lower DPI was not associated with increased odds ratios for 90-day mortality or any secondary outcomes. Cox proportional hazards models and time-adjusted analysis confirmed these findings. CONCLUSIONS In the RENAL study, mean DPI was low. Within the confines of such low DPI, greater amounts of DPI were not independently associated with improved clinical outcomes. Video Journal Club "Cappuccino with Claudio Ronco" at www.karger.com/?doi=363175.
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No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38.
Chew, EY, Klein, ML, Clemons, TE, Agrón, E, Ratnapriya, R, Edwards, AO, Fritsche, LG, Swaroop, A, Abecasis, GR, ,
Ophthalmology. 2014;(11):2173-80
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OBJECTIVE To determine whether genotypes at 2 major loci associated with late age-related macular degeneration (AMD), complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), influence the relative benefits of Age-Related Eye Disease Study (AREDS) supplements. DESIGN Unplanned retrospective evaluation of a prospective, randomized, placebo-controlled clinical trial of vitamins and minerals for the treatment of AMD. SUBJECTS AREDS participants (mean age, 69 years) who were at risk of developing late AMD and who were randomized to the 4 arms of AREDS supplement treatment. METHODS Analyses were performed using the Cox proportional hazards model to predict progression to late AMD (neovascular or central geographic atrophy). Statistical models, adjusted for age, gender, smoking status, and baseline AMD severity, were used to examine the influence of genotypes on the response to therapy with 4 randomly assigned arms of AREDS supplement components: placebo, antioxidants (vitamin C, vitamin E, β-carotene), zinc, or a combination. MAIN OUTCOME MEASURES The influence of the genotype on the relative treatment response to the randomized components of the AREDS supplement, measured as progression to late AMD. RESULTS Of the 1237 genotyped AREDS participants of white ethnicity, late AMD developed in 385 (31.1%) during the mean follow-up of 6.6 years. As previously demonstrated, CFH genotype (P = 0.005), ARMS2 (P< 0.0001), and supplement were associated individually with progression to late AMD. An interaction analysis found no evidence that the relative benefits of AREDS supplementation varied by genotype. Analysis of (1) CFH rs1061170 and rs1410996 combined with ARMS2 rs10490924 with the 4 randomly assigned arms of AREDS supplement and (2) analysis of the combination of CFH rs412852 and rs3766405 with ARMS2 c.372_815del443ins54 with the AREDS components resulted in no interaction (P = 0.06 and P = 0.45, respectively, before multiplicity adjustment). CONCLUSIONS The AREDS supplements reduced the rate of AMD progression across all genotype groups. Furthermore, the genotypes at the CFH and ARMS2 loci did not statistically significantly alter the benefits of AREDS supplements. Genetic testing remains a valuable research tool, but these analyses suggest it provides no benefits in managing nutritional supplementation for patients at risk of late AMD.