Intensive Lowering Research Articles

Short-term effects of intensive LDL-cholesterol lowering with alirocumab on vascular structure and function

Short-term effects of intensive LDL-cholesterol lowering with alirocumab on vascular structure and function

Hidrox® and Chronic Cystitis: Biochemical Evaluation of Inflammation, Oxidative Stress, and Pain.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder condition characterized by frequent urination, inflammation, oxidative stress, and pain. The aim of the study was to evaluate the anti-inflammatory and antioxidant effects of an oral administration of Hidrox® (10 mg/kg) in the bladder and spinal cord in a rodent model of IC/BPS. The chronic animal model of cystitis was induced by repeated intraperitoneal injections of cyclophosphamide (CYP) for five consecutive days. Treatment with Hidrox® began on the third day of the CYP injection and continued until the 10th day. CYP administration caused macroscopic and histological bladder changes, inflammatory infiltrates, increased mast cell numbers, oxidative stress, decreased expression of the tight endothelial junction (e.g., zonula occludens-1 (ZO-1) and occludin), and bladder pain. Treatment with Hidrox® was able to improve CYP-induced inflammation and oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. It was also able to reduce bladder pain which was aggravated by the activation of neuroinflammation in the central nervous system. In particular, Hidrox® reduced the brain-derived neurotrophic factor (BDNF), as well as the activation of astrocytes and microglia, consequently reducing mechanical allodynia. These results indicate that nutritional consumption of Hidrox® can be considered as a new therapeutic approach for human cystitis, increasing the conceivable potential of a significant improvement in the quality of life associated with a lowering of symptom intensity in patients with IC/BPS.

19-LB: Statin Use as a Primary Prevention in Patients with Type 1 Diabetes: Where Do We Stand?

Type 1 diabetes (T1D) carries a high cardiovascular risk (CVD). Statins reduce risk of non-fatal myocardial infarction when used as primary prevention in selected patients[1]. We reviewed 205 electronic records of patients with T1D at our center from July 2019 to September 2019. We followed 2018 NICE guidelines for statin use as a primary prevention for our analysis (1)age ≥40 years (2)diabetes duration ≥10 years (3)established nephropathy (4)established other CVD risks. Our cohort consisted of 119 males (58%) with a mean BMI of 25.5±4.4 kg/m2 and mean age of 43±16 years. The median duration of diabetes was 16 [IQR 8 - 27] years. More than 50% of our patients had attended “Dose Adjustment For Normal Eating, DAFNE” course. Approximately 71% had T1D for ≥10 years and 56% were ≥40 years. Mean systolic and diastolic blood pressures were 128 (±15.3) mmHg and 77 (±10) mmHg, respectively. Mean LDL was 2.4 (±0.74) mmol/L. In total 24.8% were on statin therapy, 2.4% on fibrates and 4.4% declined statin. Of the patients reviewed, 180 (87.8%) met the criteria for primary prevention; however, of those 51/180 (28.3%) were on statin, 44/146 (30.1%) with diabetes ≥10 years, 46/115 (40.0%) ≥40, 34/93 (36.6%) with established retinopathy. Regarding macro and microvascular complications, 3.4% had CAD, 6.8% chronic kidney disease (eGFR<60) and 47.8% retinopathy. Patients with T1D have higher CVD risk, for which statin therapy is advised[2, 3]. Our patients are undertreated with statins as primary prevention.

Novel Therapeutical Approaches to Managing Atherosclerotic Risk.

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem.

Blood pressure reduction and anti-hypertensive treatment choice: A post-hoc analysis of the SPRINT trial.

BackgroundUncontrolled blood pressure (BP) increases the risk of major adverse cardiovascular events. In SPRINT an intensive versus standard BP lowering strategy resulted in a lower rate of cardiovascular events and death. Whether BP reduction only or also the choice of anti‐hypertensive drugs is associated with outcomes remains to be elucidated.AimsWe aim to study the association of BP and different anti‐hypertensive drugs with several cardiovascular outcomes.MethodsTime‐updated Cox and mixed‐effects models. The primary outcome was a composite of first myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death.ResultsA total of 9361 patients were included. The anti‐hypertensive agents most frequently used were ACEi/ARBs, with an almost 20% higher prescription rate in the intensive arm (80% vs. 61%), followed by thiazide‐type diuretics (65% vs. 42%), calcium‐channel blockers (57% vs. 39%), and beta‐blockers (52% vs. 26%). Mineralocorticoid receptor antagonists were rarely used (≤7% of the observations). In multivariate analysis, the use of ACEi/ARBs, especially in combination with thiazides, were independently associated with a lower primary outcome event‐rate (HR [95%CI] 0.75 [0.61–0.92], p = .006), whereas a DBP <60 mmHg was independently associated with a higher event‐rate (HR [95%CI] 1.36 [1.07–1.71], p = .011). SBP <120 mmHg was associated with lower rate of cardiovascular and all‐cause death on intensive treatment but not on the standard arm (interaction p < .05 for both).ConclusionsIn SPRINT, an intensive therapy strategy achieving SBP <120 mmHg with a DBP ≥60 mmHg, and using ACEi/ARBs plus thiazides was associated with a lower event‐rate.

A Compendium on Hypertension: New Advances and Future Impact.

A Compendium on Hypertension: New Advances and Future Impact.

INFLUENCE OF RESTING HEART RATE ON BLOOD PRESSURE LOWERING EFFECT

Objective: Elevated resting heart rate (RHR) identifies hypertensive subjects at higher cardiovascular risk. The study was aimed to compare benefit of intensive blood pressure (BP) lowering in subjects with higher and lower RHR. Design and method: The analysis was performed using Systolic Blood Pressure Intervention Trial (SPRINT) data shared by National Heart, Lung and Blood Institute. SPRINT trial assessed intensive lowering of systolic BP to a target &lt; 120 mm Hg in comparison to standard goal (&lt; 140 mm Hg). Baseline RHR was estimated as a pulse rate obtained during automated office BP measurements at first study visit. RHR higher than 80 b.p.m. was defined as increased according to current European Society of Cardiology guidelines. Composite outcome event (CE) included myocardial infarction and other acute coronary syndrome, stroke, heart failure decompensation and cardiovascular death. Cox proportional model was used to assess impact of BP lowering in subjects with RHR higher and lower than 80 bpm. P-value for interaction between study BP intervention and baseline RHR. Results: Data of 9361 SPRINT participants, aged 67.9 ± 9.4 years, were analyzed. 3332 (35.6%) were female an 1877 (20.1%) were diagnosed with prior cardiovascular disease. Mean baseline RHR was 66.3 ± 11.6 b.p.m. Baseline HR in both treatment arms was similar (standard arm 66.3 ± 11.7 b.p.m. vs intensive arm 66.2 ± 11.5 b.p.m., p = 0.762) 1198 (12.8%) participants had baseline RHR higher than 80 b.p.m. and experienced 78 (6.8%) CE events. There were 484 (5.9%) events among subjects with RHR lower than 80 b.p.m. Intensive lowering of systolic BP was beneficial both in subjects with elevated RHR (hazard ratio 0.79 with 95% confidence interval 0.51–1.24, p = 0.311) and non-elevated RHR (hazard ratio 0.75 with 95% CI 0.62–0.89, p = 0.002). The intervention between study BP intervention and baseline RHR was not significant (p for interaction 0.819). Conclusions: Elevated RHR does not influence effect of BP reduction on cardiovascular events risk.

Novel high-intensive cholesterol-lowering therapies do not ameliorate knee OA development in humanized dyslipidemic mice

High systemic cholesterol levels have been associated with osteoarthritis (OA) development. Therefore, cholesterol lowering by statins has been suggested as a potential treatment for OA. We investigated whether therapeutic high-intensive cholesterol-lowering attenuated OA development in dyslipidemic APOE∗3Leiden.CETP mice. Female mice (n=13-16 per group) were fed a Western-type diet (WTD) for 38 weeks. After 13 weeks, mice were divided into a baseline group and five groups receiving WTD alone or with treatment: atorvastatin alone, combined with PCSK9 inhibitor alirocumab and/or ANGPTL3 inhibitor evinacumab. Knee joints were analysed for cartilage degradation, synovial inflammation and ectopic bone formation using histology. Aggrecanase activity in articular cartilage and synovial S100A8 expression were determined as markers of cartilage degradation/regeneration and inflammation. Cartilage degradation and active repair were significantly increased in WTD-fed mice, but cholesterol-lowering strategies did not ameliorate cartilage destruction. This was supported by comparable aggrecanase activity and S100A8 expression in all treatment groups. Ectopic bone formation was comparable between groups and independent of cholesterol levels. Intensive therapeutic cholesterol lowering per se did not attenuate progression of cartilage degradation in dyslipidemic APOE∗3Leiden.CETP mice, with minor joint inflammation. We propose that inflammation is a key feature in the disease and therapeutic cholesterol-lowering strategies may still be promising for OA patients presenting both dyslipidemia and inflammation.

The comparative effects of intensive glucose lowering in diabetes patients aged below or above 65 years: Results from the ADVANCE trial.

For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (<65 and ≥ 65 years), and examine whether the effects differ according to patients' characteristics in the older patient group. The effects of intensive glucose lowering (to a target glycated haemoglobin [HbA1c] concentration of ≤48 mmol/mol [6.5%]) on major clinical outcomes were evaluated by Cox regression models according to subgroups defined by baseline age of <65 or ≥ 65 years in the ADVANCE trial (n = 11 140). Over a median follow-up of 5 years, intensive glucose lowering significantly decreased the risk of the composite of major macrovascular and microvascular events (hazard ratio 0.90, 95% confidence interval 0.82-0.98), with no heterogeneity in the effects across age subgroups (p for heterogeneity = 0.44). Relative effects on all-cause death, cardiovascular death, and components of major vascular events were also similar (P for heterogeneity ≥0.06), except for severe hypoglycaemia, which was of greater risk for patients aged <65 years. Absolute benefits and harms were broadly consistent across subgroups. Among patients aged ≥65 years, randomized treatment effects did not differ significantly across different levels of cognitive function or coexisting chronic illnesses. Our results suggest that an intensive glycaemic control strategy to reduce HbA1c to 48 mmol/mol (6.5%) provided broadly similar benefits and harms and may be recommended for older, as well as younger, patients.

Association Between BMI and Cardiovascular Benefits After More Intensive LDL-C Lowering Strategy: A Systematic Review and Meta-Analysis

Objective: To assess the influencing factors, especially BMI level contributing to the cardiovascular benefits of more intensive LDL-C lowering strategy. Methods: We systematically searched MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials and Embase for randomized controlled trials of statins, ezetimibe, proprotein convertase subtilisin-kexin type 9 inhibitors, ATP Citrate Lyase inhibitors published before April, 2021. Results: A total of 263787 participants from 33 trials were included. BMI level, baseline LDL-C level and type of lipid-lowering agents are the main factors affecting the cardiovascular benefits from more intensive LDL-C lowering strategies. Among them, the influence of BMI is more prominent. Each 1kg/m2 increase in BMI level reduced the benefit of cardiovascular mortality by 8% (RR 1.08, 95% CI 1.03-1.13), and this effect still exists when only statins are used as the LDL-C lowering strategy. The same trend was also found in myocardial infarction (RR 1.06, 95% CI 1.01-1.11) and revascularization events (RR 1.06, 95% CI 1.02-1.10) by 6%, respectively. Compared to 44% reduction of cardiovascular mortality when the BMI level was less than 25kg/m2 (RR 0.56, 95%CI 0.36-0.86), the reduction gradually vanished as the BMI increased, no benefit of cardiovascular mortality was found when the BMI was higher than 28kg/m2, this cut point is 29kg/m2 in myocardial infarction and 30kg/m2 in revascularization events. Conclusions: With the increase of BMI level, some cardiovascular benefits of intensive LDL-C lowering strategy gradually vanished. Funding Information: This work was partially supported by the National Natural Science Foundation of China (No. 81570732, Shaohua Wang and No. 81870568, Shaohua Wang). Declaration of Interests: The authors declare that they have no competing interests.

Impact of Age, Frailty, and Dementia on Prescribing for Type 2 Diabetes at Hospital Discharge 2012-2016

The risks of intensive blood glucose lowering may outweigh the benefits in vulnerable older people. Our primary aim was to determine whether age, frailty, or dementia predict discharge treatment types for patients with type 2 diabetes (T2D) and related complications. Secondly, we aimed to determine the association between prior hypoglycemia and discharge treatment types. We conducted a cohort study involving 3,067 patients aged 65-99 years with T2D and related complications, discharged from Melbourne's Eastern Health Hospital Network between 2012 and 2016. Multinomial logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CI) for the association between age, frailty, dementia and hypoglycemia, and being prescribed insulin-only, non-insulin glucose-lowering drugs (GLDs) or combined insulin and non-insulin GLDs compared to no GLD. International Classification of Diseases-10 codes were used to identify dementia status and prior hypoglycemia; frailty was quantified using the Hospital Frailty Risk Score. Insulin-only, non-insulin GLDs, combined insulin and non-insulin GLDs, and no GLDs were prescribed to 19%, 39%, 20%, and 23% of patients, respectively. Patients >80 years were less likely than patients aged 65-80 to be prescribed any of the GLD therapies, (eg. non-insulin GLDs [OR 0.67; 95%CI 0.55-0.82]), compared to no GLD. Similarly, high vs. low frailty scores were associated with not being prescribed any of the three GLD therapies, (eg. non-insulin GLDs [OR 0.63; 95%CI 0.45-0.87]). However, dementia was not associated with discharge prescribing of GLD therapies. Patients with a hypoglycemia-related admission were more likely than those not hospitalized with hypoglycemia to receive insulin-only (OR 4.28; 95%CI 2.89-6.31). Clinicians consider age and frailty when tailoring diabetes treatment regimens for patients discharged from hospital with T2D and related complications. There is scope to optimize prescribing for patients with dementia and for those admitted with hypoglycemia.

Роль статинотерапии в профилактике сердечно-сосудистых заболеваний в реальной клинической практике

Objective: To discuss the role of statins, also as a part of a combined lipid-lowering therapy, in reduction of the risk of atherosclerosis and associated cardiovascular diseases and complications. Key Points. Main risk factors of atherosclerosis and associated cardiovascular diseases (CVDs) are arterial hypertension, hypercholesterolemia, diabetes mellitus, etc. Prevention of cardiovascular events by modifying cardiovascular risk factors is a focal point in the recent new recommendations developed by the European Society of Cardiology for prevention of CVDs in real clinical practice. Statin-based lipid-lowering therapy with mandatory addition of Ezetemibe and proprotein convertase subtilisin/kexin type 9 inhibitors, where needed, is one of the most efficient and safe approaches both in primary and secondary prevention. Conclusion. Early statins initiation and more intense LDL cholesterol lowering depending on the cardiovascular risk severity allow not only preventing cardiovascular complications, but also increasing life expectancy. Keywords: cardiovascular diseases, LDL cholesterol, atherosclerosis, statins, Rosuvastatin, prevention of cardiovascular complications.

TRADE LIBERALIZATION, ENERGY‐SAVING TECHNOLOGICAL CHANGE AND ENERGY INTENSITY: SOME EMPIRICAL EVIDENCE FROM CHINA

This paper discusses the transmission mechanism and effects that trade liberalization influences energy intensity through energy‐saving technological change (ESTC). We construct panel data from manufacturing industries in China over the period of 1994–2017, thereby conducting empirical tests through mediation models and discontinuity regression models. The results find that trade liberalization significantly promotes the lowering of energy intensity through ESTC. Heterogeneity test results show that the trade liberalization effect is higher in industries with low barriers to entry and industries with high pollution. Fuzzy regression discontinuity (FRD) results show that energy intensity decreasing as China's accession to the World Trade Organization (WTO). (JEL F10, F18, L60, Q43)

Abstract 15575: The Clonal Hematopoiesis Mutation Jak2 V617F Aggravates NETosis and Endothelial Injury in Mouse Arteries With Erosion-like Intimas

Introduction: In the current era of intense LDL lowering, superficial erosion may be on the rise as a cause of ACS (25-30%). Experimental data on human atheromata support a role for neutrophils and the formation of neutrophil extracellular traps (NETs) in the pathogenesis of superficial erosion and subsequent thrombosis. The common mutation of Janus kinase 2 ( Jak2 V617F ) borne by clones of leukocytes derived from bone marrow stem cells sensitizes neutrophils to undergo NETosis and linked NET formation to increased thrombosis. Jak2 V617F associates with accelerated atherosclerosis and venous thrombosis in patients with myeloproliferative neoplasms (MPN) and in individuals harboring this mutation but without a demonstrable MPN. Hypothesis We hypothesized that i) the Jak2 V617F associated with clonal hematopoiesis and increased atherosclerotic and thrombotic risk in humans, predisposes to NETosis and subsequent endothelial injury and thrombosis at sites of flow disturbance in arteries with erosion-like intimas; and ii) the clinically approved Jak-1,2 inhibitor, ruxolitinib (Rux), can preserve endothelial integrity and reduce thrombosis in mice with myeloid Jak2 V617F . Methods: We generated cohorts of mice harboring Jak2 V617F or wild-type Jak2 . We used a surgical preparation recapitulating features of superficial erosion and assessed endothelial integrity, thrombosis, and NET formation in relation to genotype and in vivo Rux treatment. Results and Conclusions: Evans blue extravasation following introduction of flow disturbance at sites of erosion-prone intimas showed significant impairment of endothelial barrier in the group of mice bearing the Jak2 V617F mutation compared to control (WT) mice ( ** p&lt;0.005). We further observed more thrombosis in mice bearing the Jak2 V617F mutation. Immunohistochemical evaluation of the regions of experimental superficial erosion revealed reduced endothelial continuity and increased NET accumulation in Jak2 V617F vs. WT mice. Rux treatment mitigated the adverse effects of Jak2 V617F on both NET accumulation and endothelial integrity, supporting the translational potential of these observations in individuals with clonal hematopoiesis due to Jak2 V617F and acute coronary syndromes.

Heart failure events in a clinical trial of arterial hypertension. The acquittal of the SPRINT trial

Abstract Introduction The Systolic Blood Pressure Intervention Trial (SPRINT) was a randomized trial showing that intensive lowering of systolic blood pressure (BP), as compared to standard treatment (i.e. &amp;lt;120 vs &amp;lt;140 mm Hg) was associated with a reduced risk (HR 0.75 [95% CI 0.64–0.79], p&amp;lt;0.001) for the primary composite outcome (CE), defined as myocardial infarction, an acute coronary syndrome other than myocardial infarction, stroke, acute exacerbation of heart failure and cardiovascular death. primary outcome event in subjects at high cardiovascular risk. However, the primary endpoint events in the intensive treatment arm were only 76 fewer than in the standard treatment arm (243 vs 319 events), and he reduction in heart failure events was responsible for half of the effect (62 vs 100 events, i.e. 38 events fewer). Thus, several experts in hypertension argued that these results were mainly driven by a reduction of heart failure events, and questioned the main conclusion of the study. Aim To assess the effect of SPRINT intervention on a redefined CE: the primary SPRINT endpoint with HF events excluded. Material and methods We used limited SPRINT data, available from the NHLBI Biologic Specimen and Data Repository to assess the impact of BP intervention in SPRINT on a redefined CE excluding HF events. The Chi-square test, Cox proportional model and survival analysis were applied. Results Among 9361 SPRINT participants (mean age 67.9±9.5 years, 35.6% female, 20% with previous cardiovascular disease), there was 461 CE events. There were fewer CE events in the intensive treatment arm than in the standard treatment arm (204 [4.4%] vs 257 [5.5%], p=0.0117, respectively). Intensive systolic BP lowering was associated with lower risk for CE than standard treatment (HR 0.79 [95% CI 0.66–0.95], p=0.0115). Kaplan-Meier curves show that intensive treatment was associated with better outcome (Figure 1). Analyses in subgroups (age &amp;gt;75 vs &amp;lt;75 years, female vs male, black vs non-black, prior cardiovascular disease vs no cardiovascular disease, prior chronic kidney disease vs no chronic kidney disease) showed no difference in benefit of intensive treatment (p for interaction &amp;gt;0.05 in all subgroup). Conclusion The reduction in cardiovascular events by intensive BP lowering in SPRINT was not explained by a difference in heart failure events. This supports the concept that more intensive BP reduction may provide benefit in reducing cardiovascular event risk. Figure 1. Kaplan-Meier curves Funding Acknowledgement Type of funding source: None

The impact of resting heart rate measured on cardiovascular events in subject with hypertension

Abstract Background Available evidence does not indicate whether resting heart rate (RHR) is an independent risk factor or just marker of elevated risk. None of the studies assessed impact of RHR on cardiovascular events, when RHR was measured using automated blood pressure measurements (AOBPM). Purpose To assess the relationship between RHR (measured using AOBPM) and cardiovascular events risk in subjects with hypertension. Methods The data of SPRINT trial obtained via NHLBI were used to perform the analysis. SPRINT trial assessed intensive lowering of systolic BP to a target &amp;lt;120 mm Hg in comparison to standard goal (&amp;lt;140 mm Hg). RHR was measured using AOBPM device and calculated as an average of 3 measurements during the baseline visit of the study. Clinical composite endpoint (CE) of the study was defined as: myocardial infarction, acute coronary syndrome, decompensation of heart failure, stroke or cardiovascular death. The relationship between RHR and CE was assessed according to presence of cardiovascular disease (CVD) in past medical history. The statistical methods included t-test and chi-square test, Cox proportional risk models. The Cox models were adjusted for adjusted for age, sex, current smoking status and mean SBP during the trial. Restricted cubic splines were used to describe the relationship between RHR and hazard ratio. Results Data of 1877 participants with CVD and 7484 participants without CVD were analyzed. Subjects with cardiovascular disease were older (69.7±9.5 vs 67.5 years ± 9.4, p&amp;lt;0.001), more often were men (72.8% vs 62.3%, p&amp;lt;0.001) and had prior chronic kidney disease (34.3% vs 26.8%, p&amp;lt;0.001) than subjects without CVD. CE was more than twice often when CVD was present (10.9% vs 4.8%, p&amp;lt;0.001). RHR was lower in subjects with CVD disease than in subjects without CVD (63.6±11 vs 66.9±11.6 bpm, p=0&amp;lt;00.1). Elevated RHR was associated with increased risk both in subjects with and without CVD (Figure 1). The multivariable Cox proportional hazard risk model revealed that RHR&amp;gt;80 bpm is an independent risk factor for CE in subjects without CVD (hazard ratio 1.37, 95% CI 1.01–1.85, p=0.043) while not in subjects with CVD (hazard ratio 0.99, 95% CI 0.57–1.71, p=0.98). Conclusion Elevated RHR (&amp;gt;80 bpm) measured using AOBPM is an independent risk factor for cardiovascular events in subjects with hypertension and without CVD. Figure 1. Heart ratio vs hazard ratio. Funding Acknowledgement Type of funding source: None

Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial

Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks:-38.6% (90% CI,-60.9% to-3.6%),-39.4% (90% CI,-61.8% to-3.8%), and-49.3% (90% CI,-68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. This study was supported by AstraZeneca. Registered at ClinicalTrials.gov with study number NCT03118739.

Effects of intensive versus standard blood pressure control on domain-specific cognitive function: a substudy of the SPRINT randomised controlled trial

Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov, NCT01206062. From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7-5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of -0·005 (95% CI -0·010 to 0·001) in the intensive treatment group and -0·001 (-0·006 to 0·005) in the standard treatment group (between-group difference -0·004, 95% CI -0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference -0·010, 95% CI -0·017 to -0·002; p=0·02), with an annual decline of -0·025 (-0·030 to -0·019) for the intensive treatment group and -0·015 (-0·021 to 0·009) for the standard treatment group. Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.

Nonadiabatic effects in the double ionization of atoms driven by a circularly polarized laser pulse.

We study the double ionization of atoms subjected to circularly polarized (CP) laser pulses. We analyze two fundamental ionization processes: the sequential (SDI) and nonsequential (NSDI) double ionization in the light of the rotating frame (RF) which naturally embeds nonadiabatic effects in CP pulses. We use and compare two adiabatic approximations: The adiabatic approximation in the laboratory frame (LF) and the adiabatic approximation in the RF. The adiabatic approximation in the RF encapsulates the energy variations of the electrons on subcycle timescales happening in the LF and this, by fully taking into account the ion-electron interaction. This allows us to identify two nonadiabatic effects including the lowering of the threshold intensity at which over-the-barrier ionization happens and the lowering of the ionization time of the electrons. As a consequence, these nonadiabatic effects facilitate over-the-barrier ionization and recollision-induced ionizations. We analyze the outcomes of these nonadiabatic effects on the recollision mechanism. We show that the laser envelope plays an instrumental role in a recollision channel in CP pulses at the heart of NSDI.

Prospects of application and possibilities of electric modular-launch furnaces with a new design of the heating system

We perform the analysis of the methods aimed at improving the energy efficiency of the electric modular-launch furnaces for firing of vermiculite. The first method is reduced to the analysis of the energy efficiency of the original six-module furnace with heat emitters made of U-shaped nichrome and structural transformation of the furnace unit with reinstallation of the least efficient bottom module in parallel with the most efficient top module. In this way, we get a furnace with series-and-parallel pairing of modules (SPP-furnace). The second method proposed in the previous works of the author is based on the application of new heating systems with top arrangement of wire emitters with round cross sections mounted on the thermal covers made of ceramic-vermiculite plates. Both these methods are implemented in modified SPP furnaces and give a synergistic effect with lowering of the specific energy intensity of firing of the vermiculite concentrates down to 105.9 mJ/m3 in a six-module SPP furnace and to 63.5 mJ/m3 in a four-module furnace with the use of a “zero” nonelectrified module.