Study design and rationale for the Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study (OCEAN(a)-DOSE).

BACKGROUND Data support lipoprotein(a) (Lp[Lp(a)]) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in hepatocytes. STUDY DESIGN The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing. CONCLUSIONS OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial

Inter- and intra-individual variation in brain structural-cognition relationships in aging

The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ±4.9 years) and late-life (mean age = 67.7 ± 4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ± 4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive decline and maintenance across diverse cognitive functions are both positively and negatively associated with markers of cortical structure

Antithrombotic Treatment in Transcatheter Aortic Valve Implantation Insights for Cerebrovascular and Bleeding Events

Transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic alternative for patients with symptomatic aortic stenosis at high or prohibitive surgical risk. However, patients undergoing TAVI are also at high risk for both bleeding and stroke complications, and specific mechanical aspects of the procedure itself can increase the risk of these complications. The mechanisms of periprocedural bleeding complications seem to relate mainly to vascular/access site complications (related to the use of large catheters in a very old and frail elderly population), whereas the pathophysiology of cerebrovascular events remains largely unknown. Further, although mechanical complications, especially the interaction between the valve prosthesis and the native aortic valve, may play a major role in events that occur during TAVI, post-procedural events might also be related to a prothrombotic environment or state generated by the implanted valve, the occurrence of atrial arrhythmias, and associated comorbidities. Antithrombotic therapy in the setting of TAVI has been empirically determined, and unfractionated heparin during the procedure followed by dual antiplatelet therapy with aspirin (indefinitely) and clopidogrel (1 to 6 months) is the most commonly recommended treatment. However, bleeding and cerebrovascular events are common; these may be modifiable with optimization of periprocedural and post-procedural pharmacology. Further, as the field of antiplatelet and anticoagulant therapy evolves, potential drug combinations will multiply, introducing variability in treatment. Randomized trials are the best path forward to determine the balance between the efficacy and risks of antithrombotic treatment in this high risk-population

Variability of Individual Platelet Reactivity Over Time in Patients Treated With Clopidogrel Insights From the ELEVATE–TIMI 56 Trial

AbstractBackgroundThe degree of antiplatelet response to clopidogrel has been associated with clinical outcomes. Studies have investigated whether adjustment of antiplatelet therapies based on a single platelet function test is beneficial.ObjectivesThe aim of the study was to test the stability of platelet reactivity measurements over time among patients treated with standard and double doses of clopidogrel.MethodsThe ELEVATE–TIMI 56 (Escalating Clopidogrel by Involving a Genetic Strategy–Thrombolysis In Myocardial Infarction 56) investigators genotyped 333 patients with coronary artery disease and randomized them to various clopidogrel regimens. Patients with at least 2 platelet function results on the same maintenance dose of clopidogrel (75 mg or 150 mg) were analyzed. Platelet aggregation was measured using P2Y12 reaction units (PRU).ResultsIn total, the mean platelet reactivity and the total number of nonresponders (PRU ≥230) with clopidogrel did not change between 2 periods for the 75-mg (22.4% vs. 21.9%; p = 0.86) and 150-mg doses of clopidogrel (11.5% vs. 11.5%; p = 1.00). In contrast, when evaluating each patient individually, 15.7% of patients taking clopidogrel 75 mg and 11.4% of patients taking 150 mg had a change in their responder status when tested at 2 different time points (p < 0.001). Despite being treated with the same dose of clopidogrel, >40% of patients had a change in PRU >40 on serial sampling, which approximates the average PRU difference caused by increasing the clopidogrel dose from 75 mg to 150 mg.ConclusionsMeasurements of platelet reactivity vary over time in a significant proportion of patients. Thus, treatment adjustment according to platelet function testing at a single time point might not be sufficient for guiding antiplatelet therapy in clinical or research settings. (Escalating Clopidogrel by Involving a Genetic Strategy–Thrombolysis In Myocardial Infarction 56 [ELEVATE–TIMI 56]; NCT01235351

The SOS-framework (Systems of Sedentary behaviours): An international transdisciplinary consensus framework for the study of determinants, research priorities and policy on sedentary behaviour across the life course: A DEDIPAC-study

© 2016 The Author(s).Background: Ecological models are currently the most used approaches to classify and conceptualise determinants of sedentary behaviour, but these approaches are limited in their ability to capture the complexity of and interplay between determinants. The aim of the project described here was to develop a transdisciplinary dynamic framework, grounded in a system-based approach, for research on determinants of sedentary behaviour across the life span and intervention and policy planning and evaluation. Methods: A comprehensive concept mapping approach was used to develop the Systems Of Sedentary behaviours (SOS) framework, involving four main phases: (1) preparation, (2) generation of statements, (3) structuring (sorting and ranking), and (4) analysis and interpretation. The first two phases were undertaken between December 2013 and February 2015 by the DEDIPAC KH team (DEterminants of DIet and Physical Activity Knowledge Hub). The last two phases were completed during a two-day consensus meeting in June 2015. Results: During the first phase, 550 factors regarding sedentary behaviour were listed across three age groups (i.e., youths, adults and older adults), which were reduced to a final list of 190 life course factors in phase 2 used during the consensus meeting. In total, 69 international delegates, seven invited experts and one concept mapping consultant attended the consensus meeting. The final framework obtained during that meeting consisted of six clusters of determinants: Physical Health and Wellbeing (71 % consensus), Social and Cultural Context (59 % consensus), Built and Natural Environment (65 % consensus), Psychology and Behaviour (80 % consensus), Politics and Economics (78 % consensus), and Institutional and Home Settings (78 % consensus). Conducting studies on Institutional Settings was ranked as the first research priority. The view that this framework captures a system-based map of determinants of sedentary behaviour was expressed by 89 % of the participants. Conclusion: Through an international transdisciplinary consensus process, the SOS framework was developed for the determinants of sedentary behaviour through the life course. Investigating the influence of Institutional and Home Settings was deemed to be the most important area of research to focus on at present and potentially the most modifiable. The SOS framework can be used as an important tool to prioritise future research and to develop policies to reduce sedentary time

Interleukin‐6 and the Risk of Adverse Outcomes in Patients After an Acute Coronary Syndrome: Observations From the SOLID‐TIMI 52 (Stabilization of Plaque Using Darapladib—Thrombolysis in Myocardial Infarction 52) Trial

Background: Interleukin‐6 (IL‐6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL‐6 post‐ACS. Methods and Results: IL‐6 concentration was assessed at baseline in 4939 subjects in SOLID‐TIMI 52 (Stabilization of Plaque Using Darapladib—Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS. Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS, ACS type, and randomized treatment arm. For every SD increase in IL‐6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR] 1.10, 95% confidence interval [CI] 1.01‐1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11‐1.34). Patients in the highest IL‐6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22‐2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6‐3.29). After further adjustment for biomarkers (high‐sensitivity C‐reactive protein, lipoprotein‐associated phospholipase A2 activity, high‐sensitivity troponin I, and B‐type natriuretic peptide), IL‐6 remained significantly associated with the risk of major adverse cardiovascular events (adj HR Q4:Q1 1.43, 95% CI 1.09‐1.88) and cardiovascular death or heart failure (adj HR 1.79, 95% CI 1.22‐2.63). Conclusions: In patients after ACS, IL‐6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL‐6 as a potential therapeutic target in patients with unstable ischemic heart disease

Proteomic analysis of pollination-induced corolla senescence in petunia

Senescence represents the last phase of petal development during which macromolecules and organelles are degraded and nutrients are recycled to developing tissues. To understand better the post-transcriptional changes regulating petal senescence, a proteomic approach was used to profile protein changes during the senescence of Petunia×hybrida ‘Mitchell Diploid’ corollas. Total soluble proteins were extracted from unpollinated petunia corollas at 0, 24, 48, and 72 h after flower opening and at 24, 48, and 72 h after pollination. Two-dimensional gel electrophoresis (2-DE) was used to identify proteins that were differentially expressed in non-senescing (unpollinated) and senescing (pollinated) corollas, and image analysis was used to determine which proteins were up- or down-regulated by the experimentally determined cut-off of 2.1-fold for P <0.05. One hundred and thirty-three differentially expressed protein spots were selected for sequencing. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the identity of these proteins. Searching translated EST databases and the NCBI non-redundant protein database, it was possible to assign a putative identification to greater than 90% of these proteins. Many of the senescence up-regulated proteins were putatively involved in defence and stress responses or macromolecule catabolism. Some proteins, not previously characterized during flower senescence, were identified, including an orthologue of the tomato abscisic acid stress ripening protein 4 (ASR4). Gene expression patterns did not always correlate with protein expression, confirming that both proteomic and genomic approaches will be required to obtain a detailed understanding of the regulation of petal senescence

The SOS-framework (Systems of Sedentary behaviours): an international transdisciplinary consensus framework for the study of determinants, research priorities and policy on sedentary behaviour across the life course: a DEDIPAC-study.

BACKGROUND: Ecological models are currently the most used approaches to classify and conceptualise determinants of sedentary behaviour, but these approaches are limited in their ability to capture the complexity of and interplay between determinants. The aim of the project described here was to develop a transdisciplinary dynamic framework, grounded in a system-based approach, for research on determinants of sedentary behaviour across the life span and intervention and policy planning and evaluation. METHODS: A comprehensive concept mapping approach was used to develop the Systems Of Sedentary behaviours (SOS) framework, involving four main phases: (1) preparation, (2) generation of statements, (3) structuring (sorting and ranking), and (4) analysis and interpretation. The first two phases were undertaken between December 2013 and February 2015 by the DEDIPAC KH team (DEterminants of DIet and Physical Activity Knowledge Hub). The last two phases were completed during a two-day consensus meeting in June 2015. RESULTS: During the first phase, 550 factors regarding sedentary behaviour were listed across three age groups (i.e., youths, adults and older adults), which were reduced to a final list of 190 life course factors in phase 2 used during the consensus meeting. In total, 69 international delegates, seven invited experts and one concept mapping consultant attended the consensus meeting. The final framework obtained during that meeting consisted of six clusters of determinants: Physical Health and Wellbeing (71% consensus), Social and Cultural Context (59% consensus), Built and Natural Environment (65% consensus), Psychology and Behaviour (80% consensus), Politics and Economics (78% consensus), and Institutional and Home Settings (78% consensus). Conducting studies on Institutional Settings was ranked as the first research priority. The view that this framework captures a system-based map of determinants of sedentary behaviour was expressed by 89% of the participants. CONCLUSION: Through an international transdisciplinary consensus process, the SOS framework was developed for the determinants of sedentary behaviour through the life course. Investigating the influence of Institutional and Home Settings was deemed to be the most important area of research to focus on at present and potentially the most modifiable. The SOS framework can be used as an important tool to prioritise future research and to develop policies to reduce sedentary time

Delivery of maternal health care in Indigenous primary care services: baseline data for an ongoing quality improvement initiative

Extent: 10p.BACKGROUND: Australia's Aboriginal and Torres Strait Islander (Indigenous) populations have disproportionately high rates of adverse perinatal outcomes relative to other Australians. Poorer access to good quality maternal health care is a key driver of this disparity. The aim of this study was to describe patterns of delivery of maternity care and service gaps in primary care services in Australian Indigenous communities. METHODS: We undertook a cross-sectional baseline audit for a quality improvement intervention. Medical records of 535 women from 34 Indigenous community health centres in five regions (Top End of Northern Territory 13, Central Australia 2, Far West New South Wales 6, Western Australia 9, and North Queensland 4) were audited. The main outcome measures included: adherence to recommended protocols and procedures in the antenatal and postnatal periods including: clinical, laboratory and ultrasound investigations; screening for gestational diabetes and Group B Streptococcus; brief intervention/advice on health-related behaviours and risks; and follow up of identified health problems. RESULTS: The proportion of women presenting for their first antenatal visit in the first trimester ranged from 34% to 49% between regions; consequently, documentation of care early in pregnancy was poor. Overall, documentation of routine antenatal investigations and brief interventions/advice regarding health behaviours varied, and generally indicated that these services were underutilised. For example, 46% of known smokers received smoking cessation advice/counselling; 52% of all women received antenatal education and 51% had investigation for gestational diabetes. Overall, there was relatively good documentation of follow up of identified problems related to hypertension or diabetes, with over 70% of identified women being referred to a GP/Obstetrician. CONCLUSION: Participating services had both strengths and weaknesses in the delivery of maternal health care. Increasing access to evidence-based screening and health information (most notably around smoking cessation) were consistently identified as opportunities for improvement across services.Alice R. Rumbold, Ross S. Bailie, Damin Si, Michelle C. Dowden, Catherine M. Kennedy, Rhonda J. Cox, Lynette O’Donoghue, Helen E. Liddle, Ru K. Kwedza, Sandra C. Thompson, Hugh P. Burke, Alex D. H. Brown, Tarun Weeramanthri and Christine M. Connor