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AimsThough statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular (CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4 g/day will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography than placebo in statin-treated patients.Methods and resultsEVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography (CCTA) (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40-115 mg/dL, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9, and 18 months. Here, we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9 months (age = 57 ± 6 years, male = 36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs. 94%, P = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque) (35% vs. 43%, P = 0.010), total plaque (non-calcified + calcified plaque) (15% vs. 26%, P = 0.0004), fibrous plaque (17% vs. 40%, P = 0.011), and calcified plaque (-1% vs. 9%, P = 0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use.ConclusionEVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high triglyceride levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial.Clinicaltrials. govidentifierNCT029226027.

AimsDespite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients.Methods and resultsA total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P

Subtype-selective antagonists for muscarinic acetylcholine receptors (mAChRs) have long been elusive, owing to the highly conserved orthosteric binding site. However, allosteric sites of these receptors are less conserved, motivating the search for allosteric ligands that modulate agonists or antagonists to confer subtype selectivity. Accordingly, a 4.6 million-molecule library was docked against the structure of the prototypical M2 mAChR, seeking molecules that specifically stabilized antagonist binding. This led us to identify a positive allosteric modulator (PAM) that potentiated the antagonist N-methyl scopolamine (NMS). Structure-based optimization led to compound '628, which enhanced binding of NMS, and the drug scopolamine itself, with a cooperativity factor (α) of 5.5 and a KB of 1.1 μM, while sparing the endogenous agonist acetylcholine. NMR spectral changes determined for methionine residues reflected changes in the allosteric network. Moreover, '628 slowed the dissociation rate of NMS from the M2 mAChR by 50-fold, an effect not observed at the other four mAChR subtypes. The specific PAM effect of '628 on NMS antagonism was conserved in functional assays, including agonist stimulation of [35S]GTPγS binding and ERK 1/2 phosphorylation. Importantly, the selective allostery between '628 and NMS was retained in membranes from adult rat hypothalamus and in neonatal rat cardiomyocytes, supporting the physiological relevance of this PAM/antagonist approach. This study supports the feasibility of discovering PAMs that confer subtype selectivity to antagonists; molecules like '628 can convert an armamentarium of potent but nonselective GPCR antagonist drugs into subtype-selective reagents, thus reducing their off-target effects.

Despite reducing progression and promoting regression of coronary atherosclerosis, statin therapy does not fully address residual cardiovascular (CV) risk. High-purity eicosapentaenoic acid (EPA) added to a statin has been shown to reduce CV events and induce regression of coronary atherosclerosis in imaging studies; however, data are from Japanese populations without high triglyceride (TG) levels and baseline EPA serum levels greater than those in North American populations. Icosapent ethyl is a high-purity prescription EPA ethyl ester approved at 4 g/d as an adjunct to diet to reduce TG levels in adults with TG levels >499 mg/dL. The objective of the randomized, double-blind, placebo-controlled EVAPORATE study is to evaluate the effects of icosapent ethyl 4 g/d on atherosclerotic plaque in a North American population of statin-treated patients with coronary atherosclerosis, TG levels of 200 to 499 mg/dL, and low-density lipoprotein cholesterol levels of 40 to 115 mg/dL. The primary endpoint is change in low-attenuation plaque volume measured by multidetector computed tomography angiography. Secondary endpoints include incident plaque rates; quantitative changes in different plaque types and morphology; changes in markers of inflammation, lipids, and lipoproteins; and the relationship between these changes and plaque burden and/or plaque vulnerability. Approximately 80 patients will be followed for 9 to 18 months. The clinical implications of icosapent ethyl 4 g/d treatment added to statin therapy on CV endpoints are being evaluated in the large CV outcomes study REDUCE-IT. EVAPORATE will provide important imaging-derived data that may add relevance to the clinically derived outcomes from REDUCE-IT.

BackgroundWhen a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy).MethodsWe review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting.ResultsOf 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death.ConclusionsAlthough our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

Climate change is driving rapid changes in environmental conditions and affecting population and species' persistence across spatial and temporal scales. Integrating climate change assessments into biological resource management, such as conserving endangered species, is a substantial challenge, partly due to a mismatch between global climate forecasts and local or regional conservation planning. Here, we demonstrate how outputs of global climate change models can be downscaled to the watershed scale, and then coupled with ecophysiological metrics to assess climate change effects on organisms of conservation concern. We employed models to estimate future water temperatures (2010-2099) under several climate change scenarios within the large heterogeneous San Francisco Estuary. We then assessed the warming effects on the endangered, endemic Delta Smelt, Hypomesus transpacificus, by integrating localized projected water temperatures with thermal sensitivity metrics (tolerance, spawning and maturation windows, and sublethal stress thresholds) across life stages. Lethal temperatures occurred under several scenarios, but sublethal effects resulting from chronic stressful temperatures were more common across the estuary (median >60 days above threshold for >50% locations by the end of the century). Behavioral avoidance of such stressful temperatures would make a large portion of the potential range of Delta Smelt unavailable during the summer and fall. Since Delta Smelt are not likely to migrate to other estuaries, these changes are likely to result in substantial habitat compression. Additionally, the Delta Smelt maturation window was shortened by 18-85 days, revealing cumulative effects of stressful summer and fall temperatures with early initiation of spring spawning that may negatively impact fitness. Our findings highlight the value of integrating sublethal thresholds, life history, and in situ thermal heterogeneity into global change impact assessments. As downscaled climate models are becoming widely available, we conclude that similar assessments at management-relevant scales will improve the scientific basis for resource management decisions.

There is a well-established body of evidence that intergenerational bonding programs (IGPs) can improve the overall well-being of older adults and strengthen relationships and understanding between generations. There is limited literature on the experience of IGPs in an Asian context, despite many of these countries facing faster rates of population ageing than other Western countries. In Singapore, intergenerational bonding is a priority in national efforts to encourage successful ageing. This paper presents a case study of the development and implementation of a co-located (shared site) model IGP in Singapore. Drawing on interviews with key stakeholders, the aim of this case study is to present the realities of the evolution of an IGP from conceptualisation through to implementation, and used the nursing home’s COVID-19 experience to illustrate issues of sustainability affecting IGPs with vulnerable populations. The findings will inform the development and implementation of similar future programs.

Large satellite discrepancies and model biases in representing precipitation over the Southern Ocean (SO) are related directly to the region's limited surface observations of precipitation. To help address this knowledge gap, the study investigated the precipitation characteristics and rain rate retrievals over the remote SO using ship‐borne data of the Ocean Rainfall And Ice‐phase precipitation measurement Network disdrometer (OceanRAIN) and dual‐polarimetric C‐band radar (OceanPOL) aboard the Research Vessel (RV) Investigator in the Austral warm seasons of 2016–2018. Seven distinct synoptic types over the SO were analyzed based on their radar polarimetric signatures, surface precipitation phase, and rain microphysical properties. OceanRAIN observations revealed that the SO precipitation was dominated by drizzle and light rain, with small‐sized raindrops (diameter <1 mm) constituting up to 47% of total accumulation. Precipitation occurred most frequently over the warm sector of extratropical cyclones, while concentrations of large‐sized raindrops (diameter >3 mm) were prominent over synoptic types with colder and more convectively unstable environments. OceanPOL observations complement and extend the surface precipitation properties sampled by OceanRAIN, providing unique information to help characterize the variety of potential precipitation types and associated mechanisms under different synoptic conditions. Raindrop size distributions (DSD) measured with OceanRAIN over the SO were better characterized by analytical DSD forms with two‐shape parameters than single‐shape parameters currently implemented in satellite retrieval algorithms. This study also revised a rainfall retrieval algorithm for C‐band radars to reflect the large amount of small drops and provide improved radar rainfall estimates over the SO. Plain Language Summary: Precipitation is a major component of the hydrologic cycle in high‐latitude regions including the remote Southern Ocean (SO). However, large differences continue to exist among current precipitation products in the region, owing in part to the absence of high‐quality surface observational records suitable for evaluation across a range of temporal and spatial scales. This work uses two instruments aboard the RV Investigator over the Australian sector of the SO in the Austral warm seasons of 2016–2018: the OceanRAIN disdrometer and OceanPOL radar. We found variability in radar features and surface precipitation properties among seven distinct synoptic conditions over the SO. This work also discussed two important findings related to remote sensing retrievals of SO rain. First, we demonstrated why the rainfall retrieval assumptions in satellite algorithms may need to be refined to account for the unique rainfall properties in the SO. Second, we formulated a new set of equations suitable for shipborne C‐band radars in improving rain rate estimates over the region. This work leads toward more accurate, high‐resolution estimates of precipitation over the measurement‐sparse SO to better understand a range of climatological and meteorological processes in the region. Key Points: Different synoptic types across the Southern Ocean exhibit distinctive polarimetric signatures and surface precipitation propertiesSmall raindrops of less than one millimeter contribute up to 47% of total accumulation during the Austral warm seasons over the regionA new formulation for radar rainfall estimates that reflects the large numbers of small drops over the Southern Ocean is proposed [ABSTRACT FROM AUTHOR]

Abstract Background Women often lag behind men in their risk of cardiovascular events. However, with age and the onset of menopause, women’s cardiovascular risk eventually becomes similar to that of men. This change in risk may, in part, be attributable to a shift to a more atherogenic lipid profile. Our objective was to evaluate standard- and sub-lipid parameters and the apo A1 remnant ratio: (apo A1/[VLDL3-C+IDL-C]) for their associations with death/myocardial infarction among peri- and post-menopausal women. Methods Women (N=711) >50 years of age undergoing coronary angiography were evaluated. Baseline clinical and angiographic characteristics, lipids, and sub-lipid levels (Vertical Auto Profile method) were collected. Cox regression analysis, adjusted by standard cardiovascular risk factors, was utilized to determine associations of lipid and sub-lipid tertiles(T) with death/myocardial infarction at 1 and 3 years. Results Patients averaged 67.7±9.4 years and 53.6% had underlying severe (≥70% stenosis) coronary artery disease. The apo A1 remnant ratio was found to have stronger associations for 1 year (T1 vs. T3: HR=2.13, p=0.03, T2 vs. T3: HR=1.57, p=0.21) and 3 year (T1 vs. T3: HR=2.32, p=0.002, T2 vs. T3: HR=1.97, p=0.01) death/myocardial infarction than any individual lipid (LDL-C, HDL-C, triglycerides, non-HDL-C) or sub-lipid (apo A1, apo B, VLDL3-C+IDL-C) measure, or any other well-known ratio (triglyercies/HDL-C, apo B/A1, TChol/HDL-C, HDL-C/[VLDL3-C+IDL-C]). Conclusions The apo A1 remnant ratio was a significant predictor of short and intermediate-term death/myocardial infarction risk among women >50 years of age. Furthermore, this ratio was found to have greater predictive ability than traditional lipid and sub-lipid parameters and represents a potential new risk marker.

Abstract Background Evidence-based practice (EBP) is imperative for ensuring patient safety. Although teaching strategies to enhance EBP knowledge and skills are recommended, recent research indicates that nurses may not be well prepared to apply EBP. A three-level hierarchy for teaching and learning evidence-based medicine is suggested, including the requirement for interactive clinical activities in EBP teaching strategies. This literature review identifies the teaching strategies for EBP knowledge and skills currently used in undergraduate nursing education. We also describe students’ and educators’ experiences with learning outcomes and barriers. Methods We conducted literature searches using Medline, Embase, CINAHL, ERIC and Academic Search Premier. Six qualitative studies and one mixed-method study met the inclusion criteria and were critically evaluated based on the Critical Appraisal Skills Programme. Using Braun and Clarke’s six phases, the seven studies were deductively and thematically analysed to discover themes. Results Four teaching strategy themes were identified, including subthemes within each theme: i.e., interactive teaching strategies; interactive and clinical integrated teaching strategies; learning outcomes; and barriers. Although four studies included a vague focus on teaching EBP principles, they all included research utilisation and interactive teaching strategies. Reported learning outcomes included enhanced analytical and critical skills and using research to ensure patient safety. Barriers included challenging collaborations, limited awareness of EBP principles and poor information literacy skills. Conclusion Four of the seven analysed studies included a vague focus on the use of EBP teaching strategies. Interactive teaching strategies are used, but primary strategies focus on searching for and critically appraising research for practice-based application. Although this review included a relatively small sample of literature, the findings indicate a need for more qualitative research investigating interactive and clinically integrated teaching strategies towards further enhancing EBP undergraduate nursing students’ knowledge and skills.

Graduate nursing students can face varied and significant stressors during their programs of study. The need for interventions to promote nursing student resiliency has been reported in the literature, by accrediting bodies, and in previous research conducted with students at the same university. Thus, the purpose of this project was to pilot a resilience course for Doctor of Nursing Practice (DNP) students. The theoretical frameworks guiding the design and implementation of the resiliency pilot program were andragogy (the science of adult learning) and rapid cycle quality improvement. The course included eleven monthly modules addressing resiliency content with written material, original videos, and online discussions and meetings. The first module overviewed the resiliency skills (Belief, Persistence, Trust, Strength, and Adaptability), five modules were dedicated to a specific resiliency skill, two modules addressed recent and anticipated challenges, two modules concentrated on the application (clinical and academic) of the resiliency skills, and the last module focused on reflection. Results of this pilot program indicate that DNP students can benefit from receiving resiliency content during their studies, especially from faculty involvement and increased peer support; however, future resiliency content may be more accepted and effective if embedded into nursing program curriculum and activities. • Providing evidence-based resiliency content can benefit graduate nursing students. • Online nursing resiliency courses can be feasible and promote connectedness. • Resiliency content may be most effective embedded in nursing program curricula. [ABSTRACT FROM AUTHOR]

Providing freshwater to human populations while protecting or rehabilitating ecosystem health is a significant challenge to water resource managers and requires accurate knowledge of aquatic resources. Previous studies of fish assemblages in the San Francisco Estuary and watershed have focused on specific habitat types, water bodies, or geographic subregions. In this study, we use seining data from two monitoring programs to provide an integrated view of spring nearshore resident fish species composition and life history characteristics in five regions: the San Joaquin River, the upper Sacramento River, the lower Sacramento River, the northern Sacramento-San Joaquin Delta (North Delta), and the Interior Delta. Data for the period March-May from 1994 to 2002, showed that spring species composition of the San Joaquin River was very different from the other four regions. Total catch in the San Joaquin River was dominated by small, short-lived batch spawning alien species (93%), particularly red shiner Cyprinella lutrensis (>75% of total catch). The upper and lower Sacramento River were very similar in species composition and life history characteristics and less dominated by alien fish (

Recent voyages of the Australian R/V Investigator across the remote Southern Ocean have provided unprecedented observations of precipitation made with both an Ocean Rainfall and Ice-Phase Precipitation Measurement Network (OceanRAIN) maritime disdrometer and a dual-polarization C-band weather radar (OceanPOL). This present study employs these observations to evaluate the Global Precipitation Measurement (GPM) Integrated Multi-satellitE Retrievals for GPM (IMERG) and the fifth major global reanalysis produced by ECMWF (ERA5) precipitation products. Working at a resolution of 60 min and 0.25° (∼25 km), light rain and drizzle are most frequently observed across the region. The IMERG product overestimated precipitation intensity when evaluated against the OceanRAIN but captured the frequency of occurrence well. Looking at the synoptic/process scale, IMERG was found to be the least accurate (overestimated intensity) under warm-frontal and high-latitude cyclone conditions, where multilayer clouds were commonly present. Under postfrontal conditions, IMERG underestimated the precipitation frequency. In comparison, ERA5's skill was more consistent across various synoptic conditions, except for high pressure conditions where the precipitation frequency (intensity) was highly overestimated (underestimated). Using the OceanPOL radar, an area-to-area analysis (fractional skill score) finds that ERA5 has greater skill than IMERG. There is little agreement in the phase classification between the OceanRAIN disdrometer, IMERG, and ERA5. The comparisons are complicated by the various assumptions for phase classification in the different datasets. Significance Statement: Our best quantitative estimates of precipitation over the remote, pristine Southern Ocean (SO) continue to suffer from a high degree of uncertainty, with large differences present among satellite-based and reanalysis products. New instrumentation on the R/V Investigator, specifically a dual-polarization C-band weather radar (OceanPOL) and a maritime disdrometer (OceanRAIN), provide unprecedented high-quality observations of precipitation across the SO that will aid in improving precipitation estimates in this region. We use these observations to evaluate the IMERG and ERA5 precipitation products. We find that, in general, IMERG overestimated precipitation intensity, but captured the frequency of occurrence well. In comparison, ERA5 was found to overestimate the frequency of precipitation. Using the OceanPOL radar, an area-to-area analysis finds that ERA5 has greater skill than IMERG. [ABSTRACT FROM AUTHOR]