World Heart Federation Roadmap for Secondary Prevention of Cardiovascular Disease: 2023 Update.

Background: Secondary prevention lifestyle and pharmacological treatment of atherosclerotic cardiovascular disease (ASCVD) reduce a high proportion of recurrent events and mortality. However, significant gaps exist between guideline recommendations and usual clinical practice. Objectives: Describe the state of the art, the roadblocks, and successful strategies to overcome them in ASCVD secondary prevention management. Methods: A writing group reviewed guidelines and research papers and received inputs from an international committee composed of cardiovascular prevention and health systems experts about the article's structure, content, and draft. Finally, an external expert group reviewed the paper. Results: Smoking cessation, physical activity, diet and weight management, antiplatelets, statins, beta-blockers, renin-angiotensin-aldosterone system inhibitors, and cardiac rehabilitation reduce events and mortality. Potential roadblocks may occur at the individual, healthcare provider, and health system levels and include lack of access to healthcare and medicines, clinical inertia, lack of primary care infrastructure or built environments that support preventive cardiovascular health behaviours. Possible solutions include improving health literacy, self-management strategies, national policies to improve lifestyle and access to secondary prevention medication (including fix-dose combination therapy), implementing rehabilitation programs, and incorporating digital health interventions. Digital tools are being examined in a range of settings from enhancing self-management, risk factor control, and cardiac rehab. Conclusions: Effective strategies for secondary prevention management exist, but there are barriers to their implementation. WHF roadmaps can facilitate the development of a strategic plan to identify and implement local and national level approaches for improving secondary prevention.

How the "Are We Drinking Ourselves Sick?" Communication Campaign Built Support for Policy Action on Sugary Drinks in Jamaica.

Background: This study assesses the effectiveness of a campaign "Are We Drinking Ourselves Sick?" that ran nationally in Jamaica in four phases from 2017 to 2019 to increase knowledge about the harms of sugary drinks, shift attitudes, and build support for policy actions to address sugary drink consumption, including a tax and a ban in schools. Methods: Campaign impact was measured in representative cross-sectional household surveys of adults ages 18 to 55. A baseline survey was conducted before the launch of the campaign (n = 1430). Evaluation surveys were conducted mid-campaign (n = 1571) and post-campaign (n = 1500). Campaign impact was assessed by comparing changes across survey periods on key knowledge, attitudinal and policy support outcome indicators. The independent association between campaign awareness and outcomes was analyzed using logistic regression analyses. Results: The campaign was recalled by more than 80% of respondents and was well-received with 90% or more respondents describing it as believable and relevant. There was a decline in knowledge on the harms of sugary drinks from the baseline to post-campaign period, notably on risks of diabetes (adjusted odds ratio or AOR = 0.62, p < 0.001), overweight and obesity (AOR = 0.58, p < 0.001), and heart disease (AOR = 0.79, p < 0.003). However, post-campaign awareness was independently associated in logistic regression analysis with improved knowledge of the harms of sugary drinks, including risks of diabetes (AOR = 1.45, p = 0.019), overweight or obesity (AOR = 1.65, p = 0.001), and heart disease (AOR = 1.44, p = 0.011). Support for government action remained high across survey waves (≥90%), and campaign awareness was independently associated with increased policy support for sugary drinks taxes (Mid-campaign: AOR = 1.43, p = 0.019; post-campaign: AOR = 1.46, p = 0.01) and restrictions on sugary drinks in schools (AOR = 1.55, p = 0.01). Conclusion: This study demonstrates the role that media campaigns can play in maintaining knowledge and concern about the health harms of sugary drinks and increasing support for policy passage.

Equity and Prevention of Cardiovascular Diseases in Latin America and the Caribbean.

Non-communicable diseases, particularly cardiovascular diseases, are the leading cause of decreased life expectancy and death in Latin America and the Caribbean. Although a lifestyle, which includes no tobacco use, good nutrition, and regular physical activity is touted as key to health, the environmental, racial, social and economic conditions, which underpin lifestyle are often ignored or considered only secondarily. Placing the main responsibility on a patient to change their lifestyle or to simply comply with pharmacological treatment ignores the specific conditions in which the individual lives. Furthermore, there are major disparities in access to both healthy living conditions as well as access to medical care. There is sufficient evidence to support advocating for policies that support healthy living, particularly healthy food choices. Progress is being made to improve the food environment with enactment of front of package nutritional labels. However, policies were enacted only after intense regional research and advocacy supporting their implementation. Government officials must rise above the pressures of commercial interests and support health-promoting policies or be exposed as self-interest groups themselves. Strong advocacy is required to persuade officials that all policies should take health into consideration both to improve lives and economies.

Coercion, dissatisfaction, and social stigma: an ethnographic study of compensated living kidney donation in Iran.

This article updates the qualitative research on Iran reported in the 2012 article by Tong et al. "The experiences of commercial kidney donors: thematic synthesis of qualitative research" (Tong et al. in Transpl Int 25:1138-1149, 2012). The basic approach used in the Tong et al. article is applied to a more recent and more comprehensive study of Iranian living organ donors, providing a clearer picture of what compensated organ donation is like in Iran since the national government began regulating compensated donation. Iran is the only country in the world where kidney selling is legal, regulated, and subsidized by the national government. This article focuses on three themes: (1) coercion and other pressures to donate, (2) donor satisfaction with their donation experience, and (3) whether donors fear social stigma. We found no evidence of coercion, but 68% of the paid living organ donors interviewed felt pressure to donate due to extreme poverty or other family pressures. Even though 27% of the living kidney donors interviewed said they were satisfied with their donation experience, 74% had complaints about the donation process or its results, including some of the donors who said they were satisfied. In addition, 84% of donors indicated they feared experiencing social stigma because of their kidney donation.

Improved in vitro quality of stored red blood cells upon oxygen reduction prior to riboflavin/UV light treatment of whole blood.

BACKGROUND: The application of riboflavin/UV-based pathogen inactivation (PI) to whole blood (WB) is currently limited by its negative impact on red blood cell (RBC) quality. The generation of reactive oxidative species in RBC products contributes to increased hemolysis. This study evaluated the impact of deoxygenation of WB prior to riboflavin/UV light treatment versus deoxygenation of RBC concentrates after PI treatment by monitoring RBC in vitro quality parameters. STUDY DESIGN AND METHODS: Six ABO-matched WB units were pooled and split. Within three pairs, one unit was treated with riboflavin/UV light while the other was kept as an untreated control prior to manufacture into red cell concentrates (RCCs). The first pair (Cntr; Cntr-PI) served as the normoxic controls. Deoxygenation was performed at the RCC level for the second pair (RCCdeox; PI-RCCdeox), and at the WB level of the third pair (WBdeox; WBdeox-PI). In vitro qualities of the respective RBC units were assessed throughout storage. RESULTS: The data for the Cntr and Cntr-PI units were comparable to previous reports. The PI-RCCdeox units exhibited worse in vitro quality for most parameters tested compared to Cntr-PI and WBdeox-PI units throughout storage. Hemolysis and microvesicle release was significantly (p < 0.05) higher on Days 21 and 42 in Cntr-PI units compared to WBdeox-PI units. CONCLUSION: WB deoxygenation may help to decrease the accelerated deterioration in RCC in vitro quality caused by treatment with riboflavin/UV light. Treatment of WB under reduced oxygen levels needs to be assessed for PI effectiveness.

The VWFA Is the Home of Orthographic Learning When Houses Are Used as Letters.

Learning to read specializes a portion of the left mid-fusiform cortex for printed word recognition, the putative visual word form area (VWFA). This study examined whether a VWFA specialized for English is sufficiently malleable to support learning a perceptually atypical second writing system. The study utilized an artificial orthography, HouseFont, in which house images represent English phonemes. House images elicit category-biased activation in a spatially distinct brain region, the so-called parahippocampal place area (PPA). Using house images as letters made it possible to test whether the capacity for learning a second writing system involves neural territory that supports reading in the first writing system, or neural territory tuned for the visual features of the new orthography. Twelve human adults completed two weeks of training to establish basic HouseFont reading proficiency and underwent functional neuroimaging pre and post-training. Analysis of three functionally defined regions of interest (ROIs), the VWFA, and left and right PPA, found significant pre-training versus post-training increases in response to HouseFont words only in the VWFA. Analysis of the relationship between the behavioral and neural data found that activation changes from pre-training to post-training within the VWFA predicted HouseFont reading speed. These results demonstrate that learning a new orthography utilizes neural territory previously specialized by the acquisition of a native writing system. Further, they suggest VWFA engagement is driven by orthographic functionality and not the visual characteristics of graphemes, which informs the broader debate about the nature of category-specialized areas in visual association cortex.

Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis.

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.

Drugs' development in acute heart failure: what went wrong?

Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development. Our review has identified limitations at both preclinical and clinical levels. At the preclinical level, the major shortcoming is represented by animal models looking at short-term endpoints which do not recapitulate the complexity of the human disease. At the clinical level, the main weakness is given by the disconnect between short-term endpoints assessed in the early stage of drug development, and medium-long-term endpoints requested in Phase 3 for regulatory approval. This is further amplified by the lack of validation and standardisation of short- and long-term endpoints; absence of predictive biomarkers; conduct of studies on heterogeneous populations; and use of different eligibility criteria, time of assessments, drug schedules and background therapies. Key goals remain a better understanding of AHF and the construction of a successful drug development program. A reasonable way to move forward resides in a strong collaboration between main stakeholders of therapeutic innovation: scientific community, industry and regulatory agencies.

Proteomic analysis of red blood cells from donors exhibiting high hemolysis demonstrates a reduction in membrane-associated proteins involved in the oxidative response.

BACKGROUND: The development of hemolysis during ex vivo hypothermic storage is multifaceted. Standardization of collection and production processes is used to minimize variability in biologics manufacturing and to maximize product quality. However, the influence of various donor characteristics on product quality is often difficult to evaluate and to control. Using a proteomic approach, we aimed to decipher relevant donor characteristics that may predict red blood cell (RBC) quality during storage. STUDY DESIGN AND METHODS: Ten healthy volunteer donors exhibiting repeated high hemolysis at outdate (>0.8%; RBCHH ) and 10 age- and sex-matched control donors (RBCCtrl ) were studied. Common quality variables were measured on Days 5, 14, 21, 28, and 42 of storage. Protein profiles of hemoglobin-depleted membrane fractions from RBCHH and RBCCtrl donors were analyzed using a quantitative proteomics approach based on iTRAQ (isobaric tags for relative and absolute quantitation). RESULTS: Time-dependent lesion development was apparent in both donor populations. RBCHH exhibited reduced 2,3-bisphosphoglycerate levels (p < 0.001) and morphologic score (p < 0.001), but displayed elevated hemolysis level (p < 0.001), RBC-derived microvesicle formation (p < 0.001), and mean corpuscular fragility (p < 0.001) compared to RBCCtrl , indicating notable differences at the membrane between the two donor populations. Proteomic findings revealed a significant reduction in the level of proteins involved in oxidative response pathways at early time points in RBCHH compared to that of RBCCtrl . CONCLUSION: The recruitment of these candidate proteins might be part of a response mechanism altered in RBCHH donors and therefore may be useful as a donor screening tool.

Using Raman spectroscopy to assess hemoglobin oxygenation in red blood cell concentrate: an objective proxy for morphological index to gauge the quality of stored blood?

Blood banking is an essential aspect of modern medical care. When red blood cells (RBCs) are stored, they become damaged by various chemical processes, such as accumulation of their own waste products and oxidative injury, among others. These processes lead to the development of the RBC storage lesion, a complex condition where the severity is reflected through the morphology of the stored cells. It was hypothesized that Raman spectroscopy could be used to monitor certain structural and compositional changes associated with such ageing effects and that a relationship between these features and traditional morphology (as measured using a morphology index) could be observed. The hypothesis was tested by measuring spectral features associated with hemoglobin oxygenation from dry-fixed smears and liquid RBCs for twenty-nine different donors (combined), and comparing the trends with morphological scoring from seven of these donors. After appropriately fitting the two data sets to either power or linear curves, the oxygenation state was shown to change in a manner that was donor-dependent and that closely tracked morphological changes. This study suggests Raman analysis has promise for providing a rapid and objective measure of the cell quality of stored RBCs through measurements of hemoglobin oxygenation that is comparable to traditional morphological assessment.

Identification of potential protein quality markers in pathogen inactivated and gamma-irradiated red cell concentrates.

PURPOSE: Post-collection manipulations (PCMs) aim to increase blood product safety. However, PCMs improve safety at a cost to quality, causing elevated hemolysis. As hemolysis is linked to red blood cell membrane integrity, a quantitative proteomics approach was employed to assess membrane proteome alterations induced by PCMs. EXPERIMENTAL DESIGN: Three ABO-matched whole blood (WB) units were pooled-and-split into three identical units. One WB unit was treated with riboflavin/ultraviolet illumination prior to red cell concentrate (RCC) production (RCCWB* ). Two WB units were produced into RCC; one was gamma-irradiated (RCCγ ) and the other was left untreated as control (RCCØ ). In vitro quality parameters were measured during storage. Membrane protein profiles of RCCØ , RCCγ , and RCCWB* were assessed on selected hemoglobin-depleted membrane fractions using a quantitative proteomics approach based on iTRAQ. RESULTS: Quantitative proteomic analysis identified 100 proteins at the membrane, with seven unique proteins exhibiting significant changes in RCCWB* at day 28 of storage. Membrane peroxiredoxin-2, catalase, and proteasome levels demonstrated robust negative correlation with percentage hemolysis. CONCLUSION: Overall, the in vitro parameters and alterations of membrane protein profiles indicated that pathogen inactivation treatment impacts RCC quality more severely than gamma-irradiation and that it may induce damage through a predominately oxidative mechanism.

Pathogen inactivation by riboflavin and ultraviolet light illumination accelerates the red blood cell storage lesion and promotes eryptosis.

BACKGROUND: Pathogen reduction treatment using riboflavin and ultraviolet light illumination (Mirasol) effectively reduces the risk of transfusion-transmitted infections. This treatment is currently licensed for only platelets and plasma products, while its application to whole blood (WB) to generate pathogen-inactivated red blood cells (RBCs) is under development. RBC storage lesion, constituting numerous morphologic and biochemical changes, influences RBC quality and limits shelf life. Stored RBCs further show enhanced susceptibility to RBC programmed cell death (eryptosis) characterized by increased cytosolic Ca2+ -provoked membrane phosphatidylserine (PS) externalization. STUDY DESIGN AND METHODS: Using a "pool-and-split" approach, we examined multiple variables of RBC storage lesion and eryptosis in RBC units, derived from Mirasol-treated or untreated WB, after 4 to 42 days of storage, under blood bank conditions. RESULTS: In comparison to untreated RBC units, Mirasol treatment significantly altered membrane microvesiculation, supernatant hemoglobin, osmotic fragility, and intracellular adenosine triphosphate levels but did not influence membrane CD47 expression and 2,3-diphosphoglycerate levels. Mirasol-treated RBCs showed significantly higher PS exposure after 42, but not after not more than 21, days of storage, which was accompanied by enhanced cytosolic Ca2+ activity, ceramide abundance, and oxidative stress, but not p38 kinase activation. Mirasol treatment significantly augmented PS exposure, Ca2+ entry, and protein kinase C activation after energy depletion, a pathophysiologic cell stressor. Mirasol-treated RBCs were, however, more resistant to cell shrinkage. CONCLUSIONS: Prolonged storage of Mirasol-treated RBCs significantly increases the proportion of eryptotic RBCs, while even short-term storage enhances the susceptibility of RBCs to stress-induced eryptosis, which could reduce posttransfusion RBC recovery in patients.

Raman spectroscopy as a novel tool for monitoring biochemical changes and inter-donor variability in stored red blood cell units.

Individual units of donated red blood cells (RBCs) do not ordinarily undergo analytical testing prior to transfusion. This study establishes the utility of Raman spectroscopy for analyzing the biochemistry of stored RBC supernatant and reveals interesting storage-related changes about the accumulation of lactate, a chemical species that may be harmful to certain patients. The data show measurable variations in supernatant composition and demonstrate that some units of donated RBCs accumulate lactate much more readily than others. The spectra also indicate a higher relative concentration of lactate in units collected from male donors than female donors (p = 0.004) and imply that there is a greater degree of variability at later stages of storage in units from older male donors (>45 years). The study proves that Raman analysis has promise for elucidating the relationship between the metabolism of stored RBCs and donor characteristics. It also suggests that there may be benefit in developing a Raman instrument for the rapid non-invasive assessment of blood-bag biochemistry by measuring through plastic over-layers.

Can We Fix This? Parent-Child Repair Processes and Preschoolers' Regulatory Skills.

The repair of difficult parent-child interactions is a marker of healthy functioning in infancy, but less is known about repair processes during early childhood. We used dynamic systems methods to investigate dyadic repair in mothers and their 3-year-old children (N = 96) and its prediction of children's emotion regulation and behavior problems at a four-month follow-up. Mothers and children completed free play and challenging puzzle tasks. Repair was operationalized as the conditional probability of moving into a dyadic adaptive behavior region after individual or dyadic maladaptive behavior (e.g., child noncompliance, parental criticism). Overall, dyads repaired approximately half their maladaptive behaviors. A greater likelihood of repair during the puzzle task predicted better child emotion regulation and fewer behavior problems in preschool. Results suggest dyadic repair is an important process in early childhood and provide further evidence for the connection between parent-child coregulation and children's developing regulatory capacities. Implications for family-based interventions are discussed.

Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor.

AIMS: The NADPH oxidase (NOX) family of enzymes catalyzes the formation of reactive oxygen species (ROS). NOX enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. To date, while numerous small molecule inhibitors have been reported (in particular for NOX2), none have demonstrated inhibitory activity in vivo. As such, there is a need for the identification of improved NOX inhibitors to enable further evaluation of the biological functions of NOX enzymes in vivo as well as the therapeutic potential of NOX inhibition. In this study, both the in vitro and in vivo pharmacological profiles of GSK2795039, a novel NOX2 inhibitor, were characterized in comparison with other published NOX inhibitors. RESULTS: GSK2795039 inhibited both the formation of ROS and the utilization of the enzyme substrates, NADPH and oxygen, in a variety of semirecombinant cell-free and cell-based NOX2 assays. It inhibited NOX2 in an NADPH competitive manner and was selective over other NOX isoforms, xanthine oxidase, and endothelial nitric oxide synthase enzymes. Following systemic administration in mice, GSK2795039 abolished the production of ROS by activated NOX2 enzyme in a paw inflammation model. Furthermore, GSK2795039 showed activity in a murine model of acute pancreatitis, reducing the levels of serum amylase triggered by systemic injection of cerulein. INNOVATION AND CONCLUSIONS: GSK2795039 is a novel NOX2 inhibitor that is the first small molecule to demonstrate inhibition of the NOX2 enzyme in vivo.