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Michele Odorico,1 Delphine Le Goff,1 Naomi Aerts,2 Hilde Bastiaens,2 Jean Yves Le Reste1 1Department of General Practice, EA 7479 SPURBO, Université de Bretagne Occidentale (UBO – University of West Brittany), Brest, France; 2Department of Primary and Interdisciplinary Care, University of Antwerp, Antwerp, BelgiumCorrespondence: Michele OdoricoDepartment of General Practice, EA 7479 SPURBO, Université de Bretagne Occidentale (UBO – University of West Brittany), 22 rue Camille Desmoulins, Brest 29238, FranceTel +33644973078Email m.odoricobrest@gmail.comIntroduction: Smoking is a major risk factor for cardiovascular diseases (CVDs) and for many types of cancers. Despite recent policies, 1.1 billion people are active smokers and tobacco is the leading cause of mortality and illness throughout the world. The aim of this work was to identify smoking cessation interventions which could be implemented in primary care and/or at a community level.Methods: A systematic review of CVDs prevention guidelines was realized using the ADAPTE Process. These were identified on G-I-N and TRIP databases. Additionally, a purposive search for national guidelines was successfully undertaken. Guidelines focusing on non-pharmacological lifestyle interventions, published or updated after 2011, were included. Exclusion criteria were specific populations, management of acute disease and exclusive focus on pharmacological or surgical interventions. After appraisal with the AGREE II tool, high-quality guidelines were included for analysis. High-grade recommendations and the supporting bibliographic references were extracted. References had to be checked in detail where sufficient information was not available in the guidelines.Results: Nine hundred and ten guidelines were identified, 47 evaluated with AGREE II and 26 included. Guidelines recommended that patients quit smoking and that health care professionals provided advice to smokers but failed to propose precise implementation strategies for such recommendations. Only two guidelines provided specific recommendations. In the guideline bibliographic references, brief advice (BA) and multiple session strategies were identified as effective interventions. These interventions used Prochaska theory, motivational interviewing or cognitive-behavioral therapies. Self-help documentation alone was less effective than face-to-face counseling. Community-based or workplace public interventions alone did not seem effective.Discussion: Behavioral change strategies were effective in helping patients to give up smoking. BA alone was less effective than multiple session strategies although it required fewer resources. Evidence for community-based interventions effectiveness was weak, mainly due to the lack of robust studies.Keywords: cardiovascular diseases, primary prevention, smoking cessation, primary health care

Abstract Background Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM) has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers. Methods We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1), aldolase C (Aldoc), triosephosphate isomerase (Tpi1), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), phosphoglycerate mutase 1 (Pgam1), phosphoglycerate kinase 1 (Pgk1) and enolase 2 (Eno2). The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats. Results Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls. Conclusions This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia.

A method to improve the reliability of data transmission between two terminals without using multiple antennas is cooperative communication, where spatial diversity is introduced by the presence of a relay terminal. The Quantize and Forward (QF) protocol is suitable to implement in resource constraint relays, because of its low complexity. In prior studies of the QF protocol, all channel parameters are assumed to be perfectly known at the destination, while in reality these need to be estimated. This paper proposes a novel quantization scheme, in which the relay compensates for the rotation caused by the source-relay channel, before quantizing the phase of the received M-PSK data symbols. In doing so, channel estimation at the destination is greatly simplified, without significantly increasing the complexity of the relay terminals. Further, the destination applies the expectation maximization (EM) algorithm to improve the estimates of the source-destination and relay-destination channels. The resulting performance is shown to be close to that of a system with known channel parameters.

Purpose: Cardiovascular diseases (CVD) are the leading cause of death globally. The current model of care for high-income countries involves preventive medication and highly trained healthcare professionals, which is expensive and not transposable to low-income countries. An innovative, effective approach adapted to limited human, technical, and financial resources is required. Measures to reduce CVD risk factors, including diet, are proven to be effective. The survey "Scaling-up Packages of Interventions for Cardiovascular disease prevention in selected sites in Europe and Sub-Saharan Africa" aims to develop non-pharmacological cardiovascular prevention and control programs in primary care and community settings in high, middle, and low-income countries. This review aims to identify the existing, validated dietary interventions for primary CVD prevention from national and international clinical guidelines that can be implemented in primary care and communities., Methods: A systematic review of CVD prevention guidelines was conducted between September 2017 and March 2023 using the Turning Research Into Practice medical database, the Guidelines International Network, and a purposive search. The ADAPTE procedure was followed. Two researchers independently conducted the searches and appraisals. Guidelines published after 01/01/2012 addressing non-pharmacological, dietary interventions for primary CVD prevention or CVD risk factor management, in the adult general population in primary care or in community settings were included and appraised using the Appraisal of Guidelines Research and Evaluation II score. Individual dietary recommendations and the studies supporting them were extracted. Then supporting data about each specific dietary intervention were extracted into a matrix., Results: In total, 1375 guidelines were identified, of which 39 were included. From these, 383 recommendations, covering 10 CVD prevention themes were identified. From these recommendations, 165 studies for effective dietary interventions for CVD prevention were found. Among these, the DASH diet was the most effective on multiple CVD risk factors. Combining diet with other interventions such as exercise and smoking cessation increased efficacy. No guidelines provided detailed implementation strategies., Conclusion: The DASH diet combined with other interventions was the most effective on an individual basis. However, expansion in the wider population seems difficult, without government support to implement regulations such as reducing salt content in processed food., Trial Registration: Clinical Trials NCT03886064., (© 2023. The Author(s).)

Aim: Our aim was to evaluate the implementation process of a comprehensive cardiovascular disease prevention program in general practice, to enhance understanding of influencing factors to implementation success and sustainability, and to learn how to overcome barriers., Background: Cardiovascular disease and its risk factors are the world's leading cause of mortality, yet can be prevented by addressing unhealthy lifestyle behavior. Nevertheless, the transition toward a prevention-oriented primary health care remains limited. A better understanding of factors facilitating or hindering implementation success and sustainability of prevention programs, and how barriers may be addressed, is needed. This work is part of Horizon 2020 project 'SPICES', which aims to implement validated preventive interventions in vulnerable populations., Methods: We conducted a qualitative process evaluation with participatory action research approach of implementation in five general practices. Data were collected through 38 semi-structured individual and small group interviews with seven physicians, 11 nurses, one manager and one nursing assistant, conducted before, during, and after the implementation period. We applied adaptive framework analysis guided by RE-AIM Qualitative Evaluation for Systematic Translation (RE-AIM QuEST) and Consolidated Framework for Implementation Research (CFIR)., Findings: Multiple facilitators and barriers affected reach of vulnerable target populations: adoption by primary health care providers, implementation and fidelity and intention to maintain the program into routine practice. In addition, our study revealed concrete actions, linked to implementation strategies, that can be undertaken to address identified barriers. Prioritization of prevention in general practice vision, ownership, and shared responsibility of all team members, compatibility with existing work processes and systems, expanding nurse's roles and upskilling competence profiles, supportive financial and regulatory frameworks, and a strong community - health care link are crucial to increase implementation success and long-term maintenance of prevention programs. COVID-19 was a major barrier to the implementation. RE-AIM QuEST, CFIR, and participatory strategies are useful to guide implementation of prevention programs in primary health care.

Cardiovascular diseases are the world's leading cause of mortality, with a high burden especially among vulnerable populations. Interventions for primary prevention need to be further implemented in community and primary health care settings. Context is critically important to understand potential implementation determinants. Therefore, we explored stakeholders' views on the evidence-based SPICES program (EBSP); a multicomponent intervention for the primary prevention of cardiovascular disease, to inform its implementation. In this qualitative study, we conducted interviews and focus groups with 24 key stakeholders, 10 general practitioners, 9 practice nurses, and 13 lay community partners. We used adaptive framework analysis. The Consolidated Framework for Implementation Research guided our data collection, analysis, and reporting. The EBSP was valued as an opportunity to improve risk awareness and health behavior, especially in vulnerable populations. Its relative advantage, evidence-based design, adaptability to the needs and resources of target communities, and the alignment with policy evolutions and local mission and vision, were seen as important facilitators for its implementation. Concerns remain around legal and structural characteristics and intervention complexity. Our results highlight context dimensions that need to be considered and tailored to primary care and community needs and capacities when planning EBSP implementation in real life settings.

Valid and reliable measurement of an individual's knowledge and risk perception is pivotal to monitor and evaluate the effectiveness of interventions aimed at preventing cardiovascular diseases (CVDs). The recently developed Attitudes and Beliefs about Cardiovascular Disease (ABCD) knowledge and risk questionnaire is shown to be valid in England. In this study, we evaluated the psychometric properties of the modified and Dutch (Flemish)-translated ABCD questionnaire using both the classical test and item response theory (IRT) analysis. We conducted a community-based survey among 525 adults in Antwerp city, Belgium. We assessed the item- and scale-level psychometric properties and validity indices of the questionnaire. Parameters of IRT, item scalability, monotonicity, item difficulty and discrimination, and item fit statistics were evaluated. Furthermore, exploratory and confirmatory factorial validity, and internal consistency measures were explored. Descriptive statistics showed that both the knowledge and risk scale items have sufficient variation to differentiate individuals' level of knowledge and risk perception. The overall homogeneity of the knowledge and risk subscales was within the acceptable range (> 0.3). The exploratory and confirmatory factor analyses of the risk scale supported a three-factor solution corresponding to risk perception (F1), perceived benefits and intention to change physical activity (F2), and perceived benefit and intention to change healthy dietary habit (F3). The two parametric logistic (2-PL) and rating scale models showed that the item infit and outfit values for knowledge and risk subscales were within the acceptable range (0.6 to 1.4) for most of the items. In conclusion, this study investigated the Dutch (Flemish) version of the ABCD questionnaire has good psychometric properties to assess CVD related knowledge and risk perception in the adult population. Based on the factor loadings and other psychometric properties, we suggested a shorter version, which has comparable psychometric properties.

Plant hormones are essential for regulating the interactions between plants and their complex biotic and abiotic environments. Each hormone initiates a specific molecular pathway and these different hormone pathways are integrated in a complex network of synergistic, antagonistic and additive interactions. This inter-pathway communication is called hormone crosstalk. By influencing the immune network topology, hormone crosstalk is essential for tailoring plant responses to diverse microbes and insects in diverse environmental and internal contexts. Crosstalk provides robustness to the immune system but also drives specificity of induced defense responses against the plethora of biotic interactors. Recent advances in dry-lab and wet-lab techniques have greatly enhanced our understanding of the broad-scale effects of hormone crosstalk on immune network functioning and have revealed underlying principles of crosstalk mechanisms. Molecular studies have demonstrated that hormone crosstalk is modulated at multiple levels of regulation, such as by affecting protein stability, gene transcription and hormone homeostasis. These new insights into hormone crosstalk regulation of plant defense are reviewed here, with a focus on crosstalk acting on the jasmonic acid pathway in Arabidopsis thaliana, highlighting the transcription factors MYC2 and ORA59 as major targets for modulation by other hormones., (© 2020 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Correct flower formation requires highly specific temporal and spatial regulation of gene expression. In Arabidopsis thaliana the majority of the master regulators that determine flower organ identity belong to the MADS-domain transcription factor family. The canonical DNA binding motif for this transcription factor family is the CArG-box, which has the consensus CC(A/T) 6 GG. However, so far, a comprehensive analysis of MADS-domain binding patterns has not yet been performed., Results: Eight publicly available ChIP-seq datasets of MADS-domain proteins that regulate the floral transition and flower formation were analyzed. Surprisingly, the preferred DNA binding motif of each protein was a CArG-box with an NAA extension. Furthermore, motifs of other transcription factors were found in the vicinity of binding sites of MADS-domain transcription factors, suggesting that interaction of MADS-domain proteins with other transcription factors is important for target gene regulation. Finally, conservation of CArG-boxes between Arabidopsis ecotypes was assessed to obtain information about their evolutionary importance. CArG-boxes that fully matched the consensus were more conserved than other CArG-boxes, suggesting that the perfect CArG-box is evolutionary more important than other CArG-box variants., Conclusion: Our analysis provides detailed insight into MADS-domain protein binding patterns. The results underline the importance of an extended version of the CArG-box and provide a first view on evolutionary conservation of MADS-domain protein binding sites in Arabidopsis ecotypes.

Introduction: Oxidative stress seems to be a role in the atherosclerosis process, but research in human beings is scarce., Objective: To evaluate the role of oxidative stress on human aortas of patients submitted to surgical treatment for advanced aortoiliac occlusive disease., Methods: Twenty-six patients were divided into three groups: control group (n=10) formed by cadaveric organ donors; severe aortoiliac stenosis group (patients with severe aortoiliac stenosis; n=9); and total aortoiliac occlusion group (patients with chronic total aortoiliac occlusion; n=7). We evaluated the reactive oxygen species concentration, nicotinamide adenine dinucleotide phosphate-oxidase, superoxide dismutase and catalase activities as well as nitrite levels in samples of aortas harvested during aortofemoral bypass for treatment of advanced aortoiliac occlusive disease., Results: We observed a higher level of reactive oxygen species in total aortoiliac occlusion group (48.3±9.56 pmol/mg protein) when compared to severe aortoiliac stenosis (33.5±7.4 pmol/mg protein) and control (4.91±0.8 pmol/mg protein) groups (P<0.05). Nicotinamide adenine dinucleotide phosphate oxidase activity was also higher in total aortoiliac occlusion group when compared to the control group (3.81±1.7 versus 1.05±0.31 µmol/min.mg protein; P<0.05). Furthermore, superoxide dismutase and catalase activities were significantly higher in the severe aortoiliac stenosis and total aortoiliac occlusion groups when compared to the control cases (P<0.05). Nitrite concentration was smaller in the severe aortoiliac stenosis group in comparing to the other groups., Conclusion: Our results indicated an increase of reactive oxygen species levels and nicotinamide adenine dinucleotide phosphate-oxidase activity in human aortic samples of patients with advanced aortoiliac occlusive disease. The increase of antioxidant enzymes activities may be due to a compensative phenomenon to reactive oxygen species production mediated by nicotinamide adenine dinucleotide phosphate oxidase. This preliminary study offers us a more comprehensive knowledge about the role of oxidative stress in advanced aortoiliac occlusive disease in human beings.

Purpose: To evaluated the role of oxidative stress on aging process in patients submitted to carotid endarterectomy., Methods: Twenty patients were divided into two groups: older group (≥ 70 years old); and the younger group (< 70 years old). We evaluated the reactive oxygen species (ROS) concentration, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, superoxide dismutase (SOD) and catalase (CAT) activities as so as nitrite levels in fragments of carotid arteries harvested during carotid endarterectomy for treatment of high grade carotid stenosis., Results: We observed a higher levels of ROS and NADPH oxidase activity in the older group (p<0.05). Furthermore, the nitrite concentration was lower in the older group (14.55 ± 5.61 x 10-3 versus 26.42 ± 8.14 x 10-3 µM; p=0.0123). However, the activities of antioxidant enzymes (CAT and SOD) were similar in both the groups., Conclusions: : Arterial aging is associated with increased concentrations of oxygen species and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity as so as nitrite reduction in human carotid artery specimens. Maybe therapies that block NADPH oxidase activity and enhance nitrite stores would be a good strategy to reduce the effect of oxidative stress in arterial aging.

Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinson's disease (PD). We have characterized the dual adenosine A2A/A1 receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50's of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D2 antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinson's disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD.

We present a patient with therapy resistant multicentric reticulohistiocytosis (MRH). MRH is a rare granulomatous, multisystem disease characterised most frequently by disfiguring papulonodular skin lesions and sometimes a destructive polyarthritis, though any organ can be involved. Abnormal histiocytic reactions to an undetermined stimulus (possibly an associated mycobacterial infection, auto immune process or neoplastic process) have been proposed as an underlying mechanism. The diagnosis is confirmed by histopathology of the cutaneous nodules and/or synovial membrane by the presence of CD68-positive histiocytes and multinucleated giant cells with an eosinophilic 'ground-glass' cytoplasm. Recent studies have identified TNFalpha and other inflammatory cytokines to be highly expressed in the synovium and synovial fluid of affected joints in patients with MRH. Based on these findings, we treated our patient with infliximab in combination with methotrexate with marked improvement of morning stiffness, tender and swollen joint count, visual analogue scale and health assessment questionnaire after his third infusion. However, the nodules did not markedly resolve. When treating patients with MRH with TNFa neutralizing drugs, one has to keep the possible association with malignancy in 15-30% of cases in mind and these products should be used with caution.

Objectives: TNF-alpha inhibition therapy affects the systemic immune response in rheumatoid arthritis by influencing T cell subtypes (Th1, Th2, Treg), but its effect on the intracellular signal transduction in T cells remains largely unexplored. Here we studied the activation of Th1-associated signalling molecule STAT4 and Th2-associated STAT6 in CD4+ T cells., Methods: Eight rheumatoid arthritis patients were studied before and after 12 weeks of adalimumab therapy and compared to 8 healthy individuals. Peripheral blood mononuclear cells (PBMC) were analysed flow cytometrically either directly after isolation or after 24 hours of anti-CD3/anti-CD28 stimulation, to determine spontaneous and IL-4/IL-12-induced STAT4 and STAT6 phosphorylation in CD4+ T cells. Cytokine production by stimulated PBMC was measured in the supernatant using a cytometric bead array. Non-parametric statistical tests were applied., Results: After adalimumab therapy, phospho-STAT6 increased, both in freshly isolated and anti-CD3/anti-CD28-stimulated CD4+ T cells. The STAT6 response to brief IL-4 stimulation did not change. In healthy individuals and adalimumab-treated patients, anti-CD3/anti-CD28 induced the phosphorylation of STAT4, but not in untreated patients. IFN-gamma production in untreated patients was significantly lower than in healthy individuals or adalimumab-treated patients. In contrast, the production of IL-4, IL-6 and IL-12 was not influenced., Conclusions: Adalimumab therapy increases Th2-associated STAT6 phosphorylation and restores the activation-induced STAT4 phosphorylation to the levels in healthy individuals. This advocates against a pro-inflammatory effect of Th1-associated STAT4 and might provide an explanation for the influence of TNF inhibition therapy on the systemic T cell response in rheumatoid arthritis.

Objective: To investigate whether anti-TNF therapy could have an effect on dendritic cells (DCs) and regulatory T cells in rheumatoid arthritis (RA) patients., Methods: A four-colour flow cytometric technique was used to measure CD4+CD25+ T cells i.e. CD4+CD25high+ (regulatory T cells) and CD4+CD25low+ (activated T cells)), DCs as well as the in vitro, intracellular, lipopolysaccharide-stimulated cytokine production of DCs., Results: Clinical and laboratory parameters of disease activity decreased after anti-TNF treatment. Before anti-TNF therapy, RA patients demonstrated a decreased count of Th2-promoting lymphoid DCs as compared to controls and after anti-TNF therapy this decrease was sustained. Intracellular cytokine production was only found in the myeloid DCs population and there was a higher production of TNF-alpha and IL1-b as compared to healthy controls. Treatment did not alter this cytokine production. Before anti-TNF therapy, the percentage CD4+CD25+ T cells was significantly elevated in RA patients than in healthy controls., Conclusion: These results demonstrate anti-TNF to be a potent anti-inflammatory drug, as mirrored by the decrease in clinical and biological parameters as well as the decrease in activated CD4+ T cells. However, in this study no demonstrable effect on DCs and regulatory T cells was found.

Antagonism of the discriminative stimulus properties of 10 mg/kg cocaine was studied in rats by use of the dopamine D1 antagonist SCH 23390 and the D2 antagonist haloperidol. Whereas SCH 23390 and haloperidol were by themselves unable to antagonize the cueing properties of cocaine, the combination of both dopamine antagonists resulted in a complete blockade of the cocaine cue. In the presence of a fixed dose of 0.01 and 0.04 mg/kg haloperidol, the ED50's (it is the effective dose in 50% of the animals) of SCH 23390 for cocaine antagonism were 0.043 and 0.012 mg/kg, respectively. Similarly, the ED50's of haloperidol in combination with 0.01 and 0.04 mg/kg SCH 23390 were 0.021 and 0.024 mg/kg. The combined treatment of haloperidol and SCH 23390 resulted in strong response-rate reductions. At all combination regimens resulting in a complete blockade of the cocaine cue, response rate was reduced to less than 20% of the control values. These results indicate that the cueing properties of cocaine are both dopamine D1- and D2-mediated and that a combined antagonism of both receptor subtypes can lead to a complete antagonism of the cueing properties of cocaine which is associated with severe attenuation of response rate.