Understanding the implementation and sustainability needs of evidence-based programs for racial and ethnic minoritized older adults in under-resourced communities with limited aging services.

BACKGROUND: Evidence-based programs (EBPs) for older adults effectively improve health outcomes. However, there is a limited understanding of the unique needs of service providers as they consider adopting, implementing, and maintaining programs for older minority adults in low-income communities with limited aging services. METHODS: We conducted semi-structured interviews with key informants of community-based organizations (CBOs) to understand implementation and sustainability needs of CBOs within four racial and ethnically diverse Los Angeles County geographic areas. We performed thematic analysis of interview transcripts. RESULTS: Interviews were conducted with representatives from 25 senior-serving agencies providing aging-related EBPs. CBO representatives reported implementing EBPs in 8 domains: Falls Prevention (68%), Mental Health (64%), Caregiver Health (48%), Chronic Disease Management (48%), Diabetes Management (36%), Arthritis Management (28%), Physical Activity (24%), and Multiple Conditions Management (8%). Themes are presented using the six domains of the Bass and Judge framework for factors impacting successful and sustained EBP implementation. CBOs in low-income and diverse communities described unique challenges with tailoring interventions based on local community context (literacy, language), cultural context, and locally available resources (technology, safe community spaces, transportation) and faced resource-intensive administrative burdens through staff turnover, data collection, sustainable funding, and networking. CONCLUSIONS: Serving racial and ethnic communities has unique challenges that require tailored approaches and additional resources to ensure equitable access to EBPs for all communities. We describe suggestions for enhancing the effective adoption of EBPs among service agencies in under-resourced and diverse aging communities serving populations with aging-related health disparities.

Activity of plant essential oils against clinically and environmentally isolated Salmonella enterica serotypes: in vitro assays and molecular docking.

This research aimed to evaluate the antimicrobial activity of essential oils (EOs) against clinically and environmentally isolated Salmonella serotypes. Oregano, thyme, and grapefruit EO compounds were identified, and the antimicrobial activity was evaluated against the S. Saintpaul, Oranienburg, and Infantis serotypes. In addition, molecular docking was performed to explore the possible mechanisms between compounds of EOs with microbial enzymes. Thymol was the main compound identified in oregano (44.0%) and thyme (31%) EOs, while d-limonene was present in a greater proportion in grapefruit EO. Oregano EO had the highest antimicrobial activity, followed by thyme and grapefruit EOs. Oregano and thyme EOs illustrated a greater inhibitory capacity to all serotypes, particularly with the environmental S. Saintpaul. Oregano EO presented values of minimum inhibitory concentration (MIC) and minimum bactericidal concentration of 0.1 µL/mL for all serotypes, while thyme and grapefruit EOs presented MIC values of 0.1 µL/mL for the clinical serotypes S. Infantis and S. Oranienburg, respectively. Molecular docking analysis showed the optimal binding free energies for thymol and carvacrol with glucokinase, ATP-dependent-6-fructokinase, outer membrane porin C, and topoisomerase IV. Our results indicate that these EOs can inhibit clinically and environmentally isolated Salmonella serotypes and can be used as alternatives for developing natural food preservatives.

Biostimulated-sesame sprout extracts as potential agents against Leishmania mexicana.

Leishmania mexicana is one of the causal agents of cutaneous leishmaniasis. Current antileishmanial chemotherapeutics have demonstrated adverse side effects; thus, alternative treatments are needed. In this study, we performed in silico and in vitro analyses of the leishmanicidal potential of the most abundant phenolic compounds identified in black sesame sprouts biostimulated with Bacillus clausii. The molecular docking analysis showed strong interactions (binding free energies between -6.5 and -9.5 kcal/mol) of sesaminol 2-O-triglucoside, pinoresinol dihexoside, isoverbascoside, and apigenin with the arginase, leishmanolysin, cysteine peptidase B, and pyruvate kinase leishmanial enzymes. Furthermore, almost all phenolic compounds interacted with the active site residues of L. mexicana enzymes. In vitro, the B. clausii-biostimulated sprout phenolic extracts and apigenin inhibited the growth of promastigotes with IC50 values of 0.08 mg gallic acid equivalent/mL and 6.42 µM (0.0017 mg/mL), respectively. Additionally, in the macrophage infection model, cells treated with B. clausii-biostimulated sprout phenolic extracts and infected with L. mexicana exhibited significantly (P < 0.05) reduced nitric oxide production and decreased parasite burden. Altogether, our study provides important data related to high efficacy and less toxic natural antileishmanial candidates against promastigotes of L. mexicana.

Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling.

The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix-cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvß1 to establish focal adhesions and promotes nuclear shuttling of Yes-associated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation depends on the small GTPase Rap2 and Hippo pathway and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin ß1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.

[ABSI obesity index and its association with type 2 diabetes mellitus in Chilean adults: a cross-sectional study of the ENS 2016-2017]. / Índice de obesidad ABSI y su asociación con diabetes mellitus tipo 2 en adultos chilenos: un estudio transversal de la ENS 2016-2017.

INTRODUCTION: A Body Shape Index (ABSI) is a new obesity index based on body volume; this has been associated with chronic non-communicable diseases and mortality, independent of the values of the body mass index (BMI); however, its association with type 2 diabetes mellitus (T2DM) in the Chilean adult population is unknown. OBJECTIVE: To determine the association between ABSI, glycemia, glycosylated hemoglobin (HbAc1), and self-reported T2DM in the Chilean adult population. MATERIALS AND METHODS: In a cross-sectional study, 4,874 participants were included (mean age 43.3 years, 50.9% women) from the 2016-2017 National Health Survey. ABSI was calculated according to the proposed formula (based on waist circumference, BMI, and height). The Poisson regression was used to investigate the association between ABSI and T2DM, and linear regression was used to investigate the association between ABSI, glycemia, and HbAc1. Sociodemographic factors, lifestyle, and BMI adjusted the analyses. RESULTS: ABSI was positively associated with glycemia (p < 0.001), HbA1c (p < 0.001), and DMT2 (p < 0.001). In the most adjusted model, for every 0.025 unit increase in ABSI, glycemia increased by 1.78 mg/dL (95% CI: 1.21, 2.35) and HbAc1 by 0.92% (95% CI: 0.49, 1.35). Regarding T2DM, the prevalence ratio was 1.14 (95% CI: 1.09, 1.20), independent of sociodemographic factors, lifestyles, and BMI. CONCLUSIONS: ABSI was linearly associated with a higher probability of suffering from T2DM and higher levels of glycemia and HbA1c in Chilean adults. In this context, ABSI could be a complementary index, independent of BMI, to assess the risk of metabolic disorders associated with obesity.

Endothelial PHD2 deficiency induces nitrative stress via suppression of caveolin-1 in pulmonary hypertension.

BACKGROUND: Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension. However, the role of nitrative stress in the pathogenesis of obliterative vascular remodelling and severe pulmonary arterial hypertension remains largely unclear. METHOD: Our recently identified novel mouse model (Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 (PHD2)) has obliterative vascular remodelling and right heart failure, making it an excellent model to use in this study to examine the role of nitrative stress in obliterative vascular remodelling. RESULTS: Nitrative stress was markedly elevated whereas endothelial caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride or endothelial Nos3 knockdown using endothelial cell-targeted nanoparticle delivery of CRISPR-Cas9/guide RNA plasmid DNA inhibited obliterative pulmonary vascular remodelling and attenuated severe pulmonary hypertension in Egln1Tie2Cre mice. Genetic restoration of Cav1 expression in Egln1Tie2Cre mice normalised nitrative stress, reduced pulmonary hypertension and improved right heart function. CONCLUSION: These data suggest that suppression of Cav1 expression secondary to PHD2 deficiency augments nitrative stress through endothelial nitric oxide synthase activation, which contributes to obliterative vascular remodelling and severe pulmonary hypertension. Thus, a reactive oxygen/nitrogen species scavenger might have therapeutic potential for the inhibition of obliterative vascular remodelling and severe pulmonary arterial hypertension.

Pharmacological and somatic treatment effects on suicide in adults: A systematic review and meta-analysis.

BACKGROUND: Suicide is a public health crisis. We conducted a systematic review and meta-analysis of the effects of psychopharmacologic and somatic therapies on suicide risk. METHODS: A systematic search of MEDLINE for studies evaluating the effects of pharmacologic (excluding antidepressants) or somatic interventions on suicide risk was conducted. Studies were included if they used a comparison group, reported on suicide death, assessed a psychopharmacological or somatic intervention, and included adults. Study quality was assessed using the Newcastle-Ottawa scale. Fifty-seven studies were included from 2940 reviewed citations. RESULTS: In bipolar disorder, lithium was associated with a reduction in the odds of suicide compared to active controls (odds ratio [OR] = .58, p = .005; k = 12) and compared to placebo/no lithium (OR = .46, p = .009; k = 9). In mixed diagnostic samples, lithium was associated with a reduction in the odds of suicide compared to placebo/no lithium (OR = .27, p < .001; k = 12), but not compared to active controls (OR = .89, p = .468; k = 7). In psychotic disorders, clozapine was associated with a reduction in the odds of suicide (OR = .46, p = .007; k = 7). Associations between suicide death and electroconvulsive therapy (OR = .77, p = .053; k = 11), non-clozapine antipsychotics in bipolar disorder (OR = .73, p = .090; k = 6) and antipsychotics in psychotic disorders (OR = .39, p = .069; k = 6) were not significant. There was no consistent relationship between antiepileptic mood stabilizers and suicide. There were insufficient studies to meta-analyze associations of suicide risk with vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, or transcranial direct current stimulation. CONCLUSION: Lithium and clozapine have consistent data supporting protective effects against suicide in certain clinical contexts.

Behavioural insights and the evolving COVID-19 pandemic.

Behavioural sciences have complemented medical and epidemiological sciences in the response to the SARS-CoV-2 pandemic. As vaccination uptake continues to increase across the EU/EEA - including booster vaccinations - behavioural science research remains important for both pandemic policy, planning of services and communication. From a behavioural perspective, the following three areas are key as the pandemic progresses: (i) attaining and maintaining high levels of vaccination including booster doses across all groups in society, including socially vulnerable populations, (ii) informing sustainable pandemic policies and ensuring adherence to basic prevention measures to protect the most vulnerable population, and (iii) facilitating population preparedness and willingness to support and adhere to the reimposition of restrictions locally or regionally whenever outbreaks may occur. Based on mixed-methods research, expert consultations, and engagement with communities, behavioural data and interventions can thus be important to prevent and effectively respond to local or regional outbreaks, and to minimise socioeconomic and health disparities. In this Perspective, we briefly outline these topics from a European viewpoint, while recognising the importance of considering the specific context in individual countries.

In Vitro Intestinal Bioaccessibility and Colonic Biotransformation of Polyphenols from Mini Bell Peppers (Capsicum annuum L.).

To the best of our knowledge, "sweet mini bell" peppers have not been extensively investigated. In this study, we evaluated the bioaccessible phenolic compounds released during intestinal digestion and identified and quantified the microbial metabolites derived from phenolic compounds bioconversion during the in vitro colonic fermentation. A total of 66 phenolic compounds were determined. The results obtained in this study indicate that hydroxycinnamic acids (22 to 32 mg/100 g dw) and flavonoids (99 to 102 mg/100 g dw) headed by quercetin, luteolin and kaempferol glycosidic derivatives were the main bioaccessible phenolic compounds during in vitro intestinal digestion of mini bell peppers. The yellow variety contained the highest concentration of bioaccessible flavonoids (80 mg/100 g dw). For the first time in mini bell peppers, dihydroferulic acid was detected, in the three varieties studied. 3-(4-hydroxyphenyl)propionic acid was the major metabolite found after 12-24 h fermentation of all samples (44 to 102 µM/L). Further cell culture or in vivo studies are needed to elucidate the biological activities of the phenolic compounds identified in mini bell peppers.

Carcinogen-induced tumors in SFN-transgenic mice harbor a characteristic mutation spectrum of human lung adenocarcinoma.

The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen-induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non-small-cell lung cancer (NSCLC). We have previously identified stratifin (SFN) as a potent oncogene, and generated SFN-transgenic (Tg-SPC-SFN+/- ) mice, which express human SFN (hSFN) only in the lung. Here, we have found that carcinogen nicotine-derived nitrosaminoketone (NNK)-induced tumors developing in Tg-SPC-SFN+/- mice show a similar histology to human lung adenocarcinoma and exhibit high hSFN expression. In order to compare the genetic characteristics of Tg-SPC-SFN+/- tumors and human lung adenocarcinoma, the former were subjected to whole-exome sequencing. Interestingly, Tg-SPC-SFN+/- tumors showed the distinct distribution of exonic mutations and high number of mutated genes and transversion. Moreover, Tg-SPC-SFN+/- tumors showed 73 genes that were commonly detected in more than 2 tumors, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients. Additionally, mutated genes in Tg-SPC-SFN+/- tumors were closely associated with key canonical pathways such as PI3K/AKT signaling and apoptosis signaling. These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and Tg-SPC-SFN+/- tumors recapitulate key features of major human lung adenocarcinoma. Therefore, Tg-SPC-SFN+/- mice provide a useful model for clarifying the molecular mechanism underlying lung adenocarcinogenesis.

Effect of river water exposition on adhesion and invasion abilities of Salmonella Oranienburg and Saintpaul.

This study was performed to evaluate in vitro the adherence and invasiveness capacity of Salmonella Oranienburg and Saintpaul (isolated from river water) exposed to laboratory and river water growth conditions and inoculated into epithelial HEp-2 cell. Results showed that Salmonella Oranienburg and Salmonella Saintpaul showed lower ability to adhere and invade epithelial HEp-2 cells under both growth conditions as compared to Salmonella Typhimurium reference strain. S. Oranienburg adhesion capacity was not affected by the growth conditions, while S. Saintpaul exposed to river water significantly (p < 0.05) decreased its adhesion capacity by 75.7 %. On the contrary, S. Oranienburg exposed to river water reduced its invasion efficiency by 80 %, whereas S. Saintpaul showed no differences between growth conditions. In conclusion, this study suggests that the exposure to non-host conditions, such as river water, adversely affects the adhesion and invasiveness of Salmonella serotypes differently, impacting on their ability to re-enter a new host.

Increase of content and bioactivity of total phenolic compounds from spent coffee grounds through solid state fermentation by Bacillus clausii.

Spent coffee grounds are waste material generated during coffee beverage preparation. This by-product disposal causes a negative environmental impact, in addition to the loss of a rich source of nutrients and bioactive compounds. A rotating central composition design was used to determine the optimal conditions for the bioactivity of phenolic compounds obtained after the solid state fermentation of spent coffee grounds by Bacillus clausii. To achieve this, temperature and fermentation time were varied according to the experimental design and the total phenolic and flavonoid content, antioxidant activity and antimicrobial activity were determined. Surface response methodology showed that optimum bioprocessing conditions were a temperature of 37 °C and a fermentation time of 39 h. Under these conditions, total phenolic and flavonoid contents increased by 36 and 13%, respectively, in fermented extracts as compared to non-fermented. In addition, the antioxidant activity was increased by 15% and higher antimicrobial activity was observed against Gram positive and negative bacteria. These data demonstrated that bioprocessing optimization of spent coffee grounds using the surface response methodology was an important tool to improve phenolic extraction, which could be used as an antioxidant and antimicrobial agents incorporated into different types of food products.

Patient and caregiver goals for dementia care.

PURPOSE: Most health outcome measures for chronic diseases do not incorporate specific health goals of patients and caregivers. To elicit patient-centered goals for dementia care, we conducted a qualitative study using focus groups of people with early-stage dementia and dementia caregivers. METHODS: We conducted 5 focus groups with 43 participants (7 with early-stage dementia and 36 caregivers); 15 participants were Spanish-speaking. Verbatim transcriptions were independently analyzed line-by-line by two coders using both deductive and inductive approaches. Coded texts were grouped into domains and developed into a goal inventory for dementia care. RESULTS: Participants identified 41 goals for dementia care within five domains (medical care, physical quality of life, social and emotional quality of life, access to services and supports, and caregiver support). Caregiver goals included ensuring the safety of the person with dementia and managing caregiving stress. Participants with early-stage dementia identified engaging in meaningful activity (e.g., work, family functions) and not being a burden on family near the end of life as important goals. Participants articulated the need to readdress goals as the disease progressed and reported challenges in goal-setting when goals differed between the person with dementia and the caregiver (e.g., patient safety vs. living independently at home). While goals were similar among English- and Spanish-speaking participants, Spanish-speaking participants emphasized the need to improve community education about dementia. CONCLUSIONS: Patient- and caregiver-identified goals for care are different than commonly measured health outcomes for dementia. Future work should incorporate patient-centered goals into clinical settings and assess their usefulness for dementia care.

Inhibition of α-glucosidase activity by potential peptides derived from fermented spent coffee grounds.

The control of α-glucosidase activity has been associated with managing diabetes. We previously identified three peptides with high bioactive indices derived from protein hydrolysates of fermented spent coffee grounds. In this study, the peptides YGF, GMCC, and RMYRY were synthesized and tested in vitro for their α-glucosidase inhibition activity, complemented by in silico analyses. Two of the three peptides significantly inhibited α-glucosidase activity, with the more efficient peptides being YGF and GMCC (0.42 mg/mL), resulting in decreased enzymatic activity of 95.31% and 89.79%, respectively. These peptides exhibited binding free energies with the α-glucosidase complex of -8.5 and - 6.6 kcal/mol, respectively, through hydrogen bonds and van der Waals interactions with amino acids from the active site. Pharmacokinetic analysis indicated that YGF and GMCC profiles were unrelated to toxicity. These results underscore the importance of focusing on food waste bioprocessing products to expand the range of alternatives that could aid in diabetes treatment.

A Novel Animal Model for Pulmonary Hypertension: Lung Endothelial-Specific Deletion of Egln1 in Mice.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by high blood pressure in the pulmonary arteries, which can potentially lead to heart failure over time. Previously, our lab found that endothelia-specific knockout of Egln1, encoding prolyl 4-hydroxylase-2 (PHD2), induced spontaneous pulmonary hypertension (PH). Recently, we elucidated that Tmem100 is a lung-specific endothelial gene using Tmem100-CreERT2 mice. We hypothesize that lung endothelial-specific deletion of Egln1 could lead to the development of PH without affecting Egln1 gene expression in other organs. Tmem100-CreERT2 mice were crossed with Egln1 flox/flox mice to generate Egln1 f/f ;Tmem100-CreERT2 (LiCKO) mice. Western blot and immunofluorescent staining were performed to verify the knockout efficacy of Egln1 in multiple organs of LiCKO mice. PH phenotypes, including hemodynamics, right heart size and function, pulmonary vascular remodeling, were evaluated by right heart catheterization and echocardiography measurements. Tamoxifen treatment induced Egln1 deletion in the lung endothelial cells (ECs) but not in other organs of adult LiCKO mice. LiCKO mice exhibited an increase in right ventricular systolic pressure (RVSP, ~35 mmHg) and right heart hypertrophy. Echocardiography measurements showed right heart hypertrophy, as well as cardiac and pulmonary arterial dysfunction. Pulmonary vascular remodeling, including increased pulmonary wall thickness and muscularization of distal pulmonary arterials, was enhanced in LiCKO mice compared to wild-type mice. Tmem100 promoter-mediated lung endothelial knockout of Egln1 in mice leads to development of spontaneous PH. LiCKO mice could serve as a novel mouse model for PH to study lung and other organ crosstalk.

General Capillary Endothelial Cells Undergo Reprogramming into Arterial Endothelial Cells in Pulmonary Hypertension through HIF-2α/Notch4 Pathway.

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of loss of distal capillary endothelial cells (ECs) and obliterative vascular lesion formation remain unclear. Our recent single-cell RNA sequencing, spatial transcriptomics analysis, RNASCOPE, and immunostaining analysis showed that arterial ECs accumulation and loss of capillary ECs were evident in human PAH patients and pulmonary hypertension (PH) rodents. Pseudotime trajectory analysis of the single-cell RNA sequencing data suggest that lung capillary ECs transit to arterial ECs during the development of PH. Our study also identified CXCL12 as the marker for arterial ECs in PH. Capillary EC lineage tracing approach using capillary specific-Dre;Tdtomato reporter mice demonstrated that capillary ECs gave rise to arterial ECs during PH development. Genetic deletion of HIF-2a or pharmacological inhibition of Notch4 normalized the arterial programming in PH. In conclusion, our study demonstrates that capillary endothelium transits to arterial endothelium through the HIF-2a-Notch4 pathway during the development of PAH. Thus, targeting arterial EC transition might be a novel approach for treating PAH patients.

Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of Egln1Tie2Cre (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both Fabp4 and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/- ,TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that Fabp4/5 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2α expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

Meeting statement: Call to action for step-change in health behaviours.

Background: Enabling, supporting and promoting positive health-related behaviours is critical in addressing the major public health challenges of our time, and the multifaceted nature of behaviours requires an evidence-based approach. This statement seeks to suggest how a much-needed enhanced use of behavioural and cultural science and insights for health could be advanced. Study design and methods: and methods: Public health authorities of Europe and Central Asia and international partner organizations in September 2023 met in Copenhagen, Denmark, to discuss the way forward. Drawing on 1) country reporting to WHO, 2) interview study with public health authorities and 3) the meeting deliberations, this meeting statement was developed. Results: The meeting statement presents a joint call for step-change accelerated use of evidence-based approaches for health behaviours. Actionable next steps for public health authorities and international and regional development partners in health are presented. Conclusions: The way forward involves increased resource allocation, integration of behavioural insights into health strategies, advocacy through case and cost-effectiveness examples and capacity building.

Partial endothelial-to-mesenchymal transition mediated by HIF-induced CD45 in neointima formation upon carotid artery ligation.

AIMS: Endothelial-to-mesenchymal transition (EndMT) is a fundamental process in vascular remodelling. However, the precise regulatory mechanism of vascular remodelling during neointima formation and the source of neointima cells are not entirely understood. METHODS AND RESULTS: To investigate the origin of neointima cells and their relevance to vascular wall remodelling, we used an endothelial cell (EC)-specific lineage tracing system [VE-Cadherin (Cdh5)-BAC-CreERT2 mice] and carotid artery ligation model and showed evidence that resident ECs transdifferentiate into neointima cells with the expression of CD45. During the early stages of neointima formation, ECs transiently expressed CD45, a haematopoietic marker, accompanied by a host of EndMT markers, and CD31 and αSMA were prominently expressed in developing neointima. In vitro, CD45-positive EndMT was induced by stabilization of HIF1α with cobalt chloride or with a VHL inhibitor in human primary ECs, which mimicked the hypoxic condition of the ligated artery, and promoted the formation of an integrin α11-shank-associated RH domain-interacting protein (SHARPIN) complex. Notably, a CD45 phosphatase inhibitor disrupted this integrin α11-SHARPIN complex, thereby destabilizing cell-cell junctions. Deletion of Hif1α in ECs suppressed expression of CD45 and EndMT markers and ameliorated neointima formation. CONCLUSION: These results suggest that the HIF-induced CD45 expression is normally required for the retention of an EC fate and cell-cell junctions, CD45-positive EndMT (termed as 'partial EndMT') contributes to neointima formation and vascular wall remodelling.