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.

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.

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.

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.

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.

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.

BACKGROUND: Rare genetic variants and genetic variation at loci in an enhancer in SOX17 (SRY-box transcription factor 17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutations in SOX17 in PAH pathogenesis has not been reported. METHODS: SOX17 expression was evaluated in the lungs and pulmonary endothelial cells (ECs) of patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion were generated to determine the role of SOX17 deficiency in the pathogenesis of PAH. Human pulmonary ECs were cultured to understand the role of SOX17 deficiency. Single-cell RNA sequencing, RNA-sequencing analysis, and luciferase assay were performed to understand the underlying molecular mechanisms of SOX17 deficiency-induced PAH. E2F1 (E2F transcription factor 1) inhibitor HLM006474 was used in EC-specific Sox17 mice. RESULTS: SOX17 expression was downregulated in the lung and pulmonary ECs from patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion induced spontaneously mild pulmonary hypertension. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced pulmonary hypertension in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and antiapoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP (bone morphogenetic protein) signaling. E2F1 signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction. Pharmacological inhibition of E2F1 in Sox17 EC-deficient mice attenuated pulmonary hypertension development. CONCLUSIONS: Our study demonstrated that endothelial SOX17 deficiency induces pulmonary hypertension through E2F1. Thus, targeting E2F1 signaling represents a promising approach in patients with PAH.

Repeat Discectomy for the Management of Same-Level Recurrent Disc Herniation: A Study of 50 Patients.

Background Same-level recurrent disc herniation remains a challenge in spine surgery. Although most surgeons agree on discectomy as the treatment of choice for primary lumbar disc herniation, the management of recurrent disc herniation remains ambiguous and largely depends on the operating surgeon. Many surgeons recommend repeat discectomy over fusion because it is cheaper and less invasive. In this study, we analyzed 50 patients who underwent a repeat discectomy. Materials and methods The patients in the study had previously been managed for lumbar disc herniation and then presented with either recurrent same-level herniation or symptoms attributed to the same level. The patients were then managed with a repeat discectomy without fusion. We analyzed the preoperative and postoperative Oswestry Disability Index (ODI), duration of surgery, blood loss, duration of hospitalization, and complications. Results Fifty patients were included: 27 females (54%), and 23 males (46%). They were followed up for an average of 2.81 years (range: 1-4). The mean duration of hospitalization was 4.06 ± 1.5 days (range: 2-8). The operative time was 104.60 minutes (range: 50-195), with an intraoperative blood loss of 85.40 mL (range: 50-150 mL). Durotomy occurred as a complication in eight (16%) patients. The recurrence rate was 26%, with 36% progressing to fusion. The change in preoperative ODI and postoperative ODI was 20.94 ± 7.24 (6-37), with a p-value of 0.04. There were no long-term complications recorded. Conclusion Repeat discectomy is a good management option for same-level recurrent disc herniation. The procedure is associated with low intraoperative blood loss and a short operating time, but there is a significant risk of durotomy. The risk of recurrence remains a concern due to the progression of degenerative changes, especially in the presence of Modic-2 changes. These advantages and disadvantages should be discussed with patients.

Giant Invasive Intradural Extramedullary Lumbar Schwannoma: A Case Report and Literature Review.

Schwannomas are benign nerve sheath tumors that arise from Schwann cells, which are responsible for producing the myelin sheath that surrounds nerves. They are typically slow-growing and can occur in various locations in the body, including the lumbar region of the spine. We present a case of giant invasive intradural extramedullary schwannoma managed with posterior lumbar interbody fusion (PLIF) and laminectomy with excellent results. A 58-year-old man presented with lower back pain radiating to the right leg for six months. He had no history of trauma or systemic disease. Lumbosacral magnetic resonance imaging (MRI) showed a well-defined mass at the L3-L4 level compressing the right nerve root. The patient was managed with L3-L4-L5 transpedicular fixation and right-side laminectomy L3-L4 for resection of the tumor. Histopathological examination confirmed the diagnosis of schwannoma. The patient had a favorable postoperative recovery and experienced a resolution of symptoms. Lumbar schwannomas are rare they can cause significant symptoms and require appropriate diagnosis and management. Microsurgery is the preferred treatment, and endoscopic microsurgery is the most promising technique.

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.Reprinted from Depress Anxiety 2022; 39:100-112, with permission from John Wiley and Sons. Copyright © 2022.

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.

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.

Rationale: Rare genetic variants and genetic variation at loci in an enhancer in SRY-Box Transcription Factor 17 (SOX17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutation in SOX17 in PAH pathogenesis has not been reported. Objectives: To investigate the role of SOX17 deficiency in pulmonary hypertension (PH) development. Methods: Human lung tissue and endothelial cells (ECs) from IPAH patients were used to determine the expression of SOX17. Tie2Cre-mediated and EC-specific deletion of Sox17 mice were assessed for PH development. Single-cell RNA sequencing analysis, human lung ECs, and smooth muscle cell culture were performed to determine the role and mechanisms of SOX17 deficiency. A pharmacological approach was used in Sox17 deficiency mice for therapeutic implication. Measurement and Main Results: SOX17 expression was downregulated in the lungs and pulmonary ECs of IPAH patients. Mice with Tie2Cre mediated Sox17 knockdown and EC-specific Sox17 deletion developed spontaneously mild PH. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced PH in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and anti-apoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP signaling. E2F Transcription Factor 1 (E2F1) signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction and PH development. Conclusions: Our study demonstrated that endothelial SOX17 deficiency induces PH through E2F1 and targeting E2F1 signaling represents a promising approach in PAH patients.

Exploring nurses' experiences of a tailored intervention to increase MMR vaccine acceptance in a Somali community in Stockholm, Sweden: a qualitative interview study.

OBJECTIVES: To explore nurses' experiences of a tailored intervention that supported them with knowledge and tools to use during encounters and dialogue with parents with low vaccine acceptance. DESIGN: A qualitative study with in-depth interviews conducted in 2017. Data were analysed using thematic analysis. SETTING: This study was part of a multicomponent intervention targeting Somali parents and the nurses at child health centres in the Rinkeby and Tensta neighbourhoods of Stockholm. An area with documented low measles, mumps and rubella (MMR) vaccination coverage. Previous research has revealed that Somali parents in the community delayed MMR vaccination due to fear of autism despite lack of scientific evidence. The interventions were implemented in 2015-2017. PARTICIPANTS: Eleven nurses employed at the child health centres involved in the intervention participated in interviews. The tailored intervention targeting nurses included a series of seminars, a narrative film and an information card with key messages for distribution to parents. RESULTS: The qualitative analysis revealed an overarching theme: perception of improved communication with parents. Two underlying themes were identified: (1) feeling more confident to address parents' MMR vaccine concerns and (2) diverse tools as useful support to dispel myth and reduce language barriers. CONCLUSION: From the nurses' perspective, the tailored intervention was useful to improve communication with parents having vaccine concerns. Nurses have a crucial role in vaccine uptake and acceptance. Interventions aiming to strengthen their communication with parents are therefore essential, especially in areas with lower vaccine acceptance.

Population structure of the Salmonella enterica serotype Oranienburg reveals similar virulence, regardless of isolation years and sources.

Salmonella enterica serotype Oranienburg is a multi-host, ubiquitous, and prevalent Non-typhoidal Salmonella (NTS) in subtropical rivers, particularly in sediments; little studied so far possible the adaptation and establishment of this microorganism based on its genetic content. This study was focused on the first five genomes of S. Oranienburg in sediments through whole-genome sequencing (WGS) and 61 river water genomes isolated in previous studies. Results showed an open pangenome with 5,594 gene clusters (GCs), and the division of their categories showed; 3,303 core genes, 741 persistent genes, 1,282 accessory genes, and 268 unique genes. Additionally, it showed three main subclades within the same serotype and showed a conserved genetic content, suggesting the display of different adaptation strategies to its establishment. Nine genes for antimicrobial resistance were detected: aac (6') - Iy, H-NS, golS, marA, mdsABC, mdtK, and sdiA, and a mutation in the parC gene p. T57S generating a resistance. In addition, virulence genes and pathogenicity islands (SPI's) were analyzed, finding 92 genes and an identity above 80 % in the SPI's 1 to 5, and the centisomes 54 and 63. The environmental strains of S. Oranienburg do not represent a concern as multidrug resistance (MDR) bacterium; however, virulence genes remain a potential health risk. This study contributes to understanding its adaptation to aquatic environments in Mexico.

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.

[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.

Design and implementation of tailored intervention to increase vaccine acceptance in a Somali community in Stockholm, Sweden - based on the Tailoring Immunization Programmes approach.

Objectives: Sweden has had a high and stable vaccination coverage for measles-mumps-rubella (MMR) vaccine (>96%) through the national immunization program (NIP), but coverage rates highlight local pockets of lower vaccination coverage. This project addressed low MMR vaccine acceptance among parents in a Somali community, in Stockholm. The objective of the intervention was to increase vaccine confidence and MMR-vaccine uptake and also to inform practices addressing vaccine acceptance. Study design: This paper describes the design and implementation of a multi-component intervention based on the Tailoring Immunization Programmes (TIP) approach, developed by the WHO European Regional Office. Methods: The theoretical underpinning of TIP is the Capability, Opportunity, and Motivation Model (COM-B model) and Behaviour Change Wheel framework (BCW), adapted for vaccination. The COM-model was used to identify barriers and drivers to vaccination and intervention types. The TIP-phases described in this paper are: pre-TIP (planning), three succeeding TIP phases (situational analysis, formative research, intervention design) and the post-TIP phase (implementation). Results: The situation analysis and formative research revealed that parents feared the MMR vaccine due to autism or that their child would stop talking following vaccination, despite lack of scientific evidence for an association between autism and MMR vaccines. Barriers were linked to their associated COM-B factors and mapped to appropriate intervention types for two target groups: Somali parents and nurses at the Child Health Centres (CHC). Selected intervention types targeting parents were education, persuasion and modelling whereas education and training were selected for CHC nurses. The intervention activities included community engagement for parents, while the activities for nurses focused on improving encounters and dialogue with parents having low vaccine acceptance. Following the intervention design the activities were developed, pilot tested and implemented. Conclusion: This study confirm that the TIP approach is valuable for guiding a stepwise working process for a thorough understanding of barriers and drivers for MMR vaccination among parents in this Somali community. It facilitated the design of a theory and evidence-informed intervention targeting parents and nurses.

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.

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.