Circadian ABCG2 Expression Influences the Brain Uptake of Donepezil across the Blood-Cerebrospinal Fluid Barrier.

Donepezil (DNPZ) is a cholinesterase inhibitor used for the management of Alzheimer's disease (AD) and is dependent on membrane transporters such as ABCG2 to actively cross brain barriers and reach its target site of action in the brain. Located in the brain ventricles, the choroid plexus (CP) forms an interface between the cerebrospinal fluid (CSF) and the bloodstream, known as the blood-CSF barrier (BCSFB). Historically, the BCSFB has received little attention as a potential pathway for drug delivery to the central nervous system (CNS). Nonetheless, this barrier is presently viewed as a dynamic transport interface that limits the traffic of molecules into and out of the CNS through the presence of membrane transporters, with parallel activity with the BBB. The localization and expression of drug transporters in brain barriers represent a huge obstacle for drug delivery to the brain and a major challenge for the development of therapeutic approaches to CNS disorders. The widespread interest in understanding how circadian clocks modulate many processes that define drug delivery in order to predict the variability in drug safety and efficacy is the next bridge to improve effective treatment. In this context, this study aims at characterizing the circadian expression of ABCG2 and DNPZ circadian transport profile using an in vitro model of the BCSFB. We found that ABCG2 displays a circadian pattern and DNPZ is transported in a circadian way across this barrier. This study will strongly impact on the capacity to modulate the BCSFB in order to control the penetration of DNPZ into the brain and improve therapeutic strategies for the treatment of AD according to the time of the day.

Atherosclerotic plaque features relevant to rupture-risk detected by clinical photon-counting CT ex vivo: a proof-of-concept study.

BACKGROUND: To identify subjects with rupture-prone atherosclerotic plaques before thrombotic events occur is an unmet clinical need. Thus, this proof-of-concept study aims to determine which rupture-prone plaque features can be detected using clinically available photon-counting computed tomography (PCCT). METHODS: In this retrospective study, advanced atherosclerotic plaques (ex vivo, paraffin-embedded) from the Carotid Plaque Imaging Project were scanned by PCCT with reconstructed energy levels (45, 70, 120, 190 keV). Density in HU was measured in 97 regions of interest (ROIs) representing rupture-prone plaque features as demonstrated by histopathology (thrombus, lipid core, necrosis, fibrosis, intraplaque haemorrhage, calcium). The relationship between HU and energy was then assessed using a mixed-effects model for each plaque feature. RESULTS: Plaques from five men (age 79 ± 8 [mean ± standard deviation]) were included in the study. Comparing differences in coefficients (b1diff) of matched ROIs on plaque images obtained by PCCT and histology confirmed that calcium was distinguishable from all other analysed features. Of greater novelty, additional rupture-prone plaque features proved discernible from each other, particularly when comparing haemorrhage with fibrous cap (p = 0.017), lipids (p = 0.003) and necrosis (p = 0.004) and thrombus compared to fibrosis (p = 0.048), fibrous cap (p = 0.028), lipids (p = 0.015) and necrosis (p = 0.017). CONCLUSIONS: Clinically available PCCT detects not only calcification, but also other rupture-prone features of human carotid plaques ex vivo. RELEVANCE STATEMENT: Improved atherosclerotic plaque characterisation by photon-counting CT provides the ability to distinguish not only calcium, but also rupture-prone plaque features such as haemorrhage and thrombus. This may potentially improve monitoring and risk stratification of atherosclerotic patients in order to prevent strokes. KEY POINTS: • CT of atherosclerotic plaques mainly detects calcium. • Many components, such as intra-plaque haemorrhage and lipids, determine increased plaque rupture risk. • Ex vivo carotid plaque photon-counting CT distinguishes haemorrhage and thrombus. • Improved plaque photon-counting CT evaluation may refine risk stratification accuracy to prevent strokes.

Type 2 diabetes exacerbates changes in blood pressure-independent arterial stiffness: cross-sectional and longitudinal evidence from the SUMMIT study.

Greater central artery stiffness is observed in people with type 2 diabetes (T2DM). Elevated blood pressure (BP) and altered arterial wall structure/composition in T2DM are generally considered as main drivers for this alteration. However, because conventional arterial stiffness measures are BP-dependent and as such an influence of BP remains in a measure, it is unclear if greater central artery stiffness is a function of greater BP, or due to changes in the structure and composition of the arterial wall. We aimed to measure BP-independent arterial stiffness (ß0) cross-sectionally and longitudinally in T2DM. We studied 753 adults with T2DM (DM+) and 436 adults without (DM-) at baseline (Phase 1), and 310 DM+ and 210 DM- adults at 3-yr follow-up (Phase 2). We measured carotid-femoral pulse wave velocity and used it to calculate ß0. In Phase 1, ß0 was significantly greater in DM+ than DM- after adjusting for age and sex [27.5 (26.6-28.3) vs. 23.6 (22.4-24.8) au, P < 0.001]. Partial correlation analyses after controlling for age and sex showed that ß0 was significantly associated with hemoglobin A1c (r = 0.15 P < 0.001) and heart rate [(HR): r = 0.23 P < 0.001)] in DM+. In Phase 2, percentage-change in ß0 was significantly greater in DM+ than DM- [19.5 (14.9-24.0) vs. 5.0 (-0.6 to 10.6) %, P < 0.001] after adjusting for age, sex, and baseline ß0. ß0 was greater in DM+ than DM- and increased much more in DM+ than in DM- over 3 yr. This suggests that T2DM exacerbates BP-independent arterial stiffness and may have a complemental utility to existing arterial stiffness indices.NEW & NOTEWORTHY We demonstrate in this study a greater BP-independent arterial stiffness ß0 in people with type 2 diabetes (T2DM) compared to those without, and also a greater change in ß0 over 3 yr in people with T2DM than those without. These findings suggest that the intrinsic properties of the arterial wall may change in a different and more detrimental way in people with T2DM and likely represents accumulation of cardiovascular risk.

Plasma levels of PRO-C3, a type III collagen synthesis marker, are associated with arterial stiffness and increased risk of cardiovascular death.

BACKGROUND AND AIMS: The N-terminal propeptide of type III collagen (PRO-C3) assay measures a pro-peptide released during type III collagen synthesis, an important feature of arterial stiffening and atherogenesis. There is a clinical need for improved non-invasive, cheap and easily accessible methods for evaluating individuals at risk of cardiovascular disease (CVD). In this study, we investigate the potential of using circulating levels of PRO-C3 to mark the degree of vascular stenosis and risk of cardiovascular events. METHODS: Baseline plasma levels of PRO-C3 were measured by ELISA in subjects belonging to the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort (N = 1354). Associations between PRO-C3 levels with vascular characteristics, namely stiffness and stenosis, and risk of future cardiovascular events were explored. Subjects were followed up after a median of 35 months (interquartile range 34-36 months), with recorded outcomes cardiovascular death and all-cause mortality. RESULTS: We found a correlation between PRO-C3 levels and pulse wave velocity (rho 0.13, p = 0.000009), a measurement of arterial stiffness. Higher PRO-C3 levels were also associated with elevated blood pressure (rho 0.07, p = 0.014), as well as risk of cardiovascular mortality over a three-year follow-up period (OR 1.56, confidence interval 1.008-2.43, p = 0.046). CONCLUSIONS: Elevated circulating PRO-C3 levels are associated with arterial stiffness and future cardiovascular death, in the SUMMIT cohort, suggesting a potential value of PRO-C3 as a novel marker for declining vascular health.

Red cell distribution width and its polygenic score in relation to mortality and cardiometabolic outcomes.

Introduction: Elevated red cell distribution width (RDW) has been associated with a range of health outcomes. This study aims to examine prognostic and etiological roles of RDW levels, both phenotypic and genetic predisposition, in predicting cardiovascular outcomes, diabetes, chronic kidney disease (CKD) and mortality. Methods: We studied 27,141 middle-aged adults from the Malmö Diet and Cancer study (MDCS) with a mean follow up of 21 years. RDW was measured with a hematology analyzer on whole blood samples. Polygenic scores for RDW (PGS-RDW) were constructed for each participant using genetic data in MDCS and published summary statistics from genome-wide association study of RDW (n = 408,112). Cox proportional hazards regression was used to assess associations between RDW, PGS-RDW and cardiovascular outcomes, diabetes, CKD and mortality, respectively. Results: PGS-RDW was significantly associated with RDW (Pearson's correlation coefficient = 0.133, p < 0.001). RDW was significantly associated with incidence of stroke (hazard ratio (HR) per 1 standard deviation = 1.06, 95% confidence interval (CI): 1.02-1.10, p = 0.003), atrial fibrillation (HR = 1.09, 95% CI: 1.06-1.12, p < 0.001), heart failure (HR = 1.13, 95% CI: 1.08-1.19, p < 0.001), venous thromboembolism (HR = 1.21, 95% CI: 1.15-1.28, p < 0.001), diabetes (HR = 0.87, 95% CI: 0.84-0.90, p < 0.001), CKD (HR = 1.08, 95% CI: 1.03-1.13, p = 0.004) and all-cause mortality (HR = 1.18, 95% CI: 1.16-1.20, p < 0.001). However, PGS-RDW was significantly associated with incidence of diabetes (HR = 0.96, 95% CI: 0.94-0.99, p = 0.01), but not with any other tested outcomes. Discussion: RDW is associated with mortality and incidence of cardiovascular diseases, but a significant association between genetically determined RDW and incident cardiovascular diseases were not observed. However, both RDW and PGS-RDW were inversely associated with incidence of diabetes, suggesting a putative causal relationship. The relationship with incidence of diabetes needs to be further studied.

Genetic Predisposition to Elevated Levels of Circulating ADAM17 Is Associated with the Risk of Severe COVID-19.

High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian randomization (MR) analyses demonstrated that a 1 standard deviation increase in genetically determined circulating ADAM17 (extracellular domain) was associated with an increased risk of developing critical ill COVID-19 (odds ratio [OR] = 1.26, 95% confidence interval [CI]:1.03-1.55). The multivariable MR analysis suggested a direct causal role of circulating ADAM17 (extracellular domain) in the risk of developing critical COVID-19 (OR = 1.09; 95% CI:1.01-1.17) when accounting for body mass index. No causal effect for the cytoplasmic domain of ADAM17 on COVID-19 was observed. Our results suggest that an increased genetic susceptibility to elevated levels of circulating ADAM17 (extracellular domain) is associated with a higher risk of suffering from severe COVID-19, strengthening the idea that the timely selective inhibition of ADAM17 could be a potential therapeutic target worthy of investigation.

Invariant natural killer T cells and incidence of first-time coronary events: a nested case-control study.

Aims: Invariant natural killer T (iNKT) cells, a T cell subset that is CD1d-restricted and expresses a semi-invariant T cell receptor, have been proposed to contribute to dyslipidaemia-driven cardiovascular disease due to their ability to specifically recognize lipid antigens. Studies in mice have attributed pro-atherogenic properties to iNKT cells, but studies in humans investigating associations of iNKT cells with incident coronary events (CE) are lacking. Methods and results: Here, we used flow cytometry to enumerate circulating iNKT cells (CD3+ CD1d-PBS57-Tetramer+) in a case-control cohort nested within the prospective population-based Malmö Diet and Cancer Study (n = 416) to explore associations with incident first-time CE during a median follow-up of 14 years. We found a significant inverse association between CD4- and CD8- double negative (DN) iNKT cells and incident CE, with an odds ratio of 0.62 [95% confidence interval (CI) 0.38-0.99; P = 0.046] comparing the highest vs. the lowest tertile of DN iNKT cells. The association remained significant after adjustment for cardiovascular risk factors with an odds ratio of 0.57 (95% CI 0.33-0.99; P = 0.046). In contrast, total iNKT cells were not significantly associated with incident CE after adjustment, with an odds ratio of 0.74 (95% CI 0.43-1.27; P = 0.276). Conclusion: Our findings indicate that animal studies suggesting an atherosclerosis-promoting role for iNKT cells may not translate to human cardiovascular disease as our data show an association between high circulating numbers of DN iNKT cells and decreased risk of incident CE.

Task Force for a rapid response to an outbreak of severe acute hepatitis of unknown aetiology in children in Portugal in 2022.

On 5 April 2022, the United Kingdom reported an increase of cases of severe acute hepatitis of unknown aetiology in children, several needing hospitalisation and some required liver transplant or died. Thereafter, 35 countries reported probable cases, almost half of them in Europe. Facing the alert, on 28 April, Portugal created a multidisciplinary Task Force (TF) for rapid detection of probable cases and response. The experts of the TF came from various disciplines: clinicians, laboratory experts, epidemiologists, public health experts and national and international communication. Moreover, Portugal adopted the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) case definition and recommendations. By 31 December 2022, 28 probable cases of severe acute hepatitis of unknown aetiology were reported: 16 male and 17 aged under 2 years. Of these cases, 23 were hospitalised but none required liver transplant or died. Adenovirus was detected from nine of 26 tested cases. No association was observed between adenovirus infection and hospital admission after adjusting for age, sex and region in a binomial regression model. The TF in Portugal may have contributed to increase awareness among clinicians, enabling early detection and prompt management of the outbreak.

Circulating soluble IL-6 receptor associates with plaque inflammation but not with atherosclerosis severity and cardiovascular risk.

BACKGROUND: The residual cardiovascular risk in subjects receiving guideline-recommended therapy is related to persistent vascular inflammation and IL-6 represents a target for its treatment. IL-6 binds to receptors on leukocytes and hepatocytes and/or by forming complexes with soluble IL-6 receptors (sIL-6R) binding to gp130 which is present on all cells. Here we aimed to estimate the associations of these two pathways with risk of cardiovascular disease (CVD). METHODS: IL-6 and sIL-6R were analyzed using the proximity extension assay. Baseline plasma samples were obtained from participants in the prospective Malmö Diet and Cancer (MDC) study (n = 4661), the SUMMIT VIP study (n = 1438) and the Carotid Plaque Imaging Project (CPIP, n = 285). Incident clinical events were obtained through national registers. Plaques removed at surgery were analyzed by immunohistochemistry and biochemical methods. RESULTS: During 23.1 ± 7.0 years follow-up, 575 subjects in the MDC cohort suffered a first myocardial infarction. Subjects in the highest tertile of IL-6 had an increased risk compared to the lowest tertile (HR and 95% CI 2.60 [2.08-3.25]). High plasma IL-6 was also associated with more atherosclerosis, increased arterial stiffness, and impaired endothelial function in SUMMIT VIP, but IL-6 was only weakly associated with plaque inflammation in CPIP. sIL-6R showed no independent association with risk of myocardial infarction, atherosclerosis severity or vascular function, but was associated with plaque inflammation. CONCLUSIONS: Our findings show that sIL-6R is a poor marker of CVD risk and associated vascular changes. However, the observation that sIL-6R reflects plaque inflammation highlights the complexity of the role of IL-6 in CVD.

Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes

Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters expression, with a focus in the most important ATP-binding cassette transporters involved in multidrug resistance. (AU)

Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture.

BACKGROUND: Atherosclerotic plaque ruptures, triggered by blood flow-associated biomechanical forces, cause most myocardial infarctions and strokes. OBJECTIVES: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. METHODS: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort. RESULTS: In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk. CONCLUSIONS: Our findings show plaque site-specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture.

Transforming growth factor-ß2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events.

AIMS: Transforming growth factor-beta (TGF-ß) exists in three isoforms TGF-ß1, -ß2, and -ß3. TGF-ß1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-ß2 and -ß3 in atherosclerosis remains to be investigated.This study explores the association of the three isoforms of TGF-ß with plaque stability in the human atherosclerotic disease. METHODS AND RESULTS: TGF-ß1, -ß2, and -ß3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-ß2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events.TGF-ß2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-ß2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-ß2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-ß2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-ß2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-ß2 levels had a lower risk to suffer from future CV events. CONCLUSIONS: TGF-ß2 is the most abundant TGF-ß isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.

High-quality annotations for deep learning enabled plaque analysis in SCAPIS cardiac computed tomography angiography.

Background: Plaque analysis with coronary computed tomography angiography (CCTA) is a promising tool to identify high risk of future coronary events. The analysis process is time-consuming, and requires highly trained readers. Deep learning models have proved to excel at similar tasks, however, training these models requires large sets of expert-annotated training data. The aims of this study were to generate a large, high-quality annotated CCTA dataset derived from Swedish CArdioPulmonary BioImage Study (SCAPIS), report the reproducibility of the annotation core lab and describe the plaque characteristics and their association with established risk factors. Methods and results: The coronary artery tree was manually segmented using semi-automatic software by four primary and one senior secondary reader. A randomly selected sample of 469 subjects, all with coronary plaques and stratified for cardiovascular risk using the Systematic Coronary Risk Evaluation (SCORE), were analyzed. The reproducibility study (n = 78) showed an agreement for plaque detection of 0.91 (0.84-0.97). The mean percentage difference for plaque volumes was -0.6% the mean absolute percentage difference 19.4% (CV 13.7%, ICC 0.94). There was a positive correlation between SCORE and total plaque volume (rho = 0.30, p < 0.001) and total low attenuation plaque volume (rho = 0.29, p < 0.001). Conclusions: We have generated a CCTA dataset with high-quality plaque annotations showing good reproducibility and an expected correlation between plaque features and cardiovascular risk. The stratified data sampling has enriched high-risk plaques making the data well suited as training, validation and test data for a fully automatic analysis tool based on deep learning.

Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk.

AIMS: Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. METHODS AND RESULTS: Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe-/- mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1ß secretion by macrophages in the plaque. CONCLUSIONS: We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe-/- mice. These results point toward a promising treatment to combat atherosclerosis.

Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes.

Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters expression, with a focus in the most important ATP-binding cassette transporters involved in multidrug resistance.

Tricarbonyl-Pyrazine-Molybdenum(0) Metal-Organic Frameworks for the Storage and Delivery of Biologically Active Carbon Monoxide.

Metal-organic frameworks (MOFs) have high potential as nanoplatforms for the storage and delivery of therapeutic gasotransmitters or gas-releasing molecules. The aim of the present study was to open an investigation into the viability of tricarbonyl-pyrazine-molybdenum(0) MOFs as carbon monoxide-releasing materials (CORMAs). A previous investigation found that the reaction of Mo(CO)6 with excess pyrazine (pyz) in a sealed ampoule gave a mixture comprising a major triclinic phase with pyz-occupied hexagonal channels, formulated as fac-Mo(CO)3(pyz)3/2·1/2pyz (Mo-hex), and a minor dense cubic phase, formulated as fac-Mo(CO)3(pyz)3/2 (Mo-cub). In the present work, an open reflux method in toluene has been optimized for the large-scale synthesis of the pure Mo-cub phase. The crystalline solids Mo-hex and Mo-cub were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), FT-IR and FT-Raman spectroscopies, and 13C{1H} cross-polarization (CP) magic-angle spinning (MAS) NMR spectroscopy. The release of CO from the MOFs was studied by the deoxy-myoglobin (deoxy-Mb)/carbonmonoxy-myoglobin (MbCO) UV-vis assay. Mo-hex and Mo-cub release CO upon contact with a physiological buffer in the dark, delivering 0.35 and 0.22 equiv (based on Mo), respectively, after 24 h, with half-lives of 3-4 h. Both materials display high photostability such that the CO-releasing kinetics is not affected by irradiation of the materials with UV light. These materials are attractive as potential CORMAs due to the slow release of a high CO payload. In the solid-state and under open air, Mo-cub underwent almost complete decarbonylation over a period of 4 days, corresponding to a theoretical CO release of 10 mmol per gram of material.

Coronary artery restenosis and target lesion revascularisation in women by pregnancy history.

BACKGROUND: Women's pregnancy history is associated with incident risk of coronary artery disease with some evidence also suggesting a relevance for prognosis following treatment. OBJECTIVES: To study the associations between maternal history of preterm delivery, a history of small for gestational age infant, parity and age at first delivery with clinical restenosis after percutaneous coronary intervention (PCI). METHODS: In this prospective cohort study, we included 6027 women <65 years undergoing their first PCI 2006-2017, merging clinical register data on PCI procedures in Sweden with comprehensive registry data on deliveries since 1973. We used proportional hazards regression to study the association between aspects of pregnancy history and clinical restenosis in per-segment analyses, and with target lesion revascularisation (TLR) in per-patient analyses. We adjusted models for procedural-related and patient-related predictors of restenosis. RESULTS: During 15 981 segment-years of follow-up, 343 (3.7%) events of clinical restenosis occurred. We found no strong evidence of associations between the studied aspects of pregnancy history and clinical restenosis following PCI. For example, the restenosis HR for a history of preterm delivery in the fully adjusted model was 1.09 (95% CI 0.77 to 1.55) and the TLR HR was 1.18 (95% CI 0.91 to 1.52). CONCLUSION: Risk of restenosis following treatment with PCI did not differ by the studied aspects of pregnancy history, including preterm delivery, in young and middle-aged women. Larger studies are needed to obtain more precise estimates.

Genetic Susceptibility to Mood Disorders and Risk of Stroke: A Polygenic Risk Score and Mendelian Randomization Study.

BACKGROUND: Mood disorders and strokes are often comorbid, and their health toll worldwide is huge. This study characterizes prognostic and causal roles of mood disorders in stroke. METHODS: We tested if genetic susceptibilities for mood disorders were associated with all strokes, ischemic strokes in the Malmö Diet and Cancer cohort (24 631 individuals with a median follow-up of 21.3 (interquartile range: 16.6-23.2) years. We further examined the causal effects for mood disorders on all strokes and ischemic strokes using summary statistics from large genome-wide association studies of mood disorders (up to 609 424 individuals, Psychiatric Genomics Consortium), all strokes and ischemic strokes (up to 446 696 individuals, MEGASTROKE Consortium). RESULTS: Among 24 366 stroke-free participants at baseline, 2632 individuals developed strokes, 2172 of them ischemic, during follow-up. After properly adjusting for well-known risk factors, participants in the highest quintile of polygenic risk scores for mood disorders had 1.45× (95% CI, 1.21-1.74) higher risk of strokes and 1.44× (95% CI, 1.18-1.76) higher risk of ischemic strokes compared with the lowest quintile in women. Mendelian randomization analyses suggested that mood disorders had a causal effect on strokes (odds ratio, 1.07 [95% CI, 1.03-1.11]) and ischemic strokes (odds ratio, 1.09 [95% CI, 1.04-1.13]). CONCLUSIONS: Our results suggest a causal role of mood disorders in the risk of stroke. High-risk women could be identified early in life using polygenic risk scores to ultimately prevent mood disorders and strokes.