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Several factors that underlie health inequality have been studied and defined as the social determinants of health (SDHs). The main SDHs are gender, socioeconomic status (SES), and ethnicity. In this study, disparity was analyzed in the context of vascular diseases (VDs) such as Peripheral Artery Disease (PAD), Chronic Venous Disease (CVD), Abdominal Arterial Aneurysm (AAA), and Carotid Stenosis (CS). This article aims to provide a comprehensive overview of the published evidence of the SDHs in VDs. For this purpose, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Published articles using the Scopus and ScienceDirect databases were searched. The criteria for the articles' inclusion/exclusion were decided using a modified PICOTS framework. For the selected articles, the data sheets were organized in such a way to extract all data of potential relevance. Our findings showed that in VDs, gender, SES, and ethnicity are very important, with some specific problems for VDs analyzed. In conclusion, having detected the presence of SDHs that act negatively on VDs, a model based on action items for the SDHs associated with VDs was proposed. [ABSTRACT FROM AUTHOR]

Placental mesenchymal dysplasia (PMD) is an uncommon placental lesion, which may mimic molar pregnancy at gross and microscopic examination. PMD can be associated with fetal growth restriction, Beckwith-Wiedemann syndrome, intrauterine fetal death, and preterm delivery. Nonetheless, it may also be associated with a normal appearing fetus. Objective: We aimed to emphasize that clinicians, radiologists, and pathologists should be aware of PMD as one of the etiologies of intrauterine growth restriction (IUGR). We presented the case of a 27-year-old gravida 1, para 1 woman who was admitted to Ayatollah Rouhani hospital, in Babol, Iran, at 30 weeks of gestation due to severe IUGR and fetal tachycardia. Ultrasound examination showed uteroplacental insufficiency and increased resistive index (RI) of umbilical artery. At last, a normal female fetus (1320 g) with no definitive anomalies was delivered by cesarean section. Pathological examination revealed cystically dilated stem villi with peripherally located thick-walled muscular stem vessels, and also stromal fibroblasts overgrowth in some stem villi. None of the examined sections revealed trophoblastic proliferation or stromal trophoblastic inclusion. The findings confirmed the diagnosis of PMD. Careful radiological and pathological examination should be performed in the case of IUGR for ruling out the rare placental abnormalities, including PMD. [ABSTRACT FROM AUTHOR]

To investigate the clinical characteristics, risk factors, and outcomes of inpatients with peripheral arterial disease (PAD) including lower extremity PAD, abdominal aortic aneurysm (AAA), and carotid artery disease in a large cohort of critically ill patients aged ≥ 90 years. A retrospective analysis was conducted of all adult patients aged ≥ 90 years consecutively admitted to the intensive care unit at a tertiary care centre in Hamburg, Germany, between 1 January 2008 and 30 April 2019. Multivariable regression and Kaplan–Meier methods were used to determine the independent impact of PAD on short and long term mortality endpoints. The analyses were adjusted for confounding by several sociodemographic and clinical parameters including Charlson Comorbidity Index (CCI) and established clinical risk scores. A total of 1 108 eligible patients were identified (92.3 years, 33% men). Of these, 24% had PAD (9% lower extremity PAD, 2% AAA, 15% coronary artery disease) and 76% did not have any history of PAD and were used as a comparison group. When compared with the comparison group, patients with PAD had a higher CCI (2 vs. 1, p <.001), more often had chronic kidney disease (28% vs. 21%, p =.019), and renal replacement therapy (5% vs. 2%, p =.016). Furthermore, they needed vasopressors (48% vs. 40%, p =.027) and parenteral nutrition (10% vs. 6%, p =.041) more often. After adjusting for confounding, PAD was independently associated with increased in hospital (hazard ratio [HR] 1.97, 95% confidence interval [CI] 1.39 – 2.81, p <.001) and long term mortality rates (HR 1.32, 95% CI 1.05 – 1.66, p =.019). One of four critically ill nonagenarians and centenarians in an ICU in Germany had PAD. PAD was associated with both higher short and long term mortality rates while its impact outweighed higher age. Future studies should address this increasingly important population beyond 89 years of age. [ABSTRACT FROM AUTHOR]

The effectiveness of community-based walking programs for patients with peripheral artery disease (PAD) can be limited by calf claudication during exercise. Recent evidence finds adding carbon fiber ankle foot orthoses (AFO) to a walking program can result in improvements in patient mobility and delay claudication onset when walking. How may carbon fiber AFO alter ankle walking mechanics and corresponding triceps surae muscle recruitment in a manner that could improve patient mobility? In this repeated measures cohort study, fifteen patients with PAD were fit with bilateral AFO before completing self-paced gait analysis including electromyography. Patients were then given standard advice to walk at home using the devices for 12 weeks. Twelve patients completed follow-up testing. There were no significant interactions between main effects for any variable of interest (p ≥ 0.189). Further, there were no within-subjects main effects for testing time for self-selected gait speed or any of the kinetic or kinematic variables (p ≥ 0.435). There were significant main effects for AFO use with reductions in dorsi flexion (p < 0.001), plantar flexion at toe off (p < 0.001), ankle plantar flexor moment (p = 0.037), and ankle plantar flexor power (p < 0.001). Triceps surae recruitment did not change between AFO conditions (p > 0.05). Adding carbon fiber AFO limits peak ankle motion and joint power during self-paced walking for people with PAD while maintaining their walking speed. These gait adaptions were maintained over our 12 weeks of walking practice time. A resulting decrease in plantar flexor power while maintaining gait speed may provide the mechanism by which AFO can delay claudication onset which are major barrier to PAD walking programs. Calf muscle recruitment was maintained when adding the AFO which suggests sufficient muscle exertion could exist to maintain muscle integrity with sustained AFO use. • PAD patients retain their walking speed but reduce ankle power demands by using AFO. • AFO induced ankle power drop stems from limiting ankle motion; not reduced moments. • Reductions in ankle power may explain how AFO can delay walking claudication onset. • Using AFO for PAD did not negatively reduce triceps surae muscle recruitment patterns. • AFO induced alterations in walking patterns did not change with 12 weeks of use. [ABSTRACT FROM AUTHOR]

Xylem anatomy may change in response to environmental or biotic stresses. Vascular occlusion, an anatomical modification of mature xylem, contributes to plant resistance and susceptibility to different stresses. In woody organs, xylem occlusions have been examined as part of the senescence process, but their presence and function in leaves remain obscure. In grapevine, many stresses are associated with premature leaf senescence inducing discolorations and scorched tissue in leaves. However, we still do not know whether the leaf senescence process follows the same sequence of physiological events and whether leaf xylem anatomy is affected in similar ways. In this study, we quantified vascular occlusions in midribs from leaves with symptoms of the grapevine disease esca, magnesium deficiency and autumn senescence. We found higher amounts of vascular occlusions in leaves with esca symptoms (in 27% of xylem vessels on average), whereas the leaves with other symptoms (as well as the asymptomatic controls) had far fewer occlusions (in 3% of vessels). Therefore, we assessed the relationship between xylem occlusions and esca leaf symptoms in four different countries (California in the USA, France, Italy and Spain) and eight different cultivars. We monitored the plants over the course of the growing season, confirming that vascular occlusions do not evolve with symptom age. Finally, we investigated the hydraulic integrity of leaf xylem vessels by optical visualization of embolism propagation during dehydration. We found that the occlusions lead to hydraulic dysfunction mainly in the peripheral veins compared with the midribs in esca symptomatic leaves. These results open new perspectives on the role of vascular occlusions during the leaf senescence process, highlighting the uniqueness of esca leaf symptoms and its consequence on leaf physiology. [ABSTRACT FROM AUTHOR]

Dedifferentiated vascular smooth muscle cells (vSMCs) play an essential role in neointima formation, and we now aim to investigate the role of the bone morphogenetic protein (BMP) modulator BMPER (BMP endothelial cell precursor-derived regulator) in neointima formation. To assess BMPER expression in arterial restenosis, we used a mouse carotid ligation model with perivascular cuff placement. Overall BMPER expression after vessel injury was increased; however, expression in the tunica media was decreased compared to untreated control. Consistently, BMPER expression was decreased in proliferative, dedifferentiated vSMC in vitro. C57BL/6_Bmper+/− mice displayed increased neointima formation 21 days after carotid ligation and enhanced expression of Col3A1, MMP2, and MMP9. Silencing of BMPER increased the proliferation and migration capacity of primary vSMCs, as well as reduced contractibility and expression of contractile markers, whereas stimulation with recombinant BMPER protein had the opposite effect. Mechanistically, we showed that BMPER binds insulin-like growth factor-binding protein 4 (IGFBP4), resulting in the modulation of IGF signaling. Furthermore, perivascular application of recombinant BMPER protein prevented neointima formation and ECM deposition in C57BL/6N mice after carotid ligation. Our data demonstrate that BMPER stimulation causes a contractile vSMC phenotype and suggest that BMPER has the potential for a future therapeutic agent in occlusive cardiovascular diseases. [ABSTRACT FROM AUTHOR]

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Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the time of lung transplantation, and control tissue was obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4-mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies and organ collection were performed 3 weeks after instillation. Only significant results (P,0.05) are presented. In PF lung tissue, GCN2 protein expression was decreased compared with control tissue. GCN2 expression was reduced in CD311 endothelial cells. In line with human data, GCN2 protein expression was decreased in the lung of bleomycin rats compared with saline. EIF2AK4-mutated rats treated with bleomycin showed increased parenchymal fibrosis (hydroxyproline concentrations) and vascular remodeling (media wall thickness) as well as increased right ventricular systolic pressure compared with wild-type animals. Our data show that GCN2 is dysregulated in both humans and in an animal model of combined PF and PH. The possibility of a causative implication of GCN2 dysregulation in PF and/or PH development should be further studied. [ABSTRACT FROM AUTHOR]

The biologically important amino acid homocysteine links sulfur, methionine, and one-carbon metabolism. This review describes its initial discovery, the identification of the clinical condition of “homocystinuria” and the recognition of its close relationship to folate and vitamin B12 metabolism. It discusses the history behind its current association with diverse diseases including neural tube defects, cardio- and cerebrovascular disease and, more recently, dementia and Alzheimer’s Disease. It also explores current controversies and considers potential future research directions. It is intended to give a general overview of homocysteine in relation to health and disease.

A 50-year-old cohort from the Tampere adult population cardiovascular risk study having hypertension and their controls were examined retrospectively at the age of 35 years, and followed up prospectively up to the age of 65 years to determine whether an early hematocrit (HCR) measurement predicts later hypertension or cardiovascular complications. A total of 307 subjects having hypertension and 579 non-hypertensive controls were chosen from the 50-year-old cohort and regrouped according to HCR values obtained when they were 35 years old, one with HCT

81-year-old female presented with subacute right lower extremity edema due to iliac vein compression by a markedly enlarged external iliac lymph node later identified as newly relapsed metastatic endometrial carcinoma. The patient underwent a full evaluation of the iliac vein lesion and cancer and had an intravenous stent placed with complete resolution of symptoms post-procedure.

Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several factors regulate homocysteine levels, including the activity of several enzymes and adequate levels of their coenzymes, including pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin (vitamin B12). To better understand the biological influence of HHcy on the development and progression of atherosclerosis, apolipoprotein-E-deficient (apoE−/− mice), a model for human atherosclerosis, were fed a hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a control diet (CD). After eight weeks, the plasma, aorta, and liver were collected to quantify methylation metabolites, while plasma was also used for a broad targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe accumulation of plasma and hepatic homocysteine and an increased BCA plaque burden were observed, thus confirming the atherogenic effect of the HHD. Moreover, a decreased methylation capacity in the plasma and aorta, indirectly assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) was detected in HHD mice together with a 172-fold increase in aortic cystathionine levels, indicating increased flux through the transsulfuration pathway. Betaine and its metabolic precursor, choline, were significantly decreased in the livers of HHD mice versus CD mice. Widespread changes in the plasma metabolome of HHD mice versus CD animals were detected, including alterations in acylcarnitines, amino acids, bile acids, ceramides, sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional lipid metabolism. This study confirms the relevance of severe HHcy in the progression of vascular plaque and suggests novel metabolic pathways implicated in the pathophysiology of atherosclerosis.

Diabetic retinopathy affects more than 100 million people worldwide and is projected to increase by 50% within 20 years. Increased blood glucose leads to the formation of advanced glycation end products (AGEs), which cause cellular and molecular dysfunction across neurovascular systems. These molecules initiate the slow breakdown of the retinal vasculature and the inner blood retinal barrier (iBRB), resulting in ischemia and abnormal angiogenesis. This project examined the impact of AGEs in altering the morphology of healthy cells that comprise the iBRB, as well as the effects of AGEs on thrombi formation, in vitro. Our results illustrate that AGEs significantly alter cellular areas and increase the formation of blood clots via elevated levels of tissue factor. Likewise, AGEs upregulate the expression of cell receptors (RAGE) on both endothelial and glial cells, a hallmark biomarker of inflammation in diabetic cells. Examining the effects of AGEs stimulation on cellular functions that work to diminish iBRB integrity will greatly help to advance therapies that target vision loss in adults.

Therapeutic interventions for vascular diseases aim at achieving long-term patency by controlling vascular remodeling. The extracellular matrix (ECM) of the vessel wall plays a crucial role in regulating this process. This study introduces a novel photochemical treatment known as Natural Vascular Scaffolding, utilizing a 4-amino substituted 1,8-naphthimide (10-8-10 Dimer) and 450 nm light. This treatment induces structural changes in the ECM by forming covalent bonds between amino acids in ECM fibers without harming vascular cell survival, as evidenced by our results. To further investigate the mechanism of this treatment, porcine carotid artery segments were exposed to 10-8-10 Dimer and light activation. Subsequent experiments subjected these segments to enzymatic degradation through elastase or collagenase treatment and were analyzed using digital image analysis software (MIPAR) after histological processing. The results demonstrated significant preservation of collagen and elastin structures in the photochemically treated vascular wall, compared to controls. This suggests that photochemical treatment can effectively modulate vascular remodeling by enhancing the resistance of the ECM scaffold to degradation. This approach shows promise in scenarios where vascular segments experience significant hemodynamic fluctuations as it reinforces vascular wall integrity and preserves lumen patency. This can be valuable in treating veins prior to fistula creation and grafting or managing arterial aneurysm expansion.

Yersinia enterocolitica is a foodborne pathogen, mainly associated with disorders involving the gastrointestinal tract, including diarrhea, ileitis, and mesenteric lymphadenitis. Extraintestinal presentation is uncommon in healthy individuals, but bacteremia is reported in immunocompromised hosts. We present a 74-year-old male with Y. enterocolitica serogroup O:3 bacteremia who complicated to rupture of an abdominal aortic aneurysm. With the current case report, we aimed to emphasize the association of Y. enterocolitica bacteremia with abdominal aortic aneurysm rupture. Better surveillance is needed, not only to reduce morbidity and mortality but also to update current epidemiological data on the incidence of such associations.

The rising prevalence of chronic metabolic disorders, such as obesity and type 2 diabetes, most notably associated with cardiovascular diseases, has emerged as a major global health concern. Reactive oxygen species (ROS) play physiological functions by maintaining normal cellular redox signaling. By contrast, a disturbed balance occurring between ROS production and detoxification of reactive intermediates results in excessive oxidative stress. Oxidative stress is a critical mediator of endothelial dysfunction in obesity and diabetes. Under a hyperglycemic condition, the antioxidant enzymes are downregulated, resulting in an increased generation of ROS. Increases in ROS lead to impairment of endothelium-dependent vasodilatations by reducing NO bioavailability. Chronic treatments with antioxidants were reported to prevent the development of endothelial dysfunction in diabetic patients and animals; however, the beneficial effects of antioxidant treatment in combating vascular complications in diabetes remain controversial as antioxidants do not always reverse endothelial dysfunction in clinical settings. In this review, we summarize the latest progress in research focused on the role of ROS in vascular complications of diabetes and the antioxidant properties of bioactive compounds from medicinal plants and food in animal experiments and clinical studies to provide insights for the development of therapeutic strategies.

Background Patients who undergo coronary artery bypass graft (CABG) surgery receive regular physical examinations and medications on an outpatient basis. However, these patients are at risk of developing other vascular diseases, such as postoperative arterial steno-occlusive disease (SOD). This study investigated the incidence of SOD and related factors. Methods In total, 246 patients who underwent CABG surgery from January 1, 2017 to December 31, 2021 were investigated. The incidence and risk factors of vascular disease were analyzed by dividing the included patients into SOD and non-SOD groups. Laboratory tests, medical history, surgical information, and family history were investigated through an electronic chart review. Results Data from 193 patients who met the criteria were analyzed. SOD occurred in 19.1% of patients, and the cerebral artery (38%) was the most common artery involved, followed by the peripheral artery (32%), the coronary artery (22%), and the retinal artery (8%). Risk factors for the development of SOD included estimated glomerular filtration rate (eGFR; odds ratio [OR]=0.977, p=0.008), cholesterol (OR=1.020, p=0.001), and patients with diabetes complications (OR=5.077, p=0.010). The 3-year cumulative incidence rate was 21.6%, and the risk factors for cumulative occurrence were a low eGFR, elevated cholesterol, and complications of diabetes. Conclusions Low eGFR, high cholesterol, and the presence of diabetic complications before CABG surgery may be associated with postoperative vascular disease. In these cases, close monitoring, proper drug administration, and patient warnings may be required.

Abstract Children with chronic kidney disease (CKD) suffer from inflammation and reactive metabolite-induced stress, which massively accelerates tissue and vascular aging. Peritoneal dialysis (PD) is the preferred dialysis mode in children, but currently used PD fluids contain far supraphysiological glucose concentrations for fluid and toxin removal and glucose degradation products (GDP). While the peritoneal membrane of children with CKD G5 exhibits only minor alterations, PD fluids trigger numerous molecular cascades resulting in major peritoneal membrane inflammation, hypervascularization, and fibrosis, with distinct molecular and morphological patterns depending on the GDP content of the PD fluid used. PD further aggravates systemic vascular disease. The systemic vascular aging process is particularly pronounced when PD fluids with high GDP concentrations are used. GDP induce endothelial junction disintegration, apoptosis, fibrosis, and intima thickening. This review gives an overview on the molecular mechanisms of peritoneal and vascular transformation and strategies to improve peritoneal and vascular health in patients on PD.

Background Peripheral arterial disease (PAD) is estimated to affect 7% of the adult population in the United States; however, there is currently little understanding of the key cellular and molecular pathways at play. With PAD characterized by vascular inflammation and associated calcification, the current study set out to elucidate the role of NLRP3 (nucleotide oligomerization domain‐like receptor family, pyrin domain containing 3) inflammasome activation in the current cohort. Methods and Results Global proteomics of human vessels with and without PAD from a total of 14 donors revealed an increase of proinflammatory associated ontologies, specifically acute phase and innate immunity. Targeted mass spectrometry showed a significant increase in NLRP3, confirmed by NLRP3 ELISA. Histological analysis from the same patients demonstrated expression of NLRP3, colocalizing in immunoreactive CD68 (cluster of differentiation 68) and CD209 (cluster of differentiation 209) macrophages. Moreover, transmission electron microscopy showed the locality of macrophage‐like cells in the presence of calcification, with confocal microscopy further validating the localization of CD68, NLRP3, and calcification via near‐infrared calcium tracer. Systemic inflammation and the presence of the NLRP3 inflammasome was assessed via flow cytometry and ELISA, respectively. Compared with patients without PAD, NLRP3 expression was significantly increased in serum. In addition, proinflammatory cytokine presence was significantly increased in disease versus control, with IL (interleukin)‐1β, TNF‐α (tumor necrosis factor α), and IL‐33 demonstrating the greatest disparity, correlating with NLRP3 activation. Conclusions The current findings demonstrate a link between NLRP3, macrophage accumulation, and calcification in arteries of patients with PAD, suggesting an association or possible driver of PAD in these patients.

A 60-year-old man with Loeys-Dietz syndrome (LDS) underwent surgery for multiple left deep femoral artery aneurysms (DFAAs). An intraoperative graft replacement was performed from the common femoral artery to the distal DFAAs; the superficial femoral artery was sutured to the graft. DFAAs in association with LDS and the occurrence of multiple DFAAs are rare. To the best of our knowledge, no studies have reported their coexistence. Graft replacement was decided as the optimal treatment for our patient. However, treatment should be considered on a patient-by-patient basis. Therefore, a lower limb arterial examination should accompany the screening of patients with LDS.

Aim: It is not well known how comorbidities may change the prognosis of atrial fibrillation (AF) patients. This study was aimed to analyze the impact of cardiovascular disease on this population. Materials & methods: EMIR was a multicenter, prospective study, including 1433 AF patients taking rivaroxaban for ≥6 months. Data were analyzed according to the presence of vascular disease. Results: Coronary artery disease was detected in 16.4%, peripheral artery disease/aortic plaque in 6.7%, vascular disease in 28.3%. Patients with coronary artery disease had higher rates (per 100 patient-years) of major adverse cardiovascular events (2.98 vs 0.71; p < 0.001) and cardiovascular death (1.79 vs 0.41; p = 0.004). Those with vascular disease had higher rates of thromboembolic events (1.47 vs 0.44; p = 0.007), major adverse cardiovascular events (2.03 vs 0.70; p = 0.004), and cardiovascular death (1.24 vs 0.39; p = 0.025). Patients with peripheral artery disease/aortic plaque had similar rates. Conclusion: AF patients with vascular disease have a higher risk of non-embolic outcomes.

Vascular disease affects many different arterial beds throughout the body. Yet the brain is susceptible to several vascular disorders that either are not found in other parts of the body or when found are much less likely to cause clinical syndromes in other organs. This specific vulnerability of the brain may be explained by structural and functional differences between the vessels of the brain and those of vessels in other parts of the body. In this review, we focus on how cerebrovascular anatomy and physiology may make the brain and its vessels more susceptible to unique vascular pathologies. To highlight these differences, we use our knowledge of five diseases and syndromes that most commonly manifest in the intracranial vasculature. For each, we identify characteristics of the intracranial arteries that make them susceptible to these diseases, while noting areas of uncertainty requiring further research. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD), characterized by atherosclerosis of the peripheral arteries or even amputation, has threatened public life and health. However, the underlying mechanism remains largely obscure. SUV39H1, a histone methyltransferase, could specifically methylate lysine 9 of histone H3 and act as a repressor in transcriptional activity. The study aimed to investigate the role of SUV39H1 in limb ischemia. C57BL/6 male mice were randomly divided into Sham or Model groups to investigate the expression of SUV39H1 in the ischemic limbs. Then, pharmaceutical inhibition or genetic deletion of SUV39H1 in the limb ischemia mice model was performed to confirm its effect on limb ischemia. The blood perfusion was quantified by laser speckle contrast imaging (LSCI). Capillary density and muscle edema were measured by CD31 immunohistochemical staining and HE staining. The expressions of SUV39H1 and Catalase were confirmed by western blot. Transcriptome sequencing of siSUV39H1 in human umbilical vein endothelial cells (HUVECs) was used to explore the regulation mechanism of SUV39H1 on angiogenesis. The results showed that SUV39H1 was highly expressed in the ischemic muscle tissue of the mice. Pharmaceutical inhibition or genetic deletion of SUV39H1 significantly improved blood perfusion, capillary density, and angiogenesis in ischemic muscle tissue. Cell experiments showed that SUV39H1 knockdown promoted cell migration, tube formation, and mitochondrial membrane potential in endothelial cells under oxidative stress. The transcriptome sequencing results unmasked mechanisms of the regulation of angiogenesis induced by SUV39H1. Finally, Salvianolic acid B and Astragaloside IV were identified as potential drug candidates for the improvement of endothelial function by repressing SUV39H1. Our study reveals a new mechanism in limb ischemia. Targeting SUV39H1 could improve endothelial dysfunction and thus prevent limb ischemia. [ABSTRACT FROM AUTHOR]

Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) are techniques used to evaluate brain perfusion using MRI. DSC requires dynamic image acquisition with a rapid administration of gadolinium-based contrast agent. In contrast, ASL obtains brain perfusion information using magnetically labeled blood water as an endogenous tracer. For the evaluation of brain perfusion in pediatric neurological diseases, ASL has a significant advantage compared to DSC, CT, and single-photon emission CT/positron emission tomography because of the lack of radiation exposure and contrast agent administration. However, in ASL, optimization of several parameters, including the type of labeling, image acquisition, background suppression, and postlabeling delay, is required, because they have a significant effect on the quantification of cerebral blood flow (CBF). In this article, we first review recent technical developments of ASL and age-dependent physiological characteristics in pediatric brain perfusion. We then review the clinical implementation of ASL in pediatric neurological diseases, including vascular diseases, brain tumors, acute encephalopathy with biphasic seizure and late reduced diffusion (AESD), and migraine. In moyamoya disease, ASL can be used for brain perfusion and vessel assessment in pre- and post-treatment. In arteriovenous malformations, ASL is sensitive to detect small degrees of shunt. Furthermore, in vascular diseases, the implementation of ASLbased time-resolved MR angiography is described. In neoplasms, ASL-derived CBF has a high diagnostic accuracy for differentiation between low- and high-grade pediatric brain tumors. In AESD and migraine, ASL may allow for accurate early diagnosis and provide pathophysiological information. [ABSTRACT FROM AUTHOR]

Despite the rise in morbidity and mortality associated with vascular diseases, the underlying pathophysiological molecular mechanisms are still unclear. RNA N6-methyladenosine modification, as the most common cellular mechanism of RNA regulation, participates in a variety of biological functions and plays an important role in epigenetics. A large amount of evidence shows that RNA N6-methyladenosine modifications play a key role in the morbidity caused by vascular diseases. Further research on the relationship between RNA N6-methyladenosine modifications and vascular diseases is necessary to understand disease mechanisms at the gene level and to provide new tools for diagnosis and treatment. In this study, we summarize the currently available data on RNA N6-methyladenosine modifications in vascular diseases, addressing four aspects: the cellular regulatory system of N6-methyladenosine methylation, N6-methyladenosine modifications in risk factors for vascular disease, N6-methyladenosine modifications in vascular diseases, and techniques for the detection of N6-methyladenosine-methylated RNA. [ABSTRACT FROM AUTHOR]

Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine‐like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH. Methods: We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories. Results: We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin). Conclusion: Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH. [ABSTRACT FROM AUTHOR]

Purpose: Pseudoexfoliation (PEX) syndrome is an age-related disease characterized by the accumulation of extracellular material in many ocular structures, skin and internal organs. Recent studies have shown that the Triglyceride-Glucose (TyG) index has clinical importance for the evaluation of vascular damage. The purpose of this study was to determine the relationship between PEX syndrome and TyG index, and to detect the risk in terms of vascular diseases. Methods: In the present study, 50 patients with PEX syndrome who were admitted to the ophthalmology outpatient clinic were evaluated along with 50 others who made up the control group. The Triglyceride-Glucose index was calculated with fasting plasma glucose and triglyceride values. Results: The mean age was 68.2 ± 1.2 years and 61.0% of the patients were male. There was no statistically significant difference between the two groups in terms of blood sugar and lipid profile (except triglyceride) (p > 0.05). The TyG index value was 8.9 ± 0.5 in the PEX group and 8.6 ± 0.6 in the control group. This difference was statistically significant (p = 0.003). In univariate regression analysis, TyG index (OR = 2.81; CI: 1.37–5.75; p = 0.005) was found to be correlated with PEX. In multivariate logistic regression analysis, this correlation remained statistically significant when adjusted for age and sex (OR = 2.89; CI: 1.35–6.18; p = 0.006). Conclusion: Results showed that the TyG index was high in patients diagnosed with PEX. The risk of vascular diseases can be determined by examining the TyG index in patients with PEX, and this predetermination would have significant consequences for public health. [ABSTRACT FROM AUTHOR]

About 230 million people worldwide suffer from peripheral arterial disease (PAD), and the prevalence is increasing year by year. Multiple risk factors, including smoking, dyslipidemia, diabetes, and hypertension, can contribute to the development of PAD. PAD is typically characterized by intermittent claudication and resting pain, and there is a risk of severe limb ischemia, leading to major adverse limb events, such as amputation. Currently, a major progress in the research field of the pathogenesis of vascular remodeling, including atherosclerosis and neointima hyperplasia has been made. For example, the molecular mechanisms of endothelial dysfunction and smooth muscle phenotype switching have been described. Interestingly, a series of focused studies on fibroblasts of the vessel wall has demonstrated their impact on smooth muscle proliferation and even endothelial function via cell-cell communications. In this review, we aim to focus on the functional changes of peripheral arterial cells and the mechanisms of the pathogenesis of PAD. At the same time, we summarize the progress of the current clinical treatment and potential therapeutic methods for PAD and shine a light on future perspectives. [ABSTRACT FROM AUTHOR]

Introduction: Post-stroke fatigue and increased need for daytime sleep are multidimensional and insufficiently understood sequelae. Our aimwas to study the relationships of self-reported cognitive and psychiatric symptoms at 3 months with fatigue and daytime sleep at 12 months post-stroke. Methods: Ischemic stroke patients without reported history of dementia or depression completed postal surveys 3- and 12-months post-stroke. At 3 months, psychiatric symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS), and self-reported changes in cognitive symptoms (concentration and memory) compared to pre-stroke were assessed using single-item measures. At 12 months, single-item questions about changes in self-reported difficulties sleeping at night, fatigue and daytime sleep were included. First, we studied whether self-reported cognitive and/or psychiatric symptoms at 3 months were associated with daytime sleep and fatigue at 12 months using multiple logistic regression. Second, we fitted 2 structural equation models (SEMs) predicting fatigue and 2 models predicting daytime sleep. We compared a model where only age, sex, stroke severity (National Institutes of Health Stroke Scale; NIHSS), and diffculties sleeping at night predicted fatigue and daytime sleep at 12 months to a model where mental distress (i.e., a latent variable built of cognitive and psychiatric symptoms) was included as an additional predictor of fatigue and daytime sleep at 12 months. Results: Of 156 patients (NIHSS within 24 hours after admission (mean ± SD) = 3.6 ± 4.3, age = 73.0 ± 10.8, 41% female) 37.9% reported increased daytime sleep and 50.0% fatigue at 12 months. Increased psychiatric symptoms and worsened cognitive symptoms were associated with fatigue and daytime sleep at 12 months, after controlling for NIHSS, age, sex, and didfficulties sleeping at night. SEM models including mental distress as predictor showed adequate model fit across 3 fit measures (highest RMSEA = 0.063, lowest CFI and TLI, both 0.975). Models without mental distress were not supported. Conclusion: Self-reported cognitive and psychiatric symptoms at 3 months predict increased daytime sleep and fatigue at 12 months. This highlights the relevance of monitoring cognitive and psychiatric symptoms in the subacute phase post-stroke. However, future research using validated measures of self-reported symptoms are needed to further explore these relationships. [ABSTRACT FROM AUTHOR]

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes.Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology.Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology.Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p < 0.01) and lower Braak stage (p = 0.01).Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old. [ABSTRACT FROM AUTHOR]

We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post‐mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen‐positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ‐independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) line the inner surface of blood vessels and play a substantial role in vascular biology. Endothelial dysfunction (ED) is strongly correlated with the initiation and progression of many vascular diseases. Regulated cell death, such as ferroptosis, is one of the multiple mechanisms that lead to ED. Ferroptosis is an iron-dependent programmed cell death associated with various vascular diseases, such as cardiovascular, cerebrovascular, and pulmonary vascular diseases. This review summarized ferroptosis of ECs in vascular diseases and discussed potential therapeutic strategies for treating ferroptosis of ECs. In addition to lipid peroxidation inhibitors and iron chelators, a growing body of evidence showed that clinical drugs, natural products, and intervention of noncoding RNAs may also inhibit ferroptosis of ECs. [ABSTRACT FROM AUTHOR]

Mild photothermal therapy (MPTT) generates heat therapeutic effect at the temperature below 45 °C under near-infrared (NIR) irradiation, which has the advantages of controllable treatment efficacy, lower hyperthermia temperatures, reduced dosage, and minimized damage to surrounding tissues. Despite significant progress has been achieved in MPTT, it remains primarily in the stage of basic and clinical research and has not yet seen widespread clinical adoption. Herein, a comprehensive overview of the recent NIR MPTT development was provided, aiming to emphasize the mechanism and obstacles, summarize the used photothermal agents, and introduce various biomedical applications such as anti-tumor, wound healing, and vascular disease treatment. The challenges of MPTT were proposed with potential solutions, and the future development direction in MPTT was outlooked to enhance the prospects for clinical translation. [ABSTRACT FROM AUTHOR]

In this study, a new diagnostic assay to detect Plenodomus tracheiphilus , the causative agent of mal secco of citrus, was developed based on the recombinase polymerase amplification (RPA) technology. Mal secco is a well-known and damaging vascular disease, affecting primarily lemon (Citrus limon) and, to a lesser extent, other citrus species, including those in the genera Citrus, Fortunella, Poncirus and Severina. The disease poses a considerable threat to lemon production in most of the citrus-producing countries of the Mediterranean region and in the Black Sea area. RPA primers and probes were designed to amplify a 142 bp amplicon from the ITS regions of P. tracheiphilus. The inclusivity and specificity of the RPA assay were tested on gDNA isolated from a panel including 29 strains of various origin of P. tracheiphilus and 18 non-target fungal and oomycete plant pathogens typically isolated from citrus trees. The assay was specific to P. tracheiphilus and had a detection threshold of 1.0 pg of gDNA. Preliminary tests carried out on plant crude extract highlighted RPA's potential for the rapid, user-friendly, and cost-effective field diagnosis of mal secco. [Display omitted] • Novel RPA assay to detect Plenodomus tracheiphilus , causative agent of mal secco. • Validation of inclusivity and full specificity. • High specificity in non-purified DNA tests. • Demonstrated field applicability for rapid, reliable and user-friendly diagnosis. [ABSTRACT FROM AUTHOR]

Increasing the levels of physical activity (PA) is widely recommended for people with chronic venous insufficiency (CVI). However, studies investigating the patterns of PA and adherence to PA guidelines using objective measures are lacking.The primary aim was to examine the patterns of PA and adherence to PA guidelines among patients with CVI. A secondary aim was to identify whether adherence to PA recommendations differed according to patients’ sociodemographic and clinical characteristics.This cross-sectional study included 96 patients with CVI with Clinical-Etiology-Anatomy-Pathology (CEAP) C3 to C6 (69.1% women 59 ± 11 years; 51.5% C5-C6 on CEAP classification). Objective time spent in PA was measured by a triaxial accelerometer. To examine adherence to PA guidelines, patients were grouped as meeting (or) the recommendations if they had at least 150 min/week of moderate to vigorous PA. Sociodemographic and clinic characteristics were obtained by self-report. Binary logistic regression was employed to examine whether sociodemographic and clinical characteristics were associated with adherence to PA guidelines. T-tests were employed to compare PA levels at different intensities according to patients’ age.Patients spent an average of 311.4 ± 91.5 min/week, 42.1 ± 28.0 min/week, and 19.8 ± 17.8 min/week in low-light PA, high-light PA, and moderate-to-vigorous PA, respectively. The proportion of patients meeting PA recommendations was 36.2%, and older patients had lower odds (OR = 0.94; 95%CI: 0.89 to 0.99). Additional analysis reinforced that by showing lower time in high-light PA (51.2 ± 30.0 min/day vs. 31.9 ± 21.8 min/day; p = .001) and moderate-to-vigorous PA (24.3 ± 15.8 min/day vs. 14.8 ± 18.8 min/day; p = .012) among older patients than their peers younger.Our findings showed that 36,2% of CVI patients met PA recommendations, with lower odds found among older patients. Public health interventions to enhance PA engagement among CVI patients should prioritize those who are older. [ABSTRACT FROM AUTHOR]

The iridoid class of phytochemicals includes important phytochemicals found in many traditional medicinal plants. Plumieride and plumericin have been isolated from Allamanda schottii , Himatanthus sucuuba , Himatanthus fallax , Himatanthus articulatus and other medicinal plants. The aim of this review is to provide an overview of the known medicinal properties, pharmacological activities and analytical aspects of plumieride and plumericin in medicine. All scientific data and information on plumieride and plumericin were collected from PubMed, Science Direct, Google Scholar and Google. Furthermore, molecular mechanistic studies with important analytical aspects of plumieride and plumericin in medicine have also been studied. Scientific data have indicated the biological potential of plumericin against ulcerative colitis, inflammatory bowel disease, vascular disease, inflammatory conditions and cancer. This review also describes the anti-mycobacterial, antiparasitic, antibacterial, antifungal and cytotoxic potential of plumericin in medicine. Plumieride have neuropharmacological, anti-inflammatory, antioxidant, immunostimulatory, anticancer, anti-malarial, anti-dermatophytic, antimicrobial, anti-fungal, anti-viral, cytotoxic potential and insecticidal properties. Furthermore, plumieride is also effective on spermatogenesis and other enzymes. Moreover, the analytical aspects of plumieride and plumericin have also been described in the present review in order to know their separation, isolation and identification. Further scientific studies on the pharmacokinetics and molecular mechanism of plumieride and plumericin will contribute to understand their pharmacological effects. Scientific data from published studies demonstrate the therapeutic effect of plumieride and plumericin in medicine. However, scientific research is needed to know the long-term in vivo toxicity and clinical efficacy of plumieride and plumericin. [Display omitted] • Plumieride and plumericin has been isolated from Allamanda schottii , Himatanthus sucuuba , Himatanthus fallax , Himatanthus articulatus and other medicinal plants. • This review mainly focuses on the pharmacological activities of plumieride and plumericin in medicine with their molecular mechanism and analytical aspects. • Scientific data signified the biological potential of plumericin against ulcerative colitis, inflammatory bowel diseases, vascular disease, inflammatory disorders, and cancer. Present work also described the antimycobacterial, antiparasitic, antibacterial, antifungal and cytotoxic potential of plumericin in medicine. • Plumieride have neuropharmacological, anti-inflammatory, antioxidant, immunostimulatory, anticancer, anti-malarial, anti-dermatophytic, antimicrobial, anti-fungal, anti-viral, cytotoxic potential, insecticidal activities and effectiveness on spermatogenesis and other enzymes. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has generated an unprecedented challenge for healthcare systems worldwide. Currently, the scientific community wonders if liver injury in patients suffering from severe forms is a direct consequence of the virus or secondary manifestations of systemic inflammation. The liver plays an essential role in the development of the inflammatory storm typical of this disease, and its involvement is associated with worse clinical outcomes and a higher risk of morbidity and mortality from Coronavirus disease 2019 (COVID-19). Methods: Ten patients suffering from severe COVID-19 disease who died between January 2020 and December 2021 were included in the present analysis. These subjects underwent a post mortem examination with a focused evaluation of the hepatic injury. Also, several laboratory parameters have been evaluated, with a primary focus on prothrombin time, partial thromboplastin time, fibrinogen, antithrombin III, and D-dimers to detect coagulative changes. Results: The main cause of death was represented by pulmonary thromboembolism events (50%). The analysis of coagulation laboratory parameters and liver biomarkers revealed a statistically significant rise in aPTT and ALP, and a decrease in albumin, when comparing the blood value at admission and death. We also found high levels of D-dimers in most of the subjects at the time of hospitalization. Interestingly, the post mortem analysis of the liver showed ample morphologic variability, with several disease features. In detail, the liver histology revealed the following: the presence of a variable degree of micro- and macrovacuolar steatosis, inflammation (also, hepato-cholangitis), and variable fibrosis. Of mention, we were also able to detect organized fibrinous material. Conclusions: Our results indicate that in subjects with a severe form of COVID-19, liver disease is related to changes in coagulative and fibrinolytic pathways. In particular, we noted low fibrinogen levels and high D-dimer levels with histological liver findings. Our data suggest that fibrinogen and D-dimers may be used as prognostic markers to detect the severity of liver disease in patients with COVID-19. Finally, we underline the crucial role of coagulation balance in subjects with severe forms of COVID-19.

Abstract Background Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. Methods Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. Results In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). Conclusions Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.

Abstract Objective To assess trends in primary and specialist care consultation rates and average length of consultation by cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), or cardiometabolic multimorbidity exposure status. Methods Observational, retrospective cohort study used linked Clinical Practice Research Datalink primary care data from 01/01/2000 to 31/12/2018 to assess consultation rates in 141,328 adults with newly diagnosed T2DM, with or without CVD. Patients who entered the study with either a diagnosis of T2DM or CVD and later developed the second condition during the study are classified as the cardiometabolic multimorbidity group. Face to face primary and specialist care consultations, with either a nurse or general practitioner, were assessed over time in subjects with T2DM, CVD, or cardiometabolic multimorbidity. Changes in the average length of consultation in each group were investigated. Results 696,255 (mean 4.9 years [95% CI, 2.02–7.66]) person years of follow up time, there were 10,221,798 primary and specialist care consultations. The crude rate of primary and specialist care consultations in patients with cardiometabolic multimorbidity (N = 11,881) was 18.5 (95% CI, 18.47–18.55) per person years, 13.5 (13.50, 13.52) in patients with T2DM only (N = 83,094) and 13.2 (13.18, 13.21) in those with CVD (N = 57,974). Patients with cardiometabolic multimorbidity had 28% (IRR 1.28; 95% CI: 1.27, 1.31) more consultations than those with only T2DM. Patients with cardiometabolic multimorbidity had primary care consultation rates decrease by 50.1% compared to a 45.0% decrease in consultations for those with T2DM from 2000 to 2018. Specialist care consultation rates in both groups increased from 2003 to 2018 by 33.3% and 54.4% in patients with cardiometabolic multimorbidity and T2DM, respectively. For patients with T2DM the average consultation duration increased by 36.0%, in patients with CVD it increased by 74.3%, and in those with cardiometabolic multimorbidity it increased by 37.3%. Conclusions Annual primary care consultation rates for individuals with T2DM, CVD, or cardiometabolic multimorbidity have fallen since 2000, while specialist care consultations and average consultation length have both increased. Individuals with cardiometabolic multimorbidity have significantly more consultations than individuals with T2DM or CVD alone. Service redesign of health care delivery needs to be considered for people with cardiometabolic multimorbidity to reduce the burden and health care costs.

In this report, we describe the functional imaging findings of systemic artery to pulmonary artery shunt in V/Q SPECT CT imaging. A 63-year-old man with small-cell lung cancer underwent CT pulmonary angiography (CTPA) for suspected acute pulmonary embolism (PE). The CTPA showed an isolated segmental filling defect in the right lower lobe, which was initially interpreted as positive for PE but was actually the consequence of a systemic artery to pulmonary artery shunt due to the recruitment of the bronchial arterial network by the adjacent tumor. A V/Q SPECT/CT scan was also performed, demonstrating a matched perfusion/ventilation defect in the right lower lobe.

Objective: The objective of the present study was to determine whether elevated levels of S100A8 and S100A9 (S100A8/A9) alarmins contribute to ischemic limb pathology. Methods: Gastrocnemius muscle was collected from control patients without peripheral arterial disease (PAD; n = 14) and patients with chronic limb threatening limb ischemia (CLTI; n = 14). Mitochondrial function was assessed in permeabilized muscle fibers, and RNA and protein analyses were used to quantify the S100A8/A9 levels. Additionally, a mouse model of hindlimb ischemia with and without exogenous delivery of S100A8/A9 was used. Results: Compared with the non-PAD control muscles, CLTI muscles displayed significant increases in the abundance of S100A8 and S100A9 at both mRNA and protein levels (P < .01). The CLTI muscles also displayed significant impairment in mitochondrial oxidative phosphorylation and increased mitochondrial hydrogen peroxide production compared with the non-PAD controls. The S100A8/A9 levels correlated significantly with the degree of muscle mitochondrial dysfunction (P < .05 for all). C57BL6J mice treated with recombinant S100A8/A9 displayed impaired perfusion recovery and muscle mitochondrial impairment compared with the placebo-treated mice after hindlimb ischemia surgery. These mitochondrial deficits observed after S100A8/A9 treatment were confirmed in the muscle cell culture system under normoxic conditions. Conclusions: The S100A8/A9 levels were increased in CLTI limb muscle specimens compared with the non-PAD control muscle specimens, and the level of accumulation was associated with muscle mitochondrial impairment. Elevated S100A8/A9 levels in mice subjected to hindlimb ischemia impaired perfusion recovery and mitochondrial function. Together, these findings suggest that the inflammatory mediators S100A8/A9 might be directly involved in ischemic limb pathology. : Clinical Relevance: Despite improvements in the surgical management of chronic limb threatening limb ischemia (CLTI), the rates of major adverse limb events have remained high. Skeletal muscle has emerged as a strong predictor of outcomes in peripheral arterial disease (PAD)/CLTI; however, a complete understanding of muscle pathology in CLTI is lacking. This study identified elevated S100A8 and S100A9 alarmin proteins as a characteristic of CLTI muscle specimens and that the S100A8/A9 levels are associated with the degree of mitochondrial impairment in patient limb muscle specimens. Using a mouse model of PAD, treatment with S100A8/A9 exacerbated ischemic limb pathology, including impaired limb perfusion recovery and muscle mitochondrial impairment. Taken together, these findings connect the inflammatory milieu in the CLTI limb to exacerbated limb muscle outcomes via mitochondrial alterations.