Study protocol of a randomized controlled clinical trial investigating the effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes.

BACKGROUND: Type 1 diabetes is a main health burden with several related comorbidities. It has been shown that endothelial function, vascular structure, and metabolic parameters are considerably disrupted in patients with type 1 diabetes. Omega-3 as an adjuvant therapy may exert profitable effects on type 1 diabetes and its complications by improving inflammation, oxidative stress, immune responses, and metabolic status. Because no randomized clinical trial has examined the effects of omega-3 consumption in children and adolescents with type 1 diabetes; the present study aims to close this gap. METHODS: This investigation is a randomized clinical trial, in which sixty adolescents with type 1 diabetes will be randomly assigned to receive either omega-3 (600 mg/day) or placebo capsules for 12 weeks. Evaluation of anthropometric parameters, flow-mediated dilation (FMD) as an endothelial function marker, carotid intima-media thickness (CIMT) as a vascular structure marker, proteinuria, biochemical factors including glycemic and lipid profile, blood urea nitrogen (BUN), creatinine, high-sensitivity C-reactive protein (hs-CRP), and erythrocyte sedimentation rate (ESR), as well as blood pressure will be done at the baseline and end of the trial. Also, dietary intake and physical activity will be assessed throughout the study. Statistical analysis will be performed using the SPSS software (Version 24), and P < 0.05 will be considered statistically meaningful. DISCUSSION: It is hypothesized that omega-3 supplementation may be beneficial for the management of type 1 diabetes and its complications by reducing inflammation and oxidative stress and also modulating immune responses and glucose and lipid metabolism through various mechanisms. The present study aims to investigate any effect of omega-3 on patients with type 1 diabetes. ETHICAL ASPECTS: This trial received approval from Medical Ethics Committee of Iran University of Medical Sciences, Tehran, Iran (IR.IUMS.REC.1400.070). TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT20210419051010N1 . Registered on 29 April 2021.

NAG-Net: Nested attention-guided learning for segmentation of carotid lumen-intima interface and media-adventitia interface.

Cardiovascular diseases (CVD), as the leading cause of death in the world, poses a serious threat to human health. The segmentation of carotid Lumen-intima interface (LII) and Media-adventitia interface (MAI) is a prerequisite for measuring intima-media thickness (IMT), which is of great significance for early screening and prevention of CVD. Despite recent advances, existing methods still fail to incorporate task-related clinical domain knowledge and require complex post-processing steps to obtain fine contours of LII and MAI. In this paper, a nested attention-guided deep learning model (named NAG-Net) is proposed for accurate segmentation of LII and MAI. The NAG-Net consists of two nested sub-networks, the Intima-Media Region Segmentation Network (IMRSN) and the LII and MAI Segmentation Network (LII-MAISN). It innovatively incorporates task-related clinical domain knowledge through the visual attention map generated by IMRSN, enabling LII-MAISN to focus more on the clinician's visual focus region under the same task during segmentation. Moreover, the segmentation results can directly obtain fine contours of LII and MAI through simple refinement without complicated post-processing steps. To further improve the feature extraction ability of the model and reduce the impact of data scarcity, the strategy of transfer learning is also adopted to apply the pretrained weights of VGG-16. In addition, a channel attention-based encoder feature fusion block (EFFB-ATT) is specially designed to achieve efficient representation of useful features extracted by two parallel encoders in LII-MAISN. Extensive experimental results have demonstrated that our proposed NAG-Net outperformed other state-of-the-art methods and achieved the highest performance on all evaluation metrics.

The 2000HIV study: Design, multi-omics methods and participant characteristics.

Background: Even during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets. Methods: The 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort. Results: Overall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine. Conclusion: The 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

Regional and demographic variations of Carotid artery Intima and Media Thickness (CIMT): A Systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Carotid artery intima media thickness (CIMT) is a strong predictor of Coronary Heart Disease (CHD) and independent phenotype of early atherosclerosis. The global variation of CIMT and its demographic association is yet unclear. We evaluated regional variations of CIMT based on WHO regions and assessed the differences by age and sex. METHODS: A systematic search was conducted on studies published between 1980 January up to December 2020. PubMed, Oxford Medicine Online, EBSCO, Taylor & Francis, Oxford University Press and Embase data bases were used for searching. Supplementary searches were conducted on the Web of Science and Google Scholar. Grey literature was searched in "Open Grey" website. The two major criteria used were "adults" and "carotid intima media". The search strategy for PubMed was created first and then adapted for the Oxford Medicine Online, EBSCO, Taylor & Francis, Oxford University Press and Embase databases. Covidence software (Veritas Health Innovation, Melbourne, Australia; http://www.covidence.org) was used to manage the study selection process. Meta-analyses were done using the random-effects model. An I2 ≥ 50% or p< 0:05 were considered to indicate significant heterogeneity. RESULTS: Of 2847 potential articles, 46 eligible articles were included in the review contributing data for 49 381 individuals (mean age: 55.6 years, male: 55.8%). The pooled mean CIMT for the non-CHD group was 0.65mm (95%CI: 0.62-0.69). There was a significant difference in the mean CIMT between regions (p = 0.04). Countries in the African (0.72mm), American (0.71mm) and European (0.71mm) regions had a higher pooled mean CIMT compared to those in the South East Asian (0.62mm), West Pacific (0.60mm) and Eastern Mediterranean (0.60mm) regions. Males had a higher pooled mean CIMT of 0.06mm than females in the non CHD group (p = 0.001); there were also regional differences. The CHD group had a significantly higher mean CIMT than the non-CHD group (difference = 0.23mm, p = 0.001) with regional variations. Carotid artery segment-specific-CIMT variations are present in this population. Older persons and those having CHD group had significantly thicker CIMTs. CONCLUSIONS: CIMT varies according to region, age, sex and whether a person having CHD. There are significant regional differences of mean CIMT between CHD and non-CHD groups. Segment specific CIMT variations exist among regions. There is an association between CHD and CIMT values.

Healthy lifestyle changes favourably affect common carotid intima-media thickness: the Healthy Lifestyle Community Programme (cohort 2).

Common carotid intima-media thickness (ccIMT) progression is a risk marker for cardiovascular disease (CVD), whereas healthy lifestyle habits are associated with lower ccIMT. The objective of the present study was to test whether a healthy lifestyle intervention can beneficially affect ccIMT progression. A community-based non-randomised, controlled lifestyle intervention was conducted, focusing on a predominantly plant-based diet (strongest emphasis), physical activity, stress management and social health. Assessments of ccIMT were made at baseline, 6 months and 1 year. Participants had an average age of 57 years and were recruited from the general population in rural northwest Germany (intervention: n 114; control: n 87). From baseline to 1 year, mean ccIMT significantly increased in both the intervention (0⋅026 [95 % CI 0⋅012, 0⋅039] mm) and control group (0⋅045 [95 % CI 0⋅033, 0⋅056] mm). The 1-year trajectory of mean ccIMT was lower in the intervention group (P = 0⋅022; adjusted for baseline). In a subgroup analysis with participants with high baseline mean ccIMT (≥0⋅800 mm), mean ccIMT non-significantly decreased in the intervention group (-0⋅016 [95 % CI -0⋅050, 0⋅017] mm; n 18) and significantly increased in the control group (0⋅065 [95 % CI 0⋅033, 0⋅096] mm; n 12). In the subgroup, the 1-year trajectory of mean ccIMT was significantly lower in the intervention group (between-group difference: -0⋅051 [95 % CI -0⋅075, -0⋅027] mm; P < 0⋅001; adjusted for baseline). The results indicate that healthy lifestyle changes may beneficially affect ccIMT within 1 year, particularly if baseline ccIMT is high.

Long-term cardio-vascular risk assessment in chronic kidney disease and kidney transplanted patients following SARS-COV-2 disease: protocol for multi-center observational match controlled trial.

BACKGROUND: The coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced a pandemic since March 2020 by affecting more than 243 million people with more than 5 million deaths globally. SARS-CoV-2 infection is produced by binding to angiotensin-converting enzyme, which among other sites is highly expressed in the endothelial cells of the blood vessels, pericytes and the heart, as well as in renal podocytes and proximal tubular epithelial cells. SARS-CoV-2 and cardiovascular disease (CVD) are interconnected by risk factors association with an increased incidence of the disease and by determining de novo cardiac complications. At the same time, COVID-19 disease can lead to acute kidney injury directly, or due to sepsis, multi-organ failure and shock. Therefore, the pre-existence of both CVD and chronic kidney disease (CKD) is linked with a higher risk of severe disease and worse prognosis. METHODS: The main aim of this study is to assess the CV risk in a CKD (stage 3 to 5), dialysis and kidney transplanted population, following SARS-CoV-2 infection, with focus on the endothelial dysfunction as compared to a control group of matched patients. By using clinical evaluation, flow-mediated dilatation, carotid-femoral pulse wave velocity, intima-media thickness, echocardiographic parameters, lung ultrasound, bioimpedance spectroscopy and a series of novel biomarkers, the investigators will determine the long-term impact of this disease on CV and renal outcomes. DISCUSSION: This study will address the challenges and implications in long-term CV sequeale of COVID-19 and focus on a better understanding of the underlying mechanisms and possible therapeutic options. TRIAL REGISTRATION: Patient enrolment in the trial started in January 2021 and is expected to finish at the end of 2022. The study can be found on ClinicalTrials.gov database with NCT05125913 identifier. Registered on 18 November 2021 - Retrospectively registered.

Vascular Dysfunction of COVID-19 Is Partially Reverted in the Long-Term.

BACKGROUND: COVID-19 is characterized by severe inflammation during the acute phase and increased aortic stiffness in the early postacute phase. In other models, aortic stiffness is improved after the reduction of inflammation. We aimed to evaluate the mid- and long-term effects of COVID-19 on vascular and cardiac autonomic function. The primary outcome was aortic pulse wave velocity (aPWV). METHODS: The cross-sectional Study-1 included 90 individuals with a history of COVID-19 and 180 matched controls. The longitudinal Study-2 included 41 patients with COVID-19 randomly selected from Study-1 who were followed-up for 27 weeks. RESULTS: Study-1: Compared with controls, patients with COVID-19 had higher aPWV and brachial PWV 12 to 24 (but not 25-48) weeks after COVID-19 onset, and they had higher carotid Young's elastic modulus and lower distensibility 12 to 48 weeks after COVID-19 onset. In partial least squares structural equation modeling, the higher the hs-CRP (high-sensitivity C-reactive protein) at hospitalization was, the higher the aPWV 12 to 48 weeks from COVID-19 onset (path coefficient: 0.184; P=0.04). Moreover, aPWV (path coefficient: -0.186; P=0.003) decreased with time. Study-2: mean blood pressure and carotid intima-media thickness were comparable at the end of follow-up, whereas aPWV (-9%; P=0.01), incremental Young's elastic modulus (-17%; P=0.03), baroreflex sensitivity (+28%; P=0.049), heart rate variability triangular index (+15%; P=0.01), and subendocardial viability ratio (+12%; P=0.01×10-4) were significantly improved. There was a trend toward improvement in brachial PWV (-6%; P=0.14) and carotid distensibility (+18%; P=0.05). Finally, at the end of follow-up (48 weeks after the onset of COVID-19) aPWV (+6%; P=0.04) remained significantly higher in patients with COVID-19 than in control subjects. CONCLUSIONS: COVID-19-related arterial stiffening involves several arterial tree portions and is partially resolved in the long-term.

Carotid intima-media thickness and flow-mediated dilation do not predict acute in-hospital outcomes in patients hospitalized with COVID-19.

Studies have suggested a potential role of endothelial dysfunction and atherosclerosis in the pathophysiology of COVID-19. Herein, we tested whether brachial flow-mediated dilation (FMD) and carotid intima-media thickness (cIMT) measured upon hospital admission are associated with acute in-hospital outcomes in patients hospitalized with COVID-19. A total of 211 patients hospitalized with COVID-19 were submitted to assessments of FMD and mean and maximum cIMT (cIMTmean and cIMTmax) within the first 72 h of hospital admission. Study primary outcome was a composite of intensive care unit admission, mechanical ventilation, or death during the hospitalization. These outcomes were also considered independently. Thrombotic events were included as a secondary outcome. Odds ratios (ORs) and confidence intervals (CIs) were calculated using unadjusted and adjusted multivariable logistic regression models. Eighty-eight (42%) participants demonstrated at least one of the composite outcomes. cIMTmean and cIMTmax were predictors of mortality and thrombotic events in the univariate analysis (cIMTmean and mortality: unadjusted OR 12.71 [95% CI 1.71-94.48]; P = 0.014; cIMTmean and thrombotic events: unadjusted OR 11.94 [95% CI 1.64-86.79]; P = 0.015; cIMTmax and mortality: unadjusted OR 8.47 [95% CI 1.41-51.05]; P = 0.021; cIMTmax and thrombotic events: unadjusted OR 12.19 [95% CI 2.03-73.09]; P = 0.007). However, these associations were no longer present after adjustment for potential confounders (P > 0.05). In addition, FMD% was not associated with any outcome. In conclusion, cIMT and FMD are not independent predictors of clinical outcomes in patients hospitalized with COVID-19. These results suggest that subclinical atherosclerosis and endothelial dysfunction may not be the main drivers of COVID-19 complications in patients hospitalized with COVID-19.NEW & NOTEWORTHY Studies have suggested a role of endothelial dysfunction and atherosclerosis in COVID-19 pathophysiology. In this prospective cohort study, we assessed the prognostic value of carotid intima-media thickness (IMT) and flow-mediated dilation (FMD) in patients with COVID-19. Carotid IMT and FMD were not independent predictors of major outcomes. These results suggest that other risk factors may be the main drivers of clinical outcomes in patients with COVID-19.

Risk for Subsequent SARS-CoV-2 Infection and Severe COVID-19 Among Community-Dwellers With Pre-Existing Cervicocephalic Atherosclerosis: A Population-Based Study.

BACKGROUND: COVID-19 patients may develop atherosclerosis-related complications. Whether a proportion of these patients already had asymptomatic cervicocephalic atherosclerosis before SARS-CoV-2 infection is not known. This study assessed whether pre-existing cervicocephalic atherosclerosis increased the susceptibility to SARS-CoV-2 infection or resulted in more severe or fatal COVID-19. METHODS: Individuals enrolled in the Atahualpa Project cohort who received head CT (for assessing carotid siphon calcifications) and B-mode ultrasounds (for measurement of the carotid intima-media thickness) prior to the pandemic were eligible for this study. Among this cohort, those who also received serological tests for detection of SARS-CoV-2 antibodies and clinical evaluations for assessment of COVID-19 severity were enrolled. Multivariate logistic regression and exposure-effect models were fitted to assess the association between pre-existing atherosclerosis biomarkers, and SARS-CoV-2 seropositivity and COVID-19 severity. RESULTS: Overall, 154 of 519 study participants (30%) had evidence of cervicocephalic atherosclerosis. A total of 325 (63%) individuals became SARS-CoV-2 positive, and 65 (23.5%) of seropositive individuals had severe or fatal COVID-19. The risk of SARS-CoV-2 seropositive status did not differ across individuals with and without atherosclerosis biomarkers (P = .360). Likewise, seropositive individuals with pre-existing atherosclerosis were not more prone to develop severe or fatal COVID-19 than those without evidence of atherosclerosis (P = .274). Average estimated exposure effects of pre-existing cervicocephalic atherosclerosis versus no atherosclerosis over SARS-CoV-2 seropositivity and COVID-19 severity were not significant. CONCLUSIONS: Pre-existing cervicocephalic atherosclerosis does not increase the risk of acquiring SARS-CoV-2 infection nor the severity of COVID-19 among seropositive individuals.

An Augmented Reality Device for Remote Supervision of Ultrasound Examinations in International Exercise Science Projects: Usability Study.

BACKGROUND: Support for long-distance research and clinical collaborations is in high demand and has increased owing to COVID-19-related restrictions on travel and social contact. New digital approaches are required for remote scientific exchange. OBJECTIVE: This study aims to analyze the options of using an augmented reality device for remote supervision of exercise science examinations. METHODS: A mobile ultrasound examination of the diameter and intima-media thickness of the femoral and carotid arteries was remotely supervised using a head-mounted augmented reality device. All participants were provided with a link to a YouTube video of the technique in advance. In part 1, 8 international experts from the fields of engineering and sports science were remotely connected to the study setting. Internet connection speed was noted, and a structured interview was conducted. In part 2, 2 remote supervisors evaluated 8 physicians performing an examination on a healthy human subject. The results were recorded, and an evaluation was conducted using a 25-item questionnaire. RESULTS: In part 1, the remote experts were connected over a mean distance of 1587 km to the examination site. Overall transmission quality was good (mean upload speed: 28.7 Mbps, mean download speed: 97.3 Mbps, mean ping: 21.6 milliseconds). In the interview, participants indicated that the main potential benefits would be to the fields of education, movement analysis, and supervision. Challenges regarding internet connection stability and previous training with the devices used were reported. In part 2, physicians' examinations showed good interrater correlation (interclass correlation coefficient: 0.84). Participants valued the experienced setting as highly positive. CONCLUSIONS: The study showed the good feasibility of the chosen design and a highly positive attitude of all participants toward this digital approach. Head-mounted augmented reality devices are generally recommended for collaborative research projects with physical examination-based research questions.

COVID-19 and its effects on endothelium in HIV-positive patients in sub-Saharan Africa: Cardiometabolic risk, thrombosis and vascular function (ENDOCOVID STUDY).

BACKGROUND: COVID-19 has affected almost every country in the world, especially in terms of health system capacity and economic burden. People from sub-Saharan Africa (SSA) often face interaction between human immunodeficiency virus (HIV) infection and non-communicable diseases such as cardiovascular disease. Role of HIV infection and anti-retroviral treatment (ART) in altered cardiovascular risk is questionable and there is still need to further carry out research in this field. However, thus far it is unclear, what impact the COVID-19 co-infection in people living with HIV (PLHIV), with or without therapy will have. The ENDOCOVID project aims to investigate whether and how HIV-infection in COVID-19 patients modulates the time course of the disease, alters cardiovascular risk, and changes vascular endothelial function and coagulation parameters/ thrombosis risk. METHODS: A total of 1026 patients will be included into this study. Cardiovascular research PLHIV with (n = 114 in each of the three recruiting centers) - or without - ART (n = 114 in each of the three recruiting centers) with COVID-19 and HIV-negative with COVID-19 (n = 114 in each of the three recruiting centers) will be carried out via clinical and biochemical measurements for cardiovascular risk factors and biomarkers of cardiovascular disease (CVD). Vascular and endothelial function will be measured by brachial artery flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) assessments, and retinal blood vessel analyses, along with vascular endothelial biomarkers and cogualation markers. The correlation between HIV-infection in COVID-19 PLHIV with or without ART and its role in enhancement of cardiovascular risk and endothelial dysfunction will be assessed at admission, weekly, at discharge and, 4 weeks post-discharge (if possible). IMPACT OF PROJECT: The ENDOCOVID project aims to evaluate in the long-term the cardiovascular risk and vascular endothelial function in PLHIV thus revealing an important transitional cardiovascular phenotype in COVID-19. The study was registered under clinicaltrials.gov (NCT04709302).

Carotid stiffness, intima-media thickness and aortic augmentation index among adults with SARS-CoV-2.

NEW FINDINGS: What is the central question of this study? We sought to investigate whether carotid stiffness, carotid intima-media thickness and the aortic augmentation index are altered in young adults 3-4 weeks after contraction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with young healthy adults. What is the main finding and its importance? We found that carotid stiffness, Young's modulus and the aortic augmentation index were greater in young adults who tested positive for SARS-CoV-2 compared with healthy young adults. These findings provide additional evidence for detrimental effects of SARS-CoV-2 on young adult vasculature, which might have implications for cardiovascular health. ABSTRACT: Contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed to cause decrements in vascular function of young adults. However, less is known about the impact of SARS-CoV-2 on arterial stiffness and structure, which might have additional implications for cardiovascular health. The purpose of this study was to assess the carotid artery stiffness and structure using ultrasound and the aortic augmentation index (AIx) using applanation tonometry in young adults after they tested positive for SARS-CoV-2. We hypothesized that carotid artery stiffness, carotid intima-media thickness (cIMT) and aortic AIx would be elevated in young adults with SARS-CoV-2 compared with healthy young adults. We evaluated 15 young adults (six male and nine female; 20 ± 1 years of age; body mass index, 24 ± 3 kg m-2 ) 3-4 weeks after a positive SARS-CoV-2 test result compared with young healthy adults (five male and 10 female; 23 ± 1 years of age; body mass index, 22 ± 2 kg m-2 ) who were evaluated before the coronavirus 2019 pandemic. Carotid stiffness, Young's modulus and cIMT were assessed using ultrasound, whereas aortic AIx and aortic AIx standardized to 75 beats min-1 (AIx@HR75) were assessed from carotid pulse wave analysis using SphygmoCor. Group differences were observed for carotid stiffness (control, 5 ± 1 m s-1 ; SARS-CoV-2, 6 ± 1 m s-1 ), Young's modulus (control, 396 ± 120 kPa; SARS-CoV-2, 576 ± 224 kPa), aortic AIx (control, 3 ± 13%; SARS-CoV-2, 13 ± 9%) and aortic AIx@HR75 (control, -3 ± 16%; SARS-CoV-2, 10 ± 7%; P < 0.05). However, cIMT was similar between groups (control, 0.42 ± 0.06 mm; SARS-CoV-2, 0.44 ± 0.08 mm; P > 0.05). This cross-sectional analysis revealed higher carotid artery stiffness and aortic stiffness among young adults with SARS-CoV-2. These results provide further evidence of cardiovascular impairments among young adults recovering from SARS-CoV-2 infection, which should be considered for cardiovascular complications associated with SARS-CoV-2.