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Current Clinical Status And Vascular Complications

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Last Updated: 02 July 2021

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General | Latest Info

| Coronaviruses form enveloped spherical particles that consist of four structural proteins spike, envelope, membrane and nucleocapsid and a positive-sense, single-strand RNA genome that is 30 kb in length. B | 5-terminal two-thirds of severe acute respiratory syndrome coronavirus 2 genome encodes polyproteins pp1a and pp1ab, which are cleave into 16 different non-structural proteins. Structural proteins are encoded in 3-terminal one-third of the genome. The S protein consists of two subunits; S1 subunit contains receptor-binding domain that bind to angiotensin-converting enzyme 2 on the surface of host cells, whereas S2 subunit mediates fusion between membranes of the virus and host cell. Compared with S protein of SARS-CoV, S protein of SARS-CoV-2 has two notable features. First, within the RBD of S1 subunit, five of six residues that are crucial for binding to human ACE2 are mutate. Second, insertion of four amino acid residues at the boundary between S1 and S2 subunits is present in SARS-CoV-2 but not in SARS-CoV, which introduces novel furin cleavage site. C | SARS-CoV-2 infection is triggered by binding of S protein to ACE2 on the surface of host cells, and the viral complex is incorporated into cytoplasm either by direct fusion with cell membrane or via endocytosis with later release into cytoplasm from endocytic vesicle. S protein is cleave at the S1 / S2 boundary and the S2 subunit facilitates membrane fusion. Viral genome RNA is released into cytoplasm, and the first open reading frame is translated into polyproteins pp1a and pp1ab, which are then cleave by viral proteases into small, non-structural proteins such as RNA-dependent RNA polymerase. Viral genomic RNA is replicated by RdRP. Viral nucleocapsids are assembled from genomic RNA and N proteins in the cytoplasm, whereas budding of new particles occurs at the membrane of the endoplasmic reticulum-golgi intermediate compartment. Finally, genomic RNA and structural proteins are assemble into new viral particles, leading to their release via exocytosis. 3CL, 3-chymotrypsin-like protease. Cardiovascular comorbidities such as hypertension and coronary artery Disease are associated with high mortality in patients with coronavirus Disease 2019. Drugs used to reduce cardiovascular risk such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have numerous effects that might influence susceptibility to or severity of COVID-19. Furthermore, although the main presentation of COVID-19 is viral pneumonia, COVID-19 can also induce cardiovascular manifestations including myocardial injury, myocarditis, arrhythmias, acute coronary syndrome and thromboembolism. Among these cardiovascular manifestations, myocardial injury has been independently associated with high mortality among patients with COVID-19. Finally, medications that have been proposed as treatments for COVID-19 such as hydroxychloroquine and azithromycin have pro-arrhythmic effects. AF, atrial fibrillation; VF, ventricular fibrillation; VT, ventricular tachycardia. Angiotensin II, main effector molecule in the renin-angiotensin-aldosterone system, is upregulated in many pathological conditions, for which inhibition of angiotensin II by RAAS inhibitors is a common therapeutic strategy.

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* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Introduction

Type 2 Diabetes Mellitus is a chronic metabolic disorder. The health, social, and economic consequences of T2DM are enormous. Globally, China has the largest population with T2DM, with more than 116 million adults with T2DM, which will increase to approximately 147 million in 2045. Chronic hyperglycaemia in T2DM is related to microvascular complications, macrovascular complications, poor quality of life, and even death. In China, approximately one million deaths per year are attributed to T2DM and its associated complications. Nearly 40 % of these are premature deaths. Currently, healthcare expenditure due to T2DM is US 63 Billion, and the total economic burden of T2DM and its complications is high. Ningbo, located in Zhejiang Province of China, is an economically developed city. With modernisation, cities have experienced an epidemiological transition from infectious diseases to chronic diseases. In Ningbo, approximately 21 % of people over the age of 40 years had T2DM in 2015. Many patients with T2DM WHO receive Treatment AT Department of Endocrinology and Metabolism, Ningbo First Hospital, have poor glycaemic Control, which could lead to Vascular Complications. To date, research on Vascular Complications among people with T2DM has not been conducted AT this tertiary care Department. This Study aims to determine the prevalence of Vascular Complications among these patients and factors independently associated with Vascular Complications. Similar studies have been conducted in other populations and settings. However, evidence in this particular population and setting could be different from others, and this needs exploration and reporting. Even if the evidence is similar, it is important for policy and practice to replicate it. This context-specific information could be used by Chinese and / or international experts to develop, evaluate, and implement interventions for preventing and managing Vascular Complications locally and nationally. For example, UK-and China-base experts AS part of the China Health Initiative, unique cross-country collaboration between the UK and China, could use these findings to design future research studies. Similarly, many international funding agencies fund global Health Research, and international experts could use these findings to design future research studies. Thus, even small robustly conducted studies should be disseminated to make the evidence-base strong.

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Biology of SARS-CoV-2

Although SARS-COV-2 Infection often begins in upper airway epithelium, in a subset of patients, Virus infect or injure Alveolar epithelium diffusely, resulting in markedly impaired gas exchange and respiratory failure. As discussed above, infection is mediated by interaction of Viral S Protein with ACE2, leading to internalization of virion into endosomes. Host proteases cleave S Protein to create fusion Protein that enables the Virus to enter the cytoplasm. 45 46 Although Alveolar type I and AT2 cells express ACE2, productive infection probably occurs mainly in Surfactant-producing AT2 cells, as shown for SARS-COV. 47 There may be alternate Cell-entry mechanisms, such as Fc-receptor-mediate internalization of Antibody-bound virions. 48 Infected cells produce virions, which infect adjacent epithelial cells, endothelial cells, and macrophages. Pathology studies of late-stage cases show Viral Protein and absence of prominent interstitial inflammation and vasculitis, suggesting that persistent infection of Alveolar epithelium occurs in Severe Disease. The Likely fate of Infected Alveolar epithelial Cells is apoptosis, Although relative likelihoods of apoptosis, killing by effector T cells, other forms of Cell death, or survival are unknown. In the hamster model of SARS-COV-2 Infection, there is widespread Viral Protein expression in the lung, with many cells undergoing apoptosis as assessed by TUNEL assay. 49 Viral Proteins subvert Cell functions, including apoptosis and interferon release, to increase virion production. 50 Infected cells fuse to create syncytia, process mediated by fusion machinery mediating Viral entry. Syncytium formation promotes Cell-Cell Spread of Virus and evasion of immune surveillance. Infected cells detach, leaving behind a porous Alveolar-capillary barrier. Alveolar epithelium provides most of the barrier function of the Alveolar-capillary interface, so loss of epithelium is associated with plasma exudation or hemorrhage, and formation of hyaline membranes containing fibrin, factor VIII, and cytokeratins. 51 this process constitutes pathological finding of DAD. 52 53 However, Magro et al 27 reports cases without DAD or pneumocyte involvement, characterized by microvascular thrombotic injury with complement deposition. More observations are needed to determine whether there are distinct microvasculature phenotype without, or in addition to, prominent DAD. Infection of epithelium has consequences other than virus production and barrier loss. Infect or injure epithelium produce cytokines. In vitro, alveolar epithelial cells infected with Coronavirus or influenza Virus secrete proinflammatory molecules. 54 Loss of AT2 cells decreases Surfactant secretion, contributing to Alveolar collapse; It is not know whether infected but viable AT2 cells maintain Surfactant secretion, but in vitro, influenza infection of AT2 cells results in reduced release of Surfactant Proteins and D. 54 Surfactant Protein D, lectin, bind SARS-COV S Protein; Whether It bind SARS-COV-2 S Protein is unknown. 55 Alveolar epithelium regulates coagulation and fibrinolysis on the Alveolar surface, largely through production of urokinase and PAI1. 56 SARS-COV-2 Pathology includes both hemorrhage and fibrin deposition in Alveolar space and microvasculature, implying perturbations in coagulation and fibrinolysis. Systems biology analysis of experimental SARS-COV Infection revealed that urokinase-relate pathways predict lung injury.


1. Introduction

Coronaviruses are a diverse group of viruses infecting many different animals, and they can cause mild to severe respiratory infections in humans. In 2002 and 2012, respectively, two highly pathogenic coronaviruses with zoonotic origin, severe acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus, emerged in humans and caused fatal respiratory illness, making emerging coronaviruses new Public Health Concern in twenty-first century 1. At the end of 2019, novel Coronavirus designated as SARS-CoV-2 emerged in the City of Wuhan, China, and caused an outbreak of unusual viral pneumonia. Being highly transmissible, this novel Coronavirus disease, also know as Coronavirus disease 2019, has spread fast all over the World 2 3. It has overwhelmingly surpassed SARS and MERS in terms of both the number of infected people and spatial range of epidemic areas. Ongoing outbreak of COVID-19 has posed an extraordinary threat to global public health 4 5. In this Review, we summarize current understanding of the nature of SARS-CoV-2 and COVID-19. On basis of recently published findings, this comprehensive Review covers the basic biology of SARS-CoV-2, including genetic characteristics, potential zoonotic origin and its receptor binding. Furthermore, we will discuss clinical and epidemiological features, diagnosis of and countermeasures against COVID-19.


5. Treatments

1 Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China 2 Department of Gynecologic Oncology, Wenzhou Central Hospital, Wenzhou, China 3 First Clinical College, Wenzhou Medical University, Wenzhou, China 4 Second Clinical College, Wenzhou Medical University, Wenzhou, China 5 Center for Health Assessment, Wenzhou Medical University, Wenzhou, China 6 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China 7 Institute of Virology, Wenzhou Medical University, Wenzhou, China since First reports that novel coronavirus was showing human-to-human transmission characteristics and asymptomatic cases, number of patients with associate pneumonia has continue to rise and epidemic has grow. It now threatens the health and lives of people across the world. Governments of many countries have attached great importance to prevention of SARS-CoV-2, via research into etiology and epidemiology of this newly emerging disease. Clinical signs, treatment, and prevention characteristics of novel coronavirus pneumonia have been receiving attention worldwide, especially from medical personnel. However, owing to different experimental methods, sample sizes, sample sources, and research perspectives of various studies, results have been inconsistent, or relate to isolated aspects of virus or disease it cause. Currently, systematic summary data on novel coronavirus are limit. This review combines experimental and clinical evidence into systematic analysis and a summary of current progress of research into SARS-CoV-2, from multiple perspectives, with the aim of gaining better overall understanding of the disease. Our report provides important information for current clinicians, for prevention and treatment of COVID-19 pneumonia.


6. Conclusion and future directions

COVID-19 affects all components of the respiratory system, including neuromuscular breathing apparatus, conducting airways, respiratory airways and alveoli, pulmonary vascular endothelium, and pulmonary blood flow. As of this writing, after fewer than 6 months of clinical experience and research into disease, many publications have described gross and histological pathology, radiographic changes, and clinical manifestations of disease. Few data, however, convincingly combine these observations into a more complete mechanistic model of disease that permits researchers and clinicians to identify cause-and-effect relationships that can be targeted safely and effectively to improve clinical outcomes. Nevertheless, accumulate data to this point identify several tantalizing avenues for investigation that may successfully lead to fuller understanding of disease pathogenesis and identification of viable therapeutic targets. Although COVID-19 of the respiratory system appears to be a complex disease that may resist finding single silver bullet intervention, these observations provide promising avenues to pursue. This review summarizes much of the known data on COVID-19-induced disorders of the respiratory system, offering researchers and clinicians early and rough sketch of challenges that confront us.


Therapeutics

Replication inhibitors include remdesivir, favilavir, ribavirin, lopinavir and ritonavir. Except for lopinavir and ritonavir, which inhibit 3CLpro, other three all target RdRp 128 135. Remdesivir has shown activity against SARS-CoV-2 in vitro and in vivo 128 136. Clinical studies reveal lower need for oxygen support in patients with COVID-19. Preliminary results of Adaptive COVID-19 Treatment Trial clinical Trial by National Institute of Allergy and Infectious Diseases report that remdesivir can shorten RECOVERY time in hospitalized adults with COVID-19 by a couple days compared with placebo, but the difference in mortality was not statistically significant 138. The FDA has issued emergency use authorization For remdesivir For Treatment of hospitalized patients with severe COVID-19. It is also the first approved option by the European Union for treatment of adults and adolescents with pneumonia requiring supplemental oxygen. Several international phase III clinical trials are continuing to evaluate the safety and efficacy of remdesivir For Treatment of COVID-19. Favilavir, which is an antiviral drug developed in Japan to treat influenza, has been approved in China, Russia and India For Treatment of COVID-19. Clinical studies in China show that favilavir significantly reduces signs of improved disease signs on chest imaging and shortened time to viral clearance 139. Preliminary report in Japan show rates of clinical improvement of 73. 8 % and 87. 8 % from start of favilavir Therapy in patients with mild COVID-19 at 7 and 14 days, respectively, and 40. 1 % and 60. 3 % in patients with severe COVID-19 at 7 and 14 days, respectively 140. However, this study does not include the control arm, and most of trials of favilavir were based on small sample size. For more reliable assessment of the effectiveness of favilavir for treating COVID-19, large-scale randomized controlled trials should be conduct. Lopinavir and ritonavir were reported to have in vitro inhibitory activity against SARS-CoV and MERS-CoV 141 142. Alone, combination of lopinavir and ritonavir had little therapeutic benefit in patients with COVID-19, but appear more effective when used in combination with other drugs, including ribavirin and interferon beta-1b 143 144. Randomized Evaluation of COVID-19 Therapy Trial, National clinical Trial programme in UK, has stopped Treatment with lopinavir and ritonavir as no significant beneficial effect was observed in the Randomized Trial established in March 2020 with a total of 1 596 patients 145. Nevertheless, other clinical trials in different phases are still ongoing elsewhere.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

The cardiovascular system and COVID-19

It was originally thought Novel Coronavirus was primarily a respiratory disorder, but AS larger numbers of patients contract virus, it quickly became clear it has many physiological manifestations. The impact of COVID-19 goes well beyond lungs to impact the Cardiovascular System and cause complications in the kidneys, brain and other organs, and critical patients often require care from a multidisciplinary Care Team. This article offers an overview of cardiac and vascular complications of COVID-19 observed in the first six months of treating the new virus since the original outbreak in China, first reported in December 2019. Our understanding of this disease is changing every week and will certainly change again in weeks and months to come, says Vikramjit Mukherjee, MD, director of Medical ICU and special pathogens Program At Bellevue Hospital Center in New York City, WHO speaking at COVID-19 sessions during Society for Cardiovascular Angiography and Interventions 2020 virtual conference in May. At many Centers, cardiology was called on to help with some COVID patients. COVID patients with comorbidities were much more likely to have severe symptoms requiring hospitalization, but patients with pre-existing Cardiovascular diseases suffer highest mortality rate of all COVID patients. In some cases, COVID causes Acute Heart Failure, myocarditis, shock and thromboembolism, and drugs being used to treat viruses can compound cardiac issues by causing arrhythmias, explain Ajay J. Kirtane, MD, associate professor of Medicine At Columbia University Irving Medical Center and director of cardiac catheterization laboratories At NewYork-Presbyterian Hospital, WHO also speak At SCAI. We are literally learning AS we go along. One of the problems is that COVID is a shape shifter. Just when you think you understand what you are dealing with, it change, says David Baran, MD, director for advanced Heart Failure and transplantation, Sentara Health System, Virgina, WHO also speaks at SCAI.

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* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Conclusions

Give that numerous studies have demonstrated that SARS-CoV-2 shares many biological features with SARS-CoV, Our knowledge of pathophysiological mechanisms underlying SARS can be used to understand the disease process involved in COVID-19. Mechanistically, interaction between S protein and ACE2 is likely to have a central role in disease pathogenesis, especially in cardiovascular manifestations of this disease, and this interaction is a potential target for prevention and treatment of COVID-19. Several hurdles need to be overcome in study of mechanisms underlying COVID-19. First, biological experiments using SARS-CoV-2 can be performed only in Laboratories with biosafety level 3 rating 161 162. Second, use of animal models to mimic disease process is associated with numerous challenges 163 164 165. Give that cellular or tissue tropism is likely to be an important factor contributing to diverse phenotypes of COVID-19, mouse or rat models are not ideal for studying host tropism because they are not AS susceptible to SARS-CoV-2 AS humans owing to differences in amino acid sequence of ACE2. To use mice or rats, human ACE2 needs to be introduced artificially. Transgenic mice expressing ACE2 infected with SARS-CoV-2 have been reported to show signs of pneumonia, but overall symptoms experienced by these mice are much milder than those in humans 163. Therefore, alternative platforms might involve genome-edit mouse or rat models in which ACE2 is replaced by human ACE2, other animal species that are naturally susceptible to SARS-CoV-2 infection 164 165 167 168 169 170 or in vitro models such AS induced pluripotent stem cells 171 172 173 and organoids 114 174 175. The COVID-19 pandemic is changing our lives in unprecedented ways. Give lack of safe and effective vaccines or proven treatments for COVID-19, our main strategy to combat pandemic is social distancing. The Capacity of Health-care Systems globally has been severely test, and the effect of this pandemic on social interactions, health-care delivery and the global economy continues to mount. Reduced physical activity owing to lockdown measures might also contribute to poor control of cardiovascular risk factors. Vaccine development is expected to take 12-18 months 34. To meet the urgent need for effective treatment and preventative strategies, concerted effort must be made by researchers globally to investigate and integrate biological and clinical findings relating to COVID-19.


1. Introduction

Severe acute respiratory syndrome coronavirus 2, novel coronavirus that caused coronavirus disease 2019, was first reported in Wuhan, China, in December 2019 and has spread worldwide. As of 29 October 2020, 44 351 506 globally confirmed cases of COVID-19 have been reported on the World Health Organization COVID-19 dashboard, including 1 171 255 deaths. The Fatality rate for COVID-19 has been estimated to be 0. 5-1. 0 % 1 2 3. From 1 March to 30 May 2020, 122 300 excess all-cause deaths occurred in the USA, of which 95 235 were officially attributed to COVID-19. Of note, mortality from COVID-19 and seasonal influenza is not equivalent, as deaths associated with these diseases do not reflect frontline clinical conditions in the same way. For example, COVID-19 pandemic-hit areas have been facing critical shortages in terms of access to supplies such as ventilators and intensive care unit facilities 5. SARS-CoV-2 is a positive-strand RNA virus that is enclose by protein-decorate lipid bilayer containing a single-strand RNA genome; SARS-CoV-2 has 82 % homology with human SARS-CoV, which causes severe acute respiratory syndrome 6. In human cells, main entry receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 7, which is highly express in lung alveolar cells, cardiac myocytes, vascular endothelium and various other cell types 8. In humans, main route of SARS-CoV-2 transmission is through virus-bearing respiratory droplets 9. Generally, patients with COVID-19 develop symptoms at 5-6 days after infection. Similar to SARS-CoV and related Middle Eastern respiratory syndrome-CoV, SARS-CoV-2 infection induces mild symptoms in initial stage for 2 weeks on average but has potential to develop into severe illness, including systemic inflammatory response syndrome, acute respiratory distress syndrome, multi-organ involvement and shock 10. Patients at high risk of severe COVID-19 or death have several characteristics, including advanced age and male sex, and have underlying health issues, such as cardiovascular disease, obesity and / or type 1 diabetes mellitus or type 2 diabetes mellitus 11 12 13. Few early studies have shown that underlying CVD and diabetes mellitus are common among patients with COVID-19 admit to ICUs 14 15. T2DM is typically a disease of advanced age, and, therefore, whether diabetes mellitus is COVID-19 risk factor over and above advanced age is currently unknown. Basic and clinical science of potential inter-relationships between diabetes mellitus and COVID-19 has been Review 16. However, knowledge in this field is emerging rapidly, with numerous publications appearing frequently. This Review summarizes new advances in diabetes mellitus and COVID-19 and extends focus towards clinical recommendations for patients with diabetes mellitus at risk of or affected by COVID-19. Most available research does not distinguish between diabetes mellitus types and mainly focuses on T2DM, owing to its high prevalence. However, some limited research is available on COVID-19 and T1DM, which we highlight in this Review.

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* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

RESEARCH DESIGN AND METHODS

Primary end points for this study were incident CHD and Stroke that occurred after return of the 1976 questionnaire but before 1 June 1996. We request permission to review medical records from women who report having nonfatal MI or Stroke on follow-up questionnaire. Study physicians with no knowledge of self-report risk factor status review records. Nonfatal MI was confirmed if it met criteria of World Health Organization of symptoms plus either diagnostic electrocardiographic changes or elevated cardiac enzyme levels. Infarctions that require hospital admission and for which confirmatory information was obtained by interview or letter, but for which no medical records were available, were designated as probable. We include all confirmed and probable cases in analyses because results were the same after excluding probable cases. Stroke was confirmed by medical records according to criteria of the National Survey of Stroke, requiring constellation of neurological deficits, sudden or rapid in onset, lasting 24 h or more; events were further subclassified as hemorrhagic Stroke, ischemic Stroke, or Stroke of unknown cause. The follow-up rate for nonfatal events was 97 % of total potential person-years of follow-up. Deaths were reported by next of kin and postal system or ascertained through the National Death Index. Using all sources combine, we estimate that follow-up for deaths was > 98 % complete. Fatal CHD was defined as fatal MI if this was confirmed by hospital records or autopsy, or if CHD was listed as cause of Death on the certificate and this was the underlying and most plausible cause, and evidence of previous CHD was available. The Statement of cause of Death on Death certificate was never relied on by itself to provide sufficient confirmation of Death due to CHD. We also include sudden Death within 1 h of onset of symptoms in women with no other plausible cause other than coronary disease. Fatal strokes were cod using the same criteria as nonfatal cases, but we accept autopsy evidence as well as Death certificate listing of cause.


Results

The median duration of type 2 diabetes was 4. 1 year and the median glycated hemoglobin level was 8. 0 %. Crude prevalences of microvascular and macrovascular complications were 18. 8 % and 12. 7 %, respectively. Common microvascular complications were peripheral neuropathy, chronic kidney disease, and albuminuria. Common macrovascular complications were coronary artery disease, heart failure and stroke. The Age-and sex-standardized prevalence of microvascular complications was 17. 9 %, ranging from 14. 2 % in the Americas to 20. 4 % in Europe. Age-and sex-standardized prevalence of macrovascular complications was 9. 2 %, ranging from 4. 1 % in South-East Asia to 18. 8 % in Europe. Factors positively associated with vascular complications include age, male sex, diabetes duration, and history of hypoglycemia, with rate ratios for microvascular complications of 1. 14 1. 30 1. 03 and 1. 45, respectively, and for macrovascular complications of 1. 41 1. 29 1. 02 and 1. 24, respectively. HbA 1c levels were positively associated with microvascular but not macrovascular complications.

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RESULTS

Table 1 reports characteristics of inpatients with T2DM with and without vascular complications. The mean standard deviation age of patients with T2DM was 62. 9 13. 8 years, and nearly 51 % were men. Over a period of 5 years, prevalence of vascular, microvascular, and macrovascular complications among patients with T2DM was 73. 2 %, 57. 5 %, and 51. 4 %, respectively. In total, 25. 3 %, 29. 7 %, and 33. 1 % had diabetic retinopathy, nephropathy, and neuropathy / foot, respectively. Similarly, 7. 7 %, 10. 1 %, and 44. 1 % had CHD, stroke, and peripheral arterial disease, respectively. Table 2 reports multiple logistic regression analysesindependent of variables with P 0. 20 in simple logistic regressions were include. The data below is reported as OR, 95 % CI. Odds of vascular complications increase with age; were higher in single, divorced, or widow patients than in married patients, patients having T2DM for > 10 years compared to 1 year, patients on lifestyle modification + oral antidiabetic drug + insulin compared to lifestyle modification alone, and patients with hypertension; and were lower in women than in men. Odds of microvascular complications increase with age; decrease with education; and are higher in single, divorced, or widow patients than in married patients, patients having T2DM for > 5-10 years and > 10 years compared to 1 year, patients on lifestyle modification + insulin and lifestyle modification + OAD + insulin compare to lifestyle modification alone, and patients with hypertension. Odds of macrovascular complications increase with age; were higher in smokers and patients with hypertension; and were lower in women than in men.

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2. Diabetic Retinopathy

Diabetic Retinopathy causes significant visual loss on a global scale. Treatments for vision-threatening Complications of Diabetic macular edema and proliferative Diabetic Retinopathy have greatly improved over the past decade. However, additional therapeutic options are needed that take into account pathology associated with vascular, glial, and neuronal components of Diabetic Retina. Recent work indicates that Diabetes markedly impacts the retinal neurovascular unit and its interdependent vascular, neuronal, glial, and immune cells. This knowledge is leading to identification of new targets and therapeutic strategies for preventing or reversing retinal neuronal dysfunction, vascular leakage, ischemia, and pathologic angiogenesis. These advances, together with approaches embracing the potential of preventative or regenerative medicine, could provide means to better manage DR, including treatment at earlier stages and more precise tailoring of treatments based on individual patient variations. The global prevalence of Diabetes Mellitus is predicted to increase dramatically in coming decades, from an estimated 382 million in 2013 to 592 million by 2035. Type 2 Diabetes, in particular, has already attained epidemic levels, while Type 1 Diabetes is increasing in incidence. Patients with Diabetes suffer many life-limiting and life-threatening complications, including macrovascular-related stroke, ischemic heart disease, and peripheral artery disease and / or microvascular-relate Retinopathy, Neuropathy, and Nephropathy. Diabetic Retinopathy is the most common microvascular complication of Diabetes. Although some reports suggest that the incidence of visual impairment from DR has decreased in recent years in the US largely due to improvements in systemic Control, DR is a burgeoning problem globally. DR currently affects almost 100 million people worldwide and is set to become an ever-increasing health burden, with estimates between 1990 and 2010 showing that DR-related visual impairment and blindness increased by 64 % and 27 %, respectively. Base on their obvious manifestations during DR progression, microvascular lesions have been utilized as major criteria for evaluating and classifying Retina in DR. However, Diabetes-induced changes also occur in nonvascular cell types that play an important role in development and progression of DR, albeit in unison with vasculature. DR falls into 2 broad categories: earlier stage of nonproliferative Diabetic Retinopathy and advanced stage of PDR. The Classification of NPDR is based on Clinical findings manifested by visible features, including microaneurysms, retinal hemorrhages, intraretinal microvascular abnormalities, and venous caliber changes, while PDR is characterized by the hallmark feature of pathologic preretinal neovascularization. While these visible features of DR provide useful measures for detection and diagnosis, improving technology has enabled detection of more subtle pathologies such as retinal function deficits and neural layer abnormalities in patients. An important additional categorization in DR is Diabetic macular edema, which is an important manifestation of DR that occurs across all DR severity levels of both NPDR and PDR and represents the most common cause of vision loss in patients with DR. DME arises from Diabetes-induce breakdown of blood-retinal barrier, with consequent vascular leakage of fluid and circulating proteins into neural Retina.


Introduction

Diabetic Retinopathy diagnostic assessment and treatment options have improved dramatically since the 2002 American Diabetes Association Position Statement. These improvements include widespread adoption of optical coherence tomography to assess retinal thickness and intraretinal pathology and wide-field fundus photography to reveal clinically silent microvascular lesions. Treatment of diabetic macular edema is now achieved by intravitreous injection of anti-vascular endothelial growth factor agents, and the same drugs are now used for proliferative diabetic Retinopathy. Improvements in medications and devices for systemic therapy of Diabetes have also improved the ability of patients to optimize their metabolic control. This Position Statement incorporates these recent developments for use by physicians and patients. Diabetic Retinopathy is a highly specific neurovascular complication of both type 1 and type 2 Diabetes, prevalence of which strongly correlates to both the duration of Diabetes and level of glycemic control. Pool meta-analysis involving 35 studies conducted worldwide from 1980 to 2008 estimates the global prevalence of any diabetic Retinopathy and proliferative diabetic Retinopathy among patients to be 35. 4 % and 7. 5 %, respectively. Diabetic Retinopathy is the most frequent cause of new cases of blindness among adults aged 20-74 years in developed countries. Glaucoma, cataracts, and other disorders of the eye occur earlier and more frequently in people with Diabetes. In addition to Diabetes duration, factors that increase risk of or are associated with Retinopathy include chronic hyperglycemia, nephropathy, hypertension, and dyslipidemia. Intensive Diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and / or delay onset and progression of diabetic Retinopathy. Lowering blood pressure has been shown to decrease Retinopathy progression in people with type 2 Diabetes, although tight targets do not impart additional benefit over targets of < 140 mmHg. In patients with dyslipidemia, Retinopathy progression may be slowed by addition of fenofibrate, particularly with very mild nonproliferative diabetic Retinopathy at baseline. Several case series and control prospective studies suggest that pregnancy in patients with type 1 Diabetes may aggravate Retinopathy and threaten vision, especially when glycemic control is poor at time of conception.

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2.1. Role of the Pericyte

Ischemia is caused by inadequate arterial blood flow to specific organ, which leads to multiple degenerative cellular phenomena, namely fibrosis, necrosis, and apoptosis. In extreme cases, these cellular phenomena translate to organ function disruption and organ failure. Pericytes have an important role in the etiology of ischemic organ failure. In myocardial ischemia, pericytes have been shown to be involved in fibrosis and scar formation. Using cardiac ischemia-reperfusion injury, Mouse Model iT demonstrated that ischemia results in shortening of Pericyte extension processes and elevated expression of p75NTR. Low expression of p75NTR in microvasculature has been associated with smaller infarct size in animal models. An increase in expression in cardiac microvascular pericytes could lead to cardiac fibrosis. IT also shows that type-1 pericytes were recruited to scar tissue after myocardial infarction but do not contribute to Collagen type 1 production leading to fibrosis. Fate-tracing experiments in AT2-induced hypertensive heart disease Mouse Model and AAC injury Model show that Gli1 + cells differentiate into-SMA + myofibroblasts in perivascular and interstitial spaces. These Gli1 + cells are MSC-like perivascular cells that express MSC markers, possess trilineage potential and include a small fraction of Pericyte-like PDGFRB + cells. Further analysis revealed that approximately 60 % of Gli1 + cells had propensity to differentiate into cardiac myofibroblasts. Interestingly, pericytes seem to be major contributor to production of myofibroblastic cells and scar formation in the ischemic kidney. Acute or chronic kidney injury / disease is characterized by formation of fibrotic tissue in interstitial spaces in the kidney. There have been contradicting views about the origin of myofibroblasts involved in scar tissue formation during tissue repair. Early in vivo studies have shown that myofibroblasts were derived from multiple cell types but not pericytes. Studies performed by genetic labeling of cells in Mouse models demonstrate that production of myofibroblasts during kidney injury derives from 50 % resident fibroblasts, 35 % bone marrow cells, 10 % tubular epithelial cells and 5 % ECs. Fibrosis is result of cell proliferation, differentiation, and epithelial and endothelial to mesenchymal transition. However, further lineage analysis of FoxD1 and coll1a1 reporter mice with unilateral ureteric obstruction and I / R injury have demonstrated that pericytes / perivascular cells are the major source of myofibroblasts resulting in scar tissue formation. In cerebral ischemia, involvement of pericytes in pathophysiology seems less clear. The Mouse Model of Stroke showed that Nox4 was upregulated in cells expressing PDGFR, Pericyte marker. Upregulation of Nox4 in pericytes results in increased MMP-9 production, bringing about breakdown of BBB. IT has also been shown that during ischemia neurones secrete signals to pericytes lining cerebral capillaries. These signals cause constriction of vessels followed by their rapid death. This claim is currently being challenge, as in vivo Imaging of double transgenic mice expressing mCherry drive by-SMA promoter and endothelial GFP drive by Tie2 promoter show that capillary pericytes lack-SMA and are non-contractile in vivo.


2. Introduction

Brain vasculature has unique characteristics strongly relate to metabolic and physiologic properties of surrounding tissue. As the brain consumes large amounts of energy on demand without the possibility of energy storage, regional and dynamic differences in brain activity are matched by changes in blood flow 1. At the same time, exchange between circulation and brain tissue is tightly controlled by the blood-brain barrier, which prevents neuronal damage and is critical for brain homeostasis 2. Pericytes are capillary-associate vessel wall cells and, together with neural cells and endothelial cells, part of the so-call neurovascular unit, structure underlying BBB 3. Pericyte deficiency in mice increases BBB permeability, which involves changes in EC gene expression and enhances transport of vesicles across EC monolayer without compromising endothelial Cell-Cell junctions 4. One of the changes in brain ECs that results from loss of Pericytes is downregulation of Mfsd2a, which encode transmembrane transport protein. Interestingly, endothelial transcytosis is increased in Mfsd2a-deficient mice leading to BBB defects 5. Pericyte contractility has been implicated in regulation of cerebral blood flow 6, whereas other data attribute this function to arteriolar smooth muscle cells 7. Pericyte loss in mutant mice has been associated with a number of neuropathologies such as white matter disease, neurovascular uncoupling, Alzheimers disease, and age-dependent memory impairment 8 9 10. Here, we report that loss of transcription factor RBPJ alters fundamental aspects of brain period identity, which involve increased contractility, capillary obstruction and formation of aneurysms, increased TGF activation, haemorrhaging, and NVU dysfunction. Our data argue that these processes are triggered by loss of RBPJ repressor activity and not because of its important and well-know role as transcriptional activator in Notch signalling pathway 11. Strikingly, RBPJ deficiency in Pericytes induces acquisition of vascular lesions resembling cerebral cavernous malformations and has other detrimental effects, which are not recapitulated by mice lacking Pericytes. We therefore propose that Pericytes can acquire disease-promoting properties, which lead to vascular malformations in the brain and increase tissue damage after ischaemic injury.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

TNF-

We have read with great interest recent article from Silva et al about the clinical course of COVID-19 in rheumatic disease. 1 in this matched Cohort study of Patients with COVID-19 Infection, although authors found similar proportion of symptoms, risk of hospitalisation and mortality between patients with and without rheumatic disease, There was threefold higher odds of intensive care admission / mechanical ventilation in the former. Authors consider that certain immunosuppressive medications could explain higher risk of respiratory complications. However, risk associated with severe infections differs among immunosuppressive medications; therefore, analysis of clinical disclosures must be individualise according to therapeutic class. 2-4 in study by Silva et al, there was no detailed comparison of clinical behaviour of patients using different immunosuppressive medications. There is a record of corticosteroid use in 37 of 52 patients, probably combined with use of other immunosuppressive medications. 1 use of corticosteroids in patients with rheumatological disease has been associated with higher risk of infections from different agents, including respiratory infection. 2 Studies in patients infected with coronavirus and influenza virus treated with corticosteroids show higher risk of complications and deaths. 5 in the study, second most common group of drugs used by patients was biological disease-modifying antirheumatic drugs, with 60 % of patients using this therapy, and Among them, tumour necrosis factor inhibitor was the most used. Patients with rheumatological diseases using immunosuppressive drugs, including biological therapy, have been considered to potentially be at-risk group for COVID-19 Infection and for complications. 6 Some medical specialty societies have recommended postponing start or extending use of biological therapy, including Anti-TNF Treatment, in areas of sustained community circulation of COVID-19, though use of interleukin 6 inhibitors is considered safer. 7 8 Recently, there have been case reports of patients infected with COVID-19 who were using TNF inhibitors and experienced no respiratory complications or death. 9-11 in clinical practice of this group, we reported three patients with rheumatological diseases using Anti-TNF who were infected with severe acute respiratory syndrome coronavirus-2. One of the patients had been diagnosed with Behcets disease 8 years prior, with a history of several manifestations of vasculitis, including multiple painful and recurrent oral ulcers, recurrent abdominal pain and distension, peripheral venous thrombotic phenomena, neurological manifestations and human leukocyte antigen-b51 positivity. Past use of azathioprine 100 mg / day, oral anticoagulant and mycophenolate sodium was record. Treatment with infliximab starts 9 months prior due to neurological condition. The second patient had ankylosing spondylitis and had used golimumab. The third patient had rheumatoid arthritis for 12 years and had used infliximab for 4 years. Patients had mild form of COVID-19, not presenting with dyspnoea and not requiring hospitalisation; outpatient follow-up was sufficient. They were treated only with symptomatic medication. None of three patients used antivirals or hydroxychloroquine, and only patient with AS was prescribed azithromycin.


Introduction

Arthritides, such AS rheumatoid arthritis and ankylosing spondylitis have been associated with accelerated, inflammatory atherosclerosis, AS well AS increased cardiovascular morbidity and mortality. It is crucial to detect CV abnormalities early, possibly in the preclinical phase of CV disease. Indeed, non-invasive ultrasound-base techniques, in addition to clinical and laboratory biomarkers, may be suitable to assess preclinical vascular pathophysiology in RA and AS. Early endothelial dysfunction, overt atherosclerosis and increased arterial stiffness are indicated by abnormal endothelium-dependent, flow-mediated vasodilation of brachial artery, common carotid intima-media thickness and carotid plaques, AS well AS arterial pulse-wave velocity, respectively. These preclinical abnormalities predict development of subsequent CV events in arthritides. Systemic inflammation associated with RA and AS is a major driver of atherosclerosis and CVD in these diseases. Pro-inflammatory cytokines, such AS tumour necrosis factor are highly involved in the pathogenesis of RA-related atherosclerosis. It is not surprising that control of inflammation by targeted therapies including TNF-inhibitors may dampen atherosclerosis and may decrease CV morbidity and mortality in inflammatory arthritis, especially in patients who respond to TNF inhibition. With respect to surrogate markers, anti-TNF biologics may improve or at least stabilize vascular morphology and function including FMD, ccIMT and PWV. In this study, we wish to determine the effects of one-year anti-TNF therapy on FMD, ccIMT and PWV. We also wish to determine predictors of these parameters at baseline, AS well AS determinants on one-year change in these parameters. This study may improve our understanding of vascular pathophysiology in RA and AS.


Patients and methods

Fifty-three patients with inflammatory arthritis were selected for initiation of anti-TNF therapy but unselected for CVD were enrol in the study. Patient characteristics are seen in Table 1. The Cohort include 34 women and 19 men with a mean age of 52. 0 12. 1 years. The mean disease duration was 8. 5 7. 9 years, while the mean age at diagnosis was 43. 5 12. 1 years. Exclusion criteria include untreated, unstable hypertension, diabetes mellitus, Current inflammatory disease other than RA or AS, infectious disease or renal failure. None of the patients received aspirin, clopidogrel, heparin or warfarin or vasoactive drugs at the time of inclusion. Patients with active disease were recruited prior to initiating biological therapy. All patients start on anti-TNF therapy at baseline and receive the same biological treatment at one year. Among 36 RA patients, 20 receive etanercept 50 mg / week subcutaneous and 16 receive certolizumab pegol. Altogether, 18 RA patients were treated with ETN and 13 with CZP in combination with methotrexate. Other patients receive monotherapy. All 17 AS patients receive 50 mg / week ETN monotherapy SC. RA patients do not take DMARDs other than MTX. Altogether, 12 RA and 2 AS patients currently take low-dose methylprednisolone. Disease activity was determined by DAS28 and BASDAI in RA and AS, respectively. Clinical responder status was determined after 12 months of treatment with either ETN or CZP by EULAR response criteria originally reported by Van Gestel et al. And described by US before. The study was approved by the Hungarian Scientific Research Council Ethical Committee. Write informed consent was obtained from each patient and assessments were carried out according to the Declaration of Helsinki.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

TGF-

Inflammation is an essential process in the pathogenesis of atherosclerosis and consequently, of coronary heart disease and cerebrovascular disease. 1 2 Inflammation is influenced by many different cytokines, such as transforming growth factor-1, most common variant of 3 isoforms. 3 TGF-has many different functions, both proatherogenic and antiatherogenic. Some consider the overall effect of TGF-To be protective, by reducing risk of cardiovascular and cerebrovascular diseases. 4-10 Others describe TGF-as inducing or facilitating cardiovascular and cerebrovascular pathological states, such as vascular stenosis and thrombogenesis. The 11-16 TGF-1 gene is located on chromosome 19q13. 2 There are several commonly known functional polymorphisms in this gene. Cambien ET al 17 describes 988 C /, 800 G /, and 509 C / T polymorphisms; C insertion AT position + 72; and codons 10 Leu / Pro and 25 Arg / Pro and 263 Thr / Ile. A strong linkage disequilibrium between polymorphisms was describe. 17 18 + 72 form was in almost complete linkage disequilibrium with c25, whereas 988 C / was extremely rare. 17 Grainger ET al 19 describes 509 C / T Polymorphism as associated with levels of TGF-1. C25 Polymorphism has been associated with cardiovascular disease in several studies, as was c10 Polymorphism. 17 20-22 However, other studies have reported NO association with cardiovascular disease. 17 18 20 23 To our knowledge, no polymorphisms were ever Study in relation to risk of Stroke in the general population. We therefore study TGF-1 800 G /, 509 C / T, c10, c25, and c263 polymorphisms in relation to risk of myocardial infarction and Stroke in large population-base Study.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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