Study protocol: understanding the pathophysiologic mechanisms underlying delirium in older people undergoing hip fracture surgery

Background Postoperative delirium (POD) is a common complication of older people undergoing hip fracture surgery, which negatively affects clinical- and healthcare-related outcomes. Unfortunately, POD pathophysiology is still largely unknown, despite previous studies showing that neuroinflammation, neuroendocrine dysfunction, increased reactive oxidative stress (ROS), and endothelial dysfunctions may be involved. There is also evidence that many of the pathophysiological mechanisms which are involved in delirium are involved in sarcopenia too. This article describes the protocol of a pilot study to evaluate the feasibility of a larger one that will explore the pathophysiological mechanisms correlating POD with sarcopenia. We will analyse whether various biomarkers reflecting neuroinflammation, ROS, neuroendocrine disorders, and microvasculature lesions will be simultaneously expressed in in the blood, cerebrospinal fluid (CSF), and muscles of patients developing POD. Methods Two centres will be involved in this study, each recruiting a convenient sample of ten older patients with hip fracture. All of them will undergo a baseline Comprehensive Geriatric Assessment, which will be used to construct a Rockwood-based Frailty Index (FI). Blood samples will be collected for each patient on the day of surgery and 1 day before. Additionally, CSF and muscle fragments will be taken and given to a biologist for subsequent analyses. The presence of POD will be assessed in each patient every morning until hospital discharge using the 4AT. Delirium subtypes and severity will be assessed using the Delirium Motor Subtype Scale-4 and the Delirium-O-Meter, respectively. We will also evaluate the patient’s functional status at discharge, using the Cumulated Ambulation Score. Discussion This study will be the first to correlate biomarkers of blood, CSF, and muscle in older patients with hip fracture.

What Links an Increased Cardiovascular Risk and Inflammatory Bowel Disease? A Narrative Review

Several studies have shown increased rates of cardiovascular disease (CVD) in patients suffering from inflammatory bowel disease (IBD), particularly in cases of early atherosclerosis and myocardial infarction. IBD most frequently begins at an early age, patients usually present normal weight and remain under constant care of a physician, as well as of a nutritionist. Therefore, the classical risk factors of CVD are not reflected in the higher prevalence of CVD in the IBD population. Still, both groups are characterised by chronic inflammation and display similar physiopathological mechanisms. In the course of IBD, increased concentrations of pro-inflammatory cytokines, such as C-reactive protein (CRP) and homocysteine, may lead to endothelial dysfunctions and the development of CVD. Furthermore, gut microbiota dysbiosis in patients with IBD also constitutes a risk factor for an increased susceptibility to cardiovascular disease and atherosclerosis. Additionally, diet is an essential factor affecting both positively and negatively the course of the aforementioned diseases, whereas several dietary patterns may also influence the association between IBD and CVD. Thus, it is essential to investigate the factors responsible for the increased cardiovascular (CV) risk in this group of patients. Our paper attempts to review the role of potential inflammatory and nutritional factors, as well as intestinal dysbiosis and pharmacotherapy, in the increased risk of CVD in IBD patients.

Differential association between inflammatory cytokines and multiorgan dysfunction in COVID-19 patients with obesity

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs’ functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications.

Cardiovascular outcomes of antidiabetic drugs

Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular disease (ASCVD). Intensive blood glucose reduction with antidiabetic drugs significantly reduce microvascular complications but there is no strong evidence of reduction in cardiovascular (CV) events. In 2008, the US Food and Drug Administration (FDA) issued guidance to demonstrate cardiovascular safety of newer antidiabetic drugs in addition to reduction in blood glucose level. After which a number of CVOTs were conducted involving newer antidiabetic drugs. The newer drugs (e.g. GLP-1 RAs, SGLT2 inhibitors and DPP 4 inhibitors) might have potential effects on body weight, lipid parameters and blood pressure, as well as endothelial dysfunctions, inflammatory markers and oxidative stress. The current review summarizes the results of the main trials focused on the cardiovascular outcomes of traditional as well as newer antidiabetic drugs.

Hypoglycemia In The Emergency, But What Awaits Us For Cardiac Risks In The Future?

Introduction: Several homeostatic changes like an increase in sympathoadrenal response and oxidative stress occur in hypoglycemia. As a result of these findings, an increase in inflammation and pre-atherogenic factors is observed and these changes may lead to endothelial dysfunction. Aim: Our study aims to reveal possible cardiac risks (systolic-diastolic functions and endothelial dysfunctions) in patients who have applied to the emergency department with hypoglycemia. Methods: This cross-sectional, case-control study included 46 hypoglycemia patients who admitted to the emergency with symptoms compatible with hypoglycemia and diagnosed with hypoglycemia and 30 healthy volunteers. All patients were evaluated with baseline echocardiography, tissue-doppler imaging(carotid and brachial artery). Also, the fasting blood tests of the patients referred to the internal medicine department were examined. Results: There were no differences between the groups regarding age, weight, body mass index, and systolic blood pressure. Total cholesterol, LDL, HDL, Vitamin B12, TSH, and fasting blood glucose levels were similar in the groups’ blood tests (all p values>0.05). We observed a statistically significant decrease in diastolic dysfunction parameters: E/A and E/e’ ratios (respectively, p=0.020 and 0.026). It was shown that insulin resistance was influential in forming these considerable differences. The patient group observed that the carotid intima-media thickness was more remarkable(p=0.001), and the brachial flow-mediated dilatation value was smaller(p=0.003), giving an idea about endothelial functions.

SARS-CoV-2 and Pre-existing Vascular Diseases: Guilt by Association?

Severe Acute Respiratory Syndrome coronavirus-2 has rapidly spread and emerged as a pandemic. Although evidence on its pathophysiology is growing, there are still issues that should be taken into consideration, including its effects on pre-existing peripheral vascular disease. The aim of this review is to describe the thrombotic and endothelial dysfunctions caused by SARS-CoV-2, assess if cardiovascular comorbidities render an individual susceptible to the infection and determine the course of pre-existing vascular diseases in infected individuals. A search through MEDLINE, PubMed and EMBASE was conducted and more than 260 articles were identified and 97 of them were reviewed; the rest were excluded because they were not related to the aim of this study. Hypertension, cardiovascular disease, diabetes mellitus and cerebrovascular diseases comprised 24.30% ± 16.23%, 13.29% ± 12.88%, 14.82% ± 7.57% and 10.82% ± 11.64% of the cohorts reviewed, respectively. Arterial and venous thrombotic complications rocketed up to 31% in severely infected individuals in some studies. We suggest that hypertension, cardiovascular diseases, diabetes and cerebrovascular diseases may render an individual susceptible to severe COVID-19 infection. Pre-existing vascular diseases are expected to deteriorate with SARS-CoV-2 infection as a consequence of its increased thrombotic burden and the development of endothelial dysfunction. COVID-19 has emerged only a few months ago and it is premature to predict the long-term effects to the vascular system. Its disturbances of the coagulation mechanisms and effects on vascular endothelium will likely provoke a surge of vascular complications in the coming months.

Vascular underpinning of COVID-19

COVID-19 management guidelines have largely attributed critically ill patients who develop acute respiratory distress syndrome, to a systemic overproduction of pro-inflammatory cytokines. Cardiovascular dysfunction may also represent a primary phenomenon, with increasing data suggesting that severe COVID-19 reflects a confluence of vascular dysfunction, thrombosis and dysregulated inflammation. Here, we first consolidate the information on localized microvascular inflammation and disordered cytokine release, triggering vessel permeability and prothrombotic conditions that play a central role in perpetuating the pathogenic COVID-19 cascade. Secondly, we seek to clarify the gateways which SARS-CoV-2, the causative COVID-19 virus, uses to enter host vascular cells. Post-mortem examinations of patients' tissues have confirmed direct viral endothelial infection within several organs. While there have been advances in single-cell RNA sequencing, endothelial cells across various vascular beds express low or undetectable levels of those touted SARS-CoV-2 entry factors. Emerging studies postulate alternative pathways and the apicobasal distribution of host cell surface factors could influence endothelial SARS-CoV-2 entry and replication. Finally, we provide experimental considerations such as endothelial polarity, cellular heterogeneity in organoids and shear stress dynamics in designing cellular models to facilitate research on viral-induced endothelial dysfunctions. Understanding the vascular underpinning of COVID-19 pathogenesis is crucial to managing outcomes and mortality.