A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events.

BACKGROUND: Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the 'next-generation' epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2. RESULTS: Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant). CONCLUSIONS: We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.

Cardiovascular Risk Stratification in Diabetic Retinopathy via Atherosclerotic Pathway in COVID-19/Non-COVID-19 Frameworks Using Artificial Intelligence Paradigm: A Narrative Review.

Diabetes is one of the main causes of the rising cases of blindness in adults. This microvascular complication of diabetes is termed diabetic retinopathy (DR) and is associated with an expanding risk of cardiovascular events in diabetes patients. DR, in its various forms, is seen to be a powerful indicator of atherosclerosis. Further, the macrovascular complication of diabetes leads to coronary artery disease (CAD). Thus, the timely identification of cardiovascular disease (CVD) complications in DR patients is of utmost importance. Since CAD risk assessment is expensive for low-income countries, it is important to look for surrogate biomarkers for risk stratification of CVD in DR patients. Due to the common genetic makeup between the coronary and carotid arteries, low-cost, high-resolution imaging such as carotid B-mode ultrasound (US) can be used for arterial tissue characterization and risk stratification in DR patients. The advent of artificial intelligence (AI) techniques has facilitated the handling of large cohorts in a big data framework to identify atherosclerotic plaque features in arterial ultrasound. This enables timely CVD risk assessment and risk stratification of patients with DR. Thus, this review focuses on understanding the pathophysiology of DR, retinal and CAD imaging, the role of surrogate markers for CVD, and finally, the CVD risk stratification of DR patients. The review shows a step-by-step cyclic activity of how diabetes and atherosclerotic disease cause DR, leading to the worsening of CVD. We propose a solution to how AI can help in the identification of CVD risk. Lastly, we analyze the role of DR/CVD in the COVID-19 framework.

Effects of antidiabetic agents on steatosis and fibrosis biomarkers in type 2 diabetes: A real-world data analysis.

BACKGROUND & AIMS: There is intense research for drugs able to reduce disease progression in nonalcoholic fatty liver disease. We aimed to test the impact of novel antidiabetic drugs (dipeptidyl-peptidase-4 inhibitors - DPP-4Is, glucagon-like peptide-1 receptor agonists - GLP-1RAs, sodium-glucose cotransporter-2 inhibitors - SGLT-2Is) on non-invasive biomarkers of steatosis (fatty liver index, FLI) and fibrosis (Fibrosis-4 score, FIB-4) in patients with type 2 diabetes (T2D). METHODS: Clinical, anthropometric and biochemical parameters were retrospectively analysed in 637 consecutive T2D patients switched from metformin w/wo sulfonylureas and/or pioglitazone to DPP-4Is, GLP-1RAs and SGLT-2Is in a tertiary care setting. 165 patients maintained on original treatments served as controls. The effects on FLI and FIB-4 at 6- and 12-month follow-up were analysed by logistic regression after adjustment for baseline differences, computed by propensity scores, and additional adjustment for changes in glycosylated hemoglobin (HbA1c) and body mass index. RESULTS: Body mass index, HbA1c and aminotrasferases significantly decreased following switching to GLP-1RAs and SGLT2-Is, compared with both controls and DPP-4Is, whereas only HbA1c was reduced on DPP-4Is. FLI and FIB-4 were reduced on GLP-1RA and SGLT-2I; logistic regression analysis confirmed a significant improvement of both biomarkers after adjustment for propensity score. The shift of FIB-4 values towards the category ruling out advanced fibrosis was maintained after additional adjustment for confounders. These effects were confirmed in a sensitivity analysis on effect size. CONCLUSIONS: Glucagon-like peptide-1 receptor agonists and SGLT-2Is improve biomarkers of steatosis and fibrosis, in keeping with beneficial effects on liver disease progression, and should be considered the treatment of choice in T2D.

Biomarkers of Duchenne muscular dystrophy: current findings.

Numerous biomarkers have been unveiled in the rapidly evolving biomarker discovery field, with an aim to improve the clinical management of disorders. In rare diseases, such as Duchenne muscular dystrophy, this endeavor has created a wealth of knowledge that, if effectively exploited, will benefit affected individuals, with respect to health care, therapy, improved quality of life and increased life expectancy. The most promising findings and molecular biomarkers are inspected in this review, with an aim to provide an overview of currently known biomarkers and the technological developments used. Biomarkers as cells, genetic variations, miRNAs, proteins, lipids and/or metabolites indicative of disease severity, progression and treatment response have the potential to improve development and approval of therapies, clinical management of DMD and patients' life quality. We highlight the complexity of translating research results to clinical use, emphasizing the need for biomarkers, fit for purpose and describe the challenges associated with qualifying biomarkers for clinical applications.

O que todo intensivista deve saber a respeito da síndrome do desconforto respiratório agudo e dano alveolar difuso? / What every intensivist should know about acute respiratory distress syndrome and diffuse alveolar damage

RESUMO A síndrome do desconforto respiratório agudo é um desafio para o intensivista. A característica principal desta doença aguda é o dano alveolar difuso, presente em cerca de metade dos pacientes com a síndrome. É claro que o suporte respiratório à síndrome do desconforto respiratório agudo tem melhorado gradualmente nas últimas décadas. É também evidente que todos estes procedimentos são benéficos, já que reduzem a lesão pulmonar e mantêm o paciente vivo. Isto deve ser interpretado como uma estratégia de ganho de tempo, até que o fator desencadeante ou de risco causal melhore, assim como a tempestade inflamatória diminua e o pulmão se cure. Por outro lado, todos - exceto dois tratamentos farmacológicos (bloqueadores neuromusculares e esteroides) - são incapazes de melhorar o desfecho da síndrome do desconforto respiratório agudo. A hipótese de que os resultados farmacológicos negativos podem ser explicados pela heterogeneidade histológica da síndrome do desconforto respiratório agudo tem sido apoiada pelas recentes demonstrações de que a síndrome com dano alveolar difuso tem característica clínico-patológica específica. O dano alveolar difuso é um diagnóstico patológico, e a biópsia pulmonar a céu aberto (a técnica mais comum para obtenção de tecido pulmonar) tem efeitos colaterais graves, sendo necessário que se desenvolvam biomarcadores substitutos para o dano alveolar difuso. O objetivo desta revisão é discutir três tópicos relacionados à síndrome do desconforto respiratório agudo: o relacionamento entre a síndrome do desconforto respiratório agudo e o dano alveolar difuso; como o dano alveolar difuso pode ser representado no quadro clínico; e como o enriquecimento pode melhorar os resultados de estudos clínicos farmacológicos realizados com pacientes com a síndrome e com dano alveolar difuso.

ABSTRACT Acute respiratory distress syndrome is a challenging entity for the intensivist. The pathological hallmark of the acute phase is diffuse alveolar damage, which is present in approximately half of living patients with acute respiratory distress syndrome. It is clear that respiratory support for acute respiratory distress syndrome has gradually been improving over recent decades. However, it is also evident that these procedures are beneficial, as they reduce lung injury and keep the patient alive. This could be interpreted as a time-gaining strategy until the trigger or causal or risk factor improves, the inflammatory storm decreases and the lung heals. However, all except two pharmacological treatments (neuromuscular blockers and steroids) were unable to improve the acute respiratory distress syndrome outcome. The hypothesis that pharmacological negative results may be explained by the histological heterogeneity of acute respiratory distress syndrome has been supported by the recent demonstration that acute respiratory distress syndrome with diffuse alveolar damage constitutes a specific clinical-pathological entity. Given that diffuse alveolar damage is a pathological diagnosis and that open lung biopsy (the most common technique to obtain lung tissue) has several side effects, it is necessary to develop surrogate biomarkers for diffuse alveolar damage. The aim of this narrative review is to address the following three topics related to acute respiratory distress syndrome: (a) the relationship between acute respiratory distress syndrome and diffuse alveolar damage, (b) how diffuse alveolar damage could be surrogated in the clinical setting and (c) how enrichment in diffuse alveolar damage may improve the results of pharmacological clinical trials tried out on patients with acute respiratory distress syndrome.

Blood biomarkers reflect integration of severity and extent of endoscopic inflammation in ulcerative colitis.

BACKGROUND AND AIM: Blood markers are not always regarded as satisfactory surrogate biomarkers for predicting endoscopic activity in ulcerative colitis (UC). However, those biomarkers have been evaluated solely based on endoscopic activity at the most severe colorectal location, taking no account of the extent of inflammation. This study aimed to examine whether integrated evaluation of severity and extent of endoscopic activity improves the performance of blood biomarkers for UC. METHODS: We performed a retrospective study of UC patients who underwent colonoscopy and blood tests in our hospital. Blood tests were C-reactive protein (CRP), serum albumin (ALB), and platelet count (PLT). We compared blood markers with two versions of endoscopic activity assessed by Mayo endoscopic subscore (MES): the maximum score of MES in the colorectum (mMES, range: 0-3) and the cumulative score of MES of six colorectal regions (cMES, range: 0-18). RESULTS: All three blood markers correlated well with both mMES and cMES, and each marker showed better correlation with cMES than mMES (Spearman rank correlation coefficient: PLT: 0.54 vs 0.47, ALB: -0.65 vs -0.52, and CRP: 0.52 vs 0.38, respectively). The predictability, including sensitivity and specificity, of each marker for endoscopic activity was also better for cMES, resulting in higher degrees of area under the curve (mMES vs cMES: PLT: 0.75 vs 0.83, ALB: 0.77 vs 0.90, and CRP: 0.75 vs 0.90, respectively). CONCLUSION: When incorporating the extent of inflammation, blood markers are better at predicting endoscopic activity of UC than previously considered and could be used as a reliable biomarker in clinical practice.

Clinical utility of serum biomarkers in Duchenne muscular dystrophy.

Assessments of disease progression and response to therapies in Duchenne muscular dystrophy (DMD) patients remain challenging. Current DMD patient assessments include complex physical tests and invasive procedures such as muscle biopsies, which are not suitable for young children. Defining alternative, less invasive and objective outcome measures to assess disease progression and response to therapy will aid drug development and clinical trials in DMD. In this review we highlight advances in development of non-invasive blood circulating biomarkers as a means to assess disease progression and response to therapies in DMD.

Sustained remission in lupus nephritis: still a hard road ahead.

End-stage renal disease caused by lupus nephritis (LN) is an avoidable outcome yet there is considerable uncertainty and variability among nephrologists in their approaches to this disorder. This review discusses recent evidence relevant to the management of LN including recent consensus statements. Long-term results are encouraging compared with 30 years ago, but despite the use of the best available current therapies and achieving high levels of early clinical responses, the kidney often sustains long-term damage and nephritis relapses affect over 50%. Major hurdles to management include the complexity of the clinical presentation, histological features and serological tests, and the absence of reliable outcome predictors or markers of treatment response. The key serological and histopathological characteristics relevant to the practising nephrologist are reviewed, and the limitations of current disease activity markers discussed. There are many potential biomarkers under evaluation, and a framework for their validation is presented. Clinical trials of existing or newer agents for LN have typically been inconclusive and have raised problems of trial design and interpretation that are a barrier to new drug development. The major issues affecting clinical trial design and their potential solutions are summarized.

Cancer chemoprevention: Much has been done, but there is still much to do. State of the art and possible new approaches.

Over the past three decades great efforts have been made in search of cancer chemoprevention strategies. The increase in knowledge of the long process from normal to cancer cell has enabled interventions in terms of lifestyle modifications, natural compounds or drugs to block or reverse the process. Great successes have been achieved, especially for breast and colorectal cancer. However, these strategies have yet to find clinical application on a large scale. In this article we identify the achievements, the pitfalls and the next steps to be taken to improve the efficacy and applicability of chemoprevention strategies. Among the crucial key points to be implemented are educational activities for physicians to appropriately disseminate the aim and indeed the culture of chemoprevention. It is essential to improve the risk-benefit balance, seeking the minimal active doses, intermittent schedules, a better characterization of the risk categories via a more personalized intervention based on individual characteristics, and ensure the containment of costs of public and private health prevention programs.

Are lipid profiles true surrogate biomarkers of coronary heart disease in periodontitis patients?: A case-control study in a south Indian population.

BACKGROUND: There is abundant literature delving into whether periodontal infection contributes to atherosclerosis. However, whether periodontitis is a definite risk factor for atherosclerosis still remains empirical, with no systematic reviews or longitudinal studies to confirm this hypothesis. The prevalence of periodontitis and coronary artery disease also varies among racial and ethnic groups based on various factors such as diet, lifestyle, and genetic predisposition. This study was designed in a south Indian population with the aim of assessing and correlating the lipid levels (a surrogate biomarker for coronary heart disease) in patients with periodontitis and health. AIMS: (1) To assess the levels of total cholesterol, low density lipoproteins (LDL), high density lipoproteins (HDL), and triglycerides in periodontal disease, and health in a south Indian population. (2) To assess associations between elevated lipid profiles and periodontal disease. MATERIALS AND METHODS: This case control study included 60 individuals. Blood sampling for lipid levels and periodontal examination were performed for each study group. STATISTICAL ANALYSIS: Appropriate statistical tools like Chi-square (P<0.05) and student's "t" test were used. The lipid levels were separately regressed using logistic regression to determine any association with periodontitis cases. RESULTS: The differences between the mean lipid levels of cases and controls were not statistically significant (P>0.05) after eliminating confounding factors. Odds Ratio=(Total cholesterol (1.005), HDL (0.971), LDL (1.006), VLDL (0.997), CHO-HDL (1.358), TGL (1.007), LDL-HDL (1.180)). The odds ratio stated that there is no significant relation between the lipid levels and periodontal condition. The above findings confirm that there is still no concrete evidence which determines if periodontitis is an independent risk factor for atherosclerotic cardiovascular disease. Future periodontal interventional studies and assessment of genetic markers can ascertain the validity of this hypothesis. CONCLUSION: There is no association among periodontal disease and the levels of total cholesterol, LDL, HDL, and triglycerides.