Marital Quality-A Neglected Player in the Prevention of Cardiovascular Diseases: A Systematic Review of Longitudinal Studies.

PURPOSE OF REVIEW: Marital quality (MQ) is a psychosocial factor that has been neglected in cardiovascular prevention guidelines, although its association with cardiovascular diseases has been identified in several studies. Therefore, we aim to investigate how MQ either in positive or negative dimensions affect different cardiovascular risk factors and diseases. RECENT FINDINGS: We systematically searched different databases in September 2023 for longitudinal studies conducted to assess the contribution of MQ to well-established cardiovascular risk factors and diseases. Two independent researchers screened studies and carried out data extraction and quality assessment of included ones. From 12,175 potential studies screened, 40 were included. The presence of significant heterogeneity in methodology, follow-up, and subsequent effect estimates made it unfeasible to do a meta-analysis. Despite the variation, most studies found a significant association of negative MQ measures with physical inactivity (2/2), high levels of smoking (4/5) and alcohol (3/3) use, increased metabolic syndrome risk (3/3), elevated type 2 diabetes mellitus (T2DM) risk and poor T2DM management (3/6), elevated cardiovascular disease risk and progression (9/11), increased body weight and obesity risk (2/3), elevated blood pressure and hypertension risk (7/8). Positive MQ measures were mainly associated with improvement in blood pressure control (2/2), reduced T2DM risk and its good management (1/1), reduced body weight and obesity risk (2/2), and increased survival in cardiovascular diseases (4/4). Based on current evidence, MQ seems to play a crucial role in developing established cardiovascular risk factors and diseases and is worth considering in preventive strategies.

The Association between Acute Cardiac Injury and Outcomes of Hospitalized Patients with COVID-19: Long-Term Follow-up Results from the Sina Hospital COVID-19 Registry, Iran.

Background: The present study aimed to investigate the association between acute cardiac injury (ACI) and outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19) in Iran. Methods: The current cohort study enrolled all consecutive hospitalized patients with COVID-19 (≥ 18 y) who had serum high-sensitivity cardiac troponin-I (hs-cTnT) measurements on admission between March 2020 and March 2021. ACI was determined as hs-cTnT levels exceeding the 99th percentile of normal values. Data on demographics, comorbidities, clinical and laboratory characteristics, and outcomes were collected from Web-based electronic health records. Results: The study population consisted of 1413 hospitalized patients with COVID-19, of whom 319 patients (22.58%) presented with ACI. The patients with ACI had a significantly higher mortality rate than those without ACI (48.28% vs 15.63%; P<0.001) within a mean follow-up of 218.86 days from symptom onset. ACI on admission was independently associated with mortality (HR, 1.44; P=0.018). In multivariable logistic regression, age (OR, 1.034; P<0.001), preexisting cardiac disease (OR, 1.49; P=0.035), preexisting malignancy (OR, 2.01; P=0.030), oxygen saturation reduced to less than 90% (OR, 2.15; P<0.001), leukocytosis (OR, 1.45; P=0.043), lymphopenia (OR, 1.49; P=0.020), reduced estimated glomerular filtration rates (eGFRs) (OR, 0.99; P=0.008), and treatment with intravenous immunoglobulin during hospitalization (OR, 4.03; P=0.006) were independently associated with ACI development. Conclusion: ACI occurrence on admission was associated with long-term mortality in our hospitalized patients with COVID-19. The finding further underscores the significance of evaluating ACI occurrence on admission, particularly in individuals more prone to ACI, including older individuals and those with preexisting comorbidities, reduced oxygen saturation, and increased inflammatory responses.

Is lifestyle modification with individual face-to-face education and counseling more effective than usual care for controlling hypertension? A systematic review and meta-analysis of randomized controlled trials.

Hypertension (HTN) management continues to be a concern due to challenges with behavioral risk factors. Patient education to modify unhealthy behaviors appears to be effective in managing HTN. Therefore, this meta-analysis aimed to determine whether individualized face-to-face education and counseling have a beneficial effect on systolic and diastolic blood pressure (SBP and DBP) in hypertensive patients. Studies were extracted from PubMed, Scopus, Cochrane Library, and Web of Science databases. Nine studies, comprising 2627 participants, were included. Random effects models were used to pool estimates of mean differences (MDs) with 95% confidence intervals (CIs) in SBP and DBP between the intervention and usual care groups. SBP and DBP were significantly reduced at the 6-month (MD = -4.38 mmHg, 95% CI: -6.95 to -1.81; MD = -2.09 mmHg, 95% CI: -3.69 to -0.50, respectively) and 12-month time points (MD = -2.48 mmHg, 95% CI: -3.96 to -1.01; MD = -1.71 mmHg, 95% CI: -2.88 to -0.55, respectively) with intervention. At the 24-month time point, there was a significant change in SBP (MD = -2.13 mmHg, 95% CI: -3.94 to -0.32) with intervention compared with the usual care group. This study showed that individualized face-to-face education and counseling add significant benefits to usual care for lowering blood pressure in hypertensive patients. Graphical Abstract.

A systematic review of the effects of transcutaneous auricular vagus nerve stimulation on baroreflex sensitivity and heart rate variability in healthy subjects.

PURPOSE: This systematic review aimed to evaluate the effect of transcutaneous auricular vagus nerve stimulation on heart rate variability and baroreflex sensitivity in healthy populations. METHOD: PubMed, Scopus, the Cochrane Library, Embase, and Web of Science were systematically searched for controlled trials that examined the effects of transcutaneous auricular vagus nerve stimulation on heart rate variability parameters and baroreflex sensitivity in apparently healthy individuals. Two independent researchers screened the search results, extracted the data, and evaluated the quality of the included studies. RESULTS: From 2458 screened studies, 21 were included. Compared with baseline measures or the comparison group, significant changes in the standard deviation of NN intervals, the root mean square of successive RR intervals, the proportion of consecutive RR intervals that differ by more than 50 ms, high-frequency power, low-frequency to high-frequency ratio, and low-frequency power were found in 86%, 75%, 69%, 47%, 36%, and 25% of the studies evaluating the effects of transcutaneous auricular vagus nerve stimulation on these indices, respectively. Baroreflex sensitivity was evaluated in six studies, of which a significant change was detected in only one. Some studies have shown that the worse the basic autonomic function, the better the response to transcutaneous auricular vagus nerve stimulation. CONCLUSION: The results were mixed, which may be mainly attributable to the heterogeneity of the study designs and stimulation delivery dosages. Thus, future studies with comparable designs are required to determine the optimal stimulation parameters and clarify the significance of autonomic indices as a reliable marker of neuromodulation responsiveness.

Electromagnetic field therapy in cardiovascular diseases: A review of patents, clinically effective devices, and mechanism of therapeutic effects.

In recent years, electromagnetic field (EMF) therapy has gathered much attention for its protective effects on cardiovascular functions. From reviewing the literature, it is evident that exposure to specific EMF spectrums, such as static- and extremely low frequency (ELF)- EMFs, by EMF-generating devices can be considered as a safe method for therapeutic means in various cardiovascular diseases, including heart failure, cardiac arrhythmias, and hypertension. This review article will describe registered patents and non-invasive clinically effective devices that generate EMF to target various cardiovascular diseases based on their mechanism of therapeutic effects.

Long-term risk and predictors of cerebrovascular events following sepsis hospitalization: A systematic review and meta-analysis.

Background: Long-term risk and predictors of cerebrovascular events following sepsis hospitalization have not been clearly elucidated. We aim to determine the association between surviving sepsis hospitalization and cerebrovascular complications in adult sepsis survivors. Method: We searched MEDLINE, Embase, Scopus, Web of Sciences, Cochrane library, and Google scholar for studies published from the inception of each database until 31 August 2022. Results: Of 8,601 screened citations, 12 observational studies involving 829,506 participants were analyzed. Surviving sepsis hospitalization was associated with a significantly higher ischemic stroke [adjusted hazard ratio (aHR) 1.45 (95% CI, 1.23-1.71), I 2 = 96], and hemorrhagic stroke [aHR 2.22 (95% CI, 1.11-4.42), I 2 = 96] at maximum follow-up compared to non-sepsis hospital or population control. The increased risk was robust to several sensitivity analyses. Factors that were significantly associated with increased hazards of stroke were: advanced age, male gender, diabetes mellitus, hypertension, coronary artery disease, chronic heart failure, chronic kidney disease, chronic obstruction pulmonary disease, and new-onset atrial fibrillation. Only diabetes mellites [aHR 1.80 (95% CI, 1.12-2.91)], hypertension [aHR 2.2 (95% CI, 2.03-2.52)], coronary artery disease [HR 1.64 (95% CI, 1.49-1.80)], and new-onset atrial fibrillation [aHR 1.80 (95% CI, 1.42-2.28)], were associated with > 50% increase in hazards. Conclusion: Our findings showed a significant association between sepsis and a subsequent risk of cerebrovascular events. The risk of cerebrovascular events can be predicated by patient and sepsis-related baseline variables. New therapeutic strategies are needed for the high-risk patients.

Mechanism-based targeting of cardiac arrhythmias by phytochemicals and medicinal herbs: A comprehensive review of preclinical and clinical evidence.

Cardiac arrhythmias, characterized by an irregular heartbeat, are associated with high mortality and morbidity. Because of the narrow therapeutic window of antiarrhythmic drugs (AADs), the management of arrhythmia is still challenging. Therefore, searching for new safe, and effective therapeutic options is unavoidable. In this study, the antiarrhythmic effects of medicinal plants and their active constituents were systematically reviewed to introduce some possible candidates for mechanism-based targeting of cardiac arrhythmias. PubMed, Embase, and Cochrane library were searched from inception to June 2021 to find the plant extracts, phytochemicals, and multi-component herbal preparations with antiarrhythmic activities. From 7337 identified results, 57 original studies consisting of 49 preclinical and eight clinical studies were finally included. Three plant extracts, eight multi-component herbal preparations, and 26 phytochemicals were found to have antiarrhythmic effects mostly mediated by affecting K+ channels, followed by modulating Ca2+ channels, upstream target pathways, Na v channels, gap junction channels, and autonomic receptors. The most investigated medicinal plants were Rhodiola crenulata and Vitis vinifera. Resveratrol, Oxymatrine, and Curcumin were the most studied phytochemicals found to have multiple mechanisms of antiarrhythmic action. This review emphasized the importance of research on the cardioprotective effect of medicinal plants and their bioactive compounds to guide the future development of new AADs. The most prevalent limitation of the studies was their unqualified methodology. Thus, future well-designed experimental and clinical studies are necessary to provide more reliable evidence.

The effect of supplementation with vitamins A, B, C, D, and E on disease severity and inflammatory responses in patients with COVID-19: a randomized clinical trial.

BACKGROUND AND OBJECTIVE: Because of the effect of vitamins on modulating the immune system function, we have evaluated the effect of supplementation with vitamins A, B, C, D, and E in ICU-admitted patients with COVID-19. METHODS: This study was a randomized and single-blinded clinical trial in which 60 subjects were randomly assigned to two groups. The intervention group (n=30) received vitamins, and the control group did not receive any vitamin or placebo. The intervention was included 25,000 IU daily of vitamins A, 600,000 IU once during the study of D, 300 IU twice daily of E, 500 mg four times daily of C, and one amp daily of B complex for 7 days. At baseline and after the 7-day intervention, the serum levels of inflammatory markers, vitamins, and the SOFA score were assessed. In addition, the mortality rate and duration of hospitalization were evaluated after the intervention (IRCT registration number: IRCT20200319046819N1/registration date: 2020-04-04, https://www.irct.ir/trial/46838 ). RESULTS: Significant changes were detected in serum levels of vitamins (p < 0.001 for all vitamins), ESR (p < 0.001), CRP (p = 0.001), IL6 (p = 0.003), TNF-a (p = 0.001), and SOFA score (p < 0.001) after intervention compared with the control group. The effect of vitamins on the mortality rate was not statistically significant (p=0.112). The prolonged hospitalization rate to more than 7 days was significantly lower in the intervention group than the control group (p=0.001). Regarding the effect size, there was a significant and inverse association between receiving the intervention and prolonged hospitalization (OR = 0.135, 95% CI 0.038-0.481; p=0.002); however, after adjusting for confounders, it was not significant (OR=0.402, 95% CI 0.086-1.883; p=0.247). CONCLUSION: Supplementation with vitamins A, B, C, D, and E could improve the inflammatory response and decrease the severity of disease in ICU-admitted patients with COVID-19.

Meta-Analysis of the Usefulness of Beta-Blockers to Reduce the Risk of Major Adverse Cardiovascular Events in Patients With Stable Coronary Artery Disease Without Prior Myocardial Infarction or Left Ventricular Dysfunction.

Beta-blockers (BBs) are the core of coronary artery disease (CAD) pharmacotherapy and demonstrated a well-established benefit in the treatment of acute myocardial infarction (MI). However, the prophylactic role of BBs to affect adverse outcomes in patients with stable CAD, especially among those without a pervious history of MI or left ventricular dysfunction, is not yet addressed. We aimed to determine the effects of beta-blockers on major adverse cardiovascular events (MACE) in patients with stable CAD without prior MI or left ventricular dysfunction. We searched PubMed, EMBASE, Web of Science, Scopus, Google Scholar, and Cochrane Controlled Trials Register for studies published from inception to March 31, 2021. Two researchers independently reviewed the database searches and selected eligible studies. A third reviewer was consulted whenever necessary. A total of 6 studies were included in the final analysis. BBs therapy did not reduce the risk of a MACE (HR, 1.05; 95% CI, 0.91 to 1.20), MI (HR, 1.13; 95% CI, 0.95 to 1.34), and cardiovascular death (HR, 0.95; 95% CI, 0.79 to 1.14). No statistically significant effect was observed between the participants on beta-blocker and control groups. In conclusion, our meta-analysis did not show the benefit of BBs in reducing MACE among patients with stable CAD without previous history of MI or left ventricular dysfunction.

The association between serum levels of micronutrients and the severity of disease in patients with COVID-19.

OBJECTIVES: This study aimed to compare the serum level of micronutrients with normal amounts, and assess their association with the severity of disease and inflammatory cytokines in patients with coronavirus disease 2019 (COVID-19). METHODS: The present cross-sectional study included 60 patients admitted to the intensive care unit with COVID-19. We recorded data on demographic characteristics, anthropometric information, and medical history. Serum levels of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, interferon-gamma, tumor necrosis factor-alpha, interleukin-6), vitamins (A, B9, B12, C, D, E), and minerals (magnesium, zinc, iron) were measured. A radiologist assessed the severity of lung involvement according to patient computed tomography scans. The severity of illness was evaluated with the Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) score, oxygen saturation, and body temperature. Independent associations among the serum levels of micronutrients with the severity of COVID-19 were measured. RESULTS: Median patient age was 53.50 years (interquartile range, 12.75 years). Except for vitamin A and zinc, serum levels of other micronutrients were lower than the minimum normal. Patients with APACHE score ≥25 had a higher body mass index (P = 0.044), body temperature (P = 0.003), erythrocyte sedimentation rate (P = 0.008), C-reactive protein (P = 0.003), and lower oxygen saturation (P = 0.005), serum levels of vitamin D (P = < 0.001), and zinc (P = < 0.001) compared with patients with APACHE score <25. We found that lower serum levels of vitamin D, magnesium, and zinc were significantly and independently associated with higher APACHE scores (P = 0.001, 0.028, and < 0.001, respectively) and higher lung involvement (P = 0.002, 0.045, and < 0.001, respectively). CONCLUSIONS: Lower serum levels of vitamin D, zinc, and magnesium were involved in severe COVID-19.

Surrogate Markers of Subclinical Atherosclerosis and Its Associated Factors in Patients with ß-Thalassemia Major.

ß-Thalassemia major (ß-TM) is a severe genetic hemoglobin (Hb) disorder with cardiovascular complications such as atherosclerosis due to transfusion-dependent iron overload. We aimed to determine the associated factors with surrogate markers of subclinical atherosclerosis in these patients. Sixty subjects with ß-TM referred to the Thalassemia Clinic of the Iranian Blood Transfusion Organization (IBTO) were included in our study. The blood samples were collected for laboratory measurements. The carotid intima-media thickness (CIMT), was measured by ultrasonography, and ankle-brachial index (ABI) was calculated. The multivariate linear analysis was performed to determine the appropriate indicators of subclinical atherosclerosis in ß-TM. There was no significant difference in baseline characteristics between the study groups. In multivariate linear analysis, age and systolic blood pressure (SBP) were negatively associated with inverse-transformed CIMT [unstandardized ß coefficient (B): -0.024, 95% confidence interval (95% CI): -0.032- -0.010, p < 0.001; B: -0.009, 95% CI: -0.017- -0.001, p 0.031, respectively]. There was also a significant correlation between the serum level of high-density lipoprotein cholesterol (HDL-C) and insulin with higher ABI, after adjustment for confounding variables (B: 0.003; 95% CI: 0.000-0.005; p = 0.030, and B: 0.004, 95% CI: 0.000-0.009, p = 0.037, respectively). Our results show that advancing age and increased SBP, HDL-C and insulin, associated with higher CIMT or ABI, are appropriate indicators of subclinical atherosclerosis in ß-TM patients.

Comparison of trinitroglycerin and adenosine as provocative agents for head-up tilt test in patients with unexplained syncope: a semi-crossover randomized clinical trial with prospective follow-up.

PURPOSE: Head-up tilt test (HUTT) is a reasonable diagnostic evaluation for patients with suspected vasovagal syncope; however, its lengthy duration is a remarkable limitation. Although adenosine (AD), as an alternative provocative agent, is a promising option for tackling this shortcoming, it received little appreciation in the literature. We aimed to compare the efficacy and the time to elicit a positive response to HUTT for sublingual trinitroglycerin (TNG) and intravenous AD. Furthermore, we evaluated patients' outcomes in the follow-up. METHODS: Patients with a chief complaint of transient loss of consciousness (TLOC) were evaluated. We randomized patients with the diagnosis of unexplained syncope after diagnostic evaluations, to undergo TNG-augmented HUTT or AD-augmented HUTT. They were crossed over to receive the other medication in case of negative response to the test. In the follow-up, we evaluated traumatic and non-traumatic TLOCs, hospitalization due to syncope, and death in patients. RESULTS: We randomized 132 patients (41.70 ± 19.37 years, 52.3% female) to receive TNG (n = 66) or AD (n = 66). Respectively, the positivity rate of TNG and AD for the first and the crossover-HUTT was 31.1% and 26.7%, and 20.5% and 26.2% with no statistically significant differences in both tests (P ˃ 0.50). The time to positive response was significantly shorter for AD than TNG (P < 0.001). In the follow-up, re-admission was significantly more prevalent in HUTT-negative patients compared to HUTT-positive patients (P = 0.04). CONCLUSIONS: We found that diagnostic yield of TNG and AD in HUTT is comparable, while AD acts 4 times faster than TNG in evoking a vasovagal response.

Ratio of Serum Aspartate to Alanine Aminotransferase as a Marker of Isolated Coronary Artery Ectasia and its Severity.

BACKGROUND: Several studies have reported an association between elevated liver enzymes and increased risks for developing inflammatory diseases. The aim of our study was to examine how serum liver transaminases, as inexpensive and routinely measured markers, and the De Ritis ratio are associated with the presence of coronary artery ectasia (CAE) and its severity. METHODS: Participants were recruited from patients admitted to Tehran Heart Center for diagnostic coronary angiography due to suspected myocardial ischaemia. These participants also underwent concurrent laboratory routine biochemical and liver enzyme tests. RESULTS: A total of 104 participants were included; 59 had CAE and 45 were controls without coronary artery disease (CAD). The CAE group was split into a further two subgroups: those with isolated CAE (n=27) and those with CAD and coexisting CAE (n=32). In the adjusted multivariate analysis, a lower ratio of aspartate aminotransferase to ALT (AST/ALT) was, uniquely among the variables, a statistically significant marker for isolated CAE. In the CAD + CAE group, the AST/ALT ratio was not significant after adjustments for the confounding factors. The multivariate linear regression for the Markis score showed that the AST/ALT ratio was inversely associated with the severity of CAE. CONCLUSIONS: We conclude that the AST/ALT ratio and, to some extent, ALT independently of other inflammatory factors, can be associated with the presence and severity of isolated CAE.

Effects of high dose atorvastatin before elective percutaneous coronary intervention on highly sensitive troponin T and one year major cardiovascular events; a randomized clinical trial.

INTRODUCTION: Some studies have demonstrated that post-PCI elevated cardiac enzymes are associated with worse outcomes. In this study, we aimed to determine if high-dose treatment with atorvastatin before planned elective PCI reduces PMI or MACE at 1-year median follow-up. MATERIAL AND METHODS: Eligible participants were randomly allocated to group A (80 mg atorvastatin 12 h and 40 mg 2 h before PCI) and group B (40 mg atorvastatin daily). Blood samples were obtained before and at 24 h after PCI to measure hsTnT. All patients were followed regarding MACE (combination of death, re-hospitalizations for ACS, and unplanned coronary revascularization) during one year after PCI. RESULTS: 207 patients randomly assigned to Group A (n = 97) or group B (n = 110). The rate of PMI was lower in group A (5.2%) compared to group B (10.9%); despite near to 50% lower rate of PMI in group A, binary logistic regression showed no significant association between atorvastatin recapture and PMI. The occurrence of MACE in 97 patients of group A was 11 (11.3%), higher than 11 (10%) cases of 110 patients in group B. Cox proportional hazards regression model shows no significant difference in MACE of study groups. CONCLUSION: Pretreatment of patients with stable angina who were planned to undergo an elective PCI with 120 mg of atorvastatin before the procedure confer them the same benefit in terms of PMI and MACE as 40 mg routine daily dosage of this statin does.

Visfatin as marker of isolated coronary artery ectasia and its severity.

Several studies have demonstrated the relationship between visfatin and increased risk of diseases caused by inflammation, however, the relationship between visfatin and coronary artery ectasia (CAE) is still unknown. The aim of our study is to investigate the association between serum visfatin with presence of coronary ectasia and its severity. We enrolled 85 individuals including 35 CAE patients (mean age: 58.40 ±â€¯9.82 years) and 50 control persons (mean age: 53.24 ±â€¯8.81 years). These participants underwent some biochemical tests including visfatin, fasting blood glucose and lipid profiles. In univariate analysis, the serum level of visfatin was significantly associated with ectasia in all patients with CAE and CAD coexisting with CAE groups, but a trend toward significance in isolated CAE group. In multivariate analysis, visfatin showed independently significant association with presence of ectasia in all patients with ectasia and in CAD coexisting with ectasia groups, but not significant in isolated CAE group. Visfatin was also independently associated with severity of ectasia according to MARKIS classification. We conclude that visfatin independently can be the useful predictor for the presence and severity of coronary ectasia.

Nutritional Aspects of Treatment in Epileptic Patients.

Epilepsy is a neurological disorder characterized by interruption of normal neuronal functions that is manifested by behavioral disorders, changing of awareness level, and presence of some sensory, autonomic and motor symptoms or signs. It is resulted from many different causes. Many antiepileptic drugs (AEDs) are considered to manage epileptic attacks. Some of them change metabolism and absorption of many nutrients. Therefore, epileptic patients may be in higher risk of nutrient deficiency and its unwelcome effects. In the present paper, we intend to review the relationship between nutrition and epilepsy in two aspects. In one aspect we discuss the nutritional status in epileptic patients, the causes of nutritional deficiencies and the way of compensation of the nutrient deficiencies. It will guide these patients to have a healthy life. In another aspect we explain the role of some nutrients and specific diets in management of epileptic attacks. It can help to better control of epileptic attacks in these patients.

Effect of Vitamin A Supplementation on fatigue and depression in Multiple Sclerosis patients: A Double-Blind Placebo-Controlled Clinical Trial.

Decreasing the population and activation of inflammatory T helper cells in multiple sclerosis (MS) patients using vitamin A derivatives (retinoic acids) has been well documented. The present study determined the effect of vitamin A supplementation on psychiatric signs in MS patients. The subjects were 101 relapsing-remitting MS patients enrolled in a placebo-controlled randomized clinical trial. The treatment group was administered 25000 IU/d retinyl palmitate (RP) for 6 months followed by 10000 IU/d RP for another 6 months. The results for baseline characteristics, modified fatigue impact scale and Beck Depression Inventory-II were recorded at the beginning and end of the one-year study. The non-normal distribution data was compared between groups using a nonparametric test and normal distribution data was analyzed using a parametric test. (ClinicalTrials.gov Identifiers: NCT01417273). The results showed significant improvement in the treatment group for fatigue (p=0.004) and depression (p=0.01). Vitamin A supplementation helped during interferon therapy in the treatment process and improved psychiatric outcomes for anti-inflammatory mechanisms.