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Objectives Tissue hypoxia is the main cause of multi-organ dysfunction in sepsis. However, effective pharmacological treatments to combat sepsis-induced tissue hypoxia are not available. Emerging experimental and clinical evidence reveals an evolutionary conserved action of thyroid hormone (TH) to adapt injured tissue to hypoxic conditions via its action on p38 MAPK, Akt signaling pathways. In addition, TH has favorable effects on the immune system and viral load in infected tissue. Non-Thyroid Illness Syndrome is common in sepsis, acute myocardial infarction and trauma and is associated with increased mortality. Thus, TH may be a novel treatment in the setting of critical illness due to viral infection in which hypoxia prevails. The present study aims to address the efficacy and safety of acute administration of triiodothyronine (T3) in critically ill COVID-19 infected patients requiring mechanical respiratory support or Extra Corporeal Membrane Oxygenation (ECMO). Trial design This study is a phase II, parallel, 2-arm (1:1 ratio), multi-centre, prospective, randomized, double-blind, placebo controlled trial. Participants Male and female patients aged over 18 years old who are diagnosed with pulmonary infection due to COVID-19, admitted to Intensive Care Unit and requiring mechanical ventilation or ECMO will be enrolled in this trial. Patients will be excluded in cases of pregnancy, severe systemic disease with life expectancy less than 6 months, participation in another trial of an investigational drug or device, corticosteroid and/or sympathomimetic use before initiation of treatment. All data will be collected in electronic CRF files. Participants will start to be recruited from the ICU center of “ATTIKO” University Hospital in Greece. We aim to include two more clinical sites in the trial one from Greece and one from Germany Intervention and comparator Intervention: T3 Solution for injection 10 μg/ml. The dose administered will be 0.8g/kg i.v. bolus and will be followed by an infusion of 0.113g. kg-1.h-1 i.v. for 48 hours (therapeutic dose). After the first 48h, a maintenance dose will be administered corresponding to 50% of the therapeutic dose (0.057g. kg-1.h-1 i.v.). Drug administration will stop after successful weaning or end of follow up (maximum 30 days). Comparator: Placebo with composition and dosage identical apart from the active substance. Main outcomes The primary outcome assessed in the present study will be the percentage of patients successfully weaned after 30 days of follow-up. Successful weaning is defined as no requirement for ventilatory support after extubation (mechanical support) or support from ECMO for 48 hours. Randomisation An allocation sequence to one of the groups will be prepared by the Sponsor of the study. A 1:1 treatment allocation will be adopted. An electronic CRF will be used incorporating IWRS in order to assure proper randomization and unblinding in emergency cases. The representative of the sponsor will get a copy of randomization codes. The information of the randomization codes will then be locked in the database until the time at which an interim analysis or final analysis is performed. Blinding (masking) Participants, caregivers, and all investigators assessing the outcomes will be blinded to group assignment. Numbers to be randomised (sample size) The sample size of 60 patients (that indicates 30 subjects for each group) will have 84% power to detect the estimated difference between the two study groups. The criterion for significance (alpha) has been set at 0.05 and the test is 2-tailed. Trial Status Protocol number T3inj-02/ThySupport, version 03, May 11, 2020. The trial is not recruiting yet. The trial will start recruitment June 18 th 2020. Estimated recruitment will finish June 18 th , 2021. Trial registration Triiodothyronine for the Treatment of Critically Ill Patients With COVID-19 Infection (Thy-Support), ClinicalTrials.gov Identifier: NCT04348513, date of trial registration: April 16, 2020, EudraCT Identifier: 2020-001623-13, date of trial registration: April 22, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.

Background/Objectives: Among other substrates, the a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) protease degrades thrombospondin-5 (the cartilage oligomeric protein, COMP), thrombospondin-1 (TSP-1) and the tissue inhibitor of metalloproteinases-1 (TIMP-1) indicating a potential role of ADAMTS7 expression on coagulation cascade, tissue remodeling and wound healing. We analyzed the potential effect of direct oral anticoagulant (DOAC) treatment on ADAMTS7 promoter methylation and followed it over time to assess whether DOACs epigenetically modulate ADAMTS7 and induce pathways associated with coagulation or endothelium repair machinery. Methods: Eighty-four DOAC-treated atrial fibrillation (AF) patients followed-up from baseline (t0) to 7 days (t1, n = 70) and 28 days of treatment (t2, n = 62) and 19 non-AF controls were included in the study. Genomic DNA was extracted from blood at all timepoints and was bisulfite-converted prior to methylation analysis. ADAMTS7 promoter DNA methylation was analyzed with MIP-qMSP-PCR. Results: A total of 16 minor bleeding events occurred. The baseline percentage of ADAMTS7 methylation did not differ between AF patients and controls (15.8% vs. 16.1%, p = 0.908). In the patient cohort, DOAC therapy marginally decreased ADAMTS7 methylation from t0 to t2 (15.2% vs. 14.0%, p = 0.044). This ADAMTS7 demethylation from t0 to t2 was statistically significant only in patients experiencing bleeding (17.1%. vs. 13.4%, p = 0.010 in bleedings, 14.5% vs. 14.2%, p = 0.561 in non-bleedings). No other differences were observed. Conclusions: ADAMTS7 is demethylated during DOAC-related bleedings, a mechanism potentially leading to COMP degradation and thus thrombin-induced platelet aggregation, as well as the induction of endothelium repair through different ADAMTS7-dependent pathways.

Background/Objectives. Changes in CO2-derived variables during a fluid challenge have been proposed as markers of fluid responsiveness. We investigated whether, instead of fluid administration, passive leg raising (PLR)-induced changes in the CO2-derived variables, namely central venous-arterial carbon dioxide partial pressure (P(cv-a)CO2) and the ratio between P(cv-a)CO2 and the arterial-central venous oxygen content (P(cv-a)CO2/C(a-cv)O2), could detect preload responsiveness in critically ill patients. Methods. We studied 30 mechanically ventilated patients in whom a PLR test was performed due to acute circulatory failure. Routine hemodynamic variables, velocity-time integral (VTI), in the left ventricular outflow tract, and CO2-derived variables, were measured before, during, and after a PLR test. A PLR-induced increase in VTI of ≥10% defined preload responsiveness. The differences (Δ) of P(cv-a)CO2 and P(cv-a)CO2/C(a-cv)O2 between PLR and pre-PLR were calculated. The predictive values of PLR-induced changes in the CO2-derived variables was determined by receiver operating characteristic area under curves (ROC-AUCs). Results. Fifteen patients (50%) were classified as preload responsive. ΔP(cv-a)CO2 and ΔP(cv-a)CO2/C(a-cv)O2 were correlated with VTI changes and differed significantly between responders and non-responders −1.3 (−2–−0.6) vs. 0.6 (−0.1–1.1) mmHg, p < 0.001, and −0.38 (−0.97–−0.34) vs. 0.1 (−0.15–0.57) mmHg/mL O2, p < 0.001, respectively. The PLR-induced decrease in P(cv-a)CO2 was significantly associated with preload responsiveness (OR 0.48, CI 0.20–0.89, p = 0.016, bootstrap CI 0–0.85). The AUC curves for both ΔP(cv-a)CO2 and ΔP(cv-a)CO2/C(a-cv)O2 ratio to predict preload responsiveness were 0.89 (CI 0.74–1), p < 0.001, and 0.85 (CI 0.70–1), p < 0.001, respectively. Conclusions. In mechanically ventilated ICU patients with circulatory shock, PLR-induced changes in P(cv-a)CO2 and P(cv-a)CO2/C(a-cv)O2 ratio were correlated with VTI changes. The change in P(cv-a)CO2 was the only variable detecting preload responsiveness assessed by PLR; therefore, it could serve as an indirect marker, useful to guide fluid resuscitation when cardiac output measurement is not feasible.

The prognosis of asymptomatic subjects remains the most controversial issue in Brugada syndrome (BS). A meta-analysis on the prognostic role of spontaneous type 1 electrocardiographic (ECG) pattern and programmed ventricular stimulation (PVS) in asymptomatic subjects with Brugada electrocardiogram was performed. Current databases were searched until March 2014. Fourteen prospective observational studies were included in the present meta-analysis, accumulating data on 3,536 asymptomatic subjects (2,820 men) with BS phenotype. The mean follow-up period varied from 20 and 77 months. Data regarding 1,398 asymptomatic subjects with spontaneous type 1 ECG pattern of BS were retrieved from 6 studies. During follow-up, arrhythmic events (sustained ventricular tachycardia/fibrillation, appropriate device therapies, or arrhythmic death) occurred in 42 patients (3%). The meta-analysis of these studies demonstrated that asymptomatic subjects with spontaneous type 1 ECG pattern of BS exhibit an increased risk of future arrhythmic events (odds ratio = 3.56, 95% confidence interval 1.70 to 7.47, Z = 3.37, p = 0.0008); 1,104 asymptomatic subjects with BS ECG pattern from 12 studies underwent PVS and were available for analysis. During follow-up, arrhythmic events occurred in 36 subjects (3.3%). Inducible ventricular arrhythmias at PVS were predictive of future arrhythmic events (odds ratio = 3.51, 95% confidence interval 1.60 to 7.67, Z = 3.14, p = 0.002). In conclusion, this meta-analysis showed that asymptomatic subjects with either spontaneous diagnostic ECG pattern or inducible ventricular arrhythmias at PVS are at increased risk.

Abstract Background Takayasu arteritis (TAK) is a systemic non-inflammatory vasculitis that primarily affects large- and medium-sized arteries. Case summary We report the case of a 57-year-old woman with a history of coronary artery bypass grafting (CABG) 7 years prior, who was referred for a stress echo due to chest pain. Transthoracic echocardiography revealed the left ventricle at the upper limits of normal with preserved contractility, as well as circumferential thickening of the aortic root, causing severe aortic regurgitation (AR). Cardiac computed tomography and angiography demonstrated diffuse thickening of the aortic wall from the aortic root to the descending thoracic aorta, extending to the left carotid artery and significant stenosis of the left subclavian artery. Coronary angiography showed severe narrowing of the left main coronary ostium with ostial stenosis and total occlusion of the right coronary and left internal mammary arteries. Magnetic angiography highlighted thickening of the aortic wall, while no active inflammation was detected on positron emission tomography. These findings suggested Takayasu aortitis with chronic inflammation. Discussion In young patients, particularly women, who present with angina and coronary ostial stenosis, Takayasu arteritis should be considered in the differential diagnosis. Aortic regurgitation (AR) is a serious complication, and its surgical management can be challenging.

miR-27a-3p targets several proteins on the coagulation cascade. The potential effect of direct oral anticoagulants (DOACs) treatment on miR-27a-3p expression and their broader regulative effect on anticoagulation is unknown. Fifty-nine atrial fibrillation patients treated with rivaroxaban ( n  = 19), apixaban ( n  = 27) or dabigatran ( n  = 13), were included in the study. miR-27a-3p expression was analyzed at baseline and after 7 days of DOAC therapy by using a predesigned TaqMan assay. Relative quantitation of miR-27a-3p expression was calculated and compared in pooled population and in different sample groups. DOAC therapy did not alter miR-27a-3p expression (0.80 fold-change, p  = 0.486, pooled population; 0.839 fold-change, p  = 0.706, rivaroxaban; 0.921 fold-change, p  = 0.800, apixaban; 0.733 fold-change, p  = 0.540, dabigatran). miR-27a-3p expression did not differ between controls and bleeding cases (0.833 fold-change, p  = 0.588, baseline). Female patients had a trend towards increased baseline expression (1.564 fold-change, p  = 0.177) and reduced expression after DOAC treatment (0.683 fold-change, p  = 0.243) compared to male patients. Despite the regulatory role of miR-27a-3p on coagulation cascade, treatment with DOACs did not alter its expression. However, additional studies in different ethnic groups are necessary to fully elucidate the effect, if any, of DOACs on miR-27a-3p expression. Graphical Abstract Direct oral anticoagulant effect on miR-27a-3p expression in atrial fibrillation. Both miR-27a-3p and direct oral anticoagulants (DOACs) act on the coagulation cascade. Following over time changes in miR-27a-3p expression in DOAC treated atrial fibrillation patients, we have shown that DOAC treatment does not alter its expression