Left ventricular dysfunction with reduced functional cardiac reserve in diabetic and non-diabetic LDL-receptor deficient apolipoprotein B100-only mice

BACKGROUND: Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR(-/-)ApoB(100/100)). METHODS AND RESULTS: 18-month-old LDLR(-/-)ApoB(100/100 )(n = 12), diabetic LDLR(-/-)ApoB(100/100 )mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells (IGF-II/LDLR(-/-)ApoB(100/100), n = 14) and age-matched C57Bl/6 mice (n = 15) were studied after three months of high-fat Western diet. Compared to LDLR(-/-)ApoB(100/100 )mice, diabetic IGF-II/LDLR(-/-)ApoB(100/100 )mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60%) and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80%) despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR(-/-)ApoB(100/100 )and IGF-II/LDLR(-/-)ApoB(100/100 )mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion. CONCLUSIONS: LDLR(-/-)ApoB(100/100 )mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals

Characterization of low-density granulocytes in COVID-19

Author summary The emergence of SARS-COV-2 and the ensuing COVID-19 disease has revealed an unprecedented need to understand the pathological mechanisms of acute respiratory infections in more detail. Granulocytes are highly abundant cells of the innate immunity, and thus first responders towards acute infections. However, their excessive activation can cause unwanted tissue damage and detrimental effects in humans. This study identifies a population of low-density granulocytes (LDGs) in COVID-19 patient samples, which has been poorly described in the context of acute infections so far. These cells were subclassified and found to be mainly of immature phenotypes. Further characterization revealed COVID-19 LDGs as a phenotypically diverse population with immunosuppressive characteristics, which seemed to be in line with an elevated recruitment and activation of granulocytes. Altogether, these findings suggest LDG may play a role in COVID-19 disease progression. Severe COVID-19 is characterized by extensive pulmonary complications, to which host immune responses are believed to play a role. As the major arm of innate immunity, neutrophils are one of the first cells recruited to the site of infection where their excessive activation can contribute to lung pathology. Low-density granulocytes (LDGs) are circulating neutrophils, whose numbers increase in some autoimmune diseases and cancer, but are poorly characterized in acute viral infections. Using flow cytometry, we detected a significant increase of LDGs in the blood of acute COVID-19 patients, compared to healthy controls. Based on their surface marker expression, COVID-19-related LDGs exhibit four different populations, which display distinctive stages of granulocytic development and most likely reflect emergency myelopoiesis. Moreover, COVID-19 LDGs show a link with an elevated recruitment and activation of neutrophils. Functional assays demonstrated the immunosuppressive capacities of these cells, which might contribute to impaired lymphocyte responses during acute disease. Taken together, our data confirms a significant granulocyte activation during COVID-19 and suggests that granulocytes of lower density play a role in disease progression.Peer reviewe

Comprehensive self-tracking of blood glucose and lifestyle with a mobile application in the management of gestational diabetes : a study protocol for a randomised controlled trial (eMOM GDM study)

IntroductionGestational diabetes (GDM) causes various adverse short-term and long-term consequences for the mother and child, and its incidence is increasing globally. So far, the most promising digital health interventions for GDM management have involved healthcare professionals to provide guidance and feedback. The principal aim of this study is to evaluate the effects of comprehensive and real-time self-tracking with eMOM GDM mobile application (app) on glucose levels in women with GDM, and more broadly, on different other maternal and neonatal outcomes.Methods and analysisThis randomised controlled trial is carried out in Helsinki metropolitan area. We randomise 200 pregnant women with GDM into the intervention and the control group at gestational week (GW) 24-28 (baseline, BL). The intervention group receives standard antenatal care and the eMOM GDM app, while the control group will receive only standard care. Participants in the intervention group use the eMOM GDM app with continuous glucose metre (CGM) and activity bracelet for 1 week every month until delivery and an electronic 3-day food record every month until delivery. The follow-up visit after intervention takes place 3 months post partum for both groups. Data are collected by laboratory blood tests, clinical measurements, capillary glucose measures, wearable sensors, air displacement plethysmography and digital questionnaires. The primary outcome is fasting plasma glucose change from BL to GW 35-37. Secondary outcomes include, for example, self-tracked capillary fasting and postprandial glucose measures, change in gestational weight gain, change in nutrition quality, change in physical activity, medication use due to GDM, birth weight and fat percentage of the child.Ethics and disseminationThe study has been approved by Ethics Committee of the Helsinki and Uusimaa Hospital District. The results will be presented in peer-reviewed journals and at conferences.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Near-surface structure of the Sodankylä area in Finland, obtained by passive seismic interferometry

Abstract Controlled-source seismic exploration surveys are not always possible in nature-protected areas. As an alternative, the application of passive seismic techniques in such areas can be proposed. In our study, we show results of passive seismic interferometry application for mapping the uppermost crust in the area of active mineral exploration in northern Finland. We utilize continuous seismic data acquired by the Sercel Unite wireless multichannel recording system along several profiles during XSoDEx (eXperiment of SOdankylä Deep Exploration) multidisciplinary geophysical project. The objective of XSoDEx was to obtain a structural image of the upper crust in the Sodankylä area of northern Finland in order to achieve a better understanding of the mineral system at depth. The key experiment of the project was a high-resolution seismic reflection experiment. In addition, continuous passive seismic data were acquired in parallel with reflection seismic data acquisition. Due to this, the length of passive data suitable for noise cross-correlation was limited from several hours to a couple of days. Analysis of the passive data demonstrated that dominating sources of ambient noise are non-stationary and have different origins across the XSoDEx study area. As the long data registration period and isotropic azimuthal distribution of noise sources are two major conditions for empirical Green function (EGF) extraction under the diffuse field approximation assumption, it was not possible to apply the conventional techniques of passive seismic interferometry. To find the way to obtain EGFs, we used numerical modelling in order to investigate properties of seismic noise originating from sources with different characteristics and propagating inside synthetic heterogeneous Earth models representing real geological conditions in the XSoDEx study area. The modelling demonstrated that scattering of ballistic waves on irregular shape heterogeneities, such as massive sulfides or mafic intrusions, could produce a diffused wavefield composed mainly of scattered surface waves. In our study, we show that this scattered wavefield can be used to retrieve reliable EGFs from short-term and non-stationary data using special techniques. One of the possible solutions is application of “signal-to-noise ratio stacking” (SNRS). The EGFs calculated for the XSoDEx profiles were inverted, in order to obtain S-wave velocity models down to the depth of 300 m. The obtained velocity models agree well with geological data and complement the results of reflection seismic data interpretation

Analysis of high-frequency ambient seismic noise recorded during XSodEx experiment in Finland

Abstract Development of passive seismic methods is an important task for the solution of many practical problems where the study of shallow structure of subsurface is necessary (mineral exploration, microseismic zonic, groundwater study, etc.). Nowadays there are many techniques for estimating Empirical Greens Functions (EGF) from highfrequency seismic noise generated by industrial objects, transports or other human activity (Afonin et. al., 2016; Cheng et. al., 2015; Le Feuvre et. al., 2015; Nakata et. al., 2011; Shirzad et. al., 2014, etc.). Nevertheless, there is the necessity of using high-frequency ambient noise on quiet areas, for example, greenfield exploration tasks in remote territories. In this case, extraction of EGFs is difficult because of inhomogeneous distribution of sources and strong attenuation of high-frequency noise wavefield. That is why the study of high-frequency ambient noise behaviour in quiet areas is an important task for the development of passive seismic methods. For this purpose, we analyze ambient seismic noise recorded during XSodEx experiment by 24 3-component and 54 1-component DSU-SA MEMS seismic sensors with the autonomous data acquisition units produced by Sercel Ltd. The sensors were installed along about 1 km long line with intersensor distances of 7–15 m. The profile recorded continuous passive seismic data since 21.08.2017 to 23.08.2017 with the sampling rate of 500 sps. The data were processed by several steps including single station data analysis, prefiltering and cross-correlation of night-time records between all possible station pairs. The cross-correlation functions were used for EGFs estimation. The analysis of apparent velocities of cross-correlation functions and EGFs shows that there were several noise sources with frequencies of 1–20 Hz along the profile. In some cases, we extracted symmetric EGF from short time records (several hours), which indicates homogeneous azimuthal distribution of noise sources. Nevertheless, wavefields, generated by these sources distributed to about several dozen meters. In our paper, we concentrate mainly on details of our data processing routine and its influence on the quality of EGF extraction results

Hyperglycemia does not affect tissue repair responses in shear stress-induced atherosclerotic plaques in ApoE-/-mice

The mechanisms responsible for macrovascular complications in diabetes remain to be fully understood. Recent studies have identified impaired vascular repair as a possible cause of plaque vulnerability in diabetes. This notion is supported by observations of a reduced content of fibrous proteins and smooth muscle cell mitogens in carotid endarterectomy from diabetic patients along with findings of decreased circulating levels of endothelial progenitor cells. In the present study we used a diabetic mouse model to characterize how hyperglycemia affects arterial repair responses. We induced atherosclerotic plaque formation in ApoE-deficient (ApoE-/-) and heterozygous glucokinase knockout ApoE-deficient mice (ApoE-/-GK+/-) mice with a shear stress-modifying cast. There were no differences in cholesterol or triglyceride levels between the ApoE-/-A nd ApoE-/-GK+/-mice. Hyperglycemia did not affect the size of the formed atherosclerotic plaques, and no effects were seen on activation of cell proliferation, smooth muscle cell content or on the expression and localization of collagen, elastin and several other extracellular matrix proteins. The present study demonstrates that hyperglycemia per se has no significant effects on tissue repair processes in injured mouse carotid arteries, suggesting that other mechanisms are involved in diabetic plaque vulnerability