Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that ...relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066–1070,
2015
; Cell Stem Cell 16:477–487,
2015
; Curr Med Chem 13:1877–1893,
2006
) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway:
P
value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.
Abstract
Gamma-ray burst (GRB) afterglows have been observed across the electromagnetic spectrum, and physical parameters of GRB jets and their surroundings have been derived using broad-band ...modelling. While well-sampled light curves across the broad-band spectrum are necessary to constrain all the physical parameters, some can be strongly constrained by the right combination of just a few observables, almost independently of the other unknowns. We present a method involving the peaks of radio light curves to constrain the fraction of shock energy that resides in electrons, εe. This parameter is an important ingredient for understanding the microphysics of relativistic shocks. Based on a sample of 36 radio afterglows, we find εe has a narrow distribution centred around 0.13–0.15. Our method is suggested as a diagnostic tool for determining εe, and to help constrain the broad-band modelling of GRB afterglows. Some earlier measurements of the spreads in parameter values for εe, the kinetic energy of the shock and the density of the circumburst medium, based on broad-band modelling across the entire spectrum, are at odds with our analysis of radio peaks. This could be due to different modelling methods and assumptions, and possibly missing ingredients in past and current modelling efforts. Furthermore, we show that observations at ≳10 GHz performed 0.3–30 d after the GRB trigger are best suited for pinpointing the synchrotron peak frequency, and, consequently, εe. At the same time, observations at lower radio frequencies can pin down the synchrotron self-absorption frequency and help constrain the other physical parameters of GRB afterglows.
We explore the burst energy distribution of fast radio bursts (FRBs) in the low-twist magnetar model of Wadiasingh & Timokhin (WT19). Motivated by the power-law fluence distributions of FRB 121102, ...we propose an elementary model for the FRB luminosity function of individual repeaters with an inversion protocol that directly relates the power-law distribution index of magnetar short burst fluences to that for FRBs. The protocol indicates that the FRB energy scales virtually linearly with crust/field dislocation amplitude, if magnetar short bursts prevail in the magnetoelastic regime. Charge starvation in the magnetosphere during bursts (required in WT19) for individual repeaters implies the predicted burst fluence distribution is narrow, 3 decades for yielding strains and oscillation frequencies feasible in magnetar crusts. Requiring magnetic confinement and charge starvation, we obtain a death line for FRBs, which segregates magnetars from the normal pulsar population, suggesting only the former will host recurrent FRBs. We convolve the burst energy distribution for individual magnetars to define the distribution of luminosities in evolved magnetar populations. The broken power-law luminosity function's low-energy character depends on the population model, while the high-energy index traces that of individual repeaters. Independent of the evolved population, the broken power-law isotropic-equivalent energy/luminosity function peaks at ∼1037-1040 erg with a low-energy cutoff at ∼1037 erg. Lastly, we consider the local fluence distribution of FRBs and find that it can constrain the subset of FRB-producing magnetar progenitors. Our model suggests that improvements in sensitivity may reveal a flattening of the global FRB fluence distribution and saturation in FRB rates.
We present timing and time-integrated spectral analysis of 127 bursts from SGR J1935+2154. These bursts were observed with the Gamma-ray Burst Monitor on the Fermi Gamma-ray Space Telescope and the ...Burst Alert Telescope on the Neil Gehrels Swift Observatory during the source's four active episodes from 2014 to 2016. This activation frequency makes SGR J1935+2154 the most burst prolific transient magnetar. We find the average duration of all the detected bursts to be much shorter than the typical, anticipated value. We fit the burst time-integrated spectra with two blackbody functions, a Comptonized model and three other simpler models. Bursts from SGR J1935+2154 exhibit similar spectral properties to other magnetars, with the exception of the power-law index from the Comptonized model, which correlates with burst fluence. We find that the durations and both blackbody temperatures of the bursts have significantly evolved across the four active episodes. We also find that the burst time history exhibits two trends, which are strongly correlated with the decay of the persistent emission in each outburst.
Monocytes are critical mediators of healing following acute myocardial infarction (AMI), making them an interesting target to improve myocardial repair. The purpose of this study was a gain of ...insight into the source and recruitment of monocytes following AMI in humans.
Post-mortem tissue specimens of myocardium, spleen and bone marrow were collected from 28 patients who died at different time points after AMI. Twelve patients who died from other causes served as controls. The presence and localization of monocytes (CD14(+) cells), and their CD14(+)CD16(-) and CD14(+)CD16(+) subsets, were evaluated by immunohistochemical and immunofluorescence analyses. CD14(+) cells localized at distinct regions of the infarcted myocardium in different phases of healing following AMI. In the inflammatory phase after AMI, CD14(+) cells were predominantly located in the infarct border zone, adjacent to cardiomyocytes, and consisted for 85% (78-92%) of CD14(+)CD16(-) cells. In contrast, in the subsequent post-AMI proliferative phase, massive accumulation of CD14(+) cells was observed in the infarct core, containing comparable proportions of both the CD14(+)CD16(-) 60% (31-67%) and CD14(+)CD16(+) subsets 40% (33-69%). Importantly, in AMI patients, of the number of CD14(+) cells was decreased by 39% in the bone marrow and by 58% in the spleen, in comparison with control patients (P = 0.02 and <0.001, respectively).
Overall, this study showed a unique spatiotemporal pattern of monocyte accumulation in the human myocardium following AMI that coincides with a marked depletion of monocytes from the spleen, suggesting that the human spleen contains an important reservoir function for monocytes.
We aimed to develop and validate a deep-learning computer-aided detection (CAD) system, suitable for use in real time in clinical practice, to improve endoscopic detection of early neoplasia in ...patients with Barrett’s esophagus (BE).
We developed a hybrid ResNet-UNet model CAD system using 5 independent endoscopy data sets. We performed pretraining using 494,364 labeled endoscopic images collected from all intestinal segments. Then, we used 1704 unique esophageal high-resolution images of rigorously confirmed early-stage neoplasia in BE and nondysplastic BE, derived from 669 patients. System performance was assessed by using data sets 4 and 5. Data set 5 was also scored by 53 general endoscopists with a wide range of experience from 4 countries to benchmark CAD system performance. Coupled with histopathology findings, scoring of images that contained early-stage neoplasia in data sets 2–5 were delineated in detail for neoplasm position and extent by multiple experts whose evaluations served as the ground truth for segmentation.
The CAD system classified images as containing neoplasms or nondysplastic BE with 89% accuracy, 90% sensitivity, and 88% specificity (data set 4, 80 patients and images). In data set 5 (80 patients and images) values for the CAD system vs those of the general endoscopists were 88% vs 73% accuracy, 93% vs 72% sensitivity, and 83% vs 74% specificity. The CAD system achieved higher accuracy than any of the individual 53 nonexpert endoscopists, with comparable delineation performance. CAD delineations of the area of neoplasm overlapped with those from the BE experts in all detected neoplasia in data sets 4 and 5. The CAD system identified the optimal site for biopsy of detected neoplasia in 97% and 92% of cases (data sets 4 and 5, respectively).
We developed, validated, and benchmarked a deep-learning computer-aided system for primary detection of neoplasia in patients with BE. The system detected neoplasia with high accuracy and near-perfect delineation performance. The Netherlands National Trials Registry, Number: NTR7072
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The optimal targeted temperature in patients with shockable rhythm is unclear, and current guidelines recommend targeted temperature management with a correspondingly wide range between 32°C and ...36°C. Our aim was to study survival and neurologic outcome associated with targeted temperature management strategy in postarrest patients with initial shockable rhythm.
Observational substudy of the Coronary Angiography after Cardiac Arrest without ST-segment Elevation trial.
Nineteen hospitals in The Netherlands.
The Coronary Angiography after Cardiac Arrest trial randomized successfully resuscitated patients with shockable rhythm and absence of ST-segment elevation to a strategy of immediate or delayed coronary angiography. In this substudy, 459 patients treated with mild therapeutic hypothermia (32.0-34.0°C) or targeted normothermia (36.0-37.0°C) were included. Allocation to targeted temperature management strategy was at the discretion of the physician.
None.
After 90 days, 171 patients (63.6%) in the mild therapeutic hypothermia group and 129 (67.9%) in the targeted normothermia group were alive (hazard ratio, 0.86 95% CI, 0.62-1.18; log-rank p = 0.35; adjusted odds ratio, 0.89; 95% CI, 0.45-1.72). Patients in the mild therapeutic hypothermia group had longer ICU stay (4 d 3-7 d vs 3 d 2-5 d; ratio of geometric means, 1.32; 95% CI, 1.15-1.51), lower blood pressures, higher lactate levels, and increased need for inotropic support. Cerebral Performance Category scores at ICU discharge and 90-day follow-up and patient-reported Mental and Physical Health Scores at 1 year were similar in the two groups.
In the context of out-of-hospital cardiac arrest with shockable rhythm and no ST-elevation, treatment with mild therapeutic hypothermia was not associated with improved 90-day survival compared with targeted normothermia. Neurologic outcomes at 90 days as well as patient-reported Mental and Physical Health Scores at 1 year did not differ between the groups.
Previous studies have shown that preoperative anaemia in patients undergoing cardiac surgery is associated with adverse outcomes. However, most of these studies were retrospective, had a relatively ...small sample size, and were from a single centre. The aim of this study was to analyse the relationship between the severity of preoperative anaemia and short- and long-term mortality and morbidity in a large multicentre national cohort of patients undergoing cardiac surgery.
A nationwide, prospective, multicentre registry (Netherlands Heart Registration) of patients undergoing elective cardiac surgery between January 2013 and January 2019 was used for this observational study. Anaemia was defined according to the WHO criteria, and the main study endpoint was 120-day mortality. The association was investigated using multivariable logistic regression analysis.
In total, 35 484 patients were studied, of whom 6802 (19.2%) were anaemic. Preoperative anaemia was associated with an increased risk of 120-day mortality (adjusted odds ratio aOR 1.7; 95% confidence interval CI: 1.4–1.9; P<0.001). The risk of 120-day mortality increased with anaemia severity (mild anaemia aOR 1.6; 95% CI: 1.3–1.9; P<0.001; and moderate-to-severe anaemia aOR 1.8; 95% CI: 1.4–2.4; P<0.001). Preoperative anaemia was associated with red blood cell transfusion and postoperative morbidity, the causes of which included renal failure, pneumonia, and myocardial infarction.
Preoperative anaemia was associated with mortality and morbidity after cardiac surgery. The risk of adverse outcomes increased with anaemia severity. Preoperative anaemia is a potential target for treatment to improve postoperative outcomes.
We report on NICER observations of the magnetar SGR 1935+2154, covering its 2020 burst storm and long-term persistent emission evolution up to ∼90 days postoutburst. During the first 1120 s taken on ...April 28 00:40:58 UTC, we detect over 217 bursts, corresponding to a burst rate of >0.2 bursts s−1. Three hours later, the rate was 0.008 bursts s−1, remaining at a comparatively low level thereafter. The T90 burst duration distribution peaks at 840 ms; the distribution of waiting times to the next burst is fit with a lognormal with an average of 2.1 s. The 1-10 keV burst spectra are well fit by a blackbody, with an average temperature and area of kT = 1.7 keV and R2 = 53 km2. The differential burst fluence distribution over ∼3 orders of magnitude is well modeled with a power-law form dN/dF ∝ F−1.5 0.1. The source persistent emission pulse profile is double-peaked hours after the burst storm. We find that the burst peak arrival times follow a uniform distribution in pulse phase, though the fast radio burst associated with the source aligns in phase with the brighter peak. We measure the source spin-down from heavy-cadence observations covering days 21-39 postoutburst, Hz s−1, a factor of 2.7 larger than the value measured after the 2014 outburst. Finally, the persistent emission flux and blackbody temperature decrease rapidly in the early stages of the outburst, reaching quiescence 40 days later, while the size of the emitting area remains unchanged.
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