Transcription factor EB (TFEB) improves ventricular remodeling after myocardial infarction by inhibiting Wnt/ß-catenin signaling pathway.

Background: Adverse left ventricular remodeling after myocardial infarction (MI) compromises cardiac function and increases heart failure risk. Until now, comprehension of the role transcription factor EB (TFEB) plays after MI is limited. Objectives: The purpose of this study was to describe the effects of TFEB on fibroblasts differentiation and extracellular matrix expression after MI. Methods: AAV9 (adeno-associated virus) mediated up- and down-regulated TFEB expressions were generated in C57BL/6 mice two weeks before the MI modeling. Echocardiography, Masson, Sirius red staining immunofluorescence, and wheat germ agglutinin staining were performed at 3 days, and 1, 2, and 4 weeks after MI modeling. Fibroblasts collected from SD neonatal rats were transfected by adenovirus and siRNA, and cell counting kit-8 (CCK8), immunofluorescence, wound healing and Transwell assay were conducted. Myocardial fibrosis-related proteins were identified by Western blot. PNU-74654 (100 ng/mL) was used for 12 hours to inhibit ß-catenin-TCF/LEF1 complex. Results: The up-regulation of TFEB resulted in reduced fibroblasts proliferation and its differentiation into myofibroblasts in vitro studies. A significant up-regulation of EF and down-regulation of myocyte area was shown in the AAV9-TFEB group. Meanwhile, decreased protein level of α-SMA and collagen I were observed in vitro study. TFEB didn't affect the concentration of ß-catenin. Inhibition of TFEB, which promoted cell migration, proliferation and collagen I expression, was counteracted by PNU-74654. Conclusions: TFEB demonstrated potential in restraining fibrosis after MI by inhibiting the Wnt/ß-catenin signaling pathway.

Neuroprotective Effect of miR-483-5p Against Cardiac Arrest-Induced Mitochondrial Dysfunction Mediated Through the TNFSF8/AMPK/JNK Signaling Pathway.

Substantial morbidity and mortality are associated with postcardiac arrest brain injury (PCABI). MicroRNAs(miRNAs) are essential regulators of neuronal metabolism processes and have been shown to contribute to alleviated neurological injury after cardiac arrest. In this study, we identified miRNAs related to the prognosis of patients with neurological dysfunction after cardiopulmonary resuscitation based on data obtained from the Gene Expression Omnibus (GEO) database. Then, we explored the effects of miR-483-5p on mitochondrial biogenesis, mitochondrial-dependent apoptosis, and oxidative stress levels after ischemia‒reperfusion injury in vitro and in vivo. MiR-483-5p was downregulated in PC12 cells and hippocampal samples compared with that in normal group cells and hippocampi. Overexpression of miR-483-5p increased the viability of PC12 cells after ischemia‒reperfusion injury and reduced the proportion of dead cells. A western blot analysis showed that miR-483-5p increased the protein expression of PCG-1, NRF1, and TFAM and reduced the protein expression of Bax and cleaved caspase 3, inhibiting the release of cytochrome c from mitochondria and alleviating oxidative stress injury by inhibiting the production of ROS and reducing MDA activity. We confirmed that miR-483-5p targeted TNFSF8 to regulate the AMPK/JNK pathway, thereby playing a neuroprotective role after cardiopulmonary resuscitation. Hence, this study provides further insights into strategies for inhibiting neurological impairment after cardiopulmonary resuscitation and suggests a potential therapeutic target for PCABI.

Hypothermia preconditioning improves cardiac contractility after cardiopulmonary resuscitation through AMPK-activated mitophagy.

Hypothermia preconditioning (HPC) improves cardiac function after cardiac arrest, yet the mechanism is unclear. We hypothesized that HPC-activated adenosine monophosphate-activated protein kinase (AMPK) activity may be involved. Adult male Wistar rats were randomly divided into normothermia Control, HPC (cooling to 32-34°C for 30 min), and HPC + Compound C (Compound C 10 mg/kg was injected intraperitoneally 30 min before HPC group). The rats underwent 7 min of untreated ventricular fibrillation (VF) followed by cardiopulmonary resuscitation (CPR). Cardiac function and hemodynamic parameters were evaluated at 4 h after return of spontaneous circulation (ROSC). Survival status was determined 72 h after ROSC. Mechanistically, we further examined the AMPK-Unc-51 Like Autophagy Activating Kinase 1 (ULK1)-mitophagy pathway and autophagic flux in vivo and in vitro. Six of twelve rats in the Control group, 10 of 12 rats in the HPC group, and 7 of 12 rats in HPC + Compound C group were successfully resuscitated. The 72-h survival rates were 1 of 12 Control, 6 of 12 HPC, and 2 of 12 HPC + Compound C rats, respectively (P = 0.043). Rats in the HPC group demonstrated greater cardiac contractility and hemodynamic stability which were compromised by Compound C. Furthermore, HPC increased the protein levels of p-AMPKα and p-ULK1 and promoted the expression of mitochondrial autophagy-related genes. Compound C decreased the expression of mitochondrial autophagy-related genes and reduced autophagic flux. Consistent with the observations obtained in vivo, in vitro experiments in cultured neonatal rat cardiomyocytes (CMs) demonstrated that HPC attenuated simulated ischemia-reperfusion-induced CM death, accompanied by increased AMPK-ULK1-mitophagy pathway activity. These findings suggest that AMPK-ULK1-mitophagy pathway was activated by HPC and has a crucial role in cardioprotection during cardiac arrest. Manipulation of mitophagy by hypothermia may merit further investigation as a novel strategy to prevent cardiac ischemia-reperfusion injury.

Examining patient trust towards physicians between clinical departments in a Chinese hospital.

The purpose of this cross-sectional survey study is to quantitatively examine the differences in patient trust towards physicians between four different clinical departments in a Chinese hospital. Using a validated modified Chinese version of the Wake Forest Physician Trust Scale, we measured patient trust in each department, and also collected data on patient demographics. A total of 436 patients or family members were surveyed in the departments of emergency medicine, pediatrics, cardiology, and orthopedic surgery. Significant differences were found between the departments, especially between pediatrics (trust score 43.23, range 11-50) and emergency medicine and cardiology (trust scores 45.29 and 45.79, respectively with range of 11-50). The average total score across all four departments was 44.72. There are indications that specifically comparing departments, such as patient demographics or department structure, could be helpful in tailoring patient care to improve physician-patient relationships.

Mild hypothermia improves neurological outcome in mice after cardiopulmonary resuscitation through Silent Information Regulator 1-actviated autophagy.

Mild hypothermia treatment (MHT) improves the neurological function of cardiac arrest (CA) patients, but the exact mechanisms of recovery remain unclear. Herein, we generated a CA and cardiopulmonary resuscitation (CPR) mouse model to elucidate such function. Naïve mice were randomly divided into two groups, a normothemia (NT) group, in which animals had normal body temperature, and a MHT group, in which animals had a body temperature of 33 °C (range: 32-34 °C), after the return of spontaneous circulation (ROSC), followed by CA/CPR. MHT significantly improved the survival rate of CA/CPR mice compared with NT. Mechanistically, MHT increased the expression of Silent Information Regulator 1 (Sirt1) and decreased P53 phosphorylation (p-P53) in the cortex of CA/CPR mice, which coincided with the elevated autophagic flux. However, Sirt1 deletion compromised the neuroprotection offered by MHT, indicating that Sirt1 plays an important role. Consistent with the observations obtained from in vivo work, our in vitro study utilizing cultured neurons subjected to oxygen/glucose deprivation and reperfusion (OGD/R) also indicated that Sirt1 knockdown increased OGD/R-induced neuron necrosis and apoptosis, which was accompanied by decreased autophagic flux and increased p-P53. However, the depletion of P53 did not suppress neuron death, suggesting that P53 was not critically involved in MHT-induced neuroprotection. In contrast, the application of autophagic inhibitor 3-methyladenine attenuated MHT-improved neuron survival after OGD/R, further demonstrating that increased autophagic flux significantly contributes to MHT-linked neuroprotection of CA/CRP mice. Our findings indicate that MHT improves neurological outcome of mice after CA/CPR through Sirt1-mediated activation of autophagic flux.

Association of ventilation with outcomes from out-of-hospital cardiac arrest.

AIM OF STUDY: To determine the association between bioimpedence-detected ventilation and out-of-hospital cardiac arrest (OHCA) outcomes. METHODS: This is a retrospective, observational study of 560 OHCA patients from the Dallas-Fort Worth site enrolled in the Resuscitation Outcomes Consortium Trial of Continuous or Interrupted Chest Compressions During CPR from 4/2012 to 7/2015. We measured bioimpedance ventilation (lung inflation) waveforms in the pause between chest compression segments (Physio-Control LIFEPAK 12 and 15, Redmond, WA) recorded through defibrillation pads. We included cases ≥18 years with presumed cardiac cause of arrest assigned to interrupted 30:2 chest compressions with bag-valve-mask ventilation and ≥2 min of recorded cardiopulmonary resuscitation. We compared outcomes in two a priori pre-specified groups: patients with ventilation waveforms in <50% of pauses (Group 1) versus those with waveforms in ≥50% of pauses (Group 2). RESULTS: Mean duration of 30:2 CPR was 13 ±â€¯7 min with a total of 7762 pauses in chest compressions. Group 1 (N = 424) had a median 11 pauses and 3 ventilations per patient vs. Group 2 (N = 136) with a median 12 pauses and 8 ventilations per patient, which was associated with improved return of spontaneous circulation (ROSC) at any time (35% vs. 23%, p < 0.005), prehospital ROSC (19.8% vs. 8.7%, p < 0.0009), emergency department ROSC (33% vs. 21%, p < 0.005), and survival to hospital discharge (10.3% vs. 4.0%, p = 0.008). CONCLUSIONS: This novel study shows that ventilation with lung inflation occurs infrequently during 30:2 CPR. Ventilation in ≥50% of pauses was associated with significantly improved rates of ROSC and survival.

Capnography: A support tool for the detection of return of spontaneous circulation in out-of-hospital cardiac arrest.

BACKGROUND: Automated detection of return of spontaneous circulation (ROSC) is still an unsolved problem during cardiac arrest. Current guidelines recommend the use of capnography, but most automatic methods are based on the analysis of the ECG and thoracic impedance (TI) signals. This study analysed the added value of EtCO2 for discriminating pulsed (PR) and pulseless (PEA) rhythms and its potential to detect ROSC. MATERIALS AND METHODS: A total of 426 out-of-hospital cardiac arrest cases, 117 with ROSC and 309 without ROSC, were analysed. First, EtCO2 values were compared for ROSC and no ROSC cases. Second, 5098 artefact free 3-s long segments were automatically extracted and labelled as PR (3639) or PEA (1459) using the instant of ROSC annotated by the clinician on scene as gold standard. Machine learning classifiers were designed using features obtained from the ECG, TI and the EtCO2 value. Third, the cases were retrospectively analysed using the classifier to discriminate cases with and without ROSC. RESULTS: EtCO2 values increased significantly from 41 mmHg 3-min before ROSC to 57 mmHg 1-min after ROSC, and EtCO2 was significantly larger for PR than for PEA, 46 mmHg/20 mmHg (p < 0.05). Adding EtCO2 to the machine learning models increased their area under the curve (AUC) by over 2 percentage points. The combination of ECG, TI and EtCO2 had an AUC for the detection of pulse of 0.92. Finally, the retrospective analysis showed a sensitivity and specificity of 96.6% and 94.5% for the detection of ROSC and no-ROSC cases, respectively. CONCLUSION: Adding EtCO2 improves the performance of automatic algorithms for pulse detection based on ECG and TI. These algorithms can be used to identify pulse on site, and to retrospectively identify cases with ROSC.

Tree ring phototropism and implications for the rotation of the North China Block.

Trees grow towards the sunlight via a process of phototropism. The trunk phototropism processes are frequently observed in Northern Hemisphere from high latitude to at least the Tropic of Cancer region, and also occur in some in situ preserved vertical petrified woods in various geological ages. However, such evidence is still very limited and poorly known in fossil record; and the relationship between tree ring phototropism and rotation of tectonic blocks is unclear. Here we report the eccentricities of living and fossil trees as a proxy to determine geological block rotation at the same latitudes within the North China Block. The dominant eccentricity of living trees is southwest 219° ± 5°. By contrast, standing in situ fossil trunks in the Mid-Late Jurassic Tiaojishan Formation and the Late Jurassic Tuchengzi Formation had average eccentricities of 237° and 233.5°, respectively. These differences shed light on the palaeogeographical changes, indicating that the North China Block rotated clockwise from the Late Jurassic to the present day. This result is largely coincident with the palaeomagnetic results, indicating that the North China Block rotated clockwise by 26.5° ± 5.5° since the Middle to Late Jurassic transition.

Evolution of Staircase Structures in Diffusive Convection.

Diffusive convection (DC) occurs when the vertical stratified density is controlled by two opposing scalar gradients that have distinctly different molecular diffusivities, and the larger- and smaller- diffusivity scalar gradients have negative and positive contributions for the density distribution, respectively. The DC occurs in many natural processes and engineering applications, for example, oceanography, astrophysics and metallurgy. In oceans, one of the most remarkable features of DC is that the vertical temperature and salinity profiles are staircase-like structure, composed of consecutive steps with thick homogeneous convecting layers and relatively thin and high-gradient interfaces. The DC staircases have been observed in many oceans, especially in the Arctic and Antarctic Oceans, and play an important role on the ocean circulation and climatic change. In the Arctic Ocean, there exist basin-wide and persistent DC staircases in the upper and deep oceans. The DC process has an important effect on diapycnal mixing in the upper ocean and may significantly influence the surface ice-melting. Compared to the limitations of field observations, laboratory experiment shows its unique advantage to effectively examine the dynamic and thermodynamic processes in DC, because the boundary conditions and the controlled parameters can be strictly adjusted. Here, a detailed protocol is described to simulate the evolution process of DC staircase structure, including its generation, development and disappearance, in a rectangular tank filled with stratified saline water. The experimental setup, evolution process, data analysis, and discussion of results are described in detail.

A novel technique to assess the quality of ventilation during pre-hospital cardiopulmonary resuscitation.

BACKGROUND: Devices that measure ventilation in the pre-hospital setting are deficient especially during early cardiopulmonary resuscitation (CPR) before placement of an advanced airway. Consequently, evidence is limited regarding the role of ventilation during early CPR and its effect on outcomes. OBJECTIVE: To develop software that automatically identifies ventilation waveforms recorded by defibrillators based on changes in transthoracic impedance during standard CPR. METHODS: This was an observational, retrospective analysis of non-traumatic pre-hospital cardiac arrest patients who received 30:2 CPR by emergency medical service rescuers. Data was collected from 550 cases recorded by the bioimpedance channel of defibrillators. Two expert clinicians independently assessed all episodes from the time of initial CPR until placement of an advanced airway, defined acceptable ventilation waveforms, and annotated the pauses between compressions with ventilation waveforms. We then developed software that incorporated the expert criteria and automatically annotated pauses with acceptable ventilations. RESULTS: A total of 7396 pauses were analyzed, mean(SD) duration of 30:2 CPR was 13 (8) min, with 13 (10) pauses/patient, and mean pause duration of 6 (3) s. Reviewer 1 and reviewer 2 identified 2375 and 2249 pauses with any acceptable ventilation, respectively, with an inter-rater reliability of 0.94. The novel software program reproduced expert annotation with excellent agreement (>0.8) and high accuracy, both sensitivity and specificity above 90%, compared to two reviewers. The software presented a substantial agreement with the reviewers (κ > 0.73) for ventilation counts in the pauses. CONCLUSION: We developed a novel and reliable strategy that enables investigation of ventilation quality during standard CPR using thoracic bioimpedance. This strategy would allow a timely and reliable automatic annotation of large scale resuscitation datasets.

Evaluation of chest compression artefact removal based on rhythm assessments made by clinicians.

AIM: To evaluate the performance of a state-of-the-art cardiopulmonary resuscitation (CPR) artefact suppression method by assessing to what extent the filtered electrocardiogram (ECG) can be correctly diagnosed by emergency medicine doctors. METHODS: A total of 819 ECG segments were used. Each segment contained two consecutive 10 s intervals, an artefact free interval and an interval corrupted by CPR artefacts. Each ECG segment was digitally processed to remove CPR artefacts using an adaptive filter. Each ECG segment was split into artefact-free and filtered intervals, randomly reordered for dissociation, and independently offered to four reviewers for rhythm annotation. The rhythm annotations of the artefact-free intervals were considered as the gold standard against which the rhythm annotations of the filtered intervals were evaluated. For the filtered intervals, the rater agreement (κ, Kappa score) with the gold standard, the sensitivity and the specificity were computed individually for each reviewer, and jointly through the majority decision of the pool of reviewers (DPR). These results were also compared to those obtained using a commercial shock advisory algorithm (SAA). RESULTS: The agreement between each reviewer and the gold standard was moderate ranging between κ = 0.41-0.64. The sensitivities and specificities ranged between 64.3-95.0%, and 70.0-95.9%, respectively. The agreement for the DPR was substantial with κ = 0.64 (0.62-0.66), a sensitivity of 90.6%, and a specificity of 85.6%. For the SAA, the agreement was fair with κ = 0.33 (0.31-0.35), a sensitivity of 90.3%, and a specificity of 66.4%. CONCLUSION: Clinicians outperformed the SAA, but specificities remained below the specifications recommended by the American Heart Association. Visual assessment of the filtered ECG by clinicians is not reliable enough, and varies greatly among clinicians. Results considerably improve by considering the consensus decision of a pool of clinicians.

Out-of-hospital cardiac arrest without return of spontaneous circulation in the field: Who are the survivors?

BACKGROUND: Return of spontaneous circulation (ROSC) in the field is a vital determinant contributing to survival from out-of-hospital cardiac arrest (OHCA). However, nearly one third of survivors at the Dallas-Fort Worth (DFW) Resuscitation Outcomes Consortium (ROC) site did not obtain ROSC in the field. METHODS: A retrospective, observational analysis was performed on all adult patients with non-traumatic OHCA treated on scene and transported to hospital, who did not gain ROSC in the field at DFW ROC site between 2006 through 2011.We described the demographics, pre-hospital characteristics and outcomes of all enrolled cases. Those patients without ROSC in the field, who did and did not meet Termination of Resuscitation (TOR) criteria in the field, were also compared. RESULTS: Among a total of 5099 treated and transported non-traumatic OHCA cases, 83.2% (4243) were included in this study as patients without ROSC gained in the field, of which 66.6% (2827) met TOR criteria but still were treated and transported; 1.9% (79) survived to hospital discharge. Further analysis showed that 39.2% (31) of survivors met TOR rule, accounting for 1.1% of those patients who should have been declared dead in the field. Shockable initial rhythms, EMS-witnessed arrest, bystander CPR and age were factors significant to predict survival from OHCA without ROSC in the field. Of concern, 1.7% (47) of patients who met TOR presented initially shockable rhythms but no shocks were delivered in the field. CONCLUSIONS: We suggest that all treated non-traumatic OHCA patients should be transported to hospital.