Neoadjuvant immunotherapy improves outcomes for resectable gastroesophageal junction cancer: A systematic review and meta-analysis.

BACKGROUND: In recent years, neoadjuvant immunotherapy (NAIT) has developed rapidly in patients with gastroesophageal junction cancer (GEJC). The suggested neoadjuvant treatment regimens for patients with GEJC may vary in light of the efficacy and safety results. METHODS: A search of the Cochrane Library, PubMed, Embase, and Web of Science was completed to locate studies examining the safety and effectiveness of NAIT for resectable GEJC. We analyzed the effect sizes (ES) and 95% confidence intervals (CI) in addition to subgroups and heterogeneity. Meta-analyses were performed using Stata BE17 software. RESULTS: For these meta-analyses, 753 patients were chosen from 21 studies. The effectiveness of NAIT was assessed using the pathological complete response (pCR), major pathological response (MPR), and nodal downstage to ypN0 rate. The MPR, pCR, and nodal downstage to ypN0 rate values in NAIT were noticeably higher (MPR: ES = 0.45; 95% CI: 0.36-0.54; pCR: ES = 0.26; 95% CI: 0.21-0.32; nodal downstage to ypN0 rate: ES = 0.60; 95% CI: 0.48-0.72) than those of neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) (MPR < 30%; pCR: ES = 3%-17%; nodal downstage to ypN0 rate: ES = 21%-29%). Safety was assessed using the treatment-related adverse events (trAEs) incidence rate, surgical delay rate, surgical complications incidence rate, and surgical resection rate. In conclusion, the incidence of trAEs, incidence of surgical complications, and surgical delay rate had ES values of 0.66, 0.48, and 0.09, respectively. These rates were comparable to those from nCT or nCRT (95% CI: 0.60-0.70; 0.15-0.51; and 0, respectively). The reported resection rates of 85%-95% with nCT or nCRT were comparable to the mean surgical resection rate of 90%. CONCLUSION: NAIT is an effective treatment for resectable GEJC; additionally, the level of NAIT toxicity is acceptable. The long-term effects of NAIT require further study.

Exploration of anatomical distribution of brain metastasis from breast cancer at first diagnosis assisted by artificial intelligence.

Objectives: This study aimed to explore the spatial distribution of brain metastases (BMs) from breast cancer (BC) and to identify the high-risk sub-structures in BMs that are involved at first diagnosis. Methods: Magnetic resonance imaging (MRI) scans were retrospectively reviewed at our centre. The brain was divided into eight regions according to its anatomy and function, and the volume of each region was calculated. The identification and volume calculation of metastatic brain lesions were accomplished using an automatically segmented 3D BUC-Net model. The observed and expected rates of BMs were compared using 2-tailed proportional hypothesis testing. Results: A total of 250 patients with BC who presented with 1694 BMs were retrospectively identified. The overall observed incidences of the substructures were as follows: cerebellum, 42.1 %; frontal lobe, 20.1 %; occipital lobe, 9.7 %; temporal lobe, 8.0 %; parietal lobe, 13.1 %; thalamus, 4.7 %; brainstem, 0.9 %; and hippocampus, 1.3 %. Compared with the expected rate based on the volume of different brain regions, the cerebellum, occipital lobe, and thalamus were identified as higher risk regions for BMs (P value ≤ 5.6*10-3). Sub-group analysis according to the type of BC indicated that patients with triple-negative BC had a high risk of involvement of the hippocampus and brainstem. Conclusions: Among patients with BC, the cerebellum, occipital lobe and thalamus were identified as higher-risk regions than expected for BMs. The brainstem and hippocampus were high-risk areas of the BMs in triple negative breast cancer. However, further validation of this conclusion requires a larger sample size.

Efficacy and safety of neoadjuvant therapy in gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis.

OBJECTIVE: To determine the effectiveness and safety of neoadjuvant therapy in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and provide evidence-based suggestions for clinical treatment. METHODS: The Cochrane Library, Embase, PubMed, and Web of Science were searched for articles published that analyzed the effectiveness and safety of GEP-NEN-targeted neoadjuvant therapy before March 2023. A confidence interval (CI) of 95%, a subgroup analysis, heterogeneity, and effect size (ES) were analyzed, and a meta-analysis of the literature was performed using the Stata BE17 software. RESULTS: A total of 417 patients from 13 studies were included in this meta-analysis. The primary variables comprised the objective response rate (ORR), disease control rate (DCR), surgical resection rate, and R0 resection rate with ES values of 0.42 (95% CI: 0.25-0.60), 0.96 (95% CI: 0.93-0.99), 0.67 (95% CI: 0.50-0.84), and 0.60 (95% CI: 0.54-0.67), respectively. The secondary variables were the incidence rates of treatment-related adverse events (TRAEs), Grade 3 or higher TRAEs, and surgical complications with ES values of 0.29 (95% CI: -0.03-0.21), 0.13 (95% CI: -0.07-0.33), and 0.35 (95% CI: 0.27-0.44), respectively. CONCLUSION: Neoadjuvant therapy is an effective and safe treatment method for GEP-NENs. However, further studies are required to determine the optimal regimen for this therapy in these tumors.

Dosimetric comparison of coplanar and noncoplanar volumetric modulated arc therapy for hippocampal-sparing whole-brain radiation therapy.

Whole brain radiation therapy with hippocampal-sparing (HS-WBRT) is a novel treatment of brain metastases, which can relieve symptoms reduce recurrence in the central nervous system, and spare the hippocampus without compromising target coverage. This study aims to find out the superior combination of the treatment planning system and linear accelerator between Eclipse (version 15.6) with TrueBeam and uRT-TPOIS (vision R001.4) with uRT-linac 506c in HS-WBRT. The coplanar and noncoplanar volumetric modulated arc therapy (VMAT) for HS-WBRT plans were evaluated and compared on both combinations, respectively. Twenty patients for HS-WBRT were retrospectively selected at Peking Union Medical College Hospital (PUMCH) from 2021 to 2022. The coplanar and noncoplanar HS-WBRT treatment plans were designed by Eclipse and uRT-TPOIS referring to RTOG 0933 dose criteria, and their dosimetry parameters were compared. In addition, the plan complexity, monitor units, and beam-on time were recorded for Eclipse plans delivered on TrueBeam and uRT-TPOIS plans delivered on uRT-linac 506c. The results demonstrated that the dosimetric criteria of 4 types of HS-WBRT plans could meet the requirements of RTOG 0933. In terms of target coverage, dosimetric indexes of Eclipse plans and uRT-TPOIS plans were comparable, and the former is slightly better. As for metrics of organs-at-risk protection, coplanar and noncoplanar plans conducted by uRT-TPOIS were greatly superior to those by Eclipse. For coplanar and noncoplanar plans designed by the same treatment planning system, most of the dosimetric indexes had no significant difference. The monitor units of uRT-TPOIS plans was higher than that of Eclipse plans, but the modulation complexity of them were close, and uRT-TPOIS with uRT-linac 506c significantly reduced beam-on-time consumption by 9% on average for coplanar plans and 26% for noncoplanar plans compared to Eclipse with TrueBeam. This study firstly compared the coplanar and noncoplanar HS-WBRT treatment plans between Eclipse with TrueBeam and uRT-TPOIS with uRT-linac 506c in terms of dosimetry indexes, modulation complexity, and time consumption. It is shown that the radiation treatment solution of uRT-TPOIS with uRT-linac 506c is comparable with Eclipse with TrueBeam in terms of planning design, and significantly reduced the delivery time, which can be applied in clinical practice and promoted as a treatment format.

Potential biocontrol efficiency of Trichoderma species against oomycete pathogens.

Plant health is of utmost importance for optimal agricultural production and sustainability. Unfortunately, biotic and abiotic factors put a major constraint on crop safety and productivity. Plant diseases caused by oomycetes inflict serious damage to various crops. Moreover, the injudicious use of chemical pesticides poses threats related to pesticide resistance development in pathogens and environmental pollution. Biocontrol offers an effective solution for disease control; however, research on biocontrol of oomycete-related diseases is scarce. Thus, this study undertakes the screening of biocontrol resources for the effective management of oomycete-related plant diseases. In this regard, 86 isolates of Trichoderma spp. were assessed against Phytophthora nicotianae, P. capsici, Pythium vexans, P. ultimum, and P. dissotocum through dual culture assay. Furthermore, the antagonistic effect of selected isolates was studied against tobacco black shank disease and damping-off of cucumber seedlings in the greenhouse. The relative control effect of the three antagonistic Trichoderma strains AR-4, Tv-1, and ST4-1 on tobacco black shank was more than 60%, which was not significantly different from 6.88 gl-1 fluopicolide-propamocarb. Whereas, the relative control effect of Trichoderma AR-4 and ST4-1 on damping-off of cucumber seedlings was 80.33% and 82.67%, respectively, which were significantly higher than Trichoderma Tv-1 (35.49%) and fluopicolide-propamocarb (47.82%). According to the morphological and molecular characterization, the fungal strains AR-4, Tv-1, and ST4-1 were identified as Trichoderma koningiopsis, T. asperellum, and T. gamsii, respectively. In conclusion, the strains exhibited a strong antagonistic effect against oomycete pathogens and can be integrated into disease management strategies.

Transfer Learning-Based Autosegmentation of Primary Tumor Volumes of Glioblastomas Using Preoperative MRI for Radiotherapy Treatment.

Objectives: Glioblastoma is the most common primary malignant brain tumor in adults and can be treated with radiation therapy. However, tumor target contouring for head radiation therapy is labor-intensive and highly dependent on the experience of the radiation oncologist. Recently, autosegmentation of the tumor target has been playing an increasingly important role in the development of radiotherapy plans. Therefore, we established a deep learning model and improved its performance in autosegmenting and contouring the primary gross tumor volume (GTV) of glioblastomas through transfer learning. Methods: The preoperative MRI data of 20 patients with glioblastomas were collected from our department (ST) and split into a training set and testing set. We fine-tuned a deep learning model for autosegmentation of the hippocampus on separate MRI scans (RZ) through transfer learning and trained this deep learning model directly using the training set. Finally, we evaluated the performance of both trained models in autosegmenting glioblastomas using the testing set. Results: The fine-tuned model converged within 20 epochs, compared to over 50 epochs for the model trained directly by the same training set, and demonstrated better autosegmentation performance [Dice similarity coefficient (DSC) 0.9404 ± 0.0117, 95% Hausdorff distance (95HD) 1.8107 mm ±0.3964mm, average surface distance (ASD) 0.6003 mm ±0.1287mm] than the model trained directly (DSC 0.9158±0.0178, 95HD 2.5761 mm ± 0.5365mm, ASD 0.7579 mm ± 0.1468mm) with the same test set. The DSC, 95HD, and ASD values of the two models were significantly different (P<0.05). Conclusion: A model developed with semisupervised transfer learning and trained on independent data achieved good performance in autosegmenting glioblastoma. The autosegmented volume of glioblastomas is sufficiently accurate for radiotherapy treatment, which could have a positive impact on tumor control and patient survival.

Preoperative percutaneous oxygen saturation is a predictor of postoperative adverse events after Ebstein's anomaly reconstruction.

BACKGROUND: Ebstein's anomaly (EA) is a kind of congenital heart disease, which is currently widely treated by cone reconstruction. However, the prediction of postoperative recovery is still challenging. METHODS: A retrospective analysis was performed on EA cases undergoing cone reconstruction from January 2010 to January 2016. Univariate and multivariate logistic regression analyses were performed, with postoperative adverse events defined as dependent variable and pre- and intraoperative parameters defined as independent variables. The predictive capacity of preoperative percutaneous oxygen saturation (SPO2 ) and Great Ormond Street (GOS) score was evaluated using areas under the curve of the receiver operating characteristic (ROC). RESULTS: Preoperative SPO2 was 95.7 ± 5.20%. Cardiopulmonary bypass, aortic cross-clamp, postoperative mechanical ventilation, and hospitalization time were 101.7 ± 28.26 min, 60.9 ± 18.04 min, 16 h (8, 22), and 8 days (7, 11), respectively. The incidence of total postoperative adverse events, including low cardiac output syndrome, mechanical ventilation more than 3 days, postoperative hospitalization more than 2 weeks, postoperative reintubation, extracorporeal membrane oxygenation assistance, and death, was 13.1% (n = 13). Low preoperative SPO2 (p = .001, odds ratio [OR] = 0.834), GOS score (p = .021, OR = 0.368), and cardiopulmonary bypass time (p = .034, OR = 1.021) were risk factors for adverse events. Multivariate logistic regression analysis showed that low preoperative SPO2 (p = .002, OR = 0.846) and GOS score (p = .043, OR = 0.577) were independent risk factors for adverse events. The areas of SPO2 and GOS score under the ROC curve were 0.764 and 0.740, respectively. CONCLUSIONS: Low preoperative SPO2 and GOS score were predictors of adverse events after cone reconstruction, and SPO2 was more convenient and objective than the GOS score.

The risk factors analysis and establishment of an early warning model for healthcare-associated infections after pediatric cardiac surgery: A STROBE-compliant observational study.

The aim of this study was to identify the main risk factors for health-care-associated infections (HAIs) following cardiac surgery and to establish an effective early warning model for HAIs to enable intervention in an earlier stage.In total, 2227 patients, including 222 patients with postoperative diagnosis of HAIs and 2005 patients with no-HAIs, were continuously enrolled in Beijing Anzhen Hospital, Beijing, China. Propensity score matching was used and 222 matched pairs were created. The risk factors were analyzed with the methods of univariate and multivariate logistic regression. The receiver operating characteristic (ROC) curve was used to test the accuracy of the HAIs early warning model.After propensity score matching, operation time, clamping time, intubation time, urinary catheter time, central venous catheter time, ≥3 blood transfusions, re-endotracheal intubation, length of hospital stay, and length of intensive care unit stay, still showed significant differences between the 2 groups. After logistic model analysis, the independent risk factors for HAIs were medium to high complexity, intubation time, urinary catheter time, and central venous catheter time. The ROC showed the area under curve was 0.985 (confidence interval: 0.975-0.996). When the probability was 0.529, the model had the highest prediction rate, the corresponding sensitivity was 0.946, and the specificity was 0.968.According to the results, the early warning model containing medium to high complexity, intubation time, urinary catheter time, and central venous catheter time enables more accurate predictions and can be used to guide early intervention after pediatric cardiac surgery.

Palliative Operations for Cyanotic Congenital Heart Disease with Severely Asymmetrical Pulmonary Arteries.

BACKGROUND: Surgically managing patients with complex congenital heart disease and severely asymmetrical pulmonary arteries is challenging. Here, we report our experience using combined palliative procedures. METHOD: The medical records of 28 patients with complex congenital heart disease and severely asymmetrical pulmonary arteries who underwent combined palliative procedures between January 2004 and April 2013 were retrospectively reviewed until January 2018. The patients were divided into three groups according to shunt procedure timing: in group A (n = 15), cavopulmonary and systemic-pulmonary shunting were performed simultaneously; in group B (n = 11), systemic-pulmonary shunting was performed first; and in group C (n = 2), cavopulmonary shunt was performed first. Patients were followed for a mean ± standard deviation of 4.18 ± 2.22 years. RESULTS: No operative deaths occurred. There were no postoperative complications in groups B or C, but there was one case of pulmonary effusion and one of chylothorax in group A. The superior vena cava pressures were higher in patients in groups A and B than in those in group C. The ventilatory support duration and intensive care unit stays were longer in group A than in groups B and C (p < 0.01). Hypoplastic pulmonary artery development significantly improved after the use of three systemic-pulmonary shunts (p < 0.05), while the peripheral oxygen saturation increased from 67%±17% preoperatively to 85%±8% postoperatively (p < 0.001). Haemoglobin concentration decreased from 190 ± 34 g/L preoperatively to 136 ± 26 g/L postoperatively (p < 0.001). Two patients underwent double ventricle correction. Two patients underwent Fontan procedure. One patient underwent one and a half ventricle correction. One patient underwent collateral occlusion. CONCLUSIONS: Combined palliative procedures can achieve acceptable arterial oxygen saturation without extra volume loading and rescue the hypoplastic pulmonary artery.

The Organ-Protective Effect of Higher Partial Pressure of Arterial Carbon Dioxide in the Normal Range for Infant Patients Undergoing Ventricular Septal Defect Repair.

Hypercapnia has been reported to play an active role in protection against organ injury. The aim of this study was to determine whether a higher level of partial pressure of arterial carbon dioxide (PaCO2) within the normal range in pediatric patients undergoing cardiac surgery had a similar organ-protective effect. From May 2017 to May 2018, 83 consecutive infant patients undergoing ventricular septal defect (VSD) repair with cardiopulmonary bypass were retrospectively enrolled. We recorded the end-expiratory tidal partial pressure of carbon dioxide (Pet-CO2) as an indirect and continuous way to reflect the PaCO2. The patients were divided into a low PaCO2 group (LPG; 30 mmHg < Pet-CO2 < 40 mmHg) and a high PaCO2 group (HPG; 40 mmHg < Pet-CO2 < 50 mmHg). The regional cerebral oxygen saturation (rScO2), cerebral blood flow velocity (CBFV), and hemodynamics at five time points throughout the operation, and perioperative data were recorded and analyzed for the two groups. In total, 34 LPG and 49 HPG patients were included. Demographics and perioperative clinical data showed no significant difference between the groups. Compared with LPG, the HPG produced lower postoperative creatine kinase isoenzyme-MB (40.88 versus 50.34 ng/mL, P = 0.038). The postoperative C-reactive protein of HPG trended lower than in LPG (61.09 versus 73.4 mg/L, P = 0.056). The rScO2 and mean CBFV of HPG were significantly higher compared with LPG (P < 0.05) except at the end of cardiopulmonary bypass. Hemodynamic data showed no significant difference between the groups. As a convenient and safe approach, higher-normal PaCO2 could attenuate brain injury, heart injury, and inflammatory response in infant patients undergoing VSD repair.

Systemic-to-pulmonary shunt vs right ventricle to pulmonary artery connection in the treatment of pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries.

OBJECTIVE: The systemic-to-pulmonary shunt (SPS) and right ventricle to pulmonary artery (RV-PA) connection were evaluated to pursue the goal of rehabilitating dysplastic native PAs via establishment of antegrade blood flow. However, the application of these two palliative operations was still confusing. We compared the two operations to determine their different effects on patients who have pulmonary atresia, ventricular septal defects, and major aortopulmonary collateral arteries (MAPCAs). METHODS: From January 2011 to January 2016, 44 patients received the SPS procedure, and 54 patients received the RV-PA connection procedure; these procedures were compared based on perioperative data and follow-up data. There was no significant difference between the two groups for follow-up time (15.5 ± 11.8 vs 11.4 ± 10 months; P = .073). RESULTS: The SPS patients had a smaller preoperative pulmonary artery index (68.57 ± 38.25 vs 112.62 ± 61.63 mm2 /m2 ; P < .01), more MAPCAs (2.4 ± 1.1 vs 1.8 ± 1.5; P = .045) and had a shorter intubation time (26.73 ± 27.20 vs 40.88 ± 36.93 hours; P = .045), intensive care unit stay (3.6 ± 3.9 vs 5.7 ± 5.5 days; P = .033), and hospital stay (9.9 ± 3.9 vs 14.7 ± 11.9 days; P = .014) than the RV-PA connection patients. The cumulative complete repair rate and cumulative survival rate did not differ significantly between the two groups. CONCLUSIONS: Both the SPS and the RV-PA connection could rehabilitate the PA and produce complete repair, while the SPS could achieve better early postoperative outcomes and be suitable for patients with severe dysplastic PAs and large MAPCAs.

Correction of simple congenital heart defects by right axillary thoracotomy in adults.

BACKGROUND: Right axillary thoracotomy has been performed for open-heart procedures as a more aesthetic alternative to standard median sternotomy. This study aimed to evaluate the efficacy and safety of right axillary thoracotomy for the correction of simple congenital heart defects in adults. METHODS: Between January 2014 and December 2017, the clinical data of 180 adults who underwent right axillary thoracotomy for simple congenital heart defects were compared with the data of a paired group of 192 adults who underwent median sternotomy. RESULTS: Compared with the median sternotomy group, the right thoracotomy group showed shorter operative time, postoperative mechanical ventilation time, and postoperative hospitalization duration, as well as less drainage and transfusion volumes (P < .05). Aortic cross-clamping time, cardiopulmonary bypass time, and length of intensive care unit stay were similar between groups. No mortality or significant residual defects were reported in either group during follow-up. In total, 172 patients (95.6%) in the right thoracotomy group and 134 patients (69.8%) in the median sternotomy group were satisfied with their cosmetic results (P < .01). CONCLUSIONS: A right axillary thoracotomy is as safe and effective as a median sternotomy for the correction of simple congenital heart defects in adults. With lower trauma and better cosmetic results, this procedure provides a good alternative to the standard median sternotomy.

[Influence of valve height on the opening/closure performance of transplanted aortic valve].

Valve transplantation is often used in the treatment of aortic valve insufficiency. However, after surgery, the reconstructed aortic roots have an expansion phenomenon, in which the lack of valve height causes the aortic valve to close again. In this paper, the effects of different aortic valve height design on valve opening and closing performance were studied. The optimal surgical plan was obtained by in vitro numerical simulation, providing technical support and theoretical basis. In this paper, six groups of three-dimensional geometric models with a valve height increment of ± 0.5 mm were established with a root diameter of 26.0 mm and a valve height of 14.0 mm. Through the structural mechanics calculation and analysis of the parameters such as maximum stress, valve area and contact force of the model, reasonable geometrical dimensions are obtained. The study found that the maximum stress values of the six groups of models ranged from 640 to 690 kPa, which was consistent with the results of the literature; the three-group models with valve heights of 13.5 mm, 14.0 mm, and 14.5 mm were within a reasonable range. The contact force value of the 6 groups of leaflets increased with the increase of valve height. Studies have shown that the height of the aortic valve has an effect on the aortic valve closure performance. A valve height that is too small or too large will reduce the aortic systolic valve area and affect the aortic function.

The efficiency of systemic-to-pulmonary shunts in older children with hypoplastic pulmonary arteries.

BACKGROUND: To investigate the effects of systemic-to-pulmonary shunts (SPSs) in older children with hypoplastic pulmonary arteries and the factors affecting the development of the pulmonary arteries. METHODS: Eighty-six children (older than 3 years) who received SPSs were retrospectively analyzed. The perioperative parameters, the postoperative diameter of the pulmonary artery were collected, and the factors influencing the growth of the pulmonary arteries after an initial palliative shunt operation were analyzed. RESULTS: Two patients died postoperatively (2.33%), and the pulse oxygen saturation (SpO2 ) increased from 71.70 ± 6.75% preoperatively to 85.20 ± 11.07% at discharge. During the follow-up period of 56 (10-99) months, 37 patients (43.02%) underwent subsequent procedures, and in the remaining patients, the McGoon ratio was increased from 0.96 ± 0.48 at the surgery to 1.30 ± 0.31 at the final assessment (P < 0.05). Univariate analysis indicated that age younger than 5 years old (P < 0.05), pulmonary artery forward flow (P < 0.05) and a diagnosis of tetralogy of Fallot (P < 0.05) played positive roles in the growth of the pulmonary artery after surgery, while children with a McGoon ratio less than 0.6 showed poor development of the pulmonary arteries (P < 0.05). Multivariate analysis showed that age younger than 5 years old (P < 0.05) and pulmonary artery forward flow (P < 0.05) were positive effectors on the growth of the pulmonary artery. CONCLUSIONS: Older children with cyanotic congenital heart disease benefited from a systemic-pulmonary shunt and showed increased postoperative oxygen saturation and development of the pulmonary arteries. Age younger than 5 years and pulmonary artery antegrade flow were the positive factors influencing the growth of the pulmonary arteries postoperatively.

Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension.

Objective: To investigate the effects of angiotensin-converting enzyme 2 (ACE2) activation on pulmonary arterial cell apoptosis during pulmonary vascular remodeling associated with pulmonary arterial hypertension (PAH) and to elucidate potential mechanisms related to Hippo signaling. Methods: PAH model was developed by injecting monocrotaline combined with left pneumonectomy using Sprague-Dawley rat. Then, resorcinolnaphthalein (Res; ACE2 activator), MLN-4760 (ACE2 inhibitor), A-779 (Mas inhibitor), and 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino) benzenesulfonamide (XMU-MP-1; MST1/2 inhibitor) were administered via continuous subcutaneous or intraperitoneal injection for 3 weeks. Animals were randomly divided into six groups: control, PAH, PAH+Res, PAH+Res+MLN-4760, PAH+Res+A-779, and PAH+Res+XMU-MP-1. On 21 day, hemodynamics and pathologic lesions were evaluated. Apoptosis and apoptosis-associated proteins were detected by TUNEL and western blotting. ACE2 activity and Hippo pathway components including large tumor suppressor 1 (LATS1), Yes-associated protein (Yap), and phosphorylated Yap (p-Yap) were investigated by fluorogenic peptide assays and western blotting. Results: In the PAH models, the mean pulmonary arterial pressure, right ventricular hypertrophy index, pulmonary vascular remodeling, anti-apoptotic protein Bcl-2 and Yap were all increased but the pulmonary arterial cell apoptosis, pro-apoptotic proteins caspase-3 and Bax were lower. ACE2 activation significantly ameliorated pulmonary arterial remodeling, this action was related to increased apoptosis and up-regulation of LATS1 and p-Yap. These protective effects were mitigated by the co-administration of A779 or MLN-4760. Moreover, inhibiting the Hippo/LATS1/Yap pathway with XMU-MP-1 blocked apoptosis in pulmonary vascular cells induced by ACE2 activation during the prevention of PAH. Conclusions: Our findings suggest that ACE2 activation attenuates pulmonary vascular remodeling by inducing pulmonary arterial cell apoptosis via Hippo/Yap signaling during the development of PAH.

Angiotensin-converting enzyme 2 activation ameliorates pulmonary endothelial dysfunction in rats with pulmonary arterial hypertension through mediating phosphorylation of endothelial nitric oxide synthase.

This study aims to investigate the effect of angiotensin-converting enzyme 2 (ACE2) activation on pulmonary endothelial function in the process of preventing pulmonary arterial hypertension (PAH) in rat models and to explore the underlying mechanisms. Specific pathogen free rats were randomly divided into five groups including control group, PAH group, PAH + Resorcinolnaphthalein (Res) group (ACE2 activation), PAH + Res + MLN4760 group (ACE2 inhibition), and PAH + Res + L-NAME group (endothelial nitric oxide synthase [eNOS] inhibition). Rat PAH model was constructed using combined left pneumonectomy with a single dose of monocrotaline injection 1 week after the surgery, and the rats were then given corresponding reagents. Hemodynamics, endothelial function, and pathologic changes were evaluated 3 weeks after monocrotaline injection. The concentration of nitric oxide (NO), expression of eNOS, and phosphorylation of eNOS at Ser1177 and Thr495 in the lung tissues from rats were also investigated.The Res-induced activation of ACE2 led to decreased mean pulmonary arterial pressure (mPAP) and pulmonary artery remodeling in the PAH + Res group comparing with the PAH rats (P < .05). In addition, the reduction in mPAP induced by acetylcholine (Ach) was augmented in PAH + Res group (P < .05), but this was not observed under the treatment with sodium nitroprusside (SNP) (P > .05). The ratio of decrease in mPAP caused by Ach to that caused by SNP (Ach/SNP) was also increased (P < .05) in ACE2-activated rats. However, the protective effects of ACE2 activation on PAH were counteracted by co-administration of MLN4760, an ACE2 antagonist (all P > .05). The mechanistic study showed that the concentration of NO in the lung tissues was downregulated in the PAH group but upregulated in the PAH + Res group (P < .05), whereas the NO concentration in the PAH + Res + MLN4760 group was not obviously different from that in the PAH group (P > .05). Regarding the factors regulating NO release, we found that the eNOS was upregulated in the PAH group, and Res did not affect the expression of eNOS. The phosphorylation of eNOS at Ser1177 was increased but at Thr495 was reduced after Res injection, when compared with the PAH group (P < .05). As expected, co-injection of MLN4760 eliminated these differences (P > .05). The reduction in mPAP induced by Ach was attenuated in the PAH + Res + L-NAME group compared with the PAH + Res group (P < .05), but this was not observed in rats treated with SNP (P > .05). The Ach/SNP ratio of decline in mPAP was also decreased in the PAH + Res + L-NAME group (P < .05). Activation of ACE2 had a protective role in the development of PAH via improving the function of pulmonary arterial endothelium. This effect was potentially mediated by promoted NO release as a consequence of increased phosphorylation of eNOS at Ser1177 and dephosphorylation of eNOS at Thr495.

Efficacy of progesterone for moderate to severe traumatic brain injury: a meta-analysis of randomized clinical trials.

Progesterone has been shown to have neuroprotective effects in multiple animal models of brain injury, whereas the efficacy and safety in patients with traumatic brain injury (TBI) remains contentious. Here, a total of seven randomized controlled trials (RCTs) with 2492 participants were included to perform this meta-analysis. Compared with placebo, there was no significant decrease to be found in the rate of death or vegetative state for patients with acute TBI (RR = 0.88, 95%CI = 0.70, 1.09, p = 0.24). Furthermore, progesterone was not associated with good recovery in comparison with placebo (RR = 1.00, 95%CI = 0.88, 1.14, p = 0.95). Together, our study suggested that progesterone did not improve outcomes over placebo in the treatment of acute TBI.

Serum UCH-L1 as a Novel Biomarker to Predict Neuronal Apoptosis Following Deep Hypothermic Circulatory Arrest.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) has been used in cardiac surgery involving infant complex congenital heart disease and aortic dissection. DHCA carries a risk of neuronal apoptotic death in brain. Serum ubiquitin C-terminal hydrolase L1 (UCH-L1) level is elevated in a number of neurological diseases involving neuron injury and death. We studied the hypothesis that UCH-L1 may be a potential biomarker for DHCA-induced ischemic neuronal apoptosis. METHODS: Anesthetized piglets were used to perform cardiopulmonary bypass (CPB). DHCA was induced for 1 hour followed by CPB rewarming. Blood samples were collected and serum UCH-L1 levels were measured. Neuron apoptosis and Bax and Bcl-2 proteins in hippocampus were examined. The relationship between neuron apoptosis and UCH-L1 level was determined by receiver operating characteristics (ROC) curves and correlation analysis. RESULTS: DHCA resulted in marked neuronal apoptosis, significant increase in Bax:Bcl-2 ratio in hippocampus and UCH-L1 level elevations in serum (all P<0.05). Positive correlation was obtained between serum UCH-L1 level and the severity of neuron apoptosis (r= 0.78, P<0.01). By ROC, the area under the curve were 0.88 (95% CI: 0.74-0.99; P<0.01), 0.81 (95% CI: 0.81-0.96; P<0.05), 0.71 (95% CI: 0.47-0.92; P=0.11) for UCH-L1, Bax/Bcl-2 ratio and Bax, respectively. Using a cut-off point of 0.25, the UCH-L1 predicted neuronal apoptosis with a sensitivity of 85% and specificity of 57%. CONCLUSION: Serum UCH-L1, as an easy and quick measurable biomarker, can predict neural apoptosis induced by DHCA. The elevation in UCH-L1 concentration is consistent with the severity of neural apoptosis following DHCA.

Safety and Efficacy of Ventricular Septal Defect Repair Using a Cosmetic Shorter Right Lateral Thoracotomy on Infants Weighing Less than 5 kg.

OBJECTIVES: This study evaluated the safety and efficacy of a cosmetic right lateral thoracotomy for ventricular septal defect (VSD) repair in infants weighing less than 5 kg. METHODS: Eighty-nine infants who underwent a right lateral thoracotomy (right group) and 116 infants who underwent a median sternotomy (median group) were included. Patient characteristics, and perioperative and follow-up data were retrospectively analysed. RESULTS: Patient characteristics were comparable between the two groups as were cardiopulmonary bypass and aortic cross-clamping time, length of intensive care unit stay, ventilation duration and application of inotropic drugs. Compared to the median group, there was shorter procedure time (p < 0.05), shorter length of incision (p<0.05), and less drainage and transfusion in the right group (p<0.05). The peak airway pressure, partial oxygen pressure, partial carbon dioxide pressure, oxygenation index and alveolar-arterial oxygen gradients were similar for these two groups at the four time points analysed. No deaths occurred in either group and differences in morbidity were insignificant. No cardiac or thoracotomy-related complications occurred within the 18.4 ± 9.9 month follow-up. CONCLUSIONS: A right lateral thoracotomy reduces operative traumas and is as safe and effective as a median sternotomy at VSD repair in infants under 5 kg in weight.

Presenting features and clinical course of 34 patients with septic pulmonary embolism caused by right-sided infective endocarditis.

BACKGROUND: Misdiagnosis and missed diagnosis of septic pulmonary embolism (SPE), a rare disease, occurs among the patients with right heart infective endocarditis. The purpose of this study was to analyze the characteristics of SPE and improve the early diagnosis and treatment. METHODS: We retrospectively studied 34 patients with septic pulmonary embolism caused by right-sided infective endocarditis who were seen from June 1, 2002 to June 1, 2013. We reviewed the medical records and radiological images of these cases and extracted the following information: age, gender, and symptoms, physical examination, laboratory findings, transthoracic echocardiography (TTE) results, treatment information, comorbid medical conditions, and outcomes. Microbiological samples were collected and processed according to well-established and published guidelines. RESULTS: We identified basic heart disease in 97.1% of the patients. A high proportion of the right-sided infective endocarditis patients had congenital heart defects (82.4%); predominantly, ventricular septal defects. Clinical symptoms were fever (97.1%), cardiac murmurs (94.1%) and fatigue (88.2%). Respiratory symptoms included cough (58.8%), pleuritic chest pain (47.1%) and hyoxemia (52.9%). Positive blood cultures were grown from 35.2% of patients and 50.0% were caused by staphylococcal species. Chest X-rays or CT examinations detected patchy infiltrates and/or nodules in all cases. Transthoracic echocardiography demonstrated infectious foci of the right-side heart in all cases. Parenteral antibiotics were administered for all, and cardiac surgery was carried out for 76.5% of patients with an effective rate of 82.3%. CONCLUSIONS: SPE lacks characteristic clinical manifestation. Congenital heart disease is a common risk of SPE. Most patients with SPE have a good prognosis as long as early diagnosis and proper treatment can be provided.