Machine learning prediction model of major adverse outcomes after pediatric congenital heart surgery: a retrospective cohort study.

BACKGROUND: Major adverse postoperative outcomes (APOs) can greatly affect mortality, hospital stay, care management and planning, and quality of life. This study aimed to evaluate the performance of five machine learning (ML) algorithms for predicting four major APOs after pediatric congenital heart surgery and their clinically meaningful model interpretations. METHODS: Between August 2014 and December 2021, 23 000 consecutive pediatric patients receiving congenital heart surgery were enrolled. Based on the split date of 1 January 2019, the authors selected 13 927 participants for the training cohort, and 9073 participants for the testing cohort. Four predefined major APOs including low cardiac output syndrome (LCOS), pneumonia, renal failure, and deep venous thrombosis (DVT) were investigated. Thirty-nine clinical and laboratory features were inputted in five ML models: light gradient boosting machine (LightGBM), logistic regression (LR), support vector machine, random forest, and CatBoost. The performance and interpretations of ML models were evaluated using the area under the receiver operating characteristic curve (AUC) and Shapley Additive Explanations (SHAP). RESULTS: In the training cohort, CatBoost algorithms outperformed others with the mean AUCs of 0.908 for LCOS and 0.957 for renal failure, while LightGBM and LR achieved the best mean AUCs of 0.886 for pneumonia and 0.942 for DVT, respectively. In the testing cohort, the best-performing ML model for each major APOs with the following mean AUCs: LCOS (LightGBM), 0.893 (95% CI: 0.884-0.895); pneumonia (LR), 0.929 (95% CI: 0.926-0.931); renal failure (LightGBM), 0.963 (95% CI: 0.947-0.979), and DVT (LightGBM), 0.970 (95% CI: 0.953-0.982). The performance of ML models using only clinical variables was slightly lower than those using combined data, with the mean AUCs of 0.873 for LCOS, 0.894 for pneumonia, 0.953 for renal failure, and 0.933 for DVT. The SHAP showed that mechanical ventilation time was the most important contributor of four major APOs. CONCLUSIONS: In pediatric congenital heart surgery, the established ML model can accurately predict the risk of four major APOs, providing reliable interpretations for high-risk contributor identification and informed clinical decisions-making.

Ralstonia solanacearum effector RipAK suppresses homodimerization of the host transcription factor ERF098 to enhance susceptibility and the sensitivity of pepper plants to dehydration.

Plants have evolved a sophisticated immune system to defend against invasion by pathogens. In response, pathogens deploy copious effectors to evade the immune responses. However, the molecular mechanisms used by pathogen effectors to suppress plant immunity remain unclear. Herein, we report that an effector secreted by Ralstonia solanacearum, RipAK, modulates the transcriptional activity of the ethylene-responsive factor ERF098 to suppress immunity and dehydration tolerance, which causes bacterial wilt in pepper (Capsicum annuum L.) plants. Silencing ERF098 enhances the resistance of pepper plants to R. solanacearum infection not only by inhibiting the host colonization of R. solanacearum but also by increasing the immunity and tolerance of pepper plants to dehydration and including the closure of stomata to reduce the loss of water in an abscisic acid signal-dependent manner. In contrast, the ectopic expression of ERF098 in Nicotiana benthamiana enhances wilt disease. We also show that RipAK targets and inhibits the ERF098 homodimerization to repress the expression of salicylic acid-dependent PR1 and dehydration tolerance-related OSR1 and OSM1 by cis-elements in their promoters. Taken together, our study reveals a regulatory mechanism used by the R. solanacearum effector RipAK to increase virulence by specifically inhibiting the homodimerization of ERF098 and reprogramming the transcription of PR1, OSR1, and OSM1 to boost susceptibility and dehydration sensitivity. Thus, our study sheds light on a previously unidentified strategy by which a pathogen simultaneously suppresses plant immunity and tolerance to dehydration by secreting an effector to interfere with the activity of a transcription factor and manipulate plant transcriptional programs.

Possible role of HE4 level elevation in the pathogenesis of TH2-high asthma.

OBJECTIVES: As a heterogeneous disease, asthma is characterized by airway hyperresponsiveness, airway inflammation, and airway mucus hypersecretion. According to the pathological changes, symptoms, preventive and treatment methods, asthma can be divided into TH2-high and TH2-low asthma. We show that the expression of the tumor biomarker human epididymis protein 4 (HE4) was significantly increased in TH2-high asthma group, while there was no marked difference in its expression between TH2-low asthma and healthy control groups. HE4 levels were significantly increased in plasma, induced sputum, and alveolar lavage fluid (BALF) samples and airway epithelial cells from TH2-high asthma group, showing that HE4 has a possible role in the pathogenesis of TH2-high asthma. METHODS: Using RT-qPCR, ELISA, Western blot (WB), and immunohistochemistry, we assessed differences in HE4 expression in plasma, induced sputum, BALF, and airway epithelial cells among patients with the TH2-related asthma subtypes and healthy controls. To explore the role of HE4 in TH2-high asthma, we conducted a correlation analysis between HE4 levels in plasma, induced sputum, BALF, and airway epithelial cells and multiple indicators of airway eosinophilic inflammation, airway mucus secretion, and airway remodeling. CONCLUSION: We found for the first time that HE4 was differentially expressed in the TH2-related asthma subtypes. In TH2-high asthma, HE4 levels were markedly elevated in airway epithelial cells, plasma, induced sputum, and BALF. HE4 may play an important role in various pathogenic mechanisms of asthma, such as airway eosinophilic inflammation, airway mucus secretion, and airway remodeling. HE4 in plasma may be a clinically biomarker for differentiating TH2-related asthma subtypes.

Efficient isopropanol-butanol-ethanol (IBE) fermentation by a gene-modified solventogenic Clostridium species under the co-utilization of Fe(III) and butyrate.

To elevate the efficiency of acetone-butanol-ethanol (ABE) fermentation by the wild-type strain WK, an optimal co-utilization system (20 mM Fe3+ and 5 g/L butyrate) was established to bring about a 22.22% increment in the yield of ABE mixtures with a significantly enhanced productivity (0.32 g/L/h). With the heterologous introduction of the secondary alcohol dehydrogenase encoded gene (adh), more than 95% of acetone was eliminated to convert 4.5 g/L isopropanol with corresponding increased butanol and ethanol production by 21.08% and 65.45% in the modified strain WK::adh. Under the optimal condition, strain WK::adh was capable of producing a total of 25.46 g/L IBE biosolvents with an enhanced productivity of 0.35 g/L/h by 45.83% over the original conditions. This work for the first time successfully established a synergetic system of co-utilizing Fe(III) and butyrate to demonstrate a feasible and efficient manner for generating the value-added biofuels through the metabolically engineered solventogenic clostridial strain.

CACYBP knockdown inhibits progression of prostate cancer via p53.

PURPOSE: Prostate cancer (PC) is one of the most common malignant tumors of genitourinary system in men. CACYCLIN binding protein (CACYBP) is involved in the progression of a variety of cancers. The aim of this study was to explore the expression and functional role of CACYBP in PC. METHODS: The expression of CACYBP in PC was evaluated by immunohistochemical (IHC) staining and qRT-PCR. Subsequently, we established lentivirus-mediated CACYBP knockdown in PC cell lines. The biological roles of CACYBP on proliferation, apoptosis, cycle distribution, migration and tumor formation of PC were investigated by Celigo cell counting assay, flow cytometry, transwell assay, wound-healing assay and mice xenograft models, respectively. RESULTS: CACYBP was highly expressed in PC and was positively correlated with the pathological grade of PC patients. Knockdown of CACYBP inhibited proliferation, enhanced apoptosis, arrested cell cycle in G2 and suppressed migration of PC cell lines in vitro. In addition, CACYBP knockdown weakened the tumor growth of PC in vivo. Moreover, addition of p53 inhibitor could effectively alleviate the inhibitory effect of CACYBP knockdown on cell activity. CONCLUSION: This study revealed that knockdown of CACYBP inhibited the proliferation, migration and tumorigenicity of PC, which may serve as a potential therapeutic target for the treatment of PC.

HSPB8 facilitates prostate cancer progression via activating the JAK/STAT3 signaling pathway.

Prostate cancer (PC) is a clinically and biologically heterogeneous disease that lacks effective treatment. Heat shock protein B8 (HSPB8) is an important factor in the progression of various types of cancer. However, the clinical significance and biological role of HSPB8 in PC are still unclear. In this study, we determined HSPB8 expression in PC tissues by immunohistochemical staining and explored the in vitro functions of HSPB8 using HSPB8 knockdown DU145 and LNcap PC cell lines. The in vivo effect of HSPB8 was explored by a subcutaneous xenograft mice model. The human phospho-kinase array and signal transducer and activator of transcription (STAT) 3 activator were utilized to explore the potential mechanism of HSPB8-induced PC progression. As a result, we found that HSPB8 was abundantly expressed in PC tissues and cell lines. HSPB8 knockdown inhibited cell proliferation and migration, promoted apoptosis and cycle repression, as well as weakened tumorigenesis ability. Mechanistically, we demonstrated that HSPB8 facilitates the malignant phenotypes of PC by activating the Janus kinase/STAT3 signaling pathway. These results proposed that HSPB8 seems to be an attractive therapeutic target for PC patients.

A novel nomogram for predicting respiratory adverse events during transport after interventional cardiac catheterization in children.

Objective: The rate and predictors of respiratory adverse events (RAEs) during transport discharged from operating room after interventional cardiac catheterization in children remain unclear. This study aimed to investigate the incidence and predictors, and to construct a nomogram for predicting RAEs during transport in this pediatric surgical treatment. Methods: This prospective cohort study enrolled 290 consecutive pediatric patients who underwent ventricular septal defects (VSD), atrial septal defects (ASD), and patent ductus arteriosus (PDA) between February 2019 and December 2020. Independent predictors were used to develop a nomogram, and a bootstrap resampling approach was used to conduct internal validation. Composite RAEs were defined as the occurrence of at least 1 complication regarding laryngospasm, bronchospasm, apnea, severe cough, airway secretions, airway obstruction, and oxygen desaturation. Results: The rate of RAEs during transport was 23.1% (67 out of 290). Multivariate analysis identified age (vs. ≤3 years, adjusted odds ratio (aOR) = 0.507, 95% confidence interval (CI), 0.268-0.958, P = 0.036), preoperative upper respiratory tract infections (URI, aOR = 2.335, 95% CI, 1.223-4.460, P = 0.01), type of surgery (vs. VSD, for ASD, aOR = 2.856, 95% CI, 1.272-6.411, P = 0.011; for PDA, aOR = 5.518, 95% CI, 2.425-12.553, P < 0.001), morphine equivalent (vs. ≤0.153 mg/kg, aOR = 2.904, 95% CI, 1.371-6.150, P = 0.005), atropine usage (aOR = 0.463, 95% CI, 0.244-0.879, P = 0.019), and RAEs during extubation to transport (aOR = 5.004, 95% CI, 2.633-9.511, P < 0.001) as independent predictors of RAEs during transport. These six candidate predictors were used to develop a nomogram, which showed a C-statistic value of 0.809 and good calibration (P = 0.844). Internal validation revealed similarly good discrimination (C-statistic, 0.782; 95% CI, 0.726-0.837) and calibration. Decision curve analysis (DCA) also demonstrated the clinical usefulness of the nomogram. Conclusion: The high rate of RAEs during transport reminds us of the need for more medical care and attention. The proposed nomogram can reliably identify pediatric patients at high risk of RAEs during transport and guide clinicians to make proper transport plans. Our findings have important and meaningful implications for RAEs risk prediction, clinical intervention and healthcare quality control.

Ferroptosis in COVID-19-related liver injury: A potential mechanism and therapeutic target.

The outbreak and worldwide spread of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a threat to global public health. SARS-CoV-2 infection not only impacts the respiratory system but also causes hepatic injury. Ferroptosis, a distinct iron-dependent form of non-apoptotic cell death, has been investigated in various pathological conditions, such as cancer, ischemia/reperfusion injury, and liver diseases. However, whether ferroptosis takes part in the pathophysiological process of COVID-19-related liver injury has not been evaluated yet. This review highlights the pathological changes in COVID-19-related liver injury and presents ferroptosis as a potential mechanism in the pathological process. Ferroptosis, as a therapeutic target for COVID-19-related liver injury, is also discussed. Discoveries in these areas will improve our understanding of strategies to prevent and treat hepatic injuries caused by COVID-19.

Left Ventricular Twist Mechanics Before and After Aortic Valve Replacement: A Feasibility Study and Exploratory Analysis.

Introduction. We examined whether intraoperative assessment of left ventricular (LV) twist mechanics is feasible with transesophageal echocardiography (TEE). We then explored whether twist mechanics were altered by hemodynamic conditions or patient comorbidities. Methods. In this sub-analysis of clinical trial data, transgastric short-axis echocardiographic images of the LV base and apex were collected in patients having aortic valve replacement (AVR) at baseline and end of surgery. Transvalvular gradients and LV systolic and diastolic function were assessed using two-dimensional (2D) and Doppler echocardiography. 2D speckle-tracking echocardiography was used for off-line analysis of LV twist, twisting rate, and untwisting rate. We examined the intraoperative change in twist mechanics before and after AVR. LV twist mechanics were also explored by diabetic status, need for coronary artery bypass grafting (CABG), and use of epinephrine/norepinephrine. Results. Of 40 patients, 16 patients had acceptable TEE images for off-line LV twist analysis. Baseline median [Q1, Q3] LV twist was 12 [7, 16]°, twisting rate was 72 [41, 97]°/sec, and untwisting rate was -91 [-154, -56]°/s. Median [Q1, Q3] change in LV twist at end of surgery was -2 [-5, 3]°, twisting rate was 7 [-33, 31]°/s, and untwisting rate was 0 [-11, 43]°/s. No difference was noted between diabetic and non-diabetic patients or AVR and AVR-CABG patients. Conclusion. LV twist was augmented in patients with aortic stenosis, though twist indices were not affected by reduced afterload, diabetes, or coronary artery disease. Intraoperative assessment of twist mechanics may provide unique information on LV systolic and diastolic function, though fewer than 50% of TEE examinations successfully assessed twist. Clinical Trial Registry. This work is a sub-analysis of a clinical trial, registered on ClinicalTrials.gov on August 19, 2010 (NCT01187329), Andra Duncan, Principal Investigator.

The alleviative effect of flavonol-type Nrf2 activator rhamnazin from Physalis alkekengi L. var. franchetii (Mast.) Makino on pulmonary disorders.

Rhamnazin (RN) is a flavonol isolated from the calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino, which has been used for treating pulmonary diseases in traditional Chinese medicine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a therapeutic target for pulmonary diseases. In the present study, the underlying mechanism and pharmacological effect of RN against pulmonary disorders are investigated. Human lung epithelial Beas-2B cell and RAW 264.7 murine macrophage-based cell models, and a cigarette smoke (CS)-induced pulmonary impairment mice model are adopted for investigation in vitro and in vivo. RN is identified to be an Nrf2 activator, which promotes Nrf2 dissociation from Keap1 via reacting with the Cys151 cysteine residue of Keap1, and suppresses Nrf2 ubiquitination. In addition, RN is able to attenuate toxicant-stimulated oxidative stress and inflammatory response in vitro. Importantly, RN significantly relieves CS-induced oxidative insult and inflammation, and RN-induced inhibition of inflammation is related to inhibition of nuclear transcription factor-κB (NF-κB) and induction of cell autophagy. In conclusion, our data indicate that RN is an activator of the Nrf2 pathway and evidently alleviates pulmonary disorders via restricting NF-κB activation and promoting autophagy. RN is a promising candidate for the therapy of pulmonary disorders.

Insulin-like Growth Factor 1 Promotes Cell Proliferation by Downregulation of G-Protein-Coupled Receptor 17 Expression via PI3K/Akt/FoxO1 Signaling in SK-N-SH Cells.

Insulin-like growth factor 1 (IGF-1) not only regulates neuronal function and development but also is neuroprotective in the setting of acute ischemic stroke. G-protein-coupled receptor 17 (GPR17) expression in brain tissue serves as an indicator of brain damage. As whether IGF-1 regulates GPR17 expression remains unknown, the aim of this study is to investigate how IGF-1 regulates GPR17 expression in vitro. Human neuroblastoma SK-N-SH cells were used. Lentivirus-mediated short hairpin RNA (shRNA) was constructed to mediate the silencing of FoxO1, while adenoviral vectors were used for its overexpression. Verification of the relevant signaling cascade was performed using a FoxO1 inhibitor (AS1842856), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), and a GPR17 antagonist (cangrelor). Cell proliferation was analyzed using EdU staining; immunofluorescence staining was used to detect the expression and subcellular localization of FoxO1. Chromatin immunoprecipitation was used to analyze the binding of FoxO1 to the GPR17 promoter in SK-N-SH cells. The expression of FoxO1, GPR17, and protein kinase B (also known as Akt) mRNA and protein as well as the levels of FoxO1 and Akt phosphorylation were investigated in this study. IGF-1 was found to downregulate FoxO1 and GPR17 expression in SK-N-SH cells while promoting cell viability and proliferation. Inhibition of FoxO1 and antagonism of GPR17 were found to play a role similar to that of IGF-1. Silencing of FoxO1 by lentivirus-mediated shRNA resulted in the downregulation of FoxO1 and GPR17 expression. The overexpression of FoxO1 via adenoviral vectors resulted in the upregulation of FoxO1 and GPR17 expression. Blocking of PI3K signaling by LY294002 inhibited the effect of IGF-1 on GPR17 suppression. Results from chromatin immunoprecipitation revealed that IGF-1 promotes FoxO1 nuclear export and reduces FoxO1 binding to the GPR17 promoter in SK-N-SH cells. Here, we conclude that IGF-1 enhances cell viability and proliferation in SK-N-SH cells via the promotion of FoxO1 nuclear export and reduction of FoxO1 binding to the GPR17 promoter via PI3K/Akt signaling. Our findings suggest that the enhancement of IGF-1 signaling to antagonize GPR17 serves as a potential therapeutic strategy in the management of acute ischemic stroke.

Risk factors, resource use, and cost of postoperative low cardiac output syndrome.

OBJECTIVE: Low cardiac output syndrome complicates recovery after cardiac surgery. We examined the incidence and risk factors for low cardiac output syndrome and its association with postoperative mortality, morbidity, resource use, and cost. METHODS: This cross-sectional retrospective observational study examined patients having cardiac surgery captured in the Premier Healthcare Database. Low cardiac output syndrome was defined as the requirement for postoperative mechanical circulatory support and/or hemodynamic instability requiring prolonged inotropic support. Incidence, risk factors, and association of low cardiac output syndrome with postoperative outcomes, including mortality, hospital and intensive care unit length of stay, hospital readmission, and cost at 30 days, 90 days, and 6 months, were examined. RESULTS: Among 59,810 patients from 164 hospitals having cardiac surgery between July 1, 2012, and June 30, 2014, low cardiac output syndrome developed in 6067 (10.1%) patients. Patients presenting in cardiogenic shock or systolic (± diastolic) heart failure were at greatest risk. Risk-adjusted in-hospital mortality was 12-fold greater with low cardiac output syndrome (odds ratio, 12.0; 95% confidence interval, 10.6-13.5). Risk-adjusted hospital costs (2019$; median [Q1, Q3]) were $64,041 [21,439] in patients who developed low cardiac output syndrome versus $48,086 [16,098] without; P < .001. Increased costs were driven by longer risk-adjusted hospital stay (10.1 [4.5] vs 8.5 [3.8] days); P < .001, intensive care unit (5.5 [2.5] vs 3.3 [1.5] days; P < .001) stay, and all-cause 30-day adjusted hospital readmission rates (mean [SD] 16.6 [8.2]% vs 13.9 [7.2]%; P < .001). CONCLUSIONS: Cardiac surgical patients who develop postoperative low cardiac output syndrome suffer greater mortality and have greater resource use, health care costs, and all-cause readmission, which informs perioperative decision making, and impacts hospital performance metrics and federal priority to reduce health care costs.

Age-Related Changes in Cerebral Hemodynamics in Children Undergoing Congenital Cardiac Surgery: A Prospective Observational Study.

OBJECTIVE: To explore age-related cerebral hemodynamic characteristics before and after pediatric cardiac surgery. DESIGN: Prospective observational study. SETTING: Single-center study based at a tertiary care center in Shanghai, China. PATIENTS: Fifty-three children with congenital heart disease (CHD) aged zero-to-six years undergoing cardiac surgery with cardiopulmonary bypass were enrolled, and 44 children finally were analyzed. INTERVENTION: Cerebral hemodynamics were measured by transcranial color-coded duplex sonography in the right temporal window before and after surgery. The resistance index (RI), pulsatility index (PI), and cerebral blood flow velocity (CBFV), including time average maximum flow velocity (Vtamax), mean blood flow velocity (Vmean), and the peak systolic flow velocity (Vpeak), of the right middle cerebral artery (MCA) and regional cerebral oxygen saturation (rScO2) of the right frontal lobe were measured and analyzed. Heart rate and mean arterial pressure were also recorded during ultrasound. MEASUREMENTS AND MAIN RESULTS: RI and PI decreased exponentially with age before and after cardiac surgery. While PI remained unchanged after cardiac surgery, RI was significantly reduced. Furthermore, RI reduction after cardiac surgery was more significant in children >18 months compared to those ≤18 months. CBFV of the right MCA also showed exponential increase with age, but rScO2 linearly increased. Cardiac surgery significantly changed the cerebral hemodynamics, but it did not affect rScO2 in children regardless of age. CONCLUSIONS: Age-related cerebral hemodynamic changes exist in children with CHD. Cardiopulmonary bypass surgery led to greater cerebrovascular dilation in children aged ≤18 months than those >18 months.

Solution-focused brief therapy for adolescent and young adult cancer patients in China: a pilot randomized controlled trial.

OBJECTIVE: This pilot clinical trial investigated solution-focused brief therapy (SFBT) for psychological distress among adolescent and young adult (AYA) patients with cancer in China. METHODS: Fifty Chinese AYA patients diagnosed with cancer were randomized into the treatment group (SFBT) and control group (active control). Psychological distress was measured by the brief symptom inventory and hope was measured by the Herth-Hope-Index. Treatment effects were analyzed using analysis-of-covariance and between-group small-sample-size corrected Hedges' g. RESULTS: The results indicated that SFBT resulted in a significant reduction in the psychological distress and improvement in hope of AYA patients with cancer. Analyses of the 4-week posttreatment score suggest the short-term sustainability of SFBT for psychological distress among AYAs diagnosed with cancer. CONCLUSIONS AND IMPLICATIONS: This study has demonstrated that SFBT's impact is statistically significant and clinically meaningful. The inclusion of positive emotions, i.e., hope, as part of the investigation also highlighted the significance of promoting positive emotions among AYA patients with cancer.

Predictive value of EEG-derived pain threshold index for acute postoperative pain in children.

Background: Electroencephalogram (EEG)-derived pain threshold index (PTI) has been developed as a novel pain recognition indicator and has been proved to be useful in the prediction of acute postoperative pain in adults. Evidence of its usability in children is limited. The aim of this study was to investigate the prediction value of this novel pain indicator PTI for acute postoperative pain in children. Methods: A total of 80 patients undergoing laparoscopic surgery under general anesthesia were enrolled. Blood pressure, heart rate (HR), surgical pleth index (SPI), PTI, and EEG-derived sedative index-wavelet index (WLI) data were recorded at the end of the surgery. The postoperative pain scores Face, Legs, Activity, Cry, Consolability (FLACC) were obtained in the emergence room 5 min after the children wake up. Receiver-operating characteristic curve was performed to analyze the predictive value of PTI, SPI, HR, and mean arterial pressure (MAP). The consistency between SPI and PTI was also evaluated. Results: Results showed that the areas under curves (95%CI) of PTI and SPI were 0.796 (95% CI: 0.694-0.895) and 0.753 (95% CI: 0.632-0.874), respectively, with the best cut-off value of 58 and 45 to discriminate between mild and moderate to severe pain. Conclusion: This study suggested that PTI obtained at the end of the surgery could predict acute postoperative pain in children with an acceptable accuracy. It will help with early recognition and treatment of postoperative pain, thus reducing the pain in children. In addition, PTI had a good consistency with SPI in predicting acute postoperative pain in children.

Case Report: Toxic epidermal necrolysis associated with sintilimab in a patient with relapsed thymic carcinoma.

Immune checkpoint inhibitors (ICIs) such as anti-programmed death 1 (PD-1) receptor monoclonal antibody has been shown to be effective in patients with relapsed thymic carcinoma. However, immune-related adverse events (irAE) are increasingly recognized. There is a paucity of clinical data, especially in elderly patients. A patient in his late 80s with a history of thymic carcinoma was treated with sintilimab, an anti-PD1 antibody. After one week of administration, the patient developed diffuse rash. After two cycles of sintilimab, there was rapid progression of the rash with gradual development of blisters and skin detachment. Sintilimab was immediately discontinued, and skin biopsy was performed. The histopathological findings were consistent with the diagnosis of toxic epidermal necrolysis (TEN), which was considered as an irAE. Intravenous methylprednisolone was initially administered, followed by oral prednisone. The patient showed dramatic improvement within 72 hours of initiation of treatment. Unfortunately, the patient died of severe pneumonia three months later. We report a case of TEN, a rare toxicity induced by anti-PD-1 sintilimab in an elderly patient with thymic carcinoma. Since TEN is a life-threatening condition, early recognition and management of this complication is a key imperative.

Experiment investigation on pulsed gamma-ray fluence rate effect on Yb-doped yttrium aluminum garnet scintillator.

As an ultrafast inorganic scintillator, Yb-doped Y3Al5O12 [yttrium aluminum garnet (YAG)] crystals have potential applications in various fields, such as ultrafast radiation detection, solar neutrino detection, pulsed radiation imaging, and nuclear reaction kinetics diagnosis. In this work, the fluence rate effect of pulsed γ rays on the Yb:YAG scintillation crystal was investigated at the "QiangGuang-I" facility. The experiment results show that the fluence rate linear response upper limit of the Yb:YAG crystal is about 9.1 × 1018 MeV cm-2 s-1. The Yb:YAG crystal changed from colorless to yellow, and the relative light output decreased to 63% of its initial value after the irradiations, which were attributed to the radiation induced damage. It is deduced that oxygen vacancies and divalent Yb cations were generated after the irradiations.

The Pepper Mitogen-Activated Protein Kinase CaMAPK7 Acts as a Positive Regulator in Response to Ralstonia solanacearum Infection.

Mitogen-activated protein kinase (MAPK) pathways play a vital role in multiple plant processes, including growth, development, and stress signaling, but their involvement in response to Ralstonia solanacearum is poorly understood, particularly in pepper plants. Herein, CaMAPK7 was identified from the pepper genome and functionally analyzed. The accumulations of CaMAPK7 transcripts and promoter activities were both significantly induced in response to R. solanacearum strain FJC100301 infection, and exogenously applied phytohormones, including methyl jasmonate (MeJA), brassinolide (BR), salicylic acid (SA), and ethephon (ETN), were decreased by abscisic acid (ABA) treatment. Virus-induced gene silencing (VIGS) of CaMAPK7 significantly enhanced the susceptibility of pepper plants to infection by R. solanacearum and downregulated the defense-related marker genes, including CaDEF1, CaPO2, CaSAR82A, and CaWRKY40. In contrast, the ectopic overexpression of CaMAPK7 in transgenic tobacco enhanced resistance to R. solanacearum and upregulated the defense-associated marker genes, including NtHSR201, NtHSR203, NtPR4, PR1a/c, NtPR1b, NtCAT1, and NtACC. Furthermore, transient overexpression of CaMAPK7 in pepper leaves triggered intensive hypersensitive response (HR)-like cell death, H2O2 accumulation, and enriched CaWRKY40 at the promoters of its target genes and drove their transcript accumulations, including CaDEF1, CaPO2, and CaSAR82A. Taken together, these data indicate that R. solanacearum infection induced the expression of CaMAPK7, which indirectly modifies the binding of CaWRKY40 to its downstream targets, including CaDEF1, CaPO2, and CaSAR82A, ultimately leading to the activation of pepper immunity against R. solanacearum. The protein that responds to CaMAPK7 in pepper plants should be isolated in the future to build a signaling bridge between CaMAPK7 and CaWRKY40.

Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2-high asthma.

The epithelial cell-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) initiate type 2 inflammation in allergic diseases, including asthma. However, the signaling pathway regulating these cytokines expression remains elusive. Since microRNAs are pivotal regulators of gene expression, we profiled microRNA expression in bronchial epithelial brushings from type 2-low and type 2-high asthma patients. miR-206 was the most highly expressed epithelial microRNA in type 2-high asthma relative to type 2-low asthma but was downregulated in both subsets compared with healthy controls. CD39, an ectonucleotidase degrading ATP, was a target of miR-206 and upregulated in asthma. Allergen-induced acute extracellular ATP accumulation led to miR-206 downregulation and CD39 upregulation in human bronchial epithelial cells, forming a feedback loop to eliminate excessive ATP. Airway ATP levels were markedly elevated and strongly correlated with IL-25 and TSLP expression in asthma patients. Intriguingly, airway miR-206 antagonism increased Cd39 expression; reduced ATP accumulation; suppressed IL-25, IL-33, and Tslp expression and group 2 innate lymphoid cell expansion; and alleviated type 2 inflammation in a mouse model of allergic airway inflammation. In contrast, airway miR-206 overexpression had opposite effects. Overall, epithelial miR-206 upregulates airway IL-25 and TSLP expression by targeting the CD39-extracellular ATP axis, which represents a potentially novel therapeutic target in type 2-high asthma.

Neither Preoperative Pulse Pressure nor Systolic Blood Pressure Is Associated With Cardiac Complications After Coronary Artery Bypass Grafting.

BACKGROUND: Increased pulse pressure has been associated with adverse cardiovascular events, cardiac and all-cause mortality in surgical and nonsurgical patients. Whether increased pulse pressure worsens myocardial injury and dysfunction after cardiac surgery, however, has not been fully characterized. We examined whether cardiac surgical patients with elevated pulse pressure are more susceptible to myocardial injury, dysfunction, cardiac-related complications, and mortality. Secondarily, we examined whether pulse pressure was a stronger predictor of the outcomes than systolic blood pressure. METHODS: This retrospective observational study included adult cardiac surgical patients having elective isolated on-pump coronary artery bypass grafting (CABG) between 2010 and 2017 at the Cleveland Clinic. The association between elevated pulse pressure and (1) perioperative myocardial injury, measured by postoperative troponin-T concentrations, (2) perioperative myocardial dysfunction, assessed by the requirement for perioperative inotropic support using the modified inotropic score (MIS), and (3) cardiovascular complications assessed by the composite outcome of postoperative mechanical circulatory assistance or in-hospital mortality were assessed using multivariable linear regression models. Secondarily, the association between pulse pressure versus systolic blood pressure and the outcomes were compared. RESULTS: Of 2704 patients who met the inclusion/exclusion criteria, complete data were available for 2003 patients. Increased pulse pressure over 40 mm Hg was associated with elevated postoperative troponin-T level, estimated to be 1.05 (97.5% confidence interval [CI], 1.02-1.09; P < .001) times higher per 10 mm Hg increase in pulse pressure. The association between pulse pressure and myocardial dysfunction and the composite outcome of cardiovascular complications and death were not significant. There was no difference in the association with pulse pressure versus systolic blood pressure and troponin-T concentrations. CONCLUSIONS: Elevated preoperative pulse pressure was associated with a modest increase in postoperative troponin-T concentrations, but not postoperative cardiovascular complications or in-hospital mortality in patients having CABG. Pulse pressure was not a better predictor than systolic blood pressure.