Research Progress in Structure Synthesis, Properties, and Applications of Small-Molecule Silicone Surfactants.

Silicone surfactants have garnered significant research attention owing to their superior properties, such as wettability, ductility, and permeability. Small-molecular silicone surfactants with simple molecular structures outperform polymeric silicone surfactants in terms of surface activity, emulsification, wetting, foaming, and other areas. Moreover, silicone surfactants with small molecules exhibit a diverse and rich molecular structure. This review discusses various synthetic routes for the synthesis of different classes of surfactants, including single-chain, "umbrella" structure, double chain, bolaform, Gemini, and stimulus-responsive surfactants. The fundamental surface/interface properties of the synthesized surfactants are also highlighted. Additionally, these surfactants have demonstrated enormous potential in agricultural synergism, drug delivery, mineral flotation, enhanced oil recovery, separation, and extraction, and foam fire-fighting.

Risk factors of in-hospital mortality and discriminating capacity of NIVO score in exacerbations of COPD requiring noninvasive ventilation.

BACKGROUND: Noninvasive mechanical ventilation (NIV) is recommended as the initial mode of ventilation to treat acute respiratory failure in patients with AECOPD. The Noninvasive Ventilation Outcomes (NIVO) score has been proposed to evaluate the prognosis in patients with AECOPD requiring assisted NIV. However, it is not validated in Chinese patients. METHODS: We used data from the MAGNET AECOPD Registry study, which is a prospective, noninterventional, multicenter, real-world study conducted between September 2017 and July 2021 in China. Data for the potential risk factors of mortality were collected and the NIVO score was calculated, and the in-hospital mortality was evaluated using the NIVO risk score. RESULTS: A total of 1164 patients were included in the study, and 57 patients (4.9%) died during their hospital stay. Multiple logistic regression analysis revealed that age ≥75 years, DBP <60 mmHg, Glasgow Coma Scale ≤14, anemia and BUN >7 mmol/L were independent predictors of in-hospital mortality. The in-hospital mortality was associated with an increase in the risk level of NIVO score and the difference was statistically significant (p < .001). The NIVO risk score showed an acceptable accuracy for predicting the in-hospital mortality in AECOPD requiring assisted NIV (AUC: 0.657, 95% CI: 0.584-0.729, p < .001). CONCLUSION: Our findings identified predictors of mortality in patients with AECOPD receiving NIV, providing useful information to identify severe patients and guide the management of AECOPD. The NIVO score showed an acceptable predictive value for AECOPD receiving NIV in Chinese patients, and additional studies are needed to develop and validate predictive scores based on specific populations.

Characteristics, treatments, in-hospital and long-term outcomes among inpatients with acute exacerbation of chronic obstructive pulmonary disease in China: sex differences in a large cohort study.

BACKGROUND: Data related to the characteristics, treatments and clinical outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients in China are limited, and sex differences are still a neglected topic. METHODS: The patients hospitalized for AECOPD were prospectively enrolled from ten medical centers in China between September 2017 and July 2021. Patients from some centers received follow-up for 3 years. Data regarding the characteristics, treatments and in-hospital and long-term clinical outcomes from male and female AECOPD patients included in the cohort were analyzed and compared. RESULTS: In total, 14,007 patients with AECOPD were included in the study, and 11,020 (78.7%) were males. Compared with males, female patients were older (74.02 ± 10.79 vs. 71.86 ± 10.23 years, P < 0.001), and had more comorbidities (2.22 ± 1.64 vs. 1.73 ± 1.56, P < 0.001), a higher frequency of altered mental status (5.0% vs. 2.9%, P < 0.001), lower diastolic blood pressure (78.04 ± 12.96 vs. 79.04 ± 12.47 mmHg, P < 0.001). In addition, there were also significant sex differences in a range of laboratory and radiographic findings. Females were more likely to receive antibiotics, high levels of respiratory support and ICU admission than males. The in-hospital and 3-year mortality were not significantly different between males and females (1.4% vs. 1.5%, P = 0.711; 35.3% vs. 31.4%, P = 0.058), while female smokers with AECOPD had higher in-hospital mortality than male smokers (3.3% vs. 1.2%, P = 0.002) and male smokers exhibited a trend toward higher 3-year mortality compared to female smokers (40.7% vs. 33.1%, P = 0.146). CONCLUSIONS: In AECOPD inpatients, females and males had similar in-hospital and long-term survival despite some sex differences in clinical characteristics and treatments, but female smokers had significantly worse in-hospital outcomes than male smokers. CLINICAL TRIAL REGISTRATION: Retrospectively registered, registration number is ChiCTR2100044625, date of registration 21/03/2021. URL: http://www.chictr.org.cn/showproj.aspx?proj=121626 .

A simple clinical risk score (ABCDMP) for predicting mortality in patients with AECOPD and cardiovascular diseases.

BACKGROUND: The morbidity and mortality among hospital inpatients with AECOPD and CVDs remains unacceptably high. Currently, no risk score for predicting mortality has been specifically developed in patients with AECOPD and CVDs. We therefore aimed to derive and validate a simple clinical risk score to assess individuals' risk of poor prognosis. STUDY DESIGN AND METHODS: We evaluated inpatients with AECOPD and CVDs in a prospective, noninterventional, multicenter cohort study. We used multivariable logistic regression analysis to identify the independent prognostic risk factors and created a risk score model according to patients' data from a derivation cohort. Discrimination was evaluated by the area under the receiver-operating characteristic curve (AUC), and calibration was assessed by the Hosmer-Lemeshow goodness-of-fit test. The model was validated and compared with the BAP-65, CURB-65, DECAF and NIVO models in a validation cohort. RESULTS: We derived a combined risk score, the ABCDMP score, that included the following variables: age > 75 years, BUN > 7 mmol/L, consolidation, diastolic blood pressure ≤ 60 mmHg, mental status altered, and pulse > 109 beats/min. Discrimination (AUC 0.847, 95% CI, 0.805-0.890) and calibration (Hosmer‒Lemeshow statistic, P = 0.142) were good in the derivation cohort and similar in the validation cohort (AUC 0.811, 95% CI, 0.755-0.868). The ABCDMP score had significantly better predictivity for in-hospital mortality than the BAP-65, CURB-65, DECAF, and NIVO scores (all P < 0.001). Additionally, the new score also had moderate predictive performance for 3-year mortality and can be used to stratify patients into different management groups. CONCLUSIONS: The ABCDMP risk score could help predict mortality in AECOPD and CVDs patients and guide further clinical research on risk-based treatment. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trail Registry NO.:ChiCTR2100044625; URL: http://www.chictr.org.cn/showproj.aspx?proj=121626 .

Validation of the Rome Severity Classification of Chronic Obstructive Pulmonary Disease Exacerbation: A Multicenter Cohort Study.

Background: The Rome severity classification is an objective assessment tool for the severity of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) based on readily measurable variables but has not been widely validated. The aim of this study is to evaluate the validity of the Rome classification in distinguishing the severity of AECOPD based on short-term mortality and other adverse outcomes. Methods: The Rome severity classification was applied to a large multicenter cohort of inpatients with AECOPD. Differences in clinical features, in-hospital and 60-day mortality, intensive care unit (ICU) admission, mechanical ventilation (MV) and invasive mechanical ventilation (IMV) usage were compared among the mild, moderate and severe AECOPD according to the Rome proposal. Moreover, univariate logistic analysis and Kaplan Meier survival analysis were also performed to find the association between the Rome severity classification and those adverse outcomes. Results: A total of 7712 patients hospitalized for AECOPD were included and classified into mild (41.88%), moderate (40.33%), or severe (17.79%) group according to the Rome proposal. The rate of ICU admission (6.4% vs 12.0% vs 14.9%, P <0.001), MV (11.7% vs 33.7% vs 45.3%, P <0.001) and IMV (1.4% vs 6.8% vs 8.9%, P <0.001) increased significantly with the increase of severity classification from mild to moderate to severe AECOPD. The 60-day mortality was higher in the moderate or severe group than in the mild group (3.5% vs 1.9%, 4.3% vs 1.9%, respectively, P <0.05) but showed no difference between the moderate and severe groups (2.6% vs 2.5%, P >0.05), results for in-hospital mortality showed the same trends. Similar findings were observed by univariate logistic analysis and survival analysis. Conclusion: Rome severity classification demonstrated excellent performance in predicting ICU admission and the need for MV or IMV, but how it performs in differentiating short-term mortality still needs to be confirmed.

N-acetyltransferase NAT10 controls cell fates via connecting mRNA cytidine acetylation to chromatin signaling.

Cell fate transition involves dynamic changes of gene regulatory network and chromatin landscape, requiring multiple levels of regulation, yet the cross-talk between epitranscriptomic modification and chromatin signaling remains largely unknown. Here, we uncover that suppression of N-acetyltransferase 10 (NAT10), the writer for mRNA N4-acetylcytidine (ac4C) modification, can notably affect human embryonic stem cell (hESC) lineage differentiation and pluripotent reprogramming. With integrative analysis, we identify that NAT10-mediated ac4C modification regulates the protein levels of a subset of its targets, which are strongly enriched for fate-instructive chromatin regulators, and among them, histone chaperone ANP32B is experimentally verified and functionally relevant. Furthermore, NAT10-ac4C-ANP32B axis can modulate the chromatin landscape of their downstream genes (e.g., key regulators of Wnt and TGFß pathways). Collectively, we show that NAT10 is an essential regulator of cellular plasticity, and its catalyzed mRNA cytidine acetylation represents a critical layer of epitranscriptomic modulation and uncover a previously unrecognized, direct cross-talk between epitranscriptomic modification and chromatin signaling during cell fate transitions.

Preoperative simulation results and intraoperative image fusion guidance for transjugular intrahepatic portosystemic shunt placement: a feasibility study of nineteen patients.

PURPOSE: The purpose is to evaluate the feasibility and efficacy of preoperative simulation results and intraoperative image fusion guidance during transjugular intrahepatic portosystemic shunt (TIPS) creation. METHODS: Nineteen patients were enrolled in the present study. The three-dimensional (3D) structures of the bone, liver, portal vein, inferior vena cava, and hepatic vein in the contrast-enhanced computed tomography (CT) scanning area were reconstructed in the Mimics software. The virtual Rosch-Uchida liver access set and the VIATORR stent model were established in the 3D Max software. The puncture path from the hepatic vein to the portal vein and the release position of the stent were simulated in the Mimics and 3D Max software, respectively. The simulation results were exported to Photoshop software, and the 3D reconstructed top of the liver diaphragm was used as the registration point to fuse with the liver diaphragmatic surface of the intraoperative fluoroscopy image. The selected portal vein system fusion image was overlaid on the reference display screen to provide image guidance during the operation. As a control, the last 19 consecutive cases of portal vein puncture under the guidance of conventional fluoroscopy were analyzed retrospectively, including the number of puncture attempts, puncture time, total procedure time, total fluoroscopy time, and total exposure dose (dose area product). RESULTS: The average time of preoperative simulation was about 61.26 ± 6.98 minutes. The average time of intraoperative image fusion was 6.05 ± 1.13 minutes. The median number of puncture attempts was not significantly different between the study group (n = 3) and the control group (n = 3; P = 0.175). The mean puncture time in the study group (17.74 ± 12.78 min) was significantly lower than that in the control group (58.32 ± 47.11 min; P = 0.002). The mean total fluoroscopy time was not significantly different between the study group (26.63 ± 12.84 min) and the control group (40.00 ± 23.44 min; P = 0.083). The mean total procedure time was significantly lower in the study group (79.74 ± 37.39 min) compared with the control group (121.70 ± 62.24 min; P = 0.019). The dose area product of the study group (220.60 ± 128.4 Gy. cm2) was not significantly different from that of the control group (228.5 ± 137.3 Gy. cm2; P = 0.773). There were no image guidance-related complications. CONCLUSION: The use of preoperative simulation results and intraoperative image fusion to guide a portal vein puncture is feasible, safe, and effective when creating a TIPS. The method is cheap and may improve portal vein puncture, which may be valuable for hospitals lacking intravascular ultrasound and digital subtraction angiography (DSA) equipment equipped with a CT-angiography function.

A fast chemical reprogramming system promotes cell identity transition through a diapause-like state.

Cellular reprogramming by only small molecules holds enormous potentials for regenerative medicine. However, chemical reprogramming remains a slow process and labour intensive, hindering its broad applications and the investigation of underlying molecular mechanisms. Here, through screening of over 21,000 conditions, we develop a fast chemical reprogramming (FCR) system, which significantly improves the kinetics of cell identity rewiring. We find that FCR rapidly goes through an interesting route for pluripotent reprogramming, uniquely transitioning through a developmentally diapause-like state. Furthermore, FCR critically enables comprehensive characterizations using multi-omics technologies, and has revealed unexpected important features including key regulatory factors and epigenetic dynamics. Particularly, activation of pluripotency-related endogenous retroviruses via inhibition of heterochromatin significantly enhances reprogramming. Our studies provide critical insights into how only environmental cues are sufficient to rapidly reinstate pluripotency in somatic cells, and make notable technical and conceptual advances for solving the puzzle of regeneration.

Elevated BUN Upon Admission as a Predictor of in-Hospital Mortality Among Patients with Acute Exacerbation of COPD: A Secondary Analysis of Multicenter Cohort Study.

Background: High blood urea nitrogen (BUN) is observed in a subset of patients with acute exacerbation of COPD (AECOPD) and may be linked to clinical outcome, but findings from previous studies have been inconsistent. Methods: We performed a retrospective analysis of patients prospectively enrolled in the MAGNET AECOPD Registry study (ChiCTR2100044625). Receiver operating characteristic (ROC) was used to determine the level of BUN that discriminated survivors and non-survivors. Univariate and multivariate Cox proportional hazards regression analyses were performed to assess the impact of BUN on adverse outcomes. Results: Overall, 13,431 consecutive inpatients with AECOPD were included in this study, of whom 173 died, with the mortality of 1.29%. The non-survivors had higher levels of BUN compared with the survivors [9.5 (6.8-15.3) vs 5.6 (4.3-7.5) mmol/L, P < 0.001]. ROC curve analysis showed that the optimal cutoff of BUN level was 7.30 mmol/L for in-hospital mortality (AUC: 0.782; 95% CI: 0.748-0.816; P < 0.001). After multivariate analysis, BUN level ≥7.3 mmol/L was an independent risk factor for in-hospital mortality (HR = 2.099; 95% CI: 1.378-3.197, P = 0.001), also for invasive mechanical ventilation (HR = 1.540; 95% CI: 1.199-1.977, P = 0.001) and intensive care unit admission (HR = 1.344; 95% CI: 1.117-1.617, P = 0.002). Other independent prognostic factors for in-hospital mortality including age, renal dysfunction, heart failure, diastolic blood pressure, pulse rate, PaCO2 and D-dimer. Conclusion: BUN is an independent risk factor for in-hospital mortality in inpatients with AECOPD and may be used to identify serious (or severe) patients and guide the management of AECOPD. Clinical Trial Registration: MAGNET AECOPD; Chinese Clinical Trail Registry NO.: ChiCTR2100044625; Registered March 2021, URL: http://www.chictr.org.cn/showproj.aspx?proj=121626.

Low diastolic blood pressure and adverse outcomes in inpatients with acute exacerbation of chronic obstructive pulmonary disease: A multicenter cohort study.

BACKGROUND: Although intensively studied in patients with cardiovascular diseases (CVDs), the prognostic value of diastolic blood pressure (DBP) has little been elucidated in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). This study aimed to reveal the prognostic value of DBP in AECOPD patients. METHODS: Inpatients with AECOPD were prospectively enrolled from 10 medical centers in China between September 2017 and July 2021. DBP was measured on admission. The primary outcome was all-cause in-hospital mortality; invasive mechanical ventilation and intensive care unit (ICU) admission were secondary outcomes. Least absolute shrinkage and selection operator (LASSO) and multivariable Cox regressions were used to identify independent prognostic factors and calculate the hazard ratio (HR) and 95% confidence interval (CI) for adverse outcomes. RESULTS: Among 13,633 included patients with AECOPD, 197 (1.45%) died during their hospital stay. Multivariable Cox regression analysis showed that low DBP on admission (<70 mmHg) was associated with increased risk of in-hospital mortality (HR = 2.16, 95% CI: 1.53-3.05, Z = 4.37, P <0.01), invasive mechanical ventilation (HR = 1.65, 95% CI: 1.32-2.05, Z = 19.67, P <0.01), and ICU admission (HR = 1.45, 95% CI: 1.24-1.69, Z = 22.08, P <0.01) in the overall cohort. Similar findings were observed in subgroups with or without CVDs, except for invasive mechanical ventilation in the subgroup with CVDs. When DBP was further categorized in 5-mmHg increments from <50 mmHg to ≥100 mmHg, and 75 to <80 mmHg was taken as reference, HRs for in-hospital mortality increased almost linearly with decreased DBP in the overall cohort and subgroups of patients with CVDs; higher DBP was not associated with the risk of in-hospital mortality. CONCLUSION: Low on-admission DBP, particularly <70 mmHg, was associated with an increased risk of adverse outcomes among inpatients with AECOPD, with or without CVDs, which may serve as a convenient predictor of poor prognosis in these patients. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trail Registry, No. ChiCTR2100044625.

Harnessing endogenous transcription factors directly by small molecules for chemically induced pluripotency inception.

Chemistry-alone approach has recently been applied for incepting pluripotency in somatic cells, representing a breakthrough in biology. However, chemical reprogramming is hampered by low efficiency, and the underlying molecular mechanisms remain unclear. Particularly, chemical compounds do not have specific DNA-recognition domains or transcription regulatory domains, and then how do small molecules work as a driving force for reinstating pluripotency in somatic cells? Furthermore, how to efficiently clear materials and structures of an old cell to prepare the rebuilding of a new one? Here, we show that small molecule CD3254 activates endogenous existing transcription factor RXRα to significantly promote mouse chemical reprogramming. Mechanistically, CD3254-RXRα axis can directly activate all the 11 RNA exosome component genes (Exosc1-10 and Dis3) at transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30, which is identified as a new barrier for cell-fate determination. In turn, MMVL30-mediated inflammation (IFN-γ and TNF-α pathways) is reduced, contributing to the promotion of successful reprogramming. Collectively, our study provides conceptual advances for translating environmental cues into pluripotency inception, particularly, identifies that CD3254-RXRα-RNA exosome axis can promote chemical reprogramming, and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine.

Blood Eosinophils and Clinical Outcomes in Inpatients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study.

Purpose: The prognostic value of blood eosinophils in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains controversial. This study aimed to evaluate whether blood eosinophils could predict in-hospital mortality and other adverse outcomes in inpatients with AECOPD. Methods: The patients hospitalized for AECOPD were prospectively enrolled from ten medical centers in China. Peripheral blood eosinophils were detected on admission, and the patients were divided into eosinophilic and non-eosinophilic groups with 2% as the cutoff value. The primary outcome was all-cause in-hospital mortality. Results: A total of 12,831 AECOPD inpatients were included. The non-eosinophilic group was associated with higher in-hospital mortality than the eosinophilic group in the overall cohort (1.8% vs 0.7%, P < 0.001), the subgroup with pneumonia (2.3% vs 0.9%, P = 0.016) or with respiratory failure (2.2% vs 1.1%, P = 0.009), but not in the subgroup with ICU admission (8.4% vs 4.5%, P = 0.080). The lack of association still remained even after adjusting for confounding factors in subgroup with ICU admission. Being consistent across the overall cohort and all subgroups, non-eosinophilic AECOPD was also related to greater rates of invasive mechanical ventilation (4.3% vs 1.3%, P < 0.001), ICU admission (8.9% vs 4.2%, P < 0.001), and, unexpectedly, systemic corticosteroid usage (45.3% vs 31.7%, P < 0.001). Non-eosinophilic AECOPD was associated with longer hospital stay in the overall cohort and subgroup with respiratory failure (both P < 0.001) but not in those with pneumonia (P = 0.341) or ICU admission (P = 0.934). Conclusion: Peripheral blood eosinophils on admission may be used as an effective biomarker to predict in-hospital mortality in most AECOPD inpatients, but not in patients admitted into ICU. Eosinophil-guided corticosteroid therapy should be further studied to better guide the administration of corticosteroids in clinical practice.

Additive prognostic value of serum calcium to the ESC risk stratification in patients with acute pulmonary embolism.

BACKGROUND: Hypocalcemia has been shown to be involved in the adverse outcomes of acute pulmonary embolism (APE). We aimed to determine the incremental value of adding hypocalcemia, defined as serum calcium level ≤ 2.12 mmol/L, on top of the European Society of Cardiology (ESC) prognostic algorithm, for the prediction of in-hospital mortality in APE patients, which in turn could lead to the optimization of APE management. METHODS: This study was conducted at West China Hospital of Sichuan University from January 2016 to December 2019. Patients with APE were retrospectively analyzed and divided into 2 groups based on serum calcium levels. Associations between hypocalcemia and adverse outcomes were assessed by Cox analysis. The accuracy of risk stratification for in-hospital mortality was assessed with the addition of serum calcium to the current ESC prognostic algorithm. RESULTS: Among 803 patients diagnosed with APE, 338 (42.1%) patients had serum calcium levels ≤ 2.12 mmol/L. Hypocalcemia was significantly associated with higher in-hospital and 2-year all-cause mortality compared to the control group. The addition of serum calcium to ESC risk stratification enhanced net reclassification improvement. Low-risk group with serum calcium level > 2.12 mmol/L had a 0% mortality rate, improving the negative predictive value up to 100%, while high-risk group with serum calcium level ≤ 2.12 mmol/L indicated a higher mortality of 25%. CONCLUSION: Our study identified serum calcium as a novel predictor of mortality in patients with APE. In the future, serum calcium may be added to the commonly used ESC prognostic algorithm for better risk stratification of patients suffering from APE.

Derivation and Validation of a Prognostic Model for Mortality in Chinese Patients with Acute Pulmonary Embolism.

INTRODUCTION: We aim to explore the risk factors for in-hospital mortality and to derive a prognostic model for patients with APE in China. MATERIALS AND METHODS: Inpatients with APE were enrolled from West China Hospital between January 2016 and December 2019. Logistic regression analyses were used to explore risk factors for in-hospital mortality and develop a prognostic model. RESULTS: A total of 813 subjects with APE were included in this study, of whom 542 were in the training set and 271 were in the test set. Multivariable regression analyses indicated that age, male, heart rate, systolic blood pressure, elevated NT-proBNP or troponin T, malignancy, chronic renal insufficiency, and respiratory failure were independent risk factors for in-hospital mortality. For the training set, the area under the curve (AUC) of the ROC curve was 0.899, with a sensitivity and specificity of 89.7% and 77.7%, respectively. The model had higher prediction accuracy than the PESI and sPESI. CONCLUSIONS: The prediction model has proven excellent discrimination and calibration, which may be a useful tool to help physicians make decisions regarding the best treatment strategy.

Superior Predictive Value of D-Dimer to the Padua Prediction Score for Venous Thromboembolism in Inpatients with AECOPD: A Multicenter Cohort Study.

Background: The optimal tool for risk prediction of venous thromboembolism (VTE) in inpatients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is still unknown. This study aimed to evaluate whether D-dimer could predict the risk of VTE in inpatients with AECOPD compared to the Padua Prediction Score (PPS). Methods: Inpatients with AECOPD were prospectively enrolled from seven medical centers in China between December 2018 and June 2020. On admission, D-dimer was detected, PPS was calculated for each patient, and the incidence of 2-month VTE was investigated. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of D-dimer and PPS on VTE development, and the best cut-off value for both methods was evaluated through the Youden index. Results: Among the 4468 eligible patients with AECOPD, 90 patients (2.01%) developed VTE within 2 months after admission. The area under the receiver operating characteristic curves (AUCs) of D-dimer for predicting VTE were significantly higher than those of the PPS both in the overall cohort (0.724, 95% CI 0.672-0.776 vs 0.620, 95% CI 0.562-0.679; P<0.05) and the subgroup of patients without thromboprophylaxis (0.747, 95% CI 0.695-0.799 vs 0.640, 95% CI 0.582-0.698; P<0.05). By calculating the Youden Index, the best cut-off value of D-dimer was determined to be 0.96 mg/L with an AUC of 0.689, which was also significantly better than that of the PPS with the best cut-off value of 2 (AUC 0.581, P=0.007). After the combination of D-dimer with PPS, the AUC (0.621) failed to surpass D-dimer alone (P=0.104). Conclusion: D-dimer has a superior predictive value for VTE over PPS in inpatients with AECOPD, which might be a better choice to guide thromboprophylaxis in inpatients with AECOPD due to its effectiveness and convenience. Clinical Trial Registration: Chinese Clinical Trail Registry NO. ChiCTR2100044625; URL: http://www.chictr.org.cn/showproj.aspx?proj=121626.

Clinical spectrum transition and prediction model of nonalcoholic fatty liver disease in children with obesity.

Objective: This study aims to outline the clinical characteristics of pediatric NAFLD, as well as establish and validate a prediction model for the disease. Materials and methods: The retrospective study enrolled 3216 children with obesity from January 2003 to May 2021. They were divided into obese without NAFLD, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH) groups. Clinical data were retrieved, and gender and chronologic characteristics were compared between groups. Data from the training set (3036) were assessed using univariate analyses and stepwise multivariate logistic regression, by which a nomogram was developed to estimate the probability of NAFLD. Another 180 cases received additional liver hydrogen proton magnetic resonance spectroscopy (1H-MRS) as a validation set. Results: The prevalence of NAFLD was higher in males than in females and has increased over the last 19 years. In total, 1915 cases were NAFLD, and the peak onset age was 10-12 years old. Hyperuricemia ranked first in childhood NAFLD comorbidities, followed by dyslipidemia, hypertension, metabolic syndrome (MetS), and dysglycemia. The AUROC of the eight-parameter nomogram, including waist-to-height ratio (WHtR), hip circumference (HC), triglyceride glucose-waist circumference (TyG-WC), alanine aminotransferase (ALT), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1(ApoA1), insulin sensitivity index [ISI (composite)], and gender, for predicting NAFLD was 0.913 (sensitivity 80.70%, specificity 90.10%). Calibration curves demonstrated a great calibration ability of the model. Conclusion and relevance: NAFLD is the most common complication in children with obesity. The nomogram based on anthropometric and laboratory indicators performed well in predicting NAFLD. This can be used as a quick screening tool to assess pediatric NAFLD in children with obesity.

N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis.

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.

Optimized simplified pediatric diabetes severity warning system for the early identification of diabetic ketoacidosis in children.

OBJECTIVE: Diabetic ketoacidosis (DKA) is the leading cause of mortality in children with type 1 diabetes. Diagnosis of DKA is difficult in resource-limited areas owing to the unavailability of blood gas test, the gold standard for DKA diagnosis. The Simplified Pediatric Diabetes Severity Warning System (SPDSWS) has been developed to identify high-risk DKA patients with limited resources in China. Here we optimized and validated this system. METHODS: This study included 835 children admitted between January 2011 and June 2020 with the principal diagnosis of type 1 diabetes. Data were collected based on demographic and clinical characteristics. DKA and its severity were defined according to the criteria of ISPAD. SPDSWS was optimized based on logistic regression analyses and then was validated in a validation cohort. RESULTS: The 20-point optimized SPDSWS included strong positive urine ketone, young age, dehydration, fatigue, anorexia, vomiting, abdominal pain, abnormal pulse, and high blood glucose. The optimized SPDSWS predicted DKA with an AUC value of 0.882 in the derivation cohort. When the cut-point score ≥7 was used, the sensitivity and specificity were 75.5% and 86.0%, respectively, in the derivation cohort and were 90.0% and 85.8%, respectively, in the validation cohort. The optimized SPDSWS also predicted the moderate/severe DKA with an AUC value of 0.911 in the derivation cohort and 0.937 in the validation cohort. A score > 11 was associated with an extremely high incidence of DKA. CONCLUSIONS: The optimized SPDSWS could assist health care practitioners in underdeveloped remote areas to identify the children at high risk of DKA as early as on admission.

Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.

Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.