Risk factors and management of gastrointestinal bleeding in patients with or without antiplatelet and anticoagulation therapy: a multicenter real-world prospective study.

BACKGROUND: Antiplatelet and anticoagulation drugs complicate acute gastrointestinal bleeding (GIB) patients. Limited data about the risk factors and patient management has been presented. This study explored the association between previous antiplatelet or anticoagulant drug usage and clinical outcomes in GIB patients to improve awareness further and optimize treatment. METHODS: We conducted a multicenter, non-interventional, real-world prospective study in 106 hospitals in 23 provinces in China. GIB patients confirmed in the emergency department were included and were grouped according to previous drug histories. Univariate analysis, multivariate logistic regression, and multivariate stratification models were performed separately to investigate the associations. RESULTS: A total of 2299 patients (57.23 ± 17.21 years old, 68.3% male) were included, of whom 20.1% and 2.9% received antiplatelet and anticoagulation therapy, respectively. The all-cause 28-day mortality rates in patients without antiplatelet or anticoagulants, patients undergoing antiplatelet treatment, and patients with anticoagulation therapy were 2.8%, 4.6%, and 10.5%, respectively. After adjusting for confounding factors, both antiplatelet [odd ratio (OR), 2.92; 95% confidence interval (CI), 1.48-5.76; p = 0.002] and anticoagulation therapy (OR, 8.87; 95% CI, 3.02-26.02; p < 0.001) were associated with higher 28-day mortality. In the subgroup analysis, blood transfusion, especially red blood cell transfusion, in patients undergoing antiplatelet and anticoagulation therapy was associated with a decreased death risk. CONCLUSION: We confirmed an association between concurrent antiplatelet or anticoagulation therapy in GIB patients and elevated 28-day mortality. Blood transfusions could improve poor outcomes in such patients.

A novel predictor of unsustained return of spontaneous circulation in cardiac arrest patients through a combination of capnography and pulse oximetry: a multicenter observational study.

BACKGROUND: Unsustained return of spontaneous circulation (ROSC) is a critical barrier to survival in cardiac arrest patients. This study examined whether end-tidal carbon dioxide (ETCO2) and pulse oximetry photoplethysmogram (POP) parameters can be used to identify unsustained ROSC. METHODS: We conducted a multicenter observational prospective cohort study of consecutive patients with cardiac arrest from 2013 to 2014. Patients' general information, ETCO2, and POP parameters were collected and statistically analyzed. RESULTS: The included 105 ROSC episodes (from 80 cardiac arrest patients) comprised 51 sustained ROSC episodes and 54 unsustained ROSC episodes. The 24-hour survival rate was significantly higher in the sustained ROSC group than in the unsustained ROSC group (29.2% vs. 9.4%, P<0.05). The logistic regression analysis showed that the difference between after and before ROSC in ETCO2 (ΔETCO2) and the difference between after and before ROCS in area under the curve of POP (ΔAUCp) were independently associated with sustained ROSC (odds ratio [OR]=0.931, 95% confidence interval [95% CI] 0.881-0.984, P=0.011 and OR=0.998, 95% CI 0.997-0.999, P<0.001). The area under the receiver operating characteristic curve of ΔETCO2, ΔAUCp, and the combination of both to predict unsustained ROSC were 0.752 (95% CI 0.660-0.844), 0.883 (95% CI 0.818-0.948), and 0.902 (95% CI 0.842-0.962), respectively. CONCLUSION: Patients with unsustained ROSC have a poor prognosis. The combination of ΔETCO2 and ΔAUCp showed significant predictive value for unsustained ROSC.

Prevalence and Associated Factors of Thyroid Nodules Among 52,003 Chinese 'Healthy' Individuals in Beijing: A Retrospective Cross-Sectional Study.

Introduction: The prevalence of thyroid nodules has been increasing, and there are few research data on the risk factors of thyroid nodules in the Chinese population. In this study, we aimed to determine the prevalence and risk factors of thyroid nodules by retrospectively investigating the physical examination records of a cohort of "healthy" individuals in Beijing, China. Methods: This was a retrospective cross-sectional study. The database of a Medical Examination Centre (MEC) was searched. Physical examination data, blood test data, and ultrasound examination data, etc., from 2015 to 2017 were accessed. Only those that recorded a thyroid ultrasound were included. Chi-square test and t-test were used to compare clinical features of individuals' age, gender, body mass index, blood pressure, blood glucose, blood lipids, uric acid, and presence of fatty liver. Risk factors for thyroid nodules were determined using multivariate logistic regression. Results: A total of 52,003 records, which included 19,901 cases with thyroid nodules, were examined. The overall prevalence rate was 38.3% (19,901/52,003): 30.2% (6,726/22,305) and 44.4% (13,175/29,698) in men and women, respectively. Of 52,003 cases, only 35,420 cases had records of all nodule-related metabolic abnormalities and were selected for cross-sectional determination of related risk factors of thyroid nodules. In male, relationships were found between thyroid nodules and increased age (p < 0.001), impaired fasting glucose (p = 0.044), diabetes (p = 0.047), decreased HDL-C (p = 0.018) and prostatic hyperplasia (p < 0.001). And in female, relationships were found between thyroid nodules and increased age (p < 0.001) and decreased HDL-C (p < 0.001). Conclusion: Thyroid nodules are common in China. This study found that thyroid nodules are associated with several metabolic indicators or metabolic diseases, although the mechanism is unclear. Further research is needed.

Tipping the GVH/GVL balance by targeting HIF1α.

Promoting GVL activity while eliminating GVHD is the utmost goal to treat hematological malignancies with allo-HCT. Bailey et al. demonstrate that targeting HIF1α can favor GVL activity while limiting GVHD after allo-HCT even in combination with immune checkpoint inhibition.1.

The effect of prophylactic antibiotics in acute upper gastrointestinal bleeding patients in the emergency department.

BACKGROUND: Currently, prophylactic antibiotics are recommended only for cirrhotic patients with acute upper gastrointestinal bleeding (AUGIB); however, the benefit for other AUGIB patients remains undetermined. We aimed to compare the clinical outcomes between patients with AUGIB with and without prophylactic antibiotics to identify the population that requires this therapy. METHODS: Patients with AUGIB admitted between 1st January 2019 and 31st December 2021 in the Emergency Department of Peking Union Medical College Hospital were enrolled. Patients were divided into the antibiotic and non-antibiotic groups. The primary outcome was in-hospital mortality, and the secondary outcome was the onset of new infection. The risk factors for mortality and infection were analyzed, and stratification analysis of prophylactic antibiotics was performed. Continuous data were analyzed using the t-test or nonparametric rank sum test, and categorical data were analyzed using the Chi-square test or Fisher's exact test. Indicators with significant differences between the groups were included for logistic regression analysis. A P-value <0.05 was considered statistically significant. RESULTS: A total of 392 individuals were included, among them, 281 patients received prophylactic antibiotics, and 111 patients did not receive prophylactic antibiotics. The mortality rates were significantly lower in the antibiotic group than in the non-antibiotics group (6.41% vs. 17.12%, P=0.001). The risk factors for infection were varicose veins (P=0.045) and endotracheal intubation (P=0.005) in the prophylactic antibiotic group, and endoscopic treatment (P=0.010) in the non-prophylactic antibiotic group. Stratified analyses showed that patients with age ≥ 65 years, endotracheal intubation, endoscopic treatment, and AUGIB of variceal etiologies benefited from prophylactic antibiotics. CONCLUSION: AUGIB patients may benefit from prophylactic antibiotics to decrease mortality, especially those aged ≥ 65 years and those with endotracheal intubation, endoscopic treatment, and variceal etiologies.

Relationship between glucocorticoids and viral load during the Omicron wave in mainland China.

BACKGROUND: Coronavirus disease 19 (COVID-19) is a major public health problem that cannot be ignored. As a widely used drug in the treatment of COVID-19, whether glucocorticoids may accelerate the clearance of COVID-19 is still not clear, and the glucocorticoids may improve the prognosis of patients is also controversial. Therefore, to explore the relationship between COVID-19 viral load and the use of glucocorticoids we designed this study. METHODS: Patients with COVID-19 infection who were admitted to the emergency department of Peking Union Medical College Hospital from the end of 2022 to early 2023 were enrolled in this study. Characteristics of baseline, clinical and laboratory evaluation especially immunological indicator and daily viral load were carefully collected. Kolmogorov-Smirnov test, Student's t test, Mann-Whitney U test and proportional-hazards model (Cox model) were chosen as appropriate for comparison of variables. RESULTS: By comparing the daily COVID-19 viral load and prognosis of patients with and without glucocorticoid therapy, we found that glucocorticoids did not statistically enhance the clearance or replication of COVID-19, nor did it change the 28-days and in-hospital mortality. However, glucocorticoid therapy may be a favorable factor for COVID-19 negative conversion in Cox model. The inflammatory factors in patients with glucocorticoid therapy were significantly decreased. CONCLUSIONS: We believe that the real effect of glucocorticoids may be to improve the destruction of host immune system caused by inflammatory storm through host immune regulation and then achieve the improvement of clinical symptoms.

ER stress: an emerging regulator in GVHD development.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient's cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.

Retraction: Structural characterization and anticancer potency of centipede oligopeptides in human chondrosarcoma cancer: inducing apoptosis.

[This retracts the article DOI: 10.1039/D0RA04811A.].

GDF-15 at admission predicts cardiovascular death, heart failure, and bleeding outcomes in patients with CAD.

AIMS: We aimed to investigate the independent associations between growth differentiation factor 15 (GDF-15) level at admission and cardiovascular (CV) death, thrombotic events, heart failure (HF), and bleeding outcomes in patients with coronary artery disease (CAD). METHODS AND RESULTS: We measured the plasma concentrations of GDF-15 centrally in patients from the BIomarker-based Prognostic Assessment for patients with Stable angina and acute coronary Syndrome (BIPass) registry, which consecutively enrolled patients with CAD from November 2017 to September 2019 at five tertiary hospitals in China. The outcomes included CV death, thrombotic events [myocardial infarction (MI) and ischaemic stroke], HF events [acute HF during hospitalization and hospitalization for HF post-discharge (A/H HF) and cardiogenic shock], and bleeding outcomes [non-coronary artery bypass grafting-related major bleeding and clinically significant bleeding (CSB)] during the 12 month follow-up period after hospitalization. Among 6322 patients with CAD {65.4% male, median age 63.7 [inter-quartile range (IQR)] 56.0-70.1 years}, the median concentration of plasma GDF-15 at admission was 1091 (IQR 790.5-1635.0) ng/L. Higher concentrations of GDF-15 were associated with an increased risk of CV death [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.35-2.88, P < 0.001], A/H HF (HR 2.69, 95% CI 1.92-3.77, P < 0.001), cardiogenic shock (HR 1.46, 95% CI 1.04-2.05, P = 0.029), and CSB (HR 1.48, 95% CI 1.22-1.79, P < 0.001), but not for MI or stroke, after adjusting for clinical risk factors and prognostic biomarkers. Adding GDF-15 to the model with risk factors and biomarkers improved the net reclassification for CV death, A/H HF, cardiogenic shock, and CSB. CONCLUSIONS: In patients with CAD, admission levels of GDF-15 were associated with an increased 1 year risk of CV death, HF, and bleeding outcomes, but not with thrombotic events. GDF-15 may be a prognostic biomarker for CV death, HF, and bleeding outcomes and could be used to refine the risk assessment of these specific clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04044066.

[Effect of fraction of inspired oxygen baseline level on the mask ventilation time before intubation in emergency patients by monitoring of expiratory oxygen concentration].

OBJECTIVE: To investigate the effect of different fraction of inspired oxygen (FiO2) baseline levels before endotracheal intubation on the time of expiratory oxygen concentration (EtO2) reaching the standard in emergency patients with the EtO2 as the monitoring index. METHODS: A retrospective observational study was conducted. The clinical data of patients receiving endotracheal intubation in the emergency department of Peking Union Medical College Hospital from January 1 to November 1 in 2021 were enrolled. In order to avoid interference with the final result due to inadequate ventilation caused by non-standard operation or air leakage, the process of the continuous mechanical ventilation after FiO2 was adjusted to pure oxygen in patients who had been intubated was selected to simulate the process of mask ventilation under pure oxygen before intubation. Combined with the electronic medical record and the ventilator record, the changes of the time required to reach 0.90 of EtO2 (that was, the time required to reach the standard of EtO2) and the respiratory cycle required to reach the standard after adjusting FiO2 to pure oxygen under different baseline levels of FiO2 were analyzed. RESULTS: 113 EtO2 assay records were collected from 42 patients. Among them, 2 patients had only one EtO2 record due to the FiO2 baseline level of 0.80, while the rest had two or more records of EtO2 reaching time and respiratory cycle corresponding to different FiO2 baseline level. Among the 42 patients, most of them were male (59.5%), elderly [median age was 62 (40, 70) years old] patients with respiratory diseases (40.5%). There were significant differences in lung function among different patients, but the majority of patients with normal function [oxygenation index (PaO2/FiO2) > 300 mmHg (1 mmHg ≈ 0.133 kPa), 38.0%]. In the setting of ventilator parameters, combined with the slightly lower arterial partial pressure of carbon dioxide of patients [33 (28, 37) mmHg], mild hyperventilation phenomenon was considered to be widespread. With the increased in FiO2 baseline level, the time of EtO2 reaching standard and the number of respiratory cycles showed a gradually decreasing trend. When the FiO2 baseline level was 0.35, the time of EtO2 reaching the standard was the longest [79 (52, 87) s], and the corresponding median respiratory cycle was 22 (16, 26) cycles. When the FiO2 baseline level was increased from 0.35 to 0.80, the median time of EtO2 reaching the standard was shortened from 79 (52, 78) s to 30 (21, 44) s, and the median respiratory cycle was also reduced from 22 (16, 26) cycles to 10 (8, 13) cycles, with statistically significant differences (both P < 0.05). CONCLUSIONS: The higher the FiO2 baseline level of the mask ventilation in front of the endotracheal intubation in emergency patients, the shorter the time for EtO2 reaching the standard, and the shorter the mask ventilation time.

Management of regional citrate anticoagulation for continuous renal replacement therapy: guideline recommendations from Chinese emergency medical doctor consensus.

Continuous renal replacement therapy (CRRT) is widely used for treating critically-ill patients in the emergency department in China. Anticoagulant therapy is needed to prevent clotting in the extracorporeal circulation during CRRT. Regional citrate anticoagulation (RCA) has been shown to potentially be safer and more effective and is now recommended as the preferred anticoagulant method for CRRT. However, there is still a lack of unified standards for RCA management in the world, and there are many problems in using this method in clinical practice. The Emergency Medical Doctor Branch of the Chinese Medical Doctor Association (CMDA) organized a panel of domestic emergency medicine experts and international experts of CRRT to discuss RCA-related issues, including the advantages and disadvantages of RCA in CRRT anticoagulation, the principle of RCA, parameter settings for RCA, monitoring of RCA (mainly metabolic acid-base disorders), and special issues during RCA. Based on the latest available research evidence as well as the paneled experts' clinical experience, considering the generalizability, suitability, and potential resource utilization, while also balancing clinical advantages and disadvantages, a total of 16 guideline recommendations were formed from the experts' consensus.

Incidence and diagnostic validity of difficult airway in emergency departments in China: a cross-sectional survey.

Background: The difficult airway is a topic of concern for any physician performing intubation. Severe adverse events which can happen because of an unexpected difficult airway emphasize the importance of prediction. This study aimed to investigate the incidence of difficult airways in emergency departments in mainland China and ascertain the predictive value of common assessment formulas. Methods: This study was a multicentral, cross-sectional investigation of patients intubated in emergency departments in mainland China between March 1-30, 2021. Frequencies and percentages were calculated for patient characteristics. Diagnostic values were analyzed by sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, the area under the curve, and corresponding P values. Results: Nine hundred and eighty-five patients in 41 hospitals were enrolled in the study. Elderly male patients occupied most of the intubated patients. The difficult face mask ventilation rate (8.2%) was higher, but the difficult glottic exposure (6.8%) and intubation (2.1%) rates were low, while there was widespread use of enhanced visualization equipment (80.6%). Four combined emergency applicable evaluation methods showed a certain predictive value for the difficult airway with a sensitivity [0.71; 95% confidence interval (CI): 0.47-0.89], specificity (0.79; 95% CI: 0.76-0.81), and the area under the curve (0.75; 95% CI: 0.64-0.87, P<0.01). Conclusions: Despite an insufficient predictive ability for current difficult airway evaluation methods, there were relatively low rates of difficult airways during ED intubations in mainland China. Continuing focus on the difficult airway problems and optimizing airway assessment are required.

[Treatment and factors associated with prognosis of hyperkalemia in the emergency department].

OBJECTIVE: To survey treatment and prognosis of hyperkalemia patients in the emergency department and to analyze factors associated with all-cause in-hospital mortality. METHODS: We implemented electronic hospital information system, extracted demographic characteristics, underlying diseases, laboratory findings, potassium lowering therapy and prognosis of hyperkalemia patients [age ≥ 18 years, serum potassium (K+) concentration ≥ 5.5 mmol/L] in the emergency department of Peking Union hospital in Beijing between June 1st 2019 to May 31st 2020. The enrolled subjects were divided into the non-survival group and the survival group according to their prognosis. Univariate analysis and Cox regression model were adopted to analyze factors affecting all-cause in-hospital mortality of hyperkalemia patients. RESULTS: A total of 579 patients [median age 64 (22) years; 310 men (53.5%) and 269 women (46.5%)] with hyperkalemia were enrolled, among which, 317 (54.7%), 143 (24.7%) and 119 (20.6%) were mild, moderate, and severe hyperkalemia, respectively. 499 (86.20%) patients received potassium-lowering therapy, forty-four treatment regimens were administered. Insulin and glucose (I+G, 61.3%), diuretics (Diu, 57.2%), sodium bicarbonate (SB, 41.9%) and calcium gluconate/chloride (CA, 44.4%) were commonly used for the treatment of hyperkalemiain the emergency department. The combination of insulin and glucose, calcium gluconate/chloride, diuretics and sodium bicarbonate (I+G+CA+Diu+SB) was the most favored combined treatment regimen of hyperkalemia in the emergency department. The higher serum potassium concentration, the higher proportion of administrating combined treatment regimen and/or hemodialysis (HD) (the proportion of administrating combined treatment regimen in mild, moderate, and severe hyperkalemia patients were 58.4%, 82.5% and 94.8%; the proportion of administrating HD in mild, moderate, and severe hyperkalemia patients were 9.7%, 13.3% and 16.0%, respectively). The proportion of achievement of normokalaemia elevated as the kinds of potassium lowering treatment included in the combined treatment regimen increased. The proportion of achievement of normokalaemia was 100% in the combined treatment regimen including 6 kinds of potassium lowering therapy. Among various potassium lowering treatments, HD contributed to the highest rate of achievement of normokalaemia (93.8%). 111 of 579 (19.20%) hyperkalemia patients died in hospital. Cox regression model revealed that complicated with cardiac dysfunction predicted higher mortality [hazard ratio (HR) = 1.757, 95% confidence interval (95%CI) was 1.155-2.672, P = 0.009]. Achievement of normokalaemia and administration of diuretics attributed to lower mortality (HR = 0.248, 95%CI was 0.155-0.398, P = 0.000; HR = 0.335, 95%CI was 0.211-0.531, P = 0.000, respectively). CONCLUSIONS: Treatment of hyperkalemia in the emergency department were various. Complicated with cardiac dysfunction were associated with higher mortality. Achieving normokalaemia was associated with decreased mortality.

Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance.

Elucidating the mechanisms of resistance to immunotherapy and developing strategies to improve its efficacy are challenging goals. Bioinformatics analysis demonstrates that high CDK6 expression in melanoma is associated with poor progression-free survival of patients receiving single-agent immunotherapy. Depletion of CDK6 or cyclin D3 (but not of CDK4, cyclin D1, or D2) in cells of the tumor microenvironment inhibits tumor growth. CDK6 depletion reshapes the tumor immune microenvironment, and the host anti-tumor effect depends on cyclin D3/CDK6-expressing CD8+ and CD4+ T cells. This occurs by CDK6 phosphorylating and increasing the activities of PTP1B and T cell protein tyrosine phosphatase (TCPTP), which, in turn, decreases tyrosine phosphorylation of CD3ζ, reducing the signal transduction for T cell activation. Administration of a PTP1B and TCPTP inhibitor prove more efficacious than using a CDK6 degrader in enhancing T cell-mediated immunotherapy. Targeting protein tyrosine phosphatases (PTPs) might be an effective strategy for cancer patients who resist immunotherapy treatment.

Predictive Values of ADAMTS13, TBIL, and D-D for Prognosis of Patients with Thrombotic Thrombocytopenic Purpura.

BACKGROUND: The aim of the study was to investigate the levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), total bilirubin (TBIL), and D-dimer (D-D) in thrombotic thrombocytopenic purpura (TTP) and their values for predicting the prognosis. METHODS: The clinical data of 89 TTP patients admitted from March 2018 to December 2021 were collected for retrospective analysis. They were assigned to remission group (n = 61) and death group (n = 28) according to clinical outcomes. General clinical data were compared between the two groups. Predictors with non-zero coefficients were screened by LASSO regression analysis, and influencing factors were identified by logistic regression analysis. Then the risk factors were incorporated to construct a nomogram model, which was validated subsequently. Bivariate Pearson's correlation analysis was employed to analyze the correlations. The receiver operating characteristic curves were plotted to analyze the values of ADAMTS13, TBIL, and D-D for predicting the prognosis of TTP. RESULTS: TBIL ≥ 72.74 µmol/L, D-D ≥ 4.17 mg/L, PLASMIC score < 6 points, and absence of plasma exchange (PEx) were risk factors affecting the prognosis, and ADAMTS13 ≤ 25.04% was a protective factor for the prognosis of TTP patients (p < 0.05). ADAMTS13, TBIL, and D-D were significantly associated with death (p < 0.05). The areas under the curves of TBIL, ADAMTS13, D-D and their combination were 0.796 (95% confidence interval CI: 0.729 - 0.860), 0.721 (95% CI: 0.648 - 0.788), 0.820 (95% CI: 0.756 - 0.880), and 0.872 (95% CI: 0.823 - 0.920), respectively. CONCLUSIONS: TBIL, D-D, ADAMTS13, PLASMIC score, and absence of PEx are factors influencing the prognosis of TTP patients, among which TBIL, D-D, and ADAMTS13 are of high predictive values.

A Retrospective, Nested Case-Control Study to Develop a Biomarker-Based Model for ARDS Diagnostics.

BACKGROUND: Several biomarkers could be intercalated with traditional measures to improve ARDS diagnostics. METHODS: There were 211 ICU patients enrolled in this retrospective, nested case-control study. Participants were divided into an ARDS (n = 79) and non-ARDS (n = 132) groups, according to the Berlin criteria. Patient characteristics, vital signs, and laboratory tests were collected within three hours of admission. CC16, Ang-2, sRAGE, HMGB1, and SPD were measured within three hours and again at 24 hours, after admission to ICU. Receiver Operating Characteristic curves and multivariate logistic regression analyses were applied for predictive purposes. RESULTS: C-reactive protein (CRP), NT-proBNP, and pH values were intercalated with five established ARDS indicators, and the PaO2/FiO2 ratio. Only four potential indicators were analyzed, with CRP having high diagnostic value. Areas under curve (AUC) were as follows: CC16 (AUC: 0.752; 95% CI 0.680 - 0.824), Ang-2 (AUC: 0.695; 95% CI 0.620 - 0.770), HMGB1 (AUC: 0.668; 95% CI 0.592 - 0.744), sRAGE (AUC: 0.665; 95% CI 0.588 - 0.743), CRP (AUC: 0.701; 95% CI 0.627 - 0.776). No single indicator improved upon the PaO2/FiO2 ratio which had an AUC: 0.844 (95% CI 0.789 - 0.898). However, when the binary logistic model was transformed and the model was constructed, the AUC increased from 0.647 (95% CI 0.568 - 0.726) to 0.911 (95% CI 0.864 - 0.946). Among the combinations tested, PaO2/FiO2 + CRP + Ang-2 + CC16 + HMGB1 resulted in the highest AUC of 0.910 (95% CI 0.863 - 0.945), although there are other factors which must be considered. CONCLUSIONS: A combination of biomarkers could enhance ARDS diagnostics, which has obvious ramifications for patient care and prognosis. It may be possible to develop a predictive ARDS nomogram; however, of the combinations tested here, we tentatively recommend PaO2/FiO2 + CRP + Ang-2 + CC16 + HMGB1. This is because of the cost implications in contrast with benefit involved in utilizing the more elaborate model. Further health economics research is required to consider the opportunity cost for emergency care policy.

The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis.

Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.

The Absence of IL-12Rß2 Expression on Recipient Nonhematopoietic Cells Diminishes Acute Graft-versus-Host Disease in the Gastrointestinal Tract.

The gastrointestinal (GI) tract is a frequent target organ in acute graft-versus-host disease (aGVHD), which can determine the morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells recognize allogeneic Ags presented by host APCs, proliferate, and differentiate into Th1 and Th17 cells that drive GVHD pathogenesis. IL-12 has been shown to play an important role in amplifying the allogeneic response in preclinical and clinical studies. This study demonstrates that IL-12Rß2 expression on recipient nonhematopoietic cells is required for optimal development of aGVHD in murine models of allo-HCT. aGVHD attenuation by genetic depletion of IL-12R signaling is associated with reduced MHC class II expression by intestinal epithelial cells and maintenance of intestinal integrity. We verified IL-12Rß2 expression on activated T cells and in the GI tract. This study, to our knowledge, reveals a novel function of IL-12Rß2 in GVHD pathogenesis and suggests that selectively targeting IL-12Rß2 on host nonhematopoietic cells may preserve the GI tract after allo-HCT.

Sphingolipid metabolism in T cell responses after allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy against hematopoietic malignancies. The infused donor lymphocytes attack malignant cells and normal tissues, termed a graft-verse-leukemia (GVL) effect and graft-verse-host (GVH) response or disease (GVHD), respectively. Although engineering techniques toward donor graft selection have made HCT more specific and effective, primary tumor relapse and GVHD are still major concerns post allo-HCT. High-dose systemic steroids remain to be the first line of GVHD treatment, which may lead to steroid-refractory GVHD with a dismal outcome. Therefore, identifying novel therapeutic strategies that prevent GVHD while preserving GVL activity is highly warranted. Sphingolipid metabolism and metabolites play pivotal roles in regulating T-cell homeostasis and biological functions. In this review, we summarized the recent research progress in this evolving field of sphingolipids with a focus on alloreactive T-cell responses in the context of allo-HCT. We discussed how sphingolipid metabolism regulates T-cell mediated GVH and GVL responses in allo-HCT and presented the rationale and means to target sphingolipid metabolism for the control of GVHD and leukemia relapse.