Early prediction of mortality at sepsis diagnosis time in critically ill patients by using interpretable machine learning.

This study applied machine learning for the early prediction of 30-day mortality at sepsis diagnosis time in critically ill patients. Retrospective study using data collected from the Medical Information Mart for Intensive Care IV database. The data of the patient cohort was divided on the basis of the year of hospitalization, into training (2008-2013), validation (2014-2016), and testing (2017-2019) datasets. 24,377 patients with the sepsis diagnosis time < 24 h after intensive care unit (ICU) admission were included. A gradient boosting tree-based algorithm (XGBoost) was used for training the machine learning model to predict 30-day mortality at sepsis diagnosis time in critically ill patients. Model performance was measured in both discrimination and calibration aspects. The model was interpreted using the SHapley Additive exPlanations (SHAP) module. The 30-day mortality rate of the testing dataset was 17.9%, and 39 features were selected for the machine learning model. Model performance on the testing dataset achieved an area under the receiver operating characteristic curve (AUROC) of 0.853 (95% CI 0.837-0.868) and an area under the precision-recall curves of 0.581 (95% CI 0.541-0.619). The calibration plot for the model revealed a slope of 1.03 (95% CI 0.94-1.12) and intercept of 0.14 (95% CI 0.04-0.25). The SHAP revealed the top three most significant features, namely age, increased red blood cell distribution width, and respiratory rate. Our study demonstrated the feasibility of using the interpretable machine learning model to predict mortality at sepsis diagnosis time.

Continuous nerve block versus thoracic epidural analgesia for post-operative pain of pectus excavatum repair: a systematic review and meta-analysis.

Surgery to repair pectus excavatum (PE) is often associated with severe postoperative pain, which can impact the length of hospital stay (LOS). While thoracic epidural analgesia (TEA) has traditionally been used for pain management in PE, its placement can sometimes result in severe neurological complications. Recently, paravertebral block (PVB) and erector spinae plane block (ESPB) have been recommended for many other chest and abdominal surgeries. However, due to the more severe and prolonged pain associated with PE repair, it is still unclear whether continuous administration of these blocks is as effective as TEA. Therefore, we conducted this systematic review and meta-analysis to demonstrate the equivalence of continuous PVB and ESPB to TEA.

miR-145-5p Targets Sp1 in Non-Small Cell Lung Cancer Cells and Links to BMI1 Induced Pemetrexed Resistance and Epithelial-Mesenchymal Transition.

Pemetrexed is a folic acid inhibitor used as a second-line chemotherapeutic agent for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancers. However, prolonged treatment with pemetrexed may cause cancer cells to develop resistance. In this study, we found increased expressions of BMI1 (B Lymphoma Mo-MLV insertion region 1 homolog) and Sp1 and a decreased expression of miR-145-5p was found in pemetrexed-resistant A400 cells than in A549 cells. Direct Sp1 targeting activity of miR-145-5p was demonstrated by a luciferase based Sp1 3'-UTR reporter. Changed expression of miR-145-5p in A400 or A549 cells by transfection of miR-145-5p mimic or inhibitor affected the sensitivity of the cells to pemetrexed. On the other hand, the overexpression of Sp1 in A549 cells caused the decreased sensitivity to pemetrexed, induced cell migratory capability, and epithelial-mesenchymal transition (EMT) related transcription factors such as Snail Family Transcriptional Repressor 1 and Zinc Finger E-Box Binding Homeobox 1. In addition, the overexpression of BMI1 in the A549 cells resulted in an increase in Sp1 and a decrease in miR-145-5p accompanied by the elevations of cell proliferation and EMT transcription factors, which could be reduced by the overexpression of miR-145-5p or by treatment with the Sp1 inhibitor of mithramycin A. In conclusion, the results of this study suggest that the downregulation of miR-145-5p by BMI1 overexpression could lead to the enhanced expression of Sp1 to induce the EMT process in pemetrexed-resistant NSCLC cells. These results suggest that increasing miR-145-5p expression by delivering RNA drugs may serve as a sensitizing agent for pemetrexed-resistant NSCLC patients.

Early prediction of survival at different time intervals in sepsis patients: A visualized prediction model with nomogram and observation study.

OBJECTIVES: Sepsis is a major cause of death around the world. Complicated scoring systems require time to have data to predict short-term survival. Intensivists need a tool to predict survival in sepsis patients easily and quickly. MATERIALS AND METHODS: This retrospective study reviewed the medical records of adult patients admitted to the surgical intensive care units between January 2009 and December 2011 in National Taiwan University Hospital. For this study, 739 patients were enrolled. We recorded the demographic and clinical variables of patients diagnosed with sepsis. A Cox proportional hazard model was used to analyze the survival data and determine significant risk factors to develop a prediction model. This model was used to create a nomogram for predicting the survival rate of sepsis patients up to 3 months. RESULTS: The observed 28-day, 60-day, and 90-day survival rates were 71.43%, 52.53%, and 46.88%, respectively. The principal risk factors for survival prediction included age; history of dementia; Glasgow Coma Scale score; and lactate, creatinine, and platelet levels. Our model showed more favorable prediction than did Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment at sepsis onset (concordance index: 0.65 vs. 0.54 and 0.59). This model was used to create the nomogram for predicting the mortality at the onset of sepsis. CONCLUSION: We suggest that developing a nomogram with several principal risk factors can provide a quick and easy tool to early predict the survival rate at different intervals in sepsis patients.

BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells Is Associated with Increased SP1 Activation and Cancer Stemness.

Lung cancer is the leading cause of cancer death worldwide and the therapeutic strategies include surgery, chemotherapy and radiation therapy. Non-small cell lung cancers (NSCLCs) account for around 85% of cases of lung cancers. Pemetrexed is an antifolate agent that is currently used as the second line chemotherapy drug in the treatment of advanced NSCLC patients with a response rate of 20-40%. The search for any combination therapy to improve the efficacy of pemetrexed is required. The existence of cancer stem cells (CSCs) is considered as the main reason for drug resistance of cancers. In this study, we first found that pemetrexed-resistant NSCLC cells derived from A549 cells displayed higher CSC activity in comparison to the parental cells. The expression of CSC related proteins, such as BMI1 or CD44, and the epithelial-mesenchymal transition (EMT) signature was elevated in pemetrexed-resistant NSCLC cells. We next discovered that the overexpression of BMI1 in A549 cells caused the pemetrexed resistance and inhibition of BMI1 by a small molecule inhibitor, PTC-209, or transducing of BMI1-specific shRNAs suppressed cell growth and the expression of thymidylate synthase (TS) in pemetrexed-resistant A549 cells. We further identified that BMI1 positively regulated SP1 expression and treatment of mithramycin A, a SP1 inhibitor, inhibited cell proliferation, as well as TS expression, of pemetrexed-resistant A549 cells. Furthermore, overexpression of BMI1 in A549 cells also caused the activation of EMT in and the enhancement of CSC activity. Finally, we demonstrated that pretreatment of PTC-209 in mice bearing pemetrexed-resistant A549 tumors sensitized them to pemetrexed treatment and the expression of Ki-67, BMI1, and SP1 expression in tumor tissues was observed to be reduced. In conclusion, BMI1 expression level mediates pemetrexed sensitivity of NSCLC cells and the inhibition of BMI1 will be an effective strategy in NSCLC patients when pemetrexed resistance has developed.

Modified paramedian versus conventional paramedian technique in the residency training: an observational study.

BACKGROUND: Residency training includes positive and negative aspects. Well-trained doctors must be educated, but the process may bring additional risks to patients. Anesthesiologists' performance when conducting neuraxial anesthesia is related to their experience. We hypothesized that a modified neuraxial anesthesia method would improve both residency training and patient safety. METHODS: We recruited 518 patients who were scheduled for a cesarean section and used spinal anesthesia (n = 256), epidural anesthesia (n = 154), and combined spinal-epidural anesthesia (SEA; n = 108). We observed and evaluated the anesthesia performance of five second-year resident anesthesiologists in elective cesarean sections using the conventional and modified methods. The number of attempts, implant error rate, and the incidence of complications were recorded and analyzed. RESULTS: Better success puncture attempts occurred in all three groups when the modified method was applied. For the groups with an implant assessment, the complication rate and implant error rate were lower when using the modified method. We employed generalized estimating equation (GEE) analysis to correct for possible confounding factors. When using the conventional method, the resident anesthesiologists required more attempts, made more implant errors, and caused more complications in patients. CONCLUSIONS: We found that a modified method for neuraxial anesthesia could improve residency performance and patient safety. The modified method may be a suitable training process for resident anesthesiologists when practicing neuraxial anesthesia. TRIAL REGISTRATION: The study was approved by the Research Ethics Committee of National Taiwan University (IRB:200812040R) Clinicaltrials register: NCT03389672 .

Effects of endotoxin adsorber hemoperfusion on sublingual microcirculation in patients with septic shock: a randomized controlled trial.

BACKGROUND: Endotoxins can induce an excessive inflammatory response and result in microcirculatory dysfunction. Polymyxin-B hemoperfusion (PMX-HP) has been recognized to effectively remove endotoxins in patients with sepsis and septic shock, and a rat sepsis model revealed that PMX-HP treatment can maintain a better microcirculation. The primary aim of this study was to investigate the effect of PMX-HP on microcirculation in patients with septic shock. METHODS: Patients with septic shock were enrolled and randomized to control and PMX-HP groups. In the PMX-HP group, patients received the first session of PMX-HP in addition to conventional septic shock management within 24 h after the onset of septic shock; the second session of PMX-HP was provided after another 24 h as needed. RESULTS: Overall, 28 patients finished the trial and were analyzed. The mean arterial pressure and norepinephrine infusion dose did not differ significantly between the control and PMX-HP groups after PMX-HP treatment. At 48 h after enrollment, total vessel density (TVD) and perfused vessel density (PVD) were higher in the PMX-HP group than in the control group [TVD 24.2 (22.1-24.9) vs. 21.1 (19.9-22.9) mm/mm2; p = 0.007; PVD 22.9 (20.9-24.9) vs. 20.0 (18.9-21.6) mm/mm2, p = 0.008]. CONCLUSIONS: This preliminary study observed that PMX-HP treatment improved microcirculation but not clinical outcomes in patients with septic shock at a low risk of mortality. Nevertheless, larger multicenter trials are needed to confirm the effect of PMX-HP treatment on microcirculation in patients with septic shock at intermediate- and high-risk of mortality. Trial registration ClinicalTrials.gov protocol registration ID: NCT01756755. Date of registration: December 27, 2012. First enrollment: October 6, 2013. https://clinicaltrials.gov/ct2/show/NCT01756755.

Comparison of inhaled nitric oxide with aerosolized prostacyclin or analogues for the postoperative management of pulmonary hypertension: a systematic review and meta-analysis.

Background: This study aims to compare the effectiveness of inhaled prostacyclin or its analoguesversus nitric oxide (NO) in treating pulmonary hypertension (PH) after cardiac or pulmonary surgery remains unclear.Methods: PubMed, Cochrane, and Embase databases were searched for literature published prior to December 2019 using the following keywords: inhaled, nitric oxide, prostacyclin, iloprost, treprostinil, epoprostenol, Tyvaso, flolan, and pulmonary hypertension. Randomized controlled trials and multiple-armed prospective studies that evaluated inhaled NO versus prostacyclin (or analogues) in patients for perioperative and/or postoperative PH after either cardiac or pulmonary surgery were included. Retrospective studies, reviews, letters, comments, editorials, and case reports were excluded.Results: Seven studies with a total of 195 patients were included. No difference in the improvement of mean pulmonary arterial pressure (pooled difference in mean change= -0.10, 95% CI: -3.98 to 3.78, p = .959) or pulmonary vascular resistance (pooled standardized difference in mean change= -0.27, 95% CI: -0.60 to 0.05, p = .099) were found between the two treatments. Similarly, no difference was found in other outcomes between the two treatments or subgroup analysis.Conclusions: Inhaled prostacyclin (or analogues) was comparable to inhaled NO in treating PH after cardiac or pulmonary surgery.Key messagesThis study compared the efficacy of inhaled prostacyclin or its analogues versus inhaled NO to treat PH after surgery. The two types of agent exhibited similar efficacy in managing MPAP, PVR, heart rate, and cardiac output was observed.Inhaled prostacyclin may serve as an alternative treatment option for PH after cardiac or pulmonary surgery.

Alendronate/folic acid-decorated polymeric nanoparticles for hierarchically targetable chemotherapy against bone metastatic breast cancer.

To considerably enhance treatment efficacy for bone metastatic breast cancer via dual bone/tumor-targeted chemotherapy, a nanoparticle-based delivery system comprising poly(lactic-co-glycolic acid) (PLGA) as the hydrophobic core coated with alendronate-modified d-α-tocopheryl polyethylene glycol succinate (ALN-TPGS) and folic acid-conjugated TPGS (FA-TPGS) was developed as a vehicle for paclitaxel (PTX) in this work. The ALN/FA-decorated nanoparticles not only showed superior ALN-mediated binding affinity for hydroxyapatite abundant in bone tissue but also promoted uptake of payloads by folate receptor-overexpressing cancer cells to significantly augment PTX cytotoxicity. Notably, through dual-targetable delivery to the bone matrix and folate receptor-overexpressing 4T1 tumors, the PTX-loaded nanoparticles substantially accumulated in bone metastases in vivo and inhibited 4T1 tumor growth and lung metastasis, leading to significant improvement of the survival rate of treated mice. Upon treatment with the ALN/FA-decorated PTX-loaded nanoparticles, the bone destruction and bone loss of the tumor-bearing mice were appreciably retarded, and the adverse effects on normal tissues were alleviated. These results demonstrate that the ALN/FA-decorated PTX-loaded delivery system developed in this study shows great promise for the effective treatment of bone metastatic breast cancer.

Effects of systemic and neuraxial morphine on the immune system.

In the study, we tried to evaluate the effects of morphine injected through the systemic or neuraxial route on immune cell function and cytokine production in healthy women.In total, 29 paired samples of fresh peripheral blood were collected from healthy women who had been administered morphine for anesthetic analgesia through intravenous (IV), epidural, or spinal route postpartum. Their isolated peripheral blood mononuclear cells were mitogen-activated and stained with fluorochrome-conjugated anti-CD4, anti-CD8, anti-interleukin (IL)-2, and anti-interferon (IFN)-γ antibodies for flow cytometry, and the plasma levels of cytokines, including IL-6, IFN-α2, IL-10, IL-8, GM-CSF, and monocyte chemoattractant protein (MCP)-1, were measured through enzyme-linked immunosorbent assay.The results demonstrated that regardless of the administration route, morphine delivery slightly reduced IL-2 expression in CD4 cells after activation, and the same effect was not noted for CD8 cells. Intravenous or epidural morphine tended to reduce IFN-γ expression in CD8 cells. Spinal and IV morphine substantially increased IL-6 production, whereas epidural morphine hindered IL-10 and GM-CSF production. IV morphine injection reduced MCP-1 production in plasma. Compared with spinal morphine, IV or epidural morphine may more effectively inhibit the expression of various cytokines and thus affect immune response.All 3 routes of morphine injection tended to decrease IL-2 production by CD4 cells, whereas IV or epidural morphine injection showed lower IFN-γ production by CD8 cells. However, additional large-scale studies with longer follow-up durations are warranted.

The use of tenoxicam to prevent symptoms of discomfort induced by vagotonia during uterus manipulation in cesarean sections.

PURPOSE: Symptoms such as nausea, vomiting, tightness of the chest, bradycardia, and shoulder or abdominal discomfort, caused by vagotonia occurring during uterus manipulation, have concerned healthcare professionals for some time. Patients sometimes report these symptoms when undergoing spinal anesthesia for cesarean sections (CSs). We designed a prospective, double-blind study to investigate the effectiveness of tenoxicam in preventing these symptoms of discomfort. METHODS: A total of 105 American Society of Anesthesiologists (ASA) class I-II nulliparous pregnant women, who were scheduled for a CS, were enrolled into this prospective, double-blind study. Spinal anesthesia was conducted to reach a peak dermatome level of no more than T3. The 100 patients were randomly divided into 2 groups having completed study course: Group T (N = 50) received a 20 mg dose of tenoxicam in 5 mL of normal saline (NS) immediately after skin incision and Group N (N = 50) only received 5 mL NS. The incidence and severity of the symptoms experienced by the patients were recorded by a nurse anesthetist who was blinded to the injection regimen the patients were receiving. A chi-square test was used for statistical analysis t test and P < .05 was defined as significant. RESULTS: The incidence and degree of severity of nausea and vomiting were same in both the groups. The incidence and degree of severity of bradycardia, nausea, vomiting, tightness of the chest, shoulder discomfort, and abdominal discomfort were lower in Group T than in Group N. CONCLUSION: Tenoxicam might theoretically block the parasympathetic vagus pathway and decrease the visceral pain or visceral-specific symptoms, alleviating the symptoms caused by vagotonia. However, the prophylactic effect of tenoxicam in reducing the incidence and severity of nausea and vomiting was not statistically significant. This could be because nausea and vomiting are not solely caused by vagotonia, but also by other mechanisms.

Tumor Microenvironment-Responsive Nanoparticle Delivery of Chemotherapy for Enhanced Selective Cellular Uptake and Transportation within Tumor.

A novel drug delivery strategy featured with enhanced uptake of nanoparticles (NPs) by targeted tumor cells and subsequent intratumoral cellular hitchhiking of chemotherapy to deep tumor regions was described. The NP delivery system was obtained from assembly of poly(lactic acid-co-glycolic acid)-grafted hyaluronic acid (HA-g-PLGA) together with an anticancer drug, SN38, in aqueous phase, followed by implementing the NP surface with a layer of methoxypoly(ethylene glycol)-b-poly(histamine methacrylamide) (mPEG-b-PHMA) via hydrophobic association to improve the colloidal stability both in vitro and in vivo. Upon arrival of these PEGylated NPs at the acidic tumor site through the EPR effect, mPEG-b-PHMA became detached from the NP surface by the charge transition of the PHMA blocks from neutral (hydrophobic) to positively charged (hydrophilic) state via acid-induced protonation of their imidazole groups in tumor microenvironment. The exposure of HA shell on the naked NP thus resulted in enhanced uptake of NPs by CD44-expressed tumor cells, including cancer cells and tumor-associated macrophages (TAMs). Along with the TAMs being further chemotactically recruited by hypoxia cells, the engulfed nanotherapeutics was thus transported into the avascular area in which the anticancer action of chemotherapy occurred by virtue of the drug release alongside PLGA degradation, similar to those arising in other tumor nonhypoxia regions.