The importance of hydrology in routing terrestrial carbon to the atmosphere via global streams and rivers.

SignificanceStream/river carbon dioxide (CO2) emission has significant spatial and seasonal variations critical for understanding its macroecosystem controls and plumbing of the terrestrial carbon budget. We relied on direct fluvial CO2 partial pressure measurements and seasonally varying gas transfer velocity and river network surface area estimates to resolve reach-level seasonal variations of the flux at the global scale. The percentage of terrestrial primary production (GPP) shunted into rivers that ultimately contributes to CO2 evasion increases with discharge across regions, due to a stronger response in fluvial CO2 evasion to discharge than GPP. This highlights the importance of hydrology, in particular water throughput, in terrestrial-fluvial carbon transfers and the need to account for this effect in plumbing the terrestrial carbon budget.

High Pseudocapacitance-Driven CoC2 O4 Electrodes Exhibiting Superior Electrochemical Kinetics and Reversible Capacities for Lithium-Ion and Lithium-Sulfur Batteries.

In this study, cuboid-like anhydrous CoC2 O4 particles (CoC2 O4 -HK) are synthesized through a potassium citrate-assisted hydrothermal method, which possess well-crystallized structure for fast Li+ transportation and efficient Li+ intercalation pseudocapacitive behaviors. When being used in lithium-ion batteries, the as-prepared CoC2 O4 -HK delivers a high reversible capacity (≈1360 mAh g-1 at 0.1 A g-1 ), good rate capability (≈650 mAh g-1 at 5 A g-1 ) and outstanding cycling stability (835 mAh g-1 after 1000 cycles at 1 A g-1 ). Characterizations illustrate that the Li+ -intercalation pseudocapacitance dominates the charge storage of CoC2 O4 -HK electrode, together with the reversible reaction of CoC2 O4 +2Li+ +2e- →Co+Li2 C2 O4 on discharging and charging. In addition, CoC2 O4 -HK particles are also used together with carbon-sulfur composite materials as the electrocatalysts for lithium-sulfur (Li-S) battery, which displays a gratifying sulfur electrochemistry with a high reversibility of 1021.5 mAh g-1 at 2 C and a low decay rate of 0.079% per cycle after 500 cycles. The density functional theory (DFT) calculations show that CoC2 O4 /C can regulate the adsorption-activation of reaction intermediates and therefore boost the catalytic conversion of polysulfides. Therefore, this work presents a new prospect of applying CoC2 O4 as the high-performance electrode materials for rechargeable Li-ion and Li-S batteries.

Hydroxylated Multi-Walled Carbon Nanotubes Covalently Modified with Tris(hydroxypropyl) Phosphine as a Functional Interlayer for Advanced Lithium-Sulfur Batteries.

We have successfully constructed a new type of intercalation membrane material by covalently grafting organic tris(hydroxypropyl)phosphine (THPP) molecules onto hydroxylated multi-walled carbon nanotubes (CNT-OH) as a functional interlayer for the advanced LSBs. The as-assembled interlayer has been demonstrated to be responsible for the fast conversion kinetics of polysulfides, the inhibition of polysulfide shuttle effect, as well as the formation of a stable solid electrolyte interphase(SEI) layer. By means of spectroscopic and electrochemical analysis, we further found THPP plays a key role in accelerating the conversion of polysulfides into low-ordered lithium sulfides and suppressing the loss of polysulfides, thus rendering the as-designed lithium-sulfur battery in this work a high capacity, excellent rate performance and long-term stability. Even at low temperatures, the capacity decay rate was only 0.036 % per cycle for 1700 cycles.

Global Reconstruction of Naturalized River Flows at 2.94 Million Reaches.

Spatiotemporally continuous global river discharge estimates across the full spectrum of stream orders are vital to a range of hydrologic applications, yet they remain poorly constrained. Here we present a carefully designed modeling effort (Variable Infiltration Capacity land surface model and Routing Application for Parallel computatIon of Discharge river routing model) to estimate global river discharge at very high resolutions. The precipitation forcing is from a recently published 0.1° global product that optimally merged gauge-, reanalysis-, and satellite-based data. To constrain runoff simulations, we use a set of machine learning-derived, global runoff characteristics maps (i.e., runoff at various exceedance probability percentiles) for grid-by-grid model calibration and bias correction. To support spaceborne discharge studies, the river flowlines are defined at their true geometry and location as much as possible-approximately 2.94 million vector flowlines (median length 6.8 km) and unit catchments are derived from a high-accuracy global digital elevation model at 3-arcsec resolution (~90 m), which serves as the underlying hydrography for river routing. Our 35-year daily and monthly model simulations are evaluated against over 14,000 gauges globally. Among them, 35% (64%) have a percentage bias within ±20% (±50%), and 29% (62%) have a monthly Kling-Gupta Efficiency ≥0.6 (0.2), showing data robustness at the scale the model is assessed. This reconstructed discharge record can be used as a priori information for the Surface Water and Ocean Topography satellite mission's discharge product, thus named "Global Reach-level A priori Discharge Estimates for Surface Water and Ocean Topography". It can also be used in other hydrologic applications requiring spatially explicit estimates of global river flows.

The Association Between Timing of Routine Preoperative Blood Testing and a Composite of 30-Day Postoperative Morbidity and Mortality.

BACKGROUND: Laboratory testing is a common component of preanesthesia evaluation and is designed to identify medical abnormalities that might otherwise remain undetected. While blood testing might optimally be performed shortly before surgery, it is often done earlier for practical reasons. We tested the hypothesis that longer periods between preoperative laboratory testing and surgery are associated with increased odds of having a composite of 30-day morbidity and mortality. METHODS: We obtained preoperative data from 2,320,920 patients in the American College of Surgeons National Surgical Quality Improvement Program who were treated between 2005 and 2012. Our analysis was restricted to relatively healthy patients with American Society of Anesthesiology physical status I-II who had elective surgery and normal blood test results (n = 235,010). The primary relationship of interest was the odds of 30-day morbidity and mortality as a function of delay between preoperative testing and surgery. A multivariable logistic regression model was used for the 10 pairwise comparisons among the 5 laboratory timing groups (laboratory blood tests within 1 week of surgery; 1-2 weeks; 2-4 weeks; 1-2 months; and 2-3 months) on 30-day morbidity, adjusting for any imbalanced baseline covariables and type of surgery. RESULTS: A total of 4082 patients (1.74%) had at least one of the component morbidities or died within 30-days after surgery. The observed incidence (unadjusted) was 1.7% when the most recent laboratory blood tests measured within 1 week of surgery, 1.7% when it was within 1-2 weeks, 1.8% when it was within 2-4 weeks, 1.7% when it was between 1 and 2 months, and 2.0% for patients with most recent laboratory blood tests measured 2-3 months before surgery. None of the values within 2 months differed significantly: estimated odds ratios for patients within blood tested within 1 week were 1.00 (99.5% confidence interval, 0.89-1.12) as compared to 1-2 weeks, 0.88 (0.77-1.00) for 2-4 weeks, and 0.95 (0.79-1.14) for 1-2 months, respectively. The estimated odds ratio comparing 1-2 weeks to each of 2-4 weeks and 1-2 months were 0.88 (0.76-1.03) and 0.95 (0.78-1.16), respectively. Blood testing 2-3 months before surgery was associated with increased odds of outcome compared to patients whose most recent test was within 1 week (P = .002) and 1-2 weeks of the date of surgery. CONCLUSIONS: In American Society of Anesthesiologists physical status I and II patients, risk of 30-day morbidity and mortality was not different with blood testing up to 2 months before surgery, suggesting that it is unnecessary to retest patients shortly before surgery.

Outcomes of physician patients after non-cardiac surgery: a registry analysis.

OBJECTIVES: When physicians become patients, they may expect special privileges, extra attention from caregivers, and non-routine treatments. Consequently, physician patients may not be treated per routine-which possibly worsens care rather than improving it. We thus tested the primary hypothesis that in-hospital mortality and major complications after non-cardiac surgery are more common in physician patients than in non-physician patients. PATIENTS AND METHODS: Perioperative data were extracted for patients who had non-cardiac surgery at the Cleveland Clinic between 2005 and 2013. We used propensity score matching to identify comparable groups of physician and non-physician patients. Matched physician and non-physician patients were compared on a composite of in-hospital mortality and major postoperative complications using a generalized equation average relative effects model. Secondly, the matched patients were also compared on reoperation using logistic regression and on duration of hospitalization using Kaplan-Meier analysis with the log-rank test and Cox proportional hazards regression. RESULTS: Among 21,173 qualifying patients, we matched 522 physician patients to 2448 non-physician controls. There were no significant differences between physician and non-physician patients in the composite of in-hospital mortality and major complications, with an estimated odds ratio across the outcome components (average relative effect) of 1.20 (95% confidence interval 0.77-1.87) for physicians vs. non-physicians, P = 0.41. There was also no difference in the risk of re-operation or duration of hospitalization. CONCLUSIONS: A variety of important outcomes were similar in physician patients and matched non-physician patients after non-cardiac surgery.

Intravenous Therapies for Complex Regional Pain Syndrome: A Systematic Review.

Complex regional pain syndrome (CRPS) remains a challenging clinical pain condition. Multidisciplinary approaches have been advocated for managing CRPS. Compared with spinal cord stimulation and intrathecal targeted therapy, IV treatments are less invasive and less costly. We aimed to systemically review the literature on IV therapies and determine the level of evidence to guide the management of CRPS. We searched PubMed, Embase, Scopus, and the Cochrane databases for articles published on IV therapies of CRPS up through February 2015. The search yielded 299 articles, of which 101 were deemed relevant by reading the titles and 63 by reading abstracts. All these 63 articles were retrieved for analysis and discussion. We evaluated the relevant studies and provided recommendations according to the level of evidence. We conclude that there is evidence to support the use of IV bisphosphonates, immunoglobulin, ketamine, or lidocaine as valuable interventions in selected patients with CRPS. However, high-quality studies are required to further evaluate the safety, efficacy, and cost-effectiveness of IV therapies for CRPS.

Bivalent Cobalt as Efficient Catalyst Intercalation Layer Improves Polysulfide Conversion in Lithium-Sulfur Batteries.

Herein, we investigated in detail the effect of metal valences in different cobalt-based organic framework compounds on the kinetics of sulfur reaction in lithium-sulfur batteries (LSBs). On this basis, two organic framework compounds of zeolite-imidazole-based cobalt organic framework compound (Co-ZIF) and tetrakis(4-benzoic acid) porphyrinato-CoIII chloride [Co-TBP(III)] with different valences were constructed as the functional intercalation separators of LSBs, and explored the effects of different valences on improving the reaction kinetics of polysulfides and inhibiting the shuttle effect. Experiments and theoretical calculations prove that CoII exhibits the best catalytic activity. This is mainly due to the fact that +2 valence shows a strong adsorption energy for polysulfides and a higher Fermi level compared with +3 valence, thus improving the efficiency of the rapid catalytic conversion of sulfur species. As expected, the discharge specific capacity of Co-ZIF as the catalytic layer of the LSBs reached 772.7 mAh g-1 at a high current density of 5 C. More importantly, the initial specific capacity is 839.6 mAh g-1 at high current 3 C, and after 720 cycles, the attenuation rate of per cycle is only 0.092 %, and the coulombic efficiency remains above 92 %.

[Reasonable anesthetic management for correction of Ebstein's anomaly].

OBJECTIVE: To summarize the experience in anesthetic management for correction of Ebstein's anomaly. METHODS: A total of 79 patients with Ebstein's anomaly who underwent surgical repair in our hospital during the time from March 2004 to September 2010 were retrospectively summarized for their anesthetic management. Anesthesia was done for the patients undergoing correction of Ebstein's anomaly. The adults patients were premedicated with intramuscular morphine 0.2 mg/kg and diazepam 0.05 mg/kg. The children patients were premedicated with intramuscular ketamine 5 - 8 mg/kg and atropine 0.05 - 0.20 mg. General anesthesia was induced with midazolam 0.1 - 0.2 mg/kg, etomidate 0.2 - 0.3 mg/kg, sulfentanil 1.0 - 1.5 µg/kg, pipecuronium or vecuronium 0.1 - 0.2 mg/kg, and maintained with isoflurane inhalation and intermittent iv. midazolam and sulfentanil. RESULTS: Anesthetic course was smooth. The symptom in all cases was improved significantly after operation. No patients died during perioperative period. CONCLUSION: The key points for the anesthetic management of Ebstein's anomaly include precise preoperative evaluation, steady hemodynamic, proper maintenance of suitable pulmonary vascular resistance and cardiac function.

Assessing placement bias of the global river gauge network.

Knowing where and when rivers flow is paramount to managing freshwater ecosystems. Yet stream gauging stations are distributed sparsely across rivers globally and may not capture the diversity of fluvial network properties and anthropogenic influences. Here we evaluate the placement bias of a global stream gauge dataset on its representation of socioecological, hydrologic, climatic and physiographic diversity of rivers. We find that gauges are located disproportionally in large, perennial rivers draining more human-occupied watersheds. Gauges are sparsely distributed in protected areas and rivers characterized by non-perennial flow regimes, both of which are critical to freshwater conservation and water security concerns. Disparities between the geography of the global gauging network and the broad diversity of streams and rivers weakens our ability to understand critical hydrologic processes and make informed water-management and policy decisions. Our findings underscore the need to address current gauge placement biases by investing in and prioritizing the installation of new gauging stations, embracing alternative water-monitoring strategies, advancing innovation in hydrologic modelling, and increasing accessibility of local and regional gauging data to support human responses to water challenges, both today and in the future.

A new vector-based global river network dataset accounting for variable drainage density.

Spatial variability of river network drainage density (Dd) is a key feature of river systems, yet few existing global hydrography datasets have properly accounted for it. Here, we present a new vector-based global hydrography that reasonably estimates the spatial variability of Dd worldwide. It is built by delineating channels from the latest 90-m Multi-Error-Removed Improved Terrain (MERIT) digital elevation model and flow direction/accumulation. A machine learning approach is developed to estimate Dd based on the global watershed-level climatic, topographic, hydrologic, and geologic conditions, where relationships between hydroclimate factors and Dd are trained using the high-quality National Hydrography Dataset Plus (NHDPlusV2) data. By benchmarking our dataset against HydroSHEDS and several regional hydrography datasets, we show the new river flowlines are in much better agreement with Landsat-derived centerlines, and improved Dd patterns of river networks (totaling ~75 million kilometers in length) are obtained. Basins and estimates of intermittent stream fraction are also delineated to support water resources management. This new dataset (MERIT Hydro-Vector) should enable full global modeling of river system processes at fine spatial resolutions.

Recent changes to Arctic river discharge.

Arctic rivers drain ~15% of the global land surface and significantly influence local communities and economies, freshwater and marine ecosystems, and global climate. However, trusted and public knowledge of pan-Arctic rivers is inadequate, especially for small rivers and across Eurasia, inhibiting understanding of the Arctic response to climate change. Here, we calculate daily streamflow in 486,493 pan-Arctic river reaches from 1984-2018 by assimilating 9.18 million river discharge estimates made from 155,710 satellite images into hydrologic model simulations. We reveal larger and more heterogenous total water export (3-17% greater) and water export acceleration (factor of 1.2-3.3 larger) than previously reported, with substantial differences across basins, ecoregions, stream orders, human regulation, and permafrost regimes. We also find significant changes in the spring freshet and summer stream intermittency. Ultimately, our results represent an updated, publicly available, and more accurate daily understanding of Arctic rivers uniquely enabled by recent advances in hydrologic modeling and remote sensing.

Toward High-Performance Lithium-Sulfur Batteries: Efficient Anchoring and Catalytic Conversion of Polysulfides Using P-Doped Carbon Foam.

Rational design of the sulfur cathode structure enables effective adsorption of polysulfides and accelerates the sulfur reduction reaction, which is of great significance to the practical application of lithium-sulfur batteries. Here, P-doped carbon foam (PCF) as a sulfur host for the lithium-sulfur battery cathode was successfully synthesized by a facile strategy. The tailored hierarchical pore structure combined with P doping not only facilitates Li+ diffusion but also enhances the adsorption and accelerates the catalytic conversion of lithium polysulfides, thus significantly improving lithium storage performance of the PCF/S cathode.

Targeting Myadm to Intervene Pulmonary Hypertension on Rats Before Pregnancy Alleviates the Effect on Their Offspring's Cardiac-Cerebral Systems.

Pregnancy with pulmonary hypertension (PH) seriously threatens the life and safety of mothers and infants. Here, the long-term effect of maternal PH on the postpartum growth of rat offspring was focused for the first time, as well as explored the role of Myadm in PH rats before pregnancy based upon the previous findings. Patients with PH are prone to hypoxemia, leading to insufficient placental structure and function, which affects the organ function of fetuses, followed by evidence that differently expressed genes (DEGs) existed in the heart of maternal PH newborn rats and enriched in pathways related to cardiac and nerve development on human infants with similar birth outcome: low birth weight (LBW). LBW was one of the possible birth outcomes of pregnancy with PH, especially severe PH, accompanied by evidence that offspring derived from mothers with PH presented lower birth weights and slower growth rates than those derived from normal control mothers in a rat model. Besides, maternal PH rat offspring showed cardiac remodeling and a significant elevation of the expression levels of hypoxia- and inflammation-related markers in the cerebral cortex at both 10 and 14 weeks of age, respectively. What is more, the previous studies found that the overexpression of Myadm could result in the remodeling of the pulmonary artery. And targeting Myadm to intervene PH before pregnancy could alleviate sustained low weight growth in maternal PH rat offspring, and the pathological changes of the cardiac-cerebral system caused by maternal PH, including enlarged right heart cavity, loss of cardiomyocytes, abnormal heart index, as well as cerebral cortex hypoxia and the inflammatory state as they grew up to a certain extent. The findings show the pathological significance of maternal PH on offspring growth and the cardiac-cerebral development in a rat model, as well as point out the potential treatment target, which may provide a further reference for pregnancy outcomes in women with PH and healthy development of offspring to some extent.

Probiotic properties of Lactobacillus strains isolated from the feces of breast-fed infants and Taiwanese pickled cabbage.

This study assessed potential probiotic Lactobacillus strains isolated from the feces of breast-fed infants and from Taiwanese pickled cabbage for their possible use in probiotic fermented foods by evaluating their (i) in vitro adhesive ability, resistance to biotic stress, resistance to pathogenic bacteria, and production of ß-galactosidase; (ii) milk technological properties; and (iii) in vivo adhesive ability, intestinal survival and microbial changes during and after treatment. Five Lactobacillus isolates identified as Lactobacillus reuteri F03, Lactobacillus paracasei F08, Lactobacillus rhamnosus F14, Lactobacillus plantarum C06, and Lactobacillus acidophilus C11 that showed resistance to gastric juice and bile salts were selected for further evaluation of their probiotic properties. All the strains demonstrated the ability to adhere to Caco-2 cells, particularly, strain L. plantarum C06 and L. reuteri F03 showed satisfactory abilities, which were similar to that of the reference strain L. rhamnosus GG. The strains L. paracasei F08 and L. acidophilus C11 had the highest ß-galactosidase activity. Most of the strains were resistant to aminoglycosides and vancomycin but sensitive to ampicillin, erythromycin, and penicillin. All the 5 strains elicited antibacterial activity against both Gram-positive (Bacillus cereus, Listeria monocytogenes and Staphylococcus aureus) and -negative (Escherichia coli and Salmonella enterica) pathogens. Moreover, the strains L. reuteri F03, L. paracasei F08, and L. plantarum C06 could grow rapidly in milk without nutrient supplementation and reached 108 cfu/mL after 24 h of fermentation at 37 °C. The viable cell counts of the 3 strains remained above 107 cfu/mL after 21 d of storage at 4 °C. In the animal feeding trial, the number of intestinal lactobacilli increased significantly after administration of milk fermented with the 3 strains, and the counts of fecal coliforms and Clostridium perfringens were markedly reduced. Lactobacillus strains could also survive in the ileal intestinal tissue of the treated rats. Technologically interesting Lactobacillus isolates may be used in the future as probiotic starter cultures for manufacturing novel fermented foods.

Circular RNAs: Promising Molecular Biomarkers of Human Aging-Related Diseases via Functioning as an miRNA Sponge.

Circular RNAs (circRNAs) are a new class of noncoding single-stranded RNAs that differ from linear microRNAs (miRNAs), since they form covalently closed loop structures without free 3' poly(A) tails or 5' caps. circRNAs are the competitive endogenous RNAs (ceRNAs) by binding to miRNA through miRNA response elements (MREs) (i.e., "miRNA sponge"), thereby reducing the quantity of miRNA available to target mRNA, subsequently promoting mRNA stability or protein expression, which involves the initiation and progress of human diseases. Owing to these features of abundance, stability, conservative property, and tissue and stage specificity, widely distributing in the extracellular space and in various bodily fluids, circRNAs can be considered as potential biomarkers for various diseases. Here, we reviewed the promising circRNAs being disease biomarkers, focused on their regulatory function by acting as miRNA sponges, and described their roles in cancer, cardiovascular or neurodegenerative diseases, osteoarthritis, rheumatoid arthritis, diabetes, and other human aging-related diseases, which provide a new direction for pathogenesis, diagnosis, and treatment of human aging-related diseases.

Theacrine and strictinin, two major ingredients for the anti-influenza activity of Yunnan Kucha tea.

ETHNOPHARMACOLOGICAL RELEVANCE: Kucha tea plant (Camellia assamica var. kucha Chang et Wang) is regarded as a mutant variety of wild Pu'er tea plant found in few mountain areas of Yunnan, China. Its fresh young leaves and shoots are picked by the indigenous aborigines in these local areas to prepare an herbal tea for the treatment of common cold empirically. MATERIALS AND METHODS: Two extra compounds of relative abundance were detected in Kucha tea in comparison with Pu'er tea, and their chemical structures were identified as chlorogenic acid and theacrine. These two compounds as well as two major compounds, strictinin and caffeine, in Kucha tea were evaluated for their cytotoxicity and inhibitory effects on human influenza virus A/Puerto Rico/8/34 by analyzing viral protein expression and progeny production. RESULTS: No or low cytotoxicity was detected for the four Kucha compounds when their concentrations were below 100 µM. Expression of viral NS1 protein was significantly inhibited by chlorogenic acid, theacrine or strictinin, but not caffeine at a concentration of 100 µM. The relative inhibitory potency was detected as chlorogenic acid < theacrine < strictinin, and both theacrine and strictinin displayed significant inhibition at a concentration of 50 µM. According to a plaque assay, viral progeny production was significantly reduced by theacrine or strictinin, but not by chlorogenic acid or caffeine under the same concentration of 100 µM. CONCLUSION: It is suggested that theacrine and strictinin are two major ingredients responsible for the anti-influenza activity of Yunnan Kucha tea traditionally used for the treatment of common cold.

miR-182-3p/Myadm contribute to pulmonary artery hypertension vascular remodeling via a KLF4/p21-dependent mechanism.

Rationale: There is a continued need for investigating the roles of microRNAs and their targets on the pathogenesis of pulmonary arterial hypertension (PAH) vascular remodeling. We recently identified the association of myeloid miR-182-3p and its new target, Myeloid-Associated Differentiation Marker (Myadm), with vascular remodeling. Here, we aimed to determine the role of miR-182-3p/Myadm on PAH vascular remodeling and the underlying molecular mechanism. Methods: The miR-182-3p/Myadm expression profiles were detected in PAH patients and experimental rodent models. Loss-of-function and gain-of-function studies using gene knock-in or gene knock-out and the combinations of the proteomic technology and genome-wide ChIP-Seq were employed to determine the downstream targets of miR-182-3p/Myadm in response to monocrotaline (MCT)-induced PAH. Results: The miR-182-3p/Myadm expression was altered in PAH patients and experimental rodent models. Both miR-182-3p inhibitor and overexpression of Myadm augmented the pathological progression in rats in response to MCT-induced PAH. In contrast, miR-182-3p mimic and Myadm gene knockout attenuated the changes in the hemodynamics and structure of the cardio-pulmonary system in MCT-induced PAH in rats. Myadm mediated the proliferation of pulmonary artery smooth muscle cells (PASMCs) by altering the cell cycle kinase inhibitor (p21/Cip1) expression through the transcription factor Krüppel-like factor 4 (KLF4) translocation into the cytoplasm. Conclusion: Our findings indicate the prognostic and therapeutic significance of miR-182-3p in PAH and provide a new regulatory model of the myeloid-derived miR-182-3p/Myadm/KLF4/p21 axis in PAH vascular remodeling.

Two novel SHP-1 agonists, SC-43 and SC-78, are more potent than regorafenib in suppressing the in vitro stemness of human colorectal cancer cells.

Signal transducer and activator of transcription 3 (STAT3) has been shown to play a critical role in the maintenance of cancer stem cells (CSCs). Hence, the inhibition of STAT3 signaling has been suggested to be a viable therapeutic approach for cancers. Moreover, the efficacy of combinations of chemotherapeutic drugs and napabucasin, a small-molecule STAT3 inhibitor, have been assessed in various clinical trials, including those involving patients with metastatic colorectal cancer (CRC). Two recently developed small-molecule STAT3 inhibitors, SC-43 and SC-78, which can stimulate SHP-1 to inactivate STAT3, were found to have anti-tumor activity. In this study, the inhibitory effects of SC-43, SC-78, and regorafenib (a reference drug) on cell viability, STAT3 phosphorylation, and various stemness properties [e.g., sphere-forming and soft agar colony-forming abilities, CD133+/CD44+ (stem cell-like) subpopulations, and the expression of several CSC markers] were examined for both HCT-116 and HT-29 human CRC cells. We found that SC-43 and SC-78 but not regorafenib inhibited constitutive and IL-6-induced STAT3 phosphorylation in HCT-116 and HT-29 cells, respectively. Moreover, SC-43 and SC-78 were more potent than regorafenib in suppressing the stemness properties (except stem cell-like subpopulations) of these cells. As expected, SHP-1 knockdown almost completely abolished the suppressive effects of SC-43 and SC-78 on the sphere formation in both cell lines. Furthermore, SC-43 and SC-78 showed synergistic inhibitory effects with oxaliplatin and/or irinotecan on sphere formation. Overall, our results suggest that SC-43 and SC-78 are potent STAT3 inhibitors that may potentially be used in combination therapy for CRC.

Intravenous acetaminophen analgesia after cardiac surgery: A randomized, blinded, controlled superiority trial.

BACKGROUND: Pain after cardiac surgery traditionally has been controlled by intravenous opioids and nonsteroidal antiinflammatory drugs. An intravenous analgesic with fewer adverse effects is needed. Therefore, we tested the primary hypothesis that intravenous acetaminophen is more effective than placebo for pain management, which was defined a priori as superior on either pain intensity score and/or opioid consumption and not worse on either. METHODS: In this single-center, double-blind trial, 147 patients having cardiac surgery via median sternotomy were randomized to receive either 1 g of intravenous acetaminophen (73 patients) every 6 hours for 24 hours or comparable placebo (74 patients) starting in the operating room after sternal closure. Cumulative opioid consumption (in morphine equivalents) and pain intensity scores (on a 0-10 Numeric Rating Scale) were measured at 4, 6, 8, 12, 16, 20, and 24 hours after surgery. We estimated ratio of mean opioid consumption by using multivariable linear regression (noninferiority delta = 1.15) and pain score difference by using repeated measures regression (noninferiority delta = 1). RESULTS: Acetaminophen was superior to placebo on mean pain intensity scores and noninferior on opioid consumption, with estimated difference in mean pain (95% confidence interval) of -0.90 (-1.39, -0.42), P < .001 (superior), and estimated ratio of means in opioid consumption (90% confidence interval) of 0.89 (0.73-1.10), P = .28 (noninferior; not superior). CONCLUSIONS: Intravenous acetaminophen reduced pain after cardiac surgery, but not opioid consumption. Intravenous acetaminophen can be an effective analgesic adjunct in patients recovering from median sternotomy.